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Sarcopenia (severe muscle depletion) is a prevalent muscle abnormality in patients with cirrhosis that confers poor prognosis both pre- and post-liver transplantation. The pathogenesis of sarcopenia is multifactorial and results from an imbalance between protein synthesis and breakdown. Nutritional, metabolic, and biochemical abnormalities seen in chronic liver disease alter whole body protein homeostasis. Hyperammonemia, increased autophagy, proteasomal activity, lower protein synthesis, and impaired mitochondrial function play an important role in muscle depletion in cirrhosis. Factors including cellular energy status, availability of metabolic substrates (e.g., branched-chain amino acids), alterations in the endocrine system (insulin resistance, circulating levels of insulin, insulin-like growth factor-1, corticosteroids, and testosterone), cytokines, myostatin, and exercise are involved in regulating muscle mass. A favored atrophy of type II fast-twitch glycolytic fibers seems to occur in patients with cirrhosis and sarcopenia. Identification of muscle biological abnormalities and underlying mechanisms is required to plan clinical trials to reverse sarcopenia through modulation of specific mechanisms. Accordingly, a combination of nutritional, physical, and pharmacological interventions might be necessary to reverse sarcopenia in cirrhosis. Moderate exercise should be combined with appropriate energy and protein intake, in accordance with clinical guidelines. Interventions with branched chain amino acids, testosterone, carnitine, or ammonia-lowering therapies should be considered individually. Various factors such as dose, type, duration of supplementations, etiology of cirrhosis, amount of dietary protein intake, and compliance with supplementation and exercise should be the focus of future large randomized controlled trials investigating both prevention and treatment of sarcopenia in this patient population.

Myosteatosis, or pathological excess fat accumulation in muscle, has been widely defined as a lower mean skeletal muscle radiodensity on computed tomography (CT). It is reported in more than half of patients with cirrhosis, and preliminary studies have shown a possible association with reduced survival and increased risk of portal hypertension complications. Despite the clinical implications in cirrhosis, a standardized definition for myosteatosis has not yet been established. Currently, little data exist on the mechanisms by which excess lipid accumulates within the muscle in individuals with cirrhosis. Hyperammonemia may play an important role in the pathophysiology of myosteatosis in this setting. Insulin resistance, impaired mitochondrial oxidative phosphorylation, diminished lipid oxidation in muscle and age-related differentiation of muscle stem cells into adipocytes have been also been suggested as potential mechanisms contributing to myosteatosis. The metabolic consequence of ammonia-lowering treatments and omega-3 polyunsaturated fatty acids in reversing myosteatosis in cirrhosis remains uncertain. Factors including the population of interest, design and sample size, single/combined treatment, dosing and duration of treatment are important considerations for future trials aiming to prevent or treat myosteatosis in individuals with cirrhosis.

Myosteatosis (pathological fat accumulation in muscle) is defined by lower mean skeletal muscle radiodensity in CT. We aimed to determine the optimal cut-offs for myosteatosis in a cohort of 855 patients with cirrhosis. CT images were used to determine the skeletal muscle radiodensity expressed as Hounsfield Unit (HU). Patients with muscle radiodensity values below the lowest tertile were considered to have myosteatosis. Competing-risk analysis was performed to determine associations between muscle radiodensity and pre-transplant mortality. Muscle radiodensity less than 33 and 28 HU in males and females, respectively, were used as cut-offs to identify myosteatosis. In the univariate analysis, cirrhosis etiology, MELD score, refractory ascites, variceal bleeding, hepatic encephalopathy, sarcopenia and myosteatosis were predictors of mortality. Myosteatosis association with mortality remained significant after adjusting for confounding factors (sHR 1.47, 95% CI 1.17–1.84, p = 0.001). Patients with concurrent presence of myosteatosis and sarcopenia constituted 17% of the patient population. The cumulative incidence of mortality was the highest in patients with concomitant sarcopenia and myosteatosis (sHR 2.22, 95% CI 1.64–3.00, p < 0.001). In conclusion, myosteatosis is common in patients with cirrhosis and is associated with increased mortality. The concomitant presence of myosteatosis and sarcopenia is associated with worse outcomes.

BackgroundSkeletal muscle is known to play a role in hepatic encephalopathy. Fatty infiltration of the muscle (myosteatosis) and muscle mass depletion (sarcopenia) are frequent complications of cirrhosis.PurposeThe purposes of the study were to investigate if myosteatosis and sarcopenia are associated with overt hepatic encephalopathy in patients with cirrhosis and to evaluate their impact on mortality.MethodsA total of 675 cirrhotic patients were studied. Computed tomography scans were used to analyze the skeletal muscle. Hepatic encephalopathy was defined by either a hepatic encephalopathy-related hospitalization and/or taking ammonia-lowering treatment (i.e., lactulose, rifaximin).ResultsMyosteatosis was observed in 348 patients (52%), sarcopenia in 242 (36%), and hepatic encephalopathy in 128 (19%) patients. Both myosteatosis (70 vs. 45%, p < 0.001) and sarcopenia (53 vs. 32%, p < 0.001) were more frequent in patients with hepatic encephalopathy. By multivariable regression analysis, both myosteatosis and sarcopenia were associated with a higher risk of hepatic encephalopathy, independent of the MELD score (OR 2.25; 95% CI, 1.32–3.85, p = 0.003 and OR 2.42; 95% CI, 1.43–4.10, p = 0.001, respectively). In univariate Cox proportional hazards analysis, sarcopenia (csHR 2.02; 95% CI, 1.57–2.58, p < 0.001), myosteatosis (csHR 1.45; 95% CI, 1.16–2.91, p = 0.004), and hepatic encephalopathy (csHR 1.61; 95% CI, 1.20–2.18, p = 0.002) were associated with mortality, but only sarcopenia was significant in the multivariable analysis (csHR 2.15; 95% CI, 1.52–3.05, p < 0.001).ConclusionsMyosteatosis and sarcopenia are independently associated with overt hepatic encephalopathy in patients with cirrhosis. The association between hepatic encephalopathy and mortality may be explained at least partially by the presence of sarcopenia. These results identify the importance of muscle mass and suggest therapeutic strategies to attenuate muscle mass loss and improve muscle quality.

Sarcopenia contributes to increased risk of decompensation, healthcare utilization, death and adverse post-liver transplant outcomes [1, 4, 5]. [...]the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of Liver (EASL) have recommended systematic assessment of sarcopenia in their respective guidelines [4, 5]. Sarcopenia was associated with mortality; hazard ratio for death at 180 days, adjusted for model for end-stage liver disease-sodium (MELD-Na), age and gender, was 4.6 (p < 0.001). [...]limitations remain, which include absence of a standardized method (e.g. US probe used, its position, pressure exerted; the anatomic sites of measurement); parameters obtained (muscle thickness, muscle cross-section area, penetration angle, fascicle length and echo-intensity); ideal reference standard to define sarcopenia; sensitivity to detect changes over time [11].

Background and aim: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Given the anti-fibrotic and antioxidant properties of coffee, this systematic review and meta-analysis aims to provide updated results on the impact of coffee consumption on NAFLD incidence, prevalence, and risk of significant liver fibrosis. Methods: We conducted a comprehensive search in MEDLINE (OvidSP) and Scopus from January 2010 through January 2021. Relative risks for the highest versus the lowest level of coffee consumption were pooled using random-effects models. Heterogeneity and publication bias were evaluated using the Higgins’ I2 statistic and Egger’s regression test, respectively. Results: Eleven articles consisting of two case-control studies, eight cross-sectional studies, and one prospective cohort study were included in the meta-analysis. Of those, three studies with 92,075 subjects were included in the analysis for NAFLD incidence, eight studies with 9558 subjects for NAFLD prevalence, and five with 4303 subjects were used for the analysis of liver fibrosis. There was no association between coffee consumption and NAFLD incidence (RR 0.88, 95% CI 0.63–1.25, p = 0.48) or NAFLD prevalence (RR 0.88, 95% CI 0.76–1.02, p = 0.09). The meta-analysis showed coffee consumption to be significantly associated with a 35% decreased odds of significant liver fibrosis (RR 0.65, 95% CI 0.54–0.78, p < 0.00001). There was no heterogeneity (I2 = 11%, p = 0.34) and no evidence of publication bias (p = 0.134). Conclusion: This meta-analysis supports the protective role of coffee consumption on significant liver fibrosis in patients with NAFLD. However, the threshold of coffee consumption to achieve hepatoprotective effects needs to be established in prospective trials.

Standardized sex-specific cut-offs for sarcopenia in cirrhosis are needed to identify the risk of clinical complications and to discriminate the severity of sarcopenia. We aimed to compare clinical characteristics between patients with cirrhosis categorized according to the severity of sarcopenia. Computed tomography images were taken at the 3rd lumbar vertebra from 603 patients with cirrhosis and 129 adult donors for living liver transplantation. Patients with skeletal muscle index (SMI) two standard deviations (SD) below the sex-specific mean value of young donors (18–40 years old) were categorized as having severe sarcopenia whereas patients with SMI between −1 and −2 SD of the sex-specific young adult mean values were categorized as having sarcopenia. In the cirrhosis group, 408 patients (68%) were male with the mean age of 57 ± 0.4 years, and MELD score of 14 ± 0.4. Patients were divided into three groups: severe-sarcopenic (SMI < 30 cm2/m2 in females and <42 cm2/m2 in males), sarcopenic (30 ≤ SMI < 37 cm2/m2 in females and 42 ≤ SMI < 50 cm2/m2 in males) and non-sarcopenic (SMI ≥ 37 cm2/m2 in females and ≥50 cm2/m2 in males). Patients with cirrhosis and severe sarcopenia had lower muscle radiodensity and higher plasma neutrophil as well as neutrophil to lymphocyte ratio levels than both non- and sarcopenic groups. The frequency of alcohol-induced cirrhosis, refractory ascites, hepatic encephalopathy, CRP > 20 mg/mL, and severe malnutrition was also higher in severe-sarcopenic patients. The interval between sarcopenia and severe sarcopenia may reflect a window of opportunity in which to intervene and mitigate muscle wasting to improve patient outcomes.

BackgroundWe studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine).Patients and MethodsWe performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8–182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy.ResultsOverall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal.ConclusionsLong-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.

The authors investigated potential predictors of sarcopenia and reported lower levels of testosterone in male and female patients with muscle wasting in comparison to their counterparts with normal muscle mass. [...]lack of association between sarcopenia and wait list mortality might in part be due to misclassification of sarcopenia. [...]of these limitations, the results of this study emphasize the importance of appropriate body composition assessment concurrent with nutritional assessments as part of the LT evaluation program.

Abstract Background Immune-related adverse events can occur after treatment with immune checkpoint inhibitors (ICI), limiting treatment persistence. We aimed to evaluate the clinical course of ICI-mediated hepatitis (IMH) associated with combination ipilimumab and nivolumab treatment. Methods A retrospective cohort study including consecutive patients with metastatic melanoma treated with ipilimumab and nivolumab between 2013 and 2018 was conducted at two tertiary care centres. IMH was defined by the Common Terminology Criteria for Adverse Events (CTCAE). We determined the proportion of patients developing IMH, and compared the duration, treatment patterns and outcomes, stratified by hepatitis severity. Kaplan–Meier survival analysis was used to evaluate time to hepatitis resolution, and a linear mixed-effects model was used to compare longitudinal outcomes by treatment. Results A total of 63 patients were included. Thirty-two patients (51%) developed IMH (34% Grade 1–2, 66% Grade 3–4), at a median of 34 days (IQR 20 to 43.5 days) after the first dose. Baseline FIB4 index ≥1.45 was associated with IMH (OR 3.71 [95% CI: 1.03 to 13.38], P = 0.04). Ninety-four per cent (30/32) of patients had liver enzyme normalization after a median duration of 43 days (IQR 26 to 70 days). Corticosteroid use was not associated with faster IMH resolution or less ICI discontinuation. A total of 24 patients died during the study; no deaths were attributable to hepatitis-related complications. Fifty-three per cent (17/32) of patients resumed anti-PD-1 monotherapy and three patients developed IMH recurrence. Conclusions Approximately half of the patients treated with combination ipilimumab and nivolumab developed IMH in this cohort. However, most patients experienced uncomplicated IMH resolution.