Current management strategies for sarcopenia and frailty in cirrhosis: Missing link in transplant candidacy

Table 1 Diagnostic criteria for sarcopenia

Subtype of sarcopenia	EWGSOP 2010 definition	EWGSOP 2019 definition[9]
Probable sarcopenia	Reduced mass of muscles	Reduced strength of muscles
Sarcopenia	Reduced mass of muscles	Reduced strength of muscles
	Plus reduced strength of muscles	Plus reduced mass/quantity or function of muscles
Severe sarcopenia	Reduced mass of muscles	Reduced strength
	Plus reduced strength of muscles	Plus reduced mass/quantity of muscles
	Plus reduced function	Plus reduced function
Cutoff	< 30 kg in males, < 20 kg in females plus BMI adapted	< 27 kg in males, < 16 kg in females

BMI: Body mass index; EWGSOP: European Working Group on Sarcopenia in Older People.

Table 2 Diagnostic tools and cutoffs for assessing frailty and sarcopenia in cirrhosis

Investigation	Defined cutoff	Correlation with pretransplant mortality
Short physical performance battery	Frail = score less than or equal to 9/12	Yes (> 65 years age)
Liver Frailty Index score	Frail = 4.5	Yes
6-minute walk test	< 250 m	Yes, mortality reduces by 52%
Bioelectrical impedance analysis	ASMI; Males: < 7.0 kg/m2; Females: < 5.7 kg/m2	Yes
Hand grip test	Males: 26 kg; Females: 18 kg	Yes
Skeletal muscle index	Males: < 50 cm2/m2; Females: < 39.50 cm2/m2	Yes
Appendicular lean mass-height adjusted	Males: < 6.57 kg/50 m2; Females: < 4.61 kg/m2	Yes
DEXA upper limb lean mass-height-adjusted	Males: < 1.6 kg/m2	Yes (males)
MRI: Fat-free muscle area at the level of the superior mesenteric artery	Males: FFMA < 3197.50 mm2; Females: FFMA < 2895.50 mm2

DEXA: Dual energy X-absorption study; FFMA: Fat-free muscle area; MRI: Magnetic resonance imaging; ASMI: Appendicular Skeletal Muscle Index.

Table 3 Nutritional and exercise-based therapeutic recommendations for patients with cirrhosis

Therapeutic recommendation	Details
Nutrition	N/A
Protein intake[51,60,65,66]	1.2-1.5 g/kg body weight per day; Up to 2.0 g/kg body weight per day for critically ill
Timing and pattern[51,71,73]	Small meals every 3-4 waking hours; Early breakfast; Late evening or nighttime snack
Branched-chain amino acid supplementation[27-32]	If unable to meet daily protein requirements
Not critically ill	0.25 g/kg body weight per day; Critically ill: Insufficient evidence to supplement in this population
Exercise	Safety screening and assessment; Variceal prophylaxis as required; Supervised training programs; Start low, go slow; Moderate intensity; Motivational interviewing, maximizing engagement and adherence[51,60,91]; Aerobic exercise such as walking 4-7 days a week for a total of 150 minutes; Resistance exercises such as weight or band training for 2-3 days per week; Flexibility and balance exercises, including stretching for 2-3 days per week

Table 4 Emerging therapies for sarcopenia and their proposed mechanisms

Emerging therapies	Proposed mechanism
Mineralocorticoid receptor antagonists such as spironolactone and tolvaptan	Mineralocorticoid receptors have a central role in insulin resistance and critical catabolic pathways like aging of skeletal muscle
L-ornithine L-aspartate	Promotes ammonia metabolism by increasing glutamine synthesis in skeletal muscle
Leucine	Increases the synthesis of albumin
Beta-hydroxy-beta-methylbutyrate	Activates the mTOR pathway and promotes IGF-1 production = anabolic effects
Long-chain omega-3 polyunsaturated fatty acids and medium-chain fatty acids	Anti-inflammatory properties
Vitamin D	Enhances cell proliferation and differentiation
L-carnitine	Enhances ATP production for muscle function
Follistatin	Natural antagonist to myostatin
Landogrozumab and bimagrumab	Monoclonal antibodies targeting myostatin

mTOR: Mechanistic target of rapamycin; IGF-1: Insulin-like growth factor 1.

Table 5 Clinical outcomes associated with sarcopenia in patients with cirrhosis

Ref.	Objectives	Methodology	Findings
Montano-Loza et al[160]	To evaluate the impact of sarcopenia in cirrhosis	669 cirrhotic patients using a novel MELD-sarcopenia score derived through Cox proportional hazards regression	Patients with sarcopenia had shorter median survival than non-sarcopenic patients (20 ± 3 months vs 95 ± 24 months, P < 0.001); MELD-sarcopenia score was associated with improved prediction of mortality
Bhanji et al[153]	To evaluate if sarcopenia is associated with overt hepatic encephalopathy in cirrhotics and evaluate its impact on mortality	675 cirrhotics with CT to evaluate sarcopenia	Sarcopenia was associated with an increased risk of hepatic encephalopathy (OR 2.42; 95%CI: 1.43-4.10, P = 0.001) and mortality (csHR 2.15, P < 0.001), independent of the MELD score
Zhou et al[168]	To investigate the association between sarcopenia and 1-year overall survival in patients with decompensated cirrhosis after liver transplantation	222 cirrhotics who underwent LT were followed up to compare and evaluate postoperative outcomes	Decompensated cirrhotics with sarcopenia had a longer ICU stay (4.1 ± 2.2 days vs 3.1 ± 1.1 days, P = 0.008), higher rate of major complications (45.2% vs 22.1%, P = 0.001), higher post-LT mortality (15.1% vs 2.9%, P = 0.003) with a shorter 1-year overall survival post-LT (P < 0.001), than in those without sarcopenia
Golse et al[166]	To evaluate the impact of sarcopenia on post-LT survival	256 patients with cirrhosis who underwent liver transplantation were selected retrospectively to study for post-LT survival	Significantly lower 1- and 5-year survival rates post-LT were reported in patients with sarcopenia (59% vs 94% and 54% vs 80%, respectively P < 0.001), compared to candidates without sarcopenia. (utilized the psoas muscle area as a measurement for sarcopenia, PMA was found to offer better accuracy than L3SMI)
Lai et al[154]	To develop a novel frailty index, encompassing extrahepatic complications of cirrhosis- muscle wasting, malnutrition and functional decline, as an improved mortality predictor in ESLD	536 cirrhotics (MELD-Na > 18) listed for LT. Final Frailty Index comprised of- grip strength, chair stands, and balance which were identified by best subset selection analyses with Cox regression to predict the waitlist mortality	Addition of Novel LFI to MELD score resulted in better prediction of waitlist mortality and has potential clinical utility to predict outcomes over a longer term on waitlist. Compared with MELD-Na alone, MELD-Na + Frailty Index correctly re-classified 16% of deaths/delistings (P = 0.005) and 3% of non-deaths/delistings (P = 0.17) with a total mortality of 19% (P < 0.001)

OR: Odds ratio; csHR: Cause-specific hazard ratio; MELD: Model for end-stage liver disease; ICU: Intensive care unit; LT: Liver transplant; LFI: Liver Frailty Index; CT: Computed tomography; ESLD: End-stage liver disease.