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

Network analyses on photographic surveys reveal that invertebrate predators do not structure epibenthos in the deep (~2000m) rocky Powell Basin, Weddell Sea, Antarctica

Predator-prey interactions in marine ecosystems control population sizes, maintain species richness, and provide intermediate disturbance. Such ecosystem structuring interactions may be rare in Antarctic epibenthic communities, which are unique among marine ecosystems worldwide for their dominance of soft bodied fauna (sponges, soft and hard corals, and echinoderms) and a simultaneous paucity of shell crushing predators (sharks, rays and durophagous decapods). In the shallow benthos, instead of durophagy, important Antarctic predators such as starfish, pycnogonids (sea spiders), nemertean worms, and nudibranchs employ grazing, scavenging, or sucking strategies. Far less is known about deep sea (>1000 m) Antarctic benthic communities due to the challenging nature of polar data collection, so that photographic surveys provide one of the only means of making in situ observations of these deep sea communities. We used seabed photographs of the deep (~2000m) slope of the Powell Basin, northwest Weddell Sea, taken by the Ocean Floor Observation and Bathymetry System on board the RV Polarstern (PS118, April 2019) to investigate the epibenthic community composition, and Bayesian Network Inference (BNI) to determine the ecological network, namely the ecological associations, including potential invertebrate predator-prey relationships between taxa. Photographs show that the rocky substrates of the basin slope support between 10-22 morphotaxa per photo, and highly abundant communities (density between 106 to 553 individuals/m2). BNI results reveal a network of associations between the sessile and mobile suspension and filter feeding organisms and their physical environment. However, associations between invertebrate predators like starfish, and other organisms, were not detected in the network. This lack of inclusion within the network suggests that, despite the presence of these normally important mobile predators, invertebrate predator-prey interactions on the rocky Powell Basin slope do not have the same ecosystem-regulating impact that they do on shallow Antarctic epibenthic communities

Investigation into the controversial association of Streptococcus gallolyticus with colorectal cancer and adenoma

Background: The seroprevalence of IgG antibodies of Streptococcus gallolyticus subspecies gallolyticus, CIP 105428, was evaluated to investigate the controversial association of S. gallolyticus with colorectal carcinoma and adenoma in attempt to investigate the nature of such association if any, by exploring the mRNA expression of NF-κB and IL-8. Moreover, the serological behavior of S. gallolyticus IgG antibodies was compared to that of an indicator bacterium of bowel, Bacteroides fragilis. Methods: ELISA was used to measure IgG antibodies of S. gallolyticus and B. fragilis in sera of 50 colorectal cancer, 14 colorectal adenoma patients, 30 age- and sex- matched apparently healthy volunteers (HV) and 30 age- and sex- matched colonoscopically-proven tumor-free control subjects. NF-κB and IL-8 mRNA expression was evaluated in tumorous and non-tumorous tissue sections of carcinoma and adenoma patients in comparison with that of control subjects by using in situ hybridization assay. Results: Colorectal cancer and adenoma patients were associated with higher levels of serum S. Gallolyticus IgG antibodies in comparison with HV and control subjects (P 0.05). ELISA cutoff value for the seropositivity of S. gallolyticus IgG was calculated from tumor-free control group. The expression of NF-κB mRNA was higher in tumorous than non-tumorous tissue sections of adenoma and carcinoma, higher in carcinoma/adenoma sections than in control subjects, higher in tumorous sections of carcinoma than in adenoma patients, and higher in S. gallolyticus IgG seropositive than in seronegative groups in both tumorous and non-tumorous sections (P < 0.05). IL-8 mRNA expression in tumorous sections of adenoma and carcinoma was higher than in non-tumorous sections, higher in carcinoma/adenoma than in control subjects, and higher in S. gallolyticus IgG seropositive than in seronegative groups in tumorous rather than non-tumorous sections (P < 0.05). Conclusion: S. gallolyticus most likely plays an essential role in the oncogenic progression of normal colorectal mucosa to adenoma and to CRC. This promoting/propagating role of S. gallolyticus might take place by utilizing certain inflammatory, anti-apoptotic, and angiogenic factors of transformation including NF-κB and IL-8.Ahmed S Abdulamir, Rand R Hafidh, Layla K Mahdi, Tarik Al-jeboori and Fatimah Abubake

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

Baseline neutrophil-to-lymphocyte ratio predicts response to corticosteroids and is associated with infection and renal dysfunction in alcoholic hepatitis

Background Treating severe alcoholic hepatitis involves the exposure of patients to corticosteroids for 7 days to assess “response”. Aim To assess the prognostic and therapeutic implications of baseline neutrophil‐to‐lymphocyte ratio (NLR) in patients with severe alcoholic hepatitis. Methods Patients recruited to the STOPAH trial and an independent validation group were analysed retrospectively. Area under the receiver operating curve (AUC) analysis was performed. Kaplan‐Meier analysis was used to assess survival. Log‐rank test and odds ratio (OR) were used for comparative analysis. Results Baseline NLR was available for 789 STOPAH patients. The AUC for NLR was modest for 90‐day outcome (0.660), but was associated with infection, acute kidney injury (AKI) and severity of alcoholic hepatitis. Ninety‐day survival was not affected by prednisolone treatment if NLR 8 but mortality was reduced with prednisolone treatment when the NLR was 5‐8 (21.0% cf. 34.5%; P = 0.012). Prednisolone treatment increased the chance of Lille response if the NLR was ≥ 5 (56.5% cf. 41.1%: P = 0.01; OR 1.86) but increased the risk of day 7 infection (17.3% cf. 7.4%: P = 0.006; OR 2.60) and AKI (20.8% cf. 7.0%: P = 0.008; OR 3.46) if the NLR was > 8. Incorporation of NLR into a modified Glasgow alcoholic hepatitis score (mGAHS) improved the AUC to 0.783 and 0.739 for 28‐day and 90‐day outcome, respectively. Conclusion The NLR is associated with AKI and infection in severe alcoholic hepatitis. The NLR identifies those most likely to benefit from corticosteroids at baseline (NLR 5‐8). The mGAHS has a good predictive value for 28‐ and 90‐day outcomes

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