Background & Aims Peri-procedural blood component(s) prophylaxis is common in patients with cirrhosis undergoing invasive procedures. We evaluated whether a rotational thromboelastometry (ROTEM)-guided algorithm could reduce prophylactic transfusions without increasing bleeding complications. Methods In this randomized controlled trial, adults with cirrhosis scheduled for invasive procedures with abnormal INR and/or platelet count values requiring preprocedural correction as per standard local practice were randomized 1:1 to a ROTEM-guided or standard-of-care (SOC) transfusion strategy. The primary efficacy outcome was the proportion of procedures that required prophylactic transfusion of blood components(s). The primary safety outcome was major procedure-related bleeding. Secondary outcomes included type and volume of blood products transfused, transfusion reactions, thrombosis, and 28-day mortality. Results A total of 114 procedures in 99 patients were screened with 57 randomized (28 in ROTEM, 29 in SOC). 44 procedures (77%) were classified as having a high bleeding risk. Prophylactic blood products were administered before 20 procedures in the ROTEM group compared to 28 in the SOC group (71% vs. 97%, p<0.01). The pattern of blood product use differed between the groups, with less FFP and more cryoprecipitate in the ROTEM group than in the SOC group. There was no difference in procedure-related bleeding (no major bleeding was recorded), thrombosis, transfusion-related complications, length of stay, or mortality between the two groups. Conclusions ROTEM-guided transfusion significantly reduced blood product use without compromising safety in cirrhosis patients undergoing invasive procedures. These findings support a more conservative, goal-directed approach to periprocedural hemostatic management in patients with cirrhosis.

Cardiovascular (CV) disease is a leading cause of postoperative mortality following liver transplantation (LT). The presence of abdominal aortic calcification (AAC) has been linked to CV events in the general population. We sought to investigate whether AAC on routine pre-transplant CT can improve the prediction of coronary artery disease, post-LT major adverse cardiovascular events (MACEs) or long-term mortality. Of 461 patients undergoing LT between 2010 and 2018, 318 were included in the analysis, among whom 81 had also undergone computed tomography coronary angiography. The extent of AAC was quantified with high AAC defined as a calcium score ≥500. High AAC was identified in 84/318 (26.4%) and demonstrated moderate correlation with coronary artery calcium score (CACS) ( r =0.52, p <0.001). Thirty-two MACE events occurred in 28 patients (8.8%) within 30 days. High AAC was a strong independent predictor of moderate-to-severe coronary disease on CT coronary angiography (OR 12.6, 95% CI 1.5-103.0, p =0.02). It was also associated with a significantly increased risk of 30-day MACE (OR 2.34, 95% CI 1.08-5.05, p =0.03) and long-term mortality (HR 2.45, 95% CI 1.18-5.06, p =0.02). Following multivariate analysis adjusting for pertinent CV risk factors, high AAC remained a strong independent predictor of MACE (OR 3.10, 95% CI 1.27-7.60, p =0.02). Addition of AAC to the Revised Cardiac Risk Index significantly improved model fit for predicting MACE outcomes ( p <0.01), while the absence of heavy AAC ruled out moderate-to-severe disease on CT coronary angiography with a negative predictive value of 97.0%. High AAC on routine CT scans was associated with a 3-fold increased risk of 30-day MACE post-LT and improved CV risk prediction compared to traditional indices. Quantification of AAC may offer a simple method of improving CV risk assessment in these patients.

Background and aims Emerging evidence suggests that rotational thromboelastometry (ROTEM) is superior to conventional haemostatic tests in the assessment and management of bleeding risk in patients with cirrhosis. Whether ROTEM may also be useful for assessing the prognosis of these patients is unknown. We aimed to explore the role of ROTEM in predicting the transplant-free survival of patients with cirrhosis. Methods We conducted a prospective cohort study of patients with cirrhosis at two hospitals. All patients underwent ROTEM analysis at baseline and were followed up until death, liver transplantation or the end of follow-up (28 February 2023). Univariate and multivariate Cox regression analyses were performed to explore the association between transplant-free survivals. Results Between April 2018 and October 2021, 162 patients with cirrhosis were recruited and followed-up for a median of 42 months. During follow-up, 36 patients died and 7 underwent liver transplantation. On univariate analysis, maximum clot firmness (MCF) using both EXTEM and INTEM tests was significantly reduced in the death/liver transplant group compared to the survivor group (52 vs. 57, P = 0.02; and 51 vs. 55, P = 0.01, respectively). After adjusting for age, sex, presence of clinically significant portal hypertension, hepatocellular carcinoma, care setting, bilirubin, sodium and creatinine, only albumin (hazard ratio: 0.92, 95% CI: 0.85–0.99, P = 0.018) and MCFEXT (hazard ratio: 0.96, 95% CI: 0.92–0.99, P = 0.032) remained significant predictors of transplant-free survival. Conclusion ROTEM may be useful in assessing the survival of patients with cirrhosis. Further research is needed to determine the clinical utility of ROTEM parameters as prognostic markers in cirrhosis.

BACKGROUND:Sarcopaenia is associated with a two-fold higher mortality rate in patients with cirrhosis independent of liver disease severity. Few treatments for cirrhosis related sarcopaenia exist beyond optimal nutritional management. AIM:To assess if rifaximin-α, a minimally absorbed antimicrobial used to manage hepatic encephalopathy (HE), may improve sarcopaenia in cirrhosis through its ammonia lowering and anti-inflammatory properties. METHODS:This single-centre retrospective cohort study of patients with prior HE compared patients treated with lactulose alone to those on combination therapy with rifaximin-α. The primary outcome was a change in skeletal muscle area (SMA) as measured by computed tomography over two time points. Secondary outcomes included episodes of spontaneous bacterial peritonitis, variceal bleeding, and gastrointestinal Clostridium difficile infection. RESULTS:Of the 142 patients included, 63 were on rifaximin-α [35% female, median age 57 (51, 62)], and 79 were on lactulose without rifaximin-α [20% female, median age 55 (51, 60)]. Univariate analysis for SMA found that male sex (P < 0.001), hepatocellular carcinoma presence (P = 0.024), and greater baseline body mass index (P = 0.001) were associated with improvement of SMA. Multivariate analysis that adjusted for baseline SMA was performed and found only use of rifaximin-α (P = 0.029) to be associated with improvement of SMA. CONCLUSION:This study demonstrates a significant independent association between rifaximin-α therapy and muscle mass in patients with cirrhosis and HE. Prospective studies of rifaximin-α therapy examining its impact on sarcopenia are required to assess its potential therapeutic role in this cohort.

Background and aims: Patients with cirrhosis of the liver are in a delicate state of rebalanced haemostasis and are at risk of developing both bleeding and thrombotic complications. Conventional haemostatic tests are unable to predict bleeding and thrombosis in these patients. We aimed to explore the role of Rotational Thromboelastometry (ROTEM) in predicting bleeding and thrombotic events in patients with cirrhosis. Methods: We conducted a prospective cohort study of patients with cirrhosis at two metropolitan hospitals. All patients underwent ROTEM analysis and were then followed to record any bleeding and thrombotic events. Univariate and multivariate logistic regression analyses were performed to explore associations with bleeding and thrombotic events. Results: Nineteen of the 162 patients recruited experienced a bleeding event within one year of ROTEM analysis. On univariate analysis, maximum clot firmness (MCF) using both EXTEM and INTEM tests was significantly reduced in patients who had a bleeding event, compared to those who did not (50 mm vs. 57 mm, p < 0.01 and 48 mm vs. 54 mm, p < 0.01, respectively). In addition, on univariate analysis, clotting time (CT) in the INTEM test was prolonged in the bleeding group (214 s vs. 198 s, p = 0.01). On multivariate analysis, only MCFEX was a significant predictor of bleeding events. In contrast, there was no association found between ROTEM parameters and development of thrombosis within a one-year period. Conclusions: ROTEM may provide a useful tool in predicting future bleeding events in patients with cirrhosis. Larger studies are required to further validate this finding and explore its application in clinical practice.

Selective androgenic receptor modulators (SARMs) have not been approved by the U.S. Food and Drug Administration but they are heavily promoted as alternatives to androgenic anabolic steroids. We present two cases of liver injury associated with SARMs.

BACKGROUND Liver transplantation (LT) is a potentially curative therapy for patients with hepatocellular carcinoma (HCC). HCC-recurrence following LT is associated with reduced survival. There is increasing interest in chemoprophylaxis to improve HCC-related outcomes post-LT. AIM To investigate whether there is any benefit for the use of drugs with proposed chemoprophylactic properties against HCC, and patient outcomes following LT. METHODS This was a retrospective study of adult patients who received Deceased Donor LT for HCC from 2005-2022, from a single Australian centre. Drug use was defined as statin, aspirin or metformin therapy for ≥ 29 days, within 24 months post-LT. A cox proportional-hazards model with time-dependent covariates was used for survival analysis. Outcome measures were the composite-endpoint of HCC-recurrence and all-cause mortality, HCC-recurrence and HCC-related mortality. Sensitivity analysis was performed to account for immortality time bias and statin dosing. RESULTS Three hundred and five patients were included in this study, with 253 (82.95%) males with a median age of 58.90 years. Aetiologies of liver disease were 150 (49.18%) hepatitis C, 73 (23.93%) hepatitis B (HBV) and 33 (10.82%) non-alcoholic fatty liver disease (NAFLD). 56 (18.36%) took statins, 51 (16.72%) aspirin and 50 (16.39%) metformin. During a median follow-up time of 59.90 months, 34 (11.15%) developed HCC-recurrence, 48 (15.74%) died, 17 (5.57%) from HCC-related mortality. Statin, aspirin or metformin use was not associated with statistically significant differences in the composite endpoint of HCC-recurrence or all-cause mortality [hazard ratio (HR): 1.16, 95%CI: 0.58-2.30; HR: 1.21, 95%CI: 0.28-5.27; HR: 0.61, 95%CI: 0.27-1.36], HCC-recurrence (HR: 0.52, 95%CI: 0.20-1.35; HR: 0.51, 95%CI: 0.14-1.93; HR 1.00, 95%CI: 0.37-2.72), or HCC-related mortality (HR: 0.32, 95%CI: 0.033-3.09; HR: 0.71, 95%CI: 0.14-3.73; HR: 1.57, 95%CI: 0.61-4.04) respectively. Statin dosing was not associated with statistically significant differences in HCC-related outcomes. CONCLUSION Statin, metformin or aspirin use was not associated with improved HCC-related outcomes post-LT, in a largely historical cohort of Australian patients with a low proportion of NAFLD. Further prospective, multicentre studies are required to clarify any potential benefit of these drugs to improve HCC-related outcomes.

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.

BACKGROUND:The benefits of regular surveillance imaging for cholangiocarcinoma in patients with primary sclerosing cholangitis (PSC) are unclear. Hence, we aimed to evaluate the impact of regular magnetic resonance cholangiopancreatography (MRCP) on outcomes of patients with PSC in Australia, where the practice of MRCP surveillance is variable. METHODS:The relationship between MRCP surveillance and survival outcomes was assessed in a multicenter, retrospective cohort of patients with PSC from 9 tertiary liver centers in Australia. An inverse probability of treatment weighting approach was used to balance groups across potentially confounding covariates. RESULTS:A total of 298 patients with PSC with 2117 person-years of follow-up were included. Two hundred and twenty patients (73.8%) had undergone MRCP surveillance. Regular surveillance was associated with a 71% reduced risk of death on multivariate weighted Cox analysis (HR: 0.29, 95% CI: 0.14-0.59, p < 0.001) and increased likelihood of having earlier endoscopic retrograde cholangiopancreatography from the date of PSC diagnosis in patients with a dominant stricture (p < 0.001). However, survival posthepatobiliary cancer diagnosis was not significantly different between both groups (p = 0.74). Patients who had surveillance of less than 1 scan a year (n = 41) had comparable survival (HR: 0.46, 95% CI 0.16-1.35, p = 0.16) compared to patients who had surveillance at least yearly (n = 172). CONCLUSIONS:In this multicenter cohort study that employed inverse probability of treatment weighting to minimize selection bias, regular MRCP was associated with improved overall survival in patients with PSC; however, there was no difference in survival after hepatobiliary cancer diagnosis. Further prospective studies are needed to confirm the benefits of regular MRCP and optimal imaging interval in patients with PSC.

Background and AimThe rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population.MethodMulticenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period.ResultsThree hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate.ConclusionEqual to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.

Background and Aims: Most patients with decompensated cirrhosis fail to meet their nutrition targets. The impact of nasogastric feeding (NGF) on malnutrition in cirrhosis remains unknown. This study aims to assess the impact of pretransplant NGF on pre–liver transplant and post–liver transplant outcomes. Approach and Results: This single-center, prospective randomized controlled trial of 55 patients with severe malnutrition and low handgrip strength (HGS) compared a standard high-energy high-protein diet to diet plus supplemental nocturnal NGF while awaiting transplant. The primary outcome was a change in HGS. The median age was 58.5 years (IQR: 51.1–64), median MELD was 24 (20–28.5), and 32 (58%) patients were male. The median duration of NGF was 63.0 days (34.5–127), following which time the median between-group difference in HGS was 3.6 kg (95% CI: 1.7–5.2, p<0.001), an increase of 20% from baseline. Mid–upper-arm circumference, triceps skinfold, and immune function all increased significantly with NGF. Muscle and nutritional parameters continued to improve with increasing duration of feeding. NGF significantly increased daily energy intake between groups by 1285 kcal (95% CI: 860–1677) and protein intake by 51 g (95% CI: 32–71) (both p<0.001). All NGF patients met >100% of their measured nutritional requirements. Posttransplant clinical outcomes were similar between groups. Conclusions: Targeted enteral feeding before liver transplant improves HGS, anthropometry, and immune function in severely malnourished patients with cirrhosis. These findings provide a strong rationale for early consideration of NGF to reverse malnutrition and improve muscle strength. Appropriately powered studies should explore whether NGF can also impact clinically relevant outcomes including pretransplant and posttransplant mortality.