Frailty in end-stage liver disease: Understanding pathophysiology, tools for assessment, and strategies for management

Table 1 Definition of frailty, different types of sarcopenias, malnourishment, and cachexia

	Definition
Frailty	A condition where patients undergo a reduction in their physical abilities and become more vulnerable to health-related challenges, leading to negative health consequences. It is a multifaceted concept that involves different aspects such as physical, psychological, social, and environmental factors[8]
Malnourishment	An imbalance in the consumption of nutrients, whether it be a deficiency or an excess, can have detrimental effects on the body’s tissues and overall physical form[9]
Cachexia	A metabolic syndrome that is complex and linked to an underlying illness. It is distinguished by the reduction of muscle mass, with or without a decrease in fat mass[10]
Sarcopenia	A debilitating syndrome that is marked by a gradual and widespread decline in both skeletal muscle mass and strength[11]
Dynapenia	The pre-sarcopenia stage, in which only muscle strength is reduced[12]
Primary sarcopenia	The loss of anatomical skeletal muscle mass in the aging population[13]
Secondary sarcopenia	The loss of skeletal muscle mass in various chronic diseases[14]
Compound sarcopenia	The combination of primary (i.e., age-related) and secondary (i.e., disease-related) sarcopenia. It occurs in older patients with chronic diseases[15]
Sarcopenic obesity	A state of decreased muscle mass in the setting of increased fat mass. The muscle wasting can be obscured by increased muscle mass, making specialized testing and management necessary[16]

Table 2 Pathophysiology, effects, and management recommendations for frailty predisposing factors in cirrhosis

Predisposing factor	Pathophysiology	Morbidity and mortality	Recommendations
Ascites	Loss of appetite; Difficult ambulation; Reduced stomach capacity; Poor digestion	Odds of frailty were higher in ascitic than non-ascitic patients [adjusted odd ratio 1.56, 95% confidence interval (CI): 1.15-2.14][129]. Ascitic patients identified as frail had a 29% waitlist mortality rate, higher than the 17% rate for non-frail patients[129]	Large volume paracentesis with iv albumin; Salt intake not < 5 g NaCl/d to preserve food palatability
Hepatic encephalopathy (HE)	Decreased voluntary oral intake; Decreased capacity for ambulance and exercise	Odds of frailty were higher in HE than in non-HE patients (odd ratio 2.45, 95%CI: 1.80-3.33)[129]. Waitlist mortality was higher for HE patients identified as frail (30%) than non-frail (20%)[129]	Enteral nutrition with precautions to avoid aspiration and hyperglycemia; Parenteral nutrition if indicated; Avoid unnecessary protein restriction
Alcohol intake	Decreased oral intake; Gastrointestinal upset; Vitamin and mineral deficiency; Increased resting energy expenditure; Alcohol direct toxic muscular and neurologic effects	Frail alcoholic liver disease patients had a significantly higher risk of death or liver transplantation compared to non-frail patients (P < 0.001)[130]	Alcohol abstinence; Healthy diet with approximately 30 kcal/kg to 40 kcal/kg per day; Small and frequent meals; Enteral feeding in severe disease
Sarcopenic obesity	Challenging to diagnose; Physical disability due to decreased muscle size and high muscle fat	MASLD cirrhotic patients have an increased risk of worsening frailty over time and higher waitlist mortality than non-MASLD patients[131]	Structured exercise program to help preserve muscle mass; If caloric restriction is necessary, maintain adequate protein intake (1.2-1.5 g/kg/d)
Prolonged fasting	Accelerated catabolic state with Increased muscle breakdown		Limit fasting period to a maximum of 12 h; Daily calorie intake should be divided into 4-6 meals; Late evening snacks
Loop diuretics	May worsen muscle mass loss	Loop diuretics inversely correlated with skeletal muscle mass in cirrhotic patients (P < 0.0001) and high doses were independently associated with mortality[126]	Regular frailty assessments are recommended for patients who have been on prolonged courses of loop diuretics, particularly when the dosage exceeds 20 mg/d; Spironolactone may be a preferable option for long-term use due to its promising efficacy in treating sarcopenia
Aging	Combined muscle loss due to aging and hepatic illness (compound sarcopenia)	Elderly sarcopenic patients with cirrhosis have longer hospital stays, higher hospitalization costs, and increased risk of in-hospital mortality[15]	Frequent frailty assessment and management in elderly patients with cirrhosis

MASLD: Metabolic dysfunction-associated steatotic liver disease.

Table 3 Comparison of different frailty suggested medications in cirrhotic patients

Suggested medication	Target of action	Side effects	Dose used in clinical trials	Clinical trial results
Metformin	Insulin resistance; Proinflammatory cytokines	Gastrointestinal upset; Non responders[209]	-	-
Rifaximin	Gut dysbiosis	-	1200 mg daily for 24 wk	No significant changes in skeletal muscle index[186]
Myostatin antagonists	Hyperammonemia; Muscle mass inhibition	Spontaneous bone fractures[210]; Vascular (nasal and gum bleeding, telangiectasia)[211]	-	-
L-Carnitine	Hyperammonemia; Proinflammatory cytokines (antioxidant)	Gastrointestinal upset	(1000 mg/d) + exercise for 6 mo[201]	No significant changes in muscle mass, leg, and handgrip strength[201]
L-ornithine L-aspartate	Hyperammonemia	Gastrointestinal upset	6 g three times daily for 2 wk[207]	No significant increase in prealbumin level after use[207]
Testosterone therapy	Testosterone deficiency	Cardiovascular diseases; Prostate cancer; Erythrocytosis[212]	Intramuscular injection of testosterone undecanoate 1000 mg at 0, 6, 18, 30, 42 wk[172]	The intervention group had increased muscle and bone mass with lower fat mass[172]