Consilience in sarcopenia of cirrhosis

Abstract

Cirrhosis is the consequence of progression of many forms of necro-inflammatory disorders of the liver with hepatic fibrosis, hepatocellular dysfunction, and vascular remodeling. Reversing the primary hepatic disorder, liver transplantation, and controlling the complications are the major management goals. Since the former options are not available to the majority of cirrhotics, treating complications remains the mainstay of therapy. Sarcopenia and/or cachexia is the most common complication and adversely affects survival, quality of life, development of other complications of cirrhosis, and outcome after liver transplantation. With the increase in number of cirrhotic patients with hepatitis C and nonalcoholic fatty liver disease, the number of patients waiting for a liver transplantation is likely to continue to increase above the currently estimated 72.3/100,000 population. One of the critical clinical questions is to determine if we can treat sarcopenia of cirrhosis without transplantation. No effective therapies exist to treat sarcopenia because the mechanism(s) of sarcopenia in cirrhosis is as yet unknown. The reasons for this include the predominantly descriptive studies to date and the advances in our understanding of skeletal muscle biology and molecular regulation of atrophy and hypertrophy not being translated into the clinical practice of hepatology. Satellite cell biology, muscle autophagy and apoptosis, and molecular signaling abnormalities in the skeletal muscle of cirrhotics are also not known. Aging of the cirrhotic and transplanted population, use of mTOR inhibitors, and the lack of definitive outcome measures to define sarcopenia and cachexia in this population add to the difficulty in increasing our understanding of hepatic sarcopenia/cachexia and developing treatment options. Recent data on the role of myostatin, AMP kinase, impaired mTOR signaling resulting in anabolic resistance in animal models, and the rapidly developing field of nutriceuticals as signaling molecules need to be evaluated in human cirrhotics. Finally, the benefits of exercise reported in other disease states with sarcopenia may not be safe in cirrhotics due to the risk of gastrointestinal variceal bleeding due to an increase in portal pressure. This article focuses on the problems facing both muscle biologists and hepatologists in developing a comprehensive approach to sarcopenia in cirrhosis.

Fig. 1

Annual number of patients diagnosed with cirrhosis in the VA system and the annual liver transplants done in the USA [17, 19]. If the total number of patients with cirrhosis diagnosed each year is assumed to follow the VA system, then the widening gap between these two graphs depicts the number of cirrhotics who are not transplanted and therefore need nontransplant therapeutic options. This gap has continued to widen over the past decade and is anticipated to follow this pattern till 2020. Data compiled from OPTN / SRTR 2009 Annual Data Report. HHS/HRSA/HSB/DOT. http://optn.transplant.hrsa.gov/ar2009/data_tables_section9.htm

Fig. 2

Numbers of patients with cirrhosis who are being placed on the liver transplant list annually and are active on the waiting list. Patients aged 50 years or more are forming the most rapidly increasing population of waitlisted patients on the transplant list. These patients are likely to have more sarcopenia due to the combined effects of aging and cirrhosis. Data compiled from OPTN / SRTR 2009 Annual Data Report. HHS/HRSA/HSB/DOT. http://optn.transplant.hrsa.gov/ar2009/data_tables_section9.htm

Fig. 3

Waiting time on the active liver transplant list has not changed significantly over the past decade. Continued waiting increases the age of the patient and the severity of disease, both of which worsen sarcopenia and muscle function. Data compiled from OPTN / SRTR 2009 Annual Data Report. HHS/HRSA/HSB/DOT. http://optn.transplant.hrsa.gov/ar2009/data_tables_section9.htm

Fig. 4

Use of mTOR and calcineurin inhibitors as maintenance immunosuppression after liver transplantation. This does not include the use of steroids alone which also contributes to sarcopenia. mTOR inhibitors result in impaired muscle protein synthesis as well as autophagy, both of which could aggravate sarcopenia after liver transplantation. Data compiled from OPTN / SRTR 2009 Annual Data Report. HHS/HRSA/HSB/DOT. http://optn.transplant.hrsa.gov/ar2009/data_tables_section9.htm

Fig. 5

Potential mechanisms of sarcopenia due to impaired protein synthesis in cirrhosis and targeted interventions. Data compiled from OPTN / SRTR 2009 Annual Data Report. HHS/HRSA/HSB/DOT. http://optn.transplant.hrsa.gov/ar2009/data_tables_section9.htm