Sarcopenia in chronic viral hepatitis: From concept to clinical relevance

Table 1 Summary of main studies investigating the association between sarcopenia and adverse clinical outcomes in the context of chronic hepatopathies including patients chronically infected with hepatitis B or C virus, n (%)

Ref.	Study location	Study design	Diagnosis of sarcopenia	Study population (n)	Age, yr1	Sex (M/ F) (n)	Aetiology of liver disease, n (%)	Overall prevalence of sarcopenia (%)	Prevalence of sarcopenia according to the severity of the liver disease (%)	Clinical outcome/main results
Montano-Loza et al[105], 2012	Canada	Retrospective cohort	CT at the level of the third lumbar vertebrae (L3 SMI, ≤ 38.5 cm2/m2 for women and ≤ 52.4 cm2/m2 for men)	112 cirrhotic patients evaluated for LT	54.0 ± 1.0	78/34	Alcohol 25 (22.0); HCV 32 (29.0); Alcohol + HCV 18 (16.0); HBV 2 (2.0); Autoimmune 21 (19.0); Others 14 (13.0)	40	Not mentioned	Sarcopenia, Child-Pugh score, and MELD score were associated with mortality
Krell et al[106], 2013	United States	Retrospective cohort	CT-measured psoas muscle; Sex-stratified TPA terciles; Criteria for cutoff: Lowest TPA tercile	207 adult patients who underwent LT	51.7 ± 9.8	129/78	HCV 54 (26.1); HBV 9 (4.4); Alcohol 30 (14.5); Autoimmune 47 (22.7); NASH 8 (3.9); HCC 52 (25.1); Others 28 (13.5); More than one indication for liver transplantation 21 (10.1)	-	Not mentioned	Sarcopenia was associated with a heightened risk for post-transplant infections and mortality
Gowda et al[73], 2014	United States	Cross-sectional	MUAC below the 10th percentile for age- and sex-matched reference values	18513 NHANES participants	HCV –39.3 ± 8.5; HCV + 47 ± 5.8	HCV-8923/9287; HCV+ 197/106	303 (1.6%) had CHC	Low MUAC HCV+ 42/303 (13.8); HCV-1220/18210 (6.7)	HCV+ without significant liver fibrosis (APRI < 1.5)	CHC was associated with low MUAC, even in the absence of advanced liver disease
Yadav et al[107], 2015	United States	Prospective cohort	CT at the level of the third lumbar vertebrae; (L3 SMI, ≤ 38.5 cm2/m2 for women and ≤ 52.4 cm2/m2 for men)	213 cirrhotic patients evaluated for LT	55.3 ± 8.6	129/84	HCV 94 (44.0); Alcohol 34 (16.0); NASH 29 (13.6); PBC/PBS 16 (7.5); Cryptogenic cirrhosis 13 (6.1); Others 26 (12.2)	22.2	Not mentioned	Sarcopenia was not associated with mortality, poor quality of life, and functional capacity
Hiraoka et al[71], 2016	Japan	Cross-sectional	CT-measured psoas muscle and HGS-measured muscle strength AWGS and EWGSOP criteria	807	67.1 ± 10.0	466/341	HCV 511 (63.3); HBV 134 (16.6); HBV and HCV 3 (3.7); Alcohol 45 (5.6); Others 114 (14.1); Previous or current HCC 256 (31.7)	3.9–16.7 (AGWS); 7.1–21.9 (EWGSOP)	[CH, LC Child-Pugh (A, and B/C)]; AGWS; 3.9, 4.8, 16.7; EWGSOP; 7.1, 11.8, 21.9	Prevalence of sarcopenia increased with the progression of chronic liver disease
Montano-Loza et al[47], 2016	Canada	Retrospective cohort	CT at the level of the third lumbar vertebrae; (L3 SMI, ≤ 41.0 cm2/m2 for women and ≤ 53.0 cm2/m2 for men)	678	56.0 ± 1.0 to 58.0 ± 1.0	457/221	HCV 269 (40.0), alcohol 153 (23.0), NASH and cryptogenic cirrhosis 96 (14.0); Autoimmune liver disease 55 (8.0); HBV 43 (6.0); Others not specified 5 (1.0); Concomitant HCC 291 (43.0)	Sarcopenia 292 (43.0), Sarcopenic obesity 135 (20.0), Myosteatosis 353 (52.0), Sarcopenia and myosteatosis 176 (26.0)	Child-Pugh (A, B, C); Sarcopenia 12.7, 51.0, 36.3; Sarcopenic obesity; 8.9, 47.4, 43.7; Myosteatosis 12.2, 51.0, 36.8	Sarcopenia and myosteatosis were independently associated with a higher long-term mortality in cirrhosis
Nishikawa et al[108], 2017	Japan	Cross-sectional	BIA-measured upper limb skeletal muscle mass (kg) AWGS cutoff (SMI, ≤ 7.0 kg/m2 for men and ≤ 5.7 kg/m2 for women)	383	65.2 ± 10.3	205/178	HBV 32 (8.3); HCV 235 (61.4); Others 116 (30.3)	136 (35.5)	No association with Child-Pugh score	Sarcopenia was associated with low overall survival in male patients
Bering et al[72], 2018	Brazil	Cross-sectional	DXA-measured ASMI with EWGSOP cutoff (ASMI, ≤ 7.26 kg/m2 for men and ≤ 5.45 kg/m2 for women)HGS-measured muscle strength - EWGSOP criteria	104	50.5 ± 11.3	78/26	CHC patients without cirrhosis 70 (67.3), with compensated cirrhosis 34 (32.7)	Low muscle strength 29 (27.9), Low ASMI 15 (14.4); Sarcopenia 9 (8.7); Sarcopenic obesity 3 (3.8)	Sarcopenia without cirrhosis 5 (7.1) with compensated cirrhosis 4 (11.8)	Sarcopenia was associated with bone mineral content and malnutrition. BMI was normal in 88.9% of sarcopenic patients and in all patients with sarcopenic obesity. The mid-arm muscle circumference was positively correlated with ASMI
Han et al[93], 2018	Korea	Cross-sectional	DXA-measured ASMI with sarcopenia defined as the lowest quintile for sex-specific sarcopenia index cutoff values (< 0.89 for men and < 0.58 for women) modified from the criteria, were adapted from the FNIH Consensus	506	Non-sarcopenic 48.5 ± 12.9; Sarcopenic 48.5 ± 12.9	258/248	CHB significant fibrosis according to FIB4without sarcopenia160/407 (39.3)with sarcopenia57/99 (57.6)	99 (19.6)	Not mentioned	Sarcopenia was associated with significant fibrosis, specifically in CHB patients with obesity, insulin resistance, metabolic syndrome, and liver steatosis
Kamo et al[109], 2019	Japan	Retrospective cohort	CT at the level of the third lumbar vertebrae; Sarcopenic obesity as the combination of low SMI (< 40.31 cm2/m2 for men; < 30.88 cm2/m2 for women) and either VFA ≥ 100 cm2 or BMI ≥ 25 kg/m2	277	54.0 [18.0–69.0]	134/143	HCC 74 (26.7), HCV and/or HBV 60 (21.7), Cholestatic disease 56 (20.2); Others 87 (31.4)	Groups divided according to SMI and VFA or BMI; Without sarcopenia/non-obesity (NN); n = 167 (60.0)/n = 179 (65.0); Without sarcopenia/obesity (NO); n = 55 (20.0)/n = 43 (15.0); Sarcopenia/ non- obesity (SN); n = 46 (17.0)/n = 49 (18.0); Sarcopenia/obesity (SO); n = 9 (3.0)/n = 6 (2.0)	Groups divided according to SMI and VFA Child-Pugh A, B/C; Sarcopenia/ non-obesity (SN); 13 (28.3)/33 (71.7); Sarcopenia/obesity (SO) 4 (44.4)/5 (55.6); Groups divided according to SMI and BMIChild-Pugh A, B/C; Sarcopenia/ non- obesity (SN); 12 (24.5)/37 (75.5); Sarcopenia/obesity (SO) 5 (8.3)/1 (1.7)	Patients with sarcopenic obesity showed worse survival after LDLT compared to non-sarcopenic/non- obesity patients
Sinclair et al[110], 2019	Australia	Retrospective cohort	DXA-measured ASMI - cutoff (ASMI, ≤ 7.26 kg/m2 for men)	420	55.4 [49.1–59.4]	Male, 420	HCC 119 (28.3), HCV 102 (24.3), Alcoholic cirrhosis 53 (12.6), Primary sclerosing cholangitis 43 (10.2), NAFLD 26 (6.2); Others autoimmune and metabolic conditions, 77 (18.3)	130 (30.9)	Not mentioned	Low ASMI is strongly associated with mortality in men awaiting liver transplantation
Ohashi et al[111], 2019	Japan	Cross-sectional	CT at the level of the third lumbar vertebrae; JHS criteria (L3 SMI, ≤ 38.0 cm2/m2 for women and ≤ 42.0 cm2/m2 for men)	335	69.5 ± 10.2	169/166	HCV 139 (41.5), HBV 57 (17.0), NAFLD 44 (13.1), Alcoholic liver disease 40 (11.9) Others 55 (16.4)HCC 86/335 (25.7)	180 (53.7)	Child-Pugh A, B, C169 (94.0), 10 (5.5), 1 (0.5)	Sarcopenia was associated with low scores of quality of life using the Medical Outcomes Short-Form Health Survey (SF-36)
Saeki et al[112], 2019	Japan	Cross-sectional	BIA-measured SMISarcopenia was diagnosed using the following criteria: JSH criteria: Low HGS (< 26 kg for men and < 18 kg for women) and low SMI (< 7.0 kg/m2 for men and < 5.7 kg/m2 for women); AWGS criteria: Low HGS (< 26 kg for men and < 18 kg for women) and/or low gait speed (≤ 0.8 m/s both for men and women) and low SMI (< 7.0 kg/m2 for men and < 5.7 kg/m2 for women); FWGSOP2 criteria: Low HGS (< 27 kg for men and < 16 kg for women) and low SMI (< 7.0 kg/m2 for men and < 5.5 kg/m2 for women). Low gait speed (≤ 0.8 m/s for both men and women) is an indicator for defining severe sarcopenia	142	70.5 [58.8–76.0]	90/52	HCV 45 (31.7), HBV 16 (11.3), Alcoholic liver disease 48 (33.8); Others 33 (23.2)	JSH or AWGS criteria; 48 (33.8); EWGSOP2 criteria; 40 (28.2)	Child-Pugh A/B, C; 32 (66.7)/16 (33.3)	Sarcopenia, osteoporosis, osteosarcopenia, and vertebral fracture were highly prevalent and closely associated with one another in patients with liver cirrhosis. Specifically, patients with osteosarcopenia had the highest risk of vertebral fractures
Pinto dos Santos et al[113], 2019	Germany	Retrospective cohort	CT-measured PMA and bilateral ESA as well as the combined PSMA. Muscle areas were subsequently normalised to the patient’s height squared - PMI, ESI, and PSMI	368	49.2 [36.9–61.5]	255/113	HCC 164 (44.6), Alcoholic liver disease 147 (39.9), HCV 91 (24.7), HBV 55 (14.9), Biliary liver disease 38 (10.3) Others (11.1)	Median PSMI was used to divide the study population into high and low muscle index subgroups, which were further compared	Child-Pugh A, B, C; 53 (14.4), 92 (25.0), 197 (53.5)	Sarcopenia was a predictor of early post-OLT survival in male patients
Nishikawa et al[114], 2021	Japan	Retrospective cohort	BIA-measured SMI; Sarcopenia was diagnosed using criteria: JSH criteria: low HGS (< 26 kg for men and < 18 kg for women) and SMI (< 7.0 kg/m2 for men and < 5.7 kg/m2 for women); AWGS criteria: Low calf circumference (CC) (< 34 cm for men and < 33 cm for women); Japanese criteria: High waist circumference (WC) (> 85 cm for men and > 90 cm for women)	631 CLD	65.0 [52.0–71.0]	309/322	HCV 286 (45.3), HBV 90 (14.3), Others 255 (40.4)	Sarcopenia; Low HGS + Low SMI; 73/631 (11.6); Low HGS; men 49 (15.9); women 89 (27.6); Low SMI; men 76 (24.6); women 107 (33.2); Low CC; men 49 (15.9); women 81 (25.2); High WC; men 106 (66.7); women 103 (32.0)	Not mentioned	Multivariate analysis showed that men, presence of LC, presence of HCC, low-GS, low-CC, serum albumin, estimated glomerular filtration rate, hepatitis B virus, and hepatitis C virus were significant factors contributing to the overall survival. CC can be an alternative marker for muscle mass in CLD patients
Van Dongen et al[115], 2022	United States	Retrospective cohort	BIA-measured SMI; EWGSOP2 criteria: With sarcopenia if their SMI > 1 SD below the gender-specific meanfor young adults (aged 20–39 y) in NHANES III (≥ 36.7% in men and ≥ 26.6% in women)	12032 NHANES participants (NHANES III, 1988–1994); 4200 (34.9%) CLD; 7832 (65.1%) controls	NAFLD 46.01(0.47); ALD 43.92 (1.33); HCV 39.49 (0.94); HBV 41.12 (1.70); Control; 41.56 (0.40)	6049/5983	NAFLD 3238 (77.1%); ALD 685 (16.3%); HCV 218 (5.2%); HBV 59 (1.4%)	Prevalence of sarcopenia was higher among NAFLD than other; CLDs and controls (40.7% in NAFLD, 27.2% in ALD, 22.4% in HCV, 16.8% in HBV, and 18.5% in controls)	Not mentioned	Among 4 patients with CLDs and the controls, all-cause cumulative mortality was: 35.2% HCV, 34.7% ALD, and 29.6% NAFLD. The presence of sarcopenia was associated with a higher risk of all-cause mortality only among subjects with NAFLD. Attainment of ideal LS7 metrics (ideal body mass index, ideal blood pressure, ideal physical activity, and ideal glycaemic control) provides protection against sarcopenia in NAFLD
Santos et al[94], 2022	Brazil	Cross-sectional	DXA-measured ALMBMI and patients in the first sex-specific quintile (< 0.767 for men and < 0.501 for women) were considered to have low ALMBMI adapted from FNIH Consensus criteria, HGS-measured muscle strength, and physical performance - TUG	105 CHB outpatients	48.5 ± 12.0	61/44	105 CHB outpatients without cirrhosis 76.2% with compensated cirrhosis 23.8%	-	Not mentioned	MAFLD and central obesity were associated with low muscle mass and strength in patients with chronic hepatitis B, independent of the stage of the liver disease

¹Mean (SD) or standard error of the mean (SEM) or median [interquartile range 25^th–75^th percentile.

HBV: Hepatitis B virus; HCV: Hepatitis C virus; SD: Standard deviation; F: Female; M: Male; CT: Computerised tomography; L: Lumbar; SMI: Skeletal muscle index; LT: Liver transplantation; MELD: Model for End-stage Liver Disease; TPA: Total psoas area; NASH: Non-alcoholic steatohepatitis; HCC: Hepatocellular carcinoma; MUAC: Mid-upper arm circumference; NHANES: The National Health and Nutrition Examination Survey; APRI: Aspartate aminotransferase to Platelet Ratio Index; CHC: Chronic hepatitis C; PBC: Primary biliary cholangitis; PBS: Primary sclerosing cholangitis; HGS: Handgrip strength; CH: Chronic hepatitis; LC: Liver cirrhosis; AWGS: Asian Working Group for Sarcopenia; EWSOP: The European Working on Sarcopenia in Older People; BIA: Bioelectrical impedance analysis; ASMI: Appendicular skeletal muscle mass index; DXA: Dual-energy X-ray absorptiometry; FNIH Consensus: Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project consensus; BMI: Body mass index; FIB4: Fibrosis-4 index; VFA: Visceral fatty area; LDLT: Living donor liver transplantation; NAFLD: Non-alcoholic fatty liver disease; JSH: Japan Society of Hepatology; PMA: Psoas muscle area; ESA: Erector spinae muscle area; PSMA: Paraspinal muscle area; PMI: Psoas muscle index; ESI: Erector spinae muscle index; PSMI: Paraspinal muscle index; CC: Calf circumference; WC: Waist circumference; CLD: Chronic liver disease; NHANES III, 1988–1994, the Third National Health and Nutrition Examination Survey; ALD: Alcohol-associated liver disease; LS7: Life's Simple 7 health metrics; ALM_BMI: Appendicular lean mass was adjusted for BMI; TUG: Timed Up and- Go test; MAFLD: Metabolic-associated fatty liver disease; OLT: Orthotopic liver transplantation.