COMMENTARY

Sarcopenia in Liver Disease: Effect of Pre-transplant Intervention on Post-transplant Outcomes

Rowen K. Zetterman, MD

Disclosures

October 22, 2018

Sarcopenia, defined as the loss of muscle mass associated with aging,[1] is present in more than 30% of elderly persons[2] and observed worldwide.[3] Not surprisingly, a greater prevalence of sarcopenia is noted in patients residing in nursing homes. Although sarcopenia is common in elderly patients, the condition can develop in patients who have chronic disorders, malignancies, limited physical activity, and poor nutrition.

Patients with sarcopenia develop physical frailty resulting in muscle deconditioning, muscle weakness,[4] reduced muscle strength and muscle function, and slow gait speed,[5] which increase the risk for physical disability and falls. Sarcopenia also defines the cellular processes associated with inflammatory, hormonal, and mitochondrial changes in muscle that produce the loss of muscle mass, function, and strength.[6]

A systemic review of elderly patients with sarcopenia demonstrated an increased risk for morbidity and mortality and increased readmission rates following hospitalization. Sarcopenia, however, does not appear to be a risk factor for initial hospitalization.[7]

A healthier diet in elderly patients may improve muscle performance and lower the risk of developing sarcopenia.[8]

Primary vs Secondary Sarcopenia

While primary sarcopenia, or age-related sarcopenia, is associated with the aging process, secondary sarcopenia can develop as a result of poor dietary intake, malnutrition, and chronic disease. Chronic conditions associated with sarcopenia include malabsorption and other gastrointestinal disorders, systemic inflammatory disease, hormonal changes, insulin resistance, type 2 diabetes mellitus, neurologic disorders such as Parkinson disease, cerebrovascular accidents, and physical deconditioning.[6,9] Reduced physical activity is both a cause and a result of sarcopenia. Acute sarcopenia can develop in older adults who have been hospitalized for acute inflammatory conditions.[10]

Patient Assessment for Sarcopenia

Sarcopenia may be masked by associated obesity. This occurs in patients with end-stage liver disease (ESLD) due to nonalcoholic fatty liver disease (NAFLD) or alcoholic liver disease.[11,12] To assess the presence of sarcopenia in patients, several studies have used the measurement of the cross-sectional area of both psoas muscles at the level of lumbar vertebrae 3 (L3) during CT imaging. In elderly patients, sarcopenia is defined as more than two standard deviations below that of normal young adults.[4] The cross-sectional psoas muscle area can also be normalized to patient height.[13] In patients with cirrhosis, a combination approach that assesses body mass index (BMI) and measures the thickness of the patient's thigh muscle using ultrasound will identify sarcopenia as effectively as cross-sectional CT imaging.[14]

The focus of this article is on the association of sarcopenia with chronic liver disease and how it affects both the course and the outcome of liver disease and liver transplantation.

Liver Disease

The loss of muscle mass is common in patients with advanced cirrhosis[15] and related to the presence of significant liver fibrosis[16] and reduced caloric and protein intake.[17] The decrease of hepatic glycogen in patients with cirrhosis results in an increase in gluconeogenesis from amino acids released by the breakdown of body muscle.[18] Other associations include malnutrition, increased catabolism, and limited physical activity.[17,19,20] It is important to note that sarcopenia cannot be assumed in patients with liver disease simply based on weight loss.[5]

As many as 40% of patients with ESLD have evidence of sarcopenia.[21] The prevalence of sarcopenia is higher in male patients and in patients who have Child-Pugh class C functional status. Sarcopenia also occurs in such disorders as NAFLD, wherein treatment with reduced caloric intake and weight loss can aggravate underlying sarcopenia.[22] Sarcopenia itself may accelerate a patient's risk of developing NAFLD.[23]

The presence of sarcopenia is independent of the underlying severity of liver dysfunction as a predictor of the development of complications and mortality in ESLD.[24,25] A greater loss of muscle mass occurs in patients with advanced liver disease. The rate of development of sarcopenia is a predictor of mortality.[26] Patients with the most rapid loss of muscle are more likely to die from their liver disease. Hepatic encephalopathy also is more likely to be present in patients with sarcopenia.[27] The risks for sepsis, frailty, reduced mobility, and reduced quality of life while awaiting liver transplantation are all issues for these patients with sarcopenia as well.[5,24]

Liver Transplantation

The MELD (Model for End-Stage Liver Disease) score assesses the mortality risk of patients with advanced liver disease awaiting transplantation.[28] Yet, concerns as to how well the MELD score predicts a patient's survival following liver transplantation have been raised. In addition to the MELD score, the extent of reduced muscle mass in patients with liver disease is an indicator of waiting list mortality[21] and post-transplant survival.[29] Studies have shown that assessing a patient's nutritional status and sarcopenia prior to transplant may be a better predictor of liver transplant outcome,[30] and that a combination MELD-sarcopenia score is a more accurate predictor of mortality.[25] Findings from a recent literature review evaluating frailty and sarcopenia in liver transplant patients prompted the study authors to call for the development of an index for transplant candidates that assesses both sarcopenia and frailty.[31] Additional data, however, are indicated to further study the effects of sarcopenia on both waitlist and post-transplant mortality.

In a retrospective study of living-donor liver-transplant recipients, patients with "high-loss" sarcopenia developing during the first 7 days following transplantation had longer intensive care unit (ICU) stays, longer periods of mechanical ventilation, and lower overall survival following liver transplantation.[32] A prospective study of 256 patients receiving liver transplants from living donors[29] evaluated patients for pre-transplant sarcopenia based on psoas muscle surface area and presence of malnutrition (termed denutrition), which was defined by findings of a low BMI or an albumin level of less than 3.0 g/dL. The etiology of underlying cirrhosis did not identify patients with a greater likelihood of having sarcopenia. Patient survival was assessed at multiple time points over a 5-year period, and compared findings between patients with and without sarcopenia. Patients in the sarcopenia group were more likely to be female and have more ascites, thrombocytopenia, and a higher MELD score; this group also had longer post-transplant ICU stays, greater morbidity, and a higher postoperative mortality. At 5 years, 80% of nonsarcopenic patients were alive compared with only 54% of sarcopenic patients. Most of the mortality associated with sarcopenia occurred within the first year following transplant.

Another study also indicates that patients with pre-transplant sarcopenia have longer stays in the ICU and the hospital and a greater risk for postoperative infection following liver transplantation.[30] Not surprisingly, the cost of transplantation is also higher in patients with sarcopenia.[33]

Pre-transplant Intervention

More studies are needed to determine whether interventions such as diet, physical resistance training, and pharmacologic therapy have a positive effect on sarcopenia prior to liver transplantation. To date, only a few studies have assessed the effectiveness of these interventions on frail patients with sarcopenia. Many patients with pre-transplant hepatic encephalopathy endure low-protein diets in the belief that it reduces the risk for recurrent encephalopathy. However, these patients need dietary protein as much as patients with ESLD who lack encephalopathy.

Dietary intake needs to be improved.[34,35,36] Management should include nutritional supplementation,[5] as well as a change in attitude concerning low-protein diets in patients with encephalopathy. Patients should consume 35-40 kcal/kg/d, including 1.2-1.5 g/kg/d of protein. The administration of branched-chain amino acids also may help improve post-transplant outcomes.[37] Patients with sarcopenia should be advised to eat frequent, smaller meals and evening snacks to improve overall nutrition.[5,38] If patients cannot ingest sufficient oral nutrition on their own, enteral feeding should be used.[39]

In addition to nutritional intervention, because physical activity appears to improve muscle function and reduce sarcopenia, patients should be placed on an exercise program.[6,36,40] Patients should be advised to walk 5000 or more steps daily.[17] Progressive resistance training may also reduce sarcopenia.[41] Even short-term exercise programs of 3 to 6 months at intervals of two to three times a week can improve muscle mass and muscle strength.[40] Can moderate-intensity aerobic exercise and muscle training reduce sarcopenia and frailty in patients with liver disease?[42,43] Although this may be difficult for the deconditioned liver patient, increased physical activity should likely be attempted.

Along with lifestyle modifications, it should be ensured that patients are able to perform the usual activities of daily living. For example, they should be assessed to determine if they have any difficulties swallowing, as this can exacerbate sarcopenia.[40] Patients should also be assessed for the presence of any dental issues (eg, denture fit, infection, loss of teeth). Furthermore, to ensure adequate dietary and nutritional intake, it is important to establish whether or not patients require assistance with meal preparation.

Controlling the complications of liver disease is important. Ascites treated with large-volume paracentesis adds to protein loss. Use of transjugular intrahepatic portosystemic stent shunts (TIPS) can reduce ascites and improve overall nutrition and reduce sarcopenia.[44,45] Patients who do not experience improvement in sarcopenia following TIPS placement may have a greater overall mortality.[45]

The use of anabolic steroids to increase muscle mass[5,46] requires further study before it can be recommended for patients with ESLD.

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