Sarcopenia and frailty in decompensated cirrhosis

Abstract

In patients with decompensated cirrhosis, sarcopenia and frailty are prevalent. Although several definitions exist for these terms, in the field of hepatology, sarcopenia has commonly been defined as loss of muscle mass, and frailty has been broadly defined as the phenotypic manifestation of the loss of muscle function. Prompt recognition and accurate assessment of these conditions are critical as they are both strongly associated with morbidity, mortality, poor quality of life and worse post-liver transplant outcomes in patients with cirrhosis. In this review, we describe the complex pathophysiology that underlies the clinical phenotypes of sarcopenia and frailty, their association with decompensation, and provide an overview of tools to assess these conditions in patients with cirrhosis. When available, we highlight data focusing on patients with acutely decompensated cirrhosis, such as inpatients, as this is an area of unmet clinical need. Finally, we discuss management strategies to reverse and/or prevent the development of sarcopenia and frailty, which include adequate nutritional intake of calories and protein, as well as regular exercise of at least moderate intensity, with a mix of aerobic and resistance training. Key knowledge gaps in our understanding of sarcopenia and frailty in decompensated cirrhosis remain, including best methods to measure muscle mass and function in the inpatient setting, racial/ethnic variation in the development and presentation of sarcopenia and frailty, and optimal clinical metrics to assess response to therapeutic interventions that translate into a reduction in adverse outcomes associated with these conditions.

Keywords: Body composition; Computed tomography; End-stage liver disease; Liver transplant; Muscle function; Muscle mass; Survival.

Fig. 1.. The conceptual overlap between frailty, sarcopenia, and their contributing factors.

The common connection of impaired muscle health in the definitions of frailty and sarcopenia in patients with cirrhosis naturally results in an overlap in the factors that contribute to their development. The contributing factors can independently contribute to frailty or sarcopenia or both (centripetal arrows from the outer circle); the effect of these factors on the development of frailty or sarcopenia or both may further be potentiated by the effect of the factors on each other (bidirectional arrows in the outer circle).

Fig. 2.. Tools that have been studied in patients with cirrhosis to quantify multi-dimensional (global) frailty, physical frailty, and sarcopenia.

Tools to measure frailty and sarcopenia in patients with cirrhosis. This fig. represents the tools to operationalise the constructs of frailty and sarcopenia that have been studied in patients with cirrhosis. While each of the instruments was originally developed to capture a specific construct (e.g., global frailty, physical frailty, or sarcopenia), in practice, overlap exists and the selection of the instrument used for either clinical or research is influenced by pragmatic concerns. ADL, activities of daily living; BIA, bioelectrical impedance analysis; DXA, dual energy X-ray absorptiometry; KPS, Karnofsky performance status; SPPB, short physical performance battery.

Fig. 3.. Proposed mechanisms of frailty and sarcopenia in cirrhosis.

(A) Common drivers of frailty are present in aging and decompensated cirrhosis. Hepatic encephalopathy, sarcopenia, altered gut microbiota and bacterial translocation, endotoxemia and exacerbation of chronic inflammation are associated with liver decompensation and contribute to the general frailty phenotype. (B) Multiple mechanisms contribute to sarcopenia in cirrhosis. These include physical inactivity, a lack of adequate energy sources due to reduced dietary intake, low glycogen deposits and a rapid transition to fasting metabolism. Endotoxemia, chronic inflammation and toxic substances such as alcohol also contribute. Low testosterone levels may contribute in male patients. Molecular mechanisms are detailed in the Pathogenesis section. BCAA, branched chain amino acid.

Fig. 4.. Potential mechanisms of sarcopenia and physical frailty and their association with a higher risk of decompensation in patients with cirrhosis.

Sarcopenia and frailty are present in 40-70% and 18-43% of patients with cirrhosis. The main factors associated with these conditions include portal hypertension, a catabolic state, synthetic dysfunction, chronic inflammation, progressive immobility and deconditioning. Sarcopenia and frailty are associated with an increased risk of liver decompensation related complications, including ascites, hepatic encephalopathy and infection. Liver decompensation may also increase the risk of worsening both sarcopenia and frailty. Post-transplantation, both conditions are associated with an increased risk of morbidity and mortality.

Fig 5.. Proposed therapeutic strategies for the treatment of frailty and sarcopenia in cirrhosis.

(A) Potential therapeutic strategies to treat frailty in cirrhosis. At the current time (apart from sarcopenia based therapies), these therapies have not been evaluated in experimental studies or in patients. (B) Potential therapeutic strategies to treat sarcopenia in cirrhosis. At the current time, evidence for most of these strategies is based on a small number of experimental or human-based studies. Larger prospective interventional studies are required to determine whether the findings in molecular studies can be translated to patients. See more details in the section on Pathogenesis and the section on Therapy. BCAA, branched chain amino acid.

Fig 6.. Summary of therapies for sarcopenia and frailty^,.

BCAA, branched chain amino acid; HCC, hepatocellular carcinoma; RCT, randomised controlled trial.