Interventions to improve sarcopenia in cirrhosis: A systematic review

Table 1 Nutritional interventions to improve sarcopenia in cirrhosis

Ref.	Study participant’s characteristics	Study design	Sample size	Intervention	Duration of intervention	Diagnosis of sarcopenia	Results
Marchesini et al[29], 2003	mean age: 59 yr; males/females: 13/59; BMI: NA; CTP score: 9; setting: Europe	RCT	174	Intervention: Nutritional supplementation with BCCA (leucine, isoleucine and valine); Control: Lactalbumin or maltodextrins	1 yr	Anthropometric and BIA	Significant increase in triceps skinfold thickness and MA fat area
Okumara et al[30], 2006	Age: NA; Gender: NA; mean BMI: 21; CTP score: 6; setting: Japan	Case control	47	Regular diet and late evening snack (rice ball)	1 wk	Anthropometric measurement i.e., AMA, AC and AMC	No significant differences in BMI, AC, AMC or AMA; improvement in RQ value in intervention group
Nakaya et al[31], 2007	Age: 67; males/females: 20/18; mean BMI: 22.9; CTP score: 7; setting: Japan	RCT	48	LES with BCAA enriched mixture or ordinary food such as rice ball or bread	3 mo	Anthropometric measurements such as MAC and triceps skin fold thickness	No significant improvement in the anthropometric parameter in either group
Les et al[32], 2011	mean age: 64.1 ± 10.4; males/females: 88/28; mean BMI: NA; CTP score: 8; Setting: Barcelona	RCT	116	Intervention: Standard diet + 0.7 g of protein/kg + supplement of 30 g of BCAA; Control group: Standard diet + 0.7 g of protein/kg + maltodextrin	56 wk	Anthropometric	Increased in MA circumference and hand grip in intervention group
Sorrentino et al[33], 2012	mean age: 65; males/females: 81/39; mean BMI: NA; CTP score: 12; setting: Italy	RCT	120	Group A: parenteral nutritional support + balanced diet + LES; Group B: balanced diet + LES; Group C: low sodium or sodium free diet	12 mo	Anthropometric measurements such as MAC and triceps skin fold thickness	No significant differences in the anthropometric measures in three groups. Significantly improved in the morbidity and mortality in group A and B
Dupont et al[34], 2012	mean age: 54.6 ± 9.6; males/females: 65/43; mean BMI: 26; CTP score: 10; setting: France	RCT	99	Enteral nutrition vs a symptomatic support; i.e., 30–35 kcal/kg per day of a polymeric solution for a period of 3–4 wk, through a nasogastric feeding tube. for three oral nutritional supplements per day for 2 mo.	3 mo	Anthropometric measurements such as MAC and triceps skin fold thickness	No change in arm muscle circumference
Maharshi et al[35], 2016	mean age: 42; males/females: 5/25; mean BMI: NA; CTP score: 8; setting: India	RCT	120	Nutritional therapy (30-35 kcal/kg/d, 1.0-1.5 g vegetable protein/kg/d vs no nutritional therapy	6 mo	Anthropometric measurements such as MAC and triceps skin fold thickness	Significant improvement in the MAC, hand grip and skeletal muscle mass
Ruiz-Margain et al[36], 2017	mean age: 47.8-54.9; males/females: 13/59; mean BMI: 26; CTP score: 6; setting: Mexico	RCT	72	Intervention: BCAA + High protein and high fiber diet; Control: Only high protein and high fiber diet	6 mo	Anthropometric measurement: triceps skin fold thickness and MAC	Increase in muscle and decrease in fat mass in intervention group
Kitajima et al[37], 2017	mean age: 71.3 ± 7.9; males/females: 9/12; mean BMI: 23.9; CTP score: NA; setting: Japan	Longitudinal study; (pre-post intervention)	21	Diet supplemented with BCAA 3 x daily after meals	48 wk	CT scan and BIA	ΔIMAC and ΔSAI significantly correlated with Δserum albumin level. BCAA supplementation prevented the progression of sarcopenia in cirrhosis
Ohara et al[38], 2018	mean age: 67; males/females: 53/17; mean BMI: 24.6; CTP score: 7; setting: Japan	Matched case control; Cases: 35; Control: 35	70	Cases: Received L carnitine; Control: no supplementation	6 mo	CT images: Psoas muscle index	Significant suppression in the loss of skeletal muscle in intervention group

MA: Mid arm fat area; BIA: Bio impedance analysis; AMA: Arm muscle area; AC: Mid upper arm circumference; AMC: Arm muscle circumference; RQ: Respiratory quotient; BMI: Body mass index.

Table 2 Exercise interventions to improve sarcopenia in cirrhosis

Ref.	Study participants characteristics	Study design	Patients enrolled	Intervention	Duration of intervention	Diagnosis of sarcopenia	Results
Zenith et al[39], 2014	mean age: 57 years; males/females: 15/4; mean BMI: 28; CTP score: 6; setting: Canada	RCT ; Intervention = 9; Control = 10	19	Supervised exercise (cycle ergometer 3 d/wk). 5 min warm up on low level cycling, exercise initiated at 30 min per session and increased by 2.5 min per session until study completion	8 wk	Quadriceps muscle thickness measured by ultrasound and thigh circumference	Peak VO2 thigh thickness and circumference increased at end of intervention
Debette-Gratien et al[40], 2015	Mean Age: 51 ± 12; males/females: 6/3; mean BMI: NA; CTP score: 7; setting: France	Quasi experimental (pre-post intervention)	13	Personalized Adapted Physical Activity	12 wk	Functional capacity and muscle strength	Post intervention significant increase in the mean exercise VO2 peak and the mean quadriceps isometric strength
Roman et al[41], 2016	mean age: 63; males/females: 17/6; mean BMI: 31; CTP score: 6; setting: Spain	RCT	23	Intervention: 1-h session 3 times/wk; Control: Sham intervention	12 wk	Functional capacity by CPET, Anthropometry, DEXA and Timed up and GO study	Increase in total effort time, ventilatory anaerobic threshold time and upper thigh circumference. Decrease in MA and mid-thigh skin fold thickness. DEXA showed decrease in fat body mass and increase in lean body mass, lean appendicular mass and lean leg mass. No changes in the control group
Macias-Rodriguez et al[42], 2016	mean age: 52; males/females: 19/6; mean BMI: 27.5; CTP score: 6; setting: Mexico	RCT	25	Intervention group: PEP (personalized exercise program) (cycloergometry/kinesiotherapy plus nutrition); control: only nutrition	14 wk	BIA and CPET	Significant improvement in ventilatory efficiency (VE/VCO2) and phase angle
Kruger et al[43], 2018	mean age: 53-56; males/females: 23/17; mean BMI: 29; CTP score: 6; setting: Canada	RCT	40	Home exercise training i.e., moderate to high intensity cycling exercise, 3 d/wk vs usual care	8 wk	Measurement of peak VO2; Aerobic endurance using 6-min walk test; Ultrasound to measure thigh muscle circumference and mass	Significant increase in peak VO2, aerobic endurance, thigh circumference and insignificant improvement in thigh muscle thickness as measured by the average feather index

CPET: Cardiopulmonary exercise testing; CSA: Cross sectional area; BMI: Body mass index.

Table 3 Combined life style intervention (exercise and nutrition) to improve sarcopenia in cirrhosis

Ref.	Study participants characteristics	Study design	Sample size	Intervention	Duration of intervention	Diagnosis of sarcopenia	Results
Roman et al[44], 2014	mean age: 43-75; males/females: 12/5; mean BMI: 27; CTP score: 7; setting: Spain	RCT	17	Intervention: moderate exercise + oral leucine; Control: Placebo	12 wk	Exercise capacity (6-min walk and 2-min step tests), anthropometric measurement	Significant increase in exercise capacity. Increase in lower thigh circumference. No changes in control group
Nishida et al[45], 2017 (medium risk)	mean age: 47.8-54.9; gender: 6 females; mean BMI: 24.3; CTP score: 6; setting: Japan	Quasi experimental (pre-post intervention)	6	Homes based step exercise at AT (140 min/wk) and BCAA supplementation (12.45 g/d)	12 mo	CT scan to assess fat deposition in liver and IMAC	Significantly increased AT; No changes in TBW, liver/spleen ratio or IMAC
Hiraoka et al[46], 2017	median age (IQR): 66 (62-70); males/females: 13/20; child A/B: 30/3; median BMI (IQR): 23.2 (20.8-25.1); setting: Japan	Quasi experimental (pre-post intervention)	33	BCAA supplementation as LES and additional 2000 steps/d prescribed	6 mo	BIA Leg and Hand grip	Muscle volume, leg and handgrip strength increased after post intervention
Berzigotti et al[47], 2017	mean age: 56 ± 8; gender: 31/29; mean BMI: 33; CTP score: < 8; setting: Spain	Quasi experimental (pre-post intervention)	60 included and 50 completed the study	LS interventions which include: Reduce calorie intake of 500-1000 kCal/d (protein intake 20%-25%, Carbs: 45%-50% and fat content < 35%); Supervised exercise-60 min session of moderate exercise.	16 wk	BIA and anthropometric measurements	Decrease in TBW, fat mass; Unchanged lean mass

AT: Anaerobic threshold; IMAC: Intramuscular adipose tissue content; BMI: Body mass index.

Table 4 Trans jugular intrahepatic portosystemic shunt to improve sarcopenia in cirrhosis

Ref.	Study participants characteristics	Study design	Sample size	Intervention	Follow up, mean ± SD	Diagnosis of sarcopenia	Results
Plauth et al[48], 2004	mean age: 60; gender: 13/8; mean BMI: 22.3; decompensated; setting: Germany	Quasi experimental (pre-post intervention study)	21	TIPS	12 mo	Anthropometry, BIA, REE by indirect calorimeter and TBP	Increased muscle mass; no change in REE and fat mass
Tsein et al[49], 2013	mean age: 55.5; gender: 59/30; mean BMI: 29; CTP score: 9; setting: USA	Case control; Cases: 57; Controls: 32	57	TIPS	13.5 ± 11.9 mo	Unenhanced CT axial scan	Total psoas and paraspinal muscle area increased significantly after TIPS; post TIPS visceral fat volume decreased significantly
Montomoli et al[50], 2010	mean age: 47.8-54.9; gender: 14/7; mean BMI: 26.2; MELD: 18; setting: Denmark	Quasi experimental (pre-post intervention study)	21	TIPS	52 wk	Anthropometry: body composition parameters such as dry lean mass and fat mass	Patient with normal weight has increased in dry lean mass. No changes in the fat mass

TBP: Total body protein; REE: Resting energy expenditure; FFA: Free fatty acid; CT: Computed tomography; TIPS: Trans jugular intrahepatic portosystemic shunt; BMI: Body mass index.

Table 5 Testosterone to improve sarcopenia in cirrhosis

Ref.	Study participants characteristics	Study design	Sample size	Intervention	Intervention	Diagnosis of sarcopenia	Results
Yurci et al[51], 2011	mean age: 52.17; mean BMI: 27.17; CTP score: 7; setting: Turkey	Quasi experimental (pre-post intervention study)	16	Testosterone gel 50 mg/d in hypo gonadal men	6 mo	Anthropometric measurement: Muscle strength and skin fold thickness	Muscle strength increased significantly 3 mo post intervention
Sinclair et al[52], 2016	mean Age: 55; male 100%; mean BMI: 28.8; CTP score: 9; setting: Australia	RCT	101	Intramuscular testosterone undecanoate in men with low testosterone	12 mo	APLM by DEXA	APLM and TBM were significant higher in testosterone-treated subjects. No change in mortality

APLM: Appendicular lean mass; BMI: Body mass index.

Table 6 Summary of scoring results in terms of risk of bias (low, medium or high) of all studies included in the review

Ref.	Question and risk of bias
	Study design	Study participants	Measurements of intervention	Measurements of outcomes	Confounding factors	Blinding	% follow-up	Info on non-participants	Analysis	Sample size	Overall quality rating: Risk of bias
Debette-Gratien et al[40], 2015	+1	+1	-1	+1	-1	0	-1	+1	0	-1	0 = medium risk
Berzigotti et al[47], 2017	+1	+1	+1	+1	0	0	0	+1	+1	-1	5 = low risk
Hiraoka et al[46], 2017	+1	0	+1	+1	-1	0	+1	+1	+1	-1	4 = low risk
Nishida et al[45], 2016	+1	-1	-1	+1	-1	0	-1	+1	0	-1	-2 = medium risk
Montomoli et al[50], 2010	+1	-1	0	+1	-1	0	-1	+1	0	-1	-1 = medium risk
Ohara et al[38], 2018	+1	-1	0	0	0	0	+1	-1	+1	0	+1 = medium risk
Okumura et al[30], 2006	-1	-1	+1	0	0	0	+1	+1	+1	-1	+1 = medium risk
Plauth et al[48], 2004	+1	-1	0	+1	-1	0	0	+1	+1	-1	+1 = medium risk
Tsein et al[49], 2013	+1	0	-1	+1	0	0	-1	-1	+1	-1	-1 = medium risk
Yurci et al[51], 2011	+1	+1	-1	0	-1	0	0	-1	+1	-1	-1 = medium risk
Kitajima et al[37], 2017	+1	+1	0	+1	0	0	+1	+1	+1	-1	5 = low risk

Total score -9 to -3 = high risk of bias; -2 to +3 = medium risk of bias; +4 to +10 = low risk of bias.

Table 7 Risk of bias in randomized controlled trials

Ref.	Random sequence generation (selection bias)	Allocation concealment (Selection bias)	Blinding of participants and personnel’s (performance bias)	Blinding of outcome assessment (detection bias)	Incomplete outcome data (Attrition bias)	Selective Reporting (Reporting bias)	Other bias
Marchesini et al[29], 2003	+	-	-	-	-	?	?
Nakaya et al[31], 2007	+	-	-	-	-	?	?
Les et al[32], 2011	+	+	?	?	-	?	?
Sorrentino et al[33], 2012	+	?	-	-	-	-	?
Dupont et al[34], 2012	+	?	-	-	?	?	?
Maharshi et al[35], 2016	+	+	-	-	+	?	?
Ruiz-Margain et al[36], 2017	+	?	-	-	?	-	?
Zenith et al[39], 2014	+	+	-	-	-	?	?
Roman et al[41], 2016	+	+	-	-	-	?	?
Kruger et al[43], 2018	+	+	-	-	-	?	?
Roman et al[44], 2014	+	?	-	-	-	?	?
Macias-Rodriguez et al[42], 2016	+	+	-	-	-	?	?
Sinclair et al[52], 2016	+	+	?	?	-	?	?