力弱症對老年健康影響之探究

Dynapenia, a Worse Clinical Condition than Sarcopenia in the Elderly

高東煒(Tung-Wei Kao)

指導教授 ： 陳祈玲 ； 楊偉勛

國立臺灣大學/醫學院/臨床醫學研究所/博士(2022年)

https://doi.org/10.6342/NTU202200474

摘要

背景: 近二十年來的老年相關研究多著墨於衰弱症與肌少症，但力弱症對老年健康之影響，相關文獻並不多。肌少症族群易造成臨床上不良預後，已有相當多的文獻報告，如跌倒、住院、失能，甚至死亡等。肌肉量下降的同時，脂肪量也會上升，連帶造成肌力不足，但老化過程中，此三者之先後順序，與交互影響，仍有待進一步釐清。
2010年歐洲肌少症工作小組制定了操作型定義，2014年亞洲肌少症工作小組也發表了適合亞洲老人的共識，原則上都是測量肌肉量、握力、行走速度三項指標。然而到了2018年歐洲肌少症共識做出修訂，提出“可能肌少症”的概念，2019年亞洲肌少症工作小組也做出修正，同樣出現“可能肌少症”這個名詞。因此肌肉功能的重要性逐漸受到重視，然而針對這群“可能肌少症”的老年人，兩個工作小組僅僅呼籲可能要有介入措施；是否要更積極做進一步測量評估、追蹤預後甚至預防進展為肌少症方面，兩個工作小組都沒有明確的指引。這群“可能肌少症”的老年人，事實上應可歸類為肌肉量正常，但肌肉功能下降的族群，即所謂“力弱症”。肌肉功能的衰退，對臨床預後的影響，在近年來的研究，其重要性已逐漸超越肌肉量的下降。在此老化的同時，肌肉與脂肪量的消長，其身體組成的改變、以及臨床預後等表現，力弱症是否與肌少症存在著顯著差異，應有長期性的追蹤研究。
方法: 以前瞻性之研究設計為主軸，收案條件為65 歲(含)以上居住於社區的老年人；能用文字或語言與研究者溝通；能配合相關檢測者。以北部醫學中心年度老人健檢，同時間也從門診，以65 歲以上老年人為收案對象。排除條件為認知功能障礙者、最近運動時會胸痛、心絞痛或關節疼痛者；有鬱血性心衰竭者；醫生建議不宜運動者。癌症病患目前正接受藥物或放射治療者。人口學資料：年齡、性別、身高體重、身體質量指數、腰圍等；生活型態：飲酒、抽菸等；健康狀況:自覺健康狀況、慢性疾病、規則使用中的藥物、日常生活功能最近一年內有無跌倒等。身體活動程度包含測試握力表現、行走六公尺所需時間之測量。身體肌肉量及脂肪量之測量，以八點電極生物電阻抗分析儀獲得四肢肌肉量，並對身高平方做校正而得到四肢肌肉量指數。
以2019亞洲肌少症工作小組之共識做為肌少症之判定標準；將肌少症判定標準依據肌肉質量、握力與行走速度做區分，肌肉量減少但握力及行走速度正常則為肌少症前期，肌肉量減少合併握力降低或者行走速度變慢則為肌少症；肌肉量正常，但握力差或走路慢或兩者皆下降者，則為力弱症。同時收集血液檢體20 毫升。並於第12 個月、第24 個月、第36 個月，48個月重複測量身體肌肉脂肪組成與功能狀態，並詢問受試者或家屬，調查於這些觀察時間內是否有跌倒等臨床事件。以描述性分析呈現社區中老年人肌肉量及肌肉功能表現之流行病學概況。就基本資料，收集問卷、身體功能檢測、肌肉量、脂肪量檢查及血液生物指標各變項，進行相關性分析，並可觀察出力弱症、肌少症前期及肌少症之影響因子。初步以Markov model 預測老年人肌肉健康狀態，平均每年隨著時間進展自然老化之軌跡，再以COX 統計方法，分析四個時間點，受試者肌肉量減少、肌肉功能下降，甚至進展成為肌少症，變化消長之動態轉移情形。並分析其與健康預後如是否有跌倒、代謝症候群等之相關性。資料處理統計平台：以 Excel 來進行資料之匯整及初步處理，後續運算則以SPSS 進行包括描述性分析、卡方檢定、student t-test、ANOVA、羅吉斯複迴歸分析等。
結果: 在初步的肌肉量、脂肪量與肌肉功能分析當中，共分析了295位老年受試者，肌少症前期有24位，肌少症則有50位(16.94%)。發現肌少症前期的老年人比肌少症族群更為精瘦。肌肉量、握力與行走速度與肥胖指標如體脂肪率、脂肪肌肉比，皆存在著負相關。在迴歸分析當中，男性行走速度與體脂肪率呈負相關；而女性握力與體脂肪率及脂肪肌肉比呈負相關。
在後續的觀察性分析中，共765位受試者，發現力弱症老年人，具有較高比例的代謝方面異常，較高的體脂肪率、較粗的腰圍，較高的脂肪肌肉比；然而肌少症前期的老年人，則有較低的肥胖相關指標。臨床事件中，易跌倒族群有比較多的肌肉功能下降現象 (p<0.001)。力弱症族群有較高的代謝症候群風險(風險比:5.79; 95% 信賴區間= 2.45-13.73)，與較高的跌倒風險 (風險比= 3.11; 95%信賴區間=1.41-6.87)。肌少症之跌倒風險，與代謝症候群風險則皆較力弱症為低 (跌倒風險比:2.80, 95%信賴區間=1.18-6.69; 代謝症候群風險比: 2.95, 95%信賴區間=1.18-7.36)。所有肥胖指標當中，脂肪肌肉比具有較佳的肌肉功能下降預測力。在生物標記方面，共有460位受試者進行瘦素( leptin )分析，發現瘦素濃度越高，肌肉量與脂肪量也越高；而瘦素濃度與握力及行走速度呈負相關。在多變項迴歸分析中，將血清瘦素濃度分成四個百分位，瘦素濃度最高比起瘦素濃度最低的受試者，有較高的力弱症風險 (男性: 風險比:3.74, p for trend=0.04; 女性:風險比: 3.32, p for trend=0.042)。而瘦素濃度越高，肌少症風險則呈現下降趨勢 (男性風險比= 0.06, p for trend=0.002; 女性風險比= 0.26 , p for trend=0.023)。
在肌肉健康衰退之過程中，發現多數受試者經追蹤後，仍傾向停留在原本狀態；而原本肌肉質與量皆健康之老人，有18.29%會進展為力弱症。在肌肉健康衰退之預測模型中，依據Markov model ，若以肌少症為肌肉健康衰退之觀察終點，平均每年會有62%老年人會從肌肉健全狀態進展為力弱症，且多數停留於此狀態，僅有少數會再進展為肌少症；38%則經由肌肉健全狀態進展為肌少症前期，且較容易再轉變為肌少症。經由進展與回復之動態交互作用，最終每年有28%老人處於力弱症狀態。進展為肌少症之十年累積風險評估中，經由力弱症途徑者占10.1%; 經由肌少症前期途徑者占6.5% 。在肌肉退化之進展方面，461位肌肉健康之老人，有16.7%進展為力弱症。脂肪肌肉比值較高之老人，有較高機會進展成為力弱症。在肌肉健康惡化或回復之交互過程中，共有308位力弱症及142位肌少症前期受試者進行分析，肌少症前期比力弱症之老年人更易進展為肌少症 (風險比=2.84, 95%信賴區間=1.58-5.09). 平均所花時間為41.5±12.5 個月。力弱症則比肌少症前期之老人較易回復為肌肉健康狀態(風險比=2.98, 95%信賴區間=1.47-6.06)。平均所用時間為42.5±12.3 個月。
結論: 力弱症族群在社區的盛行率並不亞於肌少症族群。而力弱症老年人有較多肥胖的現象，肌少症前期的老年人則較為精瘦。社區老年人中，與肌肉功能相關的握力及行走速度皆與體脂肪率及脂肪肌肉比呈現負相關，而肌肉量則與肥胖指標無相關性。力弱症老年人比肌少症族群有較高的跌倒風險，與較多的代謝症候群風險，這些都與肥胖相關。在生物標記方面，瘦素濃度越高，力弱症風險愈高，肌少症風險反而下降，瘦素濃度可能代表著某種營養狀態。在肌肉健康衰退過程中，有較多比例會處在力弱症的狀態；而與肌少症前期相較，其亦較可能回復至健康狀態。盱衡歐洲及亞洲肌少症共識，仍著重如何偵測出肌少症族群，而忽略力弱症可能比肌少症存在更多肥胖與不良臨床預後之風險。因此，及早偵測出力弱症潛在族群，並給予適時之介入性措施，就預防醫學之角度而言，乃刻不容緩之議題。

關鍵字

肌肉 ； 脂肪 ； 肌力 ； 力弱症 ； 肌少症

並列摘要

Background:
During aging process, muscle mass loss and muscle function decline are critical issues associating to disability, morbidity and mortality among older adults. European Working Group on Sarcopenia in Older People (EWGSOP) defined clinical diagnosis of sarcopenia in 2010 by criteria including muscle mass, handgrip strength and gait speed. In 2014, Asian Working Groups for Sarcopenia (AWGS) also defined the cutoff points of these three parameters for sarcopenia in older Asian people. The definition of sarcopenia in both these two groups is loss of muscle mass plus muscle function decline. In recent years, more and more studies found that muscle function is more important than muscle mass on clinical outcome. EWGSOP revised the algorithm of sarcopenia screening in 2018, it addressed the concept of “probable sarcopenia”, which is indicated as loss of muscle strength only. In 2019, AWGS also revised the consensus of sarcopenia with a special term of “possible sarcopenia”, which is the same concept as probable sarcopenia in EWGSOP. However, further assessment and clinical consequences of “probable or possible sarcopenia” were not been well addressed in EWGSOP and AWGS consensus. In reality, muscle function decline without muscle mass loss might be better classified as “dynapenia”. Changes of body composition, muscle function during muscle health deterioration should be evaluated. Whether dynapenia is as important as or even worse than sarcopenia in clinical outcome also needs to be explored. We hypothesized that dynapenia is implicated with more clinical adverse outcomes than sarcopenia and the adiposity is a critical issue.
Methods:
Older people aged sixty-five and older who lived in the community attending annual health examination or visiting outpatient clinic at Tri-Service General Hospital in Taipei from 2015-2019 were enrolled. Participants were received measurement of handgrip strength and habitual gait speed. Bioelectrical impedance analyzer was used for whole body muscle mass and fat mass estimation. Participant with only muscle mass decline without poor handgrip strength nor slower gait speed is defined as presarcopenia. Sarcopenia individuals represented as muscle mass decline concomitant with poor handgrip strength or/and slow gait speed. Older people who had low handgrip strength or/and slower gait speed but reserve muscle mass were indicated as dynapenia.
The cutoff values of muscle mass decline, weakness of handgrip strength and slower walking speed were based on the AWGS consensus. The associations between different sarcopenia variables and all kinds of obesity parameters including waist circumference (WC), body mass index (BMI), fat mass, body fat percentage (BFP), fat to muscle ratio (FMR) among participants were analyzed. Risk of fall event and metabolic syndrome among the groups were analyzed by logistic regression and Cox regression model in cross-sectional and longitudinal studies respectively. Blood biomarkers related to muscle health were also evaluated. The prediction model and natural course of progression and reversibility of muscle health were also examined.
Results:
There were 295 participants enrolled initially for the association analyses among muscle mass, fat mass, handgrip strength and gait speed. There were 24 older adults had presarcopenia and 50 participants with sarcopenia (16.94%). Individuals with presarcopenia had the lowest obesity indicators comparing to robust, dynapenia and sarcopenia groups. Skeletal muscle mass index (SMI), handgrip strength, gait speed was negative associated with fat indices (BFP, FMR). In the male older people, gait speed was inversely associated with BFP (β= -0.255, p=0.009) and FMR (β= -0.272, p=0.005) in the multiple hierarchical regression model; whereas handgrip strength was negatively associated with BFP (β= -0.232, p=0.009) and FMR (β= -0.195, p=0.031).
Among 765 individuals recruited in the following observation, older adults with dynapenia were tended to have more metabolic syndrome profiles, and higher WC, BFP and FMR than participants with presarcopenia and sarcopenia. Older people with presarcopenia had the least obesity indicators. As for fall events, participants with previous fall history tended to have worse muscle function than non-fallers. Older individuals with dynapenia had the highest risk of metabolic syndrome (odds ratio [OR]= 5.79; 95% confidence interval [CI]= 2.45-13.73) as well as the highest risk of fall (OR= 3.11; 95% CI=1.41-6.87). FMR had the best diagnostic performance to estimate low muscle function, followed by BFP among all kinds of fat indices.
Among 460 older people recruited in leptin association study, the number of participants with dynapenia was more than that with sarcopenia both in men and women. Higher serum leptin level was positively associated with muscle mass and fat mass; but inversely with handgrip strength and habitual walking speed in both genders. In multiple logistic regression model, subjects with the highest leptin quartile had higher dynapenia risk than those with the lowest leptin quartile both in male and female (OR=3.74, 95% CI= 0.99- 14.17; OR= 3.32, 95% CI=1.03- 10.74, respectively). A positive trend for this association was existed in both genders (p for trend=0.040 and 0.042, respectively). Nevertheless, the highest leptin quartile had lower sarcopenia risk compared to those in the lowest leptin quartile in both genders (OR= 0.06, 95%CI=0.01- 0.48; OR= 0.26 ,95% CI=0.06- 1.17, respectively). A negative trend for this relationship was noted in both men and women participants (p for trend= 0.002 and 0.023, respectively).
Furthermore, we recruited 1044 older people for the analyses of natural course of muscle health deterioration. We analyzed the observed transition pattern between two visits regardless of the length of observation interval. In the robust group, there was 72.26% participants remained in the same stage; and 18.29% individuals transited to dynapenia, 2.44% progressed to sarcopenia. During muscle health deterioration, according to the Markov model setting sarcopenia as the endpoint, there is 62% robust participants progress to dynapenia, but less amount of them further progress to sarcopenia. Only 38% of robust older people progress to presarcopenia and further transit to sarcopenia. During this dynamic interaction, the stationary distribution per year revealed that most of the participants stagnated upon dynapneic status (28%). Ten years cumulative probability to sarcopenia from robust via presarcopenia was 6.5%; whereas through dynapenia was 10.1%.
In the longitudinal follow-up study for transition analysis, there were 461 robust participants recruited; whereas 16.70%, 3.47%, and 1.08% of older people transited to dynapenia, presarcopenia and sarcopenia, respectively. Individuals with high FMR had a higher risk of progression to dynapenia than those with low FMR.
In progression and regression cohort study, older adults with presarcopenia tended to transit to sarcopenia (hazard ratio [HR]=2.84, 95%CI=1.58-5.09). The mean time of progression to sarcopenia through presarcopenia was 41.5±12.5 months. Older people with dynapenia tended to reverse to robust status (HR= 2.98, 95%CI=1.47-6.06). The mean time of reverse to robust via dynapenia was 42.5±12.3 months.
Conclusions:
Among different kinds of muscle health status, older people with dynapenia had higher metabolic and obesity profiles than sarcopenic participants; whereas older adults with presarcopenia had the lowest fat indices. Muscle function, but not muscle mass was inversely associated with fat indices such as BFP and FMR among older people. Participants with dynapenia had higher risk of obesity related adverse outcomes than participants with sarcopenia. Higher adiposity is associated with muscle function decline independent of muscle mass loss among older people. Among all kinds of obese-related biomarkers, higher serum leptin level increased the risk of dynapenia; whereas a negative trend existed between serum leptin level and sarcopenia risk in older individuals.
In the natural course of muscle health deterioration, the subjects with normal muscle health tended to progress to dynapenia. Participants at baseline status with presarcopenia tended to progress to sarcopenia; whereas older adults with baseline status of dynapenia tended to reverse to the robust status. Nevertheless, significant number of older people tended to be stagnated in dynapenia status. Dynapenia is worse than sarcopenia on clinical outcome during aging process, early detection and intervention is a critical issue for this population.

並列關鍵字

muscle ； fat ； handgrip strength ； gait speed ； dynapenia ； sarcopenia

參考文獻

Abellan van Kan G, et al. Gait Speed at Usual Pace as a Predictor of Adverse Outcomes in Community-Dwelling Older People an International Academy on Nutrition and Aging (Iana) Task Force. J Nutr Health Aging. 2009; 13 (10): 881-9.

Alberti KG, et al. Harmonizing the Metabolic Syndrome: A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009; 120 (16): 1640-5.

Alexandre TDS, et al. Dynapenic Obesity as an Associated Factor to Lipid and Glucose Metabolism Disorders and Metabolic Syndrome in Older Adults - Findings from Sabe Study. Clin Nutr. 2018; 37 (4): 1360-66.

Antoniou GA, Rojoa D, Antoniou SA, Alfahad A, Torella F, Juszczak MT. Effect of Low Skeletal Muscle Mass on Post-Operative Survival of Patients with Abdominal Aortic Aneurysm: A Prognostic Factor Review and Meta-Analysis of Time-to-Event Data. Eur J Vasc Endovasc Surg. 2019; 58 (2): 190-98.

Antony B, Jones G, Stannus O, Blizzard L, Ding C. Body Fat Predicts an Increase and Limb Muscle Strength Predicts a Decrease in Leptin in Older Adults over 2.6 Years. Clin Endocrinol (Oxf). 2013; 79 (5): 652-60.