Impairments in signaling cascades mediating the progression of liver disease from chronic hepatitis to hepatocellular carcinoma in animal and human models

The most common risk factors for chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) include chronic alcohol abuse and infection with hepatitis B (HBV) or hepatitis C (HCV) virus. Growing evidence from human studies and experimental models suggests that pre-degenerative and premalignant abnormalities include disturbances in intracellular signaling and ongoing injury with oxidative stress, inflammation, and lipotoxicity. The major signal transduction pathways affected in both degenerative and neoplastic disease states in liver include: insulin/IGF, Wnt/β-catenin, and others

Helicobacter pylori Infection: Antibiotic Resistance and Solutions for Effective Management in Africa

Helicobacter pylori. pylori infection is ubiquitous worldwide, with prevalence rates of greater than 70% in Africa. Symptomatic patients present with foregut gastrointestinal symptoms which can be readily diagnosed with standardized non-invasive or invasive tests. The biggest challenge, however, is in the management of this condition with rising antimicrobial resistance rates to most of the antibiotics recommended for therapy. This is a problem worldwide, but more specifically in Africa, where the socio-economic and political climate is such that eradication of this organism seems impossible. Furthermore, the recommended antimicrobial susceptibility testing for drug resistance is not widely available in Africa due to the lack of infrastructural as well as human resources. With the widespread unregulated use of antibiotics in some parts of Africa, the figures of antimicrobial resistance are likely to soar. In the face of these significant challenges, this ‘perspectives’ article aims to address the issue of antimicrobial resistance in Africa, by providing achievable and targeted goals to curb the spread of infection and rising antimicrobial resistance

The impact of Helicobacter pylori and intestinal helminth infections on gastric adenocarcinoma and inflammatory bowel disease in Sub-Saharan Africa

Gastric adenocarcinoma (GCA) is the 5th leading cancer globally with an estimated 1.1 million cases reported in 2020. Ninety percent of non-cardia GCAs are attributable to Helicobacter pylori (H. pylori), the most prevalent bacterial infection globally. Rates of H. pylori infection are highest in Sub-Saharan Africa (SSA), yet surprisingly low numbers of GCAs are reported in the region. A similar phenomenon is seen with the inflammatory bowel diseases (IBD), Crohn’s disease, and ulcerative colitis. These disorders have risen dramatically over the past century in high income countries across the globe, with sharp increases noted more recently in newly industrialized regions. In contrast IBD is rare in most regions in SSA. For both diseases this may reflect under-reporting or limited access to diagnostic modalities, but an alternative explanation is the high burden of infection with gastrointestinal parasites endemic to SSA which may attenuate the risk of developing GCA and IBD. In this mini review we discuss the complex interplay between these microorganisms, GCA, and IBD, as well as a possible protective role of H. pylori and the development of IBD

Acetaldehyde adducts in alcoholic liver disease

Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD), with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC). Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver. Mechanistically, acetaldehyde promotes adduct formation, leading to functional impairments of key proteins, including enzymes, as well as DNA damage, which promotes mutagenesis. Why certain individuals who heavily abuse alcohol, develop HCC (7.2–15%) versus cirrhosis (15–20%) is not known, but genetics and co-existing viral infection are considered pathogenic factors. Moreover, adverse effects of acetaldehyde on the cardiovascular and hematologic systems leading to ischemia, heart failure, and coagulation disorders, can exacerbate hepatic injury and increase risk for liver failure. Herein, we review the role of acetaldehyde adducts in the pathogenesis of chronic ALD and HCC

Managing acute abdominal pain in the emergency centre:Lessons from a patient's experience

Pain is one of the most common reasons people present to the emergency centre with 7-10% of presentations being due to acute abdominal pain. However, pain is also often neglected by clinicians in emergency centres. The well validated South African Triage Score (SATS) incorporates pain assessment in the prioritising of patients with the aim of guiding clinicians. Based on the SATS, severe pain (a score of ≥8 out of 10) should prompt the clinician to initiate treatment within 10 min of presentation, as unmanaged pain has multiple negative consequences, including poor outcomes of the acute incident with delayed healing and increased risk of developing chronic pain. In this commentary, we present a patient's experience when attending an emergency centre for acute abdominal pain, describe relevant pain mechanisms and highlight the stages where clinical management could have been optimised

Rat Strain Differences in Susceptibility to Alcohol-Induced Chronic Liver Injury and Hepatic Insulin Resistance

The finding of more severe steatohepatitis in alcohol fed Long Evans (LE) compared with Sprague Dawley (SD) and Fisher 344 (FS) rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories) ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1–3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation

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 $$\ge$$ ≥ 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

Risk of malignancy in patients with inflammatory bowel disease treated with Azathioprine or 6-mercaptopurine : the Cape Town experience

Includes bibliographical references (leaves 55-63).The benefits of the use of Azathioprine (AZA) and its metabolite 6-mercaptopurine (6-MP) in the treatment of Inflammatory Bowel Disease (IBD) are well established. However, concern regarding the long-term use of these agents in the induction of certain malignancies particularlty lymphoma and skin cancer has been reported in renal transplant and rheumatoid arthritis patients. In IBD patients hoever, several retropsective and prospective studies have been conducted (including two meta-analyses) with divergent results. The primary objective of this study was to compare the incidence of cancer in IBD patients treated with AZA/6BMP with those not treated. Secondary objectives were to assess if skin cancer had a higher incidence of occurrence than other cancers, and to determine the independent risk factors associated with cleveloping any malignancy

Immunopathogenesis of Hepatitis B Virus Infection and Related Complications

Chronic hepatitis B (CHB) is a serious consequence of hepatitis B virus (HBV), which infects and replicates in the liver. It is characterised by prolonged hepatitis B surface antigen seropositivity; this can lead to both cirrhosis and hepatocellular carcinoma (HCC). The infection begins when HBV binds its only known functional receptor, sodium taurocholate cotransporting polypeptide (NTCP), which was identified recently. The discovery of NTCP was a significant breakthrough in the field of HBV research, and has facilitated the establishment of a susceptible hepatoma cell line model for studying the mechanisms underlying HBV pathogenesis. Following productive HBV infection, both cellular and humoral immune cells and molecules, such as T cells and chemokines, are activated to resolve infection by destroying HBV-infected hepatocytes. However, host immunity to HBV is not always protective, most likely due to immune evasion mechanisms employed by HBV. These mechanisms may result in viral persistence, accumulation of mutations, and aberrant epigenetic alterations that lead to HCC. Here we highlight our current understanding of the HBV replication cycle, immunopathogenesis, and related mechanisms underlying the progression of CHB to advanced liver disease, along with the attendant complications