Branched-chain amino acid supplementation does not improve measures of sarcopenia in cirrhosis: results of a randomised controlled trial.

BACKGROUND: Sarcopenia is associated with adverse outcomes in cirrhosis. Branched-chain amino acids (BCAA) target several pathways that lead to muscle loss in this population. AIMS: We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis. METHODS: We conducted a 12-month double-blinded, randomised, controlled trial of BCAA supplementation (30 g daily) compared to an equicaloric, equi-nitrogenous whey protein in volunteers with cirrhosis and reduced muscle strength. The primary endpoint was an increase in grip strength and upper limb lean mass measured on DEXA. Mean-adjusted differences (MAD, 95% CI) between groups at 6 and 12 months are reported as treatment effect using a linear mixed model for repeated measures. RESULTS: A total of 150 volunteers entered the trial (74 BCAA, 76 control), with a median age of 58 years [IQR 48; 63] and MELD of 14 [12; 17]. At 12 months, 57% in the BCAA arm and 61% in the control arm met the primary endpoint (p = 0.80). No significant between-group difference was found in grip strength (MAD -0.15 kg [-0.37; 0.06], p = 0.29) or upper limb lean mass (1.7 kg [-0.2; 3.6], p = 0.22) at 12 months. No significant differences in other body composition parameters, physical performance, frailty, rates of hospitalisation or mortality were found between the BCAA and the control group. Fatigue improved across the entire cohort, without significant between-group differences. 15% of volunteers reported side effects, with distaste higher in the BCAA arm (p = 0.045). CONCLUSION: BCAA supplementation did not improve measures of muscle strength, mass or performance or physical frailty compared to a whey protein supplement in a randomised controlled setting. ACTRN12618000802202.

Testosterone is lower in men with non-alcoholic fatty liver disease and alcohol-related cirrhosis and is associated with adverse clinical outcomes.

BACKGROUND/AIMS: Low serum testosterone is common in cirrhotic men, but the impact of disease aetiology remains uncertain. This study compares serum total testosterone (TT) levels by disease aetiology and assesses its prognostic value. METHODS: Single-centre retrospective study of cirrhotic men who had TT levels measured between 2002 and 2020. A cut-off of 12 nmol/L was used to define low TT and 230 pmol/L for calculated free testosterone (cFT). Linear and logistic regression used to adjust for variables known to affect testosterone levels and assess for an association between levels and outcomes. RESULTS: Of 766 cirrhotic men, 33.3% had alcohol-related liver disease (ALD) and 11.9% had non-alcoholic fatty liver disease (NAFLD). The median age was 56 years (interquartile range (IQR) 50-61), and the model for end-stage liver disease (MELD) score 14 (IQR 9-20). TT levels were low in 53.3% of patients, (median 11.0 nmol/L; IQR 3.7-19.8) and cFT low in 79.6% (median 122 pmol/L; IQR 48.6-212). Median TT was lower in men with ALD (7.6 nmol/L; IQR 2.1-16.2) and NAFLD (9.8 nmol/L; IQR 2.75-15.6) compared to other aetiologies (11.0 nmol/L; IQR 3.73-19.8) (p < 0.001 for all), which remained true after adjustment for age and MELD score. TT was inversely associated with 12-month mortality or transplant (381 events, p = 0.02) and liver decompensation (345 events, p = 0.004). CONCLUSIONS: Low serum testosterone is common in cirrhotic men and is associated with adverse clinical outcomes. TT levels are significantly lower in ALD and NAFLD compared to other disease aetiologies. Further large-scale studies are required to assess the potential benefits of testosterone therapy.

Reduced upper limb lean mass on dual energy X-ray absorptiometry predicts adverse outcomes in male liver transplant recipients.

BACKGROUND: Pre-transplant muscle wasting measured by computed tomography has been associated with adverse clinical outcomes after liver transplantation including increased rates of sepsis and hospitalisation days. Upper limb lean mass (LM) measured by dual-energy X-ray absorptiometry (DEXA) was recently identified as a novel predictor of sarcopenia-associated mortality in men waitlisted for transplantation. AIM: To investigate the use of DEXA LM in predicting gender-stratified early post-transplant outcomes. METHODS: Liver transplant recipients who underwent pre-transplant DEXA body composition imaging between 2002 and 2017 were included. Endpoints included post-transplant mortality and graft failure, bacterial infections, acute cellular rejection (ACR) and intensive care and total hospital length of stay. RESULTS: Four hundred and sixty-nine patients met inclusion criteria of which 338 were male (72%). Median age was 55.0 years (interquartile range 47.4, 59.7) and model for end-stage liver disease (MELD) score 16. Median time from assessment to transplantation was 7 mo (3.5, 12). Upper limb LM was inversely associated with bacterial infections at 180 d post-transplant (hazard ratio = 0.42; 95% confidence interval: 0.20-0.89; P = 0.024) in males only. There was a negative correlation between upper limb LM and intensive care (τb = -0.090, P = 0.015) and total hospital length of stay (τb = -0.10, P = 0.0078) in men. In women, neither MELD nor body composition parameters were associated with post-transplant adverse outcomes or increased length of stay. Body composition parameters, MELD and age were not associated with 90-d mortality or graft failure in either gender. There were no significant predictors of early ACR. CONCLUSION: Sarcopenia is an independent and potentially modifiable predictor of increased post-transplant bacterial infections and hospital length of stay in men with cirrhosis. DEXA upper limb LM provides a novel measure of muscle wasting that has prognostic value in this cohort. The lack of association in women requires further investigation.

Testosterone therapy reduces hepatic steatosis in men with type 2 diabetes and low serum testosterone concentrations.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in people with diabetes with no available treatment. AIM: To explore the effect of testosterone treatment on liver. Testosterone therapy improves insulin resistance and reduces total body fat, but its impact on the liver remains poorly studied. METHODS: This secondary analysis of a 40 wk, randomised, double-blinded, placebo-controlled trial of intramuscular testosterone undecanoate in men with type 2 diabetes and lowered serum testosterone concentrations evaluated the change in hepatic steatosis as measured by liver fat fraction on magnetic resonance imaging (MRI). RESULTS: Of 88 patients enrolled in the index study, 39 had liver MRIs of whom 20 received testosterone therapy and 19 received placebo. All patients had > 5% hepatic steatosis at baseline and 38 of 39 patients met diagnostic criteria for NAFLD. Median liver fat at baseline was 15.0% (IQR 11.5%-21.1%) in the testosterone and 18.4% (15.0%-28.9%) in the placebo group. Median ALT was 34units/L (26-38) in the testosterone and 32units/L (25-52) in the placebo group. At week 40, patients receiving testosterone had a median reduction in absolute liver fat of 3.5% (IQR 2.9%-6.4%) compared with an increase of 1.2% in the placebo arm (between-group difference 4.7% P < 0.001). After controlling for baseline liver fat, testosterone therapy was associated with a relative reduction in liver fat of 38.3% (95% confidence interval 25.4%-49.0%, P < 0.001). CONCLUSION: Testosterone therapy was associated with a reduction in hepatic steatosis in men with diabetes and low serum testosterone. Future randomised studies of testosterone therapy in men with NAFLD focusing on liver-related endpoints are therefore justified.

Clinical outcomes of patients with two small hepatocellular carcinomas.

BACKGROUND: Management of single small hepatocellular carcinoma (HCC) is straightforward with curative outcomes achieved by locoregional therapy or resection. Liver transplantation is often considered for multiple small or single large HCC. Management of two small HCC whether presenting synchronously or sequentially is less clear. AIM: To define the outcomes of patients presenting with two small HCC. METHODS: Retrospective review of HCC databases from multiple institutions of patients with either two synchronous or sequential HCC ≤ 3 cm between January 2000 and March 2018. Primary outcomes were overall survival (OS) and transplant-free survival (TFS). RESULTS: 104 patients were identified (male n = 89). Median age was 63 years (interquartile range 58-67.75) and the most common aetiology of liver disease was hepatitis C (40.4%). 59 (56.7%) had synchronous HCC and 45 (43.3%) had sequential. 36 patients died (34.6%) and 25 were transplanted (24.0%). 1, 3 and 5-year OS was 93.0%, 66.1% and 62.3% and 5-year post-transplant survival was 95.8%. 1, 3 and 5-year TFS was 82.1%, 45.85% and 37.8%. When synchronous and sequential groups were compared, OS (1,3 and 5 year synchronous 91.3%, 63.8%, 61.1%, sequential 95.3%, 69.5%, 64.6%, P = 0.41) was similar but TFS was higher in the sequential group (1,3 and 5 year synchronous 68.5%, 37.3% and 29.7%, sequential 93.2%, 56.6%, 48.5%, P = 0.02) though this difference did not remain during multivariate analysis. CONCLUSION: TFS in patients presenting with two HCC ≤ 3 cm is poor regardless of the timing of the second tumor. All patients presenting with two small HCC should be considered for transplantation.

Faecal microbiota transplantation for recurrent Clostridioides difficile infection: an Australian experience - effective, safe, yet room for improvement.

Faecal microbiota transplantation (FMT) is reportedly effective and safe for the management of recurrent or refractory Clostridioides difficile infection (CDI), yet real-world data of outcomes of FMT in Australia are limited. In this series, FMT safely resulted in resolution of CDI in 19 patients with reduced healthcare utilisation after 25 FMT, but one patient was diagnosed with an anti-nuclear antibody-positive constitutional illness and Hashimoto thyroiditis following FMT. Further prospective evaluation of the utility of FMT earlier in CDI treatment algorithms to minimise cost and morbidity, and recipient follow up for immune-mediated conditions, is required.

Nutraceuticals for the treatment of sarcopenia in chronic liver disease.

BACKGROUND AND AIMS: Sarcopenia, defined as loss of muscle mass, strength and function, is associated with adverse clinical outcomes in patients with cirrhosis. Despite improved understanding of the multifaceted pathogenesis, there are few established therapies to treat or prevent muscle loss in this population. This narrative review examines the available literature investigating the role of nutraceuticals for the prevention or treatment of muscle wasting in chronic liver disease. METHODS: A comprehensive search or Medline and PubMED databases was conducted. Reference lists were screened to identify additional articles. RESULTS: A number of nutritional supplements and vitamins target the specific metabolic derangements that contribute to sarcopenia in cirrhosis including altered amino acid metabolism, hyperammonaemia and inflammation. Branched chain amino acid (BCAA) supplementation has proposed anabolic effects through dual pathways of enhanced ammonia clearance and stimulation of muscle protein synthesis. l-carnitine also has multimodal effects on muscle and shows promise as a therapy for muscle loss through anti-inflammatory, antioxidant and ammonia lowering properties. Other nutraceuticals including l-ornithine l-aspartate, omega-3 polyunsaturated fatty acids and zinc and vitamin D supplementation, may similarly have positive effects on muscle homeostasis, however further evidence to support their use in cirrhotic populations is required. CONCLUSION: Nutraceuticals offer a promising and likely safe adjunct to standard care for sarcopenia in cirrhosis. While there is most evidence to support the use of BCAA and l-carnitine supplementation, further well-designed clinical trials are needed to elucidate their efficacy as a therapy for muscle loss in this population.

Hepatocellular carcinoma surveillance and quantile regression for determinants of underutilisation in at-risk Australian patients.

BACKGROUND: While clinical guidelines recommend hepatocellular carcinoma (HCC) surveillance for at-risk individuals, reported surveillance rates in the United States and Europe remain disappointingly low. AIM: To quantify HCC surveillance in an Australian cohort, and assess for factors associated with surveillance underutilisation. METHODS: All patients undergoing HCC surveillance liver ultrasounds between January 1, 2018 to June 30, 2018 at a tertiary hospital in Melbourne, Australia, were followed until July 31, 2020, or when surveillance was no longer required. The primary outcome was the percentage of time up-to-date with HCC surveillance (PTUDS). Quantile regression was performed to determine the impact of factors associated with HCC surveillance underutilisation. RESULTS: Among 775 at-risk patients followed up for a median of 27.5 months, the median PTUDS was 84.2% (IQR: 66.3%-96.3%). 85.0% of patients were followed up by specialist gastroenterologists. Amongst those receiving specialist care, quantile regression demonstrated differential associations at various quantile levels of PTUDS for several factors. Older age at the 25th quantile (estimate 0.002 per percent, P = 0.03), and cirrhotic status at the 75th quantile (estimate 0.021, P = 0.017), were significantly associated with greater percentage of time up-to-date. African ethnicity (estimate -0.089, P = 0.048) and a culturally and linguistically diverse (CALD) background (estimate -0.063, P = 0.01) were significantly associated with lower PTUDS at the 50th quantile, and again for CALD at the 75th quantile (estimate -0.026, P = 0.045). CONCLUSION: While median PTUDS in this Australian cohort study was 84.2%, awareness of the impact of specific factors across PTUDS quantiles can aid targeted interventions towards improved HCC surveillance.

Thiopurines vs methotrexate: Comparing tolerability and discontinuation rates in the treatment of inflammatory bowel disease.

BACKGROUND: There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD). AIM: To compare the long-term tolerability, and persistence of thiopurine and methotrexate therapy in IBD. METHODS: A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records. RESULTS: There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow-up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6-TGN was 298 pmol/8 x 108 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08). CONCLUSION: Discontinuation of methotrexate occurred at rates twice that of dose-optimised thiopurine therapy.

Hepatitis B virus activity is not associated with degree of liver steatosis in patients with hepatitis B-related chronic liver disease.

BACKGROUND & AIMS: The recently published manuscript by Zhu and colleagues "Hepatitis B virus infection and risk of non-alcoholic fatty liver disease: A population-based cohort study" found no correlation between presence of chronic HBV and presence of common risk factors for non-alcoholic fatty liver disease on primary analysis. A limitation to this study, like most population based research, is the absence of liver histology, which is considered gold standard for assessment of non-alcoholic fatty liver disease. METHODS: Our group studied the association between hepatitis B viral activity and non-alcoholic fatty liver disease activity as measured by grade of steatohepatitis/fibrosis on liver biopsy by analysing consecutive liver histology samples from patients with chronic hepatitis B at a single quaternary liver transplant centre. RESULTS: Linear regression modelling for active viral hepatitis on histological examination against degree of steatohepatitis showed no correlation (r2  = .018, all P> .1). Linear regression of degree of steatohepatitis vs hepatitis B viral load also showed no correlation. CONCLUSIONS: Our work is concordant with the manuscript from Zhu et al; we found no significant correlation between hepatitis B viral activity and degree of steatohepatitis.