Relationship between High Serum Cadmium Level and Low Muscle Mass in Korean National Health and Nutrition Examination Survey

Received: November 8, 2016 Revised: January 19, 2017 Accepted: May 31, 2017.

Corresponding author: Yon Chul Park

Department of Family Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Korea Tel: +82-33-741-1416, Fax: +82-33-741-1780, E-mail: [email protected]

Copyright Ⓒ 2017 The Korean Academy of Clinical Geriatrics

This is an open access article distributed under the term s of the Creative Com m ons Attribution Non-Com m ercial License (http://creativecom m ons.org/ licenses/by-nc/4.0) which perm its unrestricted non-com m ercial use, distribution, and reproduction in any m edium , provided the original work is properly cited.

Relationship between High Serum Cadmium Level and Low Muscle Mass in Korean National Health and Nutrition Examination Survey

Jai Soon Kim, Tae Sic Lee, Jong-Koo Kim, Yoo Jung Hwang, Yon Chul Park

Department of Family Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea

Background: Sarcopenia is a syndrome defined as progressive loss of skeletal muscle mass, strength and function, asso- ciated with mobility disorders, increased risk of falls, loss of independence and mortality. Cadmium is a non-essential heavy metal with an accumulative polluting effect and seems to have toxicity to kidneys, lungs, and bones. The present study aimed to examine the associations between the prevalence of sarcopenia and serum cadmium levels using Korean National Health and Nutrition Examination Survey (2010) data.

Methods: The total number of study subjects was 1,938 and these included 904 males and 1,038 females aged 10 years or older. Subject were allocated to two groups; a sarcopenia group (n=636) or a normal group (n=1,302). Sarcopenia was defined as an appendicular skeletal mass to body weight ratio of one SD less than the mean ratio of a young (20∼39 years), sex specific, and reference group.

Results: Serum cadmium (Cd) levels were higher in the sarcopenia group than in the normal group [1.16 (SD, ±0.73) μg/dL in the sarcopenia group and 1.00 (SD, ±0.62) μg/dL in the normal group]. Members of the sarcopenia group had a significantly higher mean serum cadmium level (OR 1.410, 95% CI 1.408∼1.414, P=0.018). After adjusting for compounding factors, the prevalence of sarcopenia increased by 5.4% (Odd ratio=1.054, 95% confidence interval (CI)=1.051∼1.056) for every 1 μg/dL increase in Cd level.

Conclusion: Sarcopenia was associated with elevated serum cadmium in the Korean population.

Key Words: Cadmium, Sarcopenia, Skeletal muscle, Korean population

INTRODUCTION

Sarcopenia is a syndrome that involves progressive loss of skeletal muscle mass, strength, and function during the ag- ing process.

Muscle loss is associated with mobility dis- orders, increased risk of falls, reduced ability to performed daily activities, and loss of independence.

Szulc et al.

re-

ported that loss of muscle mass is a strong predictor of mortality in later life. Furthermore, sarcopenia is also related to metabolic disease, and since skeletal muscles are primary sites for glucose uptake and deposition, sarcopenia increases insulin resistance, thereby progressively increases the risks of diabetes and metabolic syndrome.

Cadmium (Cd) is a non-essential heavy metal and has cu-

mulative polluting effects. The toxic effects of Cd on fish are numerous, for example, it interrupts development and growth,

prevents Ca+2 uptake through gills, disturbs liver functions,

and causes skeletal deformations

and patho- logical changes in some tissues and organs. Heavy metals tend to accumulate specifically in metabolically active tissues and organs, such as, brain and muscle.

Some studies have shown heavy metals can decrease glycogen reserves in fish

and invertebrates

by affecting the activities of enzymes participate in carbohydrate metabolism.

The present study used Korea National Health and Nutrition Examination Survey (2010) data to examine asso- ciations between the presence of sarcopenia and serum cad- mium levels in the Korean population.

MATERIALS AND METHODS

1. Design and study population

This study was performed using data obtained during the KNHANES V study (2010), which was a cross-sectional, nationally representative survey. KNHANES adopted a roll- ing sampling design for a stratified, complex, multistage, probability cluster survey with proportional allocation based on the National Census Registry for the non-institutional ci- vilian Korean population. 3,148 populations were enrolled in this study, and 1,210 populations were excluded by fol- lowing reasons: incomplete answers about social and medical histories; not checking blood pressure, weight, height, waist circumference, and laboratory markers. Finally, the remnant number of study subjects was 1,938 and these included 904 males and 1,038 females aged 10 years or older.

2. Laboratory measurements and definition Blood samples were collected by venipuncture after 10 to 12 hours of fasting. Fasting glucose, AST, ALT, total cho- lesterol, and triglyceride levels were measured using a Hitachi automatic analyzer 7600 (Hitachi, Tokyo). Further- more, in order to measure serum GGT (dependent variable), an enzymatic activity assay (G5CMP) was performed using the Hitachi Automatic Analyzer 7600 (Hitachi, Japan).

Insulin levels were determined using a gamma counter

(1470 Wizard, Perkin Elmer) with an immunoradiometric assay using an INS-IRMA kit (Biosource, Belgium). To as- sess heavy metals in serum, 3 mL blood samples were col- lected into standard evacuated tubes containing EDTA (K2 EDTS tube, Vacutainers). Serum cadmium and lead levels were measured by graphite furnace atomic absorption spec- trometry (GF-AAS) using the Zeeman background correc- tion (PerkinElmer AAS800, PerkinElmer). Blood cadmium and lead levels were analyzed by the Neodin Medical Institute (a laboratory certified by the Korean Ministry of Health and Welfare). Serum zinc levels were analyzed with an inductively coupled plasma-mass spectrometer (ICP-MS).

All blood analyses were carried out by the Seoul Medical Science Institute (SMSI), a laboratory certified by the Korean Ministry of Health and Welfare.

3. Definitions of sarcopenia

Body composition measurements, including fat mass and appendicular skeletal muscle mass (ASM), were obtained us- ing a dual-energy X-ray absorptiometry (QDR 4500A;

Hologic, Waltham, MA). ASM (kilograms) was defined as the sum of lean soft tissue masses of arms and legs, as de- scribed by Heymsfield et al.

Sarcopenia was defined as an ASM divided by body weight (ASM/Wt) value of less than 1 SD below the sex-specific mean of a young nationally representative reference group (healthy men and women aged 20∼39 years).

For men, the cutoff value for sarcopenia was 30.65%

(ASM/Wt ×100). For women, the corresponding cutoff val- ue was 23.9%.

4. Assessment of other variables

Demographic information was obtained during a health interview. Height was measured (in centimeters) using a wall-mounted measuring scale, and weight was measured (in kilograms) using calibrated electronic scales with subjects wearing light clothing without shoes. Body mass index (BMI) was calculated as follows: weight (kg)/height (m)

.

According to the Eighth Joint National Committee

(JNC-8) guidelines, hypertension was defined as a systolic

blood pressure of at least 140 mmHg or a diastolic blood

Table 1. Demographic characteristics of the study subjects

Subjects without sarcopenia (N=1,302)

Subjects with sarcopenia

(N=636) P value

Demographics

Age, mean (±SD), year 38.04 (±17.62) 45.08 (±18.16) ＜0.001

Male, No. (%) 577 (44.3%) 327 (51.4%) ＜0.001

Height, mean (±SD), cm 163.63 (±8.98) 161.23 (±9.73) ＜0.001

Weight, mean (±SD), kg 59.56 (±11.25) 65.44 (±12.70) ＜0.001

BMI, mean (±SD), kg/m

22.14 (±3.18) 25.02 (±3.38) ＜0.001

SBP (mmHg) 115.44 (±15.96) 122.76 (±17.89) ＜0.001

DBP (mmHg) 74.53 (±10.93) 78.25 (±11.33) ＜0.001

Medical history, No. (%)

Hypertension 154 (11.8) 171 (26.9) ＜0.001

Diabetes mellitus 65 (5.0) 58 (9.1) ＜0.001

Current smoking 238 (18.3) 125 (19.7) 0.466

Regular exercise 407 (31.3) 183 (28.8) 0.264

Biological and hematologic characteristics, mean (SD)

Glucose (mg/dL) 93.76 (±18.32) 100.43 (±25.02) ＜0.001

Insulin (uIU/mL) 10.68 (±4.72) 12.24 (±6.83) ＜0.001

TC (mg/dL) 178.58 (±35.349) 192.19 (±38.26) ＜0.001

HDL (mg/dL) 54.25 (±12.27) 51.29 (±12.40) ＜0.001

TG (mg/dL) 112.91 (±97.0) 145.44 (±106.63) ＜0.001

LDL (mg/dL) 106.07 (±30.21) 117.01 (±31.90) ＜0.001

AST (IU/L) 20.56 (±9.35) 23.80 (±14.78) ＜0.001

ALT (IU/L) 18.88 (±12.93) 24.63 (±24.63) ＜0.001

rGT (IU/L) 26.94 (±37.45) 38.65 (±51.02) ＜0.001

Hg (g/dL) 4.20 (±3.07) 4.91 (±4.32) ＜0.001

Cd (g/dL) 1.00 (±0.62) 1.16 (±0.73) ＜0.001

Zn (g/dL) 136.62 (±30.07) 138.02 (±28.32) 0.33

ASM/Wt(%) 29.7 (±40.92) 25.6 (±34.95) ＜0.001

SD: standard deviation, BMI: body mass index, SBP: systolic blood pressure, DBP: diastolic blood pressure, TC: total cholesterol, HDL:

high density lipoprotein, TG: triglyceride, LDL: low density lipoprotein, AST: aspartate aminotransferase, ALT: alanine transaminase, rGT: gamma-glutamyl transpeptidase, Hg: mercury, Cd: cadmium, Zn: zinc, ASM: appendicular skeletal muscle, Wt: weight.

pressure of at least 90 mmHg, or current use of anti- hypertensive agents. Diabetes mellitus was defined as fasting serum glucose of at least 126 mg/dL or current use of blood glucose?lowering agents at baseline.

Regular exercise was defined as “yes” when a subject ex- ercised for more than 20 minutes more than three times per week. Smoking indicated a current smoking status; this in- formation was obtained after the provision of written in- formed consent. Blood pressure was measured using a sphyg- momanometer in a sitting position. Three measurements were taken at 5-minute intervals, and the average of the second and third measurements was used in the analysis.

5. Statistical analyses

Statistical analysis was performed using the Statistical

Package for the Social Sciences (SPSS ver. 20.0; IBM Corp.,

Armonk, NY, USA). The X2 test was used to compare

demographic characteristics and the Student’s T test was

used to compare continuous variables. Simple and multiple

logistic regression analyses were used to examine the associ-

ation between blood cadmium levels and sarcopenia. Data

was weighted using weightings provided by KNHANES to

reflect national distributions. All variables entered into the

logistic regression analysis were examined for multi-

collinearity, and only variables with a variance inflation fac-

tor of ＜10 were used. P values were two-tailed and values

of ＜0.05 were considered statistically significant.

Table 2. Multivariate logistic regression models of cadmium for sarcopenia.

OR 95% CI for OR P value Crude odds ratio of Cd 1.410 1.408∼1.414 ＜0.001

Model 1 1.065 1.062∼1.067 ＜0.001

Model 2 1.115 1.113∼1.117 ＜0.001

Model 3 1.054 1.051∼1.056 ＜0.001

Model 1: OR for sarcopenia adjusted by age, sex. Model 2: OR for sarcopenia adjusted by model 1+HTN, DM, regular exercise, and smoking. Model 3: OR for sarcopenia adjusted by model 2+laboratory test results, that is, fasting glucose, total chole- sterol. OR: odds ratio, CI: confidence interval, HTN: hyper- tension, DM: diabetes mellitus.

RESULTS

Of the 4,443 eligible subjects that had blood cadmium levels measured, 1,938 subjects were included in the analysis. Reasons for not having undergone analysis were as follows: Did not attend health interview or examination (n=417), and no DEXA examination (n=2,088).

The demographic characteristics of the 1938 study sub- jects are summarized in Table 1. Subjects in the sarcopenia group were older (P＜0.001) and had higher systolic and diastolic blood pressures (P＜0.001). Subject characteristics, such as, medical history, life style, and laboratory test re- sults are presented in Table 1.

The sarcopenia group had greater prevalences of hyper- tension (P＜0.001), diabetes mellitus (P＜0.001), and current smokers (P＜0.001), members of this group exercised regu- larly less often (P＜0.001). In addition, the sarcopenia group had higher mean levels of fasting glucose (P＜0.001), insulin (P＜0.001), total cholesterol (P＜0.001), LDL (P＜0.001), mercury (P＜0.001), cadmium (P＜0.001), zinc (P＜0.001).

Table 2 shows odds ratios for the association between sarcopenia and cadmium levels. This analysis included weighting to reflect national population data. The crude odds ratio of this association was 1.41 (95% CI, 1.408∼

1.414; P＜0.001). The adjusted OR for sarcopenia after ad- justing for age and sex (Model 1) was 1.065 (95% CI, 1.062∼1.067; P＜0.001). After adjusting for medical his- tory, life style (Model 2) and laboratory test (Model 3) odd ratios are each 1.115 (95% CI, 1.113∼1.117; P＜0.001)

and 1.054 (95% CI, 1.051∼1.056; P＜0.001).

DISCUSSION

The present study was the first epidemiologic study to evaluate the association between blood cadmium levels and sarcopenia. Our study shows the risk of sarcopenia is sig- nificantly higher for those with higher serum cadmium levels.

Cadmium is commonly found in oxidation state II and is mainly present as CdCl

and CdCl+ complexes in seawater.

Cadmium can readily cross biological membranes, and once inside living cells binds to ligands with high affinity to form stable Cd complexes.

For example, in fish muscle most of the Cd present tends to bind to proteins.

Cadmium is highly toxic in man and has a long biological half-life, which prevents reductions in accumulated body burdens. Its effects on health include hypertension and cardiovascular function, neurological disorders, carcinogenic effects, and skeletal weaknesses and defects.

In addition, many reports suggest it has toxic effects on fish, for example, it has been reported to interrupt development and growth,

prevent Ca

uptake through gills, disturb liver functions,

and cause skeletal deformations

and pathological changes in some tissues and organs.

Carbohydrates are stored as glycogen in fish tissues and organs, such as, muscle and liver, and supply energy needs in hypoxic conditions or when food is scarce. It has been re- ported heavy metals can create stress in fish

and that Cd decreases glycogen reserves in the American eel (Anguilla rostrata) by increasing catecholamine production in the adre- nal medulla.

Some investigators have also showed that heavy metals can decrease glycogen reserves in fish

and in- vertebrates

by affecting the activities of enzymes that par- ticipate in carbohydrate metabolism. Thus, it appears cad- mium decreases glycogen levels in muscle and induces mus- cle degradation.

Kidney disease is another pathophysiology associated with

cadmium. Several epidemiologic studies have associated en-

demic outbreaks of cadmium-induced kidney disease in Japan

with the consumption of cadmium contaminated rice.

Other studies conducted in Belgium, China, Japan, and Sweden have demonstrated associations between cadmium burden and kidney dysfunction.

In addition, cadmium causes Itai-Itai (“Ouch-Ouch”) disease, which is charac- terized by multiple fractures, a mixed pattern of osteopo- rosis and osteomalacia, and kidney damage.

One hypothesis suggests that the accumulation of cad- mium in kidney tubular cells reduces the conversion of cal- cidiol to calcitriol, which reduces calcium absorption in the gut, impairs bone mineralization, and eventually leads to os- teoporosis or osteomalacia.

Several epidemiological studies have documented a direct toxic effect of cadmium on the bone by identifying relations between cadmium exposure and lower bone mineral density in the absence of any evi- dence of renal tubular injury.

Vitamin D is known to have wide-ranging effects on muscle health as well as bone health. Girgis found that vi- tamin D deficiency was linked to muscle weakness,

and similar studies have reported that low vitamin D levels were associated with reduced muscle function and increased fall risk in the elderly.

As yet no definitive mechanism ex- plains the association between vitamin D and muscle health, but several mechanistic studies have been performed on vi- tamin D receptor (VDR), This receptor is a member of the steroid receptor transcription factor family, and is present in many organs, including kidneys, brain, GI tract, and skin and controls.

In addition, Vitamin D receptor is expressed in skeletal muscle and is a crucial mediator of 1,25(OH)2D, and thus, affects muscle contractility.

The strength of our study is that the data used were ob- tained from a nationwide, objective survey conducted in Korea. Furthermore, this is the first population based study to investigate the relationship between cadmium and sarcopenia. Nevertheless, it has several limitations.

First, because of its cross sectional design, the causal rela- tionship between cadmium and sarcopenia could not be established. Second, in this study, the definition used for sarcopenia did not include muscle strength or poor muscle function, although these components of the disease were de- scribed by the European Working Group on Sarcopenia in Older People and the European Society for Clinical

Nutrition and Metabolism special interest group.

Thus, future studies should be performed to confirm the associa- tion between cadmium and sarcopenia defined by muscle amount, function, and strength.

Summarizing, the present study is the largest pop- ulation-based study to examine the association between cad- mium and sarcopenia. It was found a high serum cadmium level was closely associated with an elevated risk of sarcopenia. The finding provides new insight of a relation between cadmium burden and muscle physiology. Further longitudinal studies based on a more sophisticated definition of sarcopenia, are needed to confirm the effect of cadmium on sarcopenia and to determine the nature of the biological mechanism responsible for this association.

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