Standards of liver cirrhosis care in Central Australia.

BACKGROUND: Liver cirrhosis and hepatocellular carcinoma (HCC) are highly prevalent in Australia's Northern Territory. Contributing factors include high levels of alcohol consumption, viral hepatitis and metabolic syndrome. Rural Aboriginal residents form a significant proportion of the Central Australian population and present a challenge to traditional models of liver care. HCC surveillance and variceal screening are core components of liver cirrhosis management. AIM: To assess participation in HCC and variceal surveillance programmes in a Central Australian liver cirrhosis patient cohort. METHODS: Retrospective cohort study of patients with liver cirrhosis presenting to Alice Springs Hospital, Australia between January 1, 2012 and December 31, 2017. Demographic data, disease severity, attendance at hepatology clinics, participation in variceal and/or HCC surveillance programmes was recorded. Regression analyses were conducted to assess factors associated with two independent outcomes: Participation in HCC and variceal surveillance. RESULTS: Of 193 patients were identified. 82 patients (42.4%) were female. 154 patients (80%) identified as Aboriginal. Median Model for End-stage Liver Disease Score at diagnosis was 11. Alcohol was the most common cause of cirrhosis. Aboriginal patients were younger than non-Aboriginal patients (48.4 years vs 59.9 years, P < 0.001). There were similar rates of excess alcohol intake (72.6% vs 66.7%, P = 0.468) and obesity (34.5% vs 38.4%, P = 0.573 across non-Aboriginal and Aboriginal cohorts. 20.1% of patients took part in HCC surveillance and 42.1% of patients completed variceal screening. Aboriginal patients were less likely to engage with either HCC surveillance (OR: 0.38, 95%CI: 0.16-0.9, P = 0.025) or undergo variceal screening (OR: 0.31, 95%CI: 0.14-0.65, P = 0.002). CONCLUSION: HCC or variceal surveillance programmes had less uptake amongst Aboriginal patients. Greater emphasis needs to be placed on eliminating cultural obstacles to accessing hepatology services.

Controversies in and challenges to our understanding of hepatitis C.

Discovered in 1989, the hepatitis C virus (HCV) continues to cause significant morbidity and mortality world-wide despite a huge research commitment to defining and understanding the virus and the disease it causes. This paper discusses a number of areas where progress in the management of the HCV have not kept pace with the scientific understanding of the HCV. It is suggested that in the fields of HCV prevention and providing access to treatment, practice falls short of what could be achieved. The role of alcohol in the pathogenesis of HCV liver injury is discussed. Discrimination against those with HCV infection and particularly those in prison settings fails to match good clinical practice. The complicated processes of sharing information between specialty groups is also discussed in an attempt to optimise knowledge dissemination in this field.

Pegylated interferon-alpha2beta in combination with ribavirin does not aggravate thyroid dysfunction in comparison to regular interferon-alpha2beta in a hepatitis C population: meta-analysis.

BACKGROUND: Interferon (IFN) has been well documented to cause thyroid dysfunction, especially in high risk patients and when combined with ribavirin (RBV). There is very sparse data to assess if pegylated IFN will further aggravate the thyroid disease risk in comparison to regular IFN. The purpose of this study was to assess the risk of developing thyroid disease with pegylated IFN (pIFN) versus regular IFN (rIFN) therapy (in combination with RBV). We also pooled our results with previous studies in a meta-analysis. METHODS: An observational study was made retrospectively of 24 patients who underwent a combination of rIFN and RBV therapy for hepatitis C virus (HCV) infection. As these patients failed to obtain an initial satisfactory response, they were retreated using pIFN and RBV. Monthly thyrotropin (TSH) levels were assessed while undergoing both treatment regimens. A meta-analysis was performed using available published data in PubMed. RESULTS: No difference in TSH levels was observed when comparing rIFN/RBV with pIFN/RBV. None of the patients developed hypo- or hyperthyroidism. TSH levels fluctuated during the treatment but did not extend outside the reference range. No further investigation was carried out in the absence of clinical and biochemical thyroid disease. The result of the meta-analysis failed to find any excess risk of thyroid dysfunction using pIFN above that of rIFN. CONCLUSIONS: The pegylation of IFN, in combination with RBV, did not aggravate thyroid diseases in the hepatitis C population. This finding is reassuring and dictates that no deviation from current practice regarding thyroid surveillance is required whilst undergoing HCV treatment.

Role of ethanol in the regulation of hepatic stellate cell function.

Evidence has accumulated to suggest an important role of ethanol and/or its metabolites in the pathogenesis of alcohol-related liver disease. In this review, the fibrogenic effects of ethanol and its metabolites on hepatic stellate cells (HSCs) are discussed. In brief, ethanol interferes with retinoid metabolism and its signaling, induces the release of fibrogenic cytokines such as transforming growth factor beta-1 (TGFbeta-1) from HSCs, up-regulates the gene expression of collagen I and enhances type I collagen protein production by HSCs. Ethanol further perpetuates an activated HSC phenotype through extracellular matrix remodeling. The underlying pathophysiologic mechanisms by which ethanol exerts these pro-fibrogenic effects on HSCs are reviewed.

The spectrum of thyroid dysfunction in an Australian hepatitis C population treated with combination Interferon-alpha2beta and Ribavirin.

BACKGROUND: The study aims to assess the pattern of thyroid response to combination Interferon-alpha2beta (IFN-alpha) and Ribavirin (RBV) anti-viral therapy in an Australian hepatitis C cohort. These include the prevalence of thyroid dysfunction (TD) including hyperthyroidism and hypothyroidism and their possible predictors, the common overall pattern of thyroid function tests whilst receiving therapy and TD outcomes, and the correlation with HCV status outcome. METHODS: A retrospective analysis of all medical records was performed to assess thyroid function in Hepatitis C Virus (HCV) patients who were treated at the Hunter Area hepatitis C treatment center between 1995 and March 2004. The centre is part of the John Hunter hospital, a major tertiary referral centre in New South Wales, Australia. RESULTS: There were 272 cases available for review. The prevalence of TD is 6.7 percent and is made up predominantly of females (80 percent). There were 3 (1.1 percent) cases of hyperthyroidism with 2 (67 percent) females. Thirteen out of fifteen (80 percent) cases of hypothyroidism were females with the overall prevalence of 5.5 percent. The majority of hypothyroid patients still required Thyroxine supplement at the end of follow up. CONCLUSION: Ninety three percent of HCV treated patients have intact thyroid function at the end of treatment. The predominant TD is hypothyroidism. The predominant pattern of thyrotoxicosis (TTX) is that of thyroiditis although the number is small. Graves' like disease was not observed. People with pre-existing thyroid auto-antibodies should be closely monitored for thyroid dysfunction, particularly hypothyroidism.

The medical complications of alcohol use: understanding mechanisms to improve management.

The use of alcohol in a dependent or even a regular heavy pattern predisposes the drinker to a range of adverse consequences. These include a risk of direct harm from alcohol, including organ damage, mental health disorders and a range of social and legal problems associated with behaviours due to alcohol's effects. The range of organ damage associated with regular heavy alcohol consumption is well described. Much new information on the mechanisms by which damage occurs is available and is reviewed in this paper. New knowledge can assist in the development of more appropriate management strategies for those affected by the medical complications of alcohol use. Genetic susceptibility to tissue injury is explored and the reasons why many heavy drinkers do not appear to experience organ damage are considered. Approaches to the management of certain alcohol-related disorders are outlined.

Complementary and alternative medicine in the treatment of chronic liver disease.

Interest in and use of complementary and alternative medicines (CAM) in the treatment of chronic liver diseases has increased in the past decade. However, this has not been supported by a significant increase in sound clinical research evidence for their efficacy. The research literature is growing, providing improved knowledge on population use of CAM, possible mechanisms of action of a large range of complementary and alternative medications, and possible specific indications for these agents in patients with liver disease. Although curative potential for CAM has not been documented consistently in any liver disorder, it is possible to identify anti-inflammatory activity and cytoprotective capacity for a number of agents from different branches of the world of CAM. Evidence grows for potential harm from an increasing number of compounds. Concurrently, clarity is increasing in relation to which specific constituents cause the harm and the mechanisms by which damage is produced.

Factors associated with severity of hepatic fibrosis in people with chronic hepatitis C infection.

OBJECTIVE: To determine factors associated with hepatic fibrosis development in people with chronic hepatitis C virus (HCV) infection. METHODS: As a requirement for access to interferon therapy through the S100 scheme in Australia, individual pretreatment demographic and clinical information was collected on 2986 patients from 61 hospital-based liver clinics from 1 October 1994 through 31 December 1996. Patients with both a hepatic fibrosis score and an estimated duration of HCV infection (910) were divided into 540 with no or minimal hepatic fibrosis (stage 0-1) and 370 with moderate to severe hepatic fibrosis (stage 2-3). Seven factors were examined: age at HCV infection, sex, ethnicity, source of infection, duration of infection, alcohol intake, and mean ALT level. A further analysis was performed for all 1135 patients with a hepatic fibrosis score disregarding age at and duration of HCV infection. RESULTS: In multivariate analysis, four factors were significantly associated with moderate to severe hepatic fibrosis: age at infection (OR, 2.33 for age 31-40 years, 5.27 for age > 40 years, and 0.20 for age < 15 years, compared with 15-20 years); duration of infection (OR, 1.44 for 11-20 years, 2.74 for 21-30 years, and 8.71 for > 30 years, compared with < 11 years); alcohol intake in previous six months (OR, 1.51 for any intake, compared with none); and mean ALT level (OR, 1.81 for 2-3 times, 2.27 for > 3 times, compared with 1.5-2 times the upper limit of normal). In the analysis disregarding age at HCV infection and duration of HCV infection, older age was strongly associated with moderate to severe hepatic fibrosis (OR, 2.32 for age 36-40 years, 2.46 for age 41-50 years, 7.87 for age 51-60 years, and 7.15 for age > 60 years, compared with 16-30 years). There was no association in either analysis with sex or source of HCV infection. CONCLUSION: These factors may assist in targeting patients for both liver biopsy-based investigation and therapeutic intervention.

Molecular pathogenesis of T lymphocyte-induced liver injury in alcoholic hepatitis.

The development of alcohol-induced liver injury is, in part, a consequence of the immunological/inflammatory response that alcohol stimulates. The abnormalities of immune function in heavy drinkers have been documented well. Cytokines, especially TNF alpha, produced from macrophages/Kupffer cells, play a role in the induction of liver cell necrosis and apoptosis. TNF alpha can cause liver cell apoptosis through the TNF alpha receptor or Fas/CD95 which is expressed by liver cells. Furthermore, chronic ethanol consumption may damage the liver by inhibiting the hepatotrophic and hepatoprotective actions of TNF alpha and other cytokines. There exists an intrinsic lymphocyte population in the normal liver. Intrahepatic T lymphocytes consist of a heterogeneous population of cells that has many and varied functional characteristics in addition to classical T cell activity. The population of intrahepatic T lymphocytes may arise via a thymus-independent pathway. Our recent work has demonstrated the role of liver-associated T lymphocytes in the pathogenesis of alcohol related liver injury initiated by a variety of stimuli such as endotoxin (lipopolysaccharide, LPS) or concanavalin A (Con A). Our studies have, for the first time, suggested that alcohol consumption alone does not lead to the development of marked liver necrosis (at least in the rat), but rather that a second insult is required for this to occur. Liver-associated T lymphocytes in rats spontaneously secrete interleukin-1 alpha, interleukin-6 and TNF alpha in vitro culture. There is a significant decline in the amounts of interleukin-1 alpha and TNF alpha secreted in ethanol-consuming rats compared with non-ethanol consuming rats. The numbers of T cells, NK cells and Kupffer cells in liver perfusates remains stable over a prolonged period of ethanol consumption. However, following Con A injection, there was an inappropriate increase in the amounts of interleukin-6 and TNF alpha secreted in in vitro culture of liver-associated T lymphocytes and a significant increase in the percentage of CD4+ T cells and CD25+ T cells in liver perfusates compared with non-ethanol consuming rats. It suggested that liver-associated T lymphocytes are involved in the inflammatory process associated with alcohol related liver injury through increased cytokine secretion (TNF alpha).

Lymphocyte-mediated liver injury in alcohol-related hepatitis.

The pathogenesis of alcohol-related liver disease (ALD) remains inadequately explained. Increasing alcohol intake is associated with an increased risk of ALD, but many heavy drinkers develop no liver damage. An explanation for ALD susceptibility requires theories that extend beyond a biochemical understanding of alcohol metabolism. Several hepatic cell populations are involved in the pathogenesis of liver injury. The liver-associated lymphocyte (LAL) response to alcohol intake plus immune stimulation may determine susceptibility to liver damage. We have isolated rat LALs and demonstrated the following: (1) Liver-associated lymphocytes differ from the peripheral blood lymphocyte pool; the CD8:CD4 ratio is higher in the LAL population than in peripheral blood. (2) Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 production by these cells is suppressed by regular alcohol intake. (3) Tumor necrosis factor-alpha and interleukin-6 production by LALs is increased after parenteral administration of concanavalin A (Con A) and by Con A in in vitro LAL cultures obtained from healthy (control) and ethanol-consuming rats. (4) In vivo stimuli that lead to increased cytokine production by LALs lead, within 12-24 h, to increased hepatocyte necrosis [elevated alanine aminotransferase (ALT) levels] and apoptosis. (5) Liver-associated lymphocytes isolated from ethanol-consuming rats, transferred to non-ethanol-consuming rats, confer on the latter animals an ethanol-consuming response to Con A. (6) Cytokine release by LALs is quantitatively as significant as that from Kupffer cells after exposure to lipopolysaccharide. (7) In co-culture studies inhibition of TNF-alpha activity reduces hepatocyte apoptosis induced in the presence of activated LALs. (8) Finally, nuclear factor-kappa B inhibition decreases production of nitric oxide and TNF-alpha, with an associated reduction in hepatocyte apoptosis. In summary, our study findings support the suggestion that a role for LALs exists in the pathogenesis of alcohol and Con A-mediated liver disease.