What is anabolic resistance in cirrhosis and how should it be managed?

Anabolic Resistance in Cirrhosis

Anabolic resistance in cirrhosis is a state where skeletal muscle fails to respond normally to anabolic stimuli—including adequate protein intake and exercise—resulting in persistent muscle loss despite nutritional supplementation. 1, 2

Pathophysiology

Anabolic resistance in cirrhosis arises from multiple interconnected mechanisms that prevent normal muscle protein synthesis:

Hyperammonemia as the Central Driver

• Elevated ammonia directly impairs muscle protein synthesis and mitochondrial function, representing the best-studied mediator of the liver-muscle axis 3, 1, 4
• Hyperammonemia causes cataplerosis of α-ketoglutarate, depleting tricarboxylic acid cycle intermediates essential for energy production 2, 4
• Ammonia increases autophagy-mediated proteolysis, accelerating muscle protein breakdown faster than replacement 1, 4
• Posttranslational modifications of contractile proteins occur due to ammonia, impairing both muscle mass and contractile function 3

Altered Amino Acid Metabolism

• Reduced circulating branched-chain amino acids (BCAAs), particularly leucine, limit the essential trigger for muscle protein synthesis 3, 1
• Increased leucine transport into muscle occurs in exchange for glutamine (for ammonia detoxification), but impaired leucine signaling prevents its anabolic effect 4
• This creates a paradox where amino acids are diverted to ammonia detoxification rather than muscle building 2

Molecular Signaling Abnormalities

• Up-regulation of myostatin suppresses muscle protein synthesis and increases proteolysis 1, 2, 4
• Increased phosphorylation of eukaryotic initiation factor 2α impairs ribosomal function and protein translation 4
• Impaired mTOR signaling prevents normal anabolic responses to nutrients 5

Metabolic Dysfunction

• Mitochondrial dysfunction with decreased ATP content and increased reactive oxygen species further impairs protein synthesis 1, 4
• Enhanced autophagic activity degrades muscle proteins faster than they can be replaced 1, 4

Systemic Factors

• Chronic systemic inflammation (elevated IL-1, IL-6, IL-10, TNF-α) promotes reduced muscle protein synthesis and increased protein degradation 3
• Reduced circulating testosterone, growth hormone, and IGF-1 levels diminish anabolic signaling 3, 1
• Obesity-associated metabolic dysregulation, insulin resistance, and visceral fat accumulation compound anabolic resistance 3

Clinical Manifestations

The key clinical consequence is that achieving neutral nitrogen balance with protein supplementation does not automatically translate into gains in lean body mass 1, explaining why:

• Nutritional supplementation alone has been of limited or no benefit in reversing sarcopenia 2
• Patients exhibit impaired skeletal muscle protein synthesis together with accelerated protein breakdown, resulting in net negative protein balance despite adequate protein intake 1
• Meta-analyses of enteral feeding have not shown significant survival benefits despite individual promising studies 3

Management Strategies to Overcome Anabolic Resistance

Nutritional Interventions (Foundation but Insufficient Alone)

Protein and Energy Requirements:

• Provide 1.2–1.5 g protein/kg/day, recognizing this is necessary but alone does not consistently increase muscle mass 3, 1
• Total energy provision of at least 35 kcal/kg/day is required; caloric deficit forces protein oxidation for fuel rather than muscle synthesis 3, 1
• Critical pitfall: Supplying protein without meeting caloric goals leads to protein oxidation rather than muscle accretion 1

BCAA Supplementation:

• Use BCAA supplements and leucine-enriched amino acid supplements in decompensated cirrhotic patients to achieve adequate nitrogen intake and stimulate muscle protein synthesis 3, 1
• This addresses the specific amino acid deficiencies characteristic of cirrhosis 1

Meal Timing Strategy:

• Implement late evening oral nutritional supplementation (approximately 7–10 PM) to interrupt accelerated nocturnal catabolism 3, 1
• Cirrhotic patients enter a starvation state after only 6–8 hours of fasting, far sooner than healthy individuals 1
• Include breakfast in the dietary regimen of malnourished decompensated cirrhotic patients 3

Physical Activity (Essential Anabolic Stimulus)

Progressive physical activity provides the anabolic stimulus necessary for muscle protein synthesis; protein intake without concurrent exercise fails to activate anabolic pathways 1:

• Encourage patients with cirrhosis to avoid hypomobility and progressively increase physical activity whenever possible 3
• A combination of resistance and endurance exercise is appropriate and beneficial, as both muscle loss and impaired contractile function are components of sarcopenia 3
• Moderate intensity exercise regimens have shown emerging benefits in cirrhosis 3
• Important caveat: Exercise increases muscle ammonia generation and portal pressure, which can have adverse effects, though beneficial effects have been reported despite these concerns 3
• Endurance exercise for up to 12 weeks is clinically tolerated in well-compensated cirrhosis 6

Ammonia-Lowering Strategies

Reducing hyperammonemia may restore the muscle's capacity to respond to protein intake, addressing a key mechanistic barrier to anabolism 1:

• Long-term ammonia-lowering strategies may result in increased muscle mass and contractile strength, though data are derived from preclinical studies and require validation in human studies 3
• Ammonia-lowering strategies represent a future therapeutic direction to reverse the underlying cause of anabolic resistance 3

Additional Considerations

Enteral Nutrition:

• In patients with malnutrition and cirrhosis unable to achieve adequate dietary intake with oral diet (even with oral supplements), a period of enteral nutrition is recommended 3

Hormone Replacement:

• Hormone replacement therapy utilizing growth hormone or testosterone has been proposed but has not been consistently effective 3
• Caution is needed when using testosterone because of the possibility of increasing hepatocellular carcinoma risk 3

Obesity Management:

• In obese cirrhotic patients (BMI >30 kg/m² corrected for water retention), implement a nutritional and lifestyle program to achieve progressive weight loss (>5–10%) 3
• Use a tailored, moderately hypocaloric (−500–800 kcal/day) diet, including adequate protein intake (>1.5 g proteins/kg/day) to achieve weight loss without compromising protein stores 3

Critical Pitfalls to Avoid

• Never restrict protein intake in cirrhotic patients with hepatic encephalopathy, as it increases protein catabolism 3
• Neglecting appropriate meal timing (omitting late-evening snack) permits prolonged overnight fasting and rapid muscle catabolism 1
• Providing protein without BCAA enrichment fails to correct specific amino acid deficiencies 1
• Expecting rapid muscle mass gains is unrealistic; even with optimal combined therapy, improvements are modest and require sustained, multimodal intervention 1
• Focusing solely on nutritional supplementation without addressing physical activity fails to provide the necessary anabolic stimulus 1

Multimodal Approach Required

The fundamental principle is that overcoming anabolic resistance requires a multimodal strategy combining adequate protein and energy intake, BCAA supplementation, strategic meal timing, progressive physical activity, and potentially ammonia-lowering therapies 1. No single intervention is sufficient because the underlying molecular and metabolic abnormalities persist unless multiple pathways are simultaneously addressed 2, 4.