Ivermectin drug induced liver injury.

Ivermectin remains a popular, albeit unproven, therapy used in both the prevention and treatment of COVID-19. We discuss a patient who developed jaundice and a liver injury 3 weeks after initiating ivermectin for COVID prevention.  Liver histology demonstrated a pattern of injury that was both portal and lobular, with a bile ductulitis as well with marked cholesasis. She was managed with low dose corticosteroids, later tapered and withdrawn. She remains well a year after presenting.

A retrospective study assessing the clinical outcomes and costs of acute hepatitis A in Cape Town, South Africa.

BACKGROUND: While some evidence has been demonstrated the cost-effectiveness of routine hepatitis A vaccination in middle-income countries, the evidence is still limited in other settings including in South Africa. Given this, the evidence base around the cost of care for hepatitis A needs to be developed towards considerations of introducing hepatitis A vaccines in the national immunisation schedule and guidelines. OBJECTIVES: To describe the severity, clinical outcomes, and cost of hepatitis A cases presenting to two tertiary healthcare centers in Cape Town, South Africa. METHODS: We conducted a retrospective folder review of patients presenting with hepatitis A at two tertiary level hospitals providing care for urban communities of metropolitan Cape Town, South Africa. Patients included in this folder review tested positive for hepatitis A immunoglobulin M between 1 January 2008 and 1 March 2018. RESULTS: In total, 239 folders of hepatitis A paediatric patients < 15 years old and 212 folders of hepatitis A adult patients [Formula: see text] 15 years old were included in the study. Before presenting for tertiary level care, more than half of patients presented for an initial consultation at either a community clinic or general physician. The mean length of hospital stay was 7.45 days for adult patients and 3.11 days for paediatric patients. Three adult patients in the study population died as a result of hepatitis A infection and 29 developed complicated hepatitis A. One paediatric patient in the study population died as a result of hepatitis A infection and 27 developed complicated hepatitis A, including 4 paediatric patients diagnosed with acute liver failure. The total cost per hepatitis A hospitalisation was $1935.41 for adult patients and $563.06 for paediatric patients, with overhead costs dictated by the length of stay being the largest cost driver. CONCLUSION: More than 1 in every 10 hepatitis A cases (13.3%) included in this study developed complicated hepatitis A or resulted in death. Given the severity of clinical outcomes and high costs associated with hepatitis A hospitalisation, it is important to consider the introduction of hepatitis A immunisation in the public sector in South Africa to potentially avert future morbidity, mortality, and healthcare spending.

Systematic review of the global epidemiology of viral-induced acute liver failure.

OBJECTIVES: The aetiology and burden of viral-induced acute liver failure remains unclear globally. It is important to understand the epidemiology of viral-induced ALF to plan for clinical case management and case prevention. PARTICIPANTS: This systematic review was conducted to synthesize data on the relative contribution of different viruses to the aetiology of viral-induced acute liver failure in an attempt to compile evidence that is currently missing in the field. EBSCOhost, PubMed, ScienceDirect, Scopus and Web of Science were searched for relevant literature published from 2009 to 2019. The initial search was run on 9 April 2019 and updated via PubMed on 30 September 2019 with no new eligible studies to include. Twenty-five eligible studies were included in the results of this review. RESULTS: This systematic review estimated the burden of acute liver failure after infection with hepatitis B virus, hepatitis A virus, hepatitis C virus, hepatitis E virus, herpes simplex virus/human herpesvirus, cytomegalovirus, Epstein-Barr virus and parvovirus B19. Data were largely missing for acute liver failure after infection with varicella-zostervirus, human parainfluenza viruses, yellow fever virus, coxsackievirus and/or adenovirus. The prevalence of hepatitis A-induced acute liver failur was markedly lower in countries with routine hepatitis A immunisation versus no routine hepatitis A immunisation. Hepatitis E virus was the most common aetiological cause of viral-induced acute liver failure reported in this review. In addition, viral-induced acute liver failure had poor outcomes as indicated by high fatality rates, which appear to increase with poor economic status of the studied countries. CONCLUSIONS: Immunisation against hepatitis A and hepatitis B should be prioritised in low-income and middle-income countries to prevent high viral-induced acute liver failure mortality rates, especially in settings where resources for managing acute liver failure are lacking. The expanded use of hepatitis E immunisation should be explored as hepatitis E virus was the most common cause of acute liver failure. REGISTRATION: PROSPERO registration number: CRD42017079730.

Mechanistic insights into antiretroviral drug-induced liver injury.

All classes of antiretroviral therapy (ART) have been implicated to induce adverse drug reactions such drug-induced liver injury (DILI) and immune-mediated adverse reactions in Human Immunodeficiency Virus (HIV) infected individuals. Patients that develop adverse drug reactions tend to have prolonged stays in hospital and may require to change to alternative regimens if reactions persist upon rechallenge or if rechallenge is contraindicated due to severity of the adverse reaction. Diagnosis of DILI remains a huge obstacle that delays timely interventions, since it is still based largely on exclusion of other causes. There is an urgent need to develop robust diagnostic and predictive biomarkers that could be used alongside the available tools (biopsy, imaging, and serological tests for liver enzymes) to give a specific diagnosis of DILI. Crucial to this is also achieving consensus in the definition of DILI so that robust studies can be undertaken. Importantly, it is crucial that we gain deeper insights into the mechanism of DILI so that patients can receive appropriate management. In general, it has been demonstrated that the mechanism of ART-induced liver injury is driven by four main mechanisms: mitochondrial toxicity, metabolic host-mediated injury, immune reconstitution, and hypersensitivity reactions. The focus of this review is to discuss the type and phenotypes of DILI that are caused by the first line ART regimens. Furthermore, we will summarize recent studies that have elucidated the cellular and molecular mechanisms of DILI both in vivo and in vitro.

Epidemiology of Liver Cancer in Africa: Current and Future Trends.

Hepatocellular carcinoma (HCC) is a disease of global public health significance with mortality on the rise, despite the preventable nature of its risk factors especially in Africa. It is now the sixth most common cancer worldwide, fifth in males, and ninth in females. HCC incidence and mortality are predicted to increase in African countries constrained by limited resources to combat endemic levels of viral infection and synergistic environmental risk factors. The changing nature of HCC etiology is particularly illustrated here with the traditional risk factors like viral hepatitis coexisting alongside high human immunodeficiency virus (HIV) prevalence and rapidly increasing urbanization that have promoted a sharp increase in additional risk factors like coinfection, type 2 diabetes mellitus, and obesity. Although there are some differences in etiology between North Africa and sub-Saharan Africa, risk factors like chronic viral hepatitis B and C, aflatoxin exposure, and iron overload predominate. Aggressive hepatitis B genotypes, combined with hepatitis B virus/hepatitis C virus/HIV coinfections and aflatoxin exposure, promote a more aggressive molecular phenotype. In parallel to a better understanding of the molecular etiology of HCC, policy and planning initiatives to address the burden of HCC must be anchored within the reality of the limited resources available. Establishment and coordination of cancer registries across Africa is needed to improve the quality of data necessary to galvanize action. Preventive measures including hepatitis B vaccination programs, measures to prevent maternal-to-child and child-to-child transmission, delivery of universally accessible antiretroviral and antiviral treatments, and reduction of dietary aflatoxin exposure can contribute markedly to reduce HCC incidence. Finally, the development of biomarkers and new therapeutic interventions will need a better understanding of the unique genetic and epigenetic characteristics of HCC on the continent. We present a narrative review of HCC in Africa, discussing present and future trends.

The global epidemiology of viral-induced acute liver failure: a systematic review protocol.

INTRODUCTION: The burden of viral-induced acute liver failure (ALF) around the world still remains unclear, with little to no data collected regarding the disease incidence in general and synthesised data on the relative contribution of different viruses to the aetiology of ALF is missing in the field. The aim of this review is to estimate the burden (prevalence, incidence, mortality, hospitalisation) of ALF following infection HAV, HBV, HCV, HDV, HEV, EBV), HSV1, HSV2, VZV, parvo-virus B19, HPIVs, YFV, HVV-6, CMV, CA16 and/or HAdVs. Establishing the common aetiologies of viral-induced ALF, which vary geographically, is important so that: (1) treatment can be initiated quickly, (2) contraindications to liver transplant can be identified, (3) prognoses can be deterined more accurately, and most importantly, (4) vaccination against viral ALF aetiologies can be prioritised especially in under-resourced regions with public health risks associated with the relevant attributable diseases. METHODS AND ANALYSIS: EBSCOhost, PubMed, ScienceDirect, Scopus and Web of Science databases will be searched for relevant literature published and grey literature from 2009 up to 2019. Published cross-sectional and cohort studies will be eligible for inclusion in this review. Qualifying studies will be formally assessed for quality and risk of bias using a standardised scoring tool. Following standardised data extraction, meta-analyses will be carried out using STATA. Depending on characteristics of included studies, subgroup analyses and meta-regression analyses will be performed. This review will be reported according to Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. ETHICS AND DISSEMINATION: No ethics approval is required as the systematic review will use only published data already in the public domain. Findings will be disseminated through publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42018110309.

The investment case for hepatitis B and C in South Africa: adaptation and innovation in policy analysis for disease program scale-up.

Even though WHO has approved global goals for hepatitis elimination, most countries have yet to establish programs for hepatitis B and C, which account for 320 million infections and over a million deaths annually. One reason for this slow response is the paucity of robust, compelling analyses showing that national HBV/HCV programs could have a significant impact on these epidemics and save lives in a cost-effective, affordable manner. In this context, our team used an investment case approach to develop a national hepatitis action plan for South Africa, grounded in a process of intensive engagement of local stakeholders. Costs were estimated for each activity using an ingredients-based, bottom-up costing tool designed by the authors. The health impact and cost-effectiveness of the Action Plan were assessed by simulating its four priority interventions (HBV birth dose vaccination, PMTCT, HBV treatment and HCV treatment) using previously developed models calibrated to South Africa's demographic and epidemic profile. The Action Plan is estimated to require ZAR3.8 billion (US$294 million) over 2017-2021, about 0.5% of projected government health spending. Treatment scale-up over the initial 5-year period would avert 13 000 HBV-related and 7000 HCV-related deaths. If scale up continues beyond 2021 in line with WHO goals, more than 670 000 new infections, 200 000 HBV-related deaths, and 30 000 HCV-related deaths could be averted. The incremental cost-effectiveness of the Action Plan is estimated at $3310 per DALY averted, less than the benchmark of half of per capita GDP. Our analysis suggests that the proposed scale-up can be accommodated within South Africa's fiscal space and represents good use of scarce resources. Discussions are ongoing in South Africa on the allocation of budget to hepatitis. Our work illustrates the value and feasibility of using an investment case approach to assess the costs and relative priority of scaling up HBV/HCV services.

Health: redefined.

For many years the definition of 'health' has remained unchanged as a narrow concept, encompassing physical wellbeing from a medical context. This somewhat focused definition has attracted criticism from individuals and professional bodies alike. Recent attempts have been made to redefine health, each offering an alternative viewpoint from sociological, environmental, societal and economic standpoints. We summarize and contextualize these definitions and provide an alternative, new, all-encompassing definition of health.

Identification of a novel and severe pattern of efavirenz drug-induced liver injury in South Africa.

Efavirenz now forms part of many antiretroviral regimens in low and middle-income countries. Efavirenz-related drug-induced liver injury is not well characterized but is thought to occur less frequently than with nevirapine. We describe our observation of three defined clinicopathological patterns of injury, one of which, submassive necrosis, is associated with significant morbidity and mortality. A high baseline CD4, younger age and possibly female gender, predicts for the injury.

N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review protocol.

BACKGROUND: Drug-induced liver injury (DILI) refers to acute or chronic liver injury that may occur as a consequence of using drugs and herbal or dietary supplements. Specific therapies for DILI are limited. There is considerable evidence for efficacy and safety of N-acetylcysteine (NAC) in management of paracetamol-induced liver injury. More recently, research has explored the use of NAC in non-paracetamol drug-induced liver injury. It is important to summarise the evidence of NAC for non-paracetamol DILI to determine if NAC may be considered a therapeutic option in this condition. METHODS/DESIGN: We will conduct a systematic review of the benefit and harm of NAC in non-paracetamol drug-induced liver injury. Primary and secondary outcomes of interest are pre-specified. Primary outcomes include all-cause mortality, mortality due to DILI, time to normalisation of liver biochemistry (e.g. return of alanine transaminase to <100 U/l and/or international normalized ratio (INR) <1.5) and adverse events. Secondary outcomes include transplantation rate, time to transplantation, transplant-free survival and duration of hospitalisation. We will include randomized controlled trials (RCTs) and prospective cohort studies. RCTs will contribute to the evaluation of safety and efficacy of NAC, whereas, the cohort studies will contribute exclusively to the evaluation of safety. We will search several bibliographic databases (including PubMed, Scopus, CINAHL, CENTRAL), grey literature sources, conference proceedings and ongoing trials. Following data extraction and assessment of the risk of bias, we will conduct a meta-analysis if feasible, as well as subgroup analyses. We will assess and explore clinical and statistical heterogeneity. DISCUSSION: The aim of this review is to provide evidence on the effectiveness and safety of NAC in non-paracetamol DILI. We anticipate that the results could aid health care practitioners, researchers and policymakers in the decision-making regarding the use of NAC in patients with non-paracetamol DILI. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014008771.

The expression of MUC mucin in cholangiocarcinoma.

Cholangiocarcinoma (CC) is a highly malignant epithelial cancer of the biliary tract, the cellular and molecular pathogenesis of which remains unclear. Malignant transformation of glandular epithelial cells is associated with the altered expression of mucin. We investigated the type of mucins expressed in CC. Twenty-six patients with histologically confirmed CC were included in this study. The expression of mucin was studied by immunohistochemistry using antibodies to MUC1, MUC1 core, MUC2, MUC3, MUC4, MUC5AC, and MUC6. There was extensive (>50%) expression of mucin, mainly MUC1 in 11/25 and MUC5AC in 12/26 cases. In the case of MUC3, 6/26 cases expressed mucin extensively, whilst only 1/26 had MUC2, MUC4, and MUC6 expression. Well-differentiated tumors significantly expressed MUC3 extensively compared to poor or moderately differentiated tumors (p=0.003). Fifteen of 25 cases had metastatic disease. MUC1 was extensively expressed in 9/15 cases with metastatic disease. In contrast, MUC1 expression was present in 2/10 cases where metastases were absent. Hilar lesions were less likely to express MUC1, but this was not statistically significant. Fifteen of 25 cases had metastatic disease. Extensive MUC3 expression was significantly associated with well-differentiated tumors, whilst there was an approaching significance between the extensive expression of MUC1 and metastasis in cholangiocarcinoma.

The Budd-Chiari syndrome in children: the spectrum of management.

The Budd-Chiari syndrome (BCS), characterized by hepatic venous outflow occlusion, is rare in children. We describe the cases of 3 patients with BCS who presented at different stages of liver dysfunction that required tailored management. A 10-year-old boy who presented with a weeklong history of abdominal discomfort received an early diagnosis. Treatment with thrombolytic therapy and adjunctive percutaneous interventional radiologic management led to a favorable outcome in this patient. A 2-year-old girl referred with a 6-week illness not amenable to thrombolytic therapy was managed with a pericardial patch atriocavoplasty to restore hepatic venous outflow tract patency. The third patient, a 5-year-old girl, presented with established cirrhosis and massive ascites. After we controlled the ascites with an extracorporeal shunt system and nutritional resuscitation, we conducted an orthotopic liver transplantation on this patient. The stage of disease at diagnosis influences the management strategy, and an early diagnosis offers patients the best possible chance of cure without major surgery. However, a later presentation can still be successfully managed by more radical surgical interventions. The aims of this case report were to emphasize the importance of a high index of suspicion in the diagnosis of pediatric BCS and to highlight the importance of early referral to a specialized pediatric liver unit with the necessary facilities to deal with the medical and surgical aspects of management.

A novel 25 kDa protein from the venom of Bitis arietans with similarity to C-type lectins causes fibrinogen-dependent platelet agglutination.

Snake venoms affect blood coagulation and platelet functions in various ways. Venom from the Viperidae and Crotalidae family of snakes contains biologically active proteins that possess coagulant and anticoagulant activities, as well as platelet aggregating and inhibitory activities. Many of these proteins belong to the C-type lectin family. C-type lectins from viper venoms can act by prohibiting the interaction between platelet receptors, such as GPIIbIIIa and the GPIb/V/IX complex, and their ligands. We report on the purification of a novel 25 kDa protein, Ba25, from Bitis arietans with a primary structure that possesses similarity to other C-type lectins from viper venom. This protein has a profound effect on the clotting of whole blood, as well as being able to cause agglutination of platelets in platelet rich plasma without degranulation of the cells, but not of washed platelets in the absence of fibrinogen. Ba25 interacts with the platelet via the GPIb/V/IX, as well as the GPIIbIIIa receptor, and causes an increase in binding of fibrinogen to platelets. These results suggest that Ba25 may be a potent mediator of platelet-platelet interactions, and other coagulatory mechanisms.