Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

Short-term changes observed in multiparametric liver MRI following therapy with direct-acting antivirals in chronic hepatitis C virus patients.

METHODS: We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before direct-acting antiviral (DAA) therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed). RESULTS: We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35 ± 4 ms), transverse relaxation time (T2, 2.5 ± 0.8 ms; T2* 3.0 ± 0.7 ms), and liver perfusion (28.1 ± 19.7 ml/100 g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or superior mesenteric artery blood flow. CONCLUSION: For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2 and T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms. KEY POINTS: • DAAs have revolutionised the treatment of hepatitis C and achieve sustained virological response in over 95% of patients, even with liver cirrhosis. • Currently available non-invasive measures of liver fibrosis are not accurate after HCV treatment with DAAs, this prospective single-centre study has shown that MRI can sensitively measure changes within the liver, which could reflect the reduction in inflammation with viral clearance. • The ability of MRI to characterise changes in structural and haemodynamic MRI measures in the liver after intervention will enhance our understanding of the progression/regression of liver disease and could potentially influence clinical decision algorithms.

The effect of prone positioning with surgical bolsters on liver blood flow in healthy volunteers.

This study sought to identify changes in hepatic flood flow and cardiac output during prone positioning on surgical bolsters in awake volunteers, and was prompted by a local incident of significant hepatic dysfunction following surgery in the prone position. Cardiac output was determined using the non-invasive Peñáz technique, and plasma disappearance rate of indocyanine green (ICG-PDR) was measured as a surrogate maker for hepatic blood flow along with serum hepatic enzyme assays. Measurements were made after one hour in supine, prone and returned supine positions. Ten volunteers completed the study. There were significant changes in the disappearance rate of indocyanine green, which decreased this from mean (SD) 31.1 (9.70) supine to 19.6 (4.37)%.min prone, respectively (p = 0.02), increasing on return to the supine position to 24.6 (5.54)%.min (p = 0.019). Cardiac output was also significantly reduced when changing from the supine to the prone position, from mean (SD) 4.7 (1.0 to 3.5 (1.1) (l.min(-1) ), respectively (p = 0.002). We demonstrated an acute and reversible change in both hepatocellular function and cardiac output associated with the prone position.

Classifying the unclassifiable-a Delphi study to reach consensus on the fibrotic nature of diseases.

BACKGROUND: Traditionally, clinical research has focused on individual fibrotic diseases or fibrosis in a particular organ. However, it is possible for people to have multiple fibrotic diseases. While multi-organ fibrosis may suggest shared pathogenic mechanisms, yet there is no consensus on what constitutes a fibrotic disease and therefore fibrotic multimorbidity. AIM: A Delphi study was performed to reach consensus on which diseases may be described as fibrotic. METHODS: Participants were asked to rate a list of diseases, sub-grouped according to eight body regions, as 'fibrotic manifestation always present', 'can develop fibrotic manifestations', 'associated with fibrotic manifestations' or 'not fibrotic nor associated'. Classifications of 'fibrotic manifestation always present' and 'can develop fibrotic manifestations' were merged and termed 'fibrotic'. Clinical consensus was defined according to the interquartile range, having met a minimum number of responses. Clinical agreement was used for classification where diseases did not meet the minimum number of responses (required for consensus measure), were only classified if there was 100% consensus on disease classification. RESULTS: After consulting experts, searching the literature and coding dictionaries, a total of 323 non-overlapping diseases which might be considered fibrotic were identified; 92 clinical specialists responded to the first round of the survey. Over three survey rounds, 240 diseases were categorized as fibrotic via clinical consensus and 25 additional diseases through clinical agreement. CONCLUSION: Using a robust methodology, an extensive list of diseases was classified. The findings lay the foundations for studies estimating the burden of fibrotic multimorbidity, as well as investigating shared mechanisms and therapies.

Elevation of alanine transaminase and markers of liver fibrosis after a mixed meal challenge in individuals with type 2 diabetes.

BACKGROUND: Hyperalimentation for 4 weeks is associated with raised liver enzymes and liver fat content (LFC), which are two common features found in individuals with diabetes. AIM: We evaluated the effect of two mixed meal challenges on LFC, liver enzymes and serum bio-markers of liver injury and fibrosis in 16 healthy volunteers (HV) and subjects with type 2 diabetes (T2DM). METHODS: Subjects (HV: 9 male, 7 female, aged 57.9 ± 1.7 years, body mass index (BMI) 27.1 kg/m(2); and T2DM: 11 male, 5 female, aged 62.1 ± 1.3 years, BMI 28.0 ± 0.4 kg/m(2)) consumed two meals at 1 h (884 kcal) and at 6 h (1,096 kcal). LFC determined by (1)H magnetic resonance spectroscopy, serum levels of liver enzymes, hyaluronic acid (HA), procollagen III N-terminal peptide (P3NP) and tissue inhibitor metalloproteinase-1 (TIMP-1) were estimated at time 0 (fasting) and 9 h (postprandial). RESULTS: Fasting LFC was higher in the T2DM group 7.6 % (4.9, 15.4) [median (inter-quartile range)] than in the HV group 2.3 % (0.8, 5.1) (p < 0.05) while levels of HA, P3NP and TIMP-1 were similar. Following the meal challenge there was no significant change in LFC. Subjects with T2DM had higher post-prandial rise in alanine transaminase (ALT) (p = 0.014), serum HA (p = 0.007) and P3NP (p = 0.015) compared with HV. Fasting LFC correlated with a greater post-prandial increase in P3NP levels in all subjects (Pearson correlation r = 0.53, p = 0.001). CONCLUSIONS: In subjects with T2DM, a mixed meal challenge is associated with a significant elevation in the serum levels of ALT, HA and P3NP without significant changes in LFC. These markers should be performed in the fasted state.

High-resolution endoscopy and endoscopic ultrasound for evaluation of early neoplasia in Barrett's esophagus.

BACKGROUND: Endoscopic ultrasound (EUS) is useful for detecting depth of invasion and nodal involvement in patients with early Barrett's neoplasia (EBN), precluding endoscopic management. This study aimed to determine whether the lesion morphology of the EBN shown on high-resolution endoscopy predicts EUS and histologic tumor stage. METHODS: Retrospective series from two tertiary referral centers were studied. Patients with EBN referred for EUS evaluation before treatment were identified, and data were collected from endoscopies, a database, and case notes. All patients had high-resolution endoscopy followed by radial EUS. RESULTS: This study included 50 patients (22 men) with a median age of 69 years (interquartile range, 60-79 years). Visible lesions in the Barrett's segment were described as Paris types 0-1 (n = 9), 0-IIb (n = 12), 0-IIa (n = 12), 0-IIa + IIc (n = 6), and 0-IIc (n = 5). Of the 50 patients, 46 (92%) had either EMR (n = 17), esophagectomy (n = 23), or both (n = 6). All 12 patients (100%) with Paris 0-IIb lesions had T0/T1 m staging on EUS confirmed with resection histology. The sensitivity for EUS T-staging for Paris classification was 71.4% for type 0-I, 100% for type 0-IIb, 83% for type 0-IIa, 66.7% for type 0-IIa + IIc, and 66.7% for type IIc. Overall, 8 (17%) of the 46 patients were understaged and 2 (4%) were overstaged. For detecting submucosal invasion, EUS had a sensitivity of 66%, a specificity of 93%, a negative predictive value of 85%, and a diagnostic accuracy of 84.4%. CONCLUSION: Submucosal invasion is detected by EUS for 26% of patients with EBN. The value of EUS staging before resection for type 0-IIb early Barrett's cancer (flat lesions) is limited because 100% of these lesions are limited to the mucosa. For the management algorithm in this selected cohort, the use of EUS should be reconsidered.

Effectiveness of a nurse-led alcohol liaison service in a secondary care medical unit.

Alcohol misuse is a common reason for hospital admission. While there is considerable evidence from other areas that provision of specialised alcohol services can reduce alcohol intake, there is currently less evidence for medical departments in an acute hospital setting. Nottingham hospitals initiated such a service in 2002-3 based around two nurse specialists who provided input to inpatients with alcohol-related physical disease and provided links to community-based services for alcohol misuse. This service assessed 3632 patients over five years and has seen a reduction in hospital admissions, violent incidents against staff and primary care attendances. It is believed that this model of care is an effective means of intervening in people with alcohol-related problems.

The Development and Implementation of a Commissioned Pathway for the Identification and Stratification of Liver Disease in the Community.

OBJECTIVE: To describe the development of the Nottingham liver disease stratification pathway, present a 12-month evaluation of uptake, stratification results and compare the pathway to current British Society of Gastroenterology (BSG) guidelines. DESIGN: A referral pathway between primary and secondary care for the detection and risk stratification of liver disease. SETTING: Four Nottinghamshire Clinical Commissioning Groups (700,000 population). PATIENTS: Patients are referred to the pathway with i) raised AST/ALT ratio ii) harmful alcohol use or iii) risk or presence of non-alcoholic fatty liver disease (NAFLD). INTERVENTIONS: Clinic attendance within secondary care for transient elastography (TE) and brief lifestyle intervention. The TE result is reported back to the GP with advice on interpretation and referral guidance. MAIN OUTCOME MEASURES: Pathway uptake, patient characteristics, liver disease stratification results and stakeholder feedback. RESULTS: Over the first 12 months 968 patients attended a TE clinic appointment, with raised AST/ALT ratio being the most common single reason for referral (36.9%). Of the total, 222 (22.9%) patients had an elevated liver stiffness (≥8kPa) and in 60 (27.0%) liver stiffness was indicative of advanced chronic liver disease. If a traditional approach based on raised liver enzymes (BSG guidance) had been followed, 38.7% of those with significant liver disease (≥8kPa) would have gone undetected among those referred for either NAFLD or raised AST:ALT. CONCLUSIONS: Targeting patients with risk factors for chronic liver disease and stratifying them using TE can detect significant chronic liver disease above and beyond the approach based on liver enzyme elevation.

The antecedents of biliary cancer: a primary care case-control study in the United Kingdom.

In a case-control study using a large UK primary care database, we found that non-steroidal anti-inflammatory drugs had no protective effect against biliary carcinomas (cholangiocarcinoma and gall bladder cancer). Increased risks were observed for cigarette smoking, diabetes, gallstone disease and obesity.

Endoscopic-ultrasound-guided mural trucut biopsy in the investigation of unexplained thickening of esophagogastric wall.

BACKGROUND AND AIMS: Esophageal and/or gastric wall thickening raises the possibility of malignancy. Endoscopic-ultrasound-(EUS-)guided targeted biopsy of the thickened wall is possible. We aimed to evaluate the efficacy and safety of EUS-guided mural trucut biopsies (TCB) in detecting underlying malignancy in patients with thickened esophagogastric wall and negative mucosal biopsies. METHODS: Patients with alarm symptoms referred for EUS-guided sampling after negative endoscopy and mucosal biopsy were included in the study. All patients had radial EUS reporting abnormal thickening of the esophageal/gastric wall. A linear-array echoendoscope and a 19-gauge trucut needle were used for sampling. Clinical and investigatory data were collected prospectively between 2004 and 2008. RESULTS: Thirty-one patients (20 men) aged 60 - 74 years (median 67 years) were included. All patients had thickened esophageal wall (n = 10), gastric wall (n = 21), or both on radial EUS. Prior to EUS, patients had undergone 1 - 5 endoscopies (median 1.2) and 2 - 8 mucosal biopsies (median 4). The median esophageal and gastric wall thicknesses were 12 and 18 mm respectively. During sampling 1 - 5 needle punctures (median 3) were made. On EUS-TCB, an adequate specimen for histology was obtained in 28/31 patients (90 %). The size of the tissue cores was 4 - 10 mm (median 6mm). Malignancy was confirmed in 16/31 patients (54 %) on histology, and in 11/31 patients (35.4 %) an underlying malignancy was excluded. There was no significant correlation between wall thickness and biopsy size (rho = 0.11, 95 %CI- 0.25 to - 0.45, two-sided P = 0.53). EUS-TCB had sensitivity, specificity, and positive and negative predictive values of 85 %, 100 %, 100 %, and 74 % respectively. There were no immediate or late complications. CONCLUSIONS: EUS-guided mural TCB is a safe and effective technique in the investigation of esophagogastric wall thickening in patients with alarm symptoms and has high sensitivity and specificity for the diagnosis of a cancer.

Obesity in acute alcoholic hepatitis increases morbidity and mortality.

BACKGROUND: Alcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH) and the underlying inflammatory crosstalk between adipose tissue (AT) and the liver. METHODS: A cohort of 233 patients with AH from the UK and USA provided data to analyse the effects of obesity in AH. Body mass index was corrected for the severity of ascites, termed cBMI. Inflammatory and metabolic profiling was undertaken by proteome analysis of human serum samples. The effect of alcohol on adipose tissue and CXCL11 expression was studied in 3 T3-derived adipocytes and in mice using the high-fat diet-plus-binge ethanol model. FINDINGS: Obesity was common amongst patients with AH, seen in 19% of individuals. Obesity (HR 2.22, 95%CI 1.1-4.3, p = .022) and underweight (HR 2.38, 1.00-5.6, p = .049) were independently associated with mortality at 3 months. Proteome analysis demonstrated multiple metabolic and inflammatory factors differentially expressed in obese AH verse lean AH, with CXCL11 being the most elevated factor in obese AH. In vitro analysis of cultured adipocytes and in vivo analysis of mouse models showed that alcohol induced CXCL11 expression in AT, but not in liver. INTERPRETATION: Obesity is common in AH and associated with a greater than two-fold increase in short-term mortality. Obese AH is associated with a different inflammatory phenotype, with the greatest elevation in CXCL11. These data confirm that adiposity is clinically important in acute alcohol-related liver disease and illustrate the adipose-liver inflammatory axis in AH. FUND: This work was supported in part by an EASL Sheila Sherlock Physician Scientist Fellowship. The funder played no role in gathering or analysing data or writing the manuscript. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Obesity and type 2 diabetes are important risk factors underlying previously undiagnosed cirrhosis in general practice: a cross-sectional study using transient elastography.

BACKGROUND: Rising cirrhosis incidence and mortality in the United Kingdom has been attributed predominantly to excess alcohol consumption. However, metabolic risk factors such as Type 2 diabetes and obesity may also be important. AIM: To screen at-risk individuals in general practice for undetected cirrhosis using transient elastography and study the risk factors underlying these cases. METHODS: The study was undertaken in 4 general practices (adult patient population 20 868) between February 2012 and September 2014. Patients with defined risk factors for chronic liver disease (hazardous alcohol use and/or Type 2 diabetes) were identified from the General Practice electronic records and invited for transient elastography. Elevated liver stiffness was defined as ≥8 kPa. Cirrhosis was confirmed by established histological, radiological and biochemical methods. RESULTS: Two thousand three hundred and sixty eight patients were invited for transient elastography and 899/919 who attended (97.8%) had valid measurements. Of these 230 patients had elevated liver stiffness (25.6%) and 27 had cirrhosis (2.9%). Risk factors for new cirrhosis diagnoses were obesity and/or Type 2 diabetes in 16 patients (59.3%), alcohol alone in 3 (11.1%) and both alcohol and obesity and/or diabetes in eight (29.6%). Presence of cirrhosis was significantly increased in obese patients with Type 2 diabetes or hazardous alcohol use compared to non-obese (odds ratio 9.4 [95% CI 2.2-40.9] and 5.6 [95% CI 1.6-19.7] respectively). CONCLUSIONS: The number of new cases of cirrhosis diagnosed clearly demonstrates that existing estimates of prevalence are likely to be gross underestimates. Obesity was an important risk factor for cirrhosis within both alcohol users and diabetics.

The effect of exercise training on intrahepatic triglyceride and hepatic insulin sensitivity: a systematic review and meta-analysis.

This systematic review and meta-analysis determined the impact of structured exercise training, and the influence of associated weight loss, on intrahepatic triglyceride (IHTG) in individuals with non-alcoholic fatty liver disease (NAFLD). It also examined its effect on hepatic insulin sensitivity in individuals with or at increased risk of NAFLD. Analyses were restricted to studies using magnetic resonance spectroscopy or liver biopsy for the measurement of IHTG and isotope-labelled glucose tracer for assessment of hepatic insulin sensitivity. Pooling data from 17 studies (373 exercising participants), exercise training for one to 24 weeks (mode: 12 weeks) elicits an absolute reduction in IHTG of 3.31% (95% CI: -4.41 to -2.22%). Exercise reduces IHTG independent of significant weight change (-2.16 [-2.87 to -1.44]%), but benefits are substantially greater when weight loss occurs (-4.87 [-6.64 to -3.11]%). Furthermore, meta-regression identified a positive association between percentage weight loss and absolute reduction in IHTG (ß = 0.99 [0.62 to 1.36], P < 0.001). Pooling of six studies (94 participants) suggests that exercise training also improves basal hepatic insulin sensitivity (mean change in hepatic insulin sensitivity index: 0.13 [0.05 to 0.21] mg m-2  min-1 per µU mL-1 ), but available evidence is limited, and the impact of exercise on insulin-stimulated hepatic insulin sensitivity remains unclear.

Seeding of hepatocellular carcinoma into the stomach wall following endoscopic ultrasound and fine-needle aspiration biopsy.

Delayed gastrointestinal metastasis is a rare complication of hepatocellular carcinoma (HCC). We present the case of a patient who presented with melaena and microcytic anaemia 6 years after receiving an orthotopic liver transplant for hepatitis B-induced HCC. Oesophagogastroduodenoscopy revealed a fungating gastric mass at the lesser curve and histology from biopsies confirmed metastatic recurrence of HCC in the stomach. The route of metastasis is likely due to iatrogenic seeding of tumour cells during pre-transplant endoscopic ultrasound (EUS) and fine needle aspiration (FNA) biopsy. Subsequent positron emission tomography and magnetic resonance imaging failed to reveal further metastatic disease and the patient was managed with a total gastrectomy. This is the first reported description in the literature of needle-track metastasis in the stomach due to liver EUS-FNA for HCC.

EUS-guided tissue sampling: comparison of "dual sampling" (Trucut biopsy plus FNA) with "sequential sampling" (Trucut biopsy and then FNA as required).

BACKGROUND AND STUDY AIMS: Both endoscopic ultrasound- (EUS-) guided tissue sampling techniques, fine-needle aspiration (FNA) and Trucut biopsy, have advantages and limitations. The aim of this study was to develop a strategy of combining these two EUS-guided sampling techniques in order to maximize the diagnostic accuracy and minimize duplication. PATIENTS AND METHODS: In this multicenter study we performed "dual sampling" (i. e. with both FNA and Trucut biopsy) in 95 patients during phase 1 of the study and "sequential sampling" (i. e. performing FNA only when Trucut biopsy tissue cores were macroscopically inadequate) in 72 patients during phase 2. RESULTS: During the study period, 167/401 patients referred for EUS-guided sampling were eligible for the study; only solid lesions were included. In 143/167 patients (86 %), sampling was performed via the transesophageal or transgastric routes. When the dual sampling strategy was used, an accurate diagnosis was achieved in 78/95 patients by FNA, compared with 85/95 by Trucut biopsy ( P = 0.21). The combined accuracy of the dual sampling strategy was higher than FNA alone (88/95 vs. 78/95, P = 0.048), but was not significantly higher than Trucut biopsy alone (88/95 vs. 85/95, P = 0.61). Using the sequential sampling strategy, an accurate diagnosis was achieved in 66/72 patients (92 %) compared with 88/95 (93 %) for dual sampling ( P = 1.0), and 8/72 patients (11 %) had to undergo FNA after Trucut biopsy failed to obtain an adequate sample. One patient with mediastinal tuberculosis developed a cold abscess following Trucut biopsy. CONCLUSION: A sequential sampling strategy, in which EUS-guided Trucut biopsy is attempted first, and FNA performed only when Trucut biopsy fails to obtain a macroscopically adequate sample, achieves a diagnostic accuracy of 92 %, with 11 % of patients requiring both sampling procedures.

Risk of hepatocellular carcinoma among individuals with different aetiologies of cirrhosis: a population-based cohort study.

BACKGROUND: Among patients with cirrhosis, only those determined to be at risk for hepatocellular carcinoma (HCC) should undergo surveillance. However, little is known about how different aetiologies of cirrhosis affect risk for HCC. AIM: To quantify the cumulative incidence of HCC among a representative population of people with cirrhosis of the liver of varying aetiology. METHODS: We identified subjects with hepatic cirrhosis from the UK's General Practice Research Database (1987-2006). Diagnoses of HCC were obtained from linked national cancer registries (1971-2006). Cox proportional hazards regression was used to estimate hazard ratios. The predicted 10-year cumulative incidence of HCC for each aetiology of cirrhosis was estimated while accounting for competing risks of death from any cause and liver transplant. RESULTS: Among 3107 people with cirrhosis, the adjusted relative risk of HCC was increased twofold to threefold among people with viral and autoimmune/metabolic aetiologies, compared to those with alcohol-associated cirrhosis. The 10-year predicted cumulative incidence estimates of HCC for each aetiology were alcohol, 1.2%; chronic viral hepatitis, 4.0%; autoimmune or metabolic disease, 3.2%; and cryptogenic, 1.1%. CONCLUSIONS: In a population-based study in the UK, people with cirrhosis have an estimated cumulative 10-year incidence of HCC of 4% or lower. Cumulative incidence varies with aetiology such that individuals with alcohol or cryptogenic cirrhosis have the lowest risk for HCC. These findings provide important information for cost-effectiveness analyses of HCC surveillance.

Spontaneous central venous thrombosis and shunt occlusion following peritoneovenous shunt placement for intractable ascites.

A 43-year-old man had a peritoneovenous shunt inserted for the treatment of chylous ascites secondary to myelofibrosis. Despite being on anticoagulation for superior mesenteric vein thrombosis, he developed shunt dysfunction within two weeks of insertion. Superior venacavography showed multiple filling defects in the right axillary vein, no filling of the right brachiocephalic and right subclavian vein, and thrombotic occlusion of the internal jugular veins bilaterally. The shunt was removed 11 days after insertion, and there was extensive thrombosis of the venous end of the shunt and the compressible pump chamber. Shunt thrombosis is known to occur but remains a rare complication, with 87% of such obstructions being due to a thrombus at the tip of the venous end of the shunt. Extensive thrombosis of the shunt (as in the present case) is very rare.

Elevated serum alanine transaminase in patients with type 1 or type 2 diabetes mellitus.

BACKGROUND: The risk of chronic liver disease is higher in diabetics, and serum alanine transaminase (ALT) is a sensitive predictor of mortality from liver disease. AIM: To estimate the prevalence of elevated ALT in type 1 and type 2 diabetes, and identify possible risk factors. METHODS: We identified all patients (n = 2077) attending review between September 2002 and August 2003. We excluded those with no ALT measurement (n = 73); those whose alcohol consumption was >14 units/week (women) (n = 276) or >21 units/week (men) (n = 324); and those with a diagnosis of Maturity Onset Diabetes of the Young, secondary diabetes, gestational diabetes or uncertain type of diabetes (n = 51). We calculated the prevalences of elevated ALT in both type 1 and type 2 diabetes patients, and compared the demographic, microvascular risk factors and current drug use between each group using multivariate logistic regression. RESULTS: Of 1353 patients included, 836 (61.9%) had type 2 diabetes. Elevated ALT was found in 9.5% (95%CI 7.1-12.3%) of patients with type 1 diabetes, and 12.1% (95%CI 9.9-14.5%) of those with type 2 diabetes. The risk of elevated ALT in patients with type 2 diabetes increased with increasing body mass index (p(trend) = 0.04), and was lower in those taking insulin (OR 0.38, 95%CI 0.22-0.65). DISCUSSION: The prevalence of elevated ALT is 3-4 times higher in patients with either type 1 or type 2 diabetes than in the general population. Further studies investigating the aetiology and mechanisms of this elevation may suggest appropriate early interventions.