An emerging predictor of outcomes in chronic liver disease

Myosteosis, the pathological infiltration of fat into skeletal muscle, is increasingly recognized as a key predictor of poor clinical outcomes in a spectrum of liver diseases. However, the field faces significant challenges, including a lack of standardized assessment methods, definitions, and diagnostic criteria, as well as an incomplete understanding of its pathophysiological mechanisms. This narrative review aims to synthesize the current knowledge of myosteatosis in liver disease, covering its assessment, clinical impact in various etiologies, proposed pathogenesis, and potential management strategies.

Assessment and definition of myosteatosis

Myosteatosis represents muscle wasting qualitydifferent from sarcopenia (reduced muscle quantity). Its assessment has gone beyond the limited scope of Body Mass Index (BMI). Computed tomography (CT) is the most widely used and validated tool in clinical research, mainly using two measurements at the third lumbar vertebra (L3): muscle radiation attenuation (RA, measured in Hounsfield units, HU) and the ratio of intramuscular adipose tissue content (IMAC). Lower RA values ​​or higher IMAC values ​​indicate greater fat infiltration. However, diagnostic thresholds differ significantly between studies (eg, using BMI-adjusted RA values ​​or sex-specific IMAC thresholds), leading to widened prevalence estimates and complicating comparisons between studies. Magnetic resonance imaging (MRI) provides superior accuracy for quantification of the intramuscular fat fraction, but is less accessible. Ultrasound shows potential as a point-of-care tool, but lacks standardized criteria. Method selection balances accuracy, practicality, and patient-specific factors.

Clinical effect on liver diseases

• Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD): Myosteatosis is prevalent in MAFLD and is independently associated with more severe disease phenotypes, including non-alcoholic steatohepatitis (NASH) and significant liver fibrosis. It may serve as a biomarker for disease progression and is associated with an increased risk of hepatocellular carcinoma (HCC) and all-cause mortality.

• Cirrhosis of the liver: Myosteatosis is common in cirrhosis and is a strong, independent prognostic marker. It is associated with higher Child-Pugh scores, hepatic encephalopathy, portal hypertension, other compensatory events, and significantly increased long-term mortality. Predictive models such as MELD are improved by incorporating myostosis.

• Hepatocellular carcinoma (HCC): In patients with HCC, myosteatosis is associated with worse outcomes, including reduced response to transarterial chemoembolization, shorter progression-free survival in those receiving immunotherapy, and higher rates of postoperative complications and mortality after hepatectomy.

• Liver Transplantation (LT): Myosteatosis in LT candidates and recipients is associated with worse post-transplant outcomes, including increased infections, longer hospital stays, higher costs, and reduced graft and patient survival. Enhances the predictive value of pre-transplant risk scores.

• Chronic viral hepatitis & primary sclerosing cholangitis (PSC): Emerging evidence suggests a role for myosteatosis in chronic hepatitis C and B, although data are less extensive. In PSC, myosteatosis is an independent predictor of reduced transplant-free survival.

Proposed pathophysiological mechanisms

The development of myosteosis in liver disease is multifactorial, driven by a dysfunctional liver-muscle axis:

1. Insulin resistance: It reduces the availability of glucose in the muscles, increasing the uptake of free fatty acids and intramuscular lipogenesis.

   
   
   

2. Hyperammonemia: A hallmark of cirrhosis, ammonia is taken up by muscle, causing mitochondrial dysfunction and reducing fatty acid oxidation, leading to lipid accumulation.

3. Chronic inflammation: Proinflammatory cytokines (eg, IL-6, TNF-α) released by the diseased liver disrupt muscle lipid metabolism and promote fat storage.

4. Mitochondrial dysfunction: A central defect leading to impaired oxidative phosphorylation and reduced lipid oxidation in muscle cells.

5. Other factors: Elevated plasma cathepsin D levels correlate with myosteosis. Nutritional imbalances (both overload and deficiency), genetic factors, and changes in gene expression associated with aging (eg, adipogenic regulators are involved) also contribute.

Possible prevention and treatment strategies

Currently, there are no consensus guidelines for the treatment of myosteatosis in liver disease due to a lack of high-level evidence. The proposed strategies are multimodal:

• Nutritional intervention: Tailored to the stage of the disease, focusing on adequate intake of high-quality protein (1.2-1.5 g/kg ideal body weight/day), balanced meals low in saturated fat, and specific amino acid supplementation (eg, leucine, essential amino acids). Energy restriction must be done to avoid a concomitant loss of muscle mass.

• Exercise recipe: A combined regimen of progressive aerobic exercise and resistance exercise is fundamental. Exercise helps maintain muscle function, enhances lipid oxidation, and can reverse fat infiltration, especially when combined with dietary management.

• Pharmacological treatment: Experimental approaches include agents targeting pathogenic pathways, such as L-ornithine L-aspartate (to reduce ammonia) and adiponectin receptor agonists (eg, AdipoRon), which have shown promise in preclinical models.

Conclusion

Myosteosis is a critical, but often overlooked, component of body composition abnormalities in chronic liver disease. It independently predicts morbidity, mortality and poor treatment outcomes in all etiologies, from MAFLD to end-stage cirrhosis and HCC. Lack of standardized assessment hinders clinical translation. Its pathogenesis is complex and includes insulin resistance, hyperammonemia, inflammation, and mitochondrial dysfunction within the liver-muscle axis. Future research should prioritize establishing uniform diagnostic criteria and conducting randomized controlled trials to evaluate the effectiveness of integrated physical, nutritional, and pharmacological interventions aimed at mitigating myostosis and improving patient outcomes.