The natural history and treatment of hepatitis C in the South-East of Scotland

BACKGROUND: Since the discovery of Hepatitis C there have been studies of the natural history of the infection. The outcome is dependent on whether the research is performed in the community or in hospital and where the patients are drawn from. Scotland is a country with a low prevalence of Hepatitis C infection but Edinburgh has a large intravenous drug using population in whom the prevalence is high. The Royal Infirmary of Edinburgh is the main tertiary centre for the assessment and treatment of these patients.AIM: Describe the characteristics of those patients that have ongoing Hepatitis C infection that have been referred and assessed. Describe the progression of the disease to cirrhosis and its complications. Identify the independent factors that influence this progression. Describe the outcome of treatment with interferon monotherapy, combination standard interferon and ribavirin and combination pegylated interferon and ribavirin, and identify the predictors of response.METHODS: All patients that have been referred to the Royal Infirmary of Edinburgh and assessed between 1990 and 2004 with Hepatitis C infection. Retrospective analysis of the patient's case notes, laboratory, pathology and endoscopy records was performed. There was entry of data into a specially constructed Microsoft Access relational database. Kaplan-Meier analysis was used to describe progression. Cox regression analysis was used to identify independent predictors of progression. A sustained viral response was the primary end-point of the treatment studies, with binary logistical regression to identify predictors of this outcome. Documentation of adverse events for each treatment was made.RESULTS: Six hundred and ninety-four patients were identified that have ongoing infection. This cohort was made up of a significant proportion of middle-aged men who have acquired the infection less than 20 years ago, principally through intravenous drug use, who have a significant history of alcohol abuse. At least 22% of patients have had cirrhosis diagnosed clinically, although only about half of these have had it confirmed by biopsy or laparoscopy. In 12% of patients at least one complication of cirrhosis has been recorded. Grade 2 oesophageal varices have been found in about 7% of patients overall, but only half of these have bled. A major complication of cirrhosis has occurred in 10.5% and Hepatocellular carcinoma (HCC) in 3.3%. So far only 13 patients have been transplanted. Eleven percent of the cohort has died and in those in whom the cause is known, liver-related death is twice as common as non-liver-related death. It has not been possible to establish a median time from infection to cirrhosis or its complications but it appears to be in excess of 35 years. The age of the patient and previous alcohol intake of greater than 50 units per week for more than five years independently influences progression. A steady improvement in the efficacy of treatment with the introduction of each new treatment regime has been confirmed. In interferon nai've patients, treated with pegylated interferon and ribavirin, the sustained viral response rate was 29.0% and 59.3% for genotype 1 and genotype 2 or 3 infections respectively. Significant side effects occurred with treatment that necessitated both dose reduction and sometimes its termination. About 45% of all patients referred and assessed each year were deemed suitable for treatment and listed.CONCLUSION: Chronic Hepatitis C infection is a significant health problem in Edinburgh with large numbers being referred for assessment, treatment and management of the complications of cirrhosis. The natural history of the infection and how it is influenced by therapy is becoming clearer, in particular the influence of alcohol and the age of the patient. Treatments are effective, although do have significant side effects that affect compliance

Obesity is the most common risk factor for chronic liver disease: Results from risk stratification pathway using transient elastography

IntroductionObesity has been associated with liver fibrosis yet guidelines do not emphasise it as an independent risk factor in which to have a high index of suspicion of advanced disease. We aimed to elucidate the effect of a raised body mass index on the risk of liver disease using data from a community risk stratification pathway. MethodsWe prospectively recruited patients from a primary care practice with hazardous alcohol use and/or type 2 diabetes and/or obesity. Subjects were invited for a transient elastography reading. A threshold of ≥8.0kPa defined an elevated reading consistent with clinically significant liver disease. ResultsFive hundred and seventy six patients participated in the pathway of which, 533 patients had a reliable reading and 66 (12.4%) had an elevated reading. Thirty one percent of patients with an elevated reading had obesity as their only risk factor. The proportion of patients with an elevated reading was similar among those with obesity (8.9%) to patients with more recognised solitary risk factors (Type 2 diabetes 10.8%; Hazardous alcohol use 4.8%). Obesity in combination with other risk factors further increased the proportion of patients with an elevated reading. In multivariate logistic regression, increasing BMI and type 2 diabetes were significantly associated with an elevated reading. ConclusionObesity as a single or additive risk factor for chronic liver disease is significant. Future case finding strategies using a risk factor approach should incorporate obesity within proposed algorithms

The XL probe: a luxury or a necessity? risk stratification in an obese community cohort using transient elastography

Background: Transient elastography is a non-invasive tool which can stratify patients at risk of chronic liver disease. However, a raised body mass index has been independently associated with a failed or unreliable examination.Objective: The purpose of this study was to analyse the performance of two probes (M/XL) on a portable transient elastography device within an obese community population.Method: The method involved a prospective study with recruitment from a primary care practice. Patients identified with a risk factor for chronic liver disease were invited to a community-based risk stratification pathway for transient elastography readings with both probes. A threshold of ≥8.0 kPa defined elevated liver stiffness.Results: A total of 477 patients attended the pathway. Of the patients, 21% had no valid measurements with the M probe. There was a significant difference between the probes in the proportion achieving ≥10 valid readings (M versus XL probe: 66.2% versus 90.2%; p ≤ 0.001) and in their reliability (M versus XL probe: 77.4% versus 98.5%; p = 0.028). Unreliable readings with the M probe increased as the body mass index increased. The XL probe re-stratified 5.2% of patients to have a normal reading.Conclusion: The XL probe on a portable device significantly improves the applicability of transient elastography within a community-based risk stratification pathway

Provision and standards of care for treatment and follow-up of patients with Autoimmune Hepatitis (AIH)

Background Autoimmune hepatitis (AIH) is a substantial UK health burden, but there is variation in care, facilities and in opinion regarding management. We conducted an audit of service provision and care of patients with AIH in 28 UK hospitals. Methods Centres provided information about staffing, infrastructure and patient management (measured against predefined guideline-based standards) via a web-based data collection tool. Results Hospitals (14 university hospitals (UHs), 14 district general hospitals (DGHs)) had median (range) of 8 (3-23) gastroenterologists; including 3 (0-10) hepatologists. Eight hospitals (29%, all DGHs) had no hepatologist. In individual hospital departments, there were 50% (18-100) of all consultants managing AIH: in DGH's 92% (20-100) vs 46% (17-100) in UHs. Specialist nurses managed AIH in only 18%. Seventeen (61%) hospitals had a histopathologist with a liver interest, these were more likely to find rosettes than those without (172/795 vs 50/368; p<0.001). Of 999 steroid-treated patients with ≥12 months follow-up, 25% received steroids for <12 months. After 1 year of treatment, 82% of patients achieved normal serum alanine aminotransaminase (ALT); this was higher in UHs than DGHs. Three-monthly liver blood tests were inadequately recorded in 26%. Of potentially eligible patients with liver decompensation, transplantation was apparently not considered in 5% (n=7). The same standards were attained in different types of hospital. Conclusion Management of AIH in UK hospitals is often shared between most gastroenterologists. Blood test monitoring and treatment duration are not always in line with recommendations. Some eligible patients with decompensation are not discussed with transplant teams. Care might be improved by expanding specialist input and management by fewer designated consultants

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Event-biased referral can distort estimation of hepatitis C virus progression rate to cirrhosis, and of prognostic influences

OBJECTIVE: To investigate how cirrhosis-biased referral to liver clinics can explain the wide variation in progression rates for differently recruited cohorts and, in particular, for liver clinic cohorts compared to community-based studies of the natural history of hepatitis C virus (HCV). STUDY DESIGN AND SETTING: A simulation was designed to illustrate the sort of referral bias pattern that is capable of converting a 20-year progression rate to cirrhosis of around 5% in the community of HCV-infected individuals into a 20% progression rate for patients who have been selectively referred to a liver clinic. RESULTS: We show that event-biased recruitment, such as occurs if referral to liver clinics is increasingly likely the closer a patient is to cirrhosis, can produce severely upwardly biased estimates of progression rates, can dampen the influence of "poor prognostic" factors (such as history of excessive alcohol consumption), but overrepresents the proportion of patients in the community of HCV-infected individuals who have poor prognosis. CONCLUSION: When attempting to establish the natural history of new diseases with long incubation periods, researchers should be on the look out for potential biases that result from the way patients are referred into clinical cohorts

Treatment and Outcome of Autoimmune Hepatitis (AIH): Audit of 28 UK centres

BackgroundWith few data regarding treatment and outcome of patients with AIH outside of large centres we present such a study of patients with AIH in 28 UK hospitals of varying size and facilities.MethodsPatients with AIH were identified in 14 University and 14 District General hospitals; incident cases during 2007-2015 and prevalent cases, presenting 2000-2015. Treatment and outcomes were analysed.ResultsIn 1267 patients with AIH, followed-up for 3.8(0-15) years, 5- and 10-year death/transplant rates were 7.1+0.8% and 10.1+1.3% (all-cause) and 4.0+0.6% and 5.9+1% (liver-related) respectively. Baseline parameters independently associated with death/transplantation for all-causes were: older age, vascular/respiratory co-morbidity, cirrhosis, decompensation, platelet count, attending transplant centre and for liver-related: the last four of these and peak bilirubinAll-cause and liver-related death/transplantation was independently associated with: non-treatment with corticosteroids, non-treatment with a steroid-sparing agent (SSA), non-treatment of asymptomatic or non-cirrhotic patients and initial dose of Prednisolone >35mg/0.5mg/kg/day (all-cause only), but not with type of steroid (Prednisolone versus Budesonide) or steroid duration beyond 12-months.Subsequent all-cause and liver-death/transplant rates showed independent associations with smaller percentage fall in serum ALT after 1 and 3-months, but not with failure to normalise levels over 12-months.ConclusionsWe observed higher death/transplant rates in patients with AIH who were untreated with steroids (including asymptomatic or non-cirrhotic sub-groups), those receiving higher Prednisolone doses and those who did not receive an SSA. Similar death/transplant rates were seen in those receiving Prednisolone or Budesonide, those continuing steroids after 12-months and patients attaining normal ALT within 12-months versus not