Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease

Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease

Liver Disease in Aboriginal and Torres Strait Islander People

Aboriginal and Torres Strait Islander people have a substantially higher prevalence of liver disease than non-Indigenous Australians. Cirrhosis and its complications were the sixth leading cause of mortality for Aboriginal and Torres Strait Islander people in 2020. Liver disease has been estimated to be the third leading cause of the mortality gap between Aboriginal and Torres Strait Islander and non-Indigenous people due to chronic disease, accounting for 11% of this gap. While current trends show reducing mortality rates for Aboriginal and Torres Strait Islander people for conditions including circulatory disease, diabetes and kidney disease, there are no data to suggest a similar decline for liver disease. This review highlights the common causes of liver disease affecting Aboriginal and Torres Strait Islander people, which include hepatitis B, hepatitis C, alcohol related liver disease, metabolic dysfunction-associated fatty liver disease, and cirrhosis and its complications including hepatocellular carcinoma. Current treatments including liver transplantation as well as suggestions for improving detection, treatment and access to liver care will also be discussed. Recent revolutions in the detection and treatment of liver disease make efforts to improve access to treatment and outcomes an urgent priority for Aboriginal and Torres Strait Islander people

Critical role of general practitioners in preventing readmission following emergency department alcohol screening and brief intervention management of alcohol-related problems

Introduction/Objectives: Alcohol screening and brief intervention (ASBI) strategies are useful in general practice (GP) but their effectiveness in the emergency department (ED) is unclear. We evaluated the effect of ED-based ASBI on re-admissions. Methods: 453 ED subjects exceeding the threshold score on the three-item Alcohol Use Disorders Identification Test-Consumption (females 3+: males 4+) were randomized. We conducted telephone follow-up at 1 and 3 months and recorded hospital events 6 months pre- and post-enrolment. Results: Median weekly alcohol use was 20 standard drinks (interquartile range (IQR) 9-45) on enrolment. After 3 months, 247 (55%) were able to be re-interviewed. Median alcohol use was 10 drinks (IQR 4-26). Six months later, subjects receiving ED-ASBI without GP follow-up had significantly greater risk of re-admission compared with those having GP follow-up (OR 1.68, 95%CI 1.06-2.65; P =.028). Conclusions: ASBI reduces the likelihood of ED re-presentation only in subjects who have GP follow-up. The study has been registered as a clinical trial (Australian and New Zealand Clinical Trial Registry ACTRN12617001254381)

Tyrosine kinase Inhibitors in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma is the third leading cause of cancer-related mortality in the world. Locoregional therapy is used for early stage hepatocellular carcinoma. Tyrosine kinase inhibitors have been the mainstay of treatment for advanced hepatocellular carcinoma. Sorafenib was the first drug approved based on data from two pivotal phase III trials. Although sorafenib provided a survival benefit, development of adverse events limits its use in some patients. These adverse events, such as hand–foot syndrome and diarrhea, have a significant impact on the quality of life and, in some circumstances, are severe enough to prompt cessation of the drug. In recent times, a range of new therapeutic options have come on the scene including lenvatinib, regorafenib, and cabozantinib. Lenvatinibis now approved as an alternative first-line agent for hepatocellular carcinoma. Regorafenib and cabozantinib are both second-line agents. These medications provide a promising range of treatment options for patients who progress on sorafenib or are intolerant to it. This chapter provides an insight into the range of tyrosine kinase inhibitors available for the treatment of hepatocellular carcinoma

Critical role of general practitioners in preventing readmission following emergency department alcohol screening and brief intervention management of alcohol-related problems

Introduction/Objectives: Alcohol screening and brief intervention (ASBI) strategies are useful in general practice (GP) but their effectiveness in the emergency department (ED) is unclear. We evaluated the effect of ED-based ASBI on re-admissions. Methods: 453 ED subjects exceeding the threshold score on the three-item Alcohol Use Disorders Identification Test-Consumption (females 3+: males 4+) were randomized. We conducted telephone follow-up at 1 and 3 months and recorded hospital events 6 months pre- and post-enrolment. Results: Median weekly alcohol use was 20 standard drinks (interquartile range (IQR) 9-45) on enrolment. After 3 months, 247 (55%) were able to be re-interviewed. Median alcohol use was 10 drinks (IQR 4-26). Six months later, subjects receiving ED-ASBI without GP follow-up had significantly greater risk of re-admission compared with those having GP follow-up (OR 1.68, 95%CI 1.06-2.65; P =.028). Conclusions: ASBI reduces the likelihood of ED re-presentation only in subjects who have GP follow-up. The study has been registered as a clinical trial (Australian and New Zealand Clinical Trial Registry ACTRN12617001254381)

mTOR inhibitors induce erythropoietin resistance in renal transplant recipients

Aim: To elucidate the role of mTOR inhibitors on iron, hepcidin and erythropoietin-mediated regulation of hemopoiesis in stable renal transplant recipients (RTR). Background: Impaired hemopoiesis is common following renal transplantation managed using mTOR inhibitors. The mechanisms responsible are uncertain but include direct effects on iron, hepcidin or erythropoietin-mediated hemopoiesis. Methods: We conducted a single center prospective case-control study of 26 adult RTR with stable allograft function. RTR received stable mTOR dosing (cases, 11/26 [42%]) or stable tacrolimus dosing (controls, 15/26 [58%]). Baseline demographics, full blood count, renal function, iron studies, hepcidin-25, Interleukin-6 (IL-6) and erythropoietin (EPO) levels were determined. Results: There were no differences in age, gender or allograft function. Mean daily sirolimus dose for cases was 1.72 mg, with mean trough level of 8.46 ng/mL. Mean daily tacrolimus dose for controls was 4.3 mg, with mean trough level of 5.8 ng / mL. There were no differences in mean hemoglobin (143 vs. 147 g / L; p = 0.59), MCV (88 vs. 90 fL; p = 0.35), serum ferritin (150 vs. 85.7 μg / L; p = 0.06), transferrin saturation (26 vs. 23.3%; p = 0.46), IL-6 (11 vs. 7.02 pg / ml; p = 0.14) or hepcidin-25 (3.62 vs. 3.26 nM; p = 0.76) between the groups. EPO levels were significantly higher in the group receiving mTOR therapy (16.8 vs. 8.49 IU / L; p = 0.028). On logistic regression analysis EPO level was the only variable that had a significant impact providing an odds ratio of 0.84 (95%CI 0.66–0.98). The area under the receiver operator characteristic curve (ROC) for the analysis was 0.77 (95%CI 0.54–0.94) with p = 0.04. Conclusion: Higher levels of EPO in the absence of deranged iron biochemistry or hepcidin-25 levels suggest that EPO resistance rather than impaired iron metabolism may contribute to the impaired hemopoiesis previously demonstrated in RTR on mTOR therapy

Mouse models of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents a major and steadily increasing global health challenge as the most common primary liver malignancy and leading cause of death in cirrhotic patients. The only hope for curative treatment or significant increase in life expectancy is early detection. Once patients have progressed towards end-stage HCC, effective treatment options are extremely limited on the background of a very high degree of heterogeneity in clinical presentation and outcome. Experimental chronic liver injury and cancer have been used extensively to mimic the human disease. In particular, mouse studies have advanced the field due to the ability to easily manipulate the mouse genome and transcriptome for mechanistic evaluations. In addition, they offer the opportunity to screen new therapeutic strategies cost effectively and in quick high-throughput, large-scale formats. The most commonly used mouse models in HCC research can be categorized as chemotoxic, diet-induced, and genetically engineered models. It is important to note that no particular model mimics all features of a given HCC etiology or histological subtype, and each model poses advantages and disadvantages that need to be carefully considered

Cellular plasticity in liver regeneration - spotlight on cholangiocytes

The liver\u27s remarkable capacity to self‐repair and regenerate following tissue injury has been recognized since the ancient Greek myth of Prometheus. However, the diverse potential sources of this regenerative capacity have been an area of hot debate, and only recently have studies started to unravel the actual degree of hepatic cell plasticity. Deng et al. established through lineage tracing experiments using a double‐fluorescent reporter system that biliary epithelial cells significantly contributed to hepatocyte regeneration in two murine chronic liver injury models. Furthermore, during the cholangiocyte‐to‐hepatocyte conversion, biphenotypic cells were identified in both mouse models and human cirrhotic livers. Following analysis of liver progenitor cell markers and mature cholangiocytes, the authors concluded that cholangiocytes directly lineage‐converted to hepatocytes without a progenitor cell intermediate and suggested these biphenotypic cells as potential cellular sources for future therapeutic transplantation strategies

Utility of serum biomarker indices for staging of hepatic fibrosis before and after venesection in patients with hemochromatosis caused by variants in HFE

Background & Aims Hemochromatosis that is associated with variants in the homeostatic iron regulator gene (HFE) is characterized by intestinal absorption of iron and excessive body and hepatic iron stores; it can lead to hepatic fibrosis and cirrhosis. Fibrosis has been staged by analysis of liver biopsies, but non-invasive staging methods are available. We evaluated the ability of aspartate aminotransferase:platelet ratio index (APRI), the fibrosis-4 (FIB-4) index, and gamma-glutamyl transferase:platelet ratio (GPR) to assess hepatic fibrosis staging in subjects with HFE-associated hemochromatosis, using liver biopsy-staged fibrosis as the reference standard. Methods We performed a retrospective, cross-sectional analysis of 181 subjects with HFE-associated hemochromatosis and hepatic fibrosis staged by biopsy analysis and available serum samples. We calculated APRI, FIB-4, and GPR at diagnosis for all 181 subjects and following venesection therapy in 64 of these subjects (7 subjects had follow-up biopsy analysis). We used area under the receiver operating characteristic curve (AUROC) analysis to assess the relationships between APRI score, FIB-4 score, and GPR and advanced (F3–F4) fibrosis and to select cut-off values. Results Hepatic fibrosis stage correlated with APRI score (r = 0.54; P \u3c .0001), FIB-4 score (r = 0.35; P \u3c .0001), and GPR (r = 0.36, P \u3c .0001). An APRI score above 0.44 identified patients with advanced fibrosis with an AUROC of 0.88, 79.4% sensitivity, 79.4% specificity, and 81% accuracy. A FIB-4 score above 1.1 identified patients with advanced fibrosis with an AUROC of 0.86, 80% sensitivity, 80.3% specificity, and 81% accuracy. A GPR above 0.27 identified patients with advanced fibrosis with an AUROC of 0.76, 67.7% sensitivity, 70.3% specificity, and 69% accuracy. APRI score was significantly more accurate than GPR (P = .05) in detecting advanced fibrosis; there was no difference between APRI and FIB-4. Venesection treatment was associated with significant reductions in APRI (P \u3c .0001) and GPR (P\u3c .001), paralleling fibrosis regression observed in available liver biopsies. Post-venesection APRI identified 87% of subjects with advanced fibrosis that decreased to levels that indicate stage F1–F2 fibrosis. Conclusions In a retrospective study of 181 subjects with HFE-associated hemochromatosis, we found that APRI and FIB-4 scores identified patients with advanced hepatic fibrosis with 81% accuracy. APRI scores might also be used to monitor fibrosis regression following venesection

Alcohol consumption and cardiovascular outcomes in patients with nonalcoholic fatty liver disease: A population-based cohort study

Low-level alcohol consumption is associated with reduced cardiovascular disease (CVD) in the general population. It is unclear whether this association is seen in patients with nonalcoholic fatty liver disease (NAFLD) who have an increased risk of CVD. We examined the association between alcohol consumption and CVD-related outcomes in subjects with NAFLD from a general population cohort. Subjects participating in the 1994-1995 Busselton Health survey underwent clinical and biochemical assessment. NAFLD was identified using the Fatty Liver Index of \u3e60, and alcohol consumption quantified using a validated questionnaire. CVD hospitalizations and death during the ensuing 20 years were ascertained using the Western Australian data linkage system. A total of 659 of 4,843 patients were diagnosed with NAFLD. The average standard drinks per week was 8.0 for men and 4.0 for women. Men consuming 8-21 drinks per week had a 38% (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.43-0.90) lower risk of CVD hospitalization as compared with men consuming 1-7 drinks per week. With both men and women combined, consumption of 8-21 drinks per week was associated with a 32% (HR 0.68, 95% CI 0.49-0.93) reduction in CVD hospitalization in minimally adjusted and 29% (HR 0.71, 95% CI 0.51-0.99) in fully adjusted models. No protective association was observed with binge drinking. There was no association between alcohol consumption and CVD death. Conclusion: Low to moderate alcohol consumption is associated with fewer CVD hospitalizations but not CVD death in subjects with NAFLD