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Original Study - Brief Report
Sarcopenia and Low Serum Albumin Level Synergistically Increase the Risk of Incident Disability in Older Adults Kazuki Uemura PT, PhD a, *, Takehiko Doi PT, PhD b, Sungchul Lee PhD b, Hiroyuki Shimada PT, PhD b a
Department of Liberal arts and sciences, Toyama Prefectural University, Imizu City, Toyama Prefecture, Japan Department of Preventive Gerontology, Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Obu City, Aichi Prefecture, Japan b
a b s t r a c t Keywords: Prospective study frailty mobility malnutrition epidemiology
Objectives: This study aimed to investigate the additive effects of sarcopenia and low serum albumin level on the risk of incident disability in older adults. Design: Prospective cohort study. Setting: A Japanese community. Participants: Community-dwelling older adults aged 65 years, without disability at baseline (N ¼ 4452). Measures: Sarcopenia was defined as the presence of both poor muscle function (low physical performance or muscle strength) and low muscle mass. Low serum albumin level was defined as 4.0 g/dL. Other potential confounding factors (demographics, medical history, depressive symptoms, and cognitive function) were also assessed. Incident disability was monitored based on Long-Term Care Insurance certification during follow-up. Results: The median follow-up duration was 30 (interquartile range, 28-32) months. Participants were classified into mutually exclusive groups based on sarcopenia status and serum albumin levels: nonsarcopenia/normal serum albumin (n ¼ 3719), low serum albumin alone (n ¼ 552), sarcopenia alone (n ¼ 132), and sarcopenia/low serum albumin (n ¼ 49). A Cox hazards regression showed that the low serum albumin alone [hazard ratios (HR) ¼ 1.71, 95% confidence interval (CI) ¼ 1.26-2.33], sarcopenia alone (HR ¼ 2.74, 95% CI ¼ 1.58-4.77), and sarcopenia/low serum albumin groups (HR ¼ 3.73, 95% CI ¼ 1.87-7.44) had higher risk of disability than the nonsarcopenia/normal serum albumin group after adjusting for the covariates. Conclusions/Implications: Sarcopenia and low serum albumin level synergistically increase the risk of incident disability in older adults. Sarcopenia in older adults at risk of malnutrition should be detected early, and appropriate interventions should be implemented. Ó 2018 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
Sarcopenia, defined as age-related loss of muscle mass and function,1 is a major clinical problem in older adults that can lead to serious health consequences, such as falls, hospitalization, functional disabilities, and all-cause mortality.2e4 Additionally, sarcopenia is recognized as a distinctly reportable disease in the 10th revision of the
The authors received grants from the Japanese Ministry of Health, Labor, and Welfare (Project for optimizing long-term care, B-3) and the National Center for Geriatrics and Gerontology (Research Funding for Longevity Sciences, 22-16). The authors declare no conflicts of interest. * Address correspondence to Kazuki Uemura, PT, PhD, Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu City, Toyama Preecture, 939-0398, Japan. E-mail address:
[email protected] (K. Uemura). https://doi.org/10.1016/j.jamda.2018.06.011 1525-8610/Ó 2018 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
International Classification of Disease (code M62.84), released in September 2016, established by the World Health Organization. Malnutrition, indicating poor nutritional status, is also a major geriatric syndrome related to survival, which is often defined as weight loss or low body mass index (BMI), or low serum albumin levels among biochemical markers.5 Although individuals with clinically abnormal serum albumin levels (3.5 g/dL) are rare in community-dwelling older adults, even relatively low serum albumin levels, defined using the higher cut-off point (4.0 g/dL), predicted the risk of subsequent functional deterioration.6 Malnutrition was known as a promoting factor for sarcopenia, including loss of muscle mass.7 Malnutrition and sarcopenia are both commonly occurring conditions in older adults. Both are core elements of frailty and accelerate the negative cycle of frailty through interactive pathways.8 Thus, if
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sarcopenia and malnutrition interactively promote physical deterioration in the frailty cycle, then the co-occurrence of sarcopenia and malnutrition in older adults may result in additive effects on the risk of disability than either condition alone. However, combination effects of these conditions on disability remain unclear. This study aimed to determine whether sarcopenia and low serum albumin level, as nutritional status indicators, synergistically enhance the risk of incident disability in community-dwelling older adults, in a longitudinal study design. Methods This study has a prospective design. The participants were enrolled in the Obu Study of Health Promotion for the Elderly (OSHPE), which is part of the National Center for Geriatrics and GerontologydStudy of Geriatric Syndromes.9 Participants aged 65 years at examination in 2011 or 2012, and who had not been certified as needing support or care by the Japanese public Long-Term Care Insurance (LTCI) system (care level 3/5), were included in the study. Recruitment was conducted through letters mailed to 14,313 older adults, and only 5104 people underwent a baseline assessment. We excluded participants based on the following criteria: (1) having a disability based on the LTCI system at baseline and (2) history of Parkinson’s disease, Alzheimer’s disease, stroke, or depression. Informed consent was obtained from all participants before enrolment in the study in accordance with the Declaration of Human Rights, Helsinki, 1975. The study was approved by the ethics committee of the National Center for Gerontology and Geriatrics. We monitored the Japanese public LTCI certification for all participants during follow-up. All Japanese individuals aged 65 years are eligible for benefits (institutional and community-based services, but not cash) in cases of physical and/or mental disability. The LTCI system certifies a person in “support level 1 or 2” because of a need for support for daily activities or “care level 1, 2, 3, 4, or 5” because of a need for continuous care. In this study, we defined incident disability as a new certification of LTCI service at any level, with data updated monthly, among participants without LTCI certification at baseline assessment. The detailed process of LTCI certification has already been introduced elsewhere.10,11 Participants were censored (follow-up stopped) when they moved out of the city or died. We defined sarcopenia using the diagnostic algorithm recommended by the Asian Working Group for Sarcopenia that assesses the presence of both low muscle mass and muscle function (low physical performance or muscle strength).1 Muscle mass parameters were evaluated using a multifrequency bioelectrical impedance analyzer (BIA) (MC-980A, Tanita, Tokyo, Japan), a tool used to assess whole- and segmental body compositions.12 The BIA instrument used six electrical frequencies (1, 5, 50, 250, 500, and 1000 kHz). Using segmental body compositions, the appendicular skeletal muscle mass was determined and used for further analysis.13 The skeletal muscle mass index was calculated by dividing the muscle mass (in kilograms) by height (in meters) squared. Gait speed was assessed at comfortable walking speed and expressed in meters per second. A cut-off point of <0.8 m/s indicated low physical performance. The grip strength of the participant’s dominant hand was measured using a portable grip strength dynamometer (GRIP-D; Takei Ltd., Niigata, Japan). Low muscle strength was defined as handgrip strength of <26 kg for men and <18 kg for women. Venous blood was collected during interviews; serum was prepared from blood samples within 24 hours. Albumin levels were measured by trained staff using an automatic analyzer (JCA-BM6070; JEOL) in a laboratory at Good Life Design, Aichi-ken, Japan. In the present study, low serum albumin level was defined based on a cut-off point of 4.0 g/dL.6
Licensed nurses interviewed the participants regarding their medical condition, including the total number of prescribed medication doses taken regularly. Global cognitive function was assessed using the Mini-Mental State Examination.14 Depressive symptoms were measured using the 15-item Geriatric Depression Scale.15 Participants were classified into mutually exclusive groups based on sarcopenia status and serum albumin levels: nonsarcopenia/ normal serum albumin (n ¼ 3719), low serum albumin alone (n ¼ 552), sarcopenia alone (n ¼ 132), and sarcopenia and low serum albumin (n ¼ 49). Baseline characteristics were compared between groups using analysis of variance for continuous variables and chisquare tests for categorical variables. Using Cox proportional hazards regression analyses, we initially estimated hazard ratios (HRs) and 95% confidence intervals (CIs) of low serum albumin alone, sarcopenia alone, and both to assess the additive effects of sarcopenia and low serum albumin level on incident disability. Participants with normal serum albumin level and no sarcopenia were categorized as the reference group. The multivariate model was adjusted for age, gender, BMI, education level, number of medications, hypertension, heart disease, diabetes mellitus, hyperlipidemia, pulmonary disease, and Mini-Mental State Examination and Geriatric Depression Scale scores. Cumulative incidence function curves were generated to illustrate the incident disability. The level of significance was .05. IBM SPSS version 25 (IBM Corp, Armonk, NY) was used to perform all statistical analyses. Results Among the 5104 participants enrolled in the OSHPE who underwent baseline assessment, 652 were excluded owing to the preexisting conditions at baseline, such as disability based on the LTCI system (n ¼ 160), Parkinson’s disease (n ¼ 14), Alzheimer’s disease (n ¼ 5), stroke (n ¼ 255), and depression (n ¼ 118). Additionally, a total of 100 participants had missing baseline data. Finally, 4452 older adults were included in the analyses. Over a median follow-up of 30 (interquartile range, 28-32) months, 5.3% (n ¼ 235) experienced disability, with an overall incidence rate of 21.7 per 1000 person-years. Participants with an event, who moved to another city (n ¼ 29) or died (n ¼ 51), were considered as censored cases. Demographics and clinical characteristics of the 4 groups are presented in Table 1. Incident disability rates of the 4 groups based on the combination of sarcopenia and low albumin level were 15.7 (n ¼ 143), 47.1 (n ¼ 60), 65.2 (n ¼ 20), and 115.4 per 1000 person-years (n ¼ 12) in nonsarcopenia/normal serum albumin, low serum albumin alone, sarcopenia alone, and sarcopenia/low serum albumin groups, respectively (Figure 1). Results of Cox regression analysis using the 4 groups are shown in Table 2. A crude model showed that each group had significant relationship to incident disability relative to nonsarcopenia/ normal serum albumin (low serum albumin alone, HR ¼ 3.01, 95% CI ¼ 2.22-4.07; sarcopenia alone, HR ¼ 4.20, 95% CI ¼ 2.62-6.70; and sarcopenia/low serum albumin, HR ¼ 7.46, 95% CI ¼ 4.14-13.4). The adjusted models also suggest significantly higher incident disability rate in low serum albumin alone (HR ¼ 1.71, 95% CI ¼ 1.26-2.33) and sarcopenia alone groups (HR ¼ 2.74, 95% CI ¼ 1.58-4.77) than those of nonsarcopenia/normal serum albumin group. The rate was 3 times higher in the sarcopenia/low serum albumin group (HR ¼ 3.73, 95% CI ¼ 1.87-7.44) after adjusting for age, gender, BMI, educational level, Mini-Mental State Examination and Geriatric Depression Scale scores, number of medication, hypertension, heart disease, diabetes mellitus, hyperlipidemia, and pulmonary disease. Discussion Sarcopenia and low serum albumin level independently and synergistically increase the risk of incident disability. This is the first
K. Uemura et al. / JAMDA xxx (2018) 1e4
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Table 1 Demographics and Clinical Characteristics of Participants at Baseline Variables
All Participants (n ¼ 4452)
Nonsarcopenia/Normal Serum Albumin (n ¼ 3719)
Low Serum Albumin Alone (n ¼ 552)
Sarcopenia Alone (n ¼ 132)
Sarcopenia/Low Serum Albumin (n ¼ 49)
P Value
Age, y Gender, male BMI Education, y MMSE, points GDS, points Medications, n Chronic disease Hypertension Heart disease Diabetes mellitus Hyperlipidemia Pulmonary disease
71.9 5.4 2178 (48.9) 23.4 3.1 11.4 2.5 26.3 2.7 2.7 2.5 1.9 2.0
71.3 5.1 1789 (48.1) 23.6 3.0 11.5 2.5 26.4 2.6 2.6 2.4 1.9 2.0
74.4 6.0 290 (52.5) 23.5 3.3 11.0 2.6 25.3 3.3 3.2 2.7 2.1 2.2
75.1 6.9 63 (47.7) 19.0 1.8 11.0 2.6 25.7 2.8 3.7 2.8 1.6 2.0
77.7 7.5 36 (73.4) 18.9 1.9 10.2 2.6 24.8 3.8 4.5 3.3 2.0 2.1
<.001 .001a <.001 <.001 <.001 <.001 .008
2014 696 582 1800 490
1714 572 477 1584 387
243 103 84 167 76
42 17 13 38 17
15 4 8 11 10
.002a .077a .25a <.001a .014a
(45.2) (15.6) (13.1) (40.4) (11.0)
(46.1) (15.4) (12.8) (42.6) (10.4)
(44.0) (18.7) (15.2) (30.3) (13.8)
(32.2) (12.9) (9.8) (28.8) (12.9)
(30.6) (8.2) (16.3) (22.4) (20.4)
GDS, Geriatric Depression Scale; MMSE, Mini-Mental State Examination. Note: Values are mean SD or n (%). P values were generated from analysis of variance or chi-square (denoted by letter a).
prospective study to clarify the combined effects of sarcopenia and low serum albumin level on incident disability, which was nearly double for those with either of them alone after adjusting for demographics, global cognition, depressive symptoms, and medical conditions. Sarcopenia2e4,16,17 and malnutrition (low BMI or serum albumin levels)6,18,19 are significantly associated with the risk of functional deterioration in older adults. The findings in this study basically correspond to the existing literature; however, further evidence on the co-occurrence of sarcopenia and low serum albumin level should be identified. A plausible mechanism of the results is that co-occurring sarcopenia and poor nutritional status form a vicious cycle of physical frailty, which is related to the proposed clinical syndrome, malnutrition-sarcopenia syndrome.20 Previous studies suggested that low serum albumin level is associated with risk of reduced muscle mass, muscle strength, and gait speed in older adults.7,21,22 Therefore, muscle mass and/or function (strength and performance) may deteriorate as a result of degradation of protein synthesis caused by
Fig. 1. Cumulative incidence function curve among participants with vs without sarcopenia and low serum albumin level (4.0 g/dL). Sarcopenia was defined as the presence of both poor muscle function and low muscle mass.
malnutrition. Meanwhile, a decrease of metabolically active cell mass and muscle weakness due to sarcopenia result in reduced resting metabolic rate and amounts of physical activity. Physical activity gets progressively more difficult, and its habitual level deterioration further resulted from body composition changes. Finally, reduced physical activity and resting metabolic rate may lead to energy input and output dysregulation, causing malnutrition that may potentially further exacerbate sarcopenia status.23 In line with this hypothetical pathway, our finding indicates obvious additive effects of sarcopenia and low serum albumin levels. This study suggests that older adults with sarcopenia and malnutrition should be identified early and targeted, so that further functional deterioration and other adverse health outcomes can be prevented. Exercise and targeted nutritional interventions (eg, increased protein and vitamin D intakes) have been recognized as strategies to attenuate and even reverse age-dependent loss of muscle mass and function.24e26 Furthermore, combining exercise and nutritional supplementation is considered as a potential remedy that provides greater benefits than utilizing either intervention alone in patients with sarcopenia,27 frailty,28 and mobility limitation.29 Because older adults with sarcopenia and low serum albumin levels are supposed to be highly at risk of further muscle deterioration, combination of exercise and nutritional support should be prescribed to prevent poor health outcomes. The major strengths of this study include the large sample size, comprehensive nature of assessment, prospective study design, and an objective and mandatory assessment of incident disability based on the Japanese public LTCI certification. However, this study had several limitations: the 30-month follow-up was relatively shorter than those in previous studies.3,4,6,16 Additionally, the transition of sarcopenia and nutritional status was not monitored during followup, which would have been more beneficial to elucidate their longitudinal roles in the aging process. Future studies should provide a longer follow-up period for incident disability and investigate the effects of sarcopenia and serum albumin level trajectories over time. In conclusion, we revealed the distinct and synergistic effects of sarcopenia and low serum albumin level on the risk of incident disability among community-dwelling older adults in a longitudinal study design. Major findings of the study are that older adults with both sarcopenia and low serum albumin level showed a higher risk of disability than those with either of them alone after adjusting the confounding factors. To manage and prevent sarcopenia in older adults, nutritional assessment and interventions should be
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Table 2 HRs and CIs for Incident Disability Among Participants With vs Without Sarcopenia and Low Serum Albumin Levels
Nonsarcopenia/normal serum albumin Low serum albumin alone Sarcopenia alone Sarcopenia/low serum albumin
At Risk
Cases
n
n
3719 552 132 49
143 60 20 12
Rate per 1000 Person-Years
15.7 47.1 65.2 115.4
Crude Model
Adjusted Model*
HR (95% CI)
HR (95% CI)
Reference 3.01 (2.22-4.07) 4.20 (2.62-6.70) 7.46 (4.14-13.4)
Reference 1.71 (1.26-2.33) 2.74 (1.58-4.77) 3.73 (1.87-7.44)
*Adjusted model: adjusted for age, gender, BMI, education level, Mini-Mental State Examination and Geriatric Depression Scale scores, number of medications, hypertension, heart disease, diabetes mellitus, hyperlipidemia, and pulmonary disease.
implemented to maintain functional independence and extend healthy life span expectancy. Acknowledgments We thank the Obu City office for helping us with the recruitment of participants. References 1. Chen LK, Liu LK, Woo J, et al. Sarcopenia in Asia: Consensus report of the Asian Working group for sarcopenia. J Am Med Dir Assoc 2014;15:95e101. 2. Phillips A, Strobl R, Vogt S, et al. Sarcopenia is associated with disability statusdresults from the KORA-Age study. Osteoporos Int 2017;28:2069e2079. 3. Janssen I. Influence of sarcopenia on the development of physical disability: The Cardiovascular Health Study. J Am Geriatr Soc 2006;54:56e62. 4. Tang TC, Hwang AC, Liu LK, et al. FNIH-defined sarcopenia predicts adverse outcomes among community-dwelling older people in Taiwan: Results from I-Lan Longitudinal Aging Study. J Gerontol A Biol Sci Med Sci 2018;73:828e834. 5. Kane RL, Shamliyan T, Talley K, et al. The association between geriatric syndromes and survival. J Am Geriatr Soc 2012;60:896e904. 6. Okamura T, Hayakawa T, Hozawa A, et al. Lower levels of serum albumin and total cholesterol associated with decline in activities of daily living and excess mortality in a 12-year cohort study of elderly Japanese. J Am Geriatr Soc 2008; 56:529e535. 7. Kim H, Suzuki T, Kim M, et al. Incidence and predictors of sarcopenia onset in community-dwelling elderly Japanese women: 4-year follow-up study. J Am Med Dir Assoc 2015;16:85e81e85e88. 8. Xue QL, Bandeen-Roche K, Varadhan R, et al. Initial manifestations of frailty criteria and the development of frailty phenotype in the Women’s Health and Aging Study II. J Gerontol A Biol Sci Med Sci 2008;63:984e990. 9. Shimada H, Makizako H, Lee S, et al. Impact of cognitive frailty on daily activities in older persons. J Nutr Health Aging 2016;20:729e735. 10. Tsutsui T, Muramatsu N. Care-needs certification in the long-term care insurance system of Japan. J Am Geriatr Soc 2005;53:522e527. 11. Tsutsui T, Muramatsu N. Japan’s universal long-term care system reform of 2005: Containing costs and realizing a vision. J Am Geriatr Soc 2007;55:1458e1463. 12. Yoshida D, Suzuki T, Shimada H, et al. Using two different algorithms to determine the prevalence of sarcopenia. Geriatr Gerontol Int 2014;14:46e51. 13. Yoshida D, Shimada H, Park H, et al. Development of an equation for estimating appendicular skeletal muscle mass in Japanese older adults using bioelectrical impedance analysis. Geriatr Gerontol Int 2014;14:851e857. 14. Folstein MF, Folstein SE, McHugh PR. “Mini-Mental State”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12:189e198.
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