IL-1 Signal Inhibition in Alcohol-Related Hepatitis: a randomised, double-blind, placebo-controlled trial of canakinumab.

BACKGROUND AND AIM: Short-term mortality in alcohol-related hepatitis (AH) is high and no current therapy results in durable benefit. A role for IL-1ß has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1ß, in the treatment of patients with AH. METHODS: Participants with biopsy-confirmed AH and discriminant function ≥32 but MELD ≤27 were randomly allocated 1:1 to receive either CAN 3mg/kg or placebo (PBO). Liver biopsies were taken before, and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analysed by modified Intention-To-Treat (mITT). RESULTS: Fifty-seven participants were randomised: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data was evaluable from 48 participants. In CAN-treated participants, 14/24 (58%) demonstrated histological improvement compared to 10/24 (42%) in the PBO group (p=0.25). There was no improvement in prognostic scores of liver function. Four of the 55 participants (7%) died within 90 days; 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post-hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (p=0.04). CONCLUSION: CAN therapy in severe AH participants with MELD≤27 did not alter biochemical or clinical outcomes compared to PBO. Non-significant histological improvements did not translate into clinical benefit.

Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial.

Background: Proton pump inhibitors (PPIs) are commonly prescribed to prevent and treat upper gastrointestinal ulceration and bleeding. Studies have identified increased incidence of spontaneous bacterial peritonitis and hepatic encephalopathy (HE) in cirrhosis patients taking PPIs. However, results are conflicting, and as PPIs are prescribed for variceal bleeding, a major risk factor for infection and HE, it is challenging to discern whether these associations are causal. Methods: In this post-hoc analysis of the ATTIRE trial, we pooled all patient data to investigate the effects of PPI use on clinical outcomes. ATTIRE was a multicentre, open-label, randomised trial of targeted 20% human albumin solution (HAS) daily infusions versus standard care involving 777 adults with decompensated cirrhosis hospitalised with acute complications and albumin <30 g/L. Study recruitment was between Jan 25, 2016, and June 28, 2019, at 35 hospitals across England, Scotland, and Wales. Key exclusion criteria were advanced hepatocellular carcinoma with life expectancy <8 weeks and patients receiving palliative care. In ATTIRE, patients were grouped by PPI use at trial entry. We studied infection and HE at baseline and incidence of hospital acquired infection, new onset HE, renal dysfunction and mortality. We attempted with propensity score matching to account for differences in disease severity. Findings: Overall PPI use at baseline was not associated with increased incidence of infection, renal dysfunction or mortality, but was associated with significantly increased incidence of grade III/IV HE during hospital stay (P = 0.011). This was only significant for those taking intravenous PPIs and these patients had >10 times the incidence of variceal bleeding and near double the 28-day mortality compared to non-PPI patients. However, propensity score matching was not possible as there was such a strong selection of patients for PPI use, that we could not find sufficient non-PPI patients to match to. We found no impact of PPI use on plasma markers of bacterial translocation, infection or systemic inflammation. Interpretations: Our real-world data from a completed randomised trial show that PPIs are widely prescribed in the UK and judicious use appears safe in patients hospitalised with decompensated cirrhosis. However, patients prescribed PPIs had fundamentally different phenotypes to those not prescribed PPIs, a form of confounding by indication, which should be strongly considered when interpreting studies and making recommendations about their use. Funding: Wellcome Trust and Department of Health and Social Care.

Extra-hepatic morbidity and mortality in alcohol-related liver disease: Systematic review and meta-analysis.

BACKGROUND: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol-related liver disease (ALD) are therefore at risk from both extra-hepatic and hepatic disease. AIMS: This review synthesises information about non-liver-related mortality in persons with ALD. METHODS: A systematic literature review was performed to identify studies describing non-liver outcomes in ALD. Information about overall non-liver mortality was extracted from included studies and sub-categorised into major causes: cardiovascular disease (CVD), non-liver cancer and infection. Single-proportion meta-analysis was done to calculate incidence rates (events/1000 patient-years) and relative risks (RR) compared with control populations. RESULTS: Thirty-seven studies describing 50 302 individuals with 155 820 patient-years of follow-up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol-related fatty liver the rate of non-liver mortality was 43.4/1000 patient-years, whereas in alcoholic hepatitis the rate of non-liver mortality was 22.5/1000 patient-years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6-3.8), from non-hepatic cancer 2.2 (1.6-2.9) and from infection 8.2 (4.7-14.3). CONCLUSION: Persons with ALD are at high risk of death from non-liver causes such as cardiovascular disease and non-hepatic cancer.

Hepatocellular Carcinoma Risk Scores Predict Patients Under Surveillance at Low Risk of Benefit and High Risk of Harm.

AIMS: Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with cirrhosis. Multiple risk scores aim to stratify HCC risk, potentially allowing individualized surveillance strategies. We sought to validate four risk scores and quantify the consequences of surveillance via the calculation of numbers needed to benefit (NNB) and harm (NNH) according to classification by risk score strata. METHODS: Data were collected on 482 patients with cirrhosis during 2013-2014, with follow-up until 31/12/2019. Risk scores (aMAP, Toronto risk index, ADRESS HCC, HCC risk score) were derived from index clinic results. The area under the receiving operating characteristic curve (AUC) was calculated for each. Additionally, per-risk strata, NNB was calculated as total surveillance ultrasounds per surveillance diagnosed early HCC (stage 0/A) and NNH as total ultrasounds performed per false positive (abnormal surveillance with normal follow-up imaging). RESULTS: 22 (4.6%) patients developed HCC. 77% (17/22) were diagnosed through surveillance, of which 13/17 (76%) were early stage. There were 88 false positives and no false negatives (normal surveillance result however subsequent HCC detection). Overall NNB and NNH were 241 and 36, respectively. No score was significantly superior using AUC. Patients classified as low risk demonstrated no surveillance benefit (AMAP, THRI) or had a high NNB of > 300/900 (ADRESS HCC, HCC risk score), with low NNH (24-38). CONCLUSION: Given the lack of benefit and increased harm through false positives in low-risk groups, a risk-based surveillance strategy may have the potential to reduce patient harm and increase benefit from HCC surveillance. CLINICAL TRIALS REGISTRATION: This was not a clinical trial and the study was not pre-registered.

Association of gamma-glutamyltransferase levels with total mortality, liver-related and cardiovascular outcomes: A prospective cohort study in the UK Biobank.

Background: Gamma-glutamyltransferase (GGT) levels in the blood can be a sensitive marker of liver injury but the extent to which they give insight into risk across multiple outcomes in a clinically useful way remains uncertain. Methods: Using data from 293,667 UK Biobank participants, the relationship of GGT concentrations to self-reported alcohol intake and adiposity markers were investigated. We next investigated whether GGT predicted liver-related, cardiovascular (CV) or all-cause mortality, and potentially improved CV risk prediction. Findings: Higher alcohol intake and greater waist circumference (WC) were associated with higher GGT; the association was stronger for alcohol with evidence of a synergistic effect of WC. Higher GGT concentrations were associated with multiple outcomes. Compared to a GGT of 14.5 U/L (lowest decile), values of 48 U/L for women and 60 U/L for men (common upper limits of 'normal') had hazard ratios (HRs) for liver-related mortality of 1.83 (95% CI 1.60-2.11) and 3.25 (95% CI 2.38-4.42) respectively, for CV mortality of 1.21 (95% CI 1.14-1.28) and 1.43 (95% CI 1.27-1.60) and for all-cause mortality of 1.15 (95% CI 1.12-1.18) and 1.31 (95% CI 1.24-1.38). Adding GGT to a risk algorithm for CV mortality reclassified an additional 1.24% (95% CI 0.14-2.34) of participants across a binary 5% 10-year risk threshold. Interpretation: Our study suggests that a modest elevation in GGT levels should trigger a discussion with the individual to review diet and lifestyle including alcohol intake and consideration of formal liver disease and CV risk assessment if not previously done. Funding: British Heart Foundation Centre of Research Excellence Grant (grant number RE/18/6/34217), NHS Research Scotland (grant number SCAF/15/02), the Medical Research Council (grant number MC_UU_00022/2); and the Scottish Government Chief Scientist Office (grant number SPHSU17).

Audit of medical (non-targeted) liver biopsy specimen quality, pathology reporting and effect on patient management.

AIMS: To evaluate our medical liver pathology practice and its influence on patient management, using audit templates published by the UK Royal College of Pathologists (RCPath). METHODS: We audited medical liver biopsies reported in our centre in 2019 using RCPath proformas. Data were collected from pathology reports and corresponding electronic patient record. RESULTS: 60 cases were selected for audit from 135 eligible biopsies reported in 2019. 58/60 cases were core biopsies and 2/60 were laparoscopic wedge biopsies. 53/57 (93%) core biopsies with available data met RCPath adequacy criteria (length >15 mm and/or ≥6 portal tracts). Most reports (57/60; 95%) were judged to have helped patient management. 25/60 (42%) biopsy reports helped to clarify the clinical diagnosis and 48/60 (80%) led to altered management. CONCLUSIONS: We demonstrate the utility of the RCPath audit templates, highlighting the clinical value of medical liver biopsies in the diagnostic work-up and management of patients with liver disease.

Effect of Hepatocellular Carcinoma Surveillance Programmes on Overall Survival in a Mixed Cirrhotic UK Population: A Prospective, Longitudinal Cohort Study.

INTRODUCTION: Surveillance for hepatocellular carcinoma (HCC) is recommended by national and international guidelines. However, there are no trial data on whether surveillance improves clinical outcomes in a UK cirrhosis population of mixed aetiology. Our aim was to determine the impact of, and adherence to, surveillance on overall survival. METHODS: We prospectively collected data on consecutive patients diagnosed with HCC between January 2009 and December 2015 at two large UK centres. We assessed outcomes depending on whether they had been entered into an HCC surveillance programme, and if they had adhered to that. RESULTS: Out of 985 patients diagnosed with HCC in this study, 40.0% had been enrolled in a surveillance programme. Of these, 76.6% were adherent with surveillance and 24.4% were not. Adherence to surveillance was significantly associated with improved overall survival, even when accounting for lead-time bias using different approaches (HR for 270 days lead-time adjustment 0.64, 0.53 to 0.76, p < 0.001). CONCLUSIONS: When adjusted for lead-time bias, HCC surveillance is associated with improved overall survival; however, the beneficial effect of surveillance on survival was lower than reported in studies that did not account fully for lead-time bias.

The diagnostic and prognostic significance of liver histology in alcoholic hepatitis.

BACKGROUND: Liver biopsy may be of diagnostic and prognostic value but its role in alcoholic hepatitis (AH) has been controversial. AIM: To assess the utility of liver biopsy in the assessment of clinically severe AH METHODS: The histological features of alcoholic steatohepatitis (ASH) were recorded and scored in patients enrolled in the Steroids or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial who underwent liver biopsy. These features were then assessed relative to outcome and established clinical prognostic scores. RESULTS: The STOPAH trial recruited 1068 patients; biopsies were obtained in 182 (17%). One hundred and sixty-one biopsies were adequate for histological assessment and 140 (87%) were diagnostic for ASH. Only three biopsies (2%) did not have histological features of alcohol-related liver injury. In biopsies performed prior to randomisation, ASH was identified in 92.5% of patients meeting clinical trial definitions of severe AH. In biopsies with ASH, taken before or within 48 hours of randomisation, survival differences between Alcoholic Hepatitis Histological Score (AHHS) groups were not significant: comparison of mild / moderate (91%: 21 of 23 patients) with severe (78%: 29 of 37 patients) groups: P = 0.18. The AHHS was not superior to clinical scores of prognosis: area under the curve for 28-day mortality was 0.728, compared with 0.799 for the Glasgow alcoholic hepatitis score and 0.728 for the MELD score. CONCLUSION: Liver histology taken before treatment rarely changes the diagnosis in patients meeting strict criteria for a clinical diagnosis of AH. The AHHS is similar to clinical scores in determining prognosis. Clinical trial registration EudraCT reference number: 2009-013897-42. ISRCTN reference number: 88782125. MREC number: 09/MRE09/59. UKCRIN ID: 9143.

Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial.

BACKGROUND: Alcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey's discriminant function (DF) ≥32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published. METHODS/DESIGN: STOPAH is a multicentre, double-blind, factorial (2 × 2) trial in which patients are randomised to one of four groups:1. Group A: placebo / placebo2. Group B: placebo / prednisolone3. Group C: pentoxifylline / placebo4. Group D: pentoxifylline / prednisoloneThe trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary endpoints being mortality at 90 days and 1 year. DISCUSSION: STOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power. TRIAL REGISTRATION: EudraCT reference number: 2009-013897-42 ISRCTN reference number: ISRCTN88782125.

Improvement of parenteral nutrition-associated cholestasis in an adult using fish oil-based parenteral nutrition.

Parenteral nutrition-associated cholestasis (PNAC) is a severe complication of parenteral nutrition. Standard feed preparations contain soybean and olive oil that are rich in ω-6 polyunsaturated fats, and which studies suggest can be hepatotoxic. Preparations containing fish oil, rich in ω-3 polyunsaturated fats, may be hepatoprotective and have been used in the critical care setting as immunotherapy. A case demonstrating dramatic improvement in liver function and overall clinical condition in an adult with PNAC and intestinal failure within 8 weeks of changing to a fish oil-based parenteral feed is reported. As far as is known, this is the first report of an adult patient whose parenteral nutrition-associated liver disease resolved after a parenteral nutrition lipid emulsion was changed to the fish oil-containing emulsion, SMOFlipid.

Nodular regenerative hyperplasia of the liver: survival and associated features in a UK case series.

AIMS: Nodular regenerative hyperplasia (NRH) is a rarely identified liver disorder. It is characterized histologically by nodular hepatocyte regeneration without significant fibrosis, and clinically by portal hypertension and abnormal liver function tests (LFTs). Survival data in an unselected cohort after diagnosis of NRH have not been previously described. This study aims to identify a regional cohort with NRH, to determine survival after diagnosis and to assess the relative frequency of associated conditions. METHODS: Patients were identified retrospectively from liver biopsy reports within pathology databases, over a 13-year period from Glasgow, Scotland, UK. Case notes were retrieved, clinical information extracted and survival was determined. RESULTS: Forty-two patients were identified (19 males). Common presenting features were abnormal LFTs (predominantly cholestatic) (76%) and portal hypertension (9.5%). None had severe liver dysfunction (Child-Pugh score A: 81%, B: 19%, C: 0%). Varices were detected in 26%, and portal hypertension was detected in 31%. There were five (12%) variceal bleeds, one fatal. The patients were subdivided into four groups according to associated clinical conditions: malignancy (29%), prothrombotic (21%), rheumatological (24%) and idiopathic/other (26%). Mean survival was 8.1 years, although survival was highly variable, and was associated with age and associated disease, but not with portal hypertension or varices. No patients in the rheumatological subgroup died. CONCLUSION: NRH is usually associated with malignant, prothrombotic or rheumatological conditions. Survival is highly variable and related to age and the underlying disease process, but not to portal hypertension overall. Liver function remains well preserved.

Granulocytapheresis in the treatment of severe alcoholic hepatitis: a case series.

OBJECTIVES: The management of alcoholic hepatitis remains controversial. Anti-tumour necrosis factor treatments have been studied recently. We piloted the use of granulocytapheresis (GCAP) in the management of severe alcoholic hepatitis. METHODS: GCAP was performed on six patients with severe alcoholic hepatitis. Their clinical and laboratory progress was reviewed retrospectively. RESULTS: Six of the patients underwent at least one session of GCAP. Three of the patients had coexistent renal failure and five of the six patients were corticosteroid nonresponders. All patients tolerated the procedure. However, three of the patients died during their hospital admission within 4 days of GCAP treatment. These three patients suffered from torrential variceal haemorrhage, multiorgan failure and pneumonia, respectively. Two patients died 18 and 25 days after their GCAP treatment, both with multiorgan failure. The survivor was the sole corticosteroid responder of the group. There was a trend towards a fall in serum bilirubin level after GCAP, but this did not reach significance. CONCLUSION: GCAP is tolerated in severe alcoholic hepatitis; however, we have no evidence of survival advantage with this treatment.

The management of alcoholic hepatitis.

Alcoholic hepatitis is an increasingly common reason for hospital admission which carries a high mortality. This review describes a clinical approach to the definition, assessment and management of this condition.

Improvement in cholestasis associated with total parenteral nutrition after treatment with an antibody against tumour necrosis factor alpha.

BACKGROUND: Many patients receiving long-term total parenteral nutrition (TPN) develop liver disease; cholestasis is common and may be severe. Antitumour necrosis factor alpha (TNFalpha) antibodies have recently been used in order to treat Crohn's disease, but their effect on cholestasis in humans has not been previously described. CASE REPORT: A 45-year-old woman had complicated Crohn's disease with multiple fistulae and only 1 m of residual small bowel. She had been receiving TPN for 2.5 years when she developed cholestasis which worsened despite adjustments to her TPN regimen. Infliximab, an anti-TNFalpha antibody, was given with the aim of treating an enterocutaneous fistula, but it also produced a marked biochemical and histological improvement in the TPN-related cholestasis. CONCLUSIONS: Anti-TNFalpha antibodies appeared in this case to improve TPN-related cholestasis. This implies that TNFalpha may play an important role in the development of this condition.