INTRODUCTION:Previous guidelines considered body mass index (BMI) over 40 kg/m2 a relative contra-indication to liver transplantation (LT). The aims were to examine the selection process and study outcomes of patients with Class I-III obesity. METHODS:Retrospective analysis of outcomes of obese patients assessed for LT at our center between 2010 and 2023, divided into three groups: Class I (BMI30-34.9 kg/m2), Class II (BMI35-39.9 kg/m2), and Class III (BMI>40 kg/m2). Survival of non-obese adult patients was used for comparison. RESULTS:Three hundred fifteen patients with BMI ≥30 kg/m2 were assessed for LT. Seventeen (5.4%) were not wait-listed due to comorbidities. One hundred sixty-eight patients were transplanted: 100 Class I, 43 Class II, and 25 Class III. There were no differences in postoperative complications (Clavien-Dindo Grade 3 or more; 41%, 42%, 48% for Class I-III obesity respectively) or patient and graft survival (5-y rates 84.4% and 82.7%, respectively, for the whole cohort) according to the different classes of obesity. Furthermore, patient and graft survival was not different between non-obese and obese patients (p = 0.932). CONCLUSION:With a rigorous selection process, short-term outcomes after LT for patients with Class III obesity were comparable to patients with Class I-II obesity. Long-term survival was identical for obese and non-obese patients.

A 52-year-old male with a diagnosis of non-alcoholic fatty liver disease re-engages with the medical system and is found to have an unexpected diagnosis.

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (>= 1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0.045), and 71 (23%) in the obeticholic acid 25 mg group (p=0.0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0.18], and 36 [12%] in the obeticholic acid 25 mg group [p=0.13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

INTRODUCTION: Obeticholic acid (OCA), an FXR agonist, improved both fibrosis and histologic features of nonalcoholic steatohepatitis (NASH) in the Ph2 FLINT study. This Month 18 pre-specified interim analysis of the Ph3 REGENERATE study evaluated the effect of OCA on liver histology in patients (pts) with biopsy-confirmed NASH 1 . METHODS: Pts with NASH and fibrosis stages F2-3 (ITT), and an exploratory group of F1 pts with metabolic syndrome, were randomized to placebo (PBO), OCA 10 mg, or OCA 25 mg QD. Primary endpoints were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of liver fibrosis per liver biopsy. The safety population included all randomized and dosed pts (F1-3, N = 1968). Clinical outcomes will be evaluated at the end-of-study. RESULTS: The ITT population included 931 pts (PBO [n = 311], OCA 10mg [n = 312] or OCA 25mg [n = 308]), comprised of 44% F2 and 56% F3. Baseline characteristics were well-balanced across groups. Results in Table 1. The primary fibrosis endpoint was met by 11.9% PBO, 17.6% OCA 10 mg ( P = 0.0446 vs PBO), and 23.1% OCA 25 mg ( P = 0.0002 vs PBO) pts (ITT). The primary NASH endpoint was not statistically significant (ITT); however significantly more pts on OCA 25 mg showed improvements in hepatocellular ballooning ( P = 0.0011 vs PBO) and lobular inflammation ( P = 0.0322 vs PBO). Dose-dependent reductions in ALT, AST and GGT were observed. Pruritus was the most common AE (19% PBO, 28% OCA 10mg, 51% OCA 25 mg) and was predominantly mild to moderate in severity (severe pruritus: < 1% PBO, < 1% OCA 10mg, 5% OCA 25 mg). SAEs occurred in 11% PBO, 11% OCA 10 mg and 14% OCA 25 mg pts. Increases in LDLc with OCA were observed by Week 4, but approached baseline by Month 18 (OCA 25mg: LS mean change Wk4 +22.6 mg/dL, M18 + 4.0 mg/dL). Three deaths occurred; none were considered treatment-related (PBO n = 2; OCA 25 mg n = 1). CONCLUSION: Treatment with OCA 25mg improved liver fibrosis, key histologic features of steatohepatitis and liver biochemistry, demonstrating consistent efficacy with an overall AE profile similar to previous studies. 1 Interim analysis results at 18 months are based on surrogate endpoints and impact on clinical outcomes has not been confirmed. The REGENERATE study is ongoing to confirm the clinical benefit of OCA.

Asymptomatic liver disease is common in bariatric patients and can be diagnosed with intraoperative biopsy. This study aimed to establish the risk-benefit profile of routine liver biopsy, prevalence of clinically significant liver disease, relationship between liver pathology and body mass index, and compare outcomes between ethnic groups. This retrospective cohort study included all patients who had index bariatric surgery at Auckland City Hospital between 2009 and 2016. Diagnosis of liver disease was based on intraoperative biopsy histology. Outcomes included safety (biopsy-related complication) and utility (liver pathology meeting criteria for referral). Liver pathology and referral rates were compared between ethnic groups. Of 335 bariatric surgery patients, 234 (70%) underwent intraoperative liver biopsy. There were no biopsy-related complications. Histological findings were as follows: normal 25/234 (11%), non-alcoholic fatty liver disease (NAFLD) 207/234 (88%), and other pathological findings in 35/234 (15%). Histological finding meeting referral criteria was present in 22/234 (9%). Of these, 12/22 (55%) were referred. Number needed to biopsy to identify histology meeting referral criteria: n = 11. Māori had a similar NAFLD rate to non-Māori [51/56 versus 156/178, p = 0.48]. Pasifika patients had a higher rate than non-Pasifika [39/40 versus 168/194, p = 0.049]. Māori and Pasifika patients had similar referral rates to non-Māori and non-Pasifika [2/3 versus 5/9, p = 0.73; 2/2 versus 5/10, p = 0.19]. Intraoperative liver biopsy during bariatric surgery is safe and identified liver disease in 89%, with 9% meeting referral criteria. Pasifika patients have a higher rate of NAFLD than non-Pasifika.

Interferon (IFN)-free, direct-acting antiviral (DAA) therapy agents provide a safe and efficacious treatment for liver transplant recipients with recurrent hepatitis C virus (HCV) infection. The aim of this study is to evaluate the impact of HCV eradication on the metabolic factors in liver transplant recipients. We completed a retrospective single-center study on HCV-related liver transplant recipients treated with IFN-free DAAs including both treatment-naive and treatment-experienced patients. IFN-free DAAs impact on the metabolic profile were assessed at baseline and sustained virological response (SVR) between 24 and 48 weeks. In total, 91 liver transplant recipients with recurrent HCV infection received IFN-free DAA treatment, 62 patients had IFN-based treatment failure, and 29 were treatment-naïve, of whom 87 (96%) achieved SVR. Eradication of recurrent HCV infection was associated with reduction in the treatment of diabetes and hypertension by 38% and 22% from the baseline respectively. Hemoglobin A1c (HbA1c) levels declined from mean 35.5 ± 4.3 mmol/mol to 33.3 ±3.6 mmol/mol at 44 weeks posttreatment (P = 0.03). Total cholesterol levels increased from 3.8 ± 0.9 mmol/L to 4.9 ± 0.9 mmol/L at 41 weeks posttreatment (P < 0.0001), reflecting a significant increase in serum low-density lipoprotein (LDL) levels (2.0 ± 0.8 to 2.9 ± 0.8; P < 0.0001). Estimated glomerular filtration rate (eGFR) levels increased from 64.9 ± 20 mL/minute to 69.6 ± 20 mL/minute at 24 weeks posttreatment (P = 0.0004). Glucose, lipid profile, and eGFR changes were independent of weight changes and immunosuppression dosage and trough levels. In conclusion, eradication of recurrent HCV infection by DAA therapy has beneficial impacts on glucose metabolism and renal profile and reverses the hypolipidemic effect of HCV in liver transplant recipients. These extrahepatic effects of DAA therapy need to be validated by larger prospective studies.

Dietary copper restriction has long been considered an important aspect of treatment for Wilson’s disease (WD). However, evidence supporting this approach is limited. There are no published randomised controlled trials examining this recommendation due to rarity of the disease and variable presentation. This review summarises current knowledge on the absorption and regulation of copper in humans and its relevance to patients with WD. Studies have demonstrated that as the level of dietary copper increases, the proportion absorbed decreases. This observation implies that 'high copper' foods that WD patients are generally advised to avoid would need to be consumed in large amounts to impact markedly on the quantity absorbed. Dietary copper restriction is unlikely to reduce the amount absorbed significantly and is not only difficult to manage but restricts food groups unnecessarily, detracting from the provision of substrates essential for improving nutritional status in a nutritionally compromised group. Medical management for WD is effective in compliant patients, allowing stabilisation of the liver disease. Based on current evidence, dietary copper restrictions in stable WD patients who are adherent to medical therapy are unnecessary with two food exceptions (shellfish and liver).

Background: Non-alcoholic fatty liver disease (NAFLD) can be ameliorated by weight loss although difficult to maintain. Emerging evidence indicates that prebiotics and antibiotics improve NAFLD. Aim: To determine whether inulin supplementation after brief metronidazole therapy is effective in reducing alanine aminotransferase (ALT) and maintaining weight loss achieved through a very-low-calorie diet (VLCD) among people with NAFLD. Methods: Sixty-two people with NAFLD commenced 4-week VLCD using Optifast meal replacements (600 kcal/day). Sixty were then randomised into a 12-week double-blind, placebo-controlled, parallel three-arm trial: (1) 400 mg metronidazole twice daily in Week 1 then inulin 4 g twice daily OR (2) placebo twice daily in week one then inulin OR (3) placebo-placebo. Main outcomes were ALT and body weight at 12 weeks. Fecal microbiota changes were also evaluated. Results: Mean body mass index (BMI) and ALT reduced after VLCD by 2.4 kg/m2 and 11 U/L, respectively. ALT further decreased after metronidazole-inulin compared to after placebo-placebo (mean ALT change −19.6 vs. −0.2 U/L, respectively; p = 0.026); however, weight loss maintenance did not differ. VLCD treatment decreased the ratio of Firmicutes/Bacteroidetes (p = 0.002). Conclusion: Brief metronidazole followed by inulin supplementation can reduce ALT beyond that achieved after VLCD in patients with NAFLD.

The effects of pretransplant obesity, diabetes mellitus (DM), coronary artery disease (CAD), and hypertension (HTN) on outcomes after liver transplantation (LT) are controversial. Questions have also been raised about the appropriateness of the body mass index (BMI) for assessing obesity in patients with end‐stage liver disease. Both issues have implications for organ allocation in LT. To address these questions, we undertook a cohort study of 202 consecutive patients (2000‐2010) undergoing LT at a national center in New Zealand. BMI and body fat percentage (%BF) values (dual‐energy X‐ray absorptiometry) were measured before transplantation, and the methods were compared. The influence of pretransplant risk variables (including obesity, DM, CAD, and HTN) on the 30‐day postoperative event rate, length of hospital stay, and survival were analyzed. There was agreement between the calculated BMI and the measured %BF for 86.0% of the study population (κ coefficient = 0.73, 95% confidence interval = 0.61‐0.85), and this was maintained across increasing Model for End‐Stage Liver Disease scores. Obesity was an independent risk factor for the postoperative event rate [count ratio (CR) = 1.03, P < 0.001], as was DM (CR = 1.4, P < 0.001). Obesity with concomitant DM was the strongest predictor of the postoperative event rate (CR = 1.75, P < 0.001) and a longer hospital stay (5.81 days, P < 0.01). Independent metabolic risk factors had no effect on 30‐day, 1‐year, or 5‐year patient survival. In conclusion, BMI is an adequate tool for assessing obesity‐associated risk in LT. Early post‐LT morbidity is highest for patients with concomitant obesity and DM, although these factors do not appear to influence recipient survival. Liver Transpl 20:281‐290, 2014. © 2014 AASLD.

BACKGROUND:Increased oxidative stress and subsequent mitochondrial damage are important pathways for liver damage in chronic hepatitis C virus (HCV) infection; consequently, therapies that decrease mitochondrial oxidative damage may improve outcome. The mitochondria-targeted anti-oxidant mitoquinone combines a potent anti-oxidant with a lipophilic cation that causes it to accumulate several-hundred fold within mitochondria in vivo. AIMS:In this phase II study, we investigated the effect of oral mitoquinone on serum aminotransferases and HCV RNA levels in HCV-infected patients. METHODS:Thirty HCV patients who were either non-responders or unsuitable candidates for standard-of-care (pegylated interferon plus ribavirin) were randomized to receive mitoquinone (40 or 80 mg) or placebo once daily for 28 days, and serum aminotransferases and HCV RNA levels were measured. RESULTS:Both treatment groups showed significant decreases in absolute and percentage changes in serum alanine transaminase (ALT) from baseline to treatment day 28 (P<0.05). There was also a significant difference between incremental area under the curve for ALT between baseline and day 28 for the 40 mg treatment group against placebo (P<0.05). The differences in plasma ALT activity from baseline to day 28 in both mitoquinone groups compared with placebo did not reach significance (P>0.05). There was no change in HCV load on mitoquinone treatment. CONCLUSIONS:Administration of the mitochondria-targeted anti-oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria-targeted anti-oxidants in HCV and other liver diseases are warranted.

Background Liver transplantation (LT) is established treatment for adults and children with acute or chronic liver failure, however there are insufficient donor organs to meet demand and 14% of New Zealand patients have died waiting or were de-listed due to deterioration whilst on the waiting list. Live donor liver transplantation (LDLT) offers an alternative graft source that enables timely transplantation, but also carries the risk of morbidity and mortality for the donor.Aim To report the initial experience with LDLT in New Zealand.Methods Review of donor and recipient outcomes for the first 20 cases.Results 129 potential live liver donors were assessed for 68 recipients. Donors were evaluated according to a multi-step protocol including independent donor advocacy. Twenty LDLT were performed on 7 adults and 13 paediatric recipients using 5 right lobe, 2 extended left lobe, 2 left lobe, and 11 left lateral section grafts. Five donors (25%) experienced postoperative complications, none of which were life-threatening. Four recipients had acute liver failure and 16 had chronic liver disease including one retransplant. There was a high rate of recipient biliary complications (40%) but graft and recipient survival is 100% to date.Conclusion LDLT has been successfully introduced in New Zealand with good donor and recipient outcomes.