5 Keys to Sarcopenia in Liver Disease

The assessment of chronic liver disease has traditionally focused on biochemical and imaging data as proxies for liver health. However, a robust and growing body of hepatology and nutrition literature has demonstrated that a patient's clinical trajectory is also closely tied to the health and quantity of their skeletal muscle. Pooled data from nearly 13,000 patients with cirrhosis showed that sarcopenia was associated with twice the risk of death, underscoring the independent prognostic importance of muscle status. Clinicians frequently use the terms malnutrition, sarcopenia, and frailty interchangeably, but they represent distinct, although interconnected, clinical entities:Malnutrition is a clinical syndrome resulting from inadequate nutrient intake relative to physiologic requirements, leading to a hypercatabolic state. In liver disease, malnutrition is associated with poor clinical outcomes.Sarcopenia is the objective loss of skeletal muscle mass and quality. In liver disease, it often results from catabolic physiologic processes, reduced physical activity, and inadequate nutritional intake.Frailty is a multisystem decline in physiological reserve that manifests as diminished physical performance in daily activities. It can be objectively tested with measures such as handgrip strength and gait speed.Understanding the liver-muscle axis and addressing abnormalities early in the disease course are essential to preventing the cascade that can ultimately lead to frailty. Here are five key concepts clinicians should know about sarcopenia in liver disease. 1. Muscle Is a Metabolic OrganAlthough ammonia detoxification is primarily viewed through a hepatic lens, skeletal muscle also serves as an important metabolic organ. When hepatic function is compromised, skeletal muscle assumes a greater role in clearing systemic ammonia. Sarcopenia reduces this alternative clearance pathway and directly drives the development and worsening of hepatic encephalopathy.Recent literature has highlighted the bidirectional nature of this relationship. Hyperammonemia is directly toxic to myocytes and can trigger autophagy, in which muscle essentially consumes itself, creating a vicious and self-perpetuating cycle. A 2024 randomized trial evaluating a gut-targeted antibiotic in patients with minimal hepatic encephalopathy found that lowering ammonia was also associated with improvements in muscle mass, handgrip strength, and physical function, providing early clinical evidence that this cycle may be interrupted rather than simply observed. Therefore, an important component of managing hepatic encephalopathy is protecting the very muscle mass that helps clear ammonia from the systemic circulation.2. Sarcopenic Obesity Can Hide in Plain SightThe global rise of metabolic dysfunction-associated steatotic liver disease (MASLD) has fundamentally altered the phenotype of the patient with liver disease. Sarcopenia is not exclusive to cirrhosis; it can emerge earlier in the metabolic disease process in association with insulin resistance, cytokine-driven inflammation, and other factors.Clinicians now frequently encounter sarcopenic obesity, a high-risk phenotype in which substantial skeletal muscle depletion can be obscured by excess adipose tissue mass and fluid retention. Reliance on BMI or visual inspection alone can therefore lead to underdiagnosis. Compounding the problem is myosteatosis, or fat infiltration into skeletal muscle, which degrades muscle quality and function even when muscle bulk appears preserved. Metabolic muscle loss in early MASLD has been associated with accelerated liver disease progression and an increased risk for advanced fibrosis. A 2025 study encompassing more than 4200 patients with MASLD across cohorts in China and the United States identified sarcopenia as an independent predictor of significant fibrosis, advanced fibrosis, and cirrhosis, adding weight to the concept that muscle loss is more than simply a downstream marker of liver injury. 3. Protein Intake and Physical Activity Are KeyOne persistent legacy practice is restricting dietary protein in patients with liver disease. Modern nutritional science no longer supports this approach and suggests that it may be harmful. Because of severely depleted hepatic glycogen stores, patients with chronic liver disease enter an accelerated starvation state after just a few hours of fasting, increasing their reliance on muscle breakdown to fuel essential gluconeogenesis. Current American Association for the Study of Liver Diseases guidance recommends protein intake of 1.2-1.5 g/kg/day for adults with cirrhosis and 1.2-2.0 g/kg/day for those who are critically ill. Even these targets can be challenging to meet due to the gastrointestinal complications of liver disease. Ascites mechanically compresses the stomach, causing early satiety, whereas portal hypertension can prolong gastric emptying and small bowel transit. Restricting dietary protein in a patient already facing these metabolic and anatomical barriers can further accelerate catabolism. Nutrition alone, however, may be insufficient to address the impaired muscle protein synthesis seen in liver disease. When feasible, increased dietary protein intake should be paired with physical activity that includes resistance training. Randomized controlled trials evaluating exercise interventions in liver disease haveshown that resistance training combined with moderate-intensity aerobic activity can safely improve muscle mass, frailty, and aerobic fitness in these patients. A recently reported randomized trial, the NExT study, evaluated the addition of testosterone therapy to nutrition and structured exercise in men with cirrhosis and sarcopenia. Overall, 66% of men who received testosterone reached the trial's target increase in muscle mass compared with 25% of those who received nutrition and exercise alone, suggesting that pharmacologic augmentation may eventually have a role alongside lifestyle interventions in select patients. 4. Inpatient Nil Per Os (NPO) Status Can Accelerate Muscle WastingAlthough outpatient dietary counseling is crucial, some of the most rapid muscle loss can occur during hospitalization. A 2025 study directly comparing inpatients and outpatients with cirrhosis found that hospitalized patients had significantly greater energy and protein deficits and worse overall nutritional status, suggesting that hospitalization itself can compound the nutritional decline associated with underlying disease.Hospitalized patients may be subjected to prolonged fasting because of NPO orders or restriction to clear liquid diets for days at a time. Because of the accelerated starvation physiology associated with cirrhosis, even 24-hour periods of inpatient fasting can trigger muscle catabolism equivalent to multiple days of starvation in healthy individuals. Hospitalization can therefore act as a tipping point that pushes a compensated patient into a spiral of worsening frailty. Minimizing unnecessary fasting and returning patients to an adequate, high-protein diet as rapidly as clinically safe represent critical, modifiable steps to limit hospitalization-induced muscle wasting. 5. Power of the Late-Night SnackThe fasting physiology of individuals with chronic liver disease can mimic that of healthy individuals fasting for multiple days. As a result, total daily caloric intake may be insufficient if it is poorly distributed throughout the day, making the overnight fasting window a major catalyst for skeletal muscle destruction.A randomized controlled trial showed that long-term nocturnal nutritional supplementation significantly increased lean body mass compared with regular daytime supplementation. In addition, a late-night snack containing complex carbohydrates and protein was associated with reduced hepatic encephalopathy recurrence. The 2025 American College of Gastroenterology Clinical Guideline on Malnutrition and Nutritional Recommendations in Liver Disease strongly recommended late-evening snacks to improve lean mass and reduce the risk for ascites and hepatic encephalopathy, moving this strategy from a promising intervention toward a formal practice standard. Given the delayed gastric emptying and early satiety these patients often experience, dividing nutritional intake into smaller, more frequent meals anchored by a late-night snack can be an effective strategy for combating “midnight muscle wasting.” Overall, eliminating prolonged fasting represents another potential tool for preventing or mitigating sarcopenia in patients with liver disease. Make Muscle Part of the Liver Assessment Sarcopenia in liver disease should not be viewed as an inevitable consequence of end-stage liver disease. It is a potentially modifiable complication arising from the interplay of accelerated starvation, systemic inflammation, and hyperammonemia.Early screening that looks beyond BMI, adequate protein intake, resistance exercise when feasible, and minimizing inpatient fasting windows are practical strategies for preserving muscle mass and potentially improving outcomes.