Shimizu et al.
Journal of Physiological Anthropology(2023) 42:21
https://doi.org/10.1186/s40101-023-00338-z

ORIGINAL ARTICLE

Journal of
Physiological Anthropology

Open Access

Association between serum albumin
levels and height loss in Japanese workers:a retrospective study
Yuji Shimizu1* , Hidenobu Hayakawa2, Eiko Honda1, Nagisa Sasaki1, Midori Takada1, Takeo Okada2,
Tetsuya Ohira3 and Masahiko Kiyama2

Abstract
Background Height loss starting in middle age was previously shown to be associated with high cardiovascularmortality in later life. However, the factors associated with height loss remain unknown. Since low serum albumin
levels are reported to be associated with high mortality caused by cardiovascular disease, they may also contributeto height loss.
Methods To clarify the association between serum albumin and height loss, we conducted a retrospective studyof 7637 Japanese workers who participated in general health check-ups from 2008 to 2019. Height loss was definedas the highest quartile of height loss per year.
Results Individual with high serum concentration of albumin possess beneficial influence on preventing incidenceof height loss. In both men and women, serum albumin level was significantly inversely associated with height loss.
After adjustment for known cardiovascular risk factors, the adjusted odd ratio (OR) and 95% confidence interval(CI) for height loss per 1 standard deviation of albumin (0.2 g/dL for both men and women) were 0.92 (0.86, 0.98)
in men and 0.86 (0.79, 0.95) in women. Even when the analysis was limited to participants without hypoalbuminemia,
essentially same association was observed, with fully adjusted corresponding ORs (95%CI) of 0.92 (0.86, 0.98) in men
and 0.86 (0.78, 0.94) in women.
Conclusion Independent of known cardiovascular risk factors, higher serum albumin levels may prevent height loss
among Japanese workers. While several different diseases cause hypoalbuminemia, they may not be the main reasonsfor the association between serum albumin and height loss. Though further research is necessary, this finding mayhelp clarify the mechanisms underlying the association between height loss and higher mortality in later life.
Keywords Albumin, Height loss, Workers, Retrospective*Correspondence:
Yuji Shimizu
shimizu@osaka-ganjun.jp
1
Epidemiology Section, Division of Public Health, Osaka Instituteof Public Health, Osaka, Japan2
Department of Cardiovascular Disease Prevention, Osaka Centerfor Cancer and Cardiovascular Diseases Prevention, Osaka, Japan3
Department of Epidemiology, Fukushima Medical University Schoolof Medicine, Fukushima, Japan

Introduction
Height loss starting in middle age was previously shown
to be associated with high cardiovascular mortality inlater life [1]. Intervertebral disc degeneration, which is
associated with narrowing of the intervertebral spaces,and vertebral fracture are both well-known causes ofheight loss in adults. Since low serum albumin levels
were shown to be associated with high mortality [2],including that due to cardiovascular diseases [3], they

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
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Shimizu et al. Journal of Physiological Anthropology(2023) 42:21

may also correlate with height loss, although no studies
thus far have reported this connection.
Serum albumin is synthesized in the liver and it
accounts for the majority of total serum proteins. Serum
albumin helps maintain colloid osmotic pressure andfacilitates the transportation of many substances such as
bilirubin, uric acids, free fatty acids, electrolytes, thyroxine, and numerous drugs. A variety of health conditions
influence serum albumin levels, and therefore among
workers who are relatively healthy, these levels may act asa marker of general health even though they cannot indicate the presence of specific diseases.
Short stature in adulthood was reported to be positively associated with cardiovascular disease [4, 5], andthe incidence of cardiovascular disease was positively
correlated with low serum albumin levels [6]. Known
cardiovascular risk factors could act as confounding factors in the association between serum albumin levels andadult height loss in the general population.
To clarify the association between serum albumin levels and adult height loss, we conducted a retrospective
study with a median follow-up duration of 3.1 years in
7637 Japanese workers who participated in general healthcheck-ups at least twice between 2008 and 2019.

Methods
Study population

In 2008, the Ministry of Health, Labor, and Welfare ofJapan started a program involving medical examinations specifically aimed at cardiovascular disease prevention. Height was measured at least twice duringfollow-up (2008–2019) to calculate height loss. The initial population in this study comprised 15,435 workers
aged 40–74 years who participated in these examinations
between 2008 and 2018 (baseline) at the Osaka Center for
Cancer and Cardiovascular Diseases Prevention, whose
Ethics Committee approved this study (Project registration code: R4-Rinri-4).
Subjects without data on drinking status (n = 57), totalcholesterol (TC) (n = 1179), hemoglobin A1c (HbA1c)(n = 20), or albumin (n = 3789) at baseline were excluded
from the analysis. Subjects without a height measurementfrom 2009 to 2019 (endpoint) were also excluded from theanalysis (n = 2753). The remaining 7637 subjects, with amean age of 50.5 years (standard deviation [SD], 8.1 years;
range, 40–74 years), were included in the study.
Data collection and laboratory measurements
Baseline data

The baseline period of the present study was 2008–2018.
Trained interviewers acquired medication histories anddata on smoking and drinking habits. Briefly, subjects
wore stockings and light clothing during measurements

Page 2 of 7

of height and weight, respectively. Body mass index(BMI) was calculated as weight divided by height (kg/m2). Resting blood pressure was measured twice. Mean
blood pressure data were used in the analysis.
Fasting blood samples were collected. Hemoglobin(Hb), TC, triglycerides (TG), high-density lipoproteincholesterol (HDLc), HbA1c, and serum creatinine were
measured using the standard procedures at the Osaka
Center for Cancer and Cardiovascular Diseases Prevention. Low-density lipoprotein cholesterol (LDLc) was
calculated using the Friedewald formula: LDLc = TC(HDLc/5) mg/dL.
Between 2008 and 2012, HbA1c values were measured using the Japanese Diabetes Society (JDS) definition. Starting in 2013, HbA1c values were measured using
the National Glycohemoglobin Standardization Program(NGSP) definition. The following equation, which wasrecently proposed by a JDS working group, was used to convert these values: HbA1c(NGSP) = HbA1c(JDS) + 0.4% [7].
The World Health Organization (WHO) guidelines
state that in Asians, a high BMI is defined as ≥ 25 kg/m2[8], and we adopted this definition.
The estimated glomerular filtration rate (eGFR; mL/
min/1.73 ­m2) was calculated using an established equation modified recently by a working group of the Japanese Chronic Kidney Disease Initiative [9], as follows:
194 × (serum creatinine (enzyme method))−1.094 × (age)−0.287(× 0.739 for women). Chronic kidney disease wasdefined as eGFR < 60 mL/min/1.73 ­m2.
Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg,
or use of anti-hypertensive medication. Dyslipidemia
was defined as TG ≥ 150 mg/dL, LDLc ≥ 140 mg/dL,
HDLc < 40 mg/dL, or use of lipid-lowering medication.
Diabetes was defined as HbA1c (NGSP) ≥ 6.5% or use of
glucose-lowering medication.
Endpoint data

Height was measured during the endpoint period (2009–2019). A participant was considered to have height loss
if he or she was in the highest quartile of height loss per
year, as in a previous study [10].
Statistical analysis

Sex-specific characteristics of the study participants wereanalyzed according to tertiles of serum albumin levels.
Age is expressed as mean ± SD. Daily drinking, current
smoker status, hypertension, high BMI, dyslipidemia,
diabetes, and chronic kidney disease are presented aspercentages.
Logistic regression was used to calculate odd ratios(ORs) and 95% confidence intervals (CIs) to determineShimizu et al. Journal of Physiological Anthropology(2023) 42:21

associations between serum albumin and other variables. Two adjustment models were used. The firstadjusted only for age (age-adjusted model). The second
Table 1 Subject characteristics
Albumin tertile levelspPage 3 of 7

(multivariable model) also included established parameters of cardiovascular risk that are known to be confounding factors, specifically drinking status (none, often,
daily), smoking status (never, former, current), hypertension (no versus yes), high BMI (no versus yes), diabetes(no versus yes), dyslipidemia (no versus yes), and chronic
kidney disease (no versus yes).
All statistical analyses were performed with SAS for
Windows (version 9.4; SAS Inc., Cary, NC, USA); p values of < 0.05 were regarded as statistically significant.

T1 (Low)

T2 (Middle)

T3 (High)

No. at risk

1869

1712

1423

Age, years

53.5 ± 7.9

50.5 ± 8.1

48.5 ± 8.0< 0.001

Results

Daily drinker, %

25.3

23.6

22.6

0.185

Subject characteristics by albumin level

Current smoker, %

36.8

32.7

28.7

0.015

Hypertension, %

44.6

33.4

31.4

< 0.001

High BMI, %

31.6

34.2

36.4

0.015

Dyslipidemia, %

47.9

52.9

59.0

< 0.001

Diabetes, %

8.5

6.8

9.1

0.049

CKD, %

11.8

10.2

10.2

0.191

No. at risk

716

957

960

Age, years

49.8 ± 8.0

49.2 ± 7.4

49.5 ± 7.9

0.301

Daily drinker, %

10.2

9.2

11.6

0.233

Current smoker, %

11.7

10.4

10.3

0.606

Hypertension, %

19.8

17.1

16.7

0.208

High BMI, %

18.4

14.2

13.2

0.009

Dyslipidemia, %

32.8

32.7

38.5

0.011

Diabetes, %

2.0

2.0

1.9

0.984

CKD, %

11.9

12.7

14.3

0.331

Men

Women

BMI body mass index, CKD chronic kidney disease. Age: mean ± standard
deviation. Albumin tertile levels for men were < 4.5 g/dL for T1 (low), 4.5–4.6 g/
dL or T2 (middle), and ≥ 4.7 g/dL for T3 (high), and for women the corresponding
values were < 4.4 g/dL, 4.4–4.5 g/dL, and ≥ 4.6 g/dL

Table 1 shows the characteristics of the study population
stratified by tertiles of albumin levels. In men, the albumin level was significantly positively associated with highBMI and dyslipidemia, and inversely associated with age,current smoking status, and hypertension. In women, thealbumin level was positively associated with dyslipidemia
and inversely associated with high BMI.
Association between height loss and serum albumin level

In both men and women, the serum albumin level
was significantly inversely associated with height loss
(Table 2). These associations were unchanged even after
further adjustment for known cardiovascular risk factors.
The fully adjusted ORs and 95% CIs for height loss per
SD increment of serum albumin (0.2 g/dL for both men
and women) were 0.92 (0.86, 0.98) in men and 0.86 (0.79,0.95) in women. To avoid the influence of hypoalbuminemia (< 3.8 g/dL) [11], the association between heightloss and serum albumin among participants without

Table 2 Odds ratios (OR) and 95% confidence intervals (CI) for height loss in relation to albumin level
Albumin tertile levels
T1 (Low)p
T2 (Middle)

T3 (High)

1-SD
increment ofalbuminMen
No. of participants
No. of participants
with height loss (percentage)

1869

1712

1423

525 (28.1)

415 (24.2)

310 (21.8)

Age-adjusted ORs

Reference

0.91 (0.78, 1.06)

0.84 (0.72, 0.998)

0.043

0.92 (0.86, 0.98)

Multivariable ORs

Reference

0.91 (0.78, 1.06)

0.85 (0.72, 1.01)

0.052

0.92 (0.86, 0.98)

Women
No. of participants
No. of participants
with height loss (percentage)

716

957

960

209 (29.2)

233 (24.3)

216 (22.5)

Age-adjusted ORs

Reference

0.80 (0.64, 1.00)

0.71 (0.57, 0.89)

0.003

0.86 (0.79, 0.94)

Multivariable ORs

Reference

0.81 (0.65, 1.02)

0.71 (0.57, 0.89)

0.003

0.86 (0.79, 0.95)

Multivariable ORs: further adjusted for age, drinking status, smoking status, high BMI, hypertension, diabetes, dyslipidemia, and chronic kidney disease. Height loss:
the highest quartile of height loss per year. Albumin tertile levels for men were < 4.5 g/dL for T1 (low), 4.5–4.6 g/dL or T2 (middle), and ≥ 4.7 g/dL for T3 (High), and for
women the corresponding values were < 4.4 g/dL, 4.4–4.5 g/dL, and ≥ 4.6 g/dL. The 1-standard deviation increment of albumin was 0.2 g/dL in both men and womenShimizu et al. Journal of Physiological Anthropology(2023) 42:21

hypoalbuminemia was also evaluated and was found tobe essentially the same, with fully adjusted corresponding
ORs (95%CIs) of 0.92 (0.86, 0.98) in men (n = 4993) and
0.86 (0.78, 0.94) in women (n = 2631).
Sensitivity analysis

To assess sensitivity, we again analyzed the association
between serum albumin and height loss, this time withheight loss defined as the highest tertile of height loss per
year rather than the highest quartile. We obtained essentially the same results. In the multivariable model, theORs for height loss were 0.93 (0.87, 0.99) in men and 0.89
(0.82, 0.97) in women.

Discussion
The major finding of the present study is that in bothmale and female Japanese workers in the general population, serum albumin was significantly inversely associated with height loss.
A previous study in European men reported a modest impact of several factors, including serum albumin,on the association between marked height loss andincreased risk of all-cause mortality [12].
This is unsurprising, since height loss beginning in
middle age was previously found to be associated withhigh subsequent mortality due to cardiovascular disease[1], and low serum albumin levels were reported to be
associated with high mortality due to cardiovascular disease [3]. However, the mechanism underlying the association between albumin level and height loss has not yet
been clarified.
When we limited our analysis to participants without hypoalbuminemia, we observed essentially the same
association between serum albumin and height loss asthat seen in the full sample. Therefore, although several
different diseases cause hypoalbuminemia, such as cirrhosis, malnutrition, nephrotic syndrome, and sepsis[13], these conditions may not have been the main explanation for the association between serum albumin andheight loss observed in this study. If these diseases dostrongly influence this association, their impact was eliminated when the analysis was performed among those
without hypoalbuminemia.
In the present study, current smoking was inversely
associated with serum albumin in men but not in women.
Further, the prevalence of high BMI was positively associated with serum albumin in men but inversely associatedwith serum albumin in women. Since a significant inverse
association between serum albumin and height loss wasobserved in both men and women, current smoking andhigh BMI are also not the primary explanation for thisassociation.

Page 4 of 7

Disc degeneration and osteoporosis may be responsible since the major causes of height loss in adults are discdegeneration (which causes intervertebral narrowing)
and vertebral fracture (which is strongly associated withosteoporosis).
Inflammation is a known contributor to both intervertebral disc degeneration [14] and osteoporosis [15]. Sincechronic inflammation can cause hypoalbuminemia [16],it might also underlie the inverse association between
serum albumin and height loss. Smoking is a known
cause of low-grade chronic inflammation. In the present
study, current smoking was significantly inversely associated with serum albumin in men but not in women. The
inverse association in men may be due to chronic inflammation leading to reduced serum albumin levels.
There are strong connections between hypoxia, oxidative stress, and inflammation [17]. Hypoxic conditions
favor the increase of reactive oxygen species and oxidative stress [17]. Hypoxia plays a key role in the regulationof immunity and inflammation [18]. Specific diseases that
relate to hypoalbuminemia may not have the main explanation for the association between serum albumin andheight loss. Therefore, physical condition which relates
to normal process of aging that is shown in Fig. 1 might
took important role on present results. Aging is the process that often accompanied by hypoxia, oxidative stress,and chronic inflammation [19]. While angiogenesis contributes to inflammation [20], it also strongly contributes to reducing hypoxia and oxidative stress [21, 22].
Angiogenesis may have played an important role in thepresent results. It is reportedly positively associated withintervertebral disc degeneration [23, 24] and osteoporosis[25, 26]. However, angiogenesis per se might not be a risk
factor for height loss, but oxidative stress and hypoxia
that causes progression of angiogenesis might act as
an independent risk factor both for intervertebral disk
degeneration and osteoporosis. The development of angiogenesis should have a beneficial influence on preventing height loss by reducing oxidative stress and hypoxia.
Serum albumin strongly influences stem cell migration[27], which is known to contribute to angiogenesis [28].
Therefore, lower albumin levels could be associated withlower angiogenesis activity due to inhibition of stem
cell migration. In fact, angiogenesis inhibitor therapies
might be associated with an increased incidence of cardiovascular disease [29], which was previously shown tobe the case with low serum albumin levels [6]. In addition, independent of known cardiovascular risk factors, aprevious study of 363 men aged 60 to 69 years revealed
a significant inverse association between the number of circulating CD34-positive cells and height loss,
defined as the highest quartile of height loss per year [10](Fig. 1d). Since CD34-positive cells play a primary role inShimizu et al. Journal of Physiological Anthropology(2023) 42:21

Page 5 of 7

Fig. 1 Potential mechanism underlying the association between serum albumin and height loss. Associations shown in red [a-d] were observedin the previous studies. Red arrow indicates "stimulate". Blue arrow indicates "inhibit"

the development of angiogenesis [30], a shortage of circulating these cells could result in reduced angiogenesis
capacity and thereby increase the risk of height loss.
In addition, hypertension is induced by angiogenesis
inhibitors [31], and its risk is increased by insufficientnumbers of circulating CD34-positive cells [21, 22].
These facts are consistent with a previous study showingthat the risk of height loss was increased by hypertension[32] (Fig. 1c) and by lower angiogenesis activity. The present study demonstrated a significant inverse association
between hypertension and serum albumin in men, andeven though the statistical difference did not reach significance, the inverse relationship between these two wasalso observed in women. Therefore, serum albumin may
reflect angiogenesis activity which in turn may prevent
hypertension [33, 34].
Furthermore, chronic inflammation is also positively
associated with both hypertension [35] and hypoalbuminemia [16]. Chronic inflammation stimulates the
progression of angiogenesis [20]. However, to reducehigh levels of oxidative stress, increased angiogenesis
is required. This may explain the presence of angiogenesis in vertebral disc degeneration [23, 24] and osteoporosis [25, 26]. Then, development of angiogenesis inthese diseases might indicate the presence of insufficientangiogenesis. Further, the degree of angiogenesis may beinsufficient to reduce oxidative stress occurring at very
high levels.
Given that albumin acts as an antioxidant [36], it is possible that antioxidants play an important role in the association between serum albumin and height loss. Hypoxia
is known to cause increased oxidative stress [17].
Increased hemoglobin levels help reduce oxidative stressby increasing oxygen supply. Therefore, serum albumin

and hemoglobin could act together as antioxidants andas markers of general vascular health. This is partly supported by a previous study in which low levels of albumin
and hemoglobin were potentially useful risk markers ofphysical functional decline in older adults [37]. Our previous study in Japanese workers showed that hemoglobin
exerted a preventive effect on height loss [38] (Fig. 1a).
However, hemoglobin was also reported to be positively
associated with hypertension [39] (Fig. 1b), which is aknown risk factor for height loss [32]. These studies indicate that high oxidative stress might be a common characteristic of physical conditions in which hematopoiesis
is induced, since hematopoiesis might help reduce oxidative stress [40]. To clarify the mechanisms involved,
further studies should investigate the combined roles ofinflammation, oxidative stress, angiogenesis activity, andantioxidant activity.
This is the first study to report an independent and significant inverse association between serum albumin levels and height loss in Japanese workers. Since height loss
starting in middle age may be a marker of high mortality
in later life [1], the present findings may serve as a noveland effective means of estimating mortality risk.
Potential limitations of this study warrant consideration. First, in adults, height loss can be caused by vertebral fractures associated with osteoporosis and byintervertebral disc degeneration. We did not have data on
these conditions so further research is necessary. Second,an accurate cutoff point to define height loss has not been
established. In the present study, we used the highest
quartile of height loss per year. However, our sensitivity
analysis that used tertiles of height loss per year yielded
essentially the same results. Chronic inflammation,
angiogenesis activity, and antioxidant activity may have

Shimizu et al. Journal of Physiological Anthropology(2023) 42:21

contributed to the present results, but we had no data on
any of these. Analyses of these topics in addition to otherendocrine [41, 42] and genetic factors [43, 44] are necessary to clarify the mechanisms underlying the association
between serum albumin and height loss.

Page 6 of 7

Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 7 February 2023 Accepted: 4 September 2023

Conclusion
In conclusion, serum albumin was significantly inversely
associated with height loss in both male and female Japanese workers. Since height loss has been reported to be
associated with high mortality, these findings may help
estimate mortality risk.
AbbreviationsTC	Total cholesterol
HbA1c	Hemoglobin A1c
SD	Standard deviation
BMI	Body mass index
Hb	Hemoglobin
TG	Triglycerides
HDLc	High-density lipoprotein cholesterol
LDLc	Low-density lipoprotein cholesterol
JDS	Japanese Diabetes Society
NGSP	National Glycohemoglobin Standardization ProgramWHO	World Health OrganizationORs	Odd ratios
CIs	Confidence intervals
Acknowledgements
None
Authors’ contributions
The authors contributed to study in the following manner: study design (YS);
analysis (YS, HH, EH, NS); drafting manuscript (YS); interpretation (YS, HH)
statistical review (YS, MT, TaO, TeO, MK); revision to manuscript (all authors). All
authors read and approved the final manuscript.
Funding
This study was supported by The Japan Agency for Medical Research andDevelopment [22rea522104h0001]. The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of themanuscript.
Availability of data and materials
The datasets generated and/or analyzed during the current study are notpublicly available due to ethical considerations. Qualified researchers may
apply for access a minimal dataset by contacting Dr. Masahiko Kiyama,
General Coordinator, at kiyama@osaka-ganjun.jp or data management staff at
kenkyu_gyomu@osaka-ganjun.jp. Information regarding data requests is alsoavailable at http://​www.​osaka-​ganjun.​jp (accessed on 20 July 2022).

Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki, andapproved by the ethics committee of Osaka Center for Cancer and Cardiovascular Diseases Prevention (Project registration code: R4-Rinri-4). To obtainconsent on this study, opt-out method was performed by using the poster
description (posted inside the facility of Osaka Center for Cancer and Cardiovascular Diseases Prevention) and institutional website later. Participants had
the option to opt out of the study after viewing study information shared
via poster (posted inside the facility) and institutional website. This website isavailable at: www.​osaka-​ganjun.​jp/​effort/​cvd/r-​and-d/ (accessed on 20 July2022).

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