Daniel R. Gaya

Hepatic granulomas: a 10 year single centre experience.

Background: Epithelioid granulomas have been reported in 2–15% of unselected liver biopsies, with numerous underlying aetiologies described. However, all UK series were reported before identification of hepatitis C virus (HCV). Aim: To evaluate the current aetiologies of hepatic granulomas and to assess the prognosis for the “idiopathic” group, in which all investigations for a recognised cause were negative or normal. Methods: A retrospective review of patient case notes between 1991 and 2001; all patients who had a liver biopsy at Glasgow Royal Infirmary revealing epithelioid granulomas had their case notes and liver biopsies reviewed and a standard proforma completed. Results: Over the study period, 1662 liver biopsies were performed. Hepatic granulomas were found in 63. Of those identified, 47 were female, with a mean age of 42 years (range, 17–81). Underlying aetiologies were as follows: primary biliary cirrhosis (PBC; 23.8%), sarcoidosis (11.1%), idiopathic (11.1%), drug induced (9.5%), HCV (9.5%), PBC/autoimmune hepatitis (AIH) overlap (6.3%), Hodgkin lymphoma (6.3%), AIH (4.8%), tuberculosis (4.8%), resolving biliary obstruction (3.2%), and other single miscellaneous causes (9.5%). Of the seven patients with idiopathic hepatic granulomas, one was lost to follow up, one died of stroke, and the remaining five were well with no liver related morbidity at a mean follow up of 6.2 years. Conclusions: The aetiology of hepatic granulomas is broad ranging, with HCV an important cause in this population. Despite extensive investigations, a 10–15% of patients still had “idiopathic” hepatic granulomas. However, the prognosis for this last group appears to be excellent.

Multicentre comparison of the Glasgow Blatchford and Rockall scores in the prediction of clinical end-points after upper gastrointestinal haemorrhage

Aliment Pharmacol Ther 2011; 34: 470–475

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07–3.26, P = 2 × 10−16). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01–HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

A prospective single-centre evaluation of the intra-individual variability of faecal calprotectin in quiescent Crohn's disease

As a non‐invasive marker of gastrointestinal inflammation, faecal calprotectin (FC) is being increasingly used to guide the management of Crohns disease. It is therefore a concern that studies have shown variability in day to day levels.

Thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease: relapse and recapture rates, with predictive factors in 237 patients

Thiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohns disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long‐term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors.

Utility of faecal calprotectin analysis in adult inflammatory bowel disease

The inflammatory bowel diseases (IBD), Crohns disease and ulcerative colitis, are chronic relapsing, remitting disorders. Diagnosis, along with assessment of disease activity and prognosis present challenges to managing clinicians. Faecal biomarkers, such as faecal calprotectin, are a non-invasive method which can be used to aid these decisions. Calprotectin is a calcium and zinc binding protein found in the cytosol of human neutrophils and macrophages. It is released extracellularly in times of cell stress or damage and can be detected within faeces and thus can be used as a sensitive marker of intestinal inflammation. Faecal calprotectin has been shown to be useful in the diagnosis of IBD, correlates with mucosal disease activity and can help to predict response to treatment or relapse. With growing evidence supporting its use, over the last decade this faecal biomarker has significantly changed the way IBD is managed.

Long-term follow-up of endoscopic Histoacryl glue injection for the management of gastric variceal bleeding

BACKGROUND Variceal bleeding is an acute medical emergency with high mortality. Although less common than oesophageal variceal haemorrhage, gastric variceal bleeding is more severe and more difficult to control. The optimal therapy for gastric variceal bleeding remains unclear although endoscopic injection of N-Butyl-2-Cyanoacrylate (Histoacryl) glue is often used. However, its long-term efficacy is poorly described. We studied the immediate and long-term effects of Histoacryl glue injection as treatment for bleeding gastric varices in a large UK hospital. METHOD Endoscopy records and case notes were used to identify patients receiving Histoacryl injection for gastric variceal bleeding over a 4-year period. RESULTS Thirty-one patients received Histoacryl for gastric variceal bleeding. Seventy-four per cent patients had alcohol-related liver disease and 61% of cirrhotics were Childs Pugh grade B or C. Fifty-eight per cent were actively bleeding during the procedure with 100% haemostasis rates achieved. Two patients developed pyrexia within 24 h of injection settling with antibiotics. No other complications were encountered. Mean overall follow-up was 35 months, with mean follow-up of survivors 57 months. Forty-eight per cent patients had endoscopic ultrasound assessment of varices during follow-up with no effect on rebleeding rates. Thirteen per cent required subsequent transjugular intrahepatic portosystemic shunt placement. Gastric variceal rebleeding rate was 10% at 1 year and 16% in total. One- and two-year mortality was 23% and 35%, respectively. CONCLUSION Endoscopic injection of Histoacryl glue appears to be a safe and effective treatment for gastric variceal bleeding. Further data are required to compare it with other therapies in this situation.

Multicentre randomised controlled study comparing carvedilol with variceal band ligation in the prevention of variceal rebleeding.

BACKGROUND & AIMS Rebleeding after an initial oesophageal variceal haemorrhage remains a significant problem despite therapy with band ligation, non-selective β-blockers or a combination of these. Carvedilol is a vasodilating non-selective β-blocker with alpha-1 receptor and calcium channel antagonism. A recent study has suggested it is effective in the prevention of a first variceal bleed. Our aim was to compare oral carvedilol with variceal band ligation (VBL) in the prevention of rebleeding following a first variceal bleed. METHODS Patients who were stable 5 days after presentation with a first oesophageal variceal haemorrhage and had not been taking β-blockers were randomised to oral carvedilol or VBL. Patients were followed-up after one week, monthly, then every 3 months. The primary end point was variceal rebleeding on intention-to-treat analysis. RESULTS 64 patients were randomised, 33 to carvedilol and 31 to VBL. 58 (90.6%) patients had alcohol related liver disease. Age and Child-Pugh score were similar in both groups at baseline. Median follow-up was 26.3 (interquartile range [IQR] 10.2-46.6)months. Compliance was 68% and 65% for carvedilol and VBL respectively (p=0.993) and serious adverse events between the two groups were similar (p=0.968). Variceal rebleeding occurred during follow-up in 12 (36.4%) and 11 (35.5%) patients in the carvedilol and VBL groups, respectively (p=0.857), with 9 (27.3%) and 16 (51.6%) deaths in each group, respectively (p=0.110). CONCLUSIONS Carvedilol is not superior to VBL in the prevention of variceal rebleeding. The trend to a survival benefit for patients taking this drug compared with those undergoing banding requires further exploration.

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial

Summary Background Up to 60% of patients with Crohns disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohns disease. Methods We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohns disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohns disease (Crohns Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). Findings Between June 6, 2008, and April 23, 2012, 240 patients with Crohns disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohns disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27–1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28–0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04–0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42–1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. Interpretation Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohns disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. Funding Medical Research Council.

A prospective evaluation of the predictive value of faecal calprotectin in quiescent Crohn's disease

BACKGROUND Faecal calprotectin (FC) is a non-invasive marker of gastrointestinal inflammation. AIM To determine whether higher FC levels in individuals with quiescent Crohns disease are associated with clinical relapse over the ensuing 12 months. METHODS A single centre prospective study was undertaken in Crohns disease patients in clinical remission. The receiver operating characteristic (ROC) curve for the primary endpoint of clinical relapse by 12 months, based on FC at baseline, was calculated. Kaplan-Meier curves of time to relapse were based on the resulting optimal FC cutoff for predicting relapse. RESULTS Of 97 patients recruited, 92 were either followed up for 12 months without relapsing, or reached the primary endpoint within that period. Of these, 10 (11%) relapsed by 12 months. Median FC was lower for non-relapsers, 96 μg/g (IQR 39-237), than for relapsers, 414 μg/g (IQR 259-590), (p=0.005). The area under the ROC curve to predict relapse using FC was 77.4%. An optimal cutoff FC value of 240 μg/g to predict relapse had sensitivity of 80.0% and specificity of 74.4%. Negative predictive value was 96.8% and positive predictive value was 27.6%, FC ≥240 μg/g was associated with likelihood of relapse by 12-months 12.18 (95% CI 2.55-58.2) times higher than lower values (p=0.002). CONCLUSIONS In this prospective dataset, FC is a useful tool to help identify quiescent Crohns disease patients at a low risk of relapse over the ensuing 12 months. FC of 240 μg/g was the optimal cutoff in this cohort.