TYPE

Brief Research Report

PUBLISHED 08 May 2024
DOI 10.3389/fendo.2024.1392280

OPEN ACCESSEDITED BY

Jonatan Ising Bagger,
Steno Diabetes Center Copenhagen (SDCC),
Denmark
REVIEWED BY

Mohamad Mokadem,
The University of Iowa, United States
Giovanni Tarantino,
University of Naples Federico II, Italy*CORRESPONDENCE

Tatsuya Fukuda
fukumem@tmd.ac.jp
RECEIVED 27 February 2024
ACCEPTED 22 April 2024

Extent to which weight loss
contributes to improving
metabolic dysfunctionassociated and metabolic andalcohol related/associatedsteatotic liver disease: a study on
Japanese participants
undergoing health checkups

PUBLISHED 08 May 2024
CITATION

Fukuda T, Okamoto T, Fukaishi T,
Kawakami A, Tanaka M, Yamada T and
Monzen K (2024) Extent to which weight loss
contributes to improving metabolic
dysfunction-associated and metabolic andalcohol related/associated steatotic liverdisease: a study on Japanese participants
undergoing health checkups.
Front. Endocrinol. 15:1392280.
doi: 10.3389/fendo.2024.1392280

Tatsuya Fukuda 1,2,3*, Takahiro Okamoto 1, Takahiro Fukaishi 4,
Akio Kawakami 5, Makoto Tanaka 4, Tetsuya Yamada 3
and Koshiro Monzen 5
1
Mirraza Shinjuku Tsurukame Clinic, Tokyo, Japan, 2 Department of Endocrinology and Metabolism,
Tokyo Metropolitan Okubo Hospital, Tokyo, Japan, 3 Department of Molecular Endocrinology andMetabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University,
Tokyo, Japan, 4 Koganei Tsurukame Clinic, Tokyo, Japan, 5 Shinjuku Tsurukame Clinic, Tokyo, JapanCOPYRIGHT© 2024 Fukuda, Okamoto, Fukaishi, Kawakami,
Tanaka, Yamada and Monzen. This is an openaccess article distributed under the terms of
the Creative Commons Attribution License(CC BY). The use, distribution or reproduction
in other forums is permitted, provided theoriginal author(s) and the copyright owner(s)are credited and that the original publicationin this journal is cited, in accordance withaccepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.

Introduction: The incidence of steatotic liver disease has increased in recent
years. Thus, steatotic liver disease is a major public health issue in Japan. This
study investigated the association between weight reduction and the remissionof metabolic dysfunction-associated steatotic liver disease (MASLD)/Metabolicand alcohol related/associated liver disease (MetALD) in Japanese individuals
undergoing health checkups.
Methods: This retrospective observational study included 8,707 Japanesepatients with MASLD/MetALD who underwent health checkups from May 2015
to March 2023. The participants were monitored for its remission at theirsubsequent visit. MASLD was diagnosed on abdominal ultrasonography andbased on the presence of at least one of ﬁve metabolic abnormalities. The
impact of body mass index (BMI) reduction on MASLD/MetALD remission wasassessed via logistic regression analysis and using receiver operating
characteristic curves.
Results: Logistic regression analysis revealed that weight loss was signiﬁcantly
associated with MASLD/MetALD remission. Other factors including exercise
habits and reduced alcohol consumption were signiﬁcant predictors of
MASLD/MetALD remission in the overall cohort and in male patients. The
optimal BMI reduction cutoff values for MASLD/MetALD remission were 0.9 kg/
m2 and 4.0% decrease in the overall cohort, 0.85 kg/m2 and 3.9% decrease inmales, and 1.2 kg/m2 and 4.5% decrease in females. In participants with a BMI of
23 kg/m2, the cutoff values were 0.75 kg/m2 and 2.7% BMI reduction.

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10.3389/fendo.2024.1392280

Discussion: Weight reduction plays an important role in both MASLD and MetALD
remission among Japanese individuals. That is, targeting speciﬁc BMI reduction iseffective. This underscores the importance of targeted weight management
strategies in preventing and managing MASLD/MetALD in theJapanese population.

KEYWORDS

metabolic dysfunction-associated steatotic liver disease (MASLD), nonalcoholic fatty
liver disease (NAFLD), metabolic and alcohol related/associated liver disease (MetALD),
alcohol consumption, weight loss

1 Introduction

cardiometabolic risk factors based on its diagnostic criteria, unlike
MAFLD, which required the inclusion of two. The consensus
decision was to change the deﬁnition of MASLD to include thepresence of at least one of ﬁve cardiometabolic risk factors (10).
Furthermore, among patients with steatotic liver disease meeting
MASLD criteria, those with high alcohol intake (weekly intake 140350 g female, 210-420 g male) are newly classiﬁed as metabolic andalcohol related/associated liver disease (MetALD).
Weight loss is the most effective treatment for NAFLD, andnumerous studies have shown that losing weight can prevent the
progression of NAFLD and, in some cases, even reverse ﬁbrosis (11,12). In addition, in improving NAFLD, the degree of weight loss isdose-dependent (13). Taking these ﬁndings into consideration,weight loss signiﬁcantly contributes to MASLD/MetALD
remission, which has some similarities with NAFLD/MAFLD.
However, thus far, this aspect has not been extensively examinedamong Japanese individuals. Therefore, this retrospective
observational study aimed to investigate the association between
weight reduction and MASLD/MetALD remission using dataobtained from medical checkups at three clinics.

In recent years, there has been a signiﬁcant increase in theprevalence of nonalcoholic fatty liver disease (NAFLD) worldwide,and now it is the most common chronic liver disease (1–4). This
increase signiﬁcantly contributes to the development of liver disease
complications such as cirrhosis and liver cancer (5, 6). Furthermore,
NAFLD plays an important role in not only liver health but also
metabolic abnormalities, including type 2 diabetes andcardiovascular disease, which, in turn, are associated with a highmortality rate (7). Therefore, the increased incidence of NAFLD is asigniﬁcant public health issue, and strategies for preventing andmanaging NAFLD are urgently needed.
Recently, an international panel of experts introduced a novel
classiﬁcation for fatty liver disease known as metabolic dysfunctionassociated fatty liver disease (MAFLD) (8, 9). MAFLD ischaracterized by either overweight/obesity or type 2 diabetes andfatty liver. Moreover, it can be diagnosed in individuals with anormal weight who exhibit at least two metabolic abnormalities
along with fatty liver. Importantly, MAFLD is a more effective
identiﬁer than NAFLD in predicting the risk of future hepaticﬁbrosis, atherosclerotic cardiovascular disease, chronic kidneydisease, and overall mortality (9). The diagnosis of MAFLD,
unlike that of NAFLD, is not inﬂuenced by alcohol consumption
or viral hepatitis and is applicable across various clinical settings.
The concept of MAFLD has been accepted. However, there arereservations regarding some aspects of this condition. These
concerns include the different causes of the condition, theongoing use of the term fatty, which is viewed by many asstigmatizing, and the limitation of the population to those with atleast two metabolic risk factors. Thus, these factors can potentiallyaffect the comprehension of the natural progression of the disease(10). To address these issues, the American Association for the
Study of Liver Diseases and the European Association for the Studyof the Liver, in collaboration with the Asociació n Latinoamericana
para el Estudio del Hı́gado, have proposed the use of metabolic
dysfunction-associated steatotic liver disease (MASLD), a new term
for fatty liver disease and an alternative to NAFLD. MASLD has
been redeﬁned to include the presence of at least one of ﬁve

Frontiers in Endocrinology

2 Materials and methods
2.1 Study design and population
The participants who visited three clinics (Shinjuku Tsurukame
Clinic, Koganei Tsurukame Clinic, and Mirraza Shinjuku
Tsurukame Clinic, Tokyo, Japan) for medical checkups from May
1, 2015, to March 31, 2023, were screened for possible eligibility inthis retrospective observational study. The current research
included participants aged ≥ 20 years who had undergone
medical checkup more than twice. In patients who had three ormore medical checkups, we selected data corresponding to theperiod when the greatest reduction in body mass index (BMI)
occurred. Each participant was monitored to determine the extent
of weight change between their ﬁrst and second healthexaminations, and improvements in MASLD status wereobserved. Subsequently, the participants diagnosed with MASLD

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10.3389/fendo.2024.1392280

during their ﬁrst checkup were included in this study. None of thethree aforementioned hospitals provided health guidance topatients diagnosed with MASLD.
However, individuals with a history of cancers and thyroid
disorders (including Graves’ disease, Hashimoto’s disease, andchronic thyroiditis); those with an FIB-4 index of > 2.67, deﬁned
as age (years) × aspartate aminotransferase (AST; IU/L)/(platelet[109/L] × (alanine aminotransferase [ALT; U/L])1/2 (14), whichindicates suspected advanced-stage liver ﬁbrosis; those withexcessive alcohol intake (females who consume more than 350 g
of alcohol per week and males who consume more than 420 g ofalcohol per week); those with a history of viral hepatitis; and thosewith missing data were excluded.
This study was conducted in accordance with the principles of
the Declaration of Helsinki. The study protocol was approved by the
ethics committee of Shinjuku Tsurukame Clinic (approval no.
2,401). As the study was retrospective observational in nature, theneed for a written informed consent was waived. Patients were
provided with the option to opt out, with the details of the analysis
made available on the hospital’s website.

The eGFR of Japanese patients was assessed using the following
equation, as proposed by the Japanese Society of Nephrology: eGFR
= 194 × serum Cr−1.094 × age−0.287[(if female) × 0.739] (15). Waist
circumference (WC) was measured at the umbilical level. BMI was
calculated as weight in kilogram divided by height in meterssquared (kg/m2). In terms of comorbidities, the presence orabsence of diabetes, dyslipidemia, and hypertension wasdetermined based on self-reported data. Diabetes was deﬁned as adiagnostic history of diabetes or use of antidiabetic agents.
Dyslipidemia was deﬁned as a diagnostic history of dyslipidemia
or use of lipid-lowering agents. Hypertension was deﬁned as adiagnostic history of hypertension or use of antihypertensive agents.
BMI reduction (kg/m2) was deﬁned as the BMI at the ﬁrst
medical checkup minus the BMI at the second medical checkup.
The reduction rate of BMI (%) was calculated as (the reduction in
BMI [kg/m2])/BMI at the ﬁrst medical checkup) × 100.

2.3 Ultrasound ﬁnding analysis
Abdominal ultrasonography was performed by a trained clinicallaboratory technologist using the Aplio MX, Aplio 300, Aplio a450,
or Aplio a550 ultrasound systems (Canon Medical Systems, Tokyo,
Japan). Steatotic liver was determined, as described in a previous
study (16).

2.2 Collection of clinical data
A standardized questionnaire was used to obtain information
on medical history, current comorbidities, and lifestyle-related
factors. Smoking status was classiﬁed as either current smoker or
nonsmoker. Exercise habit was deﬁned as exercise of at least 30 min
per session, at least 2 days per week, for at least 1 year. Physicalactivity was deﬁned as walking or performing physical activity
equivalent to walking for at least 1 h per day. Fast walking was
deﬁned as walking faster than people of approximately the same age
and sex. Fast eating was deﬁned as eating at a faster rate than others.
Meal just before bedtime was deﬁned as dinner within 2 h before
bedtime at least 3 times a week. Absence of breakfast was deﬁned as
missing breakfast at least 3 times a week. Good sleeping was deﬁned
as feeling well rested after sleep. Regarding alcohol consumption,
the frequency of drinking was classiﬁed as daily, occasional, andrarely. The amount of alcohol consumed per drinking session, withapproximately 20 g of alcohol per drink, was classiﬁed as follows:less than 1 drink, 1–2 drinks, 2–3 drinks, and ≥ 3 drinks. Based on
this information, to obtain the weekly alcohol consumption, theestimated weekly alcohol consumption was calculated as follows: 1
drink deﬁned as 20 g, 1–2 drinks as 30 g, 2–3 drinks as 50 g, and ≥ 3units as 70 g, multiplied by 7 for daily and 2 for occasional. The
alcohol consumption of patients who answered rarely was assumed
to be 0 g/week. Alcohol consumption change was calculated as theamount of alcohol consumed at the second medical checkup minus
the amount of alcohol consumed at the ﬁrst medical checkup.
The following blood sampling data were collected after 8 h offasting: age; sex; fasting plasma glucose (FPG), hemoglobin A1c(HbA1c), AST, ALT, gamma-glutamyl transferase (g-GTP),
triglyceride (TG), high-density lipoprotein cholesterol (HDL-C),
low-density lipoprotein cholesterol (LDL-C), uric acid, serum
creatinine (Cr), and hemoglobin level; estimated glomerular
ﬁltration rate (eGFR); and white blood cell and platelet count.

Frontiers in Endocrinology

2.4 Deﬁnition of MASLD/MetALD
MASLD was deﬁned according to the Delphi consensus
statement (10). MASLD was deﬁned as participants with steatotic
liver on abdominal ultrasonography with a weekly alcohol
consumption of 70 g for females or 140 g for males or less, and at
least one of the following ﬁve criteria: 1) BMI of ≥ 23 kg/m2 or WCof ≥ 85 cm in men or ≥ 90 cm in women (17), 2) fasting serum
glucose level of ≥ 100 mg/dL or type 2 diabetes treatment, 3) bloodpressure of ≥ 130/85 mmHg or speciﬁc antihypertensive drug
treatment, 4) triglyceride level of ≥ 150 mg/dL or lipid-lowering
treatment, and 5) HDL-C levels of ≤ 40 mg/dL in men or ≤ 50 mg/
dL in women or lipid-lowering treatment. MetALD was deﬁned as
participants with steatotic liver on abdominal ultrasonography witha weekly alcohol consumption of 140-350 g for females or 210-420 g
for males or less, and at least one of the aforementioned ﬁve criteria.
The study endpoint was MASLD/MetALD remission at the second
medical checkup. Remission of MASLD/MetALD was deﬁned as adiagnosis of MASLD/MetALD at the ﬁrst medical checkup but not
at the second checkup.

2.5 Statistical analysis
Data were presented as mean ± standard deviation, median withinterquartile range, or percentage, in accordance with the
distribution characteristics of the data. To compare categoricalvariables, the chi-square test was used. The t-test was used forquantitative variables. The association between reduced BMI during

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10.3389/fendo.2024.1392280< 0.05 were considered statistically signiﬁcant. Statistical analyses
were conducted using the Statistical Package for the Social Sciences
software version 21.0 (IBM Corp., Armonk, NY, the USA).

follow-up and baseline covariates and MASLD remission was
examined via logistic regression analysis. The odds ratio (OR)and 95% conﬁdence interval (CI) were calculated. The selectionof variables that were incorporated into the multivariate logistic
regression analysis was performed with a stepwise procedure. We
performed logarithmic transformations on variables including gGTP, TG, and alcohol consumption to normalize theirdistributions, applying the natural logarithm (base e). For alcohol
consumption, we log-transformed the value as 1 g/week in the caseof zero. For Alcohol consumption change, which could be zero or
negative, we log-transformed it for everyone plus 500 g/week. Thistransformation was integrated into our logistic regression analysis
to improve model ﬁt and interpretability. Receiver operating
characteristic (ROC) analyses were conducted to calculate theareas under the curve (AUC) of both BMI reduction (kg/m2) and
BMI reduction rate (%) for MASLD remission. The optimal cutoff
values were determined using the Youden’s index (18). P values of

3 Results
This study enrolled 8,707 participants with a mean age of 49.1
± 9.4 years, and approximately 79% of them were male. The
participants underwent their second health checkups at an averageof 1.3 ± 0.8 years after their ﬁrst, during which the average BMI
decreased by 0.7 ± 1.3 kg/m2. Moreover, 1,350 participants were in
MASLD remission in second health checkup. Table 1 shows thebaseline clinical characteristics, comorbidities, laboratory data,
and lifestyle-related parameters of all participants (n = 8,707),
those without MASLD remission (stable group, n = 7,357), andthose with MASLD remission (remission group, n = 1,350). The

TABLE 1 Baseline clinical characteristics, comorbidities, laboratory data, lifestyle parameters of all subjects, those who achieved remission of
metabolic dysfunction-associated steatotic liver disease (MASLD) or metabolic and alcohol related/associated liver disease (MetALD), and those who
did not.

All participants

Stable group

Remission group

8707

7357

1350

Age, y49.1 ± 9.4

49.4 ± 9.4

48.0 ± 9.4<0.001

Body mass index, kg/m2

26.2 ± 3.6

26.5 ± 3.6

24.4 ± 2.7<0.001

BMI reduction, kg/m2

0.7 ± 1.3

0.5 ± 1.3

1.5 ± 1.4

<0.001

BMI reduction, %2.7 ± 4.4

2.1 ± 4.0

6.0 ± 5.3

<0.001

Male sex

6888 (79)5880 (80)1008 (75)<0.00191.6 ± 8.9

92.5 ± 8.9

86.8 ± 7.3<0.001

Waist circumference in males, cm

92.8 ± 8.7

87.4 ± 6.9<0.001

Waist circumference in females, cm

91.2 ± 9.8

84.9 ± 8.2<0.001

1.3 ± 0.8

1.3 ± 0.8

1.3 ± 0.8

0.988

Hypertension, n (%)

1643 (19)1471 (20)172 (13)<0.001Diabetes mellitus, n (%)

514 (6)476 (7)38 (3)<0.001

Dyslipidemia, n (%)

1212 (14)1091 (15)121 (9)<0.001

MAFLD, n (%)

8062 (93)6968 (95)1094 (81)<0.001

FPG, mg/dl

95.1 ± 21.1

96.0 ± 21.8

86.8 ± 7.3<0.001HbA1c, %5.7 ± 0.8

5.7 ± 0.8

5.5 ± 0.7

<0.001

TG, mg/dl

155.8 ± 112.4

160.3 ± 112.3

131.6 ± 110.3<0.001

HDL, mg/dl

52.8 ± 13.4

52.0 ± 13.0

56.9 ± 14.6

<0.001

HDL in males, mg/dl

50.4 ± 12.0

54.3 ± 13.3

<0.001

HDL in females, mg/dl

58.7 ± 14.864.4± 15.5

<0.001134.8 ± 32.8

131.5 ± 31.9

0.001

n

Waist circumference, cm

Interval between health checkups, yComorbidities

Laboratory data

LDL, mg/dl

134.3 ± 32.7

(Continued)

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TABLE 1 Continued

All participants

Stable group

Remission group

AST, IU/l

27.5 ± 13.9

28.1 ± 14.3

24.1 ± 11.1

<0.001

ALT, IU/l

36.3 ± 26.9

37.9 ± 27.7

27.7 ± 19.9

<0.001g-GTP, IU/l

57.8 ± 62.5

59.6 ± 63.5

48.0 ± 55.8

<0.001

UA, mg/dl

6.2 ± 1.4

6.3 ± 1.4

6.0 ± 1.4

<0.001

Cr, mg/dl

0.8 ± 0.2

0.8 ± 0.2

0.8 ± 0.3

0.290

eGFR, ml/min/1.73m2

76.5 ± 13.7

76.5 ± 13.8

76.9 ± 12.9

0.278

WBC,/µl6188 ± 1604

6249 ± 1617

5854 ± 1487

<0.001

Hb, g/dL

Laboratory data

15.1 ± 1.3

15.2 ± 1.3

14.8 ± 1.5<0.001

4

Plt, 10 /µL

27.0 ± 5.9

26.9 ± 5.9

27.1 ± 5.9

0.397

SBP, mmHg

126 ± 16126.3 ± 15.7

121.1 ± 15.1

<0.001

DBP, mmHg

80 ± 1280.6 ± 11.7

77.1 ± 11.3

<0.001

Current Smoker

2128 (24)1826 (25)302 (22)0.059

Exercise habit

1803 (21)1487 (20)316 (23)

0.008

Physically Active

3465 (40)2902 (39)563 (42)

0.119

Fast walking

4526 (52)3786 (52)740 (55)

0.023

Fast eating4349 (50)3642 (50)707 (52)

0.053

Meal just before bedtime

3738 (43)3161 (43)577 (43)

0.878

Absence of breakfast

2299 (26)1970 (27)329 (24)

0.065

Good sleeping

5555 (64)4664 (63)891 (66)

0.067

Daily drinking3252 (37)2757 (38)495 (37)

0.573

Alcohol consumption, g/week

105.5 ± 124.5

105.5 ± 124.4

105.7 ± 124.6

0.970

Alcohol consumption change,
g/week

-4.5 ± 77.9

-3.4 ± 76.1

-10.5 ± 86.7

0.002

Interval between health checkups, y

1.3 ± 0.8

1.3 ± 0.8

1.3 ± 0.8

0.988

lifestyle-related factors

Data are shown as mean ± SD or number (percentage). p value represents the difference between the subjects with remission and stable in means (t test), or percent (chi square test).
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; Cr, creatinine; DBP, diastolic blood pressure; eGFR, estimated glomerular ﬁltration rate; FPG, fasting
plasma glucose; g-GTP, g-glutamyl transpeptidase; Hb, hemoglobin; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MAFLD, metabolic dysfunctionassociated fatty liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; PLT; platelet; SBP, systolic blood pressure; TG, triglyceride; UA, uric acid; WBC, white blood cell;WC, waist circumference.

the stable group. Supplementary Table 1 shows the baseline
clinical characteristics, comorbidities, laboratory data, andlifestyle-related parameters categorized by MASLD or MetALD.
Patients with MetALD patients were older and had a lower BMI
than those with MASLD. Signiﬁcant differences were noted in
gender distribution, with a higher proportion of males in the
MetALD group. Differences in hypertension, dyslipidemia,
various laboratory parameters, and kidney function were alsosigniﬁcant. Lifestyle factors differed signiﬁcantly between
MASLD and MetALD patients, with the latter more likely tosmoke and exercise habit but less inclined to fast walking. The
proportions of participants having a meal just before bedtime andreporting good sleep were different between MASLD and
MetALD patients.

stable group was slightly older than the remission group. The
stable group had a higher BMI and had a signiﬁcantly lessreduction in BMI than the remission group. The remission
group had a signiﬁcantly lower proportion of male patients anda smaller WC than the stable group. The remission group had aconsistently lower prevalence of hypertension, diabetes mellitus,and dyslipidemia compared with the stable group. The FPG, TG,
HDL-C, LDL-C, AST, ALT, g-GTP, uric acid, HbA1c, andhemoglobin levels and the white blood cell count signiﬁcantly
differed between the stable and remission groups. In contrast, theCr levels, eGFR, and platelet count did not differ signiﬁcantly
between the two groups. Regarding lifestyle-related parameters,
the remission group had a signiﬁcantly higher proportion ofparticipants with exercise habits and fast walking habits thanFrontiers in Endocrinology

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TABLE 2 Logistic regression models examining the associations of body mass index reduction in follow-up with the remission of metabolic
dysfunction-associated steatotic liver disease (MASLD).

All participants

Male (n=6888)

Female (n=1819)

OR

95%CI

p

OR

95%CI

p

OR

95%CI

p

1.784

1.665-1.835<0.0011.834

1.730-1.944<0.001

1.542

1.414-1.681<0.001

2.792

2.610-2.992<0.001

3.131

2.879-3.406<0.0012.254

2.001-2.539<0.0010.700

0.678-0.722<0.0010.753

0.713-0.796<0.0010.724

0.686-0.763<0.001Age, y0.969

0.961-0.978<0.001

0.978

0.968-0.987<0.001

0.966

0.948-0.984<0.001

Dyslipidemia

0.744

0.587-0.942

0.014

0.744

0.566-0.977

0.033

NS

FPG, mg/dl

0.986

0.981-0.991<0.001

0.987

0.981-0.992<0.001

0.983

0.972-0.996

0.008

Log-TG

0.361

0.255-0.513<0.0010.457

0.307-0.681<0.001

0.268

0.128-0.563

0.001

HDL, mg/dl

1.007

1.001-1.012

0.018

1.010

1.003-1.017

0.007

NS

ALT, IU/l

0.981

0.977-0.985<0.0010.981

0.977-0.986<0.001

0.969

0.949-0.989

0.003

Log-g-GTP

NS

NS

NS

NS

NS

NS

0.369

0.187-0.730

0.004

eGFR, ml/min/1.73m2

0.992

0.986-0.997

0.004

NS

0.986

0.975-0.996

0.012

SBP, mmHg

0.992

0.987-0.996<0.001

0.983

0.976-0.991<0.001NS

Exercise habit

1.264

1.074-1.487

0.005

1.239

1.029-1.492

0.024

NS

Absence of breakfast

NS

0.798

0.662-0.962

0.018

NS

Log-Alcohol consumption change

0.374

0.356

0.192-0.663

0.001

NS

Hb, g/dl

NS

0.799-0.996

0.011

Univariate model
BMI reduction, kg/m2

Multivariate model
BMI reduction, kg/m2
Baseline BMI, kg/m

20.208-0.675

0.001

NS

0.892

ALT, alanine aminotransferase; BMI, body mass index; eGFR, estimated glomerular ﬁltration rate; FPG, fasting plasma glucose; Hb, hemoglobin; HDL, high-density lipoprotein; LDL, lowdensity lipoprotein; MASLD, metabolic dysfunction-associated steatotic liver disease; SBP, systolic blood pressure; TG, triglyceride; g-GTP, gamma-glutamyl transferase.

and in male patients. The absence of breakfast was associated with adecreased risk of MASLD remission only in male patients.
Figure 1 shows the ROC curves examining the association
between BMI reduction (kg/m2) and BMI reduction rate (%) and
MASLD remission in all participants, male patients, and female
patients, with AUC and optimal cutoff values. The AUC for BMI
reduction (kg/m2) was 0.710 in all participants, 0.721 in male patients,
and 0.678 in female patients, with the optimal cutoff values of 0.90,
0.85, and 1.20 kg/m2, respectively (Figure 1A–C). The AUCs of BMI
reduction rate (%) were 0.731 in all participants, 0.743 in malepatients, and 0.697 in female patients, with the appropriate cutoff
values of 4.0%, 3.9%, and 4.5%, respectively (Figure 1D–F).
Supplementary Figure 1 depicts the ROC curves examining theassociation between BMI reduction (kg/m2) and BMI reduction rate(%) and MASLD/MetALD remission in patients with a BMI of < 23 kg/
m2 (n = 1,214) and those with a BMI of ≥ 23 kg/m2 (n = 7,495), with
AUC and optimal cutoff values. The AUCs for BMI reduction (kg/m2)
were 0.669 in participants with a BMI of < 23 kg/m2 and 0.751 in thosewith a BMI of ≥ 23 kg/m2, with optimal cutoff values of 0.75 and 0.90
kg/m2, respectively (Supplementary Figure 1A, B). The AUCs for BMI
reduction rate (%) were 0.671 for participants with a BMI of < 23 kg/m2
and 0.767 for those with a BMI of ≥ 23 kg/m2, with optimal cutoff
values of 2.7% and 4.0%, respectively (Supplementary Figure 1C, D).

Table 2 shows the associations between BMI reduction duringfollow-up and MASLD remission based on the logistic regression
models. The univariate model revealed that an increase in BMI
reduction was signiﬁcantly associated with MASLD remission in allparticipants (OR: 1.784, 95% CI: 1.665–1.835), male patients (OR:1.834, 95% CI: 1.730–1.944), and female patients (OR: 1.542, 95%
CI: 1.414–1.681), all with p-values of < 0.001. The multivariate
model showed that the association between BMI reduction duringfollow-up and MASLD remission remained signiﬁcant across allgroups (OR: 2.792, 95% CI: 2.610–2.992 in the overall cohort; OR:
3.131, 95% CI: 2.879–3.406 in male patients; and OR: 2.254, 95% CI:
2.001–2.539 in female patients). Lower baseline BMI and younger
age were consistently associated with MASLD remission across allgroups. Dyslipidemia was signiﬁcantly and negatively associatedwith MASLD remission in all participants (OR: 0.744, p = 0.014)
and in males (OR: 0.744, p = 0.033), however, no sufﬁciently
signiﬁcant associations of dyslipidemia with endpoints weredetected in females. Lower FPG, Log-TG, and ALT levels wereassociated with MASLD remission across all groups. Higher HDL-C
levels were signiﬁcantly associated with MASLD remission in allparticipants and male patients, but not in female patients. With
regard to lifestyle-related parameters, exercise habit wassigniﬁcantly associated with MASLD remission in all participants

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A

B

C

D

E

F

FIGURE 1

Receiver operating characteristic (ROC) curves of reduction of body mass index (BMI) for predicting the remission of metabolic dysfunctionassociated steatotic liver disease in analysis of absolute decrease in BMI of all participants (A), male (B), and female (C), and analysis of percent
decrease in BMI of all participants (D), male (E), and female (F).

decrease in BMI was signiﬁcantly associated with the remission of
MASLD/MetALD regardless of sex. Therefore, weight loss can be an
important factor in managing MASLD/MetALD. Further, it wassigniﬁcantly associated with MASLD/MetALD improvement inpatients with a BMI of < 23 kg/m2. Hence, weight loss can be
useful in improving MASLD/MetALD even in lean individuals.
Weight loss also contributed independently to their improvementin each of the MASLD and MetALD patients, respectively.
Weight loss plays a signiﬁcant role in improving steatotic liverdisease. In studies on patients with NAFLD, a 5% reduction in BMI
was associated with a 25% decrease in liver fat content (19).
Similarly, patients with NASH who had a weight loss of > 5% had
a higher rate of NASH resolution and a signiﬁcant improvement in
the nonalcoholic steatotic liver disease activity score compared withthose with a weight loss of < 5% (20). Considering these ﬁndings, aweight loss of approximately 5% can be a strong contributing factor
for MASLD/MetALD remission. Several patients with MAFLD and
NAFLD overlap, and weight loss may similarly contribute toremission. Indeed, Hasegawa Y et al. reported that weight loss led
to MAFLD remission after 5 years in 3,309 Japanese individuals
who underwent health checkups, with a cutoff value of 1.9 kg or
3.1% reduction (21). Most patients with MASLD/MetALD and
MAFLD overlap. In our study, 93% of patients diagnosed with
MASLD/MetALD met the diagnostic criteria for MAFLD. Similar
to the results of Hasegawa Y et al., weight loss was found toindependently contribute to MASLD/MetALD remission. The
cutoff value for weight loss is a reduction of 0.9 kg/m2 in BMI ora 4.0% decrease in BMI. Our results can be useful in setting target
values for weight loss in Japanese patients diagnosed with MASLD.

Table 3 shows the logistic regression models of the association
between BMI reduction (kg/m2) and improvement in steatotic liverdisease in MASLD and MetALD patients separately. In individuals
with MASLD, the univariate model revealed that an increase in BMI
reduction was signiﬁcantly associated with MASLD (OR: 1.736,
95% CI: 1.643–1.834, p < 0.001), and the association was consistentafter adjustment for other covariates in multivariate model (OR:2.822, 95% CI: 2.608–3.054, p < 0.001). Similarly in individuals with
MetALD, the univariate model revealed that an increase in BMI
reduction was signiﬁcantly associated with MASLD (OR: 1.813,
95% CI: 1.630–2.017, p < 0.001), and the association was consistentafter adjustment for other covariates in multivariate model (OR:2.793, 95% CI: 2.426–3.217, p < 0.001).
Supplementary Table 2 shows AUC in ROC curves of reductionof BMI for predicting the remission of MASLD, and MetALD. In
participants with MASLD, the AUC for BMI reduction (kg/m2) was
0.716 with the optimal cutoff values of 0.85 kg/m2, and the AUC for
BMI reduction rate (%) was 0.737 with the optimal cutoff values of
3.5%. In participants with MetALD, the AUC for BMI reduction(kg/m2) was 0.695 with the optimal cutoff values of 0.75 kg/m2, and
the AUC for BMI reduction rate (%) was 0.713 with the optimal
cutoff values of 3.0%.

4 Discussion
This study aimed to elucidate the extent to which weight loss
contributes to MASLD/MetALD remission among Japaneseparticipants undergoing health checkups. Results showed that a

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TABLE 3 Logistic regression models examining the associations of body mass index reduction in follow-up with the remission of metabolic
dysfunction-associated steatotic liver disease (MASLD) or metabolic and alcohol related/associated liver disease (MetALD).

MASLD (n=6418)
OR

MetALD (n=2289)
p

95%CI

OR

95%CI

p

Univariate model
BMI reduction, kg/m2

1.736

1.643-1.834<0.0011.813

1.630-2.017<0.001

2.822

2.608-3.054<0.0012.793

2.426-3.217<0.0010.683

0.659-0.708<0.0010.717

0.675-0.761<0.001Age, y0.968

0.959-0.977<0.0010.980

0.964-0.996

0.014

Dyslipidemia

0.744

0.565-0.979

0.034

NS

HbA1c, %

NS

0.470

0.347-0.636<0.001

Log-TG, mg/dl

0.273

0.182-0.410<0.001

0.392

0.225-0.683

0.001

Log-g-GTP

0.665

0.461-0.958

0.028

NS

HDL, mg/dl

1.007

1.000-1.014

0.049

NS

ALT, IU/l

0.983

0.978-0.988<0.001

0.982

0.974-0.991<0.001eGFR, ml/min/1.73m2

0.990

0.984-0.997

0.004

NS

SBP, mmHg

0.994

0.988-0.999

0.029

0.975

0.964-0.987<0.001

Exercise habit

1.289

1.058-1.569

0.012

NS

Absence of breakfast

NS0.510-0.930

0.015

Log-Alcohol consumption

1.115

Log-Alcohol consumption changeNS

0.168-0.600<0.001

Multivariate model
BMI reduction, kg/m2
Baseline BMI, kg/m

2

0.689
1.012-1.228

0.028

NS
0.317

ALT, alanine aminotransferase; BMI, body mass index; eGFR, estimated glomerular ﬁltration rate; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL,
low-density lipoprotein; MASLD, metabolic dysfunction-associated steatotic liver disease; SBP, systolic blood pressure; TG, triglyceride.

in Japanese patients similar to those with steatotic liver diseases,
including NAFLD and MAFLD. However, further research shouldbe performed to determine the usefulness of exercise for MASLD
remission in female Japanese patients.
Numerous studies have reported that alcohol consumption,even in small quantities, contributes to the progression of liverdiseases, including NAFLD, in a dose-dependent manner.
Moreover, there is a potential for a synergistic adverse effect if
there is a co-existence of metabolic syndrome and excessive alcohol
consumption (23–26). Consequently, it was hypothesized that
alcohol use can be an inhibitory factor in MASLD/MetALD
improvement. In the overall cohort and male patients, a decrease
in alcohol consumption was signiﬁcantly associated with MASLD/MetALD improvement. However, this association was not observedin female participants, and baseline alcohol consumption was not
associated with MASLD improvement, regardless of sex. Based onthese ﬁndings, in addition to weight reduction, alcohol reduction
may contribute to MASLD/MetALD improvement in men with
MASLD/MetALD who consume alcohol to a certain extent.
Nevertheless, both baseline alcohol consumption and reduction inalcohol intake during the follow-up period were not associated with
their remission in the sensitivity analysis of MASLD and MetALD

MetALD is a condition where the effects of a certain amount of
alcohol overlap with those observed in MASLD patients (10),therefore, it was hypothesized that weight loss would also be aneffective strategy for remission in MetALD patients, similar to thosewith MASLD. As expected, our ﬁndings indeed indicate that weightloss leads to remission in MetALD patients, just as it does in
MASLD patients. Furthermore, we demonstrated that theappropriate cutoff value for BMI reduction in MetALD patients isroughly equivalent to that in MASLD patients (0.75 vs 0.85 kg/m2).
This suggests that weight management strategies could beuniversally beneﬁcial across both conditions, underscoring theimportance of weight loss in the therapeutic approach forsteatotic liver diseases associated with metabolic dysfunctions andalcohol consumption.
Exercise therapy improves NAFLD independent of weight loss
based on meta-analyses (22), therefore, it might contribute to
MAFLD improvement. Consistent with these results, our study
showed that exercise habit, deﬁned as exercise for at least 30 min persession, at least twice a week, was signiﬁcantly and independently
associated with MASLD/MetALD improvement during the next
health checkup in the overall cohort and male participants.
Therefore, exercise habit can be beneﬁcial for improving MASLD

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patients. In the current study, we prioritized registering cases inwhich weight loss was achieved and examined the association
between weight loss and MASLD reduction, therefore, it ispossible that the association between alcohol intake and changes
in alcohol intake and MASLD/MetALD has not been accurately
investigated. Further research should be performed to determine
the extent to which alcohol reduction contributes to MASLD/MetALD improvement.
In the new consensus statement, patients with a certain amount
weekly alcohol consumption (up to 140 g/week for females and 210 g/
week for males) who fulﬁll the criteria for both MASLD and alcoholrelated fatty liver disease (ALD) are classiﬁed as having MetALD (10).
MASLD and ALD share similar histological features, including
accumulation of triacylglycerol-rich lipid droplets within hepatocytes,
and share common molecular alterations. Notably, an increase in theexpression of cytokine IL-6, which is involved in inﬂammation, hasbeen implicated in promoting the progression of both MASLD and
ALD, primarily via mitochondrial dysfunction (27, 28). Given theseﬁndings, weight loss may aid in improving conditions, even in patients
predominantly affected by ALD, such as those diagnosed with
MetALD. Our data demonstrates that weight loss independently
ameliorates both MASLD and MetALD conditions, suggesting thatweight loss counseling, in conjunction with alcohol reduction advice,
may be beneﬁcial for patients with MetALD.
Patients with NAFLD who have a normal weight can exhibit thesame level of ﬁbrosis as patients with NAFLD who have obesity (29).
Some reports have recommended that patients with NAFLD who arenonobese may have a higher incidence of type 2 diabetes and a higher
fat percentage than patients with NAFLD who are obese (30, 31).
Moreover, numerous studies have revealed that weight loss contributes
to NAFLD remission in patients who are nonobese. Therefore, weight
reduction might also contribute to MASLD/MetALD remission inpatients who are nonobese. Our study reported that weight loss could
possibly be a factor for MASLD/MetALD remission in patients who
are nonobese. Further, the optimal cutoff value for weight reduction inpatients with MASLD/MetALD who are nonobese is a decrease of 0.75
kg/m2 or a 2.7% decrease in BMI.
The current study had several limitations that must be
considered. First, it included data collected from health checkups
at three clinics, thereby limiting the generalizability of our ﬁndings.
In addition, the participants were Japanese; thus, the applicability of
our results to other races has not been conﬁrmed. Second, MASLD/MetALD was diagnosed on ultrasonography. However, thisprocedure underestimates the prevalence of hepatic steatosis if
there is < 20% steatosis (32). Moreover, it is completely
impractical to perform a biopsy, which is the gold standard for
diagnosis, in all patients suspected of steatotic liver disease who areundergoing health checkups. Third, we were unable to use factorsthat could potentially inﬂuence the progression of MASLD/MetALD, such as insulin resistance and inﬂammation, as
explanatory variables. Fourth, the present study had aretrospective design, and there may be some selection bias.
Further large prospective studies are needed to conﬁrm the effectof weight loss on remission of MASLD/MetALD.

Frontiers in Endocrinology

5 Conclusion
This retrospective observational study showed that weight
reduction signiﬁcantly contributed to MASLD/MetALD remission
in participants who underwent health checkups. The optimal cutoff
values for weight loss were a decrease of 0.9 kg/m2 in BMI or a 4%
decrease in BMI in the overall cohort, a decrease of 0.85 kg/m2 in
BMI or a 3.9% decrease in BMI in male patients, and a decrease of
1.2 kg/m2 in BMI or a 4.5% decrease in BMI for female patients. In
patients with a BMI of < 23 kg/m2, the optimal cutoff value forweight loss was a decrease of 0.75 kg/m2 in BMI or a 2.7% decreasein BMI. In patients with MASLD, the optimal cutoff value forweight loss was a decrease of 0.85 kg/m2 in BMI or a 3.5% decreasein BMI. In patients with MetALD, it was 0.75 kg/m2 in BMI or a
3.0%, respectively.

Data availability statement
The raw data supporting the conclusions of this article will bemade available by the authors, without undue reservation.

Ethics statement
The studies involving human participants were reviewed andapproved by the ethics committee of Shinjuku Tsurukame Clinic(approval no. 2,401). The studies were conducted in accordance withthe local legislation and institutional requirements. Written informed
consent for participation was not required from the participants or
the participants’ legal guardians/next of kin in accordance with thenational legislation and institutional requirements.

Author contributions
TFuku: Writing – review & editing, Writing – original draft,
Visualization, Methodology, Investigation, Formal analysis, Data
curation, Conceptualization. TO: Writing – review & editing,
Validation, Supervision. TFuka: Writing – review & editing,
Validation, Supervision. AK: Writing – review & editing, Validation,
Supervision. MT: Writing – review & editing, Validation, Supervision.
TY: Writing – review & editing, Software, Project administration,
Funding acquisition. KM: Writing – review & editing, Visualization,
Supervision, Project administration.

Funding
The author(s) declare ﬁnancial support was received for the
research, authorship, and/or publication of this article. This study
was supported by fund of Department of Molecular Endocrinology
and Metabolism, Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University.

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10.3389/fendo.2024.1392280

The remaining authors declare that the research was conductedin the absence of any commercial or ﬁnancial relationships that
could be construed as a potential conﬂict of interest.

Acknowledgments
We would like to thank Koshio Kayo and Watabe Yuko for theirassistance in collecting the health checkup data and Enago(www.enago.jp) for the English language review.

Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their afﬁliated organizations,or those of the publisher, the editors and the reviewers. Any productthat may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.

Conﬂict of interest
TY has received honoraria from Kyowa Kirin, MSD, Astra
Zeneca, Kissei Pharmaceutical, Novo nordisk pharma, Taisho
Pharmaceutical, Sumitomo pharma, and Eli Lilly Japan; researchfunding from Nippon Boehringer Ingelheim, and Mitsubishi
Tanabe Pharma, Suntory; and subsidies or donations from Ono
Pharmaceutical, and Nippon Boehringer Ingelheim.

Supplementary material
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fendo.2024.
1392280/full#supplementary-material

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