NINGEN DOCK INTERNATIONAL Official Journal of Japan Society of Ningen Dock

ISSN 2187-8072

NINGEN DOCK INTERNATIONAL
Official Journal of Japan Society of Ningen Dock

2024.3 Vol.11 No.1

Vol.11 No.1

2024. 3

Ningen Dock International
Official Journal of Japan Society of Ningen Dock
Editorial Board
Editor-in-Chief
Kazuhiko INOUE (Okayama)
Associate Editor
Junichi KABURAKI (Tokyo)
Editorial Board
Tomofumi ATARASHI (Hokkaido)

Toshiki FUKUI (Kagawa)Tomoari KAMADA (Okayama)

Nobuyuki KOBAYASHI (Kanagawa) Junko KOMATSU (Tokyo)

Masahiko MURATA (Akita)

Shigeki MUTO (Shizuoka)

Takashi NAITO (Ibaraki)

Hitoshi SASAMORI (Tokyo)

Masao SHIMIZU (Saitama)

Akiko TODA (Tokyo)

Advisory Board
Yasuji ARASE (Tokyo)

Shigeru NASU (Fukuoka)

International Advisory Board
HH LIU (Taiwan)

PK SUNG (Taiwan)

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Ningen Dock International Vol. 11 No. 1 March, 2024
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CONTENTS
Vol. 11 No. 1
March, 2024

Ningen Dock International
Official Journal of Japan Society of Ningen Dock

Review Article( 1 ) New Aspects of Rheumatoid Arthritis (RA) in the Comprehensive Health Checkup System, Ningen Dock
Junichi Kaburaki ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 1

Original Article( 2 ) The Natural Course of Patients Four Years after Pathological Urinary Sediment Findings at Ningen Dock:
The Cost and Benefit of Urine Sediment Examination
Takashi Wada, Rei Goto ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 9( 3 ) Association Between Arterial Stiffness and Bone Mineral Density in the Japanese General Population
Yoshiko Mizuno, Koki Nakanishi, Kohei Uemura, Hidehiro Kaneko, Masao Daimon, Nobutake Yamamichi,
Issei Komuro ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 14( 4 ) Predictive Factors for Diabetes Development in Ningen Dock Examinees with
Very Mild Glucose Intolerance
Kazumasa Ogawa, Akira Seya, Koji Nomura ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 23( 5 ) Investigation of Factors Involved in the Prevention of Gastric Cancer Using Health Checkup Data from
Our Facility
Kyoko Ito, Toyokazu Yukawa, Hiroko Kobayashi-Ouchi, Yasuyuki Mima, Masahiro Nakata,
Tomohiro Kato ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 30( 6 ) The Favorable Effect of Continuous Glucose Monitoring (CGM) on Hyperglycemia andGlycemic Fluctuations in Elderly People with Untreated Glucose Intolerance
Kazuko Watanabe, Kazumasa Hashimoto ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 39( 7 ) The Correlation Between Brachial-ankle Pulse Wave Velocity (baPWV) and Atherosclerosis Risk Factors,
as well as the Risk Score for Development of Atherosclerotic Diseases in Ningen Dock Health Checkup:
A Prospective Collaborative Study at Six Health Checkup Facilities
Toshiki Fukui, Yuko Ishizaka, Izuru Masuda, Kiminori Kato, Shigeki Muto, Tomofumi Atarashi‥‥‥‥‥ 47( 8 ) HDL Subclass Is Associated with Metabolic Dysfunction-associated Fatty Liver Disease in Japanese
Kengo Moriyama, Nagamu Inoue, Yumi Masuda, Chizumi Yamada, Noriaki Kishimoto, Yurina Sakai,
Shinji Takashimizu, Akira Kubo, Yasuhiro Nishizaki ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 55

Case Report( 9 ) Incidental Detection of a Papillary Fibroelastoma During a Health Check-up
Takeshi Oda, Ryo Kanamoto, Chie Yasuoka, Daisuke Nakatomi, Ryoji Yoshida, Seiya Kato,
Eiki Tayama ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 63

Breast Screening Assessment Manual ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 67
Notifications
Acknowledgments ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 80
The Regulations of ISND ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 81
Instructions to Authors ‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥‥ 86

Review Article

Ningen Dock International 2024 ; 11 : 1–8
DOI: https://doi.org/10.11320/ningendockitn.NDI-2024-R001

New Aspects of Rheumatoid Arthritis (RA) in theComprehensive Health Checkup System,
Ningen Dock
Junichi Kaburaki

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease. Recently developed
drugs and guidelines have improved the working ability and prognosis of RA patients. Survival
in RA has been extended, and RA patients have increased opportunity to visit Preventive HealthCare Centers to undergo the Comprehensive Health Checkup System, or Ningen Dock. The healthproblems experienced by patients with RA are characteristically similar to those of the general
population without RA. These include frailty, sarcopenia and locomotive syndrome. Basically, cytokines which cause chronic inflammation play important roles in both arthritis and sarcopenia,
including tumor necrosis factor-α (TNF-α ) and interleukin-2 (IL-2 ). In addition, recent studies
have recognized that RA is a risk factor for cardiovascular disease, as well as for bone fragility andrefracture. Clinical care of these patients therefore includes explanations of exercise and diet, as
recognized in the 2022 American College of Rheumatology (ACR) guidelines for exercise, rehabilitation, diet, and additional integrative interventions.
Keywords rheumatoid arthritis, chronic inflammation, frailty, sarcopenia

Rheumatoid arthritis (RA), a chronic systemic
inflammatory disease, which is fundamentally
characterized as an autoimmune phenomenon
involving polyarthritis and joint destruction 1–3 . Givenan estimated prevalence of between 0.6% and 1.0% inJapan, there at least 800 thousand patients with RA 4 .
Recently, outcomes have been improved by early diagnosis and appropriate management, especially when
conducted in accordance with criteria for the classification and management of RA 5–7 . The IORRA study,
conducted by the Division of Rheumatology at Tokyo
Women’s Medical University School of Medicine, estimated a standardized mortality ratio (SMR) for RA of
between 1.46 and 1.90 4 . This value is similar to the
SMR in a general population without RA.
Therefore, as RA patients can now survive into older
age, they have the possibility of experiencing work disability before clinical remission, and to develop otherconditions such as frailty, sarcopenia and locomotive
syndrome. Recently, the American College of Rheumatology (ACR) proposed in its 2022 guideline for theprovision of exercise, rehabilitation, dietary support,
and additional integrative interventions for RA patientsto improve their physical activity, in addition to drug
therapy 8 . Clinicians should also consider these manage-

ment practices in Preventive Health Care Medicine forpatients with RA.
The classification and clinical features of RA havebeen described elsewhere 1–3 . In this article, we review
new aspects of RA bought to light by advances thisdecade.

Factors Influencing the Onset of RA

The pathophysiology of RA was reviewed in 20141 .
More recent advances in the decade since then haveclarified additional factors which influence the onset of
RA 3 .
The onset of RA has recently been attributed to a
combination of genetic and environmental factors(Table 1 ).
Table 1. Genetic Factors and Environmental Factors in theOnset of Rheumatoid Arthritis
Genetic factors
HLA-DR gene, especially a shared epitope in HLA-DRB1
More than 100 susceptibility genes in a genome-wide
association study (GWAS)
Environmental factors
Smoking
Periodontal disease
Intestinal flora

Preventive Health Care Center of Jiseikai Medical Group
Contact : Junichi Kaburaki, Preventive Health Care Center of Jiseikai Medical Group, 4–35–10, Tokiwadai, Itabashi-ku, Tokyo 174–
0071, Japan. E-mail : j-kaburaki@ningen-doc.kaikan.jp

Ningen Dock International Vol.11 No.1 2024

1 (1)First, the HLA-DR gene plays an important role
among genetic factors 3 . In particular, the 70 th to 74 th
amino acid sequence in the HLA-DRB1 region, called ashared epitope, is a risk factor for RA onset. The sharedepitope promotes antigen presentation, leading to an
autoimmune phenomenon. A genome-wide association study (GWAS) revealed at least 100 genes which
confer susceptibility to RA onset. Although these genes
vary among different races, FCRL3 (Fc receptor like3 ), which controls the activity of PAD (peptidyl arginine deaminase) for citrullination, is found in Japanesepatients with RA. This result can be associated withthe clinical significance of anti-citrullinated protein
antibodies (anti-CCP antibodies: ACPA) in these RA
patients 1,2 .
Among environmental factors, smoking is a wellknown risk factor 1 . Smoking in people with the sharedepitope is associated with the dose-dependent frequency of RA onset. Periodontal disease is also important in the onset of RA. Porphyromonas gingivalis has
PAD activity, resulting in an increase in citrullinatedprotein in the mouth and production of ACPA, leading
to arthritis 3 . Patients with unclassified arthritis or RA
undergoing the Comprehensive Health Checkup System, Ningen Dock should therefore be asked whether
they smoke, and if they have periodontal disease, andthe importance of non-smoking and regular consultation with a dentist should be explained. In addition,
recent advances have found that the intestinal flora also
play a role in the onset of RA: Prevotella corpi can activate the immune response of Th 17 cells, leading to the
autoimmune phenomenon of RA 3 .

Additional Problems in the Management of
RA Patients Arising in the Past Decade

In 2010, Smolen et al. advocated a concept for the
management of RA termed the “Treatment to target(T2T)” recommendations 5 . These outlined the necessity of treating RA patients in the early stage to prevent
articular destruction and subsequent deterioration inquality of life (QOL) based on the idea that previous
increases in tenosynovitis and synovitis during RA progression are followed by an increase in osteitis 9 .
The “T2T” recommendations state that the primary
goal of RA management is to maximize long-term
health-related QOL through the control of symptoms,
prevention of structural damage, normalization of joint
function, and participation in social and work-related
activities 5 . Recent advances have achieved clinicalremission, and subsequently improved prognosis and
QOL in RA patients. We should keep in mind that RA
patients now have increased opportunity to visit Preventive Health Care Centers, to a degree similar to thatof the general population without RA.
2 (2)The purpose of the T2T recommendations include
economic measures to reduce absenteeism (percentageof work time missed due to RA activity) and presenteeism (percentage of impaired work time due to RA activity). Absenteeism and presenteeism are major problems
for RA patients who work. Among the many patientswith RA who experience work disability before clinicalremission, one-third are obliged to temporarily discontinue work or retire early 10–12 . Sakai et al. reported
that improvement in a visual analogue scale for pain,
namely the global assessment visual analogue scale(pain-VAS), as well as in the Japanese version of the
Healthcare Assessment Questionnaire Disability Index(J-HAQ), is strongly associated with improvements inwork productivity and activity impairment (WPAI)13 .
Furthermore, new drugs such as biologic disease
modifying anti-rheumatic drugs (bDMARDs) and targeted synthetic disease modifying anti-rheumatic drugs(tsDMARDs) have been developed for use in addition to methotrexate (MTX) and other conventional
synthetic disease-modifying anti-rheumatic drugs(csDMARDs). Guidelines have proposed appropriate
management for individual patients with RA, for example the Japan College of Rheumatology (JCR) Guideline
2020 7 . MTX is included among csDMARDs, but isconsidered to be an anchor drug in therapy for RA 7,14 .
However, rheumatologists have commonly experienced
patients whose RA was difficult to treat in spite of theuse of MTX and csDMARDs, a situation which subsequently lead to the development of bDMARDs andtsDMARDs (Table 2 ) 7,15 . bDMARDs inhibit the actionof inflammatory cytokines such as TNF-α and IL-6, as
well as lymphocyte interaction, while tsDMARDs are
known to be Janus kinase (JAK)-inhibitors which blockan intracellular signal pathway.
The availability of these new drugs has allowed
patients with RA to improve their ability to work andto survive longer than before, to a similar extent as thegeneral population without RA 16 . Nevertheless, these
improvements have in turn lead to the developmentof new problems, which will require management in
the future. These problems include the management
Table 2. Approved Target Molecules of DMARDS in RA
Management
bDMARDs (Biologic disease-modifying anti-rheumatic drugs)
TNF- α (tumor necrosis factor- α )TNF- α R (tumor necrosis factor- α receptor)
IL-6R (interleukin-6 receptor)
IL-1 β R (interleukin-1 β receptor)
CD80/86 (T cell)
CD 20 (B cell)
tsDMARDs（Targeted synthetic disease-modifying anti-rheumatic
drugs)JAK (Janus kinase)
DMARDs=disease-modifying anti-rheumatic drugs

Ningen Dock International Vol.11 No.1 2024

Kaburaki : New Aspects of Rheumatoid Arthritis (RA) in the Comprehensive Health Checkup System, Ningen Dockfrailty and social frailty (Fig. 1 ). Various kinds of symptom are found in each category. While frailty is a broadconcept which presents physical as well as mental andsocial manifestations, the starting point is often physical frailty, which then proceeds to sarcopenia and locomotive syndrome through chronic inflammation, andpresents clinically with a range of disabling manifestations (Fig. 2 ).
The concept of sarcopenia was originally advocatedby Rosenberg in 198919 as an age-related decrease inmuscle mass. Recent reviews have characterized sarcopenia as a steady reduction in skeletal muscle mass andstrength which is associated with poor physical perfor-

of frailty, sarcopenia and locomotive syndrome, which
occur in RA patients to a similar extent to their occurrence in the general population without RA. Moreover,atherosclerosis and bone fragility have now become
important clinical aspects of RA.

General Concepts of Frailty, Sarcopenia
and Locomotive Syndrome
Frailty is a condition of increased vulnerability due tothe failure of homeostatic coping under certain stresses.
It is associated with increases in various adverse events
such as falls, hospitalization and mortality 17,18 . Frailty
is divided into three categories: physical frailty, mental

Activityrobust,no frailty

Reduced activity throughchronic inflammation

frailtydisability

Physical frailty＝

Reducedactivity of swallowing,

Malnutrition, Reduced

volume of muscle and muscle
weakness

Mental frailty ＝Social frailty ＝Dementia,

No social activity,

Depression

Shut-inFig. 1. Classification of Frailty and Representative Symptoms
Frailty consists of physical frailty, mental frailty and social frailty.
【Physical frailty】 chronic inﬂammation
Weight loss

Reduced activity

Loss of muscle mass 【Sarcopenia】
Muscle weakness
Diﬃculty of movement

Slow movement

Imbalance【Locomotive syndrome】【Disability】
Support for life

Fig. 2. Association between Physical Frailty, Sarcopenia and Locomotive Syndrome
Frailty, especially physical frailty, proceeds to sarcopenia and locomotive syndrome through chronic
inflammation.

Ningen Dock International Vol.11 No.1 2024

3 (3)mance, functional impairment and disability, which inturn result in high mortality and significant medical
costs 20 .
Locomotive syndrome is a condition in which themusculoskeletal system, including bones, joints, andskeletal muscles, experiences a decrease in function 21 .
This concept was proposed by the Japanese Orthopaedic Association in 2011. As a concept, locomotive
syndrome is considered to overlap with physical frailty
and is focused on musculoskeletal disorders, whereas
sarcopenia is a concept within frailty which focuses on
muscles. Locomotive syndrome is particularly applicable to insurance for the long-term care of invalids inJapan.
Given these relationships, sarcopenia should be
detected early, in the Comprehensive Health Checkup
System, Ningen Dock and treated with medicine, nutrition and rehabilitation to prevent the progression offrailty to locomotive syndrome. Chronic inflammation,
especially inflammation involving inflammatory cytokines such as TNF-α and IL-6, plays an important rolein sarcopenia as well as in arthritis (Fig. 3 ) 20,22,23 .
Sarcopenia occurs by several pathways. In muscle
growth, growth hormone is first released from the
hypothalamus by stimulation such as exercise, andinduces insulin-like growth factor-1 (IGF-1 ) in the liverand skeletal muscle. Then, IGF-1 activates the phosphatidylinositol 3-kinase (PI3-K)-Akt signaling pathway
via insulin receptor substrate-1 (IRS-1 ), PI3-K and Akt
through insulin-like growth factor-1 receptor (IGF-1R).
Finally, IGF-1 increases protein synthesis for the pre-vention of sarcopenia.
In contrast, TNF-α, IL-6 and myostatin inhibit protein synthesis, and thereby promote muscle atrophy.
TNF-α activates nuclear factor kappa B (NF-kB) via
the TNF-α receptor (TNF-αR). IL-6 triggers the Janus
kinase (JAK)-signal transducer and activator of thetranscription (STAT-3 ) pathways via IL-6R, like gp130,
while chronic exposure to IL-6 exerts inhibitory effects
on IGF-1. In addition, myostatin inhibits the Akt pathway through ActRII, while myostatin promotes IL-1β(interleukin-1β) expression, especially in RA synovial
fibroblasts 24 . These pathways inhibit protein synthesis
in myocytes, and thereby induce sarcopenia.

Epidemiology and Clinical Characteristics

Ozeki et al. reported that frailty is observed in 37.6%
of patients with RA but in only 15.7% of community
dwellers 25 . Multivariate models have shown that bodymass index (BMI) and social participation are independently associated with frailty in RA patients. Accordingly, maintaining an appropriate body weight and participating in social activities are important in preventing
frailty in RA patients to the same degree that they arein the general population without RA.
It has been reported that the prevalence of sarcopenia in patients with RA is relatively high, from 25%
to 44 %, versus approximately only 10 % in the general population without RA 19,26–30 . When RA patientsdevelop sarcopenia, they experience imbalance, leading
to falls, bone fractures and reduced QOL. Risk factors
for sarcopenia in RA patients include severe functional【Molecule】

IGF-1

TNF-α

IL-6

Myostatin【Membrane
receptor】

IGF-1R

TNF-αR

IL-6R

ActRⅡ

IRS-1

NF-kB

JAK1/2 STAT3

Inhibits Akt【Pathways】

PI3-K
Akt

Protein synthesis ↑Protein Synthesis ↓Fig. 3. Molecules and Intracellular Pathways Controlling Protein Synthesis and Breakdown in Muscle

Insulin-like growth factor 1 (IGF- 1 ) activates the phosphatidylinositol 3 -kinase (PI 3 -K)-Akt signaling pathway, including insulin receptor
substrate-1 (IRS-1 ), PI3-K and Akt through insulin-like growth factor-1 receptor (IGF-1R). In this process, IGF-1 increases protein synthesis in
myocytes.
To the contrary, tumor necrosis factor- α (TNF- α ), interleukin-6 (IL-6 ) and myostatin have opposite eﬀects. TNF- α activates nuclear factor kappa
B (NF-kB) through the TNF- α receptor (TNF- α R). IL-6 triggers Janus kinase (JAK)-signal transducer and activator of the transcription (STAT3 ) pathways through IL-6R, like gp130, while chronic exposure to IL-6 exerts inhibitory eﬀects on IGF-1. In addition, myostatin inhibits the Aktpathway through ActRII. These pathways finally inhibit protein synthesis in myocytes.

4 (4)Ningen Dock International Vol.11 No.1 2024

Kaburaki : New Aspects of Rheumatoid Arthritis (RA) in the Comprehensive Health Checkup System, Ningen Dock
limitations arising due to articular destruction, highC-reactive protein and positive reaction of serum rheumatoid factor, suggesting chronic inflammation as abasic mechanism 31 . In addition, several studies havereported that RA patients with sarcopenia are clinicallydistinguished by features such as higher Steinbrocker
Stage and Health Assessment Questionnaire (HAQ)
scores than those without sarcopenia 29,32,33 .
When patients with RA undergo the Comprehensive
Health Checkup System, Ningen Dock, it is necessary that clinicians perform not only the usual physical examination and laboratory tests, but also provide
explanations of exercise and nutrition.

Medications for RA Patients with Sarcopenia

Drug therapy for sarcopenia, either with or withoutRA, has not been established. Given that inflammatory
cytokines such as TNF-α and IL-6 and the JAK pathway
have effects on muscle metabolism, bDMARDs such as
TNF-α or IL-6 inhibitors, and JAK inhibitors may havethe potential to treat sarcopenia in patients with RA.
However, there is little evidence that medical treatment
is able to influence muscle metabolism. Tournade et al.
reported that tocilizumab, an anti-IL-6 receptor monoclonal antibody, is associated with increasing muscle
mass in patients with RA 34 . However, treatment withetanercept, a TNF-αR inhibitor, did not increase muscle
mass over 6 months, compared to MTX treatment 35 .
Thus, although bDMARDs and JAK-inhibitors may
theoretically improve muscle metabolism, we do nothave sufficient evidence to show that they improve not
only muscle mass but also muscle strength.
Therefore, while adequate treatment control of
inflammation in RA is a prerequisite, additional adjunctive management, such as exercise and nutrition, arerequired to improve sarcopenia in RA patients to bringthem to a similar incidence to that in the general population without RA. Moreover, steroid therapy should be
avoided, as these drugs can cause steroid myopathy.
It is against this background that the ACR’s 2022
guideline calls for exercise, rehabilitation, diet and additional integrative interventions for RA, in conjunction
with drugs such as DMARDs 8 .

Exercise Therapy

The 2022 ACR guideline reflects the ACR’s strong
recommendation for consistent engagement in exercise, as regular exercise results in improved physicalfunction in RA patients 8 . The ACR also conditionally
recommends consistent engagement in aerobic exercise and aquatic exercise, and consistent engagement inresistance exercise, especially very low to low intensity
resistance exercise, to improve physical function. Baillet
et al. reported that resistance training significantly

improves isokinetic muscle strength, isometric muscle
strength and grip strength, and also improves inflammatory state as assessed by erythrocyte sedimentation
rate 36 . Moreover, it has also been reported that resistance training or a combination of aerobic exercise
and resistance training effectively improves muscle
strength and physical activity in patients with RA, evenin patients with RA diagnosed with locomotive syndrome 37–41 .

Diet Therapy

Appropriate nutritional management is required toincrease muscle strength and mass, even in patientswith RA. The 2022 ACR guideline states that the ACR
conditionally recommends adherence to a Mediterranean-style diet over no formally defined diet, andconditionally recommends against adherence to any
formally defined diet other than a Mediterranean-style
diet 8 . The Mediterranean-style diet consists of vegetables, fruits, whole grains, nuts, seeds, and olive oil in
conjunction with moderate amounts of low-fat dairy
and fish, and limits the intake of added sugars, sodium,highly processed foods, refined carbohydrates and saturated fats.
The relationship between low protein intake and lossof muscle strength and mass has been reported in thegeneral population 42,43 . Based on this knowledge, it has
been reported that average protein intake should be
at least 1–1.5 g/kg/day, and increased up to an upper
limit of 2 g/kg/day during severe disease activity due to
inflammation 44,45 .
Among other nutrients, Vitamin D has attracted
attention as a potential target for muscle as well as bonemetabolism in RA patients. Vitamin D is reportedly
effective in inducing improvements in muscle strengthand mass 46,47 .
On the other hand, obesity is a risk factor for theworsening of RA disease activity 48 . Obesity is associatedwith higher disease activity, impairment in physicalfunction and poorer treatment response, in addition topoor long-term health outcomes. Obesity may also be
associated with atherosclerosis, as discussed in the next
section.

Other Problems Recently Found in RA
Patients

Two other problems have been recently highlighted
in patients with RA, apart from side effects of DMARD
therapy such as infection. These are atherosclerosis andbone fragility.
It is well-known that cardiovascular risk is substantially increased in patients with RA 49–51 . In a meta-analysis, both cardiovascular morbidity and mortality were
1.5-fold higher in RA patients than in the general pop-

Ningen Dock International Vol.11 No.1 2024

5 (5)Percentage of
constitution inbone tissue
(%)

100
90

Bone mineralization

80
70

Collagen cross-links

60
50
40
30
20

AGEs cross-links

10
0

Born

Age

Fig. 4. Chronological Change in Bone Strength (Bone Mineralization plus Bone Quality)

Bone mineralization and normal collage cross-linking decrease, while advanced glycation end products ( AGEs ) andhomocysteine cross-linking, indicating poor bone quality, increase with aging.

ulation. Peter et al. reported that the 3-year incidenceof cardiovascular disease was 9.0% in patients with RA
and 4.3% in the general population, corresponding toan incidence rate of 3.30 per 100 patient-years [95%confidence interval ( 95%CI) 2.08–4.25 )] and 1.51 per
100 person-years ( 95%CI 1.18–1.84 ), respectively 52 .
Moreover, compared with the nondiabetic population,
nondiabetic patients with RA and those with type 2
diabetes mellitus (DM) had comparable age- and thesex-adjusted hazard ratios of 2.16 ( 95%CI 1.28–3.63
p=0.004 ) and 2.04 ( 95%CI 1.12–3.67 p=0.029 ), respectively. From that study, it is evident that the risk of cardiovascular disease in patients with RA is significantly
elevated when compared with the general population,and comparable with the magnitude of risk in patientswith type 2 DM. These observational studies hypothesized a common basis ̶namely systemic inflammation
by cytokines̶ for both arthritis and atherosclerosis.
Moreover, a recent study by Yuan et al. demonstrated
a genetic liability to RA in relation to both coronary
artery disease and stroke 53 .
Therefore, when aged patients with RA visit the Preventive Health Care Centers, close attention should be
paid to the possibility of atherosclerosis, as it is in thegeneral population without RA.
The second newly identified problem is bone fragility,
which causes locomotive syndrome as well as frailty 17 .
RA is a well-known cause of secondary osteoporosis 54 .
Recent studies showed that bone fragility resulting inbone fracture is associated with both bone mineralization and bone quality, such as normal collagen crosslinks 55–57 . Bone fragility and fracture can be caused
by a reduction in normal collagen cross-links with anincrease in levels of advanced glycation end products(AGEs) or homocysteine cross-links. Chronologicalchange in bone strength is shown in Fig. 4. Althoughbone mineralization and normal collagen cross-linking,as measures of bone quality, decrease with aging, AGEs
6 (6)or homocysteine cross-links increase as a constituent
percentage. It has been reported that patients with ahistory of multiple fractures and women aged 75 years
are at increased risk of refracture 58,59 . Recently, Ishizu
et al. demonstrated that a cohort of RA patients withan average age of 75 . 4 years who had experienced
bone fragility and fracture were at increased risk (OR:2.714 95%CI: 1.015–7.255 p=0.040 ) of refracture,compared to the general population without RA 60 . This
result was independent of the use of steroid therapy inthese RA patients.
These findings highlight the need for close attention
to atherosclerosis and bone fragility, which is associatedwith both bone mineralization and bone quality, in theComprehensive Health Checkup System, Ningen Dock.

Conclusion

Prognosis in RA has been improved by recently
developed drugs such as bDMARDs and tsDMARDs,
in addition to MTX and other csDMARDs. Accordingly, we face new problems in RA patients, such as
in their ability to work. Moreover, as patients with RA
survive longer than before, maintenance of a good QOL
requires clinicians to take a similar degree of care forfrailty, sarcopenia and locomotive syndrome, as well as
for atherosclerosis and bone fragility, in these patientsas they do in the general population without RA.

Conflict of Interest

The author declares no conflict of interest.

References

1. Kaburaki J, Kuwana M: How to detect early stage rheumatoid
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Ningen Dock International 2024 ; 11 : 9–13
DOI: https://doi.org/10.11320/ningendockitn.ND22-037

Original Article

The Natural Course of Patients Four Years after
Pathological Urinary Sediment Findings at
Ningen Dock: The Cost and Benefit ofUrine Sediment Examination
Takashi Wada 1 , Rei Goto 2

Abstract

Objective: Urinary sediment is examined in Ningen Dock. We sought to evaluate the costs anddiagnostic value associated with abnormal urinary sediment findings, in addition to estimated glomerular filtration rate (eGFR), urinary protein, and occult blood measurement, in Ningen Dock
after 4 years.
Methods: In the patients who underwent Ningen Dock in 2015, urinalysis was performed using
a fully-automated urinalysis system at the central laboratory of each hospital. Urine sediment was
microscopically examined by laboratory technicians. Granular casts, epithelial casts, and tubularepithelium were defined as pathological findings. Seventy-six patients who showed these findings
in 2015 and were re-examined in 2019. The eGFR, urinary protein, and occult blood were statistically analyzed.
Results: Pathological urinary sediment findings detected in 2015 spontaneously disappeared after
4 years in 91% of the patients. No significant change was observed in eGFR, urinary protein or occult blood in the patients who continued to have pathological findings after 4 years. At least \ 157
was spent per sample in supplies and personnel.
Conclusions: Almost the pathological urine sediment was disappeared after four years. The benefit of urine sediment examinations was small for the cost. The eGFR, urine protein and occult
blood test are sufficient in the kidney function examinations in Ningen Dock.
Keywords urine sediment test, Ningen Dock, natural course, costA

urinary sediment examination is performed
routinely in Ningen Dock 1 . Assessment criteria
are set for each item 2 . Detailed examination isrequired if at least one tubular epithelial cell, epithelial
cast, granular cast, fatty cast, red blood cell cast, and/or
white blood cell cast is detected per high-power field.
In this study, the value of urine sediment examination in Ningen Dock was evaluated from the natural
course of pathological urine sediment examination
findings that require detailed examination after 4 years.
Since the Guidelines for the Diagnosis of Hematuria 3
mention that there is the possibility of renal parenchymal disease if microscopic hematuria persists for≥ 3 years, we assessed the follow-up examination performed after 4 years. While most of the items examinedin Ningen Dock can be measured automatically, urine
sediment is examined microscopically by laboratory
technicians. In the basic examination items in NingenDock, the urinary sediment test can be omitted if urine
protein and occult test are negative. In the urinalysis
laboratory, time may be saved if performing a urine
sedimentation test does not need to be done. Thus, we
examined the cost and benefit of urine sediment examination, through the natural course of patients after four
years with pathological sediment findings.

Methods

We selected 78 cases with abnormal urine sedimentation tests in 2015 and underwent Ningen Dock again
in 2019 (Table 1 ). In Ningen Dock, blood tests andurine tests are performed by the central laboratory of
the affiliated hospital. Renal tests include the estimatedglomerular filtration rate (eGFR: mL/min/1.73 m 2 )calculated from the serum creatinine level (HMMPS
method), correcting for age and sex. Proteinuria and occult hematuria are assessed for with a fully-automated

1

The Jikei University School of Medicine ; 2 Graduate School of Business Administration, Keio University
Contact : Takashi Wada, The Jikei University School of Medicine, 3–25–8, Nishi-shimbashi, Minato-ku, Tokyo 105–8461, Japan.
Tel : +81–3–3433–1111 ; Fax : +81–3–3987–0777 ; E-mail : t_wada@jikei.ac.jp

Ningen Dock International Vol.11 No.1 2024

9 (9)Table 1. The Profile of Patients with Granular Casts, Epithelial Casts, And/or Tubular Epithelial Cells Which Were
Severe Urinary Sediment Findings
All subjects in 2015
n=9210Sex (male)
67.5%
Age (y)52.1 ± 10.7
23.0 ± 3.4
BMI (kg/m 2 )Smoking
18.8%
Ethanol intake
70.7%
72.3 ± 13.0
eGFR (mL/min/1.73m 2 )SBP (mmHg)
118.3 ± 15.4
DBP (mmHg)
74.7 ± 11.3
FPG (mg/dL)
100.9 ± 17.2
HbA1c (%)
5.68 ± 0.58
Serum uric acid (mg/dL)
5.72 ± 0.58
57.9%
Urine protein ( − )Urine protein ( ± )31.6%
Urine protein (+)
9.4%
Urine protein ( 2+)0.9%Urine protein ( 3+ and over) 0.1%
Mean urine protein score
0.54 ± 0.71
Urine occult ( − )Urine occult ( ± )Urine occult ( 1+)Urine occult ( 2+)Urine occult ( 3+ and over)
Mean urine occult score

76.7%
11.4%
8.1%
2.7%
1.1%
0.40 ± 0.83

Granular casts
n=24
70.8%
50.2 ± 9.3
22.7 ± 4.4
33.3%
66.7%
67.2 ± 14.1
122.2 ± 16.4
80.8 ± 15.3
102.0 ± 19.1
5.60 ± 0.52
5.79 ± 1.12
0.0%
62.5%
37.5%
0.0%
0.0%
1.38 ± 0.50
（p<0.001）
58.3%
20.8%
12.5%
8.3%
0.0%
0.71 ± 1.00
(p=0.072 )Epithelial casts
n=50
68.0%
53.7 ± 10.4
23.8 ± 4.8
18.0%
68.0%
66.7 ± 13.0
123.0 ± 20.0
77.3 ± 15.1
104.5 ± 22.1
5.81 ± 0.75
6.27 ± 1.39
10.0%
52.0%
32.0%
4.0%
2.0%
1.36 ± 0.80
（p<0.001）
62.0%
16.0%
10.0%
10.0%
2.0%
0.74 ± 1.12
(p=0.004 )Tubular epithelial cells
n=4
50.0%
44.0 ± 1.8
22.9 ± 2.1
25.0%
50.0%
65.5 ± 12.6
121.3 ± 30.6
79.0 ± 30.6
91.5 ± 5.8
5.38 ± 0.17
6.08 ± 1.47
25.0%
25.0%
50.0%
0.0%
0.0%
1.25
100.0%
0.0%
0.0%
0.0%
0.0%
0

BMI: body mass index
SBP: systolic blood pressure, DBP: diastolic blood pressure
FPG: fasting plasma glucose
eGFR: estimated glomerular filtration rate

urinalysis system (AUTION MAX AX-4060, ARKRAY,
Inc., Kyoto, Japan).
Urinary sediment was examined on microscopy bylaboratory technicians. If there were multiple findings,
the finding with the highest score was adopted according to the grading system of the Japan Society of Ningen Dock. Findings of proteinuria and occult blood of(−), (±), ( 1+), ( 2+), and ( 3+) were scored as 0, 1, 2, 3,
and 4, respectively, and were statistically analyzed withthe variance method.
The information concerning the personnel expense
for laboratory technicians was obtained from the tableof Wages by Occupational Categories in the Basic
Survey on Wage Structure by the Ministry of Health,Labour and Welfare 4 . The mean hourly wage of parttime laboratory technicians was \ 1 , 842 – 2 , 266 in
2013–2015. In this study it was assumed to be \ 2,000
per hour.
The data are expressed as mean±SD. Statical analysis
was used Wilcoxon signe rank test (SPSS software version 28, Japan IBM Corp, Tokyo, Japan). p<0.05 wasconsidered statistically significant.
This study was conducted in compliance with the
Declaration of Helsinki and was approved by the institutional review board of the Jikei University School
10 ( 10 )of Medicine (approval no., 17-015 ). The results of thisstudy have not been previously published.

Results

Table 1 shows the profile of Ningen Dock in 2015
and patients with granular casts, epithelial casts, andtubular epithelial cells, which were the pathological urinary sediment findings. No red blood cell casts, whiteblood cell casts, waxy casts, or fatty casts were observed.
The 4-year courses of the pathological urinary sediment findings are shown in Table 2.
Granular casts were observed in 24 patients but disappeared in 19 ( 79%) after 4 years. Of the remaining
5, 1 ( 4 %) continued to show granular casts, 2 ( 8%)showed epithelial casts, and 2 showed hyaline casts.
eGFR was 67.2–67.8 and showed no significant difference. The urinary protein score improved significantly
from 1.38 to 0.79 (p=0.004 ). The urinary occult bloodscore remained unchanged at 0 . 71. Epithelial casts
were observed in 50 but were normalized in 37 ( 74%).
Of the remaining 13, 9 showed hyaline casts, 1 ( 2%)showed granular casts, and 3 ( 6%) showed epithelial
casts. eGFR was 66.7–67.7 and showed no significant
difference. The urinary protein score improved significantly from 1.36 to 0.7 (p<0.001 ). The urinary occult

Ningen Dock International Vol.11 No.1 2024

Wada, et al. : Natural Course of Pathological Urinary Sediment Findings
Table 2. The Natural Course of the Pathological Urinary Sediment Findings after 4 Years
Granular casts
2015
NormalGranular casts
Epithelial casts
Renal tubular epithelium
Hyaline casts

Epithelial casts

2019
n=19 ( 79%)
n=1 ( 4%)n=2 ( 8%)

n=24

2015

n=50

n=2 ( 8%)Mean eGFR

67.2 ± 13.8

Tubular epithelial cells

2019
n=37 ( 74%)n=1 ( 2%)n=3 ( 6%)n=9 ( 18%)

2015

2019
n=4 ( 100%)n=467.8 ± 11.8
(ns)

66.7 ± 12.8

67.7 ± 14.4
(ns)

65.5 ± 10.9

65.5 ± 9.9

Urine protein ( − ): score 0
n=0Urine protein ( ± ): score 1
n=15
Urine protein ( 1+): score 2n=9Urine protein ( 2+): score 3
Urine protein ( 3+ and over): score 4
Mean protein score1.38 ± 0.50

n=9
n=11
n=4

n=5
n=26
n=16
n=2
n=1
1.36 ± 0.80

n=22
n=21
n=7

n=1
n=1
n=2

n=3

0.70 ± 0.70
(p<0.001 )

1.25

0.5

Urine occult ( − ): score 0
Urine occult ( ± ): score 1
Urine occult ( 1+): score 2
Urine occult ( 2+): score 3
Urine occult ( 3+ and over): score 4
Mean occult score

n=14
n=5
n=3
n=2

n=15
n=3
n=4
n=2

n=3

0.71 ± 1.02
(ns)

n=37
n=6
n=3
n=3
n=1
0.50 ± 0.98
(p=0.038 )n=40.71 ± 1.00

n=31
n=8
n=5
n=5
n=1
0.74 ± 1.12

0.79 ± 0.71
(p=0.004 )

n=1

n=1

0

0.5

eGFR: estimated glomerular filtration rate

Table 3. Cases Showing Granular Casts and Epithelial Casts in Both 2015 and 2019
age
in
case
2015
(y)
1
2
3
4
5
6
7

43
44
49
54
57
62
66

mean 53.6

sex
femalemale
male
female
male
male
male

urine urine
BMI in BMI in SBP in SBP in DBP in DBP in FPG inprotein protein
2015
2019
2015
2019
2015
2019
2015
score score(kg/m 2 ) (kg/m 2 ) (mmHg) (mmHg) (mmHg) (mmHg) (mg/dL)
2015 2019

urine urine
eGFR in 2015
occult occult
eGFR in 2019score score (mL/min/1.73 m 2 ) (mL/min/1.73 m 2 )2015 2019

22.8
23.3
19.3
15.4
25.4
21
26.7

27.1
24.3
20.8
16.9
23.1
21.5
26.3

117
137
105
110
100
101
131

113
113
143
91
119
94
105

65
92
82
62
64
70
86

59
75
102
55
86
67
68

94
102
86
106
97
99
133

1
1
1
1
3
2
2

0
1
1
1
1
2
2

0
1
0
2
0
2
1

0
0
0
2
0
3
2

70
75
58
90
52
53
52

73
75
72
61
62
50
52

22.0

22.9
(ns)

114.4

111.1
(ns)

74.4

73.1
(ns)

102.4

1.6

1.1
(ns)

0.9

1.0
(ns)

64.3

63.6
(ns)

BMI: body mass index
SBP: systolic blood pressure, DBP: diastolic blood pressure
FPG: fasting plasma glucose
eGFR: estimated glomerular filtration rate

blood score improved significantly from 0.74 to 0.5(p=0.038 ). Urinary tubular epithelium was normal in
all 4. Mean eGFR was 66.5 and remained unchanged.
Urinary protein changed from 1.25 to 0.5, and urinary
occult blood changed from 0 to 0.5, but statistical analysis was not performed, because there were only 4 cases. Seven patients ( 9.2%) who continued to have both
granular and epithelial casts after 4 years were evaluated(Table 3 ). There was no difference of eGFR, urine protein and occult in 2015 and 2019 in those subjects. Case
4 showed a striking decrease in eGFR. Serum creatininechanged from 0.54 mg/dL to 0.75 mg/dL after 4 years;
muscle mass from 31.2 kg to 32.3 kg by impedance
method; systolic blood pressure decreased from 110
mmHg to 91 mmHg, and diastolic blood pressure de-creased from 62 mmHg to 55 mmHg. Hemoglobin wasfrom 14.6g/dL to 13.8g/dL; serum uric acid was from
4.7 mg/dL to 4.1 mg/dL, serum albumin was from 4.0
g/dL to 4.1 mg/dL. These data are all within the normal
range. Ultrasound findings were only simple renal cysts
and renal calcifications in 2015, and simple renal cysts
in 2019. The cause of decreased eGFR was unknown.
Concerning the cost of examination, the supplies expense per examination is assumed to be \ 30. As for thecapital cost, if a microscope worth \ 1,000,000 is used
for 5 years, its cost per year is \ 200,000 by fixed installment depreciation. If it is assumed to be used for theexamination of 30 samples per day on 250 days a year,
the capital cost of the microscope per sample was calculated at \ 27. Since the examination takes 3 minutes

Ningen Dock International Vol.11 No.1 2024

11 ( 11 )per sample, and since the hourly wage is assumed to be\ 2,000 as mentioned above, the personnel expense persample was calculated at \ 100. The total cost of urine
sediment examination per sample was calculated at\ 157 as the sum of the supplies expense of \ 30, capital
cost for the microscope of \ 27, and personnel expenseof \ 100.

Discussion

If pathological urinary sediment findings are observed in Ningen Dock, a detailed examination is indicated. However, there are few patients in whom eGFR islow, or the urinary protein or urinary occult blood levelis extremely high. There is also no drug that can correct
urinary sediment findings themselves. Therefore, we
examined and analyzed the natural course of pathological urinary sediment findings after 4 years. As a result,pathological urinary sediment findings persisted in only
7 of the 78 patients, and no patient showed impairmentof renal function such as a decrease in eGFR and exacerbation of the urinary protein or urinary occult bloodlevel. Ultrasonography showed no pathological findingsin the subjects with the pathological urine sediments.
The pathological urinary sediment in the subjects without kidney dysfunction may appear temporary and disappear without medical intervention.
This study focused on granular casts, epithelial casts,
and tubular epithelial cells. Particularly, the granular
components are reported to be closely related to chronic kidney disease 5 . Ishibashi et al. 6 compared urinary
sediment findings using three models of a urinary solid
component analyzer with those by visual examination and reported that the results of examination withall 3 analyzers showed generally high concordance
rates with the results of visual examination, but thatthe results concerning casts were unsatisfactory, andthat microscopy by laboratory technician was necessary. According to Harada et al.7 , they adopted a fullyautomatic urinary solid component analyzer, but visual
re-examination was needed when the sample contained
a high level of solid components or when the results ofautomated analysis differed from the results of qualitative examination. Hishiki et al. 8 reported correlations
between the results obtained with an automatic urinary
sediment analyzer and those by microscopy. The sensitivity and specificity were 69.0% and 95.1%, respectively, for red blood cells, 60.9% and 99.4% for whiteblood cells, 34.1% and 99.6% for squamous epithelial
cells, and 52.6% and 77.4% for hyaline casts. Regarding the reasons for the discrepancies with the resultsof microscopy, they suggested the difficulty of distinguishing components with similar shapes and the lackof recognition of special shapes. As observed above,
automatic urinary sediment analyzers have limitations,
12 ( 12 )and microscopy by laboratory technicians is necessary
for casts of special importance. On the other hand,
Ichimura et al. 9 examined the concordance rate among
technicians concerning each sediment component andreported that components with a poor concordance rateof <60% varied among technicians, which means thatthe diagnosis is limited concerning components that
require comprehensive evaluation, including the patient
history. Morita et al.10 analyzed qualitative urinary protein test results and cast-positive rate by visual examination and reported that the concordance rate was 8.5%
in the urinary protein (−) group, but 80.0–93.5% in
the (±)–( 2+) groups, and 100% in the ( 3+) group. Also,
concerning red blood cell casts, which is a pathologicalfinding but was excluded from analysis in this study,
occult blood was positive in 89% of the 85 samples by
qualitative urinalysis 11 . From these reports, tests of urinary protein and urinary occult blood are considered tobe generally sufficient as Ningen Dock items of urine
examination.
The cost of microscopy was calculated to be at least\ 157 per sample. This does not include the costs ofelectricity and the facility. It also does not include thecost for training to improve or maintain skills. Therefore, this figure is considered to be the minimum cost of
examination. On the other hand, the medical treatment
fee for microscopic examination of urinary sedimentis 27 points. Although the balance is not in the red, thebenefit of examining urinary sediment in Ningen Dockis considered small from the viewpoint of the efficientuse of personnel.
Limitations of this study include that there were notmany patients who had pathological urinary sedimentfindings because of the rarity of patients with chronic
kidney disease among Ningen Dock examinees. And
only those who could be followed up after 4 years were
evaluated. Thus the clarification of the reality is insufficient. The references were limited to reports from Japandue to the lack of Western literature concerning thissubject.
This study does not deny the significance of urinary
sediment examination itself. However, the results suggest that the medical significance of urinary sedimentexamination is limited in the stage of screening in thehealthy subjects. Dependence on an automatic urine
sediment analyzer in Ningen Dock for explanation of
the results on the day of examination causes a decline
in the diagnostic accuracy, eventually requiring microscopy by clinical laboratory technicians. The diagnosisof the most important casts relies on the image reading
ability of laboratory technicians. The items of Ningen
Dock examinations related to the kidney and urinary
tract are the serum creatinine level and eGFR calculated from it, urinary protein, urinary occult blood, andNingen Dock International Vol.11 No.1 2024

Wada, et al. : Natural Course of Pathological Urinary Sediment Findings
abdominal ultrasonography. It is considered more important to prevent kidney and urinary tract diseases by
sufficiently utilizing the results of these examinations.

Conclusions

Pathological urinary sediment findings detected in
Ningen Dock (granular casts, epithelial casts, tubularepithelium) disappeared in the natural course after 4
years in 91% of the patients. Even in those who continued to have these findings after 4 years, no significant
change was observed in eGFR, urinary protein, or urinary occult blood. Therefore, the significance of examining urinary sediment in Ningen Dock by spending
money on the personnel and equipment is considered
to be low compared to measurement of eGFR, urinary
protein, and urinary occult blood.

Acknowledgments

This work was supported by the Ministry of Health,Labour and Welfare (MHLW) Sciences Research Grant(Comprehensive Research on Life-Style Related Diseases including Cardiovascular Diseases and Diabetes
Mellitus, 20FA1021, PI: Dr. Takashi WADA).
We also thank Kyoko Hayashi, who is chief of theclinical laboratory in the Health-Care Center, Jikei University Hospital, for providing the economic data in thepresent study.

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Japan Society of Ningen Dock: Basic Test Items. https://www.ningen-dock.jp/en/other/inspection (accessed July 25,
2022 )
2. Japan Society of Ningen Dock: Criteria category. https://www.ningen-dock.jp/wp/wp-content/uploads/ 2018 / 06 /Criteria-category.pdf (accessed July 25, 2022 )3. Japanese Society of Nephrology, The Japanese Urological
Association, Japanese Society for Pediatric Nephrology, etal.: Guidelines for diagnosis of hematuria. https://www.jslm.
org/others/news/hugl20140523.pdf (in Japanese) (accessed
July 25, 2022 )4. Ministry of Health, Labour and Welfare: Basic Survey on
Wage Structure by Occupations. https://www.mhlw.go.jp/
file/05-Shingikai-10701000-DaijinkanboutoukeijouhoubuKikakuka/shiryo2-9.pdf (in Japanese) (accessed July 25,
2022 )
5. Nozawa K, Takahashi J, Watanabe Y, et al.: The relationshipbetween CKD severity classification and urinary cylindricalcomponent. The Journal of Hokkaido Medical Technologists
Association 2014; 12: 12–15. (in Japanese)
6. Ishibashi N, Yoshizawa R, Fujii Y, et al.: Comparison of
3 models of urinary solid component analyser. Japanese
Journal of Medicine and Pharmaceutical Science 2020; 77:
1189–1200. (in Japanese)
7. Harada T, Yamazaki Y, Hoshi N: Criteria for visual examination
using UF-5000 at our hospital. Journal of Asahikawa Medical
Center 2020; 6: 52–54. (in Japanese)
8. Hishiki K, Akiyama Y, Karube K, et al.: Evaluation of
performance of urine sediment analyzer ARKREY AUTION
EYE AI- 4510 . Japanese Journal of Medical Technology
2021; 70: 456–464. (in Japanese)
9. Ichimura N, Koyama S, Sato A, et al.: Development ofinternal quality control system for microscopic urinary
sediment examination and evaluation of an effect of aquality improvement on intralaboratory error among staff
members. Japanese Journal of Medical Technology 2018;
67: 708–715. (in Japanese)
10. Morita Y, Shukuya K, Tanaka M, et al.: Validation of threeautomated urine sediment analyzers and the efficient
workflow using criteria. Japanese Journal of ClinicalLaboratory Automation 2019; 44: 602–609. (in Japanese)
11. Inoue T, Nakagawa R, Watanabe T, et al.: Evaluation of
occult blood reaction and red blood cell count in urine
samples with red blood cell casts. The Ehime Journal of
Medical Technology 2019; 38: 57–60. (in Japanese)(Received September 12, 2022 ; Accepted February 24, 2023 ;J-STAGE Advance published date June 28, 2023)

Ningen Dock International Vol.11 No.1 2024

13 ( 13 )Ningen Dock International 2024 ; 11 : 14–22
DOI: https://doi.org/10.11320/ningendockitn.ND22-041

Original Article

Association Between Arterial Stiffness
and Bone Mineral Density in theJapanese General Population
Yoshiko Mizuno 1,2 , Koki Nakanishi 1 , Kohei Uemura 3 , Hidehiro Kaneko 1 ,Masao Daimon 1 , Nobutake Yamamichi 4 , Issei Komuro 1

Abstract

Objective: Cardiovascular disease and osteoporosis are major public health problems that sharecommon pathophysiological mechanisms besides aging. This study aimed to investigate the possible association between bone mineral density (BMD) and arterial stiffness measured by cardioankle vascular index (CAVI) in the Japanese general population without overt cardiac disease.
Methods: The study population was 1,242 consecutive participants who underwent cardiovascular health check-ups at the University of Tokyo Hospital. After excluding participants withcoronary artery disease, peripheral arterial disease, atrial fibrillation/atrial flutter, decreased left
ventricular systolic function, and pacemaker implantation, 1,169 men and women were analyzed.
The calcaneus BMD was assessed by quantitative ultrasound methods. Cardiovascular functions
were evaluated with CAVI, left ventricular global longitudinal strain (LVGLS), peak early diastolictransmitral velocity (E)/peak early diastolic mitral annular velocity(e ) (E/e ), and carotid intimamedia thickness (IMT) measurements.
Results: In univariate analysis, BMD was associated with CAVI, E/e and IMT along with othercardiovascular risk factors except for diabetes (r= − 0.162, p<0.001, r= − 0.203, p<0.001,
r= − 0.113, p<0.001, respectively), whereas no association was identified between BMD and
LVGLS. In multivariate analysis, after adjustment for pertinent confounding variables, only CAVI
remained associated with low BMD (estimated coefficient=0.0050, p=0.004 ), but the directionof association was opposite and smaller in size compared to univariate analysis.
Conclusions: This study is the first to examine the relationship between BMD and multiple cardiovascular measurements in the Japanese general population without overt cardiovascular disease
and has demonstrated the partial relationship of osteoporotic state and enhanced arterial stiffness,
as evaluated by CAVI.
Keywords cardiovascular disease, bone mineral density (BMD), arterial stiffnessCardiovascular disease and osteoporosis are major public health problems that are known toshare common pathophysiological mechanisms
besides aging. Over the last decades, we are facing aging society. Although a global increase in life expectancy is a huge achievement driven by improvementsin public health and health care, many societies acrossthe world are not prepared for this problem. Especiallyin elderly people, so-called multimorbidity, the coexistence of multiple chronic diseases, is a problematic issue that needs to be solved 1 . For example, prevalence ofmultimorbidity ranges from 55–98% worldwide. For

this reason, acting on aging biology itself rather thanmodifying a single disease-specific process is highly
recommended.
Osteoporosis and cardiovascular disease are frequently seen comorbidities, therefore preventive strategy and early detection are important. In clinical settings, there have been large-scale clinical trials showing
links between osteoporosis and cardiovascular disease.
In terms of heart failure, the EPIC-Norfolk Prospective study from the United Kingdom and the Cardiovascular Health study conducted in the United States
have shown that a history of osteoporosis and low bone1

Department of Cardiovascular Medicine, The University of Tokyo ; 2 Development Bank of Japan ; 3 Department of Biostatistics andBioinformatics, The University of Tokyo ; 4 Center for Epidemiology and Preventive Medicine, The University of Tokyo
Contact : Yoshiko Mizuno, Clinic of Japan Bank for International Cooperation and Development Bank of Japan, Development Bankof Japan, Otemachi Financial City South Tower, 1–9–6 Otemachi, Chiyoda-ku, Tokyo 100–8178, Japan. Tel : 81–3–3244–1941 ; Fax :81–3–3270–6691 ; E-mail : ysmizun@dbj.jp

14 ( 14 )Ningen Dock International Vol.11 No.1 2024

Mizuno, et al. : Arterial Stiffness and Bone Mineral Density
mineral density (BMD) was an independent predictor
for future occurrence of heart failure 2,3 . And the EPICNorfolk Prospective study, the same study from UK,
has shown the correlation between osteoporosis andfuture stroke risk 4 .
Similarly, several studies have investigated the correlations between osteoporosis and artery diseases,
namely atherosclerosis and arteriosclerosis. First, inanimal models, both osteoprotegerin-deficient miceand apoprotein E-deficient mice have a greater ability
to develop early vascular calcification, osteoporosis,
and increased risk of cardiovascular disease (CVD) 5 .
Second, in humans, two studies have shown the links
between bone mineral density and atherosclerosis measured by carotid intima-media thickness (IMT) 6,7 . On
the other hand, the correlation between BMD and arterial stiffness, usually measured by pulse wave velocity(PWV) or cardio-ankle vascular index (CAVI), is undercontroversial debate, and only one study from China
showed the correlation between CAVI and BMD in thegeneral population 8 . In the current study, we exploredthe relationship between BMD and multiple cardiovascular parameters to investigate a possible association
between the osteoporotic state and arterial stiffness in
the Japanese population.

Methods

Study population
The study population was derived from 1,242 consecutive subjects who participated in extensive cardiovascular health check-ups from August 2014 to May
2018 at the University of Tokyo Hospital. Among a
total of 1,242 participants who underwent laboratory
testing, lifestyle questionnaires, ultrasonographic examination and BMD measurement, patients with a historyof coronary artery disease, peripheral arterial disease,atrial fibrillation or atrial flutter, decreased LV systolic
function (LV ejection function <50%), valvular disease,or pacemaker implantation were excluded. Informed
consent was obtained from all study participants. The
study was approved by the ethics committee of the University of Tokyo.
Risk factor assessment and definition
Cardiovascular risk factors were ascertained throughdirect examination and interviews conducted by healthcare professionals. Hypertension was defined as systolic
BP (SBP) ≥140 mmHg or diastolic BP (DBP) ≥90 mmHg,
or the use of antihypertensive medication. Diabetes
mellitus was defined by a fasting blood glucose ≥126
mg/dL or the current use of insulin or oral hypoglycemic agents. Hyperlipidemia was defined as total serum
cholesterol >240 mg/dL or the use of lipid-lowering
medications. Body mass index (BMI) was calculated
as weight (kg) divided by height squared (m 2 ). Venous

blood samples were collected under fasting conditions on the same day as cardiovascular examinations.
The glomerular filtration rate (GFR) was estimated in
the equation: eGFR=194×age−0.287×creatinine−1.094 +(×0.739 if female). Predictive indices for insulin resistance, Triglyceride-glucose (TyG) index and TG/HDLC, were calculated as follows: TyG index=ln [Fasting
triglyceride (mg/dL)×Fasting glucose (mg/dL)]/2, and
TG/HDL-C=Fasting triglyceride/HDL cholesterol, respectively.
Quantitative ultrasound assessment of calcaneus
Although dual-energy X ray absorptiometry (DXA)
is recommended for BMD evaluation by numerous
guidelines and World Health Organization (WHO)criteria, quantitative ultrasound (QUS) has been developed and proven to be an alternative method to DXA
for assessing osteoporotic status 9,10 . In this study, theSOS (speed of sound, m/s) of the calcaneus bone wasmeasured using an ultrasound bone densitometer (CM300, Furuno Electric Co. Ltd., Nishinomiya, Japan). The
T-score was calculated from the manufacturer-specific
SOS reference population database. %YAM (young adultmean) represents % value relative to the standard SOSof the young age. Subjects were screened for presence of
low BMD and classified into osteopenia and osteoporosis based on WHO criteria.
Measurement of CAVICAVI was measured using an automatic vascular
screening system (Vasera VS-1500, Fukuda Denshi,
Tokyo, Japan) with the patients in the supine position
after 5 minutes of rest. The electrocardiogram, phonocardiogram, and SBP and DBP of the brachial and ankle
arteries were simultaneously recorded. The formula todetermine CAVI was as follows:
CAVI=a[( 2ρ/ Δ P)×ln (SBP/DBP) PWV 2 ]+b, where
Δ P=SBP−DBP, ρ=blood density, PWV=pulse wave
velocity, and a and b are scale conversion constants tomatch aortic PWV. The mean of the right and left CAVI
values was used for analysis.
Measurement of carotid IMTCarotid IMT measurement was performed withpatients in the supine position using high resolution
B-mode ultrasonography with linear-array 7.5 MHz
transducer ( Aplio 300 , Toshiba Medical Systems,
Tokyo, Japan). The maximal IMT in both right and leftcommon carotid artery was recorded according to thecurrent guideline 11 , and the mean was used for analysis
as max IMT.
Echocardiographic assessment or echocardiographic
examination
Two-dimensional echocardiographic examina tion was performed utilizing a commercially available
system (Aplio 300, Toshiba Medical Systems, Tokyo,
Japan) by registered cardiac sonographers blinded to

Ningen Dock International Vol.11 No.1 2024

15 ( 15 )the participants’ clinical information according to a
standardized protocol. The dimensions of the cardiac
chambers and left ventricular ejection function (LVEF)
were measured in the standard manner 12 . LV diastolic
function assessment was performed based on the current guidelines 13 . Transmitral diastolic flow was obtained
from an apical four-chamber view. Pulsed-wave Doppler
examination of mitral inflow was performed to measure
early (E) peak velocity, and peak early diastolic mitral annular velocity (e ) was also measured from tissue Doppler
imaging in the lateral and the septal mitral annulus. The
mean value of E/e was used for analysis, and impaired
diastolic function was defined as mean E/e >14.
Speckle-tracking analysis was performed offline using vendor-independent commercially available software ( 2D Cardiac Performance Analysis; Tomtec Imaging System, Germany). LV global longitudinal strain(LVGLS) was calculated by averaging the negative peakof longitudinal strain from 18 ventricular segments inall 3 apical views, including the 4-chamber, 2-chamberand long-axis views, according to the current guidelines 14 . As for the definition of strain, negative strain denotes shortening for LV which indicates that a smaller
value (a larger absolute value) shows better LV contraction.
Statistical analysis
Data are expressed as mean±SD for continuous
variables and as number (percentage) for categoricalvariables. Statistical significance was set at p<0.05. The
differences in baseline characteristics between men andwomen were determined by Student’s t-tests for continuous variables and χ2 tests for categorical variables.
Linear regression analysis was performed to evaluate associations between BMD and each dependent variable,
and Pearson’s correlation coefficients were calculated.
Multivariate regression analysis was used to determine
the effects of BMD on cardiovascular measurements
before and after incorporating potential confounding
factors. All statistical analyses were performed with
JMP 15 statistical software (SAS Institute, Cary, NC,
USA).

Results

Flow chart of participant enrollment and exclusion
A population flow chart is summarized in Fig. 1. We
enrolled 1,242 participants who underwent extensive
cardiovascular health check-ups in our institute from2014 to 2018.
After exclusion of cardiovascular diseases, such as
coronary artery disease (n=29 ), peripheral arterial disease (n=1 ), atrial fibrillation or atrial flutter (n=14 ),decreased LV systolic function (n=6 ), pacemaker implantation (n=1 ), and missing clinical data (n=22 ), thefinal study group comprised 1,169 participants without
16 ( 16 )1,242 participants underwent extensive cardiovascular healthcheck-ups from August 2014 to May 2018
History of CAD (n=29)
History of PAD (n=1)
AF or atrial flutter (n=14)
LVEF <50% (n=6)
Pacemaker implantation (n=1)
1,191 participants without overt cardiovascular disease
Incomplete clinical measurements (n=22)
1,169 participants in final sample

Fig. 1. Flow Chart of Participant Enrollment and Exclusion
Abbreviations: CAD indicates coronary artery disease; PAD,
peripheral arterial disease; AF, arterial fibrillation; and LVEF, left
ventricular ejection fraction.

overt cardiovascular disease. None of the participants
had a history of valvular disease.
Baseline characteristics of men and women
Table 1 shows the baseline characteristics of theparticipants stratified by sex. The prevalence of hypertension, diabetes, and smoking habit was significantly
higher in men, whereas the prevalence of hyperlipidemia and osteoporosis was higher in women. Similarly,
the gender differences were recognized in most of thedemographics and laboratory data except for estimatedglomerular filtration rate (eGFR) and thyroid stimulating hormone (TSH). Men had higher blood pressure,and women had higher levels of brain natriuretic peptide (BNP), HDL cholesterol, and lipoprotein (a). Regarding cardiovascular measurements, CAVI and max
IMT were higher in men, while LVGLS and mean E/ewere lower in men. Regarding BMD, %YAM was higher
in male subjects in accordance with the lower prevalence of osteoporosis in men.
Linear regression analysis for BMD
Table 2 shows linear regression analysis between
BMD and the clinical variables from baseline characteristics. BMI (r=+0.129, p<0.001 ), eGFR (r=+0.069,
p=0.018 ), TyG index (r=+0.030, p<0.001 ), albumin(r=+0.164, p<0.001 ), uric acid (r=+0.120, p<0.001 )were positively correlated with BMD, whereas age (r=−0.349, p<0.001 ), systolic blood pressure (r=−0.060,
p= 0 . 004 ), HDL cholesterol (r=−0 . 099 , p< 0 . 001 ),BNP ( r= −0 . 17 0 , p< 0 . 0 01 ) , lipoprotein ( a ) ( r=
−0 . 066 , p< 0 . 001 ) were negatively correlated with
BMD. Among cardiovascular parameters, mean CAVI,
mean E/e and max IMT showed negative correlation
with BMD (r=−0.162, p<0.001, r=−0.203, p<0.001,
r=−0.113, p<0.001, respectively), nonetheless LVGLS
demonstrated no correlation with BMD.

Ningen Dock International Vol.11 No.1 2024

Mizuno, et al. : Arterial Stiffness and Bone Mineral Density
Table 1. Baseline Characteristics of Men and Women
Men(n=651 )Age, years
61.4 ± 11.6
Body mass index (BMI), kg/m 2
24.5 ± 3.3
Systolic blood pressure, mmHg
121.6 ± 14.7
Diastolic blood pressure, mmHg
76.6 ± 10.9
Current smoking, n (%)
90 ( 13.8 )Alcohol intake, n (%)
426 ( 65.4 )Hypertension, n (%)
251 ( 38.6 )Hyperlipidemia, n (%)
208 ( 32.0 )Diabetes mellitus, n (%)
97 ( 14.9 )Osteoporosis, n (%)
5 ( 0.77 )Creatinine, g/dL
0.91 ± 0.49
eGFR, mL/min/1.73 m 2
71.2 ± 15.9
Fasting plasma glucose, %103.8 ± 22.1
Hemoglobin A1c, %5.91 ± 0.68
LDL-cholesterol, mg/dL
123.9 ± 30.6
HDL-cholesterol, mg/dL
58.9 ± 15.5
Triglyceride (TG), mg/dL
127.8 ± 94.2
non HDL-cholesterol, mg/dL
141.8 ± 33.2
TG/HDL-C
2.53 ± 2.49
TyG index
4.65 ± 0.31
Lipoprotein (a), mg/dL
11.3 ± 10.9
Albumin, g/dL
4.3 ± 0.3
Uric acid, mg/dL
6.2 ± 1.2
Thyroid stimulating hormone (TSH), μ lU/mL
2.3 ± 1.9
Serum iron, μ g/mL
113.5 ± 35.5
Brain natriuretic peptide (BNP), pg/mL
19.9 ± 21.3
%YAM
82.9 ± 14.8
mean CAVI
8.16 ± 1.18
LVGLS, %− 20.60 ± 2.39
LVEF, %
68.33 ± 6.57
mean e , cm/s
8.16 ± 2.14
8.56 ± 2.36
mean E/e
max IMT, mm
1.08 ± 0.34

Women(n=518 )63.4 ± 11.6
22.3 ± 3.5
117.7 ± 15.9
73.43 ± 10.3
25 ( 4.8 )
187 ( 36.1 )
155 ( 29.9 )
221 ( 42.7 )
22 ( 4.3 )
61 ( 11.78 )0.66 ± 0.17
72.7 ± 15.5
94.6 ± 15.0
5.76 ± 0.51
126.4 ± 30.3
74.0 ± 19.0
91.4 ± 55.2
139.3 ± 32.4
1.43 ± 1.36
4.47 ± 0.26
14.3 ± 12.8
4.2 ± 0.2
4.9 ± 1.1
2.3 ± 1.6
99.6 ± 30.4
27.5 ± 29.1
77.6 ± 13.7
7.90 ± 1.02
− 22.09 ± 2.90
69.95 ± 6.45
8.21 ± 2.44
9.67 ± 3.14
0.98 ± 0.25

p value0.001＊<0.001＊<0.001＊<0.001＊<0.001＊
0.062
0.002＊<0.001＊<0.001＊<0.001＊<0.001＊
0.097<0.001＊<0.001＊
0.162<0.001＊<0.001＊0.211<0.001＊<0.001＊<0.001＊<0.001＊<0.001＊
0.879<0.001＊<0.001＊<0.001＊<0.001＊<0.001＊<0.001＊
0.662<0.001＊<0.001＊

Values represent mean ± SD or number of participants and prevalence rate (%) in parentheses.
Abbreviations: eGFR indices estimated glomerular filtration rate; LDL-cholesterol, low-density lipoproteincholesterol; HDL-cholesterol, high-density lipoprotein-cholesterol; TyG, triglyceride-glucose; CAVI, cardio-ankle
vascular index; LVGLS, left ventricular global longitudinal strain; LVEF, left ventricular ejection fraction; e , early
diastolic mitral annular velocity; E, early diastolic transmitral flow velocity; and max IMT, maximal intima-media
thickness.

Correlation between osteoporotic state and cardiovascular parameters
Fig. 2 shows the correlations between the cardiovascular parameters and BMD in a categorized manner,namely normal (n=524 ), osteopenia (n=383 ), and osteoporosis (n=262 ). Variables other than LVGLS hadsignificant correlations with osteoporotic state (CAVI,
p<0.001; mean E/e , p<0.001; max IMT, p<0.001 ).
Correlation between BMD and cardiovascular parameters in multivariate analysis
In Table 3, multivariate analysis of BMD for cardiovascular parameters was performed with the variables
that showed significant correlations with BMD in thelinear regression analysis shown in Table 2. After adjusting for age and sex (Model 1 ), BMI, diabetes, hyperlipidemia, hypertension, current smoking, and alcohol
intake (Model 2 ), albumin, eGFR, HDL-cholesterol,uric acid, serum iron, and BNP (Model 3 ), lipoprotein(a) and TyG index (Model 4 ), the correlation between
BMD and CAVI remained statistically significant(Model 1, estimated coefficient=+0.0037, p=0.041;
Model 2 , estimated coefficient=+ 0.0046 , p= 0.009 ;Model 3, estimated coefficient=+ 0.0046 , p= 0.009 ;Model 4, estimated coefficient=+0.0050, p=0.004 );however the association between BMD and the remaining cardiovascular parameters (LVGLS, mean E/e , max
IMT) fell short of statistical significance.
Correlation between BMD and cardiovascular parameters in multivariate analysis stratified by sex
As gender difference was not negligible in this study
population, we stratified subjects into two groups bysex. In sub-analyses stratified by sex (Table 4, 5 ), thecorrelation between BMD and CAVI was attenuatedbut still statistically significant in all adjusted models in men (Model 1, estimated coefficient=+0.0056,
p= 0 . 015 ; Model 2 , estimated coefficient=+ 0.0055 ,Ningen Dock International Vol.11 No.1 2024

17 ( 17 )Table 2. Linear Regression Analysis for BMD
Age, years
Body mass index (BMI), kg/m 2
Systolic blood pressure, mmHg
Diastolic blood pressure, mmHg
Creatinine, g/dL
eGFR, mL/min/1.73 m 2
Fasting plasma glucose, %Hemoglobin A1c, %LDL-cholesterol, mg/dL
HDL-cholesterol, mg/dL
Triglyceride (TG), mg/dL
non HDL-cholesterol, mg/dL
TG/HDL-Cholesterol
TyG index
Albumin, g/dL
Uric Acid, mg/dL
Thyroid stimulating hormone (TSH), μ lU/mL
Serum iron, μ g/mL
Brain natriuretic peptide (BNP), pg/mL
Lipoprotein (a) , mg/dL
mean CAVILVGLS, %LVEF, %
mean e , cm/s
mean E/e
max IMT, mmrp value+0.129− 0.060+0.040+0.033+0.069− 0.017− 0.051− 0.009− 0.099+0.048+0.006+0.047+0.030+0.164+0.120− 0.032+0.066− 0.170− 0.066− 0.162− 0.035− 0.033+0.207− 0.203− 0.113<0.001＊0.004＊
0.170
0.266
0.018＊
0.555
0.082
0.747
<0.001＊
0.103
0.830
0.110
<0.001＊<0.001＊<0.001＊
0.278
0.024＊<0.001＊<0.001＊<0.001＊0.231
0.256<0.001＊<0.001＊<0.001＊− 0.349 <0.001＊

r=Pearson’s correlation coefficient
Abbreviations: eGFR indices estimated glomerular filtration rate; LDLcholesterol, low-density lipoprotein-cholesterol; HDL-cholesterol, highdensity lipoprotein-cholesterol; TyG, triglyceride-glucose; CAVI, cardioankle vascular index; LVGLS, left ventricular global longitudinal strain;
LVEF, left ventricular ejection fraction; e , early diastolic mitral annularvelocity; E, early diastolic transmitral flow velocity; and max IMT, maximal
intima-media thickness.

p= 0. 016 ; Model 3, estimated coefficient=+ 0.0059 ,
p=0.011 ), while as for women, the correlation between
BMD and CAVI virtually all vanished. Regarding theother parameters (LVGLS, mean E/e , max IMT), nocorrelation with BMD was observed in all models(Models 1–3 ), which was consistent with the results
shown in Table 3.

Discussion

In this study, we explored the relationship between
BMD and cardiovascular variables including CAVI,LVGLS, E/e , and IMT in the population without overt
cardiac disease. Each of the parameters are of importance in terms of arterial aging (arteriosclerosis for
CAVI and atherosclerosis for IMT), or preclinically
impaired cardiac function (systolic function for LVGLS
and diastolic function for E/e ) respectively. In univariate analysis, BMD was associated with CAVI, E/e , andIMT along with other cardiovascular risk factors except
for diabetes, whereas no association was identified between BMD and LVGLS. In multivariate analysis, after
adjustment for pertinent confounding variables, only
CAVI remained associated with low BMD, but unexpectedly the direction of association was opposite andsmaller in size compared to univariate analysis. Thiscan be explained that the observed association between
BMD and CAVI in univariate analysis was due to confounding through the association between age and
BMD or CAVI, but still does not completely deny theclinical significance of the correlation between CAVI

CAVI

7.903

p < 0.001*
r = 0.155

8.349

8.021

5

0

normal0

LVGLS (%)

CAVI

10

LVGLS

p < 0.001*
p < 0.001*
n.s.

osteopenia osteoporosis

osteopenia osteoporosis

normalp < 0.172
r = 0.055-10-20-21.282

mean E/e’mean E/e’10

p < 0.001*
p < 0.001*
p = 0.045*
10.031
9.018
8.579

5

0

n.s.
n.s.

max IMTp < 0.001*
r = 0.202

max IMT (mm)15-21.000-21.408
n.s.

-30

1.012

p < 0.001*
p = 0.005*
1.105
1.027

normalosteopenia osteoporosisn.s.
1

p < 0.001*
r = 0.119

0.5

normalosteopenia osteoporosis

0Fig. 2. Correlation Between Osteoporotic State and Cardiovascular Parameters

normal (n=524 ), osteopenia (n=383 ), osteoporosis (n=262 )Abbreviations: CAVI indices cardio-ankle vascular index; LVGLS, left ventricular global longitudinal strain; e , early
diastolic mitral annular velocity; E, early diastolic transmitral flow velocity; and max IMT, maximal intima-media
thickness.

18 ( 18 )Ningen Dock International Vol.11 No.1 2024

Mizuno, et al. : Arterial Stiffness and Bone Mineral Density
Table 3. Correlation Between BMD and Cardiovascular Parameters in Multivariate
Analysisparameters
CAVI

LVGLS

mean E/e

max IMT

Model
Model 1Model 2Model 3Model 4Model 1Model 2Model 3Model 4Model 1Model 2Model 3Model 4Model 1Model 2Model 3Model 4B
0.00370.00460.00460.0050− 0.0049− 0.0067− 0.0073− 0.0067− 0.0033− 0.0045− 0.0035− 0.0036
0.00040.00030.00040.0004Lower 95 ％ CI Upper 95 ％ CI
0.00020.00720.00120.00800.00120.00800.00160.0084− 0.0159
0.0061− 0.0175
0.0041− 0.01800.0035− 0.0175
0.0041− 0.0136
0.0070− 0.0146
0.0056− 0.0135
0.0065− 0.0136
0.0065− 0.0008
0.0015− 0.0008
0.0015− 0.0007
0.0016− 0.0007
0.0015p value
0.041＊
0.009＊
0.009＊
0.004＊
0.382
0.225
0.185
0.221
0.529
0.379
0.493
0.487
0.499
0.593
0.463
0.502

Model 1: adjusted for age and sex
Model 2 : adjusted for Model 1 plus BMI, diabetes, hyperlipidemia, hypertension, current smoking andalcohol intake
Model 3: adjusted for Model 2 plus albumin, eGFR, HDL-cholesterol, uric acid, serum iron and BNP
Model 4: adjusted for Model 3 plus lipoprotein (a) and TyG index
Abbreviations: B indicates regression coefficient; 95 %CI, 95 % confidence interval; BMI, body massindex; eGFR, estimated glomerular filtration rate; HDL-cholesterol, high-density lipoprotein-cholesterol;
TyG, triglyceride-glucose; BNP, brain natriuretic peptide; CAVI, cardio-ankle vascular index; LVGLS, left
ventricular global longitudinal strain; e , early diastolic mitral annular velocity; E, early diastolic transmitralflow velocity; and max IMT, maximal intima-media thickness.

Table 4. Correlation Between BMD and Cardiovascular Parameters in Multivariate
Analysis Stratified by Sex (Men)parameters
CAVI

LVGLS

mean E/e

max IMT

Model
Model 1Model 2Model 3Model 1Model 2Model 3Model 1Model 2Model 3Model 1Model 2Model 3B
0.00560.00550.0059− 0.0052− 0.0055− 0.0051
0.00050.00100.00120.00040.00060.0005Lower 95 ％ CI Upper 95 ％ CI
0.00110.01000.00100.01010.00140.0104− 0.0176
0.0073− 0.0180
0.0070− 0.0175
0.0073− 0.0101
0.0112− 0.0097
0.0117− 0.0095
0.0119− 0.0012
0.0020− 0.0010
0.0022− 0.0011
0.0022p value0.015＊
0.016＊
0.011＊
0.416
0.386
0.419
0.919
0.854
0.830
0.640
0.486
0.515

Model 1: adjusted for age, BMI, diabetes, hyperlipidemia, hypertension, current smoking and alcohol intake
Model 2: adjusted for Model 2 plus albumin, eGFR, HDL-cholesterol, uric acid, serum iron and BNP
Model 3: adjusted for Model 3 plus lipoprotein (a) and TyG index
Abbreviations: B indicates regression coefficient; 95 %CI, 95 % confidence interval; BMI, body massindex; eGFR, estimated glomerular filtration rate; HDL-cholesterol, high-density lipoprotein-cholesterol;
TyG, triglyceride-glucose; BNP, brain natriuretic peptide; CAVI, cardio-ankle vascular index; LVGLS, left
ventricular global longitudinal strain; e , early diastolic mitral annular velocity; E, early diastolic transmitralflow velocity; and max IMT, maximal intima-media thickness.

and BMD. Overall, this study is the first to examine therelationship between BMD and multiple cardiovascular measurements in the Japanese general population
without overt cardiovascular disease and has partiallydemonstrated the independent relationship of osteoporotic state and enhanced arterial stiffness, as evaluatedby CAVI.
In general, cardiovascular disease and osteoporosis

are two major factors that severely affect the quality oflife and mortality of middle-aged and elderly people.
There is growing evidence that the coincidental occurrence of both diseases may be related to common
pathophysiological mechanisms regardless of age 15 .
Indeed, bone formation and vascular calcification share
underlying biological mechanisms, mainly throughinflammation and the RANK (receptor activator of nu-

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19 ( 19 )Table 5. Correlation Between BMD and Cardiovascular Parameters in Multivariate
Analysis Stratified by Sex (Women)parameters
CAVI

LVGLS

mean E/e

max IMT

Model
Model 1Model 2Model 3Model 1Model 2Model 3Model 1Model 2Model 3Model 1Model 2Model 3B
0.00180.00100.0017− 0.0062− 0.0090− 0.0086− 0.0077− 0.0095− 0.0096− 0.0001− 0.0001− 0.0001

Lower 95 ％ CI Upper 95 ％ CI
− 0.0038
0.0073− 0.0045
0.0066− 0.0038
0.0072− 0.0268
0.0144− 0.0296
0.0116− 0.0293
0.0121− 0.0283
0.0129− 0.0299
0.0110− 0.0300
0.0108− 0.0017
0.0014− 0.0016
0.0015− 0.0017
0.0015p value
0.535
0.714
0.538
0.556
0.391
0.417
0.464
0.363
0.354
0.869
0.947
0.925

Model 1: adjusted for age, BMI, diabetes, hyperlipidemia, hypertension, current smoking and alcohol intake
Model 2: adjusted for Model 2 plus albumin, eGFR, HDL-cholesterol, uric acid, serum iron and BNP
Model 3: adjusted for Model 3 plus lipoprotein (a) and TyG index
Abbreviations: B indicates regression coefficient; 95 %CI, 95 % confidence interval; BMI, body massindex; eGFR, estimated glomerular filtration rate; HDL-cholesterol, high-density lipoprotein-cholesterol;
TyG, triglyceride-glucose; BNP, brain natriuretic peptide; CAVI, cardio-ankle vascular index; LVGLS, left
ventricular global longitudinal strain; e , early diastolic mitral annular velocity; E, early diastolic transmitralflow velocity; and max IMT, maximal intima-media thickness.

clear factor-kappaB (NFκB))/RANKL (RANK ligand)/OPG (osteoprotegerin) system 16 . Recently, it was proven by positron emission tomography that vascular inflammation precedes vascular calcification in both theintimal and medial layers of the vasculature wall 17 . As
for intimal layer calcification, it is explained by the atherosclerotic state, which is characterized by the death oflipid-laden macrophages and the sequential formationof calcium phosphate crystals. For the calcification in
the medial layer, in addition to saturated fatty acids, inflammatory mediators such as interleukin (IL)-1β, IL6, IL8, insulin-like growth factor (IGF)-1, and tumor
necrosis factor (TNF)-α are responsible for inducing
osteogenic differentiation of vascular smooth muscle
cells (VSMCs) 18 . In this process, the RANK/RANKL/OPG system that belongs to TNF family is postulated
to be important inducers and inhibitors of VSMC calcification. As inducers, the binding of RANKL to RANK
receptor promotes differentiation of preosteoclasts into
mature osteoclasts through the activation of the NFκB
intracellular signaling pathway, a process that is also
important in bone resorption in osteoporosis. As inhibitors, on the contrary, OPG, which is protective ofbone tissue through inhibition of the RANK/RANKL
system, not only protects bones from resorption, butalso hampers the differentiation of preosteoclasts into
mature osteoclasts in VSMCs. OPG as well as RANK
and RANKL proteins are detected in atherosclerotic
plaques, and RANKL was also shown to be elevated inheart failure patients 19,20 . It should be also noted thatangiotensin II, which is a well-known promoter of atherosclerosis and arterial stiffness, has been reported toactivate osteoclasts 21 , leading to osteoporosis throughthe RANK/RANKL pathway 22 . These pathophysiologi20 ( 20 )cal mechanisms could be a plausible explanation for theclinical trials that showed the association between low
BMD and cardiovascular diseases.
In our study, we observed an association of BMD andarterial stiffness after adjusting for other pertinent cardiovascular risk factors and the variables that had significant univariate linear correlation with BMD, however the direction of association was opposite and smaller
in size compared to univariate analysis. Although several studies have suggested an association between PWVor CAVI and BMD, these studies were mostly conducted in specific populations, for example, postmenopausal
women, patients with chronic kidney disease, patients
undergoing hemodialysis, or hypertensive patients 23–25 .
In contrast, few studies have been conducted in a general population, and there is only one study from Chinasuggesting an association between BMD and arterial
stiffness as assessed by CAVI 8 . Hence the results of ourstudy are in accordance with the controversial debate
which has been conducted worldwide.
The degree of arterial stiffness is often used as animportant predictor for the prognosis of cardiovasculardiseases. Therefore, early detection of arterial stiffness
before the structure becomes abnormal gives us crucial
information to prevent cardiovascular events. Compared to PWV, CAVI is a newer noninvasive indicatorof arterial stiffness, which is performed by integrating
ECG, phonocardiogram, and arterial pulse waveform
techniques 26 . CAVI can reflect the overall arterial elasticity from the origin of the aorta to the ankle arterywithout being affected by blood pressure. In 2001,
Framingham’s study showed that patients with low
BMD had more severe abdominal aortic calcification
after adjusting for age and cardiovascular risk factors 27 .

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Mizuno, et al. : Arterial Stiffness and Bone Mineral Density
It has been observed that the association between osteoporosis and vascular calcification is also detected incoronary and peripheral arteries 28 . If we focus on the
results of univariate analysis in terms of clinical interpretation, these findings support the results of our study
showing that low BMD is associated with increased riskof arterial stiffness, with the concept that calcificationof the aorta and peripheral arteries foster arterial stiffness and central blood pressure augmentation, which
can enhance CAVI and ultimately develop cardiac dysfunction, that could have been evaluated by LVGLS or
E/e if the participants of the current study were in theadvanced stage of cardiovascular diseases.
Another important finding of our study is that the association between BMD and arterial stiffness vanishedin female subjects. The reason for this lack of association in women is unclear. One possible explanation isthat the prevalence of osteoporosis in women is higher
than in men and the clinical condition of osteoporosis
gets worse in the postmenopausal state. To address thispossibility, we performed a sub-analysis focusing on
women >50 years, but the observed insignificant association between BMD and CAVI in women persisted
after adjustment for these factors (data not shown).
Several epidemiological studies have reported similar results. For example, in the Cardiovascular HealthStudy, there was no evidence of a significant association
between BMD measured by DXA scan and incident
heart failure in women, whereas significant association
was found in nonblack men >65 years old 2 . Also, theEPIC-Norfolk study found that lower BMD in the calcaneus measured by quantitative ultrasound was associated with a higher incidence of heart failure, however
the association was not significant in women 3 . In thesestudies, the reason for the lack of association of BMD
and heart failure in women was uncertain; nonethelessthe effect of estrogen could have substantial effect onthese bone-cardiovascular interactions. Overall, it canbe postulated in our study that estrogen could overshadow other potentially weaker factors linking atrial
stiffness, such as BMD, in female subjects.
In fact, estrogen deficiency may have a crucial role in
the association between osteoporosis and cardiovascular diseases. First, estrogen receptors are widely distributed not only in osteoclasts and osteoblasts, but also in
vascular endothelial and smooth muscle cells 29 . Second,in the postmenopausal state, the decline in productionof estrogen causes secretion of pro-inflammatory cytokines such as IL-6, IL-1, and TNF-α. These proinflammatory cytokines increase the level of RANKL, and theaction of RANKL results in bone loss and vascular calcification, causing calcium to transfer from bone to theblood vessel walls 30 . Although these mechanisms areplausible, further research is needed.

The present study has some limitations. First, there
is a selection bias, as the participants are from single
center. Second, the adjustment may not have been sufficient to account for covariates and hence the results
are susceptible to residual confounding. Third, due tothe nature of cross-sectional studies, our study has not
yet revealed the causal relationship between arterial
stiffness and osteoporosis. Fourth, we lack the information for anti-osteoporotic medications and supplement
intakes. Fifth, we used quantitative ultrasound of theheel as a measure of osteoporosis, although DXA is thestandard method recommended in current guidelines.
Finally, the selection processes in this study resulted ina bias for healthy subjects and would lead to smaller
variances in BMD and arterial stiffness, making it difficult to reach significant differences.

Conclusion

Although our study is in accordance with the controversial debate and could not reach a solid conclusion showing a correlation between BMD and CAVI,
the results give us an indication that increased arterial
stiffness is likely to be comorbid with osteoporosis in
the Japanese general population. During treatment,
clinicians should pay attention to arterial stiffness inpatients with low BMD and vice versa.

Acknowledgement

We gratefully thank Yoshiko Takano and Keiko
Harada for their excellent technical assistance.

Funding

This study was supported by grants-in-aids fromthe Japan Society of Ningen Dock (to Y. Mizuno), andgrants-in-aid from Japan Health promotion foundation(to Y. Mizuno).

Conflicts of Interest

The authors have no conflicts of interest to declare.

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(Received November 7, 2022 ; Accepted March 14, 2023 ;J-STAGE Advance published date December 21, 2023)

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Original Article

Ningen Dock International 2024 ; 11 : 23–29
DOI: https://doi.org/10.11320/ningendockitn.NDI-2023-004

Predictive Factors for Diabetes Development in
Ningen Dock Examinees
with Very Mild Glucose Intolerance
Kazumasa Ogawa, Akira Seya, Koji Nomura

Abstract

Objective: This study aimed to identify predictive factors for diabetes development in Ningen
Dock examinees with very mild glucose intolerance.
Methods: We retrospectively analyzed medical records, interview responses, and Ningen Dock results of 11,313 examinees from April 2015 to March 2016 and followed them until March 2021.
Results: Over five years, 2.6% of examinees were newly diagnosed with diabetes. Those who developed diabetes had statistically significantly higher median age, body weight, and BMI comparedto those who did not develop diabetes (p<0.001 ). Almost all laboratory values, including FPG
and HbA1c, were worse in the former group. When their FPG and HbA1c levels were not high(Ningen Dock category A or B), their incidence rate of developing diabetes over the next five years
was extremely low ( 0.09–0.7%). We conducted multivariate analysis regarding predictive factors
for the development of diabetes among examinees in Ningen Dock category B, which identified
BMI ≥25 kg/m 2 (OR 5.356, p<0.001 ), LDL-C ≥140 mg/dL (OR 2.415, p=0.023 ), smoking (OR2.320, p=0.042 ), and family history of diabetes (OR 2.510, p=0.016 ) as significant predictive
factors. The incidence rate of developing diabetes over the next five years increased from 0.7% to12.5% when these predictive factors were present.
Conclusions: FPG and HbA1c levels are the most important variables in predicting the development of diabetes. However, individuals with multiple risk factors should be carefully monitored
for the development of diabetes, even if their FPG and HbA1c levels are not high.
Keywords diabetes, risk factor, life style habits, Ningen DockDiabetes is known to be associated with reduced
life expectancy and reduced healthy life expectancy 1–5 . However, epidemiologic studies ofdiabetes in Japanese populations have largely taken across-sectional approach, with few longitudinal studies
available. In addition, even when longitudinal studies
are conducted, they may be hampered by imprecise
diagnostic criteria, limited study populations, or inadequate follow-up data 6–9 . Therefore, longitudinal studies of diabetes in Japanese populations are extremely
valuable.
One of the major challenges of the Ningen Dock, anannual medical examination that originated and is now
widely used in Japan, is to diagnose diabetes at an earlystage and prevent its progression 10,11 . Our center is a
hospital-based medical check-up center located in Mitaka City, Tokyo, Japan, which receives approximately
15,000 Ningen Dock examinees annually. All examinees receive detailed medical interviews conductedby medical professionals, and their medical history
and visit records are strictly recorded. As it provides acomprehensive health examination, detailed examination data of the entire body is recorded annually. Approximately 80% of our examinees return annually forfollow-up examinations, allowing for continuous andlongitudinal data collection. In addition, on the dayof the examination at our center, almost all examinees
have a discussion with a doctor to explain the results
and receive health advice from a public health nurse.
Therefore, the Ningen Dock database of our center, although from a single institution, has a large number of
examinees, making it one of the most suitable populations for conducting longitudinal studies. Moreover, if a
population at risk for developing diabetes can be identified, this population would be the most optimal group
to implement immediate preventive measures.
Several risk factors and predictive models for diabetes have been proposed 12–17 , but their target patients

Center for Preventive Medicine, Nomura Hospital
Contact : Kazumasa Ogawa, Center for Preventive Medicine, Nomura Hospital, 8–3–6, Shimorenjyaku, Mitaka-shi, Tokyo 181–8503,
Japan. Tel : +81–422–47–4848 ; Fax : +81–422–47–4877 ; E-mail : k_ogw@nomurahp.or.jp

Ningen Dock International Vol.11 No.1 2024

23 ( 23 )and accuracy have been mixed. While fasting plasma
glucose (FPG) and HbA1c levels are the greatest predictors of diabetes in these studies, little is known about
non-glycemia-related predictors/indicators, especiallyin patients who develop diabetes from a very mildly
impaired glucose tolerance state. In our study, we aimed
to use our extensive database to identify predictors thatcan be used more practically and easily, with the goal of
implementing approaches to prevent the progression ofdiabetes from very early stages.

Table 1. Glycemic Criteria Categories Published by theJapan Society of Ningen Dock

Methods

FPG, fasting plasma glucose

Among the 14,458 Ningen Dock examinees at ourcenter between April 2015 and March 2016, we excluded examinees who had previously been diagnosed withdiabetes and those whose FPG and HbA1c levels attheir first visit were greater than 126 mg/dL and 6.5%,
respectively. We also excluded examinees who did not
return to our center after March 2016. This retrospective study is based on the records of the remaining
11,313 examinees. We analyzed the medical records,
interview responses, and Ningen Dock results of these
individuals between April 2015 and March 2021 anddetermined whether they developed diabetes during
this period. For questions regarding lifestyle habits suchas diet, exercise, and sleep, we used the answers to aquestionnaire for specific health checkups and specifichealth guidance by the Japan Ministry of Health, Labour and Welfare 18 , as well as sleep time records provided by the examinees.
The definition of the development of diabetes in thisstudy is based on the following criteria: 1 ) examinees
who were newly diagnosed with diabetes after their first
visit between April 2015 and March 2016 and up to
their last visit to our center by March 2021, or 2 ) those
whose FPG and HbA1c levels were both above 126 mg/
dL and 6.5% at their last visit to our center, although
they had not received an official diagnosis of diabetes
until that time.
The severity classification of glycemic factors usedin this study were based on the criteria categories published by the Japan Society of Ningen Dock 19 . These
categories define the following four states: A (normal),with FPG ≤ 99 mg/dL and HbA1c ≤ 5.5%; B (slightly
abnormal), with 1 ) 100 mg/dL ≤FPG ≤109 mg/dL and
HbA 1 c ≤ 5 . 9 %, or 2 ) FPG ≤ 99 mg/dL and 5 . 6 % ≤HbA1c≤5.9%; C (requires re-examination and lifestyle
improvement), with 1 ) 110 mg/dL ≤ FPG ≤ 125 mg/
dL, 2 ) 6.0%≤HbA1c≤6.4%, 3 ) FPG≥126 mg/dL andHbA1c ≤ 6.4%, FPG ≤125 mg/dL and HbA1c ≥ 6.5%;
and D (medical consultation required), with FPG≥126
mg/dL and HbA1c≥6.5% (Table 1 ).
Statistical analysis was performed using IBM SPSS
Statistics version 26 . 0 (IBM Corp., Armonk, NY).
24 ( 24 )Reference interval
Category A FPG ≤ 99 mg/dL and HbA1c ≤ 5.5%
Category B 1 ) or 2 )1 ) 100 mg/dL ≤ FPG 109 mg/dL and HbA1c≤ 5.9%
2 ) FPG ≤ 99 mg/dL and 5.6% ≤ HbA1c ≤ 5.9%
Category C 1 ) or 2 ) or 3 ) or 4 )1 ) 110 mg/dL ≤ FPG ≤ 125 mg/dL
2 ) 6.0% ≤ HbA1c ≤ 6.4%
3 ) FPG ≥ 126 mg/dL and HbA1c ≤ 6.4%
4 ) FPG ≤ 125 mg/dL and HbA1c ≥ 6.5%
Category D FPG ≥ 126 mg/dL and HbA1c ≥ 6.5%

Characteristics of examinees with and without thedevelopment of diabetes were compared using theMann–Whitney U test and the chi-squared test whereappropriate. The cumulative incidence of diabetes wasanalyzed using the Kaplan–Meier method. Multivariate
logistic regression analysis was performed to examine
the development of diabetes in examinees with glycemic category B by Ningen Dock using the following
factors: age, male sex, BMI 25 kg/m 2 or higher, systolicblood pressure 140 mmHg or higher, LDL-C 140 mg/
dL or higher, current smoking status, skipping breakfast
3 or more times per week, exercising 2 or more times
per week, sleeping less than 6 hours, having sleep apnea syndrome, and having a family history of diabetes.
These factors were selected on the basis of previous
studies as known predictors of the development ofdiabetes 12–17,20 . Statistical significance was defined asp<0.05.
The study was approved by the Institutional Review
Board of Nomura Hospital (R4-10 ). Informed consent
was obtained from patients using an opt-out procedure.

Results

The clinical characteristics of the 11,313 examinees
who visited our center between April 2015 and March
2016 are summarized in Table 2. Their median age was
50 years (range: 19–92 ), and 6,552 of them were male.
The median values of body weight, BMI, and waist circumference were 62.2 kg, 22.4 kg/m 2 , and 81.8 cm, respectively. As shown in Fig. 1, the cumulative incidenceof newly diagnosed diabetes during the 5-year period
between April 2015 and March 2021 was 2.6% ( 296
examinees).
We compared the characteristics of the 296 examinees who developed newly diagnosed diabetes with those
who did not (Table 3 ). The median age of examinees
with diabetes was 54 years, which was significantly
higher than the median age of examinees without diabetes of 50 years (p<0.001 ). The median body weight( 73.2 kg vs. 62.0 kg, p<0.001 ) and BMI ( 25.7 kg/m 2
vs. 22.3 kg/m 2 , p<0.001 ) of examinees with diabetes

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Ogawa, et al. : Predictive Factors for Diabetes
Table 2. Characteristics of 11,313 Ningen Dock Examinees Between April 2015 and March 2016
All examinees
Male examinees
Female examinees(n=11313 )(n=6552 )(n=4761 )Age, years
50 ( 19–92 )50 ( 20–92 )49 ( 19–92 )Body weight, kg
62.2 ( 30.1–137.7 ) 68.2 ( 42.3–137.7 ) 52.4 ( 30.1–105.6 )BMI, kg/m 2
22.4 ( 12.8–45.2 ) 23.3 ( 15.8–45.2 ) 20.9 ( 12.8–45.2 )Anthropometric data Abdominal circumference, cm 81.8 ( 54.0–138.6 ) 84.0 ( 61.3–138.6 ) 77.7 ( 54.0–121.7 )SBP, mmHg
117 ( 75–196 )
120 ( 78–192 )
112 ( 75–196 )DBP, mmHg
71 ( 31–128 )
74 ( 38–128 )
67 ( 31–124 )TC, mg/dL
210 ( 87–412 )
208 ( 87–412 )
212 ( 111–378 )LDL-C, mg/dL
123 ( 33–284 )
126 ( 34–284 )
120 ( 33–260 )HDL-C, mg/dL
67 ( 26–168 )
60 ( 26–161 )
77 ( 33–168 )TG, mg/dL
85 ( 19–1920 )
101 ( 28–1920 )
68 ( 19–1068 )FPG, mg/dL
98 ( 61–163 )
100 ( 61–163 )
95 ( 61–144 )Laboratory data
HbA1c, %5.4 ( 3.8–8.0 )
5.4 ( 3.8–8.0 )
5.4 ( 4.0–6.9 )UA, mg/dL
5.5 ( 0.6–13.5 )
6.3 ( 0.6–13.5 )
4.5 ( 0.6–9.0 )AST, IU/L
21 ( 10–281 )
22 ( 10–281 )
20 ( 10–180 )ALT, IU/L
18 ( 5–886 )
22 ( 5–886 )
15 ( 5–190 )Data are presented as number or median (range).
Data in this table are described using data from visits between April 2015 and March 2016.
BMI, body-mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; LDL-C, low-density
lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; FPG, fasting plasma glucose; UA, uric acid; AST,
aspartate aminotransferase; ALT, alanine aminotransferase

Fig. 1. Cumulative Incidence of Newly Diagnosed Diabetes
During the 5-year Study Period
This figure shows the cumulative incidence of newly diagnosed
diabetes over the 5-year period between April 2015 and March 2021.
Out of 11 , 313 examinees, 296 developed diabetes, resulting in acumulative incidence rate of 2.6%.

were also significantly higher than those of examinees
without diabetes. The proportions of male examinees ( 78% vs. 57%, p<0.001 ), smokers ( 26% vs. 18%,
p<0.001 ), examinees with sleep apnea syndrome ( 3%vs. 1%, p<0.001 ), and examinees with a family historyof diabetes ( 42% vs. 24%) were significantly higher in
examinees with diabetes than in examinees without diabetes. There were no significant differences in lifestylefactors such as dietary habits, exercise habits, and sleep
habits between examinees with and without diabetes.
As shown in Table 3, laboratory test results, including
blood pressure, cholesterol, blood glucose, uric acid,and liver function tests, were worse in examinees withdiabetes. Notably, the differences in median FPG ( 119
mg/dL vs. 98 mg/dL, p<0.001 ) and HbA1c ( 6.0% vs.
5.4%, p<0.001 ) were extremely higher in examinees
with diabetes.
Fig. 2 shows the impact of FPG and HbA1c in thedevelopment of diabetes. The incidence rates of developing diabetes during the 5-year follow-up period were0.09%, 0.7%, and 18% for categories A, B, and C, respectively (Fig. 3 ).
We performed multivariate analysis to identify predictive factors for the development of newly diagnosed
diabetes over a 5-year period in the examinees withglycemic category B (Table 4 ). Our results showedthat BMI≥ 25 kg/m 2 (odds ratio [OR] 5 . 356 , 95 %confidence interval [CI]: 2.359 –12.158 ; p< 0 .001 ),LDL-C≥140 mg/dL (OR 2.415, 95%CI: 1.127–5.177;
p=0.023 ), current smoker (OR 2.320, 95%CI: 1.031–
5.221; p=0.042 ), and family history of diabetes (OR2.510, 95%CI: 1.186–5.310; p=0.016 ) were significant predictive factors for the development of diabetes.
The incidence rate for diabetes in examinees withglycemic category B increased from 0.7 % to 12.5%
when they had multiple risk factors, such as BMI≥ 25
kg/m 2 , LDL-C ≥140 mg/dL, smoking, and family history of diabetes, as shown in Fig. 3.

Discussion

In this study, 296 ( 2.6%) of 11,313 examinees developed newly diagnosed diabetes during a 5-year followup period. The incidence rate of diabetes in Japanese isvaluable data in itself, as most studies of diabetes havefocused only on its prevalence 6,7,21,22 while limited studies focused on its incidence rate 8,9,23–25 .

Ningen Dock International Vol.11 No.1 2024

25 ( 25 )Table 3. Characteristics of Examinees With and Without Development of Diabetes

Age, years
Gender (male), n (%)
Body weight, kg
BMI, kg/m 2
Anthropometric data
SBP, mmHg
DBP, mmHg
SBP ≥ 140 mmHg, n (%)
TC, mg/dL
LDL-C, mg/dL
LDL-C ≥ 140 mg/dL, n (%)
HDL-C, mg/dL
TG, mg/dL
Laboratory data
FPG, mg/dL
HbA1c, %UA, mg/dL
AST, IU/L
ALT, IU/L
Current smoker, n (%)
Skipping breakfast 3 or more times per
week, n (%)
Lifestyle
Physical activity 2 or more times per
week, n (%)
Sleep duration <6 hours, n (%)
Present history of sleep apnea
syndrome, n (%)
Comorbidity and family history Family history of hypertension, n (%)
Family history of diabetes, n (%)
Family history of dyslipidemia, n (%)

Examinees whodeveloped diabetes(n=296 )
54 ( 20–82 )230 ( 78 )73.2 ( 38.1–127.4 )25.7 ( 16.7– 42.1 )
126 ( 90–195 )
77 ( 43–124 )
52 ( 18 )
215 ( 126–389 )
132 ( 59–284 )
122 ( 41 )
56 ( 30–119 )
134 ( 35–606）
119 ( 77–163 )
6.0 ( 5.1–8.0 )
6.4 ( 2.1–9.9 )
24 ( 13–76）
27 ( 9–149 )
78 ( 26 )Examinees who did not
develop diabetes(n=11017 )
50 ( 19–92 )6322 ( 57 )62.0 ( 30.1–137.7 )22.3 ( 12.8–45.2 )
116 ( 75–196 )
71 ( 31–128 )
876 ( 8 )
209 ( 87–412 )
123 ( 33–260 )
3353 ( 30 )
67 ( 26–168 )84 ( 62–1920 )
98 ( 61–155 )
5.4 ( 3.8–6.7 )
5.5 ( 0.6–13.5 )
21 ( 10–281）
18 ( 5–886 )1985 ( 18 )p value<0.001<0.001<0.001<0.001<0.001<0.001<0.0010.0014<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.00150 ( 17 )

1576 ( 14 )

N.S.

70 ( 24 )

2830 ( 26 )

N.S.

88 ( 30 )2788 ( 25 )

N.S.

10 ( 3 )

111 ( 1 )<0.001127 ( 43 )
125 ( 42 )
25 ( 8 )4621 ( 42 )
2660 ( 24 )
891 ( 8 )N.S.
<0.001
N.S.

Data are presented as number or median (range).
Data in this table are described using data from visits between April 2015 and March 2016.
BMI, body-mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol;
HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; FPG, fasting plasma glucose; UA, uric acid; AST, aspartate aminotransferase; ALT, alanine
aminotransferase; N.S., not significant

Fig. 2. Predicted Incidence Rate Over the Next Five Years Based on the Levels of FPG and HbA1c Levels
This figure shows the predicted incidence rate of new-onset diabetes over the next five years for each individual variable. The
predicted incidence rate increases as both FPG and HbA1c levels increase. Both FPG and HbA1c are strong predictors of new-onset
diabetes.

26 ( 26 )Ningen Dock International Vol.11 No.1 2024

Ogawa, et al. : Predictive Factors for Diabetes
Table 4. Multivariate Analysis for the Development of Diabetes During the Study
Period in Examinees in Glycemic Category B
Odd ratio 95% Confidence Interval p valueAge, years
1.027
0.984–1.071
0.222
Male sex
1.070
0.449–2.549
0.879
5.356
2.359–12.158<0.001
BMI ≥ 25 kg/m 2
SBP ≥ 140 mmHg
1.085
0.364–3.231
0.884
LDL-C ≥ 140 mg/dL
2.415
1.127–5.177
0.023
Current smoker
2.320
1.031–5.221
0.042
Skipping breakfast 3 or more times per week 0.582
0.190–1.783
0.343
Exercise 2 or more times per week
0.369
0.109–1.247
0.109
Sleep duration <6 hours
1.479
0.678–3.228
0.325
Present history of sleep apnea syndrome
1.646
0.361–7.499
0.520
Family history of diabetes
2.510
1.186–5.310
0.016This analysis was conducted using data from visits between April 2015 and March 2016.
BMI, body-mass index; SBP, systolic blood pressure; LDL-C, low-density lipoprotein cholesterol

Fig. 3. Predicted Incidence Rate Over the Next Five Years Based on the Glycemic Criteria Category
This figure shows the predicted incidence rate of new-onset diabetes over the next five years for each individual category. The
incidence rate of diabetes is extremely low in categories A and B, and extremely high in category C. On the other hand, it is clearthat the incidence rate increases substantially when multiple risk factors accumulate even in category B.

In a comparative analysis between examinees whodeveloped diabetes and those who did not, almost allof the variables we compared were worse in the formergroup (Table 3 ). As previously reported and as expected 12–17,20 , there were significant differences in weight, as
well as in biochemical tests for variables known to be
associated with lifestyle diseases, between the group ofindividuals who developed diabetes and those who did
not. It is believed that health and lifestyle counselingtargeting these variables can be expected to prevent theonset of diabetes in the future.
We would like to refer to the diabetes criteria category published by the Japan Society of Ningen Dock 19 .
This categorization is based on the results of FPG and
HbA1c (Table 1 ). It is clear from Fig. 2 and previous
studies 7,12,20,25 that FPG and HbA1c are the strongest
risk factors for developing diabetes. The incidence
rates of developing diabetes during the 5-year followup period were 0.09%, 0.7%, and 18% for categories
A, B, and C, respectively (Fig. 3 ). This result confirms

the appropriateness of the cut-off values for this categorization. This could mean that factors other than thiscategory, i.e., factors other than FPG and HbA1c, are
not needed to determine the risk of developing diabetes
in the future. However, some patients with very mild
glucose intolerance, such as those in category B, may
develop diabetes, albeit only a mild case, and using thiscategory alone would put them in the low-risk groupfor developing diabetes and exclude them from healthcare counselling for lifestyle improvement. Therefore,
we decided to investigate risk factors for developing
diabetes in patients with very mild impairment of glucose tolerance.
In the multivariate analysis (Table 4 ), BMI≥ 25 kg/
m 2 , LDL-C≥140 mg/dL, smoking, and family historyof diabetes were identified as risk factors for developing
diabetes in examinees in glycemic category B. Althoughless attention may be necessary for examinees in categories A and B due to their lower incidence rate of developing diabetes, it is noteworthy that the incidence rate

Ningen Dock International Vol.11 No.1 2024

27 ( 27 )increased from 0.7% to 12.5% when there were multiple risk factors, such as BMI≥25 kg/m 2 , LDL-C≥140
mg/dL, smoking, and a family history of diabetes in
examinees in category B, as shown in Fig. 3.
BMI, LDL-C, and smoking have traditionally been
known as risk factors for the development of diabetes,
and all of these factors, unlike family history, are relatively easy to improve with intervention. Therefore,
these factors are considered to be extremely importantin a setting such as Ningen Dock, where the results canbe reviewed on the day of the examination and healthguidance can be provided promptly on the spot.
In this study, lifestyle habits such as diet, exercise, andsleep were not identified as risk factors for the development of diabetes. However, this could have been be
somewhat influenced by the number of patients and theselection of factors for analysis, and we do not mean to
downplay these lifestyle habits. In fact, these factors are
known to be closely related to BMI and LDL-C, whichwere also identified as risk factors in this study. In thisstudy, only the variables in the questionnaire 18 were examined with regard to diet and exercise habits, and thestudy did not examine the details of dietary content as,
for example, in the famous Hisayama cohort study 23,24 .
It is possible that some of the details of dietary habits
may play a significant role in the development of diabetes. Sleep, in particular, is often neglected, but several
papers have already pointed out its association with thedevelopment of diabetes 26–28 , and we have also published a paper to that effect 29 . We will continue to study
this point.
We should mention some limitations of this study.
First, this is a single-center retrospective study, and oursample was limited to the examinees of Ningen Dock,so we cannot generalize our results to all Japanesepeople. The diagnosis of diabetes is partly based on selfreported history. Several antihypertensive drugs suchas angiotensin receptor blockers and lipid-improving
drugs such as statins are known to influence the development of diabetes 8,9 . However, in this study, bloodpressure and lipid values were not taken into accountwith or without oral medications. On the other hand,
this study also has many strengths. Our sample size of
11,313 was large enough for statistical analysis, andwe followed these examinees for five years. Longitudinal studies are valuable even if they are retrospective,
because there have been few longitudinal studies ofdiabetes in Japan. We accurately recorded all results ofNingen Dock examinations and responses to medical
interviews, including medical history. In addition, mostof the examinees undergo Ningen Dock annually at ourcenter, which allowed us to conduct a precise study. We
believe that our study is unique and valuable because of
these strengths.
28 ( 28 )Conclusions

We followed 11,313 Ningen Dock examinees, and2.6% of them were newly diagnosed with diabetes during the 5-year study period. FPG and HbA1c levels
appear to be the most important variables in predicting
the development of diabetes. However, it is important tonote that even if FPG and HbA1c are not high, carefulattention should be paid to individuals who have multiple risk factors such as BMI≥ 25 kg/m 2 , LDL-C≥140
mg/dL, smoking, and a family history of diabetes.

Declarations

Ethics approval and consent to participate
The study was approved by the Institutional Review
Board of Nomura Hospital (R 4-10 ). Patient consent
was obtained using informed consent documents with
an opt-out procedure.
Competing interests
None.
Funding
This research has not received any specific grant fromany public, commercial, or nonprofit funding agency.
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(in Japanese)(Received May 17, 2023 ; Accepted August 16, 2023 ;J-STAGE Advance published date November 24, 2023)

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29 ( 29 )Original Article

Ningen Dock International 2024 ; 11 : 30–38
DOI: https://doi.org/10.11320/ningendockitn.NDI-2023-003

Investigation of Factors Involved in the Prevention of
Gastric Cancer Using Health Checkup Data
from Our Facility
Kyoko Ito, Toyokazu Yukawa, Hiroko Kobayashi-Ouchi,
Yasuyuki Mima, Masahiro Nakata, Tomohiro Kato

Abstract

Objective: It has been nearly 30 years since Helicobacter pylori (Hp) was identified as a class I carcinogen for gastric cancer (GC). However, only a small percentage of Hp-infected patients develop
cancer. Although eradication therapy is considered the most eﬀective for preventing GC, various
cases of GC have been observed after eradication. This study aimed to analyze the factors preventing GC based on health examination data.
Methods: A total of 19,278 health checkup subjects ( 12,916 males and 6,362 females; meanage, 51.9±11.3 years) who underwent physical examinations at our health checkup center from2012 to 2018 were included. Patients with a history of GC were excluded. Multiple logistic regression analysis was used to analyze the association between GC and background factors (age, sex,
smoking history, alcohol consumption history, and family history of GC), lifestyle factors (dietary
preferences, exercise, and sleep), and lifestyle-related disease factors (body-mass index, metabolic
syndrome, abdominal circumference, visceral fat, body fat, lipids, glucose tolerance, liver function,and fatty liver). We also compared GC incidence between Hp-infected and post-Hp eradication
patients.
Results: Age and salt intake were significantly associated with GC (p=0.001 and 0.003, respectively). GC incidence was 1.53% among Hp-infected patients and 0.52% among post-Hp eradication patients, approximately one-third of that in those who did not undergo eradication.
Conclusion: Aging and a high salt intake may be associated with GC, suggesting that a low-sodium diet can prevent GC, especially among the elderly. The results of this study also suggest thatHp eradication therapy is eﬀective in preventing GC.
Keywords Helicobacter pylori, gastric cancer, age, saltG

astric cancer (GC) is the fifth-most common
cancer and the third-most common cause ofcancer mortality worldwide 1 . In Japan, GC
is the third-most common cancer in terms of bothincidence and death 2 , 3 . Its prognosis is dismal, withan average 5-year survival rate of <20% mainly due
to late diagnosis because the early stages are often
symptomless 4 . In Japan, extensive programs havebeen established for the early detection of GC. Owing to the implementation of GC screening as a public
cancer prevention measure in 1983 , the incidence
and mortality rates of GC have been declining since1985 5 . Furthermore, eradication therapy for patientswith gastritis caused by Helicobacter pylori (Hp) infection, classified as a class I human carcinogen for GC in
19946 , was covered by insurance in 2013, resulting in asignificant increase in the number of patients receiving
Hp eradication therapy and possibly contributing to
the decrease in the incidence and mortality rates of thisdisease.
Over the decades, risk factors for GC have been studied. Hp infection is a well-known risk factor for GC 6 .
Hp is a gram-negative bacterium capable of colonizing
the human gastric mucosa and eliciting an immune response in the host 6 . Multifocal atrophic gastritis, a typeof gastritis associated with infection, may be linked toa precancerous process 6 . Various molecular biologicalfactors associated with Hp have been reported to be
involved in gastric carcinogenesis 6 . However, <1% of
patients with Hp infection develop GC. Other factors
are also associated with GC development: environmental factors, including age, high salt intake, smoking,Center for Preventive Medicine, The Jikei University Hospital
Contact : Kyoko Ito, Center for Preventive Medicine, The Jikei University Hospital, 3–19–18 Nishi-Shimbashi, Minato-ku, Tokyo
105–8471, Japan. Tel : +81–3–3433–1111 ; Fax : +81–3–5471–2584 ; E-mail : ito.ky8@jikei.ac.jp

30 ( 30 )Ningen Dock International Vol.11 No.1 2024

Ito, et al. : Investigating Factors Preventing Gastric Cancer
and consumption of processed meat, may be involved
in gastric carcinogenesis 4 . The consumption of fresh
fruits and vegetables has been associated with reduced
cancer risk 4 . Furthermore, host factors, including thegenetic polymorphisms of genes linked to inflammatory responses, are also involved in gastric carcinogenesis 4 . Nevertheless, these elements do not fully explain
the risk factors associated with the development of GC.
It has been recently reported that lower high-density
lipoprotein (HDL) and higher low-density lipoprotein(LDL) cholesterol levels were associated with an increased risk of GC 7 . Impaired fasting glucose and highhemoglobin A1c levels are also reportedly associatedwith an increased risk of GC 8,9 . These reports indicatethat lifestyle-related diseases may be involved in gastriccarcinogenesis.
This study aimed to explore the factors associatedwith GC, including environmental factors, lifestyle
habits, and underlying lifestyle-related diseases, using
data from seven years of physical examinations at our
institution. Through this study, we hope to contributeto future GC prevention and the ideal approach for GC
screening.

Methods

Study design
This retrospective study was performed in accordance with the principles of the Declaration of Helsinki
and approved by the Ethics Committee of the Jikei University School of Medicine (approval date: February 1st,2021; approval number: 31-349 [9928]), which waived
the requirement for informed consent owing to thenature of this study. A total of 19,278 health subjects

registered in the Ningen Dock̶the Japanese healthcheckup system̶at the Center for Preventive Medicine, Jikei University Hospital between 2012 and 2018
were included. The Ningen Dock is a periodic healthcheckup program for adults. It is comprehensive andexamines the following factors: physical characteristics(height, body weight, and waist circumference), bloodpressure, complete blood count, blood biochemistry,urinalysis, electrocardiography, chest radiography, spirometry, abdominal ultrasonography, upper gastrointestinal tract barium meal or endoscopic examination,
visual acuity test, tonometry, fundic examination (retinal photography), visual field test, hearing assessment,
physical examination by a medical doctor, and a nurse’s
medical interview. There were 12,916 males and 6,362
females, with a mean age of 51.9±11.3 (range, 22–90 )years. Subjects with a history of stomach cancer andthose already receiving treatment for lifestyle-relateddiseases such as hypertension, dyslipidemia, or diabetes
were excluded from the present study. The study profile is shown in Fig. 1. First, we analyzed factors related
to GC in the whole subject group and subsequently in
Hp-positive subjects, as Hp is a potent gastric carcinogen. In our facility, the serum anti-Hp antibody test
(Hp test) is provided as an optional examination, and3,534 people underwent the Hp test as an optional examination along with the Ningen Dock. Of these, 232
who previously received Hp eradication therapy were
excluded. A total of 959 participants tested positivefor Hp. In the whole subject group, 31 ( 0.2%) patientswith GC and 19,247 without were enrolled. In the Hppositive group, 14 ( 1.5%) patients with GC and 945
without were enrolled (Table 1 ). The mean age of the

19,278 Ningen Dock examinee subjects

3,534 Hp-tested subjects

15,744 non-Hp-tested subjects

3,302 non-Hp

232 post-Hp

1,315 post-Hp

therapy subjects

eradication subjects

eradication subjects

959 Hp-positive

1,547 post-Hp

subjects

eradication subjects

14 GC subjects

8 GC subjects

Fig. 1. Study Profile

Ningen Dock International Vol.11 No.1 2024

31 ( 31 )Table 1. Subject Characteristics
Total number ofsubjects
Total
Male
FemaleHp-positive
SmokerExcessive alcohol intake
Family history of gastric cancer
Obesity
Hypertension
Dyslipidemia
Diabetes mellitus
＊

19278
12916
6362
959
3406
1709
1663
4931
1338
8131
1191

p<0.05

Hp-positive group was 55.0±13.0 years.
Moreover, the incidence of GC after Hp eradication
was compared with that of patients infected with Hp. A
total of 959 Hp-positive and 1,547 post-Hp eradication
patients, including 232 who had undertaken the Hp test
described above, were enrolled.
Target factors for the analysis of related factors to GC
To detect GC-related factors, the following aspects
were investigated: background factors, including age,gender, smoking history, drinking history, body-massindex (BMI), body fat percentage (BFP), and family
history of GC; lifestyle factors, including dietary preference, daily activity, exercise habits, sleep, and hobbies;
factors involving lifestyle-related diseases, including
metabolic syndrome, blood pressure, visceral fat accumulation, lipids (LDL cholesterol, HDL cholesterol andtriglycerides), glucose tolerance (fasting blood glucose,hemoglobin A1c, homeostatic model assessment for
insulin resistance) renal function (estimated glomerular filtration rate (eGFR)) and liver function (alanine
aminotransferase, fibrosis 4 (FIB4 ) index, which represents the degree of liver fibrosis, and fatty liver). The
corresponding data were extracted from the medical
checkups registered in Ningen Dock. Data on lifestylefactors, family history, smoking, and drinking werebased on information obtained from the medical interview conducted upon physical examination. The medical questionnaire used herein is presented in Table 2.
This questionnaire is in accordance with the questionnaire for Lifestyle Health Check-ups and Health Guidance prepared by the Ministry of Health, Labour andWelfare. A smoker was defined as an individual who
had ever smoked. The Brinkmann index was used to
examine the association between smoking and GC. The
amount (g) of ethanol consumption per week was used
to examine the relationship between ethanol consumption and GC. Excessive drinking was defined as theconsumption of ≥300 g of ethanol per week. According
to “Health Japan 21,” a national health promotion cam32 ( 32 )Number of
Number of
subjects withsubjects without
gastric cancer
gastric cancer
31 ( 0.16%)
19247
22 ( 0.17%)12894
9 ( 0.14%)6353
14 ( 1.46%)945
5 ( 0.14%)3401
1 ( 0.06%)1708
5 ( 0.30%)
1658
5 ( 0.10%)4926
4 ( 0.30%)
1334
16 ( 0.20%)
8115
4 ( 0.34%)
1187

paign by the Japanese Ministry of Health, Labour andWelfare (https://www.mhlw.go.jp), excessive alcohol was
defined as a daily ethanol intake of >60 g 10 . Given therecommendation of 2 days of no alcohol consumption
per week by Health Japan 21, alcohol consumption was
assumed to be occurring 5 days per week. Accordingly,
excessive alcohol was defined as described above whichis the alcohol consumption of ≥300 g of ethanol per
week. Information on family history was obtained froman interview by a nurse registered in Ningen Dock. Hp
infection status was evaluated by EIA using a serumanti-Hp antibody titer test (E plate ‘eiken’ H. pylori antibody kit; SRL Inc., Tokyo, Japan). Titers with values≥10 U/mL were considered positive for Hp. Patientswith a BMI ≥25 kg/m 2 were considered obese, according to the diagnostic criteria of the Japan Society for
the Study of Obesity (https://www.jasso.or.jp). BFP wasmeasured by bioelectrical impedance analysis. Metabolic syndrome was diagnosed according to the diagnostic
criteria established by eight academic societies: The
Japanese Society of Internal Medicine, Japan Society for
the Study of Obesity, Japan Atherosclerosis Society, The
Japan Diabetes Society, The Japanese Society of Hypertension, The Japanese Circulation Society, JapaneseSociety of Nephrology, and The Japanese Society on
Thrombosis and Hemostasis̶as recommended by the
Ministry of Health, Labour and Welfare.
Statistical analysis
A logistic regression analysis was used to identify factors associated with GC. First, a univariate regression
analysis was performed to detect factors associated with
GC. Subsequently, a multivariate logistic regression
analysis of the variables that were significant with p value ≥0.05 in the univariate analysis was performed. The
dependent factor was GC, and the independent factors
were background factors, lifestyle-related factors, andlifestyle-related disease-related factors, including thosementioned above. A chi-square test was used to compare the incidence or clinicopathological characteristics

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Ito, et al. : Investigating Factors Preventing Gastric Cancer
Table 2. Questionnaire for the Medical Checkup
1. What do you tend to take a lot of in your diet?
Salt
Fat
SweetsAmount of foodHow
manyminutesofwalkingorequivalent
physical
activity
do youmin
2. engage in per day?
you exercised with lightly sweatting for at least 30 min a day at Yes
3. HaveNo
least twice a week over the last year or more?
No
4. Do you get enough rest through sleep?
Yes
No
5. Do you have any hobbies?
Yes
6. Answer if you smoke currently.
How many cigarettes do you smoke per day?
cigarettes
How many years have you smoked?
years
days
7. How many days per week do you drink alcohol?
8. What type and how much alcohol do you drink at one time?

of GC between Hp-infected and post-Hp eradication
subjects. For the comparison of age between Hp-infected and post-Hp eradication subjects, Student’s t-test wasused. Stata Software version 16 (StataCorp LP, College
Station, TX, USA) was used for statistical analysis. A pvalue of <0.05 was considered statistically significant.

Results

Table 1 presents participant characteristics; mencomprised two-thirds of the entire cohort and the GC
group. No Hp-negative patients had GC. Moreover,
42.2% of subjects had dyslipidemia; 25.6% of subjects
were obese; and 17.7% of subjects were smokers. The
incidence of GC was 0.16%, 0.17%, and 0.14% among
all subjects, males and females, respectively. The incidence of GC was 1.6% among Hp-positive subjects,
approximately ten times higher than the overall GC
incidence. GC incidence was relatively higher among
patients with a family history of GC, hypertension, anddiabetes. GC was relatively less common among women, excessive drinkers, and obese people compared tothe overall average. Smokers and heavy alcohol drinkers
had a GC incidence of 0.2% and 0.06%, respectively.
Univariate logistic regression analysis ( Table 3 )showed significant associations between GC and age,body fat percentage, high salt intake, activity, exercise
habits, LDL cholesterol levels, fasting blood glucose
levels, eGFR, and high FIB4 index. Multivariate logistic regression analysis (Table 4 ) showed a significant
association between GC and age and high salt intake.
Tables 5 and 6 present the results of the univariate andmultivariate analyses of Hp-positive subjects. In total,
27.1% of subjects who underwent Hp testing had Hp(n= 3, 534 ). Among Hp-positive patients, univariate
logistic regression analysis showed significant associations between GC and age, BMI, dyslipidemia, diabetes,
and high FIB4 index (Table 5 ). However, multivariate
logistic regression analysis did not reveal a significant
association between GC and any of these factors (Table
6 ).
Fourteen GC patients were present in the Hp-positive

group (n=959 ), while eight GC patients were present in
the post-Hp eradication group (n=1,547 ). Accordingly,
GC was prevalent in 1.53% of Hp-positive patients, but
in only 0.52% of the post-Hp eradication group, which
is approximately one-third of Hp-positive patients, indicating that the incidence of GC was significantly lower(p=0.02 ) after Hp eradication (Table 7 ). This suggested
that Hp eradication therapy can reduce the risk of GC,
because the GC incidence post-eradication therapy wasapproximately 33% of that before eradication. Table 8shows the clinicopathological characteristics of GC subjects who were Hp-positive or post-Hp eradication. No
factors, such as age, sex, tumor size, tumor macroscopic
type and tumor histological type, were significantly different between the Hp-positive and post-Hp eradication
subject groups. However, age was slightly higher in the
post-Hp eradication group than the Hp-positive group,and there was a higher proportion of females in the Hppositive group than in the post-Hp eradication group.
Tumor macroscopic type was mostly early GC 0-IIc inboth the groups, but the Hp-positive group included
more types than did the post-Hp eradication group.

Discussion

In the present study, aging and a high salt intake
were found to be factors associated with GC, as seenin previous reports 1,4 . Therefore, a low-sodium diet isimportant for the prevention of GC, especially in theelderly. However, among Hp-positive patients, we did
not find any factor associated with GC, suggesting thatHp factors themselves, including the strain, as well as
the genes and proteins it holds, are more likely to havea strong influence on gastric carcinogenesis than hostbackground factors, lifestyle factors, or factors related
to lifestyle-related diseases.
Shah et al. mentioned in their review that older age
is likely a secondary risk factor to longer exposure topotential carcinogens, increased susceptibility to mucosal damage, delayed healing of the gastric mucosa,
increased incidence of mucosal cancer stem cell markers, increased prevalence of chronic active gastritis,

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33 ( 33 )Table 3. Univariate Logistic Regression Analysis
Factor
Odds ratio
Background factors
Age
1.11
Sex
1.20
BMI
0.93
Body fat
0.93
Family history of gastric cancer
2.04
Lifestyle factors
Smoking
0.90
Alcohol intake
1.00
Dietary intake
0.48
Salt intake
2.95
Fat intake
0.52
Sugar intake
0.64
Physical activity
1.00
Sleep
1.63
Exercise
2.18
Hobby
0.65
Factors associated with lifestyle-related diseases
Visceral fat accumulation
0.97
Metabolic syndrome
1.23
Blood pressure
1.01
LDL cholesterol
0.99
HDL cholesterol
1.01
Triglyceride
1.01
Dyslipidemia
1.46
FBG
1.01
HbA1c
1.40
HOMA-IR
0.76
Diabetes mellitus
2.40
eGFR
0.97
ALT
0.97
FIB4 index
1.51
Fatty liver
0.88

SE

Z scorep-value

95%CI

0.02
0.48
0.05
0.03
0.99

6.71
0.47
− 1.29− 2.101.46

0.001 ＊
0.639
0.196
0.036 ＊
0.145

[1.077, 1.145][0.554, 2.617][0.832, 1.038][0.874, 0.995][0.782, 5.320]

0.44
0.01
0.23
1.09
0.281
0.29
0.01
0.65
0.79
0.27

− 0.22

0.822
0.911
0.133
0.003 ＊
0.227
0.329
0.034 ＊
0.217
0.030 ＊
0.291

[0.344, 2.335][0.998, 1.002][0.184, 1.249][1,433, 6.087][0.183, 1.496][0.263, 1.564][1.000, 1.006][0.751, 3.543][1.078, 4.418][0.290, 1.450]

0.36
0.61
0.01
0.01
0.01
0.01
0.53
0.01
0.25
0.23
1.29
0.01
0.02
0.15
0.40

− 0.09

0.930
0.679
0.273
0.035 ＊
0.752
0.327
0.291
0.046 ＊
0.054
0.370
0.105
0.013 ＊
0.079
0.001 ＊
0.773

[0.463, 2.021][0.463, 3.263][0.990, 1.037][0.975, 0.999][0.984, 1.023][0.999, 1.004][0.722, 2.958][1.001, 1.021][0.995, 1.978][0.425, 1.375][0.833, 6.896][0.946, 0.993][0.929, 1.004][1.231, 1.839][0.361, 2.134]

0.11− 1.502.93− 1.21− 0.98
2.12
1.23
2.17
− 1.060.41
1.10− 2.11
0.32
0.98
1.06
2.00
1.93
− 0.901.62− 2.49− 1.763.99− 0.29＊p <0.05
SE, standard error; CI, confidence interval; BMI, body-mass index; FBG, fasting blood glucose; HbA1c, hemoglobin
A 1 c; HOMA-IR, homeostatic model assessment for insulin resistance; eGFR, estimated glomerular filtration rate;
ALT, alanine aminotransferase; and FIB4, fibrosis 4

Table 4. Multivariate Logistic Regression Analysis
Factors
Odds ratio
Age
1.12
Body fat
0.96
Salt intake
3.61
Physical activity
1.01
Exercise
1.309
LDL cholesterol
0.99
FBG
1.01
eGFR
1.01
FIB4 index
0.93

SE
0.03
0.04
1.55
0.01
0.56
0.01
0.01
0.02
0.28

Z score
4.99
− 1.2
2.99
0.92
0.63
− 1.060.69
0.16− 0.22p-value0.001 ＊
0.231
0.003 ＊
0.356
0.529
0.291
0.493
0.869
0.822

95%CI
[1.073, 1.175][0.889, 1.029][1.557, 8.388][0.998, 1.007][0.566, 3.028][0.977, 1.007][0.988, 1.024][0.972, 1.033][0.515, 1.694]＊

p<0.05SE, standard error; CI, confidence interval; LDL, low-density lipoprotein; FBG, fasting blood
glucose; eGFR, estimated glomerular filtration rate; and FIB4, fibrosis 4

intestinal metaplasia, and mucosal atrophy, especiallyamong Hp-positive patients 14 . This may explain our
results which show no association between age and GC
among Hp-positive patients. High salt intake has beenreported to increase GC risk 15 . Shah et al. suggested
that there are several mechanisms via which salt may
34 ( 34 )contribute to carcinogenesis 14 . High salt concentration
has been shown to disrupt the mucosal barrier of thestomach and lead to inflammation and atrophy. Experimental studies in mice and gerbils have shown increased rates of Hp colonization among mice undergoing a high salt diet due to alterations in their protective

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Ito, et al. : Investigating Factors Preventing Gastric Cancer
Table 5. Univariate Logistic Regression Analysis in Hp-positive Subjects
Factor
Odds ratio
Background factors
Age
1.09
Sex
0.58
BMI
0.8
Body fat
0.93
Family history of gastric cancer
2.21
Lifestyle factors
Smoking
0.81
Alcohol intake
1.00
Dietary intake
0.18
Salt intake
1.64
Fat intake
0.99
Sugar intake
0.40
Physical activity
1.00
Sleep
1.21
Exercise
1.23
Hobby
0.62
Factors associated with lifestyle-related diseases
Visceral fat accumulation
0.46
Metabolic syndrome
0.44
BP
0.99
LDL cholesterol
1.00
HDL cholesterol
1.01
Triglyceride
1.00
Dyslipidemia
4.12
FBS
1.01
HbA1c
1.62
HOMA-IR
0.71
Diabetes mellitus
3.98
eGFR
0.98
ALT
0.97
FIB4 index
2.98
Fatty liver
1.09

SE

Z scorep-value

95%CI

0.03
0.30
0.08
0.05
1.45

3.25
− 1.03− 2.28− 1.391.21

0.001 ＊
0.301
0.023 ＊
0.154
0.225

[1.035, 1.150][0.209, 1.622][0.660, 0.969][0.846, 1.029][0.613, 7.983]

0.62
0.00
0.19
0.86
0.64
0.31
0.01
0.67
0.66
0.37

− 0.28− 0.55− 1.66

0.780
0.584
0.098
0.343
0.985
0.229
0.599
0.731
0.694
0.417

[0.180, 0.030][0.996, 1.002][0.023, 1.371][0.590, 4.569][0.276, 3.536][0.089, 1.782][0.996, 1.007][0.410, 3.568][0.435, 3.495][0.195, 1.969]

0.30
0.46
0.02
0.01
0.15
0.00
2.52
0.02
0.46
0.31
2.75
0.02
0.03
0.99
0.6

− 1.20− 0.78− 0.74− 0.29

0.232
0.435
0.460
0.769
0.319
0.666
0.021 ＊
0.382
0.089
0.432
0.045 ＊
0.329
0.297
0.001 ＊
0.877

[0.129, 1.64][0.057, 3.430][0.953, 1.022][0.980, 1.015][0.986, 1.044][0.995, 1.007][1.241, 13.690][0.988, 1.031][0.929, 0.283][0.308, 1.65][1.030, 15.407][0.942, 1.020][0.920, 1.026][1.552, 5.705][0.369, 3.217]

0.95− 0.02− 1.20

0.53
0.34
0.39
− 0.31

1.00
0.43
2.31
0.87
1.70
− 0.792− 0.98− 1.04
3.25
0.16

＊

p<0.05Hp, Helicobacter pylori; SE, standard error; CI, confidence interval; BMI, body-mass index; FBG, fasting blood
glucose; HbA1c, hemoglobin A1c; HOMA-IR, homeostatic model assessment for insulin resistance; eGFR, estimatedglomerular filtration rate; ALT, alanine aminotransferase; and FIB4, fibrosis 4

Table 6. Multivariate Logistic Regression Analysis in Hp-positive Subjects
Factor
Odds ratio
Age
1.06
BMI
0.86
Dyslipidemia
2.07
Diabetes mellitus
1.02
FIB4 index
5.27

SE
0.05
0.12
1.66
0.94
5.19

Z score1.29− 1.12
0.91
0.02
1.69

p-value
0.197
0.263
0.362
0.985
0.092

95%CI
[0.968, 1.168][0.660, 1.120][0.432, 9.958][0.168, 6.164][0.001, 4.779]

Hp, Helicobacter pylori; BMI, body-mass index; and FIB4, fibrosis 4

Table 7. Incidence of Gastric Cancer in the Current Study
H. pylori status of subjects
H. pylori-positive
Post-eradication of H. pylori

Incidence of gastric cancer
1.46% ( 14 out of 959 patients)
0.52% ＊ ( 8 out of 1547 patients)

H. pylori, Helicobacter pylori; ＊ p=0.02

mucin layer 16,17 . High salt intake has also been found toincrease CagA expression, a potent virulence factor in
Hp and a known risk factor for GC development in Hpinfected patients 18 . Studies also suggest that salt intake
may enhance the effect of other carcinogens, including
N-nitroso compounds 19, 20 . The National Health andNutrition Examination Survey in 201821 reported thatthe average salt intake in Japan was 11 g for males and9.3 g for females. Dietary Intake Standards for Japanese2020 by the Ministry of Health, Labour and Welfare 22
recommends a salt intake of less than 7.5 g for males
and 6.5 g for females for health maintenance. Reduced
salt intake may also be effective in inhibiting gastriccarcinogenesis, although further studies are needed toclarify how many grams of sodium an individual must
limit themselves to in order to reduce the risk of gastriccarcinogenesis.
Hp infection has been shown to increase the risk of

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35 ( 35 )Table 8. Clinicopathological Characteristics of Gastric Cancer Subjects
Age (years old)
Sex
Male
FemaleTumor size (mm)20>20 ≤Tumor macroscopic type
0-IIc
0-IIb
0-IIa
Combination
Tumor histological type
tub1
tub2
poorly differenciatedCombination＊

Current Hp infection Post-Hp eradication p value
64.7 ± 7.4
71.9 ± 6.3
0.073
N/A
8
8
6
0
0.675
9
4
5
4
0.248 ＊
10
7
1
1
1
0
2
0
0.370 ＊＊
5
3
1
1
3
1
5
3

0-IIc vs. others, ＊＊ poorly vs. others

GC three- to six-fold 23–25 . Shah et al. suggested that theunderlying mechanism of how Hp increases this risk isunclear, but there are two possible pathways: the directmodulation of gastric mucosa through virulence factors, including CagA and VacA, and the indirect actionof Hp on gastric epithelial cells 16 . What is clear is that
Hp infection induces a state of chronic active inflammation that can last decades. This chronic, active gastritis can subsequently promote gastric carcinogenesis,
typically via the Correa model, suggesting that chronic
gastric inflammation leads to a cascade of mucosal atrophy, metaplasia, dysplasia, and eventually carcinoma 26 .
Host genetic factors likely play a role as well: specificgene polymorphisms in genes encoding tumor necrosis
factor-α, interleukin (IL)-1, IL-8, and IL-10 have been
associated with an increased risk of GC in Hp-infectedpatients 27 .
Smoking and heavy alcohol intake have been shownto increase the risk of GC 14 . However, our current study
did not show an association between smoking or heavy
alcohol intake and GC. Recently, the number of smokers and heavy alcohol drinkers has been decreasing inJapan 28,29 . According to the National Health and Nutrition Survey in Japan 2019 conducted by the Ministry of
Health, Labour and Welfare, the adult smoking rate was
16.7% in 2019, demonstrating a significant decrease insmoking, especially among men (from 55.3% in 1989
to 27.1% in 2019 ) 28 . As for alcohol consumption in
Japan, according to the “Sake Bookmark” of the Liquor
Tax Division of the Taxation Department of the National Tax Administration Agency, per capita consumption of alcoholic beverages has been decreasing since199229 . This is thought to be due to increased healthawareness among the public and the progress made inquitting smoking and moderating alcohol consumption through Lifestyle Health Check-ups and Health
36 ( 36 )Guidance initialized in 2008. In this program, specialist
staff, including public health nurses, nutritionists, andso on, provide support for those who are at high risk ofdeveloping lifestyle-related diseases and for whom lifestyle-related diseases can be prevented to a great extent
by improving their lifestyle 30 . Similarly, Health Japan
21 (the second term), which was initialized in 2013 andincludes the “Basic Direction for Comprehensive Implementation of National Health Promotion” establishedby the Ministry of Health, Labour and Welfare, is also
thought to have decreased the number of smokers anddrinkers 10 . Moreover, Correa mentioned in his review
that no clear association has been found between alcohol consumption and GC 4 , consistent with the resultsof this study.
Previous studies have reported a GC incidence of
7%–17% and 0.5%–1% among Hp-positive and Hpnegative individuals, respectively 11,12 . GC incidence waslower in this study than in the aforementioned reports( 1.53% and 0% in Hp-positive and Hp-negative subjects, respectively). Accordingly, it was suggested thatsome factors other than Hp infection affected GC carcinogenesis. No factors associated with GC in Hp-positive subjects were found in the current study, althoughfurther studies to clarify these factors are warranted.
This study supports the suggestions of previous studies that Hp eradication therapy reduces the incidenceof GC by approximately one-third 13 , although Ford et
al. report a significant but limited effect of eradication
therapy on primary cancer prevention for simple Hp
gastritis without gastric cancer or peptic ulcer in theirmeta-analysis 33 . Our results suggest that Hp plays apossible role in GC carcinogenesis. However, it is not
the only factor that induces GC; aging and a high salt
intake were also important factors inducing GC, although factors associated with GC among Hp-positive

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Ito, et al. : Investigating Factors Preventing Gastric Cancer
patients were unclear in this study.

Limitations

According to the guidelines of the Japanese Society of
Helicobacter Research 31 , using multiple tests enhances
the accuracy of infection diagnosis. However, in clinical practice, according to a notice from the Ministryof Health, Labour and Welfare 32 , only one additional
test can be covered by insurance when Hp infection issuspected, even if either of the tests yields negative results. Since no other test apart from the serum antibody
method was available in our facility, only subjects who
tested positive for Hp by this method were enrolled as
Hp-positive patients in the present study. This is considered a limitation of the current study. Thus, at least
two or more testing methods need to be performed toaccurately categorize patients within the Hp-infectedgroup.
Another limitation is that the intake of salt, sugar, fat,and overall dietary intake was not calculated, but rather
assessed subjectively using a questionnaire. For a more
precise study, it is necessary to conduct an analysis
based on quantified dietary intake.

Conclusion

Aging and a high salt intake are possibly associatedwith GC, suggesting that a low-sodium diet is important for the prevention of GC, especially in the elderly.
Hp eradication therapy could be effective in preventing
GC, although further studies with a larger number of
GC patients are needed for more conclusive evidence.

Acknowledgments

We greatly thank the staff of the Center for Preventive Medicine, Jikei University Hospital for their valuable contributions and support.
We would like to express our sincere gratitude to the
63 rd Annual Scientific Meeting of Japan Society of Ningen Dock for selecting this study as the best abstract in
the General Session “Gastroenterology (Upper Gastrointestinal Tract) 3 ” and recommending it for publication in the journal “Ningen Dock International”.

Conflict of Interest

The authors have no conflicts of interest to declare.

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Cancer Res 1999; 59: 4823–4828.
17. Kato S, Tsukamoto T, Mizoshita T, et al.: High salt diets
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in Helicobacter pylori-infected Mongolian gerbils associatedwith a shift in mucin production from glandular to surface
mucous cells. Int J Cancer 2006; 119: 1558–1566.
18. Loh JT, Torres VJ, Cover TL: Regulation of Helicobacter
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67: 4709–4715.
19. Takahashi M, Nishikawa A, Furukawa F, et al.: Dosedependent promoting effects of sodium chloride (NaCl)on rat glandular stomach carcinogenesis initiated with

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37 ( 37 )N-methyl-N ’-nitro-N-nitrosoguanidine. Carcinogenesis
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20. Tatematsu M, Takahashi M, Fukushima S, et al.: Effects inrats of sodium chloride on experimental gastric cancers
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4-nitriquinoline-1-oxide. J Natl Cancer Inst 1975; 55: 101–
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21. Ministry of Health, Labour and Welfare: National Healthand Nutrition Examination Survey in 2018. https://www.
mhlw.go.jp/bunya/kenkou/kenkou_eiyou_chousa.html(accessed August 19, 2023 ) (in Japanese)
22. Ministry of Health, Labour and Welfare: Dietary Intake
Standards for Japanese 2020 . https://www.mhlw.go.jp/
content/10904750/000586565.pdf, 270 (accessed August19, 2023 ) (in Japanese)
23. Vohlonen I, Pukkala E, Malila N, et al.: Risk of gastric cancer
in Helicobacter pylori infection in a 15-year follow-up. Scand
J Gastroenterol 2006; 51: 1159–1164.
24. Helicobacter and Cancer Collaborative Group: Gastriccancer and Helicobacter pylori: a combined analysis of 12case control studies nested within prospective cohorts. Gut
2001; 49: 347–353.
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young adults. Research Group on Prevention of Gastric
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26. Correa P, Haenszel W, Cuello C, et al.: A model for gastriccancer epidemiology. Lancet 1975; 2: 58–60.

38 ( 38 )27. Shanks AM, El-Omer EM: Helicobacter pylori infection, hostgenetics and gastric cancer. J Dig Dis 2009; 10: 157–164.
28. Ministry of Health, Labour and Welfare: The National
Health and Nutrition Survey in Japan. Ministry of Health,Labour and Welfare, Tokyo, 2019, 191–208.
29. National Tax Agency: Sake Bookmark 2019. The Liquor Tax
Division of the Taxation Department of the National Tax
Administration Agency. National Tax Agency, Tokyo, 2020,
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0000161103.html (accessed April 9, 2023 ) (in Japanese)
31. The Japanese Society for Helicobacter Research Guideline
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2016, Sentan-Igakusya, Tokyo, 2016, 32. (in Japanese)
32. Notification No. 1031-5 issued by the Medical Division,
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2023 ) (in Japanese)
33. Ford AC, Yuan Y, Moayyedi P: Helicobacter pylori
eradication therapy to prevent gastric cancer: systematic
review and meta-analysis. Gut 2020; 69: 2113–2121.
(Received April 28, 2023 ; Accepted August 30, 2023 ;J-STAGE Advance published date November 24, 2023)

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Ningen Dock International 2024 ; 11 : 39–46
DOI: https://doi.org/10.11320/ningendockitn.ND22-040

Original Article

The Favorable Effect of Continuous Glucose Monitoring (CGM)
on Hyperglycemia and Glycemic Fluctuations inElderly People with Untreated Glucose Intolerance
Kazuko Watanabe 1 , Kazumasa Hashimoto 2

Abstract

Objective: To evaluate the effect of a continuous glucose monitoring (CGM) device, the FreeStyle
LibreTM, on blood glucose (BG) fluctuation in elderly people with untreated glucose intolerance.
Methods: Sixty participants aged 60 years or older with glucose intolerance ( 6.5%≤HbA1c or
125 mg/dL≤BG) who were not receiving any treatments for diabetes were enrolled in the study.
They were placed on the CGM device for 14 days. During these 14 days, they were asked to keep adetailed diary regarding daily events, focusing on diet and exercise. On the 7th day, an educational
review session was performed to assess a weekly summary of their BG levels and daily events. On
the 14th day, the BG results were summarized. Fifty-five participants completed the trial, and their
response to a questionnaire was obtained.
Results: Even with glucose intolerance (HbA1c 6.7±0.48 ), large diurnal blood glucose fluctuations and frequent hyperglycemia were observed during the first week of the study period. The
mean daily BG level significantly improved from 129.9±7.5 mg/dL in the first week to 119.1±
6.18 mg/dL in the second week (p<0.01 ). The number of hyperglycemic events exceeding 180
mg/dL decreased, from 6.8±5.8 in the first week to 4.3±4.0 in the second week (p<0.01 ). The
peak BG level also decreased, from 236±73.6 mg/mL in the first week to 218±67.8 mg/dL in thesecond week (p<0.01 ). Twenty-five of 55 participants ( 45%) lost more than 1 kg of weight. Fortynine participants ( 89%) positively responded to CGM use as effective in the post-enrollment survey. For 47 ( 85%), review on the 7th day was needed. Fifty participants ( 91%) wanted to continue
using CGM. The majority of participants stated that the CGM system helped them understand theimportance of dietary carbohydrate intake, which subsequently improved their glycemic control
after the review session and counseling.
Conclusion: In elderly people with untreated glucose intolerance, various patterns of elevated
BG were observed. However, the CGM universally improved their hyperglycemia and glucose
fluctuations, regardless of the cause. The CGM system may become a valuable tool in improving
untreated glucose intolerance in elderly people, who are highly motivated to restore and maintaintheir health status.
Keywords glucose intolerance, untreated diabetes, elderly people, CGM (continuous glucose
monitoring device)T

he number of people with glucose intolerance
increases with age. Of interest, the numberof patients with overt diabetes with fastingblood glucose (FBG) of 140 mg/dL or higher does notincrease, while the number of those who have mild glucose intolerance (FBG less than 140 mg/dL) increases
with age 1 . Further, hemoglobin A1c (HbA1c) less than
7.5 in those not undergoing treatment is often identified in regular health assessments. This is probably
because HbA1c 7.5 is the goal of glycemic control inelderly diabetics. Although many elderly people withuntreated glucose intolerance (FBG less than 140 mg/
dL or HbA1c less than 7.5 ) are identified on regular
health assessments, there are very limited data withregard to their daily glycemic fluctuations. To date,
the Clinical Practice Guideline for Diabetes for the
Elderly 20232 also states that it is important to embody
individual goals in the treatment of geriatric diabetes,but does not clearly indicate a method for embodying
them 2 . Conventional dietary and exercise guidance can1

Health Examination Center of Ashiya City Hospital ; 2 Marshfield Clinic
Contact : Kazuko Watanabe, Health Examination Center of Ashiya City Hospital, 39–1, Asahigaoka-cho, Ashiya-city, Hyogo 659–
8502, Japan. Tel : +81–797–31–2156 ; Fax : +81–797–22–8822 ; E-mail : k.watanabe@ashiya-hosp.com

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39 ( 39 )be empirically attempted, but this strategy often fails
to achieve optimal glucose control and may complicate
inappropriate weight loss, which may further lead tomuscle wastage/weakness. In addition, blind dietary
restrictions may cause symptomatic hypoglycemia andfrailty in elderly people.
In this study, we investigated daily glycemic fluctuations using a continuous glucose monitoring (CGM)
system ̶the FreeStyle LibreTM̶ in elderly people withuntreated glucose intolerance diagnosed in routine
health assessments.
The purpose of this study was to identify glycemic
fluctuations in elderly people with untreated glucose
intolerance and to evaluate the effectiveness and usefulness of the CGM system and appropriate counseling to
improve their hyperglycemia and BG fluctuations.

Subjects and Methods

Among participants who underwent routine healthassessments at our health check center, those who
were 60 years of age or older with glucose intolerance( 6.5% ≤ HbA1c or 125 mg/dL ≤ BG) were invited toparticipate in the study. Patients who were alreadyreceiving diabetic treatments were excluded. A total of
60 participants who agreed to the study were enrolled.
Estimated blood glucose (BG) levels were obtainedusing a CGM (FreeStyle Libre Continuous Glucose
Monitoring system) 3,4 . A sensor was affixed to the posterior upper arm for 14 days. Glucose levels in the interstitial fluid were obtained by simply holding the reader
over the sensor and scanning. The measurements werealso recorded in a smartphone app 5 .
While wearing the device for 14 days, participants
were asked to keep a detailed diary regarding their daily
events, focusing on diet and exercise. On the 7th day,CGM results were reviewed and interim counselingand guidance for lifestyle modification were provided.
On the 14th day, final CGM results were reviewed anddiscussed with the participants. After completion of
the study, each participant was requested to complete aquestionnaire.
Mean daily BG, frequency of hyperglycemia, duration of hyperglycemia and maximal BG were compared
between the first and second weeks. Statistical analyses
were performed using the HAD program by the paired
Student t-test. BG levels of 180 mg/dL or higher and
70 mg/dL or lower were defined as hyperglycemia andhypoglycemia, repectively 6–8 .
This study was approved by the Ethics Committeeof Ashiya Municipal Hospital (No.22.2022/5/11 ) andwere consistent with the Japanese Ethical Guideline For
Life Science And Medical Research involving Human
Participants 9 . Written informed consent was obtained
from each participant prior to enrollment.
40 ( 40 )Results

The characteristics of the participants are shown in
Table 1.
A summary of the trial is shown in Fig. 1. Five of 60
participants did not complete the study due to equipment failure (n= 2 ), sensor detachment (n= 2 ), andinappropriate scanning (n=1 ).
Fifty-five participants with 14 days of blood glucose(BG) data were included in the study. Forty-nine of the
55 participants demonstrated some improvement in BG
profile.
Weekly summaries from five representative cases ofthis study are shown in Figs. 2–6.
Case 1 (Fig. 2 ) was a 70-year-old male with BMI
26.3 kg/m 2 , abdominal circumference 86 cm, HbA1c
6.7% and FBG 145 mg/dL. He walked for 30 minutes
every morning and evening, ate Japanese food for all
three meals, had a snack at 3 p.m. and performed allhousehold chores by himself. He was very active andoften went out for social events. He was surprised tosee the high BG levels from the CGM during the first
week. These showed prolonged periods of high BG levels during the first week, with an average daily BG levelof 140–160 mg/dL. After lifestyle and dietary guidance on the 7th day, his BG significantly decreased to100–120 mg/dL and no further hyperglycemic eventswere observed in the second week.
Case 2 (Fig. 3 ) was a 76-year-old male, with a BMI
24.5 kg/m 2 , abdominal circumference 87 cm, HbA1c
7.0% and FBG 138 mg/dL. He was receiving treatment
for hypertension, but not for diabetes. He did radio calisthenics every morning. On the 7th day, lifestyle guidance was provided. He was advised to walk more than
8, 000 steps daily. He was also advised to limit highcarbohydrate meals such as noodles and rice. Additionally, he was instructed to avoid snacks after dinner andencouraged exercise for 10 minutes daily. With thesesuggestions, significant BG improvement was observedin the second week.
Case 3 (Fig. 4 ) was a 60 year-old male, with BMI 26.1
kg/m 2 , abdominal circumference 98 cm, HbA1c 6.1%
and FBG 125 mg/dL. He was under medical treatment
for hypertension and hyperlipidemia. He worked as a
Table 1. Participant Characteristics
Characteristic
Male
FemaleAge (years)
BMI (kg/m 2 )Waist circumference (cm)Fasting blood glucose (mg/dL)
HbA1c (%)
Values are mean ± standard deviation.

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n=60
40
20
68.2 ± 7.9
23.4 ± 3.4
85.1 ± 12.2
124 ± 19.3
6.7 ± 0.48

Watanabe, et al. : The Effect of CGN in Elderly People with Untreated Glucose Intolerance
60 subjects enrolled
5 participants withdrawn
equipment malfunction 2
equipment disconnected 2poor understanding 1
55 subjects completed 14days CGM wearing and detailed life records
6 participants did not improve BG proﬁle
49 participants improved BG proﬁleFig. 1. Summary of the Trial

Weekly summary

Daily average
blood glucose

Hypoglycemic
event

Weekly summary

Day 1

Day 1

Day 2

Day 2

Day 3

Day 3

Day 4

Day 4

Daily average
blood glucose

Hypoglycemic
event

Day 5

Day 5

Day 6

Day 6

Day 7

Day 7

Week 2

Week 1

Fig. 2. Case 1. 70 y.o. Male (BMI 26.3 kg/m , HbA1c 6.7%, FBG 145 mg/dL)
2

security guard and returned home late in the evening,
having dinner at 8:00–9:00 p.m. He drank sweetened
canned coffee 4 to 5 times a day at work. On the 7thday, instruction was given to him to replace canned coffee with unsweetened tea and to reduce carbohydrate
intake at dinner. Improvement in the glycemic profile
was observed in the second week.
Case 4 (Fig. 5 ) is an 80-year-old male, with a BMI
24.5 kg/m 2 , abdominal circumference 92 cm, HbA1c
7.0% and FBG 124 mg/dL. He did not have a significant medical history. He walked 4,000 steps daily. For
breakfast, he ate bread with jam and butter, vegetablejuice, yogurt with cereal, banana, mandarin oranges,
and honey. For lunch, he ate noodles such as udon, soba
and ramen. For dinner, he typically ate sushi or yakitori

with beer. He used to eat ice cream after dinner. We
advised him to walk 30 minutes twice daily, not eat ice
cream, cut down the fruit intake in the morning, stop
having cereals for breakfast, and avoid simple carbohydrate meals for lunch. He also demonstrated improvement in glycemic profile.
Case 5 (Fig. 6 ) is a 69-year-old female with BMI 27.4
kg/m 2 , abdominal circumference 88 . 0 cm, HbA 1c
6.5% and FBG 101 mg/dL. She was on anticoagulants
due to the history of coronary artery disease. She wastreated for hyperlipidemia and obstructive sleep apnea.
She exercised in a gym four times a week. Although
she reduced sugar intake in each meal, she remained
hyperglycemic after lunch and dinner. Her carbohydrate restriction was insufficient, so we provided

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41 ( 41 )Daily average
blood glucose

Weekly summary

Hypoglycemic
event

Daily average
blood glucose

Weekly summary

Hypoglycemic
event

Day 1

Day 1

Day 2

Day 2

Day 3

Day 3

Day 4

Day 4

Day 5

Day 5

Day 6

Day 6

Day 7

Day 7

Week 1

Week 2

Fig. 3. Case 2. 76 y.o. Male (BMI 24.5 kg/m , HbA1c 7.0%, FBG 138 mg/dL)
2

Weekly summary

Daily average
blood glucose

Hypoglycemic
event

Daily average
blood glucose

Weekly summary

Day 1

Day 1

Day 2

Day 2

Day 3

Day 3

Day 4

Day 4

Day 5

Day 5

Day 6

Day 6

Day 7

Day 7

Week 1

Hypoglycemic
event

Week 2

Fig. 4. Case 3. 60 y.o. Male (BMI 26.1 kg/m 2 , HbA1c 6.1%, FBG 125 mg/dL)

detailed dietary counseling, including replacing sports
drinks with plain water or unsweetened tea during theexercise. She lost 1 kg of weight in two weeks and her
glucose profile improved.
As in these five representative cases, 49 of the 55
42 ( 42 )participants ( 89%) showed significant improvement
in mean daily BG level in the second week comparedto that in the first week. Changes in mean daily BG inthese 55 cases after initiating CGM are shown in Fig.
7. BG levels began to fall on the fourth day without

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Watanabe, et al. : The Effect of CGN in Elderly People with Untreated Glucose Intolerance
Daily average
blood glucose

Weekly summary

Hypoglycemic
event

Day 1

Weekly summary

Daily average
blood glucose

Hypoglycemic
event

Day 1

Day 2

Day 2

Day 3

Day 3

Day 4

Day 4

Day 5

Day 5

Day 6

Day 6

Day 7
Day 7

Week 1

Week 2

Fig. 5. Case 4. 80 y.o. Male (BMI 24.5 kg/m 2 , HbA1c 7.0%, FBG 124 mg/dL)

Daily average
blood glucose

Weekly summary

Hypoglycemic
event

Daily average
blood glucose

Weekly summary

Day 1

Day 1

Day 2

Day 2

Day 3

Day 3

Day 4

Day 4

Day 5

Day 5

Day 6

Day 6

Day 7

Day 7

Hypoglycemic
event

Week 2

Week 1

Fig. 6. Case 5. 69 y.o. Female (BMI 27.4 kg/m 2 , HbA1c 6.5%, FBG 101 mg/dL)interventions and further decreased after the interiminterview on the 7th day. The CGM application seemed
to change behavioral attitude in the participants, manyof whom demonstrated improved glucose metabolism

without further treatment, which impressed them withsatisfaction.
Table 2 shows mean daily glucose, number of hyperglycemic events at or above 180 mg/dL, duration of BG

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43 ( 43 )Average daily glucose (mg/dL)

n=55

130

Lifestyle guidance

125
120
115
110
105
100

day1

day2

day3

day4

day5

day6

day7

day8

day9 day10 day11 day12 day13

Fig. 7. Changes in Average Daily Blood Glucose while Wearing CGM
Table 2. Effect of CGMS on Hyperglycemia
Average daily glucose (mg/dL)
Number of hyperglycemic events
Duration of hyperglycemia (hour)
Peak blood glucose (mg/dL)

Week 1

Week 2p value

129.9 ± 7.5
6.8 ± 5.8
14.2 ± 25.0
236 ± 73.6

119.1 ± 6.18
4.3 ± 4.0
8.2 ± 21.0
218 ± 67.8

0.00080.00980.16
0.0003n=55.
p values were calculated by the paired t-test.
Hyperglycemia: blood glucose ≥ 180 mg/dL

Table 3. Questionnaire Results After Participation in This
Study
Weight loss ≥ 1 kg
Is CGM effective in improving your health?
Do you need a review on the 7th day?
Would you like to apply CGM again?

25/55 ( 45%)
Yes 49 ( 89%)
Yes 47 No 8 ( 85%)
Yes 50 No 5 ( 91%)

What food raises blood sugar the most?
Baked sweet potato, Udon, Curry, Amazake, Red rice, Katsudon,
Rolled sushi, Inari sushi, Croquette, Yakisoba, Breakfast fruit,
Quick meal, Convenience store bento, Boiled root vegetables,
Rice balls, Chirashi sushi, Ice cream, Rice crackers

Table 4. Lessons Learned from CGM
・I learned what food raises my blood sugar.
・I wanted to know my blood glucose levels immediately after

eating.

・I recognized I had been taking too much food.
・Self-control in diet helped to reduce my belly size.
・I learned how much exercise and dietary intake I need everyday.

・I learned the relationship between my blood sugar levels andlife events, such as choice of food intake, exercise, and physicalcondition.
・I found I had been taking too many carbs.
・I thought my lifestyle was just fine, but I realized I did not haveappropriate knowledge.
・After reviewing my lifestyle, I learned I should not take so much
sweet and greasy food.
・I tried to cut down on snacks, but I didnʼt cut down enough tomeet my goal.
・My problem was a lack of regular exercise.

44 ( 44 )at or above 180 mg/dL, and peak BG level in the firstand second weeks of the study. Statistically significant
improvements were observed in the weekly average ofdaily glucose ( 129.9 mg/dL vs 119.1 mg/dL, p<0.01 ),number of hyperglycemic events ( 6.8 vs 4.3, p<0.01 )and peak BG ( 236 mg/dL vs 218 mg/dL, p< 0 . 01 )between the first and second weeks. Duration of BG
at or above 180 mg/dL did not differ due to large variance. No adverse effects were observed with wearing
the CGM device.
The responses to the post-CGM study questionnaires
are presented in Table 3 . Twenty-five participants( 45%) lost more than 1 kg of weight, 49 ( 89%) gave apositive response to the usefulness of CGM, 47 ( 85%)
noted that the interim counseling and guidance on the
7th day were helpful, and 50 ( 91%) expressed a desired
to use CGM again. Many participants surprised that
noodles, rice, fruit, and baked potatoes significantly
raised their BG levels. Typical comments after CGM
use are shown in Table 4. One of the most common
responses was that they learned the importance ofproper dietary carbohydrate intake and regular physicalactivity to improve glycemic profile.

Discussion

BG fluctuations are affected by multiple factors suchas age, sex, genetic background, weight, muscle mass,

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Watanabe, et al. : The Effect of CGN in Elderly People with Untreated Glucose Intolerance
fat mass, metabolic efficiency and physical activity.
They are also influenced by social factors such as work,
exercise, sleep, physical/mental stress, and dietary habits. The CGM system has a strong advantage over a
traditional self-monitoring of BG (SMBG) in that it isconvenient for patients and can continuously measure
BG levels with no time lag.
With CGM, many participants who had glucose
intolerance ( 6.0%≤HbA1c<7.5%) demonstrated large
amplitudes of diurnal BG fluctuations and prolonged/
high frequency and hyperglycemia, which may nothave been detected otherwise.
Previous studies demonstrated remarkable clinical benefits of CGM use in people with type II diabetes 10–14 . However, there are few reports with regard to
the effects of CGM in patients with untreated glucose
intolerance. The results presented in this study suggestthat introducing the CGM system to elderly people withuntreated glucose intolerance is beneficial in improving
glycemic profile. Cases of mild glucose intolerance followed by diabetes mellitus are frequent. They would be
exposed to large-amplitude diurnal BG fluctuation andhyperglycemia during the period of mild glucose intolerance. The earlier achievement of normal glycemic
control will be of benefit to them.
By recording life events, factors that were responsible
for hyperglycemia and BG fluctuations were identified.
Of interest, these factors were found very specific foreach individual. After reviewing BG pattern and lifestyle, a tailored counseling was performed to set a clear
and practical goal for each participant. Goal attainment
must be collaborative and attainable. Individual lifestyleand ability should be taken into account. Lawlor andHornyak proposed the SMART goal, which incorporates four important elements for behavioral change:
1 ) The goal is specific and defines exactly what is to beachieved (Specific); 2 ) The goal is measurable and there
is tangible evidence when it has been achieved (Measurable); 3 ) The goal is achievable but the participant feels
a bit challenged (Achievable); 4 ) The goal is achievablein a short period of time (Time bound)15,16 . The CGM
may be an important tool in achieving the goal settingthat meets this SMART goal law.
For elderly people with mild glucose intolerance, utilizing the CGM system may be effective in preventing
or delaying the onset of overt diabetes via appropriate
education and counseling. In this study, not only an
improvement in BG control but also suppression of carbohydrate intake was achieved in two weeks, and about
half of the participants lost 1 kg of weight or more.
With continuation of this behavioral change, improvements in other health aspects such as hypertension,
dyslipidemia, and abnormal liver function are anticipated, which may further prevent geriatric syndrome.

It has been reported that the long-term effect of thisintervention persists even six months after its cessation 17 . Since the participants in this study are planned
to have follow-up visits for annual health assessments,
long-term effectiveness of intervention with CGM will
be evaluated. We also plan to include a CGM application as an optional test for patients who receive healthassessments in our center.
We would like to study further applications of
CGM in clinical practice. These further studies will be
expanded to include various health conditions such as
untreated glucose intolerance in middle aged people,
gestational diabetes, diet management after gastrectomy, obesity, and emaciation.

Acknowledgments

This study funded by Research Grant commissionedby the Japan Society of Ningen Dock (Grant No.20215 ).
I express my deep gratitude here for this research
opportunity provided by the Commissioned ResearchCommittee of the Japan Society of Ningen Dock.
In addition, I would like to thank Yukiko Yahata,
Center Clerk, for her tremendous cooperation in
explaining consent to the examinees, and also for
explaining the equipment, scheduling the interviews,
and collecting and entering the data.

Disclosure

The authors declare no conflict of interest associatedwith this manuscript.

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(Received October 19, 2022 ; Accepted December 25, 2023)

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Original Article

Ningen Dock International 2024 ; 11 : 47–54
DOI: https://doi.org/10.11320/ningendockitn.NDI-2023-007

The Correlation Between Brachial-ankle Pulse Wave Velocity(baPWV) and Atherosclerosis Risk Factors, as well as the
Risk Score for Development of Atherosclerotic Diseases in
Ningen Dock Health Checkup: A Prospective Collaborative
Study at Six Health Checkup Facilities
Toshiki Fukui 1 , Yuko Ishizaka 2 , Izuru Masuda 3 ,Kiminori Kato 4 , Shigeki Muto 5 , Tomofumi Atarashi 6

Abstract

Objectives: A prospective collaborative study was conducted on subjects who underwent consecutive comprehensive health checkup system (Ningen Dock) at six health checkup facilities. This
study aimed to achieve the following objectives:
1 ) To examine the correlation between Brachial-ankle Pulse Wave Velocity (baPWV) values andatherosclerosis risk factors.
2 ) To investigate the secular changes in baPWV values in subjects who underwent Ningen
Dock for three consecutive years.
3 ) To assess the association between baPWV values and atherosclerotic disease risk scores (Suitascore, Hisayama score).
Methods: A total of 14,933 subjects were enrolled in 2019, and cross-sectional analysis was conducted. Additionally, longitudinal analysis was carried out on 4,578 subjects who had baPWV
measurements for three consecutive years ( 2019–2021 ).
Results: Regarding the relationship between atherosclerosis risk factors and baPWV values, thestrongest correlation was found with four factors: hypertension, glucose metabolism abnormalities, lipid abnormalities (excluding LDL-C), and obesity. These factors remained independent
variables in multiple regression analysis. baPWV values increased significantly in both males andfemales annually. Among 4,249 subjects ( 40 to 80 years old during the three-year study period),baPWV values increased significantly as each risk score classification elevated, despite each risk
score remained unchanged.
Conclusion: baPWV values were robustly correlated with the clustering of atherosclerosis risk
factors and risk scores for atherosclerotic disease. Furthermore, baPWV values increased annually even when risk scores remained unchanged, suggesting the importance of continuous baPWV
measurement for monitoring the progression of atherosclerosis.
Keywords baPWV, atherosclerosis risk factor, Suita score, Hisayama scoreT

he primary objective of lifestyle-related disease
management is to prevent the onset of atherosclerotic vascular disease, and the method used
to monitor the progression of atherosclerosis is a very
important issue. Brachial-ankle Pulse Wave Velocity(baPWV) measurement is a non-invasive and convenient vascular function test, widely recognized forprimarily reflecting the stiffness of large arteries 1,2 . In
our previous research, we have reported both crosssectional and longitudinal results on the usefulness of

1

Center for Preventive Medical Treatment, Olive Takamatsu Medical Clinic ; 2 Center for Multiphasic Health Testing Service, Mitsui
Memorial Hospital ; 3 Endocrinology, Metabolism and Hypertension Research, Clinical Research Institute, National Hospital Organization, Kyoto Medical Center ; 4 Niigata Association of Occupational Health ; 5 Seirei Center for Health Promotion and Preventive
Medicine ; 6 Medical Check-up Center, JA Hokkaido P.W.F.A.C. Obihiro Kosei General Hospital
Contact : Toshiki Fukui, Center for Preventive Medical Treatment, Olive Takamatsu Medical Clinic, 649–8, Kankoh-cho, Takamatsu
City, Kagawa 760–0076, Japan. Tel : +81–87–839–9620 ; Fax : +81–87–861–7079 ; E-mail : t.fukui@olive.clinic

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47 ( 47 )baPWV values in health checkups 3–8 . Among these, wehave also reported that baPWV values are affected byvarious factors, and that it is necessary to standardize
the measurement conditions and interpret the results 4 .
Furthermore, since baPWV values are greatly influenced by blood pressure, we analyzed the results of acomparative study with the cardiac-ankle vascular index (CAVI) adjusted by the stiffness parameter β 9 , andfound that the baPWV value remained more useful for
health guidance in the comprehensive health checkup
system (Ningen Dock) 6 . Subsequently, we also reported on the relationship between longitudinal changes
in baPWV values and clustering of atherosclerosis risk
factors 7 , and that the effects of smoking can be detected through secular changes in baPWV values 8 . A
recent report has suggested that CAVI values adjusted
by the stiffness parameter β attenuate the predictive
effectiveness for the onset of atherosclerotic diseases
compared to baPWV values 10 .
In this study, we conducted a prospective study on
subjects who underwent Ningen Dock at multiple
health checkup facilities nationwide. We examined
the relationship between the clustering of atherosclerosis risk factors and baPWV values. Additionally, we
explored the association of baPWV values with theSuita score and Hisayama score, both of which are predictive scores for the development of atherosclerotic
disease 11,12 .

Methods

Subjects of this study had undergone Ningen Dockand measurement of baPWV values at six healthcheckup facilities participating in this study in 2019,
and a cross-sectional analysis was carried out. Furthermore, for those who underwent Ningen Dock forthree consecutive years ( 2019 to 2021 ), and measurement of baPWV values, the secular changes of baPWV
values and the relationship between baPWV values
and atherosclerotic disease risk scores (Suita score andHisayama score) were examined.
baPWV was measured using BP- 203 RPEIII form
(Colin Fukuda, Tokyo) under conditions of maximum
rest by the same measurement method as previously
reported 7,8 .
The relationship between clustering of atherosclerosis
risk factors and baPWV values was examined using thefollowing criteria. Hypertension: systolic blood pressure≥130 mmHg or diastolic blood pressure ≥ 85 mmHg;
glucose intolerance: fasting blood glucose ≥110 mg/dL
or HbA1c ≥6.0%; dyslipidemia: HDL-C <40 mg/dL or
triglyceride ≥150 mg/dL; and obesity: BMI ≥25 kg/m 2
or waist circumference ≥90 cm.
A stepwise multiple regression analysis was performed to determine independent variables for predict48 ( 48 )ing baPWV values. Systolic blood pressure, diastolicblood pressure, pulse pressure, fasting glucose, HbA1c,
triglyceride, HDL-C, BMI, waist circumference, LDL-C,
and smoking habits were used as analysis variables.
In addition, baPWV cut-off values were calculated
from the relationship between the number of atherosclerosis risk factors and baPWV values by receiver
operating characteristic (ROC) curve analysis.
Furthermore, we examined the relationship between
baPWV values and the risk classification of the Suitascore and Hisayama score, which are atherosclerotic
disease risk scores. Since the Hisayama score targets
people aged 40 to under 80, subjects who were aged 40
to under 80 during the three-year study period wereanalyzed using both scores. According to the risk classification of the Hisayama score, a Suita score ≤40 (predicted probability ≤1%) was low risk, ≤60 was medium
risk (predicted probability ≤ 9%), and ≥ 61 was highrisk. The Hisayama score according to the Japan Atherosclerosis Society (JAS) Guidelines for Prevention of
Atherosclerotic Cardiovascular Diseases 202213 , defines
diabetes, chronic kidney disease (CKD), and peripheral
vascular disease (PAD) as high-risk diseases, and classification is carried out by risk score after excluding
high-risk diseases (Hisayama score 1 ). However, since
the initial report assessed risk using the score only 12 ,we also examined the relationship between baPWV
values and risk stratification based solely on the score(Hisayama score 2 ).
Statistical Analysis
All analyses were performed using IBM SPSS Statistics version 21 (IBM, Armonk, NY, USA). All data areexpressed as mean±SD. A p-value <0.05 was considered statistically significant.
The optimal cut-off values, determined by ROC
curve analysis, were based on the Youden index.
Wilcoxon signed rank test or McNemar’s test were performed to compare the 1st and 3rd year data of subjects
who underwent Ningen Dock for three consecutive
years. Friedman’s test with Bonferroni correction was
employed to analyze the secular changes of baPWV
values, Suita scores, Hisayama scores in subjects who
underwent Ningen Dock for three consecutive years.
The Kruskal–Wallis test with Bonferroni correction
was used to analyze the relationship between risk classification of the Suita or Hisayama score and the firstyear baPWV value in subjects who underwent Ningen
Dock for three consecutive years. A Mann Whitney u
test was performed to compare the first year baPWV
values between high-risk disease patients and scorebased high-risk subjects in the Hisayama score highrisk group.
This study was conducted prospectively and analyzed
with the approval of the Ethics Committee of Olive

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Fukui, et al. : The Correlation Between baPWV and Atherosclerosis Risk Factors, as well as the Risk Score
Takamatsu Clinic ( 2019-01 ) and each participating
health checkup facility, in accordance with the Declaration of Helsinki.

Results

Table 1 shows the background characteristics ofa total of 14 , 933 subjects, 9 , 090 males and 5 , 843
females, who were enrolled in the first year ( 2019 ) at
6 health checkup facilities. Fig. 1 shows the relationship between baPWV values and the number of atherosclerosis risk factors. It was confirmed that baPWV
values increased with an increase in the number ofatherosclerosis risk factors in both sexes, which wasconsistent with our previous results 4,6,7 . Table 2 shows
independent variables for predicting baPWV values
by stepwise multiple regression analysis. Age, systolicblood pressure (mmHg), fasting glucose (mg/dL), BMI(kg/m 2 ), triglyceride (mg/dL), and waist circumference(cm) were selected in both sexes, but LDL-C and smoking habit were not. The correlation between baPWV
value and number of atherosclerosis risk factors shownin Fig. 1 was also better without considering LDL-C
and smoking habit. Table 3 shows the optimal cut-off
values of baPWV values for the number of atherosclerosis risk factors in subjects enrolled in 2019 by ROC
analysis. The AUC (area under the curve) was greatest
in both sexes when the number of atherosclerosis risk
factors was differentiated between 0 and 1 to 4, and the
optimal cut-off values were 1,401 cm/sec and 1,308

cm/sec, respectively.
Table 4 shows the first and 3rd year characteristics
of subjects who underwent Ningen Dock for threeconsecutive years and measurement of baPWV values. A total of 4,578 subjects, 2,974 males and 1,604
females, underwent Ningen Dock for three consecutive years and measurement of baPWV values. The
number of subjects who underwent Ningen Dock andcontinued baPWV measurement for three consecutive
years decreased to 30.7% of the 14,933 enrolled in thefirst year. The number of atherosclerosis risk factors
was unchanged in both sexes. The correlation between
the number of atherosclerosis risk factors and baPWV
values was similar in subjects at first year enrollment.
Three-year baPWV values showed a significant increase
every year (males: 1st year 1, 542±290 cm/sec, 2 ndyear 1,561±305 cm/sec, 3rd year 1,586±324 cm/sec;
females: 1st year 1,428±274 cm/sec, 2nd year 1,450±
290 cm/sec, 3rd year 1,467±301 cm/sec) (Table 5 ).
A total of 4,249 subjects, consisting of 2,769 males
and 1,480 females, aged 40 to under 80 during threeyear study period, were analyzed for the Suita andHisayama scores. Suita scores were statistically slightly
increased in both males and females; however, the probability of developing coronary artery disease remained
unchanged at 2–3% for males and ≤1% for females.
On the other hand, baPWV values showed a significant increase as the risk level of the Suita score worsened (Table 6 ). Table 7 shows the change in Hisayama

Table 1. Background Characteristics of Subjects Enrolled at Six Health Checkup
Facilities in 2019
Male (n=9090 ) Female (n=5843 )Age (years old)
Height (cm)Body weight (kg)BMI (kg/m 2 )Waist circumference (cm)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Fasting glucose (mg/dL)
HbA1c (%)
LDL-C (mg/dL)
HDL-C (mg/dL)
Triglyceride (mg/dL)
baPWV (cm/sec)
Subject numbers of smoking habit (%)
Number of atherosclerosis risk factors
Subjects numbers in each number of atherosclerosis 0
risk factor (%)
1
2
3
4

56.8 ± 10.8
169.6 ± 6.3
70.1 ± 11.4
24.3 ± 3.4
86.2 ± 9.2
123 ± 1477 ± 10105 ± 195.8 ± 0.7127 ± 3058 ± 15128 ± 931537 ± 302
2254 ( 24.8 )1.6 ± 1.1
1765 ( 19.4 )2580 ( 28.4 )2636 ( 29.0 )1593 ( 17.5 )
516 ( 5.7 )55.6 ± 10.7
156.7 ± 5.8
55.8 ± 10.3
22.7 ± 4.0
80.6 ± 80.6
117 ± 1571 ± 1197 ± 145.7 ± 0.5
128 ± 3170 ± 1790 ± 55
1431 ± 292
483 ( 8.3 )0.9 ± 1.02650 ( 45.4 )1781 ( 30.5 )
929 ( 15.9 )409 ( 7.0 )
74 ( 1.3 )mean ± SD

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49 ( 49 )Male (n=9090)

baPWV (cm/sec)

2000
1800
1600

1579

1518

1404

1645

1612

1400
1200
1000

0

1

2

3

4

Number of atherosclerosis risk factors

Female (n=5843)

baPWV (cm/sec)

2000
1800
1600

1483

1625

1590

1584

1313

1400
1200
1000

0

1

2

3

4

Number of atherosclerosis risk factors

Fig. 1. Relationships Between baPWV Values and the Number ofAtherosclerosis Risk Factors in Subjects Enrolled in 2019
Table 2. Independent Variables Selected for Predicting baPWV Values in Subjects Enrolled in2019 by Stepwise Multiple Regression Analysis
MaleStandardized coefficients ( β ) Unstandardized coefficients p valueAge (years old)
Systolic blood pressure (mmHg)
Fasting glucose (mg/dL)
BMI (kg/m 2 )Triglyceride (mg/dL)
Waist circumference (cm)
Diastolic blood pressure (mmHg)
HbA1c (%)

0.461
0.326
0.093
− 0.195
0.054
0.084
0.045
0.034

0.236
0.254
0.202
1.566
0.026
0.582
0.349
6.077

<0.001<0.001<0.001<0.001<0.001<0.001<0.001
0.009

FemaleStandardized coefficients ( β ) Unstandardized coefficients p valueAge (years old)
Systolic blood pressure (mmHg)
Triglyceride (mg/dL)
Fasting glucose (mg/dL)
BMI (kg/m 2 )Waist circumference (cm)Pulse pressure (mmHg)
HDL-C (mg/dL)

0.500
0.438
0.054
− 0.191
0.071
0.114− 0.063− 0.047score over three years. No significant change was seen
in males, whereas statistically significant increases in
the 2nd and 3rd years compared to the 1st year wereseen in females. baPWV values showed a significant
50 ( 50 )

0.259
0.254
0.053
1.374
0.196
0.530
0.372
0.180

<0.001<0.001<0.001<0.001<0.001<0.001<0.001<0.001increase in both sexes as the risk level worsened for
Hisayama score 2, and in males for Hisayama score 1.
For Hisayama score 1, baPWV values were significantly
higher at high risk due to high scores than at high risk

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Fukui, et al. : The Correlation Between baPWV and Atherosclerosis Risk Factors, as well as the Risk Score
Table 3. Cut-off Values for baPWV Values in Relation to the Numberof Atherosclerosis Risk Factors in Subjects Enrolled in 2019as Determined by Receiver Operating Characteristic (ROC)
Analysis
Male
Numbers of atherosclerosis risk factors (n)0 ( 1765 )
0–1 ( 4345 )
0–2 ( 6981 )
0–3 ( 8574 )

1–4 ( 7325 )
2–4 ( 4745 )
3–4 ( 2109 )
4 ( 516 )Cut-off value (cm/sec)(AUC ( 95 ％ CI))
1401 (AUC 0.68 ( 0.67–0.69 ))1467 (AUC 0.63 ( 0.62–0.64 ))
1492 (AUC 0.61 ( 0.60–0.63 ))1483 (AUC 0.62 ( 0.60–0.65 ))FemaleNumbers of atherosclerosis risk factors (n)0 ( 2650 )
0–1 ( 4431 )
0–2 ( 5360 )0–3 ( 5769 )

1–4 ( 3193 )
2–4 ( 1412 )
3–4 ( 483 )
4 ( 74 )Cut-off value (cm/sec)(AUC ( 95 ％ CI))1308 (AUC 0.73 ( 0.72–0.75 ))
1386 (AUC 0.71 ( 0.70–0.73 ))
1397 (AUC 0.69 ( 0.67–0.72 ))
1413 (AUC 0.72 ( 0.68–0.76 ))Table 4. Background Characteristics in the First and Third Years of Subjects Who Underwent Ningen Dock for Three
Consecutive Years ( 2019–2021 )Male (n=2974 )Age (years old)
Height (cm)Body weight (kg)BMI (kg/m 2 )Waist circumference (cm)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Fasting glucose (mg/dL)
HbA1c (%)
LDL-C (mg/dL)
HDL-C (mg/dL)
Triglyceride (mg/dL)
baPWV (cm/sec)
Subject number of smoking habit (%)
Number of atherosclerosis risk factors
Subjects numbers in each number ofatherosclerosis risk factor (%)

0
1
2
3
4

Female (n=1604 )first year

3rd yearp

first year

3rd yearp56.9 ± 10.5
169.7 ± 6.2
69.8 ± 11.1
24.2 ± 3.4
86.1 ± 9.1
122 ± 1478 ± 10106 ± 195.8 ± 0.6
126 ± 3058 ± 15128 ± 941542 ± 290
747 ( 25.1 )1.6 ± 1.1
568 ( 19.1 )
848 ( 28.5 )
863 ( 28.5 )
520 ( 17.5 )
175 ( 5.9 )58.9 ± 10.5
169.6 ± 6.2
69.5 ± 11.3
24.1 ± 3.4
86.2 ± 9.3
124 ± 1478 ± 10106 ± 195.8 ± 0.6
124 ± 3058 ± 15124 ± 901586 ± 324
673 ( 22.6 )1.7 ± 1.1
509 ( 17.1 )
881 ( 29.6 )875 ( 29.6 )555 ( 18.7 )154 ( 5.2 )p<0.001p<0.001p=0.006
p=0.783
p<0.001p<0.001p<0.001p=0.145p=0.824
p=0.012p=0.158
p=0.008p<0.001p=0.053
p=0.149

55.0 ± 10.6
157.1 ± 5.8
56.0 ± 10.4
22.7 ± 4.0
81.2 ± 10.3
117 ± 1571 ± 1098 ± 145.7 ± 0.5
128 ± 3168 ± 1690 ± 54
1428 ± 274
131 ( 8.2 )0.9 ± 1.0745 ( 46.4 )477 ( 29.7 )
246 ( 15.3 )
114 ( 7.1 )
22 ( 1.4 )57.0 ± 10.6
156.9 ± 5.9
56.0 ± 10.6
22.7 ± 4.0
81.5 ± 10.3
119 ± 1673 ± 1099 ± 145.7 ± 0.5127 ± 3169 ± 1690 ± 53
1467 ± 301
122 ( 7.6 )0.9 ± 1.0675 ( 42.1 )
516 ( 32.2 )271 ( 16.9 )
125 ( 7.8 )
17 ( 1.1 )p<0.001p<0.001p=0.507p=0.005p<0.001p<0.001p<0.001p=0.004
p=0.087p=0.065
p=0.085
p=0.593p<0.001
p=0.615
p=0.160

p=0.077p=0.442p=0.792
p=0.300
p=0.270p=0.067
p=0.228p=0.291p=0.518
p=0.522

mean ± SD

due to high-risk disease in males. On the other hand,
only one or two females were at high risk due to highscores. High-risk disease subjects in the first year consisted of 700 males ( 319 diabetes, 308 CKD, 9 PAD, 57
diabetes and CKD, and 7 diabetes and PAD) and 263
females ( 86 diabetes, 108 CKD, 8 PAD, 7 diabetes and
CKD, and 1 diabetes and PAD). Similar trends wereseen in the 2nd year and 3rd year.

Discussion

One of the main purposes of Ningen Dock is toprevent the development of atherosclerotic vasculardiseases, such as coronary artery disease and cerebrovascular diseases, due to the worsening of lifestylerelated disease. As atherosclerosis advances with age, it
is important to conduct examinations that can monitor
the progression of atherosclerosis before the onset ofatherosclerotic vascular disease.

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51 ( 51 )Table 5. Relationships Between baPWV Values and Number of Atherosclerosis Risk Factors, andSecular Changes in baPWV Values in Subjects Who Underwent Ningen Dock for Three
Consecutive Years ( 2019–2021 )Number of ARFs
1st year
Male (n=2974 )
0
1
2
3
4
mean baPWV (cm/sec)
mean number of ARFs
Female (n=1604 )
0
1
2
3
4
mean baPWV (cm/sec)
mean number of ARFs

2nd year

3rd yearnbaPWV (cm/sec)nbaPWV (cm/sec)nbaPWV (cm/sec)

568
848
863
520
175

1421 ± 244
1523 ± 278
1581 ± 303
1606 ± 291
1647 ± 280

541
866
856
519
192

1438 ± 253
1550 ± 305
1590 ± 307
1620 ± 311
1672 ± 305

509
881
875
555
154

1442 ± 271
1581 ± 329
1617 ± 319
1650 ± 320
1689 ± 349

1561 ± 305 ＊1.6 ± 1.2

1542 ± 290
1.6 ± 1.1
745
477
246
114
22

1318 ± 224
1491 ± 271
1539 ± 267
1616 ± 286
1603 ± 347

707
482
253
138
24

1324 ± 228
1521 ± 297
1565 ± 285
1604 ± 290
1678 ± 306

1586 ± 324 ＊＊,#
1.7 ± 1.1
675
516
271
125
17

1450 ± 290 ＊0.9 ± 1.01428 ± 274
0.9 ± 1.01334 ± 235
1544 ± 311
1567 ± 310
1617 ± 270
1668 ± 395
1467 ± 301 ＊＊0.9 ± 1.0

mean ± SD, ARFs: atherosclerosis risk factors＊
p<0.005 1st year vs 2nd year, ＊＊ p<0.001 1st year vs 3rd year, #p<0.001 2nd year vs 3rd year

Table 6. Relationship Between Risk Classification of Suita Score and baPWV Value, and Secular
Changes in Suita Score in Subjects (aged 40–80 During the Three-year Study Period)
Who Underwent Ningen Dock for Three Consecutive Years ( 2019–2021 )Suita score
1st year
Male (n=2769 )Low risk
Middle risk
High riskmean score
Female (n=1480 )Low risk
Middle risk
High riskmean score

2nd year

3rd yearnbaPWV (cm/sec)nbaPWV (cm/sec)nbaPWV (cm/sec)

841
1540
388

1372 ± 180
1570 ± 255 ＊＊1811 ± 310 ＊＊,#

717
1543
509

1363 ± 172
1578 ± 271 ＊＊1798 ± 312 ＊＊,#

624
1600
545

1360 ± 174
1593 ± 279 ＊＊1837 ± 341 ＊＊,#

46.7 ± 9.3 ＊＊45.4 ± 9.4
1126
345
9

1363 ± 211
1673 ± 274 ＊＊1738 ± 190 ＊＊33.6 ± 9.3

1064
400
16

1368 ± 218
1681 ± 287 ＊＊1963 ± 282 ＊＊, †47.4 ± 9.1 ＊＊,#
1013
447
20

34.9 ± 9.2 ＊＊1373 ± 212
1694 ± 308 ＊＊1878 ± 310 ＊＊,†
35.7 ± 9.4 ＊＊,#

mean ± SD＊＊
p<0.001 Low risk vs Middle risk, Low risk vs High risk, 1st year vs 2nd year, 1st year vs 3rd year#
p<0.001 Middle risk vs High risk, 2nd year vs 3rd year, †p<0.05 Middle risk vs High risk

We have frequently and consistently reported on theusefulness of baPWV as a non-invasive, convenient,and highly reproducible measurement of arterial stiffness 3–8 . In this study, we aimed to investigate longitudinal changes in baPWV in subjects who underwent
Ningen Dock, across multiple health checkup facilities.
While our previous studies already revealed a robust
correlation between baPWV values and clustering ofatherosclerosis risk factors, this study reaffirmed the
52 ( 52 )same findings. Regarding atherosclerosis risk factors,
we considered various conditions such as smoking habits, LDL-C levels, and obesity measures including BMI
and waist circumference. After careful evaluation, we
identified four factors that demonstrated the strongest
correlation with baPWV values: blood pressure, diabetes, triglycerides and HDL-C as lipid abnormalities,
and obesity, which includes both BMI and waist circumference (Fig. 1 and Table 5 ). The factors influenc-

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Fukui, et al. : The Correlation Between baPWV and Atherosclerosis Risk Factors, as well as the Risk Score
Table 7. Relationship Between Risk Classification of Hisayama Score 1 and 2 and baPWV Value, and Secular Changes
in Hisayama Score 2 in Subjects ( 40–80 Years Old During the Three-year Study Period) Who Underwent
Ningen Dock for Three Consecutive Years ( 2019–2021 )Hisayama score 1
1st year
Male (n=2769 )Low risk
Middle risk
High risk
Female (n=1480 )Low risk
Middle risk
High risk

2nd year

3rd yearnbaPWV (cm/sec)nbaPWV (cm/sec)nbaPWV (cm/sec)

425
1381
963

1340 ± 154
1516 ± 237 ＊＊
1674 ± 314 ＊＊,#

391
1292
1086

1346 ± 173
1518 ± 245 ＊＊
1693 ± 322 ＊＊,#

350
1248
1171

1353 ± 176
1545 ± 276 ＊＊
1705 ± 333 ＊＊,#

947
322
211

1345 ± 205
1628 ± 280 ＊＊1565 ± 257 ＊＊,†

923
317
240

1358 ± 216
1650 ± 294 ＊＊1597 ± 297 ＊＊,†

870
348
262

1361 ± 209
1673 ± 311 ＊＊1603 ± 301 ＊＊,†

Hisayama score 2
1st year
Male (n=2769 )Low risk
Middle risk
High riskmean score
Female (n=1480 )Low risk
Middle risk
High riskmean score

nbaPWV (cm/sec)

485
1859
425

1350 ± 167
1540 ± 257 ＊＊1783 ± 304 ＊＊,#

2nd yearnnbaPWV (cm/sec)

442
1822
505

1355 ± 187
1543 ± 259 ＊＊1815 ± 319 ＊＊,#

407
1790
572

1358 ± 177
1563 ± 281 ＊＊1832 ± 330 ＊＊,#

10.7 ± 2.0
1049
430
1

1354 ± 206
1642 ± 275 ＊＊1847
2.6 ± 1.8

3rd yearbaPWV (cm/sec)

10.7 ± 2.0
1034
444
2

1366 ± 218
1673 ± 292 ＊＊2137
2.7 ± 1.9 ＊＊10.6 ± 1.9
989
489
2

1371 ± 214
1691 ± 306 ＊＊1817
2.7 ± 1.9 ＊＊mean ± SD＊＊
p<0.001 Low risk vs Middle risk, Low risk vs High risk, 1st year vs 2nd year, 1st year vs 3rd year#
p<0.001 Middle risk vs High risk, † p<0.05 Middle risk vs High risk

ing baPWV values in multiple regression analysis wereconsistent with previous reports 4,5 , demonstrating thatfactors such as smoking habits and LDL-C have minimal impact on baPWV values (Table 2 ). Nevertheless,our recent report shows that the impact of smoking on
baPWV values can be detected through the analysisof changes in baPWV values over a 10-year period 8 .
Although each atherosclerosis risk factor contributes
differently to baPWV values, the robust correlation
between the clustering of atherosclerosis risk factors
and baPWV values suggests the significance of continuous baPWV measurements in preventive strategies
during Ningen Dock.
Furthermore, we also found that baPWV values
increased annually even when atherosclerotic diseasedevelopment risk scores remained unchanged. Thisemphasizes the importance of continuous baPWV measurements for monitoring atherosclerosis progressionin Ningen Dock. Additionally, the area under the curve(AUC) analysis identified cut-off values of baPWV for
different numbers of atherosclerosis risk factors. The
highest values were observed for subjects with zero or

one to four risk factors. For male, the cutoff value was1, 401 cm/sec, and for females, it was 1,308 cm/sec.
These values are consistent with the currently accepted
normal range of 1,400 cm/sec (Table 3 ) 2 .
A notable finding of our study was the annual
increase in baPWV values among subjects who underwent baPWV measurements for three consecutive
years during Ningen Dock, despite the fact that atherosclerotic disease development prediction scores,
such as the Suita score and Hisayama score, remained
unchanged (Table 6, 7 ). The Suita score, a risk scoreused to predict the probability of developing coronary
artery disease in a 10-year period by combining atherosclerotic risk factors 11 , has been incorporated into the
JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017 for urban residents in ourcountry. The Suita score has indicated that the inclusionof CKD in the scoring system enhances the accuracyof coronary artery disease prediction in Japan. On theother hand, the Hisayama score, which assesses absolute risk, including not only coronary artery disease but
also atherothrombotic cerebral infarction, was newly

Ningen Dock International Vol.11 No.1 2024

53 ( 53 )incorporated into the JAS Guidelines for Prevention of
Atherosclerotic Cardiovascular Diseases 202213 . The
initial report on the Hisayama score assessed risk using
the score only 12 . However, in the 2022 version of theguidelines, this was modified to analyze risk classification by score after excluding high-risk diseases suchas diabetes. The analysis results revealed a robust correlation between risk score classification and baPWV
values, implying that elevated baPWV values are associated with the development of atherosclerotic diseases.
In the future, it is expected that a risk score incorporating baPWV values will be developed, further confirming the usefulness of baPWV values.

Conclusion

baPWV values were robustly correlated with theclustering of atherosclerosis risk factors and risk scoresfor atherosclerosis disease. Furthermore, baPWV values
increased annually even when the risk scores remained
unchanged, suggesting the importance of continuous
baPWV measurements for monitoring the progressionof atherosclerosis.

Conflict of Interest

The authors have no conflict of interest to declare.

Acknowledgments

This study was supported by an academic research
grant from Japan Society of Ningen Dock (Grant No.
2018-3 ). We would like to express our sincere gratitude
to all the subjects and the staff of the health checkup
facilities for their valuable participation in this study.
References

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3. Fukui T, Momoi A, Yasuda T: Usefulness for Measurementof baPWV/ABI in the patients of early stage of type II

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examination for aortic stiffness. Ningen Dock 2008; 23:
70–76. (in Japanese)
7. Fukui T, Yamauchi K, Maruyama M, et al.: Ten-year
longitudinal study of brachial-ankle pulse wave velocity( baPWV ) in middle-aged Japanese males: analysis ofrelationship with clustering of atherosclerosis risk factors.
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8. Fukui T, Yamauchi K, Matsumura S, et al.: Effects ofsmoking for 10 years on brachial-ankle velocity (baPWV),a large arterial stiffness index. Ningen Dock 2020; 35: 578–
585. (in Japanese)
9. Shirai K, Utino J, Otsuka K, et al.: A novel blood pressureindependent arterial wall stiffness parameter; cardio-ankle
vascular index (CAVI). J Atheroscler Thromb 2006 ; 13:
101–107.
10. Tomiyama H, Ohkuma T, Ninomiya T, et al.: Brachial-ankle
pulse wave velocity versus its stiffness index β-transformed
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Assoc 2019; 8: e013004. doi: 10.1161/JAHA.119.013004
11. Nishimura K, Okamura T, Watanabe M, et al.: Predicting
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13. Japan Atherosclerosis Society ( JAS ) Guidelines forPrevention of Atherosclerotic Cardiovascular Diseases
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publcations/pdf/GL 2022 _s/jas_gl 2022 _ 3 _ 230210 .pdf
(accessed October 15, 2023 )(Received November 7, 2023 ; Accepted December 27, 2023)

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Original Article

Ningen Dock International 2024 ; 11 : 55–62
DOI: https://doi.org/10.11320/ningendockitn.NDI-2023-006

HDL Subclass Is Associated with Metabolic Dysfunctionassociated Fatty Liver Disease in Japanese
Kengo Moriyama 1 , Nagamu Inoue 1 , Yumi Masuda 2 , Chizumi Yamada 2 , Noriaki Kishimoto 2 ,Yurina Sakai 2 , Shinji Takashimizu 3 , Akira Kubo 2 , Yasuhiro Nishizaki 3

Abstract

Objective: Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as a newly defined disease entity. Although high-density lipoprotein cholesterol (HDL-C) is
one of the diagnostic criteria for MAFLD, it is uncertain how HDL subclasses are associated with
MAFLD in Japanese.
Methods: Among subjects who underwent a health examination at our hospital, 1,879 subjects(men: 1,238, women: 641 ) who participated in HDL2-C and HDL3-C evaluation were includedin this cross-sectional study. The association between HDL2-C, HDL3-C, HDL2-C/HDL3-C
ratio and MAFLD was investigated using multiple logistic regression analysis.
Results: HDL2-C, HDL3-C, and HDL2-C/HDL3-C ratio were significantly lower in MAFLD
subjects in men, while HDL2-C and HDL2-C/HDL3-C ratio were significantly lower and HDL3C was significantly higher in MAFLD subjects in women. Further, as the number of MAFLD
diagnostic components increased, all indices decreased in men, while HDL2-C and HDL2-C/
HDL3-C ratio decreased as the number of MAFLD diagnostic components increased in women.
In multiple logistic regression analysis, HDL2-C and HDL2-C/HDL3-C ratio was negatively
associated with MAFLD in both men and women, while HDL3-C was positively associated.
Conclusion: Our results indicate that HDL2-C and the HDL2-C/HDL3-C ratio are negatively
associated with MAFLD, while HDL3-C is positively associated with MAFLD in both men andwomen. The associations between these indices and MAFLD vary between genders and with thenumber of MAFLD diagnostic components.
Keywords metabolic dysfunction-associated fatty liver disease, HDL2-cholesterol, HDL3cholesterol, HDL2-cholesterol/HDL3-cholesterol ratioN

on-alcoholic fatty liver disease (NAFLD) is themost common chronic liver disease globally 1
and is a primary cause of cirrhosis and liver2
cancer . Its widespread occurrence can be attributed
to the increasing prevalence of sedentary lifestyles,
low physical activity, and excessive calorie intake from
imbalanced and unhealthy diets 3 . NAFLD is characterized by the presence of fat accumulation in over 5%of hepatocytes, as observed on imaging or histologicalexamination, with no apparent causes such as alcohol
consumption, viral hepatitis, genetic liver conditions,or long-term use of steatogenic medications 4 . A definitive diagnosis typically requires a liver biopsy. NAFLD
is strongly linked to metabolic syndrome (MetS), which
encompasses factors like elevated blood glucose, highblood pressure, abdominal obesity, and dyslipidemia 5 .
This condition elevates the risk of cirrhosis and associated complications. Given the increasing prevalence of
NAFLD, there is a pressing need for a clearly defined“positive” diagnosis.
Recently, a group of international experts proposed
renaming the condition from NAFLD to metabolic
dysfunction-associated fatty liver disease (MAFLD).
The new diagnostic criteria involve evidence of liver
fat accumulation along with any of the following three
conditions: being overweight or obese, having type 2
diabetes mellitus (T2DM), or showing signs of metabolic dysfunction 6 .
High-density lipoprotein (HDL) particles are a heterogeneous population characterized by density, size,

1

Department of Clinical Health Science, Tokai University School of Medicine, Tokai University Hachioji Hospital ; 2 Department ofClinical Health Science, Tokai University School of Medicine, Tokai University Tokyo Hospital ; 3 Department of Clinical Health Science, Tokai University School of Medicine, Tokai University Hospital
Contact : Kengo Moriyama, Department of Clinical Health Science, Tokai University School of Medicine, 1838 Ishikawa-machi, Hachioji,
Tokyo 192–0032, Japan. Tel : +81–42–639–1111 ; Fax : +81–42–639–1178 ; E-mail : moriyama.kengo@hachioji-hosp.tokai.ac.jp

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55 ( 55 )composition, and surface charge, and they are constantly changing. There are several methods for identifying different types of HDL particles, but one of themost representative methods is separation of the main
subfractions of HDL2 and HDL3 using ultracentrifugation 7 . Pre-β HDL, the simplest form of discoidal-shaped
HDL, is secreted by the liver and intestine. These particles rapidly take up cholesterol and phospholipids, andthereby convert into larger HDL subclasses. Pre-β HDL
undergoes rapid lipidation, resulting in the formation of
HDL3. In the maturation process, ingested free cholesterol is esterified by lecithin-cholesterol-acyl transferase(LCAT). HDL3 is associated with anti-oxidative andanti-inflammatory activities, as well as ATP-binding
cassette transporter A1 (ABCA1 )-cholesterol efflux. On
the other hand, HDL2 is involved in ATP-binding cassette subfamily G member 1 (ABCG-1 )-mediated cholesterol efflux 8 .
We previously demonstrated the importance ofanalyzing the levels of HDL cholesterol ( HDL-C )subclasses, as well as the overall HDL-C levels, whenevaluating an individual’s lifestyle habits 9 . Both HDL2C and HDL3-C have been reported to exhibit inverse
associations with the incidence of CHD. However, therelative values of these two HDL subclasses as risk predictors remain unknown. Lagos et al. recently reported
that lower HDL-C levels in patients with MetS resulted
from reductions in both the large and small HDL subclasses 10 . As the number MetS components increases,
the HDL phenotype includes a greater percentage ofsmall HDL 3 and a lesser percentage of large HDL 2
molecules, resulting in a lower HDL 2 /HDL 3 ratio.
Furthermore, we reported that the HDL 2-C/HDL3C ratio was associated with MetS components, insulin
resistance, and high-molecular-weight adiponectin levels and was thus useful for evaluating MetS in Japanese
subjects 11 . Because metabolic factors are included in the
diagnostic criteria for MAFLD, a relationship between
MAFLD and HDL subclasses is anticipated, but thisrelationship is not well understood.
Visceral obesity is a part of a condition that involves
dysfunction in the expansion of subcutaneous fat andthe storage of TG in abnormal locations. It is closely
associated with the clustering of risk factors related
to heart and metabolic health. Some of the metabolicchanges closely linked to this condition include highlevels of TG, increased availability of free fatty acids,
the release of inflammatory substances from fat tissue,
insulin resistance and inflammation, higher production and release of very low-density lipoproteins by theliver, slower removal of TG-rich lipoproteins, the presence of small and dense low-density lipoprotein (LDL)
particles, and lower levels of HDL-C 12 . A recent study
also demonstrated that obesity markedly affects HDL
56 ( 56 )metabolism, composition, and subclass distribution
linked to changes in liver and adipose tissue 13 .
Given our 9 ,11 and other reports 10 and noting that
HDL-C measurement alone is not satisfactory for risk
assessment 14–19 , it has become apparent that not only
HDL-C, but also HDL subclasses and ratios should be
investigated with respect to the coronary heart disease(CHD) risk, obesity, MetS, and lifestyle habits. The
diagnosis of MAFLD is based on the presence of fatty
liver, and HDL-C is one of the diagnostic criteria for
MAFLD. However, the relationship between HDL subclass and MAFLD is not understood at all. Therefore,
in this study, we investigated the relationship between
HDL subclasses and MAFLD in subjects undergoing
annual health check-ups.

Subjects and Methods

Subjects
Of 1,991 subjects (men: 1,323, women: 668 ) who
underwent an annual health examination at the Health
Evaluation and Promotion Center of Tokai University
Hachioji Hospital between April 2018 and October
2020, 84 men and 27 women were excluded due toincomplete data, leaving 1,879 subjects (men: 1,238,
women: 641 ) for inclusion in this cross-sectional study.
Medical history and information on smoking, physicalactivity, and alcohol intake were obtained using selfadministered questionnaires and interviews conductedby nurses.
Verbal consent for the use of anonymized healthrecords was obtained from all study subjects. The study
protocol was approved by the Ethics Committee ofTokai University School of Medicine (protocol number
20R-279 ).
Measurements
Waist circumference (WC) was measured at the levelof the umbilicus during slight expiration while in thestanding position. Blood pressure (BP) was measured
in the upper right arm using an automatic BP monitor device (TM-2655P; A&D, Tokyo, Japan) while theparticipant was seated. Blood samples were collectedin heparin-coated tubes early in the morning after
overnight fasting. Fasting plasma glucose (FPG) levels
were measured with an L-type Glu 2 kit using the hexokinase/glucose-6-phosphate dehydrogenase method(Wako Pure Chemicals). Fasting immunoreactive insulin (FIRI) levels were measured using a fluorescence
enzyme immunoassay (ST AIA-PACK IRI; Toso, Tokyo,
Japan). Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as follows: FPG (mg/dL)×FIRI (μIU/mL)/405 20 . LDL-C, HDL-C, and TG
levels were measured using visible spectrophotometry(Determiner L LDL-C, Determiner L HDL-C, andDeterminer L TG II, respectively; Kyowa Medex, Tokyo,

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Moriyama, et al. : HDL Subclasses and MAFLD
Japan). Uric acid (UA) levels were measured with an
L-Type UA.M kit using the uricase-N-( 3-sulfopropyl)3 -methoxy- 5 -methylaniline method ( Wako Pure
Chemicals, Osaka, Japan). Aspartate aminotransferase(AST), alanine aminotransferase (ALT), and g-glutamyltranspeptidase (GGT) were measured using the
JSCC transferable method with L-Type AST.J 2 andL-Type ALT.J2 (Wako Pure Chemicals, Osaka, Japan)
and Labofit g-GT (Kanto Chemical, Tokyo, Japan),respectively. Serum high-sensitivity C-reactive protein(hsCRP) levels were measured using latex agglutination
turbidimetry.
HDL2-C and HDL3-C levels were determined via
ultracentrifugation. Briefly, after plasma was centrifuged using an L-60 centrifuge (Beckman Coulter, Brea,
USA) at 22,300×g for 4 h at a plasma density of 1.063
kg/L and solvent density of 1.125 kg/L, adjusted byadding solid KBr, 40% volume from the top was aspirated, yielding HDL (a) and HDL3 (b) fractions. The
cholesterol concentration of each fraction was measured, and HDL2-C was calculated as follows: [(a)−(b)×1.54]×0.621 .
Diagnostic criteria for fatty liver
Fatty liver was diagnosed when any two of the following three ultrasonic criteria were met: liver and kidney echo discrepancy and presence of increased liverechogenicity (bright), unclear intrahepatic duct structure, and liver far-field echo decay 22 .
Definition of metabolic dysfunction associated withfatty liver disease
Diagnosis of MAFLD was based on evidence ofhepatic steatosis, in addition to one of the following
three criteria: overweight/obesity, presence of T2DM,
or evidence of metabolic dysregulation 6 .
Statistical analyses
Data are expressed as mean±standard deviation or
median (interquartile range). Normality was examined using the Kolmogorov–Smirnov test. Student’s
t-test was used to compare mean values between thetwo groups. The chi square test was used for categorical variables. Bonferroni’s multiple comparison test
was used to compare mean values across three or moregroups. Subjects were classified as nonsmokers or current smokers. High physical activity was defined as
participation in any bodily movement equivalent to 3.0
metabolic equivalents (METs) (such as walking on flatsat 67 m/min or walking with a dog) for ≥60 min/day.
Alcohol consumption was determined per units of sakeconsumed per day, with one unit ( 180 mL) considered
equivalent to 25 g of alcohol.
A multiple logistic regression analysis to calculate
odds ratios (ORs) for quantifying the association of
HDL 2 -C, HDL 3 -C, HDL 2 -C/HDL 3 -C ratio and
MAFLD was performed. BMI, WC, systolic BP, diastolic

BP, FPG, FIRI, LDL-C, HDL 2-C, HDL 3-C, TG, andhsCRP were used as independent variables. Anotherset of the same analysis was performed using HDL2C/HDL3-C ratio instead of HDL2-C and HDL3-C as
independent variables.
All statistical analyses were performed using SAS
Studio version 3.4 (SAS Institute, Cary, NC, USA). All
p-values were two-tailed, and a p-value <0.05 was considered statistically significant.

Results

All variables evaluated in this study are shown in
Table 1, with the data stratified according to sex andthe presence of MAFLD. The mean age and BMI of subjects who were diagnosed with MAFLD was 57.1 years
and 26.4 kg/m 2 in men, and 61.6 years and 27.3 kg/m 2
in women, respectively. The prevalence of MAFLD was
41.1% in men and 17.2% in women. Most of the variables, except for HDL3-C and hsCRP in men and age
in women, were accentuated in MAFLD subjects.
Table 2 (a) shows the prevalence of underlying diseases with medication when stratified by sex and thepresence of MAFLD. The prevalence of DM, HT, anddyslipidemia was significantly higher in the MAFLD
subjects, while the prevalence of stroke, heart disease,and chronic kidney disease was not statistically different in both men and women.
Table 2 (b) and (c) show alcohol consumption, smoking status and physical activity stratified by sex and thepresence of MAFLD. In terms of alcohol consumption,
there was no significant difference in the presence of
MAFLD among men. Among women, there were more
MAFLD cases among those who consumed alcohol at
up to 100 g per week, but there was no consistent trend
observed for alcohol intake beyond that threshold. The
prevalence of current smokers was not significantly
higher in the presence of MAFLD in both men andwomen. The proportion of subjects with one hour ormore of daily physical activity was significantly lower
among both men and women who met the criteria for
MAFLD.
Fig. 1 shows a comparison of HDL 2-C, HDL 3-C,
HDL2-C/HDL3-C ratio and the presence of MAFLD
in men. HDL 2-C and HDL 2-C/HDL 3-C ratio weresignificantly lower in MAFLD subjects. The relationship between the number of MAFLD diagnostic components and HDL 2-C, HDL3-C, HDL 2-C/HDL3-C
ratio was also investigated after subjects were stratified
according to the number of MAFLD diagnostic components. All indices decreased as the number of MAFLD
diagnostic components increased.
Fig. 2 shows a comparison of HDL 2-C, HDL 3-C,
HDL2-C/HDL3-C ratio and the presence of MAFLD
in women. HDL 2 -C and HDL 2 -C/HDL 3 -C ratio

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57 ( 57 )Table 1. Characterization of Study Subjects
Men
MAFLD no (n=729 ) MAFLD yes (n=509 )Age53.9 ± 13.1
57.1 ± 11.9＊＊
2
22.8 ± 2.4
26.4 ± 2.8＊＊
BMI (kg/m )Waist circumference (cm)82.3 ± 7.1
91.9 ± 7.8＊＊
Systolic BP (mmHg)
125.7 ± 17.0
131.8 ± 17.3＊＊()
Diastolic BP mmHg
78.5 ± 11.9
83.1 ± 12.5＊＊
FPG (mg/dL)
100.1 ± 15.5
108.1 ± 21.9＊＊
FIRI ( μ IU/mL)
4.3 [3.00,6.00]
7.70 [5.50,11.40]＊＊
HOMA-IR
1.10 [0.70,1.50]
2.00 [1.40,3.00]＊＊
HbA1c (NGSP)
5.6 ± 0.5
5.9 ± 0.7＊＊
TG (mg/dL)
87.0 [64.0,118.0] 123.0 [91.0,181.0]＊＊()
HDL-C mg/dL
64.3 ± 15.6
53.7 ± 12.3＊＊
HDL2-C (mg/dL)
38.4 ± 13.3
29.5 ± 9.7＊＊
HDL3-C (mg/dL)
22.5 ± 4.0
22.1 ± 3.7
HDL2-C/HDL3-C
1.74 ± 0.66
1.34 ± 0.42＊＊
LDL-C (mg/dL)
120.9 ± 29.5
125.2 ± 29.3 ＊Non-HDL-C (mg/dL)
137.5 ± 32.2
148.3 ± 33.1＊＊()
AST U/L
22.5 ± 7.1
27.8 ± 14.2＊＊
ALT (U/L)
21.3 ± 9.7
35.6 ± 25.3＊＊
GGT (U/L)
26.0 [19.0,40.0]
38.0 [27.0,62.0]＊＊
UA (mg/dL)
5.9 ± 1.1
6.3 ± 1.3＊＊
PLT
23.4 ± 5.8
24.2 ± 5.3 ＊hsCRP (mg/dL)
0.04 [0.02,0.07]
0.07 [0.04,0.13]
No. of MAFLD
1.4 ± 1.2
4.4 ± 1.4＊＊

Women
MAFLD no (n=529 ) MAFLD yes (n=112 )59.2 ± 13.5
61.6 ± 9.8
21.6 ± 2.7
27.3 ± 3.8＊＊
78.8 ± 8.8
93.0 ± 9.0＊＊
122.6 ± 19.7
137.0 ± 17.9＊＊
72.9 ± 12.980.0 ± 12.0＊＊
95.8 ± 13.7
109.5 ± 24.6＊＊
4.50 [3.40,6.30] 10.30 [7.35,14.0]＊＊
1.10 [0.80,1.50]
2.65 [1.90,3.95]＊＊
5.6 ± 0.4
6.0 ± 0.7＊＊
74.0 [55.0,100.0] 115.0 [87.0,161.0]＊＊
77.8 ± 17.1
62.7 ± 14.2＊＊
51.0 ± 15.8
36.8 ± 12.5＊＊
21.7 ± 3.9
23.1 ± 3.8＊＊
2.42 ± 0.85
1.61 ± 0.55＊＊
124.1 ± 29.3
137.2 ± 35.7 ＊137.7 ± 32.3
158.8 ± 38.5＊＊
21.3 ± 6.4
25.2 ± 10.2＊＊
17.3 ± 11.8
29.9 ± 19.5＊＊
18.0 [13.0,25.0]
27.0 [21.0,40.5]＊＊
4.7 ± 1.0
5.3 ± 1.1＊＊
24.4 ± 5.9
26.0 ± 6.0＊＊
0.03 [0.02,0.07]
0.11 [0.06,0.18]＊＊
1.1 ± 1.3
4.9 ± 1.4＊＊

Variables are expressed as mean ± standard deviation or median [interquartile range]. MAFLD, metabolic dysfunction-associated fatty
liver disease; BMI, body mass index; BP, blood pressure; FPG, fasting plasma glucose; FIRI, fasting immunoreactive insulin; HOMAIR, homeostasis model assessment of insulin resistance; TG, triglycerides; HDL-C, high-density lipoprotein cholesterol; HDL 2 -C,
high-density lipoprotein 2 cholesterol; HDL3-C, high-density lipoprotein 3 cholesterol; HDL2-C/HDL3-C, high-density lipoprotein
2 cholesterol/ high-density lipoprotein 3 cholesterol; LDL-C, low-density lipoprotein cholesterol; non-HDL-C, non high-density
lipoprotein cholesterol; AST, aspartate transaminase; ALT, alanine aminotransferase; GGT, γ-glutamyl transpeptidase; UA, uric acid;
PLT, platelet; hsCRP, high-sensitivity C-reactive protein＊
p<0.05, ＊＊p<0.01 by paired t-test.

were significantly lower and HDL3-C was significantly
higher in MAFLD subjects. HDL 2-C and HDL 2-C/
HDL 3-C ratio decreased as the number of MAFLD
diagnostic components increased.
Determinants of MAFLD were analyzed by multiple
logistic regression analysis (Table 3 ). BMI, WC, systolicBP, diastolic BP, FPG, FIRI, LDL-C, HDL2-C, HDL3C, TG, and hsCRP were used as independent variables
in Table 3 (a). Five variables (BMI, FPG, TG, HDL2-C,
and HDL3-C) were selected by a stepwise procedure
in men. Six variables (BMI, SBP, FPG, TG, HDL2-C,
and HDL3-C) were selected by a stepwise procedure in
women. BMI had a positive and significant association
with MAFLD in both men and women. HDL2-C had
a negative and HDL3-C had a positive association with
MAFLD in both men and women.
BMI, WC, systolic BP, diastolic BP, FPG, FIRI, LDLC, HDL2-C/HDL3-C ratio, TG, and hsCRP were used
as independent variables in Table 3 (b). Four variables(BMI, FPG, TG, HDL2-C/HDL3-C ratio) were selectedby a stepwise procedure in men. Five variables (BMI,
SBP, FPG, LDL-C, HDL 2 -C/HDL 3 -C ratio ) wereselected by a stepwise procedure in women. BMI had
a positive and strong association with MAFLD in both
men and women. HDL2-C/HDL3-C ratio had a strong
58 ( 58 )negative association with MAFLD in both men andwomen.

Discussion

We showed that in MAFLD subjects, HDL2-C and
HDL2-C/HDL3-C ratio were lower in both men andwomen, while HDL3-C was higher in women. As thenumber of MAFLD diagnostic components increased,
all indices decreased in men, and in women, HDL2-C
and HDL2-C/HDL3-C ratio decreased. Multiple logistic regression analysis showed a negative association of
HDL2-C and HDL2-C/HDL3-C ratio, and a positive
association of HDL3-C with MAFLD in both genders.
In this study, differences in HDL3-C were observed
between men and women. In both genders, HDL2-C
and the HDL2-C/HDL3-C ratio showed a decreasing
trend as the number of cases meeting the diagnostic criteria for MAFLD increased. In men, there wasno difference in HDL3-C regardless of whether they
met the criteria for MAFLD or not; however, as thenumber of cases meeting the diagnostic criteria for
MAFLD increased, there was a tendency for HDL3C to decrease. Our results in women may contradicta previous report which suggested a negative association between HDL 3 and the status of carotid artery

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Moriyama, et al. : HDL Subclasses and MAFLD
Table 2. Background of Study Subjects(a) Diseases under treatment
Men
No
Yes
DM
46 ( 6.3%)
57 ( 11.2%)
HT
190 ( 26.1%) 186 ( 36.5%)
Dyslipidemia
119 ( 16.3%) 140 ( 27.5%)
Stroke26 ( 3.6%)
20 ( 3.9%)
Heart disease
60 ( 8.2%)
36 ( 7.1%)
Chronic kidney disease
7 ( 1.0%)
4 ( 0.8%)
MAFLD

p-value0.00324<0.0001<0.0001
0.86140.76170.5168Women
Yes
10 ( 8.8%)
38 ( 33.9%)
37 ( 33.0%)
3 ( 2.7%)
8 ( 7.1%)0 ( 0.0%)No
13 ( 2.5%)
89 ( 16.8%)
98 ( 18.5%)
15 ( 2.8%)
21 ( 4.0%)
3 ( 0.6%)

p-value
0.00217<0.0001<0.0001
1.00000.22340.9706

MAFLD, metabolic dysfunction associated fatty liver disease; DM, diabetes mellitus; HT, hypertension
p-value by Chi-squared test.

(b) Alcohol
Ethanol (g/w)|MAFLD
0
0–100
100–200
200–300
300–400
400–

Men
No
Yes
315 ( 43.2%) 216 ( 42.4%)
103 ( 14.1%) 73 ( 14.3%)
115 ( 15.8%) 78 ( 15.3%)
127 ( 17.4%) 95 ( 18.7%)
19 ( 2.6%)
8 ( 1.6%)
50 ( 6.9%)
39 ( 7.7%)

p-value
0.83670

Women
No
Yes
394 ( 74.5%) 92 ( 82.1%)
44 ( 8.3%)
10 ( 8.9%)
53 ( 10.0%)
2 ( 1.8%)30 ( 5.7%)
5 ( 4.5%)0 ( 0.0%)
1 ( 0.9%)8 ( 1.5%)
2 ( 1.8%)

p-value
0.02271

MAFLD, metabolic dysfunction associated fatty liver disease
p-value by Chi-squared test.

(c) Smoking status and physical activity
Men
No
Yes
140 ( 19.2%) 125 ( 24.6%)

MAFLD

Current smoker
Physical activity of one 334 ( 45.8%) 187 ( 36.7%)
hour or more a day

p-value
0.0245No
40 ( 7.6%)

Women
Yes
11 ( 9.8%)

p-value
0.442

0.0015251 ( 47.4%) 36 ( 32.1%)

0.0031

MAFLD, metabolic dysfunction associated fatty liver disease
p-value by Chi-squared test.

40
30
20
10
0

(-)

30
20
10
0

(+)

HDL3-C (mg/dL)

40
HDL2-C (mg/dL)

HDL2-C (mg/dL)

(b)

**

MAFLD

0

1

2

3

4

5

6

7

8

25

25

20

20

HDL3-C (mg/dL)

(a)

15
10
5
0

(-)

(+)

15
10
5
0

MAFLD

No. of MAFLD

0

1

2

3

4

5

6

7

8

No. of MAFLD

(c)
**

2.0
HDL2-C/HDL3-C

HDL2-C/HDL3-C

2.0
1.5
1.0
0.5
0

(-)

(+)

MAFLD

1.5
1.0
0.5
0

0

1

2

3

4

5

6

7

8

No. of MAFLD

Fig. 1. Bar Graph of Mean HDL 2 -C (a), HDL 3 -C (b), and HDL 2 -C/HDL 3 -C Ratio in Men after Stratifying
Subjects According to the Presence of MAFLD or Number of MAFLD Diagnostic Components
HDL 2 -C, high-density lipoprotein 2 cholesterol; HDL 3 -C, high-density lipoprotein 3 cholesterol; MAFLD, metabolic
dysfunction-associated fatty liver disease

Ningen Dock International Vol.11 No.1 2024

59 ( 59 )

(a)

(b)

40
30
20
10
0

(-)

25

50

20

40
30
20
10
0

(+)

MAFLD

3.0

**

2.0
1.5
1.0
0.5
(-)

2

3

4

5

6

7

8

25

15
10
5
0

(-)

(+)

20
15
10
5
0

MAFLD

0

1

2

3

4

5

6

7

8

No. of MAFLD

3.0

2.5

0

1

No. of MAFLD

HDL2-C/HDL3-C

HDL2-C/HDL3-C

(c)

0

**
HDL3-C (mg/dL)

50

60
HDL3-C (mg/dL)**
HDL2-C (mg/dL)

HDL2-C (mg/dL)

60

(+)

2.5
2.0
1.5
1.0
0.5
0

MAFLD

0

1

2

3

4

5

6

7

8

No. of MAFLD

Fig. 2. Bar Graph of Mean HDL2-C (a), HDL3-C (b), and HDL2-C/HDL3-C Ratio in Women after Stratifying
Subjects According to the Presence of MAFLD or Number of MAFLD Diagnostic Components
HDL 2 -C, high-density lipoprotein 2 cholesterol; HDL 3 -C, high-density lipoprotein 3 cholesterol; MAFLD, metabolic
dysfunction-associated fatty liver disease

Table 3. Multiple Logistic Regression Analysis for MAFLD
(a)

BMI
SBP
FPG
TG
HDL2-C
HDL3-C

Men
OR
95%CI
p
1.757 1.629–1.894 <0.0001
Not selected
0.0283 0.0385 1.029 1.019–1.038 <0.0001
0.00249 0.00464 1.002 1.000–1.005 0.0201− 0.0551 0.00107 0.946 0.931–0.962 <0.0001
0.0779 0.00842 1.081 1.037–1.127 0.0002
RC
0.5634SE
1.2544

Women
RC
SE
OR
95%CI
p
0.5653 0.0651 1.760 1.549–1.999 <0.0001
0.0216 0.00859 1.022 1.005–1.039 <0.0001
0.0859 0.00869 1.024 1.007–1.042 0.0121
0.0079 0.0284 1.008 1.002–1.014 0.0057− 0.043 0.0136 0.957 0.932–0.983 0.0055
0.2054 0.0433 1.228 1.128–1.337 <0.0001

Variable selection was made by a stepwise procedure. BMI, body mass index; SBP, systolic blood pressure; FPG, fasting plasma glucose; TG,
triglycerides; HDL2-C, high-density lipoprotein 2 cholesterol; HDL3-C, high-density lipoprotein 3 cholesterol; HDL2-C/HDL3-C, high-density
lipoprotein 2 cholesterol/high-density lipoprotein 3 cholesterol; RC, regression coeﬃcient; SE, standard error; OR, odds ratio; CI, confidence
interval
Independent variables were BMI, waist circumference, systolic and diastolic blood pressure, FPG, fasting immunoreactive insulin, low-density
lipoprotein cholesterol (LDL-C), TG, HDL2-C, HDL3-C, and high-sensitivity C-reactive protein.

(b)

BMI
SBP
FPG
TG
LDL-C
HDL2-C/HDL3-C

Men
OR
95%CI
p
1.762 1.634–1.901 <0.0001
Not selected
0.0287 0.00467 1.029 1.020–1.039 <0.0001
0.00239 0.00104 1.002 1.000–1.004 0.0210
Not selected

RC
0.5667SE
0.0386− 1.2039

0.17580.300 0.213–0.423 <0.0001

Women
RC
SE
OR
95%CI
p
0.5482 0.0630 1.730 1.529–1.958 <0.0001
0.0205 0.00854 1.021 1.004–1.038 0.0163
0.0258 0.00871 1.026 1.009–1.044 0.0030
Not selected
0.0115 0.00468 1.012 1.002–1.021 0.0137− 1.3351

0.281

0.263 0.152–0.456 <0.0001

Variable selection was made by a stepwise procedure. BMI, body mass index; SBP, systolic blood pressure; FPG, fasting plasma glucose; TG,
triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL2-C, high-density lipoprotein 2 cholesterol; HDL3-C, high-density lipoprotein
3 cholesterol; HDL2-C/HDL3-C, high-density lipoprotein 2 cholesterol/high-density lipoprotein 3 cholesterol; RC, regression coeﬃcient; SE,standard error; OR, odds ratio; CI, confidence interval
Independent variables were BMI, waist circumference, systolic and diastolic blood pressure, FPG, fasting immunoreactive insulin, LDL-C, TG,
HDL2-C/HDL3-C ratio, and high-sensitivity C-reactive protein.

60 ( 60 )Ningen Dock International Vol.11 No.1 2024

Moriyama, et al. : HDL Subclasses and MAFLD
disease, but no association for HDL2, HDL-C, or Apo
A-I levels 19 . In women, the average value of HDL3-C
was significantly higher in MAFLD cases compared to
non-MAFLD cases, but there was no observed decreasein HDL3-C with an increase in the number of cases
meeting the diagnostic criteria for MAFLD. The reason for this gender difference is not clear. Previously,
in our analysis of the relationship between HDL subclasses and lifestyle habits, we reported that HDL2-C
increases with exercise and alcohol consumption but
decreases with smoking 9 . On the other hand, we foundthat HDL3-C increases only with alcohol consumption.
Alcohol intake levels did not show a significant difference between subjects with or without MAFLD in men,
and a large proportion of women did not consume
alcohol, potentially indicating that alcohol consumption
alone may not explain the observed differences. On
comparison with the previous report, we suggest that
HDL3-C level is lower in Japanese than Caucasans 19 ,suggesting significant racial variations. Further research
specifically targeting Japanese subjects is necessary.
Obesity often comes with decreased levels of HDL-C
and an increase in TG-rich lipoproteins 23 , a conditioncommonly referred to as atherogenic dyslipidemia. A
key feature of this dyslipidemia is reduced clearanceof TG-rich lipoproteins due to a relative deficiency of
insulin-sensitive lipoprotein lipase 24–26 . The rise in TGrich lipoproteins is a contributing factor to the low
HDL-C levels observed in obesity. In individuals who
are obese and insulin-resistant, HDL becomes enrichedwith TG, and there is an increase in hepatic lipase activity 27–29 . This results in the breakdown of triglyceriderich HDL into smaller HDL3 particles, which are more
susceptible to rapid catabolism 30 .
While the extent of obesity and the distribution ofvisceral fat may vary between Japanese and Westerners,
there have been reports indicating an inverse correlation between HDL3 and various events 19,31–33 . Interestingly, in patients undergoing blood dialysis, the distribution of HDL2b and HDL3 subclasses is associatedwith macrovascular events, and a proinflammatory
state has been shown to influence this subclass distribution 32 . The relationship between proinflammatory statesand insulin resistance is well known 34 . In this study,
hsCRP, an indicator of inflammation, and HOMA-IR,
reflecting insulin resistance, were elevated in both maleand female participants with MAFLD. However, theaverage values of HDL3-C and the relationship between
MAFLD status and HDL 3-C level did not exhibit aclear trend in males as compared to females. Therefore,
this phenomenon may not be solely explained by a proinflammatory state.
The major limitation of this study was its cross-sectional design, as it prevented the assessment of causality

between HDL2-C, HDL3-C, HDL2-C/HDL3-C ratioand MAFLD. Fatty liver was diagnosed using ultrasonography alone. Additional imaging, such as CT and
MRI, might be needed for a more accurate diagnosis offatty liver. All subjects in this study were middle-aged
Japanese individuals; thus, the effects of ethnicity on
the relationship between HDL2-C, HDL3-C, HDL2-C/
HDL3-C and MAFLD were not assessed. Finally, ourdataset was not large; therefore, our findings may not
be generalizable to all Japanese individuals.

Conclusion

Our results indicated that HDL2-C and the HDL2-C/
HDL3-C ratio are negatively associated with MAFLD,
while HDL3-C is positively associated with MAFLD in
both men and women. The associations between these
indices and MAFLD vary between genders and with
the number of MAFLD diagnostic components. The
concentration of HDL-C is included in the diagnostic
criteria for MAFLD, but the addition of HDL2-C andHDL3-C analysis may allow a more detailed evaluationof MAFLD.

Acknowledgments

The author would like to thank the staff at the Health
Evaluation and Promotion Center, Tokai University
Hachioji Hospital, for assisting in data collection.

Conflicts of Interest

There are no conflicts of interest.

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8. Stadler JT, Marsche G: Obesity-related changes in highdensity lipoprotein metabolism and function. Int J Mol Sci
2020; 21: 8985.

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lipoprotein 2 and 3 cholesterols with lifestyle habit factors inJapanese adults. Ningen Dock International 2014; 1: 54–62.
10. Lagos KG, Filippatos TD, Tsimihodimos V, et al.: Alterationsin the high density lipoprotein phenotype and HDLassociated enzymes in subjects with metabolic syndrome.
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11. Moriyama K, Negami M, Takahashi E: HDL2-cholesterol/
HDL 3 -cholesterol ratio was associated with insulin
resistance, high-molecular-weight adiponectin, andcomponents for metabolic syndrome in Japanese. Diabetes
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12. Tchernof A, Després JP: Pathophysiology of human visceralobesity: an update. Physiol Rev 2013; 93: 359–404.
13. Stadler JT, Lackner S, Mörkl S, et al.: Obesity affects
HDL metabolism, composition and subclass distribution.
Biomedicines 2021; 9: 242.
14. Castelli WP: Cardiovascular disease and multifactorial risk:
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15. Barter PJ, Caulfield M, Eriksson M, et al.: Effects of
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16. Boden WE, Probstfield JL, Anderson T, et al.; AIM-HIGH
Investigators: Niacin in patients with low HDL cholesterollevels receiving intensive statin therapy. N Engl J Med 2011;
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17. Voight BF, Peloso GM, Orho-Melander M, et al.: Plasma
HDL cholesterol and risk of myocardial infarction: amendelian randomisation study. Lancet 2012; 380: 572–
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18. Rohatgi A, Khera A, Berry JD, et al.: HDL cholesterol efflux
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2014; 371: 2383–2393.
19. Kim DS, Burt AA, Rosenthal EA, et al.: HDL-3 is a superior
predictor of carotid artery disease in a case-control cohort of1725 participants. J Am Heart Assoc 2014; 3: e000902.
20. Matthews DR, Hosker JP, Rudenski AS, et al.: Homeostasis
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23. Ashen MD, Blumenthal RS: Clinical practice. Low HDL
cholesterol levels. N Engl J Med 2005; 353: 1252–1260.
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D, et al.: Adipose tissue gene expression of factors related tolipid processing in obesity. PLoS ONE 2011; 6: e24783.
25. Walton RG, Zhu B, Unal R, et al.: Increasing adipocyte
lipoprotein lipase improves glucose metabolism in high fat
diet-induced obesity. J Biol Chem 2015; 290: 11547–11556.
26. Klop B, Elte JWF, Cabezas MC: Dyslipidemia in obesity:
mechanisms and potential targets. Nutrients 2013; 5: 1218–
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27. Carr MC, Hokanson JE, Zambon A, et al.: The contributionof intraabdominal fat to gender differences in hepatic lipase
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lipoproteins, and hypertriglyceridemia. Am J Pathol 2011;
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lipase and hepatic triglyceride lipase in postheparin plasmaof patients with low concentrations of HDL cholesterol.
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31. Degoricija V, Poto č njak I, Gastrager M, et al.: HDL
subclasses and mortality in acute heart failure patients. Clin
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32. Lee WC, Chen JB, Moi SH, et al.: Association of proportionof the HDL-cholesterol subclasses HDL- 2 b and HDL- 3
and macrovascular events among patients undergoinghemodialysis. Sci Rep 2021; 11: 1871.
33. Martin SS, Khokhar AA, May HT, et al.: HDL cholesterolsubclasses, myocardial infarction, and mortality insecondary prevention: the Lipoprotein Investigators
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34. Grimble RF: Inflammatory status and insulin resistance.
Curr Opin Clin Nutr Metab Care 2002; 5: 551–559.
(Received November 3, 2023 ; Accepted January 26, 2024)

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Case Report

Ningen Dock International 2024 ; 11 : 63–66
DOI: https://doi.org/10.11320/ningendockitn.NDI-2023-005

Incidental Detection of a Papillary Fibroelastoma
During a Health Check-up
Takeshi Oda 1 , Ryo Kanamoto 1 , Chie Yasuoka 2 , Daisuke Nakatomi 2 ,Ryoji Yoshida 3 , Seiya Kato 4 , Eiki Tayama 5

Abstract

An asymptomatic 69-year-old woman exhibited slight ST-segment depression in the inferiorleads on an electrocardiogram during a health check-up. Echocardiography revealed a small
mobile tumor originating from the anterolateral papillary muscle of the left ventricle. As brain
computed tomography revealed a cerebral infarction, urgent surgery was performed. The resected
tumor was histologically diagnosed as a papillary fibroelastoma (PFE). The postoperative course
was uneventful with no tumor recurrence two years post-surgery. It is extremely rare to find PFE
during a health check-up. We emphasize that even minor abnormal findings during health checkups should be monitored vigilantly.
Keywords papillary fibroelastoma, health check-up, transesophageal echocardiographyP

rimary cardiac tumors are rare, with an incidence of 0.02% 1 , and approximately three-quarters are benign 2 . Papillary fibroelastoma (PFE)is the third-most common primary cardiac tumor, accounting for 8% of all cases of primary cardiac tumor
following myxoma and lipoma 3 . PFE is known to cause
embolic complications such as stroke or myocardial
infarction 4 , and commonly originates from the heart
valves 5 . Herein, we report a surgical case of PFE arising from the anterolateral papillary muscle of the left
ventricle that was incidentally detected during a healthcheck-up.

mass included cardiac tumors, thrombi, or vegetation.
Since the mass was highly mobile, thrombus formation was unlikely to have occurred. Because she wasafebrile and there was no evidence of infection, vegetation was unlikely. Transesophageal echocardiography

Case Report

A 69-year-old woman presented to our hospital fora health check-up. The patient was in her usual stateof good health. Physical examination revealed a bloodpressure of 144/76 mmHg and a heart rate of 75 beats
per minute with sinus rhythm. The electrocardiogram(ECG) showed slight ST-segment depressions in leads
II, III, and aVf (Fig. 1 ). Transthoracic echocardiography (TTE), which was performed based on minor abnormal ECG findings, revealed a highly echoic mobile
mass arising from the anterolateral papillary muscle(ALPM) of the left ventricle (Fig. 2 ). Left ventricularejection fraction was 81% and no asynergy of the left
ventricle was detected. The differential diagnosis of theFig. 1. Electrocardiogram Showing Slight ST-segment
Depression in Leads II, III, aVF

1

Division of Cardiovascular Surgery, Omura Municipal Hospital ; 2Division of Cardiology, Omura Municipal Hospital ; 3Division of
Health Care Center, Omura Municipal Hospital ; 4Division of Pathology, Saiseikai Fukuoka General Hospital ; 5Department of Cardiovascular Surgery, Kurume University School of Medicine
Contact : Takeshi Oda, Division of Cardiovascular Surgery, Omura Municipal Hospital, 133–22 Kogashima-machi, Omura City, Nagasaki
856–8561, Japan. Tel : +81–95–752–2161 ; Fax : +81–95–752–7607 ; E-mail : oda@jadecom.jp

Ningen Dock International Vol.11 No.1 2024

63 ( 63 )

A

A

B

B

Fig. 2. Transthoracic Echocardiogram Showing a Highechoic Mass (Arrow) Arising from the Head of theAnterolateral Papillary Muscle(TEE) was performed for further examination. TEE
results also revealed a mobile and stretched mass, 12×
6 mm in size, adhering to the head of the ALPM. The
mass had moved from under the mitral valve to the left
ventricular outflow tract (LVOT) (Fig. 3 ). Based on theappearance of the mass on TTE and TEE, PFE was themost likely diagnosis. Cardiac computed tomography(CT) revealed no significant coronary artery stenosis.
Head CT demonstrated a low-density area suggestiveof an old cerebral infarction at the border of the leftparietal and occipital lobes (Fig. 4 ). Despite the absenceof symptoms, the mass was urgently removed to avoid
further embolization.
The operation was performed through a mediansternotomy, and cardiopulmonary bypass was established via aorto-bicaval cannulation. After cardioplegic cardiac arrest was achieved, the left atrium was
opened using a transseptal approach. Inspection of theleft ventricle through the mitral valve revealed a jellylike tumor with multiple fronds originating from thehead of the ALPM (Fig. 5 ). The tumor was completely
excised with surgical margins. When placed in saline,
64 ( 64 )Fig. 3. Transesophageal Echocardiogram Showing a
Stretched Mass (Arrow) Located in the Left Ventricular
Outflow Tract During Systole

the excised tumor had a sea anemone appearance withmultiple fronds, consistent with PFE (Fig. 6 ). PFE wasconfirmed via histopathological analysis (Fig. 7 ). The
postoperative course was uneventful. No recurrence of
PFE was observed two years after surgery.

Discussion

PFE is the third-most common benign cardiac tumor and usually originates from the heart valve tissue.
When a left-heart PFE is found, early surgery is recommended because left-heart PFE frequently presents withembolic neurological symptoms. Ngaage et al. advocated that since PFE is frequently located in the high-flow
and high-pressure LVOT of the heart, the risk of embolism is comparatively high 5 . In the present case, thetumor moved back and forth from beneath the mitralvalve to the LVOT, and preoperative head CT revealed
cerebral infarction, probably due to embolization of the
PFE. PFE has a high embolic risk, given the friability of
its tissue matrix 6 .
TTE is a simple, convenient, and non-invasive tool

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Oda, et al. : Incidental Detection of a Papillary Fibroelastoma During a Health Check-up
for investigating abnormal findings. Although TEE isdifficult to perform, it is useful for obtaining detailed
information. A case-control study reported that the sensitivity and specificity of TTE were 88.9% and 87.8%,
with an overall accuracy of 88.4% for the detection of
PFEs >0.2 cm. When PFEs <0.2 cm were included, theoverall sensitivity of TTE was 61.9% and that of TEE
was 76.6% 7 . Therefore, TEE is recommended for differentiating cardiac tumors, especially small tumors.
Approximately 85% of PFEs arise from heart valvesin the following order of frequency: aortic, mitral, tricuspid, and pulmonary valves. The remaining 15% of
tumors originate from nonvalvular sites, commonly
left-sided endocardial surfaces 8 . PFE arising from thepapillary muscles of the left ventricle are rare. Tamaru
et al. reviewed nine such cases and insisted that PFEs
located on the papillary muscle tend to cause thrombosis compared with those located at other sites 9 .
There are only a few reports on the diagnosis of cardiac tumors during health check-ups 10,11 . In our case,minor ST-segment depression of the ECG during ahealth check-up triggered the discovery of PFE and led
to successful tumor resection. Since cardiac CT demonstrated no significant stenosis of the coronary arteries,
the mechanism of ST segment depression is unknown
in the present case. ST-segment elevation has been reported to occur due to myocardial invasion in patientswith metastatic cardiac tumors 12,13 . An important aspect of health check-ups is to avoid overlooking hidden
diseases. Therefore, secondary inspections should be
performed proactively, even if abnormal findings appear less significant in health check-ups.

A

B

Fig. 4. Head Computed Tomography Showing a Low Density
Area ( Circle ) Suggestive of Old Infarction at theBorder of the Left Parietal Lobe and Occipital Lobe

Conflict of Interest

No financial support was received for this study fromany specific company.

Fig. 5. Surgeonʼs View: A Jelly-like Tumor with Multiple Fronds (Arrow) Originatingfrom the Head of the Anterolateral Papillary Muscle

Ningen Dock International Vol.11 No.1 2024

65 ( 65 )patient and her family for the publication of this casereport and accompanying images.
References

Fig. 6. Macroscopic Image of the Formalin-fixed Tumor
Immersed in Water Demonstrates a Sea Anemonelike Appearance with Complex Branching of theMultiple Fronds

100 mFig. 7. Histopathological Analysis of the Tumor with Elasticavan Gieson Stain Shows Avascular Fronds Linedby Endothelial Cells, of Which Central Stalks Are
Composed of Fibroelastic Tissue

Disclosure

The authors have no potential conflict of interest to
disclose.

Ethical Consensus and Patient Consent
Statement

1. Reynen K: Frequency of primary tumors of the heart. Am J
Cardiol 1996; 77: 107.
2. Majano-Lainez RA: Cardiac tumors: a current clinical andpathological perspective. Crit Rev Oncog 1997; 8: 293–303.
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Res 2006; 4: 22–32.
4. Oda T, Aoyagi S, Yoshida S, et al.: A surgical case of papillary
fibroelastoma originating from the left atrial ridge. J Cardiol
Cases 2015; 11: 18–20.
5. Ngaage DL, Mullany CJ, Daly RC, et al.: Surgical treatmentof cardiac papillary fibroelastoma: a single center experience
with eighty-eight patients. Ann Thorac Surg 2005 ; 80 :
1712–1718.
6. Kamdar F, Win S, Manivel JC, et al.: A rare nonvalvular left
ventricular papillary fibroelastoma: a case report. J Cardiol
Cases 2014; 9: 8–10.
7. Su n JP, Asher CR , Yang X S, et al .: C l i ni c a l andechocardiographic characteristics of papillary fibroelastomas:
a retrospective and prospective study in 162 patients.
Circulation 2001; 103: 2687–2693.
8. Gowda RM, Khan IA, Nair CK, et al.: Cardiac papillary
fibroelastoma: a comprehensive analysis of 725 cases. Am
Heart J 2003; 146: 404–410.
9. Tamaru N, Abe K, Anami M, et al.: A papillary fibroelastoma
on a papillary muscle of the left ventricle. Pathology 2006;
38: 174–177.
10. Bryde R, Landolfo K, Ray JC, et al.: Subaortic membrane
papillary fibroelastoma. Case Rep Cardiol 2020; 2586730.
doi: 10.1155/2020/2586730.
11. Strecker T, Agaimy A, Zelzer P, et al.: Incidental finding of agiant asymptomatic right atrial tumor. Int J Clin Exp Pathol
2014; 7: 4528–4530.
12. Akgun T, Gulsen K, Cinier G, et al.: Electrocardiographic
characteristics of metastatic cardiac tumors presenting with
ST-segment elevation. J Electrocardiol 2020; 59: 93–99.
13. Cheon DY, Park KH, Hong SE, et al.: Metastatic cardiac
tumor manifested by persistent ST-segment elevation withcoexisting reciprocal changes on electrocardiography. Int
Heart J 2014; 55: 466–468.
(Received October 6, 2023 ; Accepted October 27, 2023 ;J-STAGE Advance published date December 21, 2023)

Written informed consent was obtained from the

66 ( 66 )Ningen Dock International Vol.11 No.1 2024

Ningen Dock International 2024 ; 11 : 67–79

Breast Screening Assessment Manual
Japan Society of Ningen Dock
Health Screening Assessment and Guidance Manual Drafting Committee
Breast Working Group (WG)
Chapter 1 Mammography Assessment Manual
Chapter 2 Ultrasound Assessment Manual
Chapter 3 Clinical Breast Examination (Visual Inspection and Palpation)
Overall Assessment Flowchart
Test Findings Sheet (Overall assessment of ultrasound, mammography, andclinical breast examination)
Ultrasound Category Assessment Checklist (Reference)
Breast Working Group (WG) List of Members

Chapter 1 Mammography Assessment
ManualIntroduction

The incidence of breast cancer has increased in recent years in Japan, and breast cancer ranks first among
malignant tumors in women. Over 90,000 women are
diagnosed with breast cancer each year. The lifetime riskof developing breast cancer is estimated to be 1 in 91 .
Breast cancer screening using mammography is the
only screening method proven to lower the rate ofbreast cancer mortality 2 . While the benefits of mammographic screening have been studied and the practice has become standard for breast cancer testing inWestern countries with high rates of breast cancer,
several issues, such as the age at which the test shouldbe performed and how dense breast tissue should be
evaluated, are still being discussed 3 .
In Japan, breast cancer screening using mammography started in 2000, and was conducted in combination
with the clinical breast examination in women aged ≥50
years every 2 years. Since 2004, the test has been available every other year for women aged ≥40 years. However, as breast cancer screening with a clinical breast
examination alone has been found to be ineffective
for lowering breast cancer mortality, today, an increasing number of municipalities have omitted the clinicalbreast examination and opted for mammography only.
Voluntary breast cancer screening provided as part ofa medical checkup package for Ningen Dock and otherservices has become widely available today, and supplements the government’s population-based screening
rate (approximately 20% for those aged 40–74 years).
The current overall breast cancer screening rate is
47 . 4 % ( 2019 ), which has yet to reach the target of
50% 4 . Due to the increase in breast cancer incidence,
the nation is taking efforts to increase population-basedbreast cancer screening rates, and Ningen Dock plays
an important role in this process. However, as describedin more detail in the ultrasound screening section, validating the accuracy of breast cancer screening within
Ningen Dock is fraught with challenges, because of thelack of standardized terms and criteria for screening
across testing facilities.
Here, we standardized terms related to breast cancer
screening and created assessment classes for interpreting screening results to improve the accuracy of breast
cancer screening. Mammography Guidelines Ver. 4(Japan Radiological Society/Japanese Society of Radiological Technology) 5 was used to standardize and maintain consistency of breast cancer screening terms.

Ⅰ. Assessment procedure

1. Identify the lesion location from the parts list
2. Assess the results
3. Select the category
4. Select the assessment classAssessment should be conducted according to theabove steps. The reason (category) for selecting the assessment class and name should be noted.

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67 ( 67 )1. Lesion location
The lesion location should be noted based on theview during screening.
(See Mammography Guideline Ver. 4 ))1 Location on mediolateral oblique (MLO) view (Fig. 1 )L: Region caudal to the perpendicular line stretching
posterior to the center of the nipple
M: Region delineated by the line drawn cranially fromthe perpendicular line of the same length as that tothe lower margin of the breast and the line drawn
parallel to the perpendicular line
U: Region cranial to M
S: Subareolar region (corresponding to the main duct);site 2 cm from the central nipple
X: Axillary region
Locations between two regions should be marked
under the main site.
Locations that cover the entire breast should bemarked as W.
2 ) Location on craniocaudal (CC) view (Fig. 2 )I: Region medial to the perpendicular line from thecenter of the nipple

O: Region lateral to the perpendicular line from thecenter of the nipple
S: Subareolar region
Locations between two regions should be marked
under the main site.
Locations that cover the entire breast should bemarked as W.
3 ) Bidirectional view (Fig. 3, 4 )For the bidirectional view, MLO and CC images
should both be taken.
Findings should be noted in the following order: “Bilateral differences,” “Location on MLO view,” and “Location on CC view.”
Locations between two regions should be marked
under the main site.
If findings can only be identified in one view, “N” toindicate “no findings” should be noted in the view inwhich the findings are not observable to indicate thatthey were only visible in one view.
2. Assessment methods
Mammography interpretations should be doublechecked by two physicians (ideally mammography

Location on CC view

Location on MLO view

LateralMedialFig. 1. Location on MLO View

Fig. 2. Location on CC View

Method for describing regions in bidirectional view

Method for describing regions in bidirectional view
when findings are not present in unidirectional viewFig. 3. Location on Bidirectional View

68 ( 68 )Fig. 4. Location When There Are No Findings on One Viewof the Bidirectional View

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interpreting physicians certified by the Japan Central
Organization on Quality Assurance of Breast Cancer
Screening).
The assessment should be made separately on the left
and right.
In the bidirectional view, the assessment should not
be made individually for each view. Instead, a category
should be selected as the overall assessment result fromthe two views for each breast. Similar findings identifiable in both directions increase the chances of finding alesion.
Assessment should be conducted with past images
for comparison, if available.
The possibility of malignancy should be consideredwhen selecting the category. Categories ≥3 require further examination.
An image that cannot be appropriately assessedshould be categorized as “unassessable.”
A reading physician should be consulted as soon as
possible to determine whether an unassessable caseshould be reinterpreted or assessed using another testing method.
3. Categories
1 ) Uninterpretable
Uninterpretable cases (Category N) can be further
divided into two categories:
N-1: Cases requiring re-examination and re-imaging
owing to body movement, poor imaging conditions, or
positioning
N-2: Cases that are expected to be categorized as N
after a re-examination owing to assessment of breast or
areolar shape via clinical breast examination (palpation).
Assessment Class
Assessment
Class A

Negative

Assessment
Class B

Mild abnormality

Assessment
Class C

Requiresre-examination(in 6/12 months) ＊2 ) Interpretable
Category 1 Negative
Category 2 Benign, findings that do not require further
examination
Category 3 Benign, but malignancy cannot be ruled out
Category 4 Suspicious abnormality
Category 5 Highly suggestive of malignancy

3 ) Uninterpretable
Uninterpretable cases should be categorized as N.
4. Assessment class※ The assessment class conforms to the Assessment
Classes of the Japanese Society of Ningen Dock.

Ⅱ. Breast composition 6

Fatty, scattered fibroglandular density, heterogeneously dense, and extremely dense
No method exists to assess the degree of the mixtureof fibroglandular and fatty tissue on mammography.
Heterogeneously dense and extremely dense breast tissue are common in Japan; these breast composition
types account for over 60 % of Japanese women. In
general, dense breast tissue (heterogeneously dense andextremely dense) decreases with age, especially after
menopause. Scattered areas of fibroglandular densityand fatty breasts are common in overweight people.
Mammography has low sensitivity in those with
dense breast tissue compared to non-dense breast tissue;thus, dense breast tissue itself is a risk factor for breast
cancer, according to some reports.
However, there is no consensus on whether ultrasound should be added in women with dense breast tissue 7,8 .

Category( Includes physiological changes. ) Corresponds toCategory 1 . Does not require further examination or reexamination.
Of Category 2 ; corresponds to clearly benign. Does not
require further examination or re-examination.
If malignancy is suspected, always make a judgmentof Class D. Of Categories 2 and 3 ; corresponds to acondition that is determined not to aﬀect vital prognosis
as assessed in a 1-year re-examination, and thus requiresa re-examination in 1 year as a general rule. The time to
re-examination can be at the discretion of the physician;however, if re-examination is required within 3 months, it
should be classed as “required detailed examination.”
Unassessable cases should be categorized as N, and theinterpreting physician should make a recommendation on
re-examination or examination using another modality.

Requires detailed
Assessment
Class D
examination/treatment Corresponds to Categories 3, 4, 5.
Receiving chemotherapy or radiotherapy in a medical
Assessment
In
treatment
institution, with the aim of improving the result of theClass E
corresponding examination.
＊

Class D if re-examination cannot be performed in the same facility.

※Categories were developed with the intention to assess benign or malignant tumors, and assessment class is anindicator of breast assessment findings and patient’s actions.

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69 ( 69 )Ⅲ. Terms for mammography findings

Terms for mass, calcification, and other findings (categorized into glandular parenchyma, skin, and lymph
node findings) were standardized based on the “Mammography Guidelines 5 .”References

1. Cancer Information Service, National Cancer Center: Latest
Cancer Statistics: Cancer-related deaths, 2017 . https://
ganjoho.jp/reg_stat/statistics/stat/summary.html#a 25 (inJapanese) (accessed June 18, 2021 )2. Cancer Information Service, National Cancer Center: Breast
Cancer Screening, 2019. https://ganjoho.jp/med_pro/pre_scr/screening/screening_breast.html (in Japanese) (accessed
June 18, 2021 )3. Checka CM, Chun JE, Schnabel FR, et al.: The relationshipof mammographic density and age: implications for breast
cancer screening. AJR Am J Roentgenol 2012; 198: 292–
295.
4. Ministry of Health, Labour and Welfare: Intensive campaign
to raise cancer screening rate to 50 %. https://www.
gankenshin 50 .mhlw.go.jp/campaign_ 30 / (in Japanese)(accessed June 18, 2021 )5. Japanese Society of Radiological Technolog y ( ed ) :Mammography Guideline Ver. 4, Igakushoin, Tokyo, 2021.
(in Japanese)
6. The American College of Radiology: https://www.acr.
org/Quality-Safety/Resources/BI-RADS/Mammography(accessed January 12, 2017 )7. Boyd NF, Guo H, Martin LJ, et al.: Mammographic density
and the risk and detection of breast cancer. N Engl J Med
2007; 356: 227–236.
8. Japan Association of Breast Cancer Screening, Japan
Breast Society, The Japan Central Organization on Quality
Assurance of Breast Cancer Screening: Countermeasures.
Proposals on tackling “dense breast tissue” issues in breast
cancer screening, 2017 . https://www.qabcs.or.jp/news/
entry-900.html (in Japanese) (accessed June 18, 2021 )Chapter 2 Ultrasound Assessment Manual
Introduction

The incidence of breast cancer has increased in recent years in Japan, and breast cancer ranks first among
malignant tumors in women. In 2019, 91,605 women
were diagnosed with breast cancer. The lifetime risk ofdeveloping breast cancer is estimated to be 10.6% forJapanese women or 1 in 91 .
The J-START trial, which tested the effectiveness ofultrasound combined with mammography in screening
for breast cancer in Japanese women aged ≥40 years 2
showed that adding ultrasound to mammography increases the detection rate of breast cancer; however,conclusions are yet to be reached on whether it decreases mortality, given it requires long-term follow-up
observation. Furthermore, as the study did not directlycompare mammography with ultrasound, ultrasound70 ( 70 )alone is not used for population-based screening. According to the Japanese Breast Cancer Society 2017 Report on clinical statistical studies on registered patientswith mammary cancer in Japan, a sizable portion of patients with breast cancer ( 5.3% of patients with breast
cancer overall, n=4,947 ) are aged ≤39 years and are noteligible for population-based screening.
Given that the aim of breast cancer screening is tolower the breast cancer mortality rate, the lack of evidence for ultrasound screening should be thoroughly
explained to people undergoing ultrasound. However,ultrasound screening is generally important in women
who are poor candidates for mammography (young
women with dense breast tissue, for whom the detection sensitivity of breast cancer is low 3 ) and are moresensitive to the effects of radiation exposure, women
who have undergone breast augmentation surgery, arepregnant or breastfeeding, high-risk young women, andwomen who cannot be screened or screened sufficiently
using mammography because of dense breast tissue or
who want to avoid it by preference.
Furthermore, the terms and criteria used in voluntarybreast cancer screening in Ningen Dock are not standardized across screening facilities and cannot be easily validated for screening accuracy. It is important tostandardize techniques, systems, and process indicators(data submitted to national data by the Japan Association of Breast Cancer Screening) to ensure accuracy. To
promote accuracy in Ningen Dock, The Health Screening Assessment and Guidance Manual Drafting Committee Breast WG (Sakurai Team) standardized “location” and “finding and diagnosis names” for presenting
screening assessment criteria. Location, finding, anddiagnosis names are in the screening standard format of
the Japan Medical Health Management Assessment Association, which comprises 10 health screening-relatedorganizations.
In the Breast Ultrasound Ningen Dock Screening
Assessment Manual, diagnoses were described with reference to the Japan Association of Breast and Thyroid
Sonology Breast Ultrasound Guideline (ver. 4 ) 4 . We
plan to promptly update the Breast Ultrasound Ningen
Dock Screening Assessment Manual when the breast
ultrasound guideline is revised. We hope that the present assessment manual will be widely used in healthscreening facilities to improve accuracy.

Ⅰ. Screening methods

See the Guideline for Breast Ultrasound Diagnosis
and Management, Ver. 4, for ultrasound devices andexamination methods.

Ⅱ. Assessment procedure

1. Identify the lesion location from the parts list

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2. Select the corresponding assessment result fromthe list of findings or diagnoses
3. Select the category
4. Select the assessment classAssessment should be conducted according to theabove steps. The reason (category) for selecting the assessment class, finding, and diagnosis should be noted.
1. Lesion location
To describe the lesion location in terms of breast
region, methods that use a clock axis centered on the
nipple and methods conforming to the Japanese Breast
Cancer Society “General Rules for Clinical and Pathological Recording of Breast Cancer” 5 should be used inscreening.
Given that the recording method in “General Rules
for Clinical and Pathological Recording of Breast Cancer” is used in clinical practice, the present guidelines
also recommend this method.
Specifically, this method entails first noting whether
the lesion is on the right or left (or both) breast(s).
The region where the lesion is located should be classified under one of the following:
Upper medial ....... region A
Lower medial ....... region B
Upper lateral ........ region C
Lower lateral ........ region D
Areolar.................. region E
Axillary................. region C’
Whole breast ........ region W
The breast is divided mediolaterally and superoinferiorly into quadrants, and the areolar and axillary regions
are marked as separate regions, as shown above.
An alphabetical letter is assigned to each quadrant toobtain regions A–D (Fig. 1 ). The areolar region, including the nipple, is designated region E, and the axillary
tail of the breast is designated C’.
If multiple lesions are present across multiple regions,they should be indicated in descending order from theregion (main seat) with the greatest number of lesions.
Example: If the main seat is in region A but lesions
are also found in region C, this should be noted as →AC
2. Findings and diagnosis
Findings should be classified as masses or non-masslesions. See Guideline for Breast Ultrasound Diagnosis
and Management, Ver. 4, for details of the classifications and diagnostic methods.
History of the finding (e.g., first examination, newonset, detection, and growth since the last examination)
should be noted to the best possible extent.
See the table below and notes on diagnosis.
Apart from the most typical cases, ultrasound alone
has limitations for making a diagnosis; thus, while it ismandatory to note the finding and category, noting thediagnosis is optional.
3. Categories※ The screening categories below are based on the
Guidelines for Breast Ultrasound Diagnosis and Management.
Category 1: Negative
Category 2: Benign findings that do not require further testing＊1
Category 3: Benign, but malignancy cannot be ruled out
Category 4: Suspicious abnormality
Category 5: Highly suggestive of malignancy
Category 0: Unassessable case＊2＊1 “Category 2 Benign,” used widely in diagnostic categories, includes“findings that do not require further testing.”＊2 “Unassessable” refers to cases that cannot be assessed owing to device

malfunction or factors related to the examinee or examiner that require
re-examination or other examination and are classified as Assessment
Class C with the necessary details.

4. Assessment class (Breast screening assessmentand management)※ Assessment classes comply with the Japan Medical
Health Management Assessment Association healthscreening standard format and the Japanese Breast
Cancer Society “Breast Cancer Detailed Screening
Report Manual based on Categories and Diagnosis
Categories 6 .”

Right
右

Left
左
Fig. 1. Location

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71 ( 71 )Breast ultrasound findings(Major items)

Standard terms(Mid-level items)

Recommendation
category

Assessment
Class

Page in Guideline for Breast
Ultrasound Diagnosis andManagement, Ver 4.
p99
p100
p104
p105
p99

Noninvasive ductal carcinoma
D
Invasive ductal breast carcinoma
D
Mucinous carcinoma
D4, 5Mammary tumor＊1
Invasive lobular carcinoma
D
Breast cancerD
Indistinguishable (Benign/malignant) Breast tumor
3
D
p110
mammary tumor＊2
Intraductal lesion
Fibroadenoma
2B
p105
Mammary tumor＊3
Mastopathy
B
p108
Fibrous disease
B
p110
B
p111
Other benign diseases of the breast Hamartoma
2
gland＊4
Hematoma
B, D
Mastitis
B, D
Subareolar abscess
B, D
Axillary lymph node enlargement＊5 Axillary lymph node enlargement
2, 3, 4, 5
B, D
p116
Intramammary lymph node＊6
Intramammary lymph node1, 2, 3A, B, D
p116
Lactation change＊7
Lactation change
1
A
p97
Gestational change
Gestational change
1A
p97
Foreign-body granuloma
Foreign-body granuloma
2
B
p112
Postoperative breast
Postoperative breast
2
B
LipomaB
Other breast findings＊8
Mondor’s disease2
B
Fat necrosis
B
p111
Subcutaneous tumor
Other breast findings＊9
2, 3, 4, 5
B, D
Skin mass
Other than the above
2, 3, 4, 5
B, D
Other breast findings＊10(includes supernumerary nipples, etc.)＊ 1: Malignant tumors are assessed as Category 4 or 5, Assessment Class D if the histology type can be predicted.
＊ 2: Masses that are not distinguishable (between benign or malignant), such as masses that cannot be identified as a tumor and phyllode tumor, are assessed
as Category 3, Assessment Class D.
＊ 3: Typical fibroadenomas and other tumors that can be easily determined to be benign tumors are assessed as Category 2.
＊ 4: Other benign diseases (mastopathy, fibrous disease, hamartoma, hematoma, mastitis, and subareolar abscess) that are clearly diagnosable are assessed asAssessment Class B.
＊ 5: Axillary lymph node enlargement that clearly indicates reactive lymph nodes are assessed as Category 2, Assessment Class B.
In other cases, assume the possibility of dormant breast cancer, malignant lymphoma, or breast cancer metastasis, and assess as Categories 3, 4, or 5,
Assessment Class D.
＊ 6: Intramammary lymph nodes that appear normal are assessed as Category 1, Assessment Class A; clear reactive enlargement as Category 2, Assessment
Class B; and others as Category 3, Assessment Class D.
＊ 7: Clear lactation changes or gestational changes are assessed as Category 1, Assessment Class A.
Foreign-body granuloma after breast augmentation surgery or post-mastectomy findings that clearly indicate a change from foreign bodies or surgery isassessed as Category 2, Assessment Class B.
＊ 8: Other subcutaneous findings should not be mentioned to examinees at the breast cancer screening; however, lipoma, fat necrosis to traumatic injury, andMondor ’s disease are assessed as Category 2, Assessment Class B.
＊ 9: Subcutaneous tumors and skin tumor alone should not be mentioned to examinees at the screening; however, clearly benign cases are assessed as
Category 2, and suspected metastasis after breast cancer surgery as Categories 3, 4, or 5, Assessment Class D.
＊ 10: Other breast findings (including supernumerary nipples) should be noted and assessed.
Assessment Class
Category
Management
Assessment
Negative
Corresponds to screening Category 1
Does not require further examination or follow-up
Class A
Mild abnormality
Assessment
Corresponds to screening Category 2; clearly benign
Does not require further examination or follow-up
Does not require detailed
Class Bor findings do not require further testingexamination
Small masses and non-mass lesions with possibilityof ductal carcinoma in situ are Category 2 , andRequires
Assessment
screening again in 6 or 12 months is allowed
re-examination
Class C
Unassessable cases are Category 0, and require the(in 6/12 months)＊
interpreting physician ’ s recommendation for reexamination or examination by another modality
Assessment
Requires detailed
Corresponds to screening Categories 3, 4, 5
Requires detailed examination
Class D
examination/treatment
In treatment
Assessment
Class E

Generally not used in
Ningen Dock Breast
Screening assessment＊
Cases that cannot be re-examined in the same facility are categorized as Class D.
※ See the Ultrasound Category Assessment Checklist for details

72 ( 72 )Not in scope of breast cancer screening

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Table of English terms
Standard terms
Mass
Cystic pattern
Mixed pattern
Solid pattern
Non-mass lesions
Abnormal lactiferous duct (bilateral, multiple)
Abnormal lactiferous duct (segmental, local)
Hypoechoic area (bilateral, multiple)
Hypoechoic area (segmental, local)
Architectural distortion
Multiple small cysts (bilateral, scattered)
Multiple small cysts (segmental, local)
Echogenic fociCoarse calcifications
Diagnosis
Ductal carcinoma in situ: DCIS
Invasive ductal carcinoma
Mucinous carcinoma
Invasive lobular carcinoma
Breast cancer
Breast tumor
Fibroadenoma
Mastopathy
Fibrous disease
Hamartoma
Hematoma
Mastitis
Subareolar abscessAxillary lymph node enlargement
Intramammary lymph nodeLactation change
Gestational change
Foreign-body granuloma
Postoperative breast
LipomaMondor’s disease
Fat necrosis
Subcutaneous tumor
Skin tumor

References

1. Cancer Information Service, National Cancer Center: Latest
Cancer Statistics: Cancer-related deaths, 2017 . https://
ganjoho.jp/reg_stat/statistics/stat/summary.html#a 25 (inJapanese) (accessed June 18, 2021 )2. Ohuchi N, Suzuki A, Sobue T, et al.: Sensitivity and specificity
of mammography and adjunctive ultrasonography toscreen for breast cancer in the Japan Strategic Anticancer
Randomized Trial (J-START): a randomised controlled trial.
Lancet 2016; 387: 341–348.
3. Checka CM, Chun JE, Schnabel FR, et al.: The relationshipof mammographic density and age: implications for breast
cancer screening. AJR Am J Roentgenol 2012; 198: 292–295.
4. Japanese Society of Breast and Thyroid Sonology: Breast
Ultrasound Diagnosis (Diagnostic ultrasound) Guideline.
Revised 4th ed, Nankodo, Tokyo, 2020. (in Japanese)
5. Japanese Association for Breast Cancer: Clinical andPathological Regulations for Handling Breast Cancer. 18thed, Kanehara Shuppan, Tokyo, 2018. (in Japanese)
6. Japan Association for Breast Cancer Screening: UltrasoundScreening Accuracy Management Committee: “Guide toBreast Cancer Screening Using Ultrasound: Accuracy Control
Manual”. 2nd ed, Nankodo, Tokyo, 2020. (in Japanese)

Chapter 3 Clinical Breast Examination(Visual Inspection and Palpation)
Breast cancer screening with clinical breast examination (visual inspection and palpation only) is notrecommended owing to its high false-positive andfalse-negative rate and ineffectiveness in increasing
the survival rate of patients with breast cancer. Clinicalbreast examination (visual inspection and palpation)
should only be performed in combination with mammography (ultrasound).
A non-negligible percentage of examinees attend
breast cancer screening with subjective symptoms suchas mass, abnormal nipple discharge, and mastalgia;
thus, information on such symptoms should be collected before the clinical breast examination.
In performing a clinical breast examination, acquiring the following information in a medical interview is
helpful:All examinees
1. Age at menarche
2. Number of pregnancies and births
3. Age at first birth
4. Family history of breast cancer (age at onset,side), family history of ovarian cancer
5. Previous biopsies
Premenopausal examinees
1. Date of the most recent menstruation, cycle
2. Use of hormone therapies
Postmenopausal examinees
1. Age at menopause
2. Use of hormone replacement therapy
Professionals in the examination room should consider the examinee’s privacy. A female assistant must
accompany a male examining physician. If possible, a
special gown should be provided as examinees will be
required to remove the clothes from their upper bodyfor the examination.

A. Visual inspection

In a sitting position, have the examinee place both
hands on their waist to examine the presence or absence of laterality of the breasts and papilla, skin tone,
breast deformity, and skin indentation. Next, have theexaminee raise both hands and check for the presenceor absence of laterality of the breasts and constriction.
In the case of an inverted nipple, inquire about when
it started. Unilateral papillary erosion may be a sign ofPaget’s disease, whereas bilateral papillary erosion may
be atopic dermatitis.

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73 ( 73 )B. Palpation

Palpation with the flats of the hand is the common
method. Palpate gently in case of a premenstrual examinee as some may experience significant pain even witha light touch.
Palpation is performed in the sitting and supine positions. In the sitting position, have the examinee raiseboth hands for palpation. Large or drooping breasts
are better examined in the supine position. If a massor induration is observed, note the location, size, margins, surface properties, mobility, and the presence orabsence of a dimpling sign. Bilateral breast comparison
is important. In the premenopausal breast, an induration observed on the upper lateral sides of both breasts
may indicate normal mammary gland tissue. However,when the examinee reports subjective symptoms suchas a mass, due caution must be paid to avoid overlooking the sign and assessing the examinee as negative.
Palpation of the axillary lymph nodes is performed
in a sitting position, with the arms lowered and the
body relaxed. The axillary lymph nodes are not usually
palpable, but in rare cases, lymph node metastases may
precede the mammary mass. Additionally, soft lymph
nodes may be palpated in the presence of inflammationin the upper arm, such as in patients with atopic dermatitis.

Overall Assessment Flowchart: Combined
Mammography and Ultrasound Screening
In population-based breast cancer screening, a mammography examination is performed once every 2 years
for women aged ≥40 years. However, since a study
reported that breast cancer can be difficult to detectin dense breast tissue in Ningen Dock screening 1 , anincreasing number of facilities have begun performing
both mammography and ultrasound. The rise in thisapproach is in part because patients have recently started to request combined screening with mammography
and ultrasound.
In addition, a single-center, randomized con trolled trial of Japanese patients aged 40 – 49 years
comparing mammography+ultrasound vs. mam mography alone showed that 1.5 times more breast
cancers were detected in examinees who underwent
mammography+ultrasound 2 . In combination screening,
there are cases where both examinations are performedat one facility and others where the two are performedat separate facilities. For patient convenience and accuracy of the assessment, it would be best if the two canbe performed in one facility. In addition, a “simultaneous combination method” is possible, in which an ultrasound is performed while viewing the mammography
result, as is a “separate combination method,” in which
an ultrasound is performed without information from

Mammography findings

No malignant findings(category 1, 2)

Prioritize ultrasoundfindings

Mass of category ≥3• If boundary is clear
and smooth (+ difficult
to assess), prioritize
ultrasound findings• If edges aremicrosporangiate,boundaries areunclear andspiculated, prioritize
mammography• If findings identified in
mammography cannot
be identified inultrasound, prioritize
the mammography
findings

Calcification of
category ≥3• Prioritize
mammography
findings• If clear benign
findings, such as
fibroadenoma, can be
confirmed inultrasound, prioritize
ultrasound findings

Asymmetric breast tissue
Focal asymmetric density• If normal mammary
glands are confirmed
in ultrasound,Category 1

Architectural distortion

Prioritize mammography
findings• If cystic or non-cystic
lesions are confirmed
in ultrasound,prioritize ultrasound• If localized
asymmetric shading isobserved in
mammography but
normal mammary
glands are confirmed
in ultrasound, detailed
examination is not
required※ If two or more tests or visual inspection and palpation are combined with mammography,
findings should be noted under the mammography section of the Test Findings Sheet.

Fig. Flowchart of the Mammography+Ultrasound Overall Assessment

74 ( 74 )Ningen Dock International Vol.11 No.1 2024

mammography. The simultaneous combination method
would certainly increase the accuracy of screening andthe reliability of the overall assessment.
To obtain the final judgment of the comprehensive
assessment, the mammography examination (investigation) and ultrasound should be judged separately, andthe judgment of the modality with findings should begiven priority. Alternatively, after obtaining each separate judgment, the findings of both should be comprehensively evaluated to obtain the final judgment. The
latter comprehensive judgment is preferable from theviewpoint of screening accuracy, especially specificity.
Below is a flowchart of the comprehensive judgmentprocess for mammography and ultrasound. For the
final overall assessment, the mammography and ultrasound results are assessed separately and assessmentof the modality with findings may be given priority
or the findings of both may be reassessed together forthe overall assessment. The latter overall assessment
method is preferable from the viewpoint of screening
accuracy, especially specificity.
A flowchart of the mammography+ultrasound overall assessment is shown below.
References

1. Yomiuri Shimbun: “Unreported difficulties in distinguishingbreast cancers,” June 12, 2016, morning edition. (in Japanese)
2. Ohuchi N, Suzuki A, Sobue T, et al.: Sensitivity and specificity
of mammography and adjunctive ultrasonography toscreen for breast cancer in the Japan Strategic Anticancer
Randomized Trial (J-START): a randomized controlled trial.
Lancet 2016; 387: 341–348.
3. Japan Association of Breast Cancer Screening Overall
Judging Committee (ed): Mammography and UltrasoundComprehensive Judgment Manual. Shinohara Publishing,Tokyo, 2015. (in Japanese)

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75 ( 75 )Test Findings Sheet for the Various Examinations (Reference)
Ultrasound Findings Sheet[Examinee information]

Name:_____________________

ID: _______________
Birthdate://

Age: ____ years[Date of examination][Location]//[Test facility]□N
No abnormalities

R

L[Tumor lesion

Large diameter× Short diameter□Solid× Height□Cystic □Mixed□Location L ()

Large diameter× Short diametermm

Large diameter× Short diameter× Height□Cystic □Mixed□Location L ()

Large diameter× Short diametermm

Large diameter× Short diameter× Height

Right

× Height

Large diameter× Short diameter

mm[Ultrasound categories]□Solid× Height

Left□1

Negative□1□2

Benign, does not require detailed examination□2□3

Benign, but malignancy cannot be ruled out□3□4

Suspicious abnormality□4□5

Highly suggestive of malignancy□5□0Unassessable□0

Assessing physician:□MG + UltrasoundLast examination□Negative □Benign□Requires detailed examination)

Pregnant / Breastfeeding /Post-breast augmentation surgery /Post-mastectomy
Other (

)

mm

)
mm

)

R: Right

L: Left□

Malignant mammary tumor□□

Indistinguishable(benign/malignant) mass□□

Benign mass (fibroadenoma)

□

□

Cyst

□

□

Axillary lymph nodeenlargement□□

Other (

Testing technician’s comments

Testing technician’s name:

Assessing physician:76 ( 76 ))[Diagnosis][Nontumor lesion]□Location L (□Abnormal lactiferous duct
□Hypoechoic region□Architectural distortion□Multiple small cysts)/[Notes at examination]

New Growth Unchanged Shrinkage]□Cystic □Mixed□Location L ()[Nontumor lesion]□Location R (□Abnormal lactiferous duct
□Hypoechoic region□Architectural distortion□Multiple small cysts□Solid/mm[Tumor lesion

New Growth Unchanged Shrinkage]□Solid× Height)

New Growth Unchanged Shrinkage][Tumor lesion□Cystic □Mixed□Location R (□Solid[Tumor lesion

New Growth Unchanged Shrinkage]□Solid□MG □Ultrasound

New Growth Unchanged Shrinkage][Tumor lesion□Cystic □Mixed□Location R (Last examination ([Tumor lesion

New Growth Unchanged Shrinkage]□Cystic □Mixed□Location R (□N
No abnormalities

Ningen Dock International Vol.11 No.1 2024)□

[Date of examination:

Mammography Findings Sheet
ID:

Name:
/

/

/

]

/

□Ultrasound::[Examinee information]

Birthdate: :/□MMG Direction::/□Visual inspection and palpation::/

Age: ____ years

Visual inspection and palpation alone is not recommended

Right

Left

Location
Breast composition:

Breast composition:

Fatty, scattered fibroglandular density, heterogeneously dense,
extremely dense

M

L

S

X

W

A

B

C

D

E

C’

U

M

L

S

X

W

A

B

C

D

E

C’

Diffuse Regional Segmental Aggregated Fibrous Other ()

Diffuse Regional Segmental Aggregated Fibrous Other ()

Findings

Tumor lesion Calcified lesion
Local
Architectural distortion
Mastopathy)

Tumor lesion Calcified lesion
Local
Architectural distortion
Mastopathy)

Category

Mammography

U

Fatty, scattered fibroglandular density, heterogeneously dense,
extremely dense

1) No findings 2) Benign 3) Probably benign
4) Suspicious of malignancy5) Strongly suspicious of malignancy6) Unassessable→ Imaging conditions
Positioning
Not eligible for mammography (Breast cancer surgery, breast
augmentation surgery, pacemaker implantation)

Physici
Assess
an’s
ment
name

1) Negative4) Suspicious malignancy

Asymmetrical
Other (

2) Benign5) Strongly suspicious malignancy

Primary interpreting physician

1) No findings 2) Benign 3) Probably benign
4) Suspicious of malignancy5) Strongly suspicious of malignancy6) Unassessable→ Imaging conditions
Positioning
Not eligible for mammography (Breast cancer surgery, breast
augmentation surgery, pacemaker implantation)

3) Probably benign
6) Unassessable

Secondary interpreting physician●Mass ○Induration
Size

Visual inspection/Palpation

×cm
Hardness
Hard / Tender
Margins
Unclear / Clear
Surface
Irregular / Unsmooth
Flat hand + / −Pain on pressure + / −Imaging technician

+

−

Mass

+

−

+

−

Induration

+

−

+

−

Diffuse nipple

+

−

+

−

Inverted

+

−

+

−

Secretion

+

−

+

−

Skin changes

+

−

+

−

Redness

+

−

+

−

Axillary lymph
nodes

+

−

+

−

Supraclavicularlymph nodes

+

−

Right
1) Negative 2) Benign 3) Probably benign
4) Suspicious of malignancy 5) Strongly suspicious ofmalignancy

Asymmetrical
Other (

Diagnosis at thetime ofexamination●Mass ○Induration
Size

×
cm
Hardness
Hard / Tender
Margins
Unclear / Clear
Surface
Irregular / Unsmooth
Flat hand + / −Pain on pressure + / −Left1) Negative 2) Benign 3) Probably benign
4) Suspicious of malignancy 5) Strongly suspicious ofmalignancy

Assessment on visual inspection and palpation:
Physician’s comments[Diagnosing physician’s name

Overall assessment

Abnormalfindings□Mammography □Ultrasound□Visual inspection and palpation (Assessment by visual inspection and palpation alone is not recommended)

Assessment class□A Negative □B Mild abnormalities □C Requires re-examination (in 6/12 months)□D Requires detailed examination/treatment □E In treatment

Physician’scomment[Diagnosing physician’s name

Ningen Dock International Vol.11 No.1 2024]]

77 ( 77 )Ultrasound Category Assessment Checklist (Reference)
Right (R)Mass
□ Cystic pattern□ Mixed pattern□ Solid pattern

Non-mass lesions
Abnormal lactiferous duct

Category ≥ 3Category ≤ 2□ Category 2□ >15 mm
□ ≤15 mm
□ Halo, with rupture of gland margin □ ≤ 20 mm small D/W ratio (approximately ≤ 0 . 5 ) and clear andsmooth margins□ Multiple echogenic foci
□ With coarse calcifications□ Anterior arch-shaped echogenic focus and posterior shadowing□ D/W ≥ 0.7, >5 mm□ D/W ≥ 0.7, ≤ 5 mm
□ D/W <0.7, >10 mm□ D/W <0.7, ≤ 10 mm
Category ≥ 3□ Segmental, local duct dilation

Category ≤ 2□ Bilateral, multiple duct dilation□ Segmental, local dilation without hypoechoic regions or floating
echoes□ Bilateral, multiple

Intraductal hypoechoic region □ Segmental, local□ Echogenic foci□ Architectural distortion
Architectural distortion□ S egmental, aggregated with □ Bilateral, scattered
Multiple small cysts
intraductal hypoechoic regions or □ Segmental, aggregated without intraductal hypoechoic regions
abnormal lactiferous ductor abnormal lactiferous duct

Left (L)Mass□ Cystic pattern□ Mixed pattern□ Solid pattern

Non-mass lesions
Abnormal lactiferous duct

Category ≥ 3Category ≤ 2□ Category 2□ >15 mm
□ ≤ 15 mm□ Halo, with rupture of gland margin □ ≤ 20 mm small D/W ratio (approximately ≤ 0 . 5 ) and clear andsmooth margins□ Multiple echogenic foci
□ With coarse calcifications□ Anterior arch-shaped echogenic focus and posterior shadowing□ D/W ≥ 0.7, >5 mm□ D/W ≥ 0.7, ≤ 5 mm
□ D/W <0.7, >10 mm□ D/W <0.7, ≤ 10 mm
Category ≥ 3□ Segmental, local duct dilation

Category ≤ 2□ Bilateral, multiple duct dilation□ Segmental, local dilation without hypoechoic regions or floating
echoes□ Bilateral, multiple

Intraductal hypoechoic region □ Segmental, local□ Echogenic foci□ Architectural distortion
Architectural distortion□ S egmental, aggregated with □ Bilateral, scattered
Multiple small cysts
intraductal hypoechoic regions or □ Segmental, aggregated without intraductal hypoechoic regions
abnormal lactiferous ductor abnormal lactiferous ducts※ This manual was created with support from the Ministry of Health, Labour, and Welfare Grant-in-

Aid for Scientific Research on Cardiovascular Disease, Diabetes Mellitus, and other Lifestyle-relatedDiseases 20FA1021.

78 ( 78 )Ningen Dock International Vol.11 No.1 2024

Japan Society of Ningen Dock Health Screening Assessment and Guidance
Manual Drafting Committee
Breast Working Group (WG) List of Members
WG leader
Kenichi Sakurai: Professor of The Nippon Dental University School of Life Dentistry at Tokyo Department of Surgery, Breast, and Endocrine Surgery
Members
Ken Uchida:
Kei Kimizuka:
Shuhei Suzuki:

Director, Meiji Yasuda Shinjuku Medical Center, Meiji Yasuda Health Development Foundation
Director, Department of Breast Surgery, Kasukabe Medical Center
Lecturer, Department of Breast and Endocrine Surgery, Nippon Dental University
Hospital(Observers)
Chairperson
Takashi Wada: Professor, Jikei University School of Medicine
Deputy chairperson (Imaging)
Masaki Adachi: Preventive Medicine Research Center, Saitama Medical University Hospital Visiting Professor/Advisor
There are no conflicts of interest related to companies that must be declared in the preparation ofthis breast screening manual.
April 2022

Ningen Dock International Vol.11 No.1 2024

79 ( 79 )Acknowledgments
We are very grateful to the following individuals who served as reviewers for the papers submitted to
Ningen Dock International Vol. 11 No.1, March 2024.
I sincerely thank their kind cooperation.
Editor-in-Chief

80 ( 80 )Akiko Toda

(1)

Akiyasu Baba

(1)

Chizumi Yamada(1)

Junichi Kaburaki(1)

Nobuyuki Kobayashi(1)Norihide Takaya(2)

Rumi Fujikawa(2)

Shigeko Hara

(1)

Takahiro Shimizu(1)

Tomoari Kamada(1)

Yoshiaki Maruyama(3)

Yoshiko Mizuno(1)

Ningen Dock International Vol.11 No.1 2024

The Regulationsof the International Society of Ningen Dock
Article 1
Name
The name of the association shall be the International Society of Ningen Dock.
Article 2
Oﬃce
The Society has its principal oﬃce in Japan Society of Ningen Dock.
Article 3
Aims
The Society, an organization of Japan Society of Ningen Dock for international operations, aims tocontribute to global health promotion by enhancing the development of ningen dock as a medical checkup system.
Article 4
Tasks
The Society conducts the following tasks to achieve the aims described in the preceding section.
1. Holds congress (World Congress on Ningen Dock), board meetings, lectures, and committee meetings
2. Publishes journals and news magazines
3. Communicates and cooperates with related academic societies both in Japan and overseas
4. Promotes research activities in ningen dock and related fields
5. Does whatever is necessary to achieve the aims of the Society
Article 5
Membership
1. The Society consists of the following members
1 ) Regular member
A regular member shall be a member of the International Society of Ningen Dock who agrees to theaims of the Society, and has expert knowledge, techniques, or experience in the areas associated with
the Society.
)
2 Supporting member
A supporting member shall be a person, a corporation, or a group that agrees to the aims of theSociety, and supports its programs.
3 ) Honorary member
An honorary member shall be recommended, from those who have significantly contributed to theareas associated with the Society, by the executive board.
2. Those who want to apply for regular or supporting membership of the Society shall submit theprescribed application form with the membership fee.
3. The board meeting will process applications mentioned in the preceding section, and promptly notify
the applicants of its decision.

Ningen Dock International Vol.11 No.1 2024

81 ( 81 )Article 6
Oﬃcials
1. The Society shall appoint the following honorary advisors and oﬃcials.
Honorary advisor: Number not decided
Congress president: 1
President: 1
Vice president: 3 (from Japan : 2, overseas: 1 )Board members: up to 25 (from Japan : 15 or less, overseas : 10 or less)
Auditor: 2
Article 7
Honorary advisor
1. An honorary advisor shall be appointed by the president from those who have contributed to thedevelopment of the Society for a long period, and approved by the executive board.
2. Honorary advisors shall be eligible to attend the board meeting, and to express opinions; honorary
advisors will not have voting rights.
Article 8
Congress president
1. The congress president shall be recommended by the executive board and appointed by the president.
2. The congress president shall represent the Society and host the World Congress on Ningen Dock as ascientific meeting.
Article 9
President
1. The president shall be selected by and from among board members and delegated by the president ofJapan Society of Ningen Dock.
2. The president shall preside the Society.
Article 10
Vice president
1. The vice president shall be appointed, from among board members, by the president.
2. The vice president shall assist the president. In the case of accident, one of the vice presidents will be
appointed by the president and will temporarily take over the duties.
Article 11
Board members
1. Board members from Japan shall be selected among candidates from regular members at Japan Societyof Ningen Dock.
2. Overseas board members shall be selected at the recommendation of the executive board.
3. Board members execute duties for the Society under the orders from the president.
4. Board members, together with the president and the vice president, comprise the executive board.

82 ( 82 )Ningen Dock International Vol.11 No.1 2024

Article 12
Board meeting
1. The president will call a board meeting on an as-needed basis, and serves as the chairman of themeeting.
2. The board meeting will pass resolutions on important matters of the Society.
3. The board meeting shall have the right to start proceedings if the majority of all the board members(including a letter of proxy) attend the meeting.
4. The board meeting shall pass resolutions with the majority votes of attendances.
Article 13
Auditor
Auditors shall audit accounts of the Society, and report to the board meeting.
Article 14
Commissioner
For the aims of successful programs of the Society, the president will set up committees and divisions
through the resolutions of the executive board, and delegate the commissioners to regular members orother members of the Society.
Article 15
Accounting
1. The fiscal year for the Society starts on April 1 every year and ends on March 31 the following year.
2. Expenses required for the Society shall be covered by the following revenues.
1 ) Membership fees2 ) Grants
3 ) Donations4 ) Others
Article 16
Modification of rules
The rules of the Society can be amended by the resolution of the executive board.
Article 17
Miscellaneous provisions
Detailed regulations necessary for the enforcement of the rules of the Society are defined elsewhere by thepresident with the approval of the executive board.
Article 18
Additional clause
The Regulations of the International Society of Ningen Dock will come into eﬀect on September 15,
2006.

Ningen Dock International Vol.11 No.1 2024

83 ( 83 )Detailed Regulationsof the International Society of Ningen Dock
Detailed regulations of the International Society of Ningen Dock are defined as follows:(Detailed regulations on members)
Article 1
1. Members shall pay the following annual membership fee; honorary members will be exempt frommembership fee.
1 ) Regular member : 2,000 yen
2 ) Supporting member : from one unit (unit: 20,000 yen)
2. Annual membership fee paid shall not be refunded for any reason.
3. Members with foreign citizenship shall pay a 3-year membership fee of 50 dollars.
Article 2
Members will be given priority in the following events :1 ) Participation in scientific meetings hosted by the Society;2 ) Contributions of articles to and receipt of the journal of the Society.
Article 3
Members shall lose their memberships in the event of the following:1 ) Withdrawal from membership;2 ) Adjudication of incompetence or quasi-incompetence;
3 ) Death or adjudication of disappearance, or dissolution of the group in the case of a member of a
supporting group;)
4 Delinquency in payment of membership fee for over three year.
Article 4
Those intending to withdraw from the Society must submit the notice of withdrawal in the prescribed form
to be approved by the executive board.
Article 5
The Society can expel a member to whom either of the following would apply, with a resolution of theexecutive board:
1 ) Those who violate their duty as members of the Society;2 ) Those who damage the honor of members of the Society or act against the aims of the Society.
Article 6
Those who satisfy Sections 1 and 2 of Article 5 of the Regulations of the International Society of Ningen
Dock will be accepted as members of the Society.
(Detailed regulations on officials)
Article 7
1. The president will be selected from the board members of Japan Society of Ningen Dock.
2. In principle, the majority of board members from Japan will be selected from among the board membersof Japan Society of Ningen Dock.
84 ( 84 )Ningen Dock International Vol.11 No.1 2024

3. Overseas board members will essentially be selected from Asia, Pacific Rim, North America, or Europe.
Article 8
1. The term of the congress president will be from the end of the congress of which he/she is in charge tothe next congress.
2. The term of board members will be six years (two terms of three years).
(Detailed regulations on congress and board meeting)
Article 9
Congress and board meeting will be held as follows :1 ) The title of the congress will be World Congress on Ningen Dock.
2 ) In principle, the congress and the board meeting will be held once every three years; with the resolutionof the executive board, however, the congress and the board meeting will be held as needed.
3 ) The congress and the board meeting will be held at the same time.
4 ) The name of the congress president and the location of the next congress will be announced.
Article 10
1. Those who want to take part in the congress shall pay the participation fee, which is defined separately.
2. Participation fee for the congress will be defined accordingly by the congress president.
3. Only regular members shall be allowed to present the results of their studies, except those who havebeen approved by the congress president.
(Enforcement of the detailed regulations)
Article 11
1. The detailed regulations will come into eﬀect on September 15, 2006.

Ningen Dock International Vol.11 No.1 2024

85 ( 85 )INSTRUCTIONS TO AUTHORS
Ningen Dock International
Official Journal of Japan Society of Ningen Dock
Ningen Dock International is the official journal of Japan Society of Ningen Dock, in which originalarticles, case reports, short reports, review articles, and clinical experience or practice report in English are
published. Ningen Dock accepts only manuscripts that are original work in the field of ningen dock andrelated areas not previously published or being considered for publication elsewhere, except as abstracts.
The manuscripts published in Ningen Dock will appear on the website of our society.
If the manuscript concerns a clinical study, it must be in accordance with the Declaration of Helsinkiof 1964 (subsequent revisions included). Therefore, for a manuscript whose content is epidemiological or
clinical research, the approval of the facility’s Institutional Review Board (IRB) or the Ethics Committeeof Japanese Society of Ningen Dock must have been obtained for the study described. Also, in the text, it
should be indicated that informed consent has been obtained from subjects. Additionally, for case reports,
it should be stated that adequate care has been taken to ensure the privacy of the subject concerned.
Online submission system
Ningen Dock International uses an online submission system called ScholoarOne Manuscripts.
Please access https://mc.manuscriptcentral.com/ndi
Preparation of manuscript
All manuscripts must be written in English with MS-Word, Excel, PowerPoint and/or a common graphic
format. Authors who are not fluent in English must seek the assistance of a colleague who is a native
English speaker and is familiar with the field of the manuscript.
The title, abstract, text, acknowledgments, references, tables, and figure legends should begin on separate
sheets, with pages numbered, and be typed double-spaced using the 12-point font size in MS-Word.
Files for submission should be prepared in English in a Microsoft Word or other file format that may be
uploaded to the online system.
Available formats for files to be uploaded: doc (docx), xls (xlsx), ppt (pptx), jpg, tiﬀ, gif, ai, eps, psd Filenames must consist of alphanumeric characters and an extension.
Example file names: Manuscript.doc, Fig1.jpg, Table1.xls, etc.
Please indicate the version of Microsoft Oﬃce used in a cover letter accompanying the uploaded files.
All measurements should be expressed in SI units. Less common abbreviations should be spelled out at
first usage and the abbreviated form used thereafter.
Title page
Titles should be concise and informative. Include the full names of authors, names and addresses ofaﬃliations, and name and address of a corresponding author to whom proofs are to be sent, including a fax
number, telephone number and e-mail address. Running title should not be more than 50 characters.

86 ( 86 )Ningen Dock International Vol.11 No.1 2024

Abstract
The abstract should not exceed 250 words, and should be arranged under the following subheadings:
Objective, Methods, Results, Conclusions, and have up to 4 keywords.
Types of articles
Original articles: An original article should not exceed 4,000 words, and should be arranged as follows:
Abstract, Objective, Methods, Results, Discussion, (Limitations), (Conclusions), (Acknowledgments), andReferences.
Case reports: A case report should not exceed 3,000 words, and be arranged as follows: Abstract (whichshould be a brief summary of the content without headings), Introduction, Case report, Discussion, andReferences.
Short reports: A short report should not exceed 3,000 words.
Review articles: Review articles should not exceed 5,000 words. Review articles are usually by invitation.
However, articles submitted without an invitation may also be considered by the Editorial Board.
Clinical experience or Practice report: Clinical experience or Practice report should not exceed 4,000
words.
References
References should be numbered consecutively in order of appearance in the text and cited in the text
using superscript numbers. For example, according to the study by Sasamori 1 . For journals, the names
and initials of the first three authors, followed by “et al.” if there are other coauthors, the complete title,
abbreviated journal name according to Index Medicus, volume, beginning and end pages, and year should
be included. For books, the names and initials of the first three authors, followed by “et al.” if there areother coauthors, the complete title, book name, edition number, beginning and end pages, name and cityof publisher, and year should be included. For websites, the names and initials of the first three authors,
followed by “et al.” if there are other coauthors, title of cited page/the document, year of posting, URL, andaccessed date in parentheses should be included. Examples of references are given below.
Journal: Frías JP, Davies MJ, Rosenstock J, et al.: Tirzepatide versus semaglutide once weekly in patientswith type 2 diabetes. N Engl J Med 2021; 385: 503–515.
Book: Kaplan NM: Measurement of blood pressure. In: Kaplan NM(ed), Kaplan’s Clinical Hypertension.
7th ed., Lippincott William & Wilkins, Philadelphia, 2002, 25–55.
Websites: Ministry of Health, Labour and Welfare: The National Health and Nutrition Survey in Japan.
2013, http://www.mhlw.go.jp/bunya/kenkou/eiyou/dl/h25-houkoku.pdf (in Japanese) (accessed March 1,2022 )
TablesTables should be cited in the text, and numbered sequentially with Arabic numerals. Each table should begiven a number and a brief informative title, and should appear on a separate page. Explain in footnotes all
abbreviations used.
FiguresFigures should be cited in the text, and numbered sequentially with Arabic numerals. A brief descriptive
legend should be provided for each figure. Legends are part of the text, and should be appended to it on a
separate page. Color figures can be reproduces if necessary, but the authors will be expected to contributetowards the cost of publication.

Ningen Dock International Vol.11 No.1 2024

87 ( 87 )Conflict of Interest (COI)
All authors are required to disclose any conflict of interest (COI) on the form designated by the Japan
Society of Ningen Dock.
If no author has any COI, this should be indicated in the manuscript.
Page proofs
The corresponding author will receive PDF proofs, the author should correct only typesetting errors. Aftercorrecting, page proofs must be returned promptly.
Reprints
Thirty reprints of each paper are free, and additional reprints are available at charge in lots of 10, but fora minimum order of 50 . Reprints should be ordered on submission of the manuscript as follows: For
example, “I order 100 reprints: 30 (free) + 70.”
The Editorial Board considers only manuscripts prepared according to the Instructions to Authors,and makes decisions regarding the acceptance of manuscripts as well as the order of printing them. All
published manuscripts become the permanent property of Japan Society of Ningen Dock, and may not be
published elsewhere without written permission from the Society.
Appendix 1: Use of figures, tables, images, etc. from other sources
Please exercise caution in the use or quotation of figures, tables, images, etc. from other sources whensubmitting to “Ningen Dock International”.
・When using figures, tables, images, etc., by either direct quotation or modification, it is the author’s
responsibility to obtain permission from any copyright holders, such as the original author, publisher, andacademic society, before submission. As part of this process, authors may be required to pay copyrightroyalties.
・The number of figures, tables, images, etc. that are used from other sources should be within an
objectively valid range (as determined by the ethical consideration of the author).
・The reputation of the original author should not be disparaged or prejudiced, and the material should not
be used in a manner contrary to the intention of the original author.
・Specify that the use is a quotation or modification, and document the source.
Updated: March 3, 2023

88 ( 88 )Ningen Dock International Vol.11 No.1 2024

Check list for submission of papers to Ningen Dock International
Official Journal of Japan Society of Ningen Dock
Categories of manuscript:□

Original article (not more than 4,000 words)□

Case report (not more than 3,000 words)□

Short report (not more than 3,000 words)□

Review article (not more than 5,000 words)□

Clinical experience or Practice report (not more than 4,000 words)

Typing:□Manuscript on A4 paper with wide margins□

Type double space using 12-point

Title page:□

Title of paper□

Full names of authors and aﬃliations without title of MD, PhD, etc□

Full name and address of a corresponding author including fax number,
telephone number and e-mail address.

□

Running title not more than 50 characters.

Abstract:□

Not more than 250 words.

□

Arranged in the order of Objective, Methods, Results, and Conclusions.

□

Up to 4 key words.

Text of paper:□

Manuscript is arranged in the order of Objective, Methods, Results,
Discussion, (Limitations), (Conclusions), (Acknowledgments), and References.

□

Papers involving ethical considerations, particularly with regard to the methods,
have described these considerations in the Methods section.

□

Measurements are expressed in SI units.

□

Abbreviations are spelled out at first usage.

References:□

References are numbered consecutively in order of appearance in the text andcited in the text using superscript numbers.

□

Format is consistent with examples in Instructions for Authors.

Ningen Dock International Vol.11 No.1 2024

89 ( 89 )Tables, figures, images:□

Each table is given a number and a brief informative title, and appears on separate page.

□All abbreviations used are explained in footnotes.

□

Figure legends are appended to the text on a separate page.

□

Permission to quote or modify figures, tables, images, etc., from the copyright holder(original author, publisher, academic society, etc.) has been obtained before submission.

Submission:□ Agreement, cover letter, manuscript (title page, abstract, text, acknowledgments,

and references), figure legends, tables, figures and/or photos prepared in due form.
□

This paper has been submitted to this journal only, and has not been submitted to or published inother journal.

□

All pages are numbered.

Date:

Name (print)

Signature

Ningen Dock International Vol.11 No.1 2024

91 ( 91 )Official Journal of Japan Society of Ningen Dock's Agreement
1. The authors undersigned hereby aﬃrm that the manuscript entitled :is original and does not infringe any copyright, and that it has not been published in whole orin part and is not being submitted or considered for publication in whole or in part elsewhere
except in the form of an abstract.
2. Assignment of Copyright. The authors hereby transfer, assign or otherwise convey all copyright ownership to Japan Society of Ningen Dock in the event this work is published by Japan
Society of Ningen Dock in any format.
3. Signature of all authors :Name (print)

Signature

Date

Name (print)

Signature

Date

Name (print)

Signature

Date

Name (print)

Signature

Date

Name (print)

Signature

Date

Name (print)

Signature

Date

Name (print)

Signature

Date

(A

)

(A

)

(A

)

(A

)

(A

)

(A

)

(A

)

If the author is a member of Japan Society of Ningen Dock, please write the membership number
on the right of the signature line.

Ningen Dock International Vol.11 No.1 2024

93 ( 93 )Abbreviations
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60

1,5-AG
17-OHCS
95% CIα -GI
β 2 -MGγ -GTPA/G ratio
ABI
ACTH
ADL
AFP
ALP
ALT
Apo (a)
APTT
AST
BMI
CA125
CA19-9
cAMP
CAPD
CBC
Ccr
cDNA
CEA
cGMP
ChE
CKD
COI
COPD
CK
CRP
CT
CVA
D-Bil
DBP
DNA
DRG
dsDNA
EBM
ECG
eGFR
EIA
ELISA
EPO
ESR
FBG
FDA
FEV
FEV 1
FEV 1 ％
FPG
FSH
FT3
FT4
FVC
GFR
GH
Hb
HbA1c

1,5-anhydroglucitol
17 α -hydroxycorticosteroid
95% confidence interval
α -glucosidase inhibitor
β 2 -microglobulin
γ -glutamyl transpeptidase
albumin-globulin ratio
ankle-brachial index
adrenocorticotropic hormone
activities of daily living
α -fetoprotein
alkaline phosphatasealanine aminotransferase
apolipoprotein (a)activated partial thromboplastin time
aspartate aminotransferase
body-mass index
carbohydrate antigen 125
carbohydrate antigen 19-9
cyclic adenosine 3 ’, 5 ’-monophosphate
continuous ambulatory peritoneal dialysis
complete blood cell countcreatinine clearancecomplementary deoxyribonucleic acidcarcinoembryonic antigen
cyclic guanosine 3 ’, 5 ’-monophosphatecholinesterase
chronic kidney disease
conflict of interest
chronic obstructive pulmonary diseasecreatinine kinasec-reactive protein
computed tomography
cerebrovascular accident
direct bilirubindiastolic blood pressure
deoxyribonucleic aciddiagnosis-related group
double stranded deoxyribonucleic acidevidence-based medicine
electrocardiogram
estimated glomerular filtration rate
enzyme immunoassay
enzyme-linked immunosorbent assay
erythropoietin
erythrocyte sedimentation rate
fasting blood glucose
Food and Drug Administration
forced expiratory volume
forced expiratory volume in one second
forced expiratory volume ％ in one second
fasting plasma glucose
follicle stimulating hormone
free triiodothyronine
free thyroxine
forced vital capacity
glomerular filtration rate
growth hormone
hemoglobin
hemoglobin A1c

61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120

hCG
HCV
HDL-C
HLA
HPLC
Ht
ICD
ICU
IFG
IGT
IMT
LAP
LDH
LDL-C
Lp(a)
LPL
MCH
MCHC
MCV
METs
MetS
MMG
MRA
MRI
mRNA
MRSA
MSW
NMR
PET
PSA
PTH
PWV
QOL
RBC
RF
RI
RIA
RNA
SBP
SD
SEM
STD
T-Bil
T3
T4
TC
TG
TIA
TIBC
tPA
TPHA
TSH
TTT
UCG
UIBC
UN
VLDL
WBC
WHO
ZTT

human chorionic gonadotropin
hepatitis C virus
high-density lipoprotein cholesterol
histocompatibility［leucocyte］antigen
high-performance liquid chromatography
hematocrit
International Classification of Diseaseintensive care unit
impaired fasting glucose
impaired glucose tolerance
intima-media thickness
leucine aminopeptidase
lactate dehydrogenase
low-density lipoprotein cholesterol
lipoprotein (a)lipoprotein lipase
mean corpuscular hemoglobinmean corpuscular hemoglobin concentration
mean corpuscular volume
meatbolic equivalentmetabolic syndrome
mammographymagnetic resonance angiographymagnetic resonance imaging
messenger RNA
methicillin-resistant Staphylococcus aureus
medical social worker
nuclear magnetic resonancepositron emission tomography
prostate-specific antigen
parathyroid hormone
pulse wave velocity
quality of life
red blood cellrheumatoid factor
radioactive isotope
radioimmunoassay
ribonucleic acidsystolic blood pressure
standard deviation
standard error of the mean
sexually transmitted disease
total bilirubin
triiodothyronine
thyroxine
total cholesterol
triglyceridetransient (cerebral) ischemic attack
total iron binding capacity
tissue plasminogen activator
Treponema pallidum hemagglutination assay
thyroid stimulating hormone
thymol turbidity test
ultrasonic echocardiography
unsaturated iron binding capacity
urea nitrogenvery-low-density lipoprotein
white blood cell
World Health Organization
zinc sulfate (turbidity) test

Ningen Dock International Vol.11 No.1 2024

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Ningen Dock International Vol.11 No.1 2024

97 ( 97 )Ningen Dock International
Official Journal of Japan Society of Ningen Dock
Editorial Board
Editor-in-Chief
Kazuhiko INOUE (Okayama)
Associate Editor
Junichi KABURAKI (Tokyo)
Editorial Board
Tomofumi ATARASHI (Hokkaido)

Toshiki FUKUI (Kagawa)Tomoari KAMADA (Okayama)

Nobuyuki KOBAYASHI (Kanagawa) Junko KOMATSU (Tokyo)

Masahiko MURATA (Akita)

Shigeki MUTO (Shizuoka)

Takashi NAITO (Ibaraki)

Hitoshi SASAMORI (Tokyo)

Masao SHIMIZU (Saitama)

Akiko TODA (Tokyo)

Advisory Board
Yasuji ARASE (Tokyo)

Shigeru NASU (Fukuoka)

International Advisory Board
HH LIU (Taiwan)

PK SUNG (Taiwan)

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Ningen Dock International Vol. 11 No. 1 March, 2024
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NINGEN DOCK INTERNATIONAL Official Journal of Japan Society of Ningen Dock

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NINGEN DOCK INTERNATIONAL
Official Journal of Japan Society of Ningen Dock

2024.3 Vol.11 No.1

Vol.11 No.1

2024. 3