Sarcopenia from mechanism to diagnosis and treatment in liver disease

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 evaluatio

Plasma Krebs Cycle Intermediates in Nonalcoholic Fatty Liver Disease

Nonalcoholic liver disease (NAFLD) is manifested with a wide spectrum of clinical symptoms and is closely associated with the metabolic syndrome, inflammation, and mitochondrial dysfunction. Although the mechanism of mitochondrial dysfunction in NAFLD is still not fully elucidated, multiple studies have demonstrated evidence of molecular, biochemical, and biophysical mitochondrial abnormalities in NAFLD. Given the association between NAFLD and mitochondrial dysfunction, the aim of this study is to analyze circulating levels of Krebs cycle intermediates in a cohort of NAFLD-affected individuals and matching healthy controls and to correlate our findings with the liver function metrics. Standard serum biochemistry and Krebs cycle intermediates were analyzed in NAFLD (n = 22) and matched control (n = 67) cohorts. Circulating levels of isocitrate and citrate were significantly (p \u3c 0.05) elevated in the NAFLD cohort of patients. The area under the curve (AUROC) for these two metabolites exhibited a moderate clinical utility. Correlations between plasma Krebs cycle intermediates and standard clinical plasma metrics were explored by Pearson’s correlation coefficient. The data obtained for plasma Krebs cycle intermediates suggest pathophysiological insights that link mitochondrial dysfunction with NAFLD. Our findings reveal that plasma isocitrate and citrate can discriminate between normal and NAFLD cohorts and can be utilized as noninvasive markers of mitochondrial dysfunction in NAFLD. Future studies with large populations at different NAFLD stages are warranted

Ammonia toxicity: from head to toe?

Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction

Diagnostic and Prognostic Significance of Complement in Patients with Alcohol-associated Hepatitis

BACKGROUND and AIMS: Given the lack of effective therapies and high mortality in acute alcohol-associated hepatitis (AH), it is important to develop rationally-designed biomarkers for effective disease management. Complement, a critical component of the innate immune system, contributes to uncontrolled inflammatory responses leading to liver injury, but is also involved in hepatic regeneration. Here we investigated if a panel of complement proteins and activation products would provide useful biomarkers for severity of AH and aid in predicting 90 days mortality. APPROACH and RESULTS: Plasma samples collected at time of diagnosis from 254 patients with moderate and severe AH recruited from four medical centers and 31 healthy individuals were used to quantify complement proteins by ELISA and Luminex arrays. Components of the classical and lectin pathways, including complement factors C2, C4b and C4d, as well as complement factor I (CFI) and C5, were reduced in AH patients compared to healthy individuals. In contrast, components of the alternative pathway, including complement factor Ba (CFBa) and factor D (CFD), were increased. Markers of complement activation were also differentially evident, with C5a increased and the soluble terminal complement complex (sC5b9) decreased in AH. Mannose binding lectin (MBL), C4b, CFI, C5 and sC5b9 were negatively correlated with model for end-stage liver disease (MELD) score, while CFBa and CFD were positively associated with disease severity. Lower CFI and sC5b9 were associated with increased 90-day mortality in AH. CONCLUSIONS: Taken together, these data indicate that AH is associated with a profound disruption of complement. Inclusion of complement, especially CFI and sC5b9, along with other laboratory indicators, could improve diagnostic and prognostic indications of disease severity and risk of mortality for AH patients

A North American Expert Opinion Statement on Sarcopenia in Liver Transplantation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151960/1/hep30828_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151960/2/hep30828.pd

Frailty in liver transplantation: An expert opinion statement from the American Society of Transplantation Liver and Intestinal Community of Practice

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149699/1/ajt15392_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149699/2/ajt15392.pd

ESPEN Practical Guideline: clinical nutrition in liver disease

Desnutrición; Insuficiencia hepática aguda grave; CirrosisMalnutrition; Acute liver failure; CirrhosisDesnutrició; Insuficiència hepàtica aguda greu; CirrosiIntroducción: la Guía Práctica se basa en la actual guía científica de la ESPEN sobre nutrición clínica en las enfermedades hepáticas. Métodos: se ha reducido y transformado en diagramas de flujo para facilitar su uso en la práctica clínica. La guía está dedicada a todos los profesionales, incluidos médicos, dietistas, nutricionistas y enfermeras, que trabajan con pacientes con enfermedad hepática crónica. Resultados: la guía presenta un total de 103 pronunciamientos y recomendaciones con breves comentarios para el manejo nutricional y metabólico de pacientes con (i) insuficiencia hepática aguda grave, (ii) esteatohepatitis alcohólica, (iii) enfermedad hepática grasa no alcohólica, (iv) cirrosis hepática, y (v) cirugía o trasplante de hígado. Conclusión: las recomendaciones relacionadas con enfermedades están precedidas por recomendaciones generales sobre el diagnóstico del estado nutricional en los pacientes hepáticos y sobre las complicaciones hepáticas asociadas a la nutrición médica.Background: the Practical Guideline is based on the current scientifi c ESPEN guide on Clinical Nutrition in Liver Disease. Methods: it has been shortened and transformed into fl ow charts for easier use in clinical practice. The guideline is dedicated to all professionals including physicians, dieticians, nutritionists and nurses working with patients with chronic liver disease. Results: a total of 103 statements and recommendations are presented with short commentaries for the nutritional and metabolic management of patients with (i) acute liver failure, (ii) alcoholic steatohepatitis, (iii) non-alcoholic fatty liver disease, (iv) liver cirrhosis, and (v) liver surgery/ transplantation. Disease-related recommendations are preceded by general recommendations on the diagnosis of nutritional status in liver patients and on liver complications associated with medical nutrition. Conclusion: this Practical Guideline gives guidance to health care providers involved in the management of liver disease on how to offer optimal nutritional care

Fibrosis Progression Rate in Biopsy-Proven Nonalcoholic Fatty Liver Disease Among People With Diabetes Versus People Without Diabetes: A Multicenter Study

Background & aimsThere are limited data regarding fibrosis progression in biopsy-proven nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes mellitus (T2DM) compared with people without T2DM. We assessed the time to fibrosis progression in people with T2DM compared with people without T2DM in a large, multicenter, study of people with NAFLD who had paired liver biopsies.MethodsThis study included 447 adult participants (64% were female) with NAFLD who had paired liver biopsies more than 1 year apart. Liver histology was systematically assessed by a central pathology committee blinded to clinical data. The primary outcome was the cumulative incidence of a ≥1-stage increase in fibrosis in participants with T2DM compared with participants without T2DM.ResultsThe mean (SD) age and body mass index (calculated as weight in kilograms divided by the square of the height in meters) were 50.9 (11.5) years and 34.7 (6.3), respectively. The median time between biopsies was 3.3 years (interquartile range, 1.8-6.1 years). Participants with T2DM had a significantly higher cumulative incidence of fibrosis progression at 4 years (24% vs 20%), 8 years (60% vs 50%), and 12 years (93% vs 76%) (P = .005). Using a multivariable Cox proportional hazards model adjusted for multiple confounders, T2DM remained an independent predictor of fibrosis progression (adjusted hazard ratio, 1.69; 95% CI, 1.17-2.43; P = .005). The cumulative incidence of fibrosis regression by ≥1 stage was similar in participants with T2DM compared with participants without T2DM (P = .24).ConclusionsIn this large, multicenter cohort study of well-characterized participants with NAFLD and paired liver biopsies, we found that fibrosis progressed faster in participants with T2DM compared with participants without T2DM. These data have important implications for clinical practice and trial design