Molecular Mechanism Contributing to Malnutrition and Sarcopenia in Patients with Liver Cirrhosis

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Abstract

Liver cirrhosis is frequently accompanied by disease-related malnutrition (DRM) and sarcopenia, defined as loss of skeletal muscle mass and function. DRM and sarcopenia often coexist in cirrhotic patients and are associated with increased morbidity and mortality. The clinical manifestation of both comorbidities are triggered by multifactorial mechanisms including reduced nutrient and energy intake caused by dietary restrictions, anorexia, neuroendocrine deregulation, olfactory and gustatory deficits. Maldigestion and malabsorption due to small intestinal bacterial overgrowth, pancreatic insufficiency or cholestasis may also contribute to DRM and sarcopenia. Decreased protein synthesis and increased protein degradation is the cornerstone mechanism to muscle loss, among others mediated by disease- and inflammation-mediated metabolic changes, hyperammonemia, increased myostatin and reduced human growth hormone. The concise pathophysiological mechanisms and interactions of DRM and sarcopenia in liver cirrhosis are not completely understood. Furthermore, most knowledge in this field are based on experimental models, but only few data in humans exist. This review summarizes known and proposed molecular mechanisms contributing to malnutrition and sarcopenia in liver cirrhosis and highlights remaining knowledge gaps. Since, in the prevention and treatment of DRM and sarcopenia in cirrhotic patients, more research is needed to identify potential biomarkers for diagnosis and development of targeted therapeutic strategies.

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EASL Clinical Practice Guidelines on nutrition in chronic liver disease

Manuela Merli, Annalisa Berzigotti, Shira Zelber-Sagi … (2019)

A frequent complication in liver cirrhosis is malnutrition, which is associated with the progression of liver failure, and with a higher rate of complications including infections, hepatic encephalopathy and ascites. In recent years, the rising prevalence of obesity has led to an increase in the number of cirrhosis cases related to non-alcoholic steatohepatitis. Malnutrition, obesity and sarcopenic obesity may worsen the prognosis of patients with liver cirrhosis and lower their survival. Nutritional monitoring and intervention is therefore crucial in chronic liver disease. These Clinical Practice Guidelines review the present knowledge in the field of nutrition in chronic liver disease and promote further research on this topic. Screening, assessment and principles of nutritional management are examined, with recommendations provided in specific settings such as hepatic encephalopathy, cirrhotic patients with bone disease, patients undergoing liver surgery or transplantation and critically ill cirrhotic patients.

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Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies

Nick Sheron, Laura Pimpin, Laura Webber … (2018)

The burden of liver disease in Europe continues to grow. We aimed to describe the epidemiology of liver diseases and their risk factors in European countries, identifying public health interventions that could impact on these risk factors to reduce the burden of liver disease. As part of the HEPAHEALTH project we extracted information on historical and current prevalence and mortality from national and international literature and databases on liver disease in 35 countries in the World Health Organization European region, as well as historical and recent prevalence data on their main determinants; alcohol consumption, obesity and hepatitis B and C virus infections. We extracted information from peer-reviewed and grey literature to identify public health interventions targeting these risk factors. The epidemiology of liver disease is diverse, with variations in the exact composition of diseases and the trends in risk factors which drive them. Prevalence and mortality data indicate that increasing cirrhosis and liver cancer may be linked to dramatic increases in harmful alcohol consumption in Northern European countries, and viral hepatitis epidemics in Eastern and Southern European countries. Countries with historically low levels of liver disease may experience an increase in non-alcoholic fatty liver disease in the future, given the rise of obesity across most European countries. Liver disease in Europe is a serious issue, with increasing cirrhosis and liver cancer. The public health and hepatology communities are uniquely placed to implement measures aimed at reducing their causes: harmful alcohol consumption, child and adult obesity, and chronic infection with hepatitis viruses, which will in turn reduce the burden of liver disease.

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Sarcopenia from mechanism to diagnosis and treatment in liver disease.

Srinivasan Dasarathy, Manuela Merli (2016)

Sarcopenia or loss of skeletal muscle mass is the major component of malnutrition and is a frequent complication in cirrhosis that adversely affects clinical outcomes. These include survival, quality of life, development of other complications and post liver transplantation survival. Radiological image analysis is currently utilized to diagnose sarcopenia in cirrhosis. Nutrient supplementation and physical activity are used to counter sarcopenia but have not been consistently effective because the underlying molecular and metabolic abnormalities persist or are not influenced by these treatments. Even though alterations in food intake, hypermetabolism, alterations in amino acid profiles, endotoxemia, accelerated starvation and decreased mobility may all contribute to sarcopenia in cirrhosis, hyperammonemia has recently gained attention as a possible mediator of the liver-muscle axis. Increased muscle ammonia causes: cataplerosis of α-ketoglutarate, increased transport of leucine in exchange for glutamine, impaired signaling by leucine, increased expression of myostatin (a transforming growth factor beta superfamily member) and an increased phosphorylation of eukaryotic initiation factor 2α. In addition, mitochondrial dysfunction, increased reactive oxygen species that decrease protein synthesis and increased autophagy mediated proteolysis, also play a role. These molecular and metabolic alterations may contribute to the anabolic resistance and inadequate response to nutrient supplementation in cirrhosis. Central and skeletal muscle fatigue contributes to impaired exercise capacity and responses. Use of proteins with low ammoniagenic potential, leucine enriched amino acid supplementation, long-term ammonia lowering strategies and a combination of resistance and endurance exercise to increase muscle mass and function may target the molecular abnormalities in the muscle. Strategies targeting endotoxemia and the gut microbiome need further evaluation.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 28 July 2020

Publication date Collection: August 2020

Volume: 21

Issue: 15

Electronic Location Identifier: 5357

Affiliations

[1 ]Department of Agriculture and Food Sciences, Neubrandenburg Institute for Evidence-Based Dietetics (NIED), University of Applied Sciences Neubrandenburg, 17033 Neubrandenburg, Germany; fmeyer@ 123456hs-nb.de (F.M.); esau@ 123456hs-nb.de (S.E.); leafranziska.sautter@ 123456med.uni-rostock.de (L.F.S.)

[2 ]Division of Gastroenterology and Endocrinology, Department of Internal Medicine II, University Medicine Rostock, 18057 Rostock, Germany; karen.bannert@ 123456med.uni-rostock.de (K.B.); luise.ehlers@ 123456med.uni-rostock.de (L.E.); robert.jaster@ 123456med.uni-rostock.de (R.J.); georg.lamprecht@ 123456med.uni-rostock.de (G.L.)

[3 ]Division of Gastroenterology, Endocrinology and Nutritional Medicine, Department of Internal Medicine A, University Medicine Greifswald, 17475 Greifswald, Germany; mats.wiese@ 123456med.uni-greifswald.de (M.W.); ali.aghdassi@ 123456med.uni-greifswald.de (A.A.A.); lerch@ 123456uni-greifswald.de (M.M.L.)

[4 ]Institute of Nutritional Physiology ‘Oskar Kellner’, Leibniz Institute for Farm Animal Biology (FBN), 18196 Dummerstorf, Germany; metges@ 123456fbn-dummerstorf.de

[5 ]Department of Agriculture and Food Sciences, University of Applied Sciences Neubrandenburg, 17033 Neubrandenburg, Germany; garbe@ 123456hs-nb.de

Author notes

[* ]Correspondence: valentini@ 123456hs-nb.de ; Tel.: +49-(0)395-5693-2512

[†]

These authors equally contributed to the manuscript.

Author information

Karen Bannert https://orcid.org/0000-0001-9779-2881

Robert Jaster https://orcid.org/0000-0002-8220-4570

Markus M. Lerch https://orcid.org/0000-0002-9643-8263

Luzia Valentini https://orcid.org/0000-0002-4313-0441

Article

Publisher ID: ijms-21-05357

DOI: 10.3390/ijms21155357

PMC ID: 7432938

PubMed ID: 32731496

SO-VID: cdbf59cc-7c24-40a3-9a92-99dcc7b67a66

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Molecular Mechanism Contributing to Malnutrition and Sarcopenia in Patients with Liver Cirrhosis

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Higher order chromatin architecture

Most cited references 100

EASL Clinical Practice Guidelines on nutrition in chronic liver disease

Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies

Sarcopenia from mechanism to diagnosis and treatment in liver disease.

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