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.

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.

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.

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.

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 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.

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.

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.

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.

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.

Investigating the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: A (31)P MRS study.

BACKGROUND: Impaired homeostasis of hepatic ATP has been associated with NAFLD. An intravenous fructose infusion has been shown to be an effective challenge to monitor the depletion and subsequent recovery of hepatic ATP reserves using (31)P MRS. AIMS: The purpose of this study was to evaluate the effects of an oral rather than intravenous fructose challenge on hepatic ATP reserves in healthy subjects. METHODS: Self-reported healthy males were recruited. Following an overnight fast, baseline liver glycogen and lipid levels were measured using Magnetic Resonance Spectroscopy (MRS). Immediately after consuming a 500 ml 75 g fructose drink (1275 kJ) subjects were scanned continuously for 90 min to acquire dynamic (31)P MRS measurements of liver ATP reserves. RESULTS: A significant effect on ATP reserves was observed across the time course (P < 0.05). Mean ATP levels reached a minimum at 50 min which was markedly lower than baseline (80 ± 17% baseline, P < 0.05). Subsequently, mean values tended to rise but did not reach statistical significance above minimum. The time to minimum ATP levels across subjects was negatively correlated with BMI (R(2) = 0.74, P < 0.005). Rates of ATP recovery were not significantly correlated with BMI or liver fat levels, but were negatively correlated with baseline glycogen levels (R(2) = 0.7, P < 0.05). CONCLUSIONS: Depletion of ATP reserves can be measured non-invasively following an oral fructose challenge using (31)P MRS. BMI is the best predictor of postprandial ATP homeostasis following fructose consumption.

End-stage methotrexate-related liver disease is rare and associated with features of the metabolic syndrome.

BACKGROUND: Methotrexate (MTX) is one of the most frequently prescribed drugs in contemporary medicine with a well-recognised hepatotoxic potential, for which stringent laboratory and histological surveillance has long been advocated. AIM: To estimate the population burden of end-stage methotrexate-related liver disease (MTX-LD) in the United States and identify independent host risk factors for this disease entity. METHODS: We analysed the records of all individuals who had been listed for, and/or received, liver transplantation in the United States, as reported to the Organ Procurement and Transplantation Network between 1 October 1987 and 31 December 2011, and identified those whose liver disease was attributed, wholly or partly, to MTX therapy. We also compared the demographic and clinical characteristics of adult individuals with MTX-LD with those listed and/or transplanted for alcoholic liver disease (ALD, n = 43,285), non-alcoholic steatohepatitis (NASH, n = 7569) and primary sclerosing cholangitis (PSC, n = 8526) using the adjusted odds ratios (AORs) derived from multi-variable logistic regression models. RESULTS: Of 158 904 adults who had been listed for, and/or received, liver transplantation during the study period, only 117 (0.07%) had MTX-LD. Compared with individuals with ALD and PSC, those with MTX-LD were more likely to be older (AORs per 5-year increase: 1.27, P < 0.001 and 1.33, P < 0.001 respectively); female (AORs: 1.78, P = 0.003 and 3.87, P < 0.001); Caucasian (AORs: 3.03, P = 0.001 and 2.05, P = 0.04); and diabetic (AORs: 2.76, P < 0.001 and 4.12, P < 0.001). With the exception of Caucasian ethnicity (AOR: 1.94, P = 0.05), the odds of these characteristics did not differ from individuals with NASH. The odds of elevated body mass index among MTX-LD individuals were higher than those with PSC (AOR per 5 kg/m(2) : 1.51, P < 0.001); similar to those with ALD (AOR per 5 kg/m(2) :1.15, P = 0.1); and lower than those with NASH (AOR per 5 kg/m(2) : 0.66, P < 0.001). CONCLUSIONS: The United States population burden of end-stage methotrexate-related liver disease is likely to be exceedingly small, suggesting the need for reappraisal of current hepatotoxicity surveillance guidelines. The risk factor profile of methotrexate-related liver disease supports the notion that it may share a common pathogenesis with NASH.

A low calorie morning meal prevents the decline of hepatic glycogen stores: a pilot in vivo (13)C magnetic resonance study.

Previous studies have reported a meal-induced rise in hepatic glycogen stores from baseline levels following a fast and it is generally assumed that glycogen levels rise steadily following meals throughout the day. However, measurements are normally taken in conditions that are not typical of the Western breakfast, which is relatively carbohydrate rich with a lower calorific content than most experimental test meals. As such, little is known about the normal metabolic response to a realistic, low calorie morning meal. Therefore, the aim of this pilot study was to evaluate the effects of a low dose oral glucose intake on hepatic glycogen levels following an overnight fast in healthy subjects. Glycogen levels were monitored in vivo using (13)C Magnetic Resonance Spectroscopy at baseline and hourly for 4 hours following either a 50 g glucose drink (773 kJ) or a control drink (0 kJ) given over two different visits. During the control visit hepatic glycogen levels decreased throughout the experiment with statistically significant decreases from baseline at 190 minutes (P < 0.05) and 250 minutes (P < 0.05). By contrast, the low dose glucose intake maintained glycogen concentrations with no significant decrease from baseline over 4 hours. A comparison between visits revealed that mean glycogen concentrations were significantly greater during the glucose visit (control visit, AUC = 218 ± 39 mol L(-1) min(-1); glucose visit, AUC = 305 ± 49 mol L(-1) min(-1); P < 0.05). Liver volume decreased significantly from baseline at 180 minutes (P < 0.05) post consumption in both groups, with no significant difference found between visits. Gastric content volumes were significantly higher for the glucose visit immediately following consumption (P < 0.001) and at 60 minutes (P = 0.007) indicating slower gastric emptying for the glucose compared with the control. In conclusion, following an overnight fast, a low dose oral glucose challenge prevents a reduction in hepatic glycogen content but does not increase it above fasted levels.

Regional anthropometric measures associated with the severity of liver injury in patients with non-alcoholic fatty liver disease.

BACKGROUND: Not all NAFLD patients are obese and many obese patients do not have NAFLD. Impaired peripheral fat storage may increase the delivery of lipids to the liver and facilitate NAFLD progression. AIM: To assess the association of anthropometric measures of regional adiposity including arm fat index (AFI) (upper body fat), waist circumference (visceral fat) and body mass index (total body fat) on liver injury and fibrosis in NAFLD. METHODS: One hundred and forty-one patients with histological evidence of NAFLD were included in this study. Multivariate logistic regression models examined the contribution of age, sex, body mass index, AFI, triceps fold thickness (TST), waist and hip circumference to the odds of liver injury (NAS scores ≥3) and fibrosis (fibrosis scores ≥2) by liver biopsy. RESULTS: Arm fat index (OR: 0.82, 95% CI: 0.59-0.91) and TST (OR: 0.13, 95% CI: 0.04-0.42) were negatively correlated with NAFLD histological severity. In women, waist circumference was positively correlated with NAFLD severity (OR: 1.21(1.02-1.44). Age (OR: 1.05, 95% CI: 1.01-1.0) and waist circumference (OR: 1.07, 95% CI: 1.00-1.15) were significantly associated with fibrosis risk. In women, AFI (OR: 0.87, 95% CI: 0.76-0.99) and TST (OR: 0.22, 95% CI: 0.05-0.95) were negatively associated with fibrosis risk. CONCLUSIONS: Regional anthropometric measures are associated with severity of NAFLD in a sex-specific manner. Men and women with lower arm fat depots and women with bigger waist circumference have a greater likelihood of liver injury. Age and waist circumference seem to be associated with liver fibrosis. Simple anthropometric measurements of peripheral fat deposits may help stratify significant liver injury risk.

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.

Development and evaluation of a nurse-led transient elastography service for the staging of hepatic fibrosis in patients with suspected chronic liver disease.

BACKGROUND AND AIMS: Establishing the presence of fibrosis and cirrhosis is an essential step in the management of patients with chronic liver diseases (CLD). Liver stiffness measurement (LSM) based on transient elastography (TE) correlates well with the stages of liver fibrosis and has been developed as a non-invasive alternative to liver biopsy. The studies performed to date have used physician operators. With the potential use of TE for screening of community-based populations for liver disease, we aimed to evaluate the performance of nurse operators. DESIGN: Retrospective analysis. METHODS: We reviewed the reliability and accuracy of LSMs performed by the nurse-led TE service at Queen's Medical Centre, Nottingham between May 2009 and January 2011. Consecutive patients with suspected CLD who underwent LSM were included. RESULTS: Over the study period 585 LSMs were performed. Analysis was performed on the 208 patients where LSM could be compared with liver biopsy findings. Of these 11 (5.3%) had unreliable LSM results (less than 10 valid shots or success rate <60%). There were no LSM failures. Inadequate liver biopsy specimen led to exclusion in 26 (12.5%) patients. For the detection of significant fibrosis (Ishak stage >2), a sensitivity of 0.78 and specificity of 0.81 was obtained, with a cut-off value of 8 kPa. Using a cut-off value of 13 kPa for detection of cirrhosis, a sensitivity and specificity of 0.8 and 0.92 was obtained. CONCLUSION: We have demonstrated that a nurse-led TE service can produce a low level of unreliable results and LSM failures, with comparable sensitivity and specificity for detecting significant fibrosis and cirrhosis to those reported in the literature. The demands on the use of TE could potentially be eased through the introduction of nurse-led service delivery.

Abnormal liver tests in people aged 75 and above: prevalence and association with mortality.

BACKGROUND: Despite their common use the occurrence and consequences of abnormal liver tests remain unclear. AIMS: To estimate the prevalence and mortality associated with abnormal liver tests in people aged 75 years and above. METHODS: A cohort study on 13,276 people aged 75 years and above, registered with general practices, with a valid measurement of one or more liver test, calculating the prevalence of abnormal aspartate transaminase (AST), alkaline phosphatase (ALP) or bilirubin. Hazard ratios (HRs) were calculated for all-cause and cause-specific mortality comparing elderly patients with abnormal liver tests to elderly patients with normal liver tests. RESULTS: At least one abnormal liver test was found in 2175 subjects (16.1%, 95% CI [15.4%, 16.7%]). The prevalence of a single abnormal liver test was 3.3% (95% CI [3.0%, 3.7%]) for AST, 9.2% (95% CI [8.8%, 9.7%]) for ALP and 5.4% (95% CI [5.1%, 5.9%]) for bilirubin. Abnormal AST, ALP and bilirubin were associated with increased risks of all-cause mortality; adjusted HRs, 1.27(95% CI [1.09, 1.47]), 1.47(95% CI [1.35, 1.61]) and 1.15(95% CI [1.02, 1.30]), respectively. Abnormal AST and ALP were associated with sevenfold and sixfold increased risk of death from liver disease, respectively. Two or more abnormal liver tests were associated with 2-fold and 17-fold increased risk of death from cancer and liver disease, respectively. Of the causes examined, absolute mortality rates were highest for cardiovascular disease in subjects with and without abnormal liver tests. CONCLUSIONS: Abnormal liver tests occur commonly in elderly people and are associated with a modest increase in all-cause mortality. There was a strong association with liver disease; however, the majority of deaths were not due to this cause.