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Learning Point for Clinicians Renal amyloid is a rare complication of Crohn’s disease (CD). Increased mortality is associated with increased serum amyloid A (SAA) protein concentration and reducing SAA improves survival. Anti-TNF-α may treat both renal amyloid and CD. NSAID use may precipitate a CD flare. Collagenous colitis is associated with CD and amyloidosis. A 35-year-old butcher was admitted from the renal outpatient clinic for investigation and management of worsening peripheral oedema. He gave a past history of Crohn’s disease (CD). This had been asymptomatic for many months and so the patient had weaned himself of immunosuppression (azathioprine) 4 months earlier. On admission, serum albumin was

Primary porcine hepatocytes (PPHs) are used in most bioartificial liver devices (BALs). Liver-specific function, however, deteriorates in these cells in culture. In this study, the PPH biotransformation profile was analyzed over a 6-day culture period, in four separate serum-free media formulations using total cytochrome P450 (P450) content as a marker of differentiation. The general health of the cells in culture was evaluated by analysis of cell morphology, total protein (TP) content, and viability. The total P450 content of bovine adrenocortical cells (BACs) was also evaluated for comparison with hepatocytes. Freshly isolated hepatocyte P450 levels were 120 ± 34 pmol/mg TP, which decreased rapidly in the first 2 days in culture in all media before maintaining P450 levels at between 17 and 28 pmol/mg TP (14%–23% of fresh cell values) at day 6 in culture. Williams' E Medium showed a significantly lower P450 level (25 ± 3 pmol/mg TP) than Hepatocyte Medium (35 ± 3 pmol/mg TP; P = 0.043) on day 4. Williams' E Medium also showed a significantly lower P450 level (17 ± 1 pmol/mg TP) on day 6 than Medium 199 (25 ± 1 pmol/mg TP; P = 0.026) and RPMI-1640 (27 ± 5 pmol/mg TP; P = 0.033). BAC P450 levels decreased to a similar but greater extent to PPHs, decreasing from a fresh cell level of 429 pmol/mg TP to 58 pmol/mg TP (13% fresh cell value) after 6 days in culture. PPHs and BACs show a similar pattern of total P450 decrease in culture. However, Williams' E Medium maintains lower P450 biotransformation potential compared to the other test media studied and is therefore not recommended for use in a BAL.

Summary Background Transnasal endoscopy (TNE) with ultrathin endoscopes has been advocated as an attractive alternative, for diagnostic upper endoscopy. Aim To assess tolerability, acceptability and quality of TNE, in comparison with standard upper endoscopy (SOGD, standard oesophago-gastro-duodenoscopy) under local anaesthetic. Methods We prospectively recruited 157 patients (83 females/74 males) mean age 57 years. The Fujinon EG530N (5.9 mm) and EG530WR (9.4 mm) endoscopes were used. The endoscopist and all patients completed detailed questionnaires regarding tolerability, acceptance and quality of endoscopy using standard visual analogue scales (VAS). Oxygen saturation (SaO2), heart rate (HR) and systolic blood pressure (SBP) were recorded. Quality of biopsies was evaluated. Results Analysis included 161 procedures (TNE:79, SOGD:82) with duodenal intubation achieved in all patients. VAS scores for patient comfort were significantly better in the TNE group (7.3 vs. 5.3 respectively, P

Brain dysfunction is common in patients with advanced liver disease; it is often manifested as hepatic encephalopathy, but its cause is not clearly understood.Intracranial blood flow velocity parameters, including peak systolic velocity, end diastolic velocity and mean velocity of both middle cerebral arteries were measured by transcranial Doppler ultrasonography in 37 patients with cirrhosis without encephalopathy (16 Child's A, 10 Child's B and 11 Child's C) and 12 normal controls. The cause was alcohol-related in 24 and non-alcohol-related in 13.No significant differences in any of the Doppler parameters were detected in Child's group A when compared with controls. However, a statistically significant decrease in middle cerebral artery blood flow velocity was evident when Child's B and C patients without clinically apparent encephalopathy were compared with controls irrespective of the cause. Our results demonstrate that intracranial blood flow is abnormal in patients with advanced liver disease without clinically apparent encephalopathy.

Gall stone disease is a common cause of morbidity and cholecystectomy represents the most common elective abdominal operation in Western society. In the United Kingdom alone about 20% of the population may expect to develop cholelithiasis.' Initially most research had been focused on the biochemical changes that occur in bile during gall stone formation. Recent years have seen significant advances in our knowledge and it is now recognised that the gall bladder is not a passive reservoir but has several absorptive, secretory, and motor functions, which are integrated to produce concentrated bile. The interactions between gall bladder bile and mucosa are of paramount importance to maintain the fine balance between concentration and precipitation of the biliary constituents. The gall bladder mucosa has one of the highest rates of water absorption in the body and an 80-90% decrease in the initial volume of bile occurs within the gall bladder. This is achieved by the coupling of active sodium transport and passive water absorption resulting in isotonic fluid absorption.2 Fluid transport is subject to a variety of influences such as chronic inflammation or the presence of pharmacological agents (prostaglandins, prostacyclin, and various gastrointestinal peptides); fluid absorption is higher in daytime and is reversed to net secretion with feeding.3 Electrolyte transport has been extensively investigated; chloride is actively absorbed in exchange for bicarbonate, and potassium moves from the mucosa to the serosa according to electrochemical gradients.4 5 Calcium is also absorbed and its distribution across the gall bladder epithelium is of importance in the formation of gall stones.6

Introduction Double balloon endoscopy (DBE) has been reported to have a high diagnostic yield in obscure overt gastrointestinal bleeding (OGB). There is paucity of studies of DBE for the indication of iron deficiency anaemia (IDA) alone particularly in the young. We investigated the utility of DBE in patients referred with IDA according to age. Methods All consecutive patients undergoing DBE for IDA and OGB, between June 2006 and January 2016, across 3 teaching hospitals in the UK and Italy were included in the study. Demographic and clinical data were collected and patients were categorised by age (≥55 and Results 213 patients underwent DBE for IDA. 142 (66.7%) were age ≥ 55 years (mean age 69.6±8.6, 49.3% male) and 71 (33.3%) age Further comparisons between young patients aged Conclusion We present the first multicentre study evidencing the safety and high diagnostic yield of DBE in patients with IDA. Although the diagnostic yield is lower in the young, significant pathology is detected including tumours and ulceration, supporting the role of DBE in young patients with IDA. Disclosure of Interest None Declared

Introduction Recent data imply young pts (≤50 yrs) investigated with capsule endoscopy(CE) for iron deficiency anaemia(IDA) show higher diagnostic yield(DY) for sinister findings. We aim to investigate DY of CE in a large cohort of young IDA pts and factors associated with sinister pathology. Methods Retrospective multicentre study (2010–2015); consecutive pts ≤ 50 yrs undergoing CE for IDA at 19 centres in 12 countries. Exclusion criteria: ongoing/previous gastrointestinal(GI) bleeding; age > 50 or Results 389 pts (262 F/127 M; mean age 39.4±9.3 yrs) were recruited. 169 pts (43.4%) were excluded from further analysis because clinically relevant data were not available; 220 pts were included in final analysis. They were grouped according to final diagnosis: neoplastic pathology (11/220; 5.0%); non-neoplastic but clinically significant findings (60/220; 27.3%); normal/minimal findings (149/220; 67.7%). The most common non-neoplastic findings were angiodysplasias(22/60) and Crohn’s disease(15/60). On multivariate analysis, MCV was associated with occurrence of neoplasia (OR: 0.96; 95%CI:0.93-0.99; p = 0.033), i.e. the odds of SB neoplasia increased 4% for every unit of decrease in MCV. Weak evidence existed for the association between use of antiplatelet drugs and risk of SB neoplasms (OR: 5.83; 95%CI: 1.0–34.0; p = 0.05). Conclusion In IDA patients ≤50 years, overall DY of SBCE for significant findings is 32.3%. Around 5% are diagnosed with SB malignancy. In this cohort, lower MCV or antiplatelet use have been associated with higher DY for SB neoplasia or clinically significant findings on CE. References 1 Koulaouzidis A, et al. The use of small-bowel capsule endoscopy in iron-deficiency anaemia alone; be aware of the young anaemic patient. Scand J Gastroenterol 2012;47:1094–100. 2 Sidhu PS, et al. The utility of capsule endoscopy in patients under 50 years of age with recurrent iron deficiency anaemia: Is the juice worth the squeeze? Gastroenterol Res Prac 2015:948574. Disclosure of Interest E. Rondonotti: None Declared, D. Yung Grant/research support from: Dr Falk/ Core F1/F2 Award 2015, A. Giannakou: None Declared, B. Rosa: None Declared, E. Toth: None Declared, A. Lucendo: None Declared, R. Sidhu: None Declared, H. Beaumont: None Declared, P. Ellul: None Declared, L. Negreanu: None Declared, V. Jimenez-Garcia: None Declared, J. Plevris: None Declared, A. Koulaouzidis: None Declared

Introduction SmartPill® (Given Imaging Corp., Yoqneam, Israel) is an ingestible, wireless, non-imaging capsule device that records physiological data including contractions, pH and temperature throughout the gastrointestinal (GI) tract. 1 There are currently scarce data looking at SmartPill® assessment of patients with known or suspected small-bowel Crohn’s Disease(CD). 2 We designed this pilot study to investigate feasibility and safety of SmartPill® assessment of gut motility in this group (local ethics committee approval ref.12/SS/0013). Methods Over one year (2012), patients with known or suspected CD, referred for small-bowel capsule endoscopy (SBCE), were invited to participate. Patients underwent hydrogen breath test to exclude small-bowel bacterial overgrowth, patency capsule (Agile®) to confirm luminal patency and provided stool samples for faecal calprotectin (FC). Patients ingested PillCam®SB2, then SmartPill®4 h afterwards. Thirty-three healthy controls were obtained from unpublished data. For statistical analysis, P Results Over the aforementioned period, 12 patients were recruited (7 F/5 M, mean age 44.2 ±16.6 years). 10 underwent complete SmartPill® examination (1 stomach retention, 1 dropout). Pillcam®SB2 was complete in 10 (1 stomach retention, 1 dropout). Mean FC was 340 ±307.7 μg/g. The study group had longer transit times and lower gut motility index (MI) compared to controls, where MI = Ln (sum of pressure amplitudes × number of contractions + 1). The difference in motility appears statistically significant (P Conclusion This study is the first pilot to attempt combining SBCE and SmartPill® in clinical assessment of small-bowel CD. Current data on motility in CD is scarce. Multimodal information could provide a clearer clinical picture. 3–5 Furthermore, despite concerns about capsule retention in CD patients, our study suggests SmartPill® appears safe for use if a patency capsule is employed beforehand. References 1 Tran K, Brun R, Kuo B. Evaluation of regional and whole gut motility using the wireless motility capsule: relevance in clinical practice. Therap Adv Gastroenterol 2012; 5 :249–260. 2 Rao SSC, Camilleri M, Haler WL, et al . Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies. Neurogastroenterol Motil 2011; 23 :8–23. 3 Koulaouzidis A, Iakovidis DK, Karargyris A, et al . Wireless endoscopy in 2020: Will it still be a capsule? World J Gastroenterol 2015; 21 :5119–30. 4 Dignass A, Van Assche G, Lindsay JO, Lemann M, Soderholm J, et al . The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management. J Crohns Colitis 2010; 4 :28–62. 5 Fireman Z, Mahajna E, Broide E, Shapiro M, Fich L, et al . Diagnosing small bowel Crohn’s disease with wireless capsule endoscopy. Gut 2003; 52 :390–92. Disclosure of Interest D. Yung: None Declared, J. Plevris: None Declared, A. Koulaouzidis Grant/research support from: ESGE- Given®Imaging Research grant 2011

Introduction Collagenous colitis (CC) is a syndrome of chronic, watery, non-bloody diarrhoea.1 Its worldwide incidence is increasing; emerging evidence suggests a possible association between CC and malignancy.2 However, studies thus far have been inconclusive and data on the incidence of metachronous extra-colonic malignancy (MEcM) in CC is scarce.3 This study aimed to determine the occurrence of MEcM in patients with CC. Methods Retrospective study; data on MEcM in patients previously diagnosed with CC was collected within NHS Lothian (Scotland) over a 14 year period (Jan 2000 – Nov 2013). Person-years at risk were calculated according to age-specific categories. The standard error (Se) was calculated using the Poisson approximation. Relative risk (RR) and confidence interval (CI) of the age-standardised rate (ASR) were compared to publicly available population data for Lothian, Scotland.4 Results are reported as average ± standard deviation or RR with confidence interval (CI). P values Results In the aforementioned period, 394 patients were diagnosed with CC and included for analysis. Thirty-three (21 F/12 M) developed MEcM, Table 1. The average age of the group with MEcM was 71.6 ±7.4 years compared to 65.9 ±13.6 years for the remainder of the patients (P Conclusion The RR of MEcM, including lung cancer, is higher in patients with CC.The increased RR for lung cancer may be explained by the association between CC and smoking.5 Further collective data will be useful to clarify other associations. References 1 Munch A, et al. Microscopic colitis: current status, present and future challenges: statements of the European Microscopic Colitis Group. J Crohn’s Colitis 2012;6:932–945. 2 Freeman HJ. Complications of collagenous colitis. World J gastroenterol 2008;14:1643. 3 Chan JL, et al. Cancer risk in collagenous colitis. Inflamm Bowel Dis 1999;5:40–43. 4 http://www.ncin.org.uk/cancer_information_tools/eatlas/guide 5 Vigren L, et al. Is smoking a risk factor for collagenous colitis? Scand J Gastroenterol 2011;46:1334–1339. Disclosure of Interest None Declared

Introduction Cancer of the small-bowel (SB) is rare accounting for Methods Retrospective study; the records of all patients who underwent SBCE at our centre from Mar 2005 – Oct 2015 were reviewed; we retrieved those whose CEs were reported as suggestive of neoplasia. Further data was gathered on preceding and subsequent investigations, management and outcome of these patients. Results From a total of 1949 CE studies (1082 PillCamTM/867 MiroCamTM), SB neoplasia was diagnosed in 7 patients (0.36%; 2 F/5 M; median age 50, range 34–67). Two had lymphoma, 2 gastrointestinal stromal tumours (GIST), 2 duodenal adenocarcinomas, 1 jejunal metastasis from a sarcomatoid lung tumour. In these patients, CE was performed for: iron-deficiency anaemia (IDA) (n = 5), diarrhoea (n = 1) & suspicion of SB lymphoma (n = 1). 6/7 patients had prior negative bidirectional GI endoscopies; 1 had a normal gastroscopy. Prior to CE, two patients had abdominal USS, 4 had CT scan, 2 had SB follow-through and 1 had a bone marrow aspirate. Two patients had capsule retention; one was removed with a gastroscope, the other with push enteroscopy. All 7 patients had further investigations after CE. Six had a chest, abdomen & pelvis CT scan for staging. Two patients had push enteroscopy, both of whom were diagnosed with duodenal adenocarcinoma. One had double balloon enteroscopy (DBE), two had colonoscopy, two had UGIE; there was one abdominal USS and one bone marrow aspirate. Four pts underwent SB resection. Following resection, 1 patient with GIST had imatinib chemotherapy. Of the two individuals with duodenal adenocarcinoma, one underwent gastroenterostomy and the other had an elective Whipple procedure. Four patients passed away. Two remain under follow up with oncology and one with the GI team. Conclusion SB cancers are rare and our experience is in agreement with other studies. The median age of 50 indicates that SB malignancy is more common in relatively younger patients. Unexplained iron deficiency anaemia was the main presenting complaint in our patients which triggered further investigation despite negative bidirectional endoscopies. CE is effective in picking up SB neoplasia where other imaging modalities have failed. References 1 Schottenfeld D, Beebe-Dimmer JL, Vigneau FD. The epidemiology and pathogenesis of neoplasia in the small intestine. Ann Epidemiol 2009;19:58–69. 2 Pennazio M, Rondonotti E, de Franchis R. Capsule endoscopy in neoplastic diseases. World J Gastroenterol 2008;14:5245–53. 3 Pennazio M, Spada C, Eliakim R, et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy 2015;47:352–86. 4 Rondonotti E, Pennazio M, Toth E, et al. Small-bowel neoplasms in patients undergoing video capsule endoscopy: a multicenter European study. Endoscopy 2008;40:488–95. Disclosure of Interest C. Johnston: None Declared, D. Yung: None Declared, A. Koulaouzidis Grant/research support from: ESGE- Given®Imaging Research grant 2011, J. Plevris: None Declared

Gall bladder epithelial cells serve numerous biological functions and abnormalities in their function are important in the pathogenesis of several gall bladder diseases. Direct studies on cell function are rare due to lack of reliable methods to culture this epithelium. This study reports a reliable and reproducible method of harvesting and culturing gall bladder epithelial cells. Normal bovine gall bladder epithelium, obtained within 20 minutes of slaughter, was rinsed with modified Hanks's balanced salt solution, the mucosa separated and incubated in trypsin--EDTA solution at 37 degrees C. The cells were isolated and resuspended in Dulbeco's modification of Eagles' medium containing 10% fetal calf serum and, after filtration and centrifugation, were plated under aseptic conditions. The growth rate was established by flow cytometry and the morphological characteristics of the growing cells by electron microscopy. Gall bladder epithelial cells grew successfully and visible clusters of cells were present by day two, confluency being reached at 8 to 10 days in collagen coated plates and 12 to 14 days in uncoated plates. Electron microscopy showed typical gall bladder epithelia with microvilli, tight junctions, and mucus droplets. This method proved reliable and reproducible for the culture of gall bladder epithelial cells and should allow direct studies of the biological properties of these cells in human tissue.

Non-alcoholic fatty liver disease affects 10-35% of the adult population worldwide; there is no consensus on its treatment. Omega-3 fatty acids have proven benefits for hyperlipidaemia and cardiovascular disease, and have recently been suggested as a treatment for non-alcoholic fatty liver disease.To review the evidence base for omega-3 fatty acids in non-alcoholic fatty liver disease and critically appraise the literature relating to human trials.A Medline and PubMed search was performed to identify relevant literature using search terms 'omega-3', 'N-3 PUFA', 'eicosapentaenoic acid', 'docosahexaenoic acid', 'non-alcoholic fatty liver disease' and 'NAFLD'.Omega-3 fatty acids are important regulators of hepatic gene transcription. Animal studies demonstrate that they reduce hepatic steatosis, improve insulin sensitivity and reduce markers of inflammation. Clinical trials in human subjects generally confirm these findings, but have significant design inadequacies.Omega-3 fatty acids are a promising treatment for non-alcoholic fatty liver disease which require to be tested in randomized placebo-controlled trials.

Introduction Portal hypertensive enteropathy (PHE) remains difficult to diagnose in patients with cirrhosis and portal hypertension. Limited test choices exist for the inspection of the small bowel in these patients. Small bowel capsule endoscopy (SBCE) would be ideal in this situation but it is rarely performed. 1–3 Aim We aimed to determine the prevalence of PHE using SBCE in a cirrhotic patient population from our centre. Methods This was a retrospective study using the SBCE data base of our unit. We searched through 1,477 patients that had SBCE between 2005 and 2013. Patients with cirrhosis who underwent SBCE were identified, data retrieved and abstracted. The Fischer’s exact or the chi-square tests were used to compare between groups. A two-tailed P value of Results We identified 53 patients with cirrhosis who underwent SCBE. We used PillCam ® SB (Given ® Imaging Ltd, Israel) system on 36 patients and the MiroCam ® capsule (IntroMedic Co, Korea) on 17 patients. Thirty patients were referred for iron deficiency anaemia, 15 for obscure gastrointestinal bleeding, and 4 for other indications. Four data sets were not available for review at the time of the study, leaving 49 patients to be reviewed. Mean age was 61.19 ± 14.54 years (M/F=27/22). Table 1 shows the aetiologies of liver disease in these patients. Six SBCE examinations were incomplete. Thirty three patients had evidence of portal hypertensive gastropathy (PHG) and 17 patients had evidence of oesophageal varices. In total, 29 patients had SCBE evidence of PHE (67%). 28/29 (96.5%) of patients with PHE had also evidence of PHG. 13/17 (76.4%) patients with oesophageal varices had also evidence of PHE. Our mean follow up was 58.0 ± 13.7 months. Twenty patients died during the follow up period. There was no correlation between the presence of PHE and aetiology of liver disease (P = 0 .4261) or subsequent death (P= 0.2145). Conclusion The prevalence of PHE in our study was 67%. SBCE is a useful tool in evaluating PHE in cirrhotic patients irrespective of aetiology. References Rondonotti E, et al . Capsule endoscopy in portal hypertension. Clin Liver Dis 2010;14:209–20. Krystallis C, et al . Update of endoscopy in liver disease: more than just treating varices. World J Gastroenterol 2012;18:401–11 Sidhu R, et al . Does small bowel capsule endoscopy alter management in patients with liver disease? Scand J Gastroenterol 2011;46:123–4 Disclosure of Interest None Declared.

Introduction Biodegradable oesophageal stents have been developed recently and the experience in their use and available literature in limited. Their usefulness has been demonstrated in refractory benign strictures in a handful of studies and their role in malignant strictures is relatively untested. We looked at our practice and the clinical outcomes in the use of these stents. Methods This is a retrospective observational study looking at electronic case record and endoscopy reports. All patients who had biodegradable stents inserted between March 2011 and September 2013 were included for analysis. Twenty-three stents were inserted in 16 patients. 5 of these patients had 2 stents and one patient had 3 stents over the period of time. Thirteen stents were inserted for benign disease and eight for malignant strictures. There were 9 males and 7 females with age range being between 47 yrs and 101 yrs 2 stents were inserted in 1 patient with postoperative tracheo-oesophageal fistula. Results In the benign group, an average of 10.5 endoscopies (0.95/month/patient) and 7.2 dilatations (0.65/month/patient) were necessary prior to stent insertion per patient. Post insertion there was a reduction to 3.5 endoscopies (0.03/month/patient) and 2 dilatations (0.016/month/patient). When the average number of dilatations was analysed pre and post stent insertions per patient per month, there was a significant reduction with a P value of 0.009 on the paired T test. In the benign group, on an average 7 endoscopies and 5 dilatations were avoided/patient. Interval between dilatations increased from 5.2 to 25 weeks. In the malignant group, all patients were successfully bridged to chemo/radiotherapy. 2 out 6 patients went on to metal stents after 3 and 5 months due to disease progression. The stent insertion was technically successful in all cases following a dilatation of the stricture to 12mm at the time of insertion. Four patients complained of some pain post stent insertion (3 in the malignant group and 1 in the benign group). One patient developed sepsis post procedure but recovered well with a course of antibiotics. No other complications were noted. In all cases where a check up endoscopy was done, the stent had disintegrated within 8–12 weeks. Conclusion BD stents are of value in recurrent benign oesophageal strictures as they reduced the number and frequency of dilatations. The BD stents successfully bridge patients with malignant strictures to oncological therapies. Insertion of a BD stent does not preclude a later insertion of a permanent metal stent. Stent insertion was technically successful and safe. Disclosure of Interest None Declared.

Retinol and other vitamin A derivatives affect the differentiation and growth of many tissues and have anti-tumour properties.To investigate serum retinol levels in patients with liver disease and hepatocellular carcinoma (HCC) and to assess its importance as a risk factor for the development of HCC.Serum retinol levels were measured in healthy volunteers and 175 patients (34 with chronic hepatitis C, 117 with cirrhosis, and 24 with HCC.The serum retinol levels (mean +/- s.e.) in ng/mL, were 972.1 +/- 37.7 in the control group and 647 +/- 41.1 in patients with chronic hepatitis C. Serum retinol levels in patients with cirrhosis and HCC were lower than in patients with cirrhosis alone (365.8 +/- 43.1 vs. 438.9 +/- 22.1, P0.04). In particular, there was a more significant difference in serum retinol levels between Child-Pugh grade A patients with cirrhosis and Child-Pugh grade A patients with cirrhosis/HCC (serum retinol levels 532.4 +/- 26.7 vs. 366.1 +/- 86.4, P0.03). There was a significant difference in serum retinol levels between normal controls and all patients' groups (P0.001). There were significantly lower serum retinol levels in cholestatic Child-Pugh grade A patients with cirrhosis compared with noncholestatic Child-Pugh grade A patients with cirrhosis/HCC (411.5 +/- 30.3 vs. 579.7 +/- 32.7, P0.0004). Sixty percent of patients with Child-Pugh grade A cirrhosis/HCC had serum retinol levels below 350 ng/mL compared with only 18.4% of cirrhotics without HCC (chi 2-test, P=0.01). No correlation was found between serum retinol levels and alpha FP or any other liver function tests, apart from serum albumin, which showed a positive correlation (r=0.61 P0.018).There was a progressive reduction in serum retinol levels from controls to patients with liver cirrhosis. Those patients with cirrhosis and HCC had significantly lower values than patients with cirrhosis alone. Serum retinol levels may be a risk factor for the development of HCC.

Indocyanine green (ICG) clearance is a useful indicator of hepatic function but most measurement methods are invasive.To validate a less invasive technique using cerebral near infrared spectrophotometry (NIRS) to measure ICG elimination, and to compare it with the established methods for the determination of ICG clearance in a group of normal controls and patients with cirrhosis.NIRS was used to measure ICG elimination in 41 cirrhotic patients and nine healthy volunteers. The first 13 of the cirrhotic patients also had their ICG clearance measured by the conventional spectrophotometric technique.NIRS ICG elimination rate (ICG-k) and spectrophotometry ICG-k values correlated strongly (r= 0. 828, P0.001, n=13). There was a significant reduction in the mean NIRS-k in cirrhotic patients and within Child-Pugh classes A, B, and C (P0.001).Measurement of ICG elimination by the NIRS method is at least as reliable as the conventional spectrophotometric technique in normals and in patients with cirrhosis. This technique merits further development for use as a bedside, less invasive liver function test.

We report the case of a young female with PSC-associated cirrhosis and chronic renal failure who developed clinical and electrocardiographic signs consistent with acute myocardial infarction after a combined kidney and liver transplant. Cardiac investigations at that time were negative and she is currently asymptomatic one year post-transplant with resolution of most of her ECG abnormalities. Although the cause of her symptoms and ECG abnormalities is not immediately apparent, this case illustrates the difficulties in interpreting abnormal cardiac investigations in transplanted patients with liver cirrhosis who may have a background of subclinical cardiac disease.

Acute liver failure (ALF) is a relatively uncommon but dramatic clinical syndrome with high mortality rates, in which a previously normal liver fails within days or weeks. Paracetamol overdose remains the major cause of ALF in the UK, while viral hepatitis is the commonest cause world-wide. Cerebral oedema is the leading cause of death in patients with ALF. Despite advances in intensive care and the development of new treatment modalities, ALF remains a condition of high mortality best managed in specialist centres. Orthotopic liver transplantation is the only new treatment modality that has made a significant impact in improving outcome. Bioartificial liver support systems and hepatocyte transplantation are new promising treatment options that may change the management of ALF in the future.

Acute cellular rejection is common after orthotopic liver transplantation and an important cause of graft dysfunction. Eosinophils, potent mediators of tissue damage, have been implicated in the pathogenesis of acute rejection. We studied 55 patients, all of whom had a protocol biopsy 7 days after transplantation and whose peripheral eosinophil count was monitored daily for 11 days after transplantation. Patients were divided clinicopathologically into two groups: group A, without rejection, group B, with rejection. Group B (36% of patients) developed rejection within the 11-day study period. The pretransplant eosinophil count was significantly higher in group B, compared with group A (0.31 +/- 0.08 v 0.10 +/- 0.01 (x10(9)/L), p.001). After transplantation, the eosinophil count fell to low levels in both groups. By day 3 there was a statistically significant rise in the eosinophil count in group B compared with group A, with a maximum at day 7 [0.51 +/- 0.06 v 0.26 +/- 0.03 (x10(9)/L) p.001]. After treatment with steroids, the eosinophil count dropped to values similar to those in group A and remained low thereafter in 16 of 20 patients. Four patients had a second episode of rejection; in each of these, eosinophils were raised again and decreased with resolution of the rejection. An eosinophil count threshold of 0.13 (x10(9)/L) before transplantation and 0.33 (x10(9)/L) on day 7 after transplantation predicted the development of rejection (sensitivity 72/70%, specificity 66/63%, negative predictive value 82/79%). We conclude that a raised eosinophil count is associated with acute rejection. The raised eosinophil count before transplantation in group B suggests that these patients are predisposed to acute rejection, and earlier intervention may be indicated.

Introduction A great proportion of haemophiliacs are considered at risk of being co-infected with hepatitis C (HCV) and variant Creutzfeldt-Jakob Disease (vCJD). 1 Chronic hepatitis C leads to liver cirrhosis, which in turn causes portal hypertension and varices. 2 Alternative endoscopic modalities have been developed for the investigation of the upper gastrointestinal (GI) tract, such as oesophageal capsule endoscopy (OCE). However, OCE is widely accepted and its indications are still under evaluation. 3 Our aim was to evaluate the use of OCE in a tertiary referral centre for GI problems in Lothian, Southeast Scotland, giving a special focus on OCE in haemophiliacs. Methods A retrospective review of the OCE database from May 2005 to March 2012. Electronic case notes and OCE reports were reviewed. Demographics and clinical background, in particular haemophilia, hepatitis C, HIV and cirrhosis, reason for referral and OCE findings were abstracted. Results A total of 65 OCEs (50 patients; 27 M/23 F; mean age: 52.7 ± 13.7 years) were carried out in the aforementioned period. 32% pts had haemophilia (16/50 patients/all male; mean age: 51.6 ± 9.8 years; range 31–78 years; 28 OCEs); 5 pts had repeat OCEs (1 pt: 1 repeat, 2 pts: 2 repeat, 1 pt: 3 repeat & 1 patient: 4 repeat OCEs). All haemophiliacs were infected with HCV; 2 pts were co-infected with HIV. 3/16 (18.75%) of haemophiliacs had established cirrhosis, 5/16 (31.25%) probable cirrhosis. In haemophiliacs, indications for OCE were: variceal surveillance (OCEs group A: 17/28; 60.7%) and/or other upper GI symptoms (OCEs group B: 11/28; 39.3%). PillCam®ESO1 was used in 15/28 (53.6%) occasions and PillCam®ESO2 for the rest (13/28; 46.4%). The overall diagnostic yield (DY) of OCE in haemophiliacs was 78% (21/28). The DY was similar in OCEs group A: 64.7% (findings in 11/17) and OCEs group B: 54.5% (findings in 6/11 ), P = 1.0. Oesophageal transit times were mean: 166s; range: 3–1171s. All capsules reached the stomach, but only 8/28 (28.5%) capsules entered the duodenum. Conclusion OCE is a useful and acceptable alternative to conventional endoscopy in selected groups of patients. In particular, OCE in haemophiliacs has a high DY and should be considered a first line investigation to guide further endoscopic intervention. Disclosure of Interest None Declared. References Meijer K, et a l. HCV-related liver cancer in people with haemophilia. Haemophilia 2012; 18:17–24 de Franchis R. Non-invasive (and minimally invasive) diagnosis of oesophageal varices. J Hepatol 2008; 49:520–7 Guturu P , et al . Capsule endoscopy with PILLCAM ESO for detecting esophageal varices: a meta-analysis. Minerva Gastroenterol Dietol 2011; 57:1–11

Introduction Oxidative stress is the central to molecular events leading to the progression of simple steatosis to steatohepatitis in nonalcoholic fatty liver disease (NAFLD). We have previously shown that an in vitro cellular steatosis model using C3A cells treated with energy substrates; lactate (L), pyruvate (P), octanoate (O) and ammonia (N), recapitulates the sequence of events in dietary-induced NAFLD; namely enhanced acute respiration and reactive oxygen species (ROS) formation leading to mitochondrial impairment. In contrast, treatment with oleate results in similar triglyceride accumulation but with relatively low ROS. Using a combined microarray, proteomic and metabolomic approach, we aimed to explore how triglyceride accumulation and enhanced ROS affect glutathione metabolism in our in vitro cell model. Methods C3A cells were treated with either LPON or oleate for 72 hours. Microarray RNA expression was measured using Illumina® Whole Human Genome BeadChip H12 Microarray. For proteomics, peptides were analysed by liquid chromatography (LC) coupled mass spectrometry (MS) (Agilent HPLC/OrbitrapXL). Data were quantified label-free using Progenesis LC-MS and MASCOT. For metabolomics, LC separation was performed using hydrophilic interaction chromatography with a ZIC–HILIC. MS was performed using Orbitrap Exactive with HESI 2 probe. Raw LC/MS data were processed with XCMS Centwave and mzMatch. Results LPON led to 2-fold downregulation of GCLC (encodes glutamate-cysteine ligase catalytic subunit, the rate limiting enzyme for glutathione synthesis) and upregulation of GPX1 and TXNDC12. Expression of GCLC and TXNDC12 was unchanged with oleate. Metabolomics confirmed that oxidised glutathione, glutathione disulfide, was higher in LPON- than oleate-treated cells. Among glutathione S -transferase genes, GSTA1 was unchanged with oleate but was upregulated by LPON (2.4-fold). Similarly, GSTT1, GSTK1 and GSTO1 were significantly increased by LPON. In contrast, MGST2 expression was higher in oleate than LPON-treated cells. Finally, proteomics showed that microsomal glutathione S -transferase 2 was downregulated by 2.5-fold by LPON. Conclusion Our data show that increased ROS formation rather than triglyceride accumulation alters glutathione metabolism. Such alterations may influence susceptibility to further insults, particularly those accelerating glutathione depletion, for example, paracetamol overdose. Disclosure of Interest None Declared

Introduction Small-bowel capsule endoscopy (SBCE) is often limited by incomplete small-bowel transit. Although there are available meta-analysis data on the use of purgatives in SBCE, there is no similar data or consensus regarding the regular use of prokinetics for capsule ingestion. Our aim was to systematically review existing literature on the use of prokinetics in SBCE. Methods Thorough and extensive, recursive search of PubMed/MEDLINE, Embase and Scopus databases for studies, published to the end of Nov 2012, was performed. No language, time or age limits were used. Abroad search strategy was employed, using the MeSH term “capsule endoscopy ” connected with the following keywords by “AND”: “ prokinetic ”, “ promotility ”, “ metoclopramide ”, “ domperidone ”, “ erythromycin ”, “ antiemetic ”, “ ondensetron ”, “ completion ”, “ gastric emptying ”, “ transit ”, “ ingestion ”, “ preparation ”, “ oral/liquid ”, “ intramuscular ” & “ retention ”. Additionally, the reference list of all the selected articles was manually checked for potentially suitable references that were not identified by the initial search. Studies were selected based on title and/or abstract. Eligible studies were included if the met all of the following criteria: (1)published as full articles of randomised control trials, (2)contained information on the type of the SBCE system used, (3)used prokinetics in (at least) one of the reported study arms/groups, (4)specified the type and dose of prokinetics used & (5)contained data on the rate of SBCE completion to caecum (CR). Data were extracted by the first author using a predifined Excel sheet. Primary end-point: the effect of prokinetics to SBCE CR. Results A total of 13 studies (all prospective, randomised-controlled, single-centre; total of 1439 subjects) was selected for final review and analysis. In 11 of them, PillCam® (Given®Imaging Ltd) was used; 2 studies were performed with OMOM® (Chongqingjinshan Science & Tech Co, Ltd). 6 studies were designed to look at the value of metoclopramide vs control. In the remainder, other type of prokinetic factors (Erythromycin, Mosapride, Lubiprostone, Deikenchuto or chewing gum) was administered. Using random effects model analysis, the use of prokinetics seem to improve CR in SBCE (OR = 1.888, 95% C.I. = 1.178, 3.02; I 2 = 52.5%, P = 0.014). Moreover, in the sub-analysis for metoclopramide studies using fixed effect model, the results were similar (OR = 1.711 95% C.I. = 1.138, 2.573; I 2 = 42.3%, P = 0.123). Conclusion Pooled data show that in comparison to no prokinetic, any type of administered prokinetic factor, before SBCE, improves the SBCE completion rate. Furthermore, most data to present are behind the use of Metoclopramide. Disclosure of Interest None Declared

Acute diarrhoea is a common but debilitating symptom with diverse aetiology. The aim of this review is to consider the important pathogens, diagnostic approaches and management of acute diarrhoea.

To determine whether acid secretion by gall bladder mucosa is influenced by alcohol and whether hydrogen ion output is increased when the gall bladder is perfused with moderate concentrations of alcohol.Fifty bovine gall bladders were studied. Twenty-five served as controls and 25 were perfused (in groups of five) with varying concentrations of alcohol (w/v): 0.05, 0.1, 0.2, 0.5 and 1.0%. Acid output was measured over 1 h and the results expressed as the mean.There was no significant difference between acid production by control gall bladders and those perfused with 0.05% alcohol (24.30 +/- 8.7 versus 18.95 x 8.41 nmol/h), but the acid output was significantly increased when the mucosa was exposed to 0.1 and 0.2% alcohol concentrations (50.28 +/- 10.2 and 29.34 +/- 9.1 nmol/h; P0.001 and P0.0004, respectively). Perfusion with alcohol concentrations of 0.5 and 1.0%, significantly inhibited mucosal acid output (2.60 +/- 2.0 and -1.70 +/- 1.2 nmol/h; P0.0001 and P0.0001, respectively).This study shows that perfusion of bovine gall bladder mucosa in vitro with moderate concentrations of alcohol stimulates acid output. This observation is important for assessing the link between alcohol and the risk of gallstone formation.

Introduction ERCP is a safe and highly effective solution to many pancreaticobiliary problems. However, surgical options also exist. After a challenging first ERCP, it can be unclear whether surgery or repeat ERCP is preferred. The aim of this study was to identify predictive factors at first ERCP which inform this decision. Methods All ERCPs performed at one hospital (April 2008–March 2011) were analysed. Patients having more than one ERCP were evaluated in detail. Demographics, disease-specific and procedure-specific variables relating to ERCPs and any subsequent surgery were extracted. The primary outcome measure was a requirement for surgery after two or more ERCPs. Descriptive statistics and logistic regression were performed. Results 1729 ERCPs were done in 1270 patients, of which 317 patients had more than one ERCP. Of these, 140 patients were randomly sampled and analysed in detail. These form the denominator for this analysis. The primary diagnosis was gallstones in 62.8%, malignancy in 16.9% and stricture in 10.2%. Combinations of these or other diagnoses occurred in 17.6%. 74.5% of first ERCPs were urgent or emergent. Cannulation was attempted in 96.3% and successful in 81.5% of patients. The operator deemed the first ERCP to be successful in 40.6%. Multiple stones requiring a stent and planned revisit occurred in 15.2% and a large stone requiring lithotripsy in 9.8%. Repeat ERCP was deemed successful by the operator in 65.2% of cases. 40.2% went on to subsequent ERCP attempts. 31.1% of patients having a second or subsequent ERCP ended up having surgery (open biliary exploration, biliary bypass and other operations). On logistic regression, a primary diagnosis of gallstones was associated with likelihood of endoscopic success (OR (95% CI): 3.8 (1.2 to 12.3, p=0.027). In those patients with a primary diagnosis of gallstones, younger patients (OR 1.07 (1.01 to 1.12, p=0.012)) and those with sepsis at presentation (OR 5.3 (1.1 to 25.2, p=0.038)) were significantly more likely to require surgery. No other pattern was predictive of subsequent ERCP success after a first attempt. Conclusion From this analysis, there are no unequivocal clinical or technical factors which make either ERCP or surgery preferable following an incomplete first ERCP. Repeat ERCP should be considered in gallstone disease. In gallstone disease, younger or septic patients should be considered for early surgery if a first ERCP is not successful. This decision is not straightforward; multidisciplinary teamwork and communication between surgeon and endoscopist are essential. Competing interests None declared.

Introduction Increased ketogenesis, in the presence of unaltered β-oxidation, is a feature of human steatohepatitis. This is thought to be attributable to decreased acetyl-coA entry to tricarboxylic acid cycle with mitochondrial impairment. In this study, we examined the diversion of acetyl-coA towards free fatty acid (FFA) biosynthesis and mevalonate pathways (including vitamin D3, steroids hormones and bile acids) in the presence of mitochondrial dysfunction and triglyceride accumulation. Methods Human hepatoblastoma C3A cells were treated with; oleate or various combinations of octanoate (O), lactate (L), pyruvate (P) and ammonia (N) for 72 h. Metabolites that correspond to the intermediates of FFA biosynthesis, mevalonate pathways were measured using metabolomics study. Results We have previously shown that LPON treatment, but not oleate, affected mitochondrial function as evidenced by decreased respiration and ROS formation with concomitant enhanced ketogenesis despite the similarities in triglyceride accumulation. Using metabolomics analysis, we identified three metabolites that correspond to FFA biosynthesis, three were bile acids and three were the derivatives of steroid hormones and vitamin D3 synthesis. We also identified mevalonate and 7-dehydrodemosterol, the intermediates of cholesterol biosynthesis. The concentrations of FFA biosynthesis intermediates were higher with LPON compared with oleate (3-oxo-tetradecanoate (p=0.005) and 3-oxo-hexadecanoate (p=0.02)). Although mevalonate (p=0.37) and 7-dehydrodesmosterol (p=0.46) levels were higher with oleate than that seen with LPON, these differences did not reach statistical significance. In contrast, bile acids were significantly elevated with oleate than LPON ((taurocholate (p=0.002), glycocholate (p=0.001), (6RS)-22-oxo-23,24,25,26,27-pentanorvitamin D3 6,19-sulphur dioxide adduct (p=0.04) and 1,25-dihydroxy-2,4-dinor-1,3-secovitamin D3 (p=0.0006). Conclusion These data suggest that, aside from enhanced ketogenesis, impaired mitochondrial function is also associated with acetyl-coA diversion towards FFA synthesis, but not mevalonate pathways. These differences are likely to reflect cellular demand in the presence of decreased ATP formation with mitochondrial dysfunction. Competing interests None declared.

Introduction Eicosapentaenoic acid (EPA), one of the major physiologically active constituents of Omega-3 fatty acids, has been suggested as a treatment for non-alcoholic fatty liver disease (NAFLD). The aim of these experiments was to assess the effects of EPA on intrahepatic triglyceride content in cell culture models of steatosis. Methods Human C3a hepatocytes were incubated in MEME (standard media) and two models of cellular steatosis: oleate (a model of isolated steatosis) and LPON (a model of steatosis and mitochondrial dysfunction containing the gluconeogenic substrates Lacate, Pyruvate, Octanoate and ammoNia). Test media was either unsupplemented, or supplemented with 50 μM or 250 μM EPA. Hepatocyte triglyceride accumulation was assessed both by microscopy (using oil red staining) and by quantifying the intracellular triglyceride concentration of cells incubated in culture media for 3 and 7 days. Each cell culture experiment was performed in triplicate. Results MEME When quantified by oil red staining a 73.1% (95% CI 63% to 83%) reduction in cell triglyceride content with 250 μM EPA compared with untreated cells was seen (7659 vs 28 564 pixels; p Oleate Here reduced triglyceride content with both 50 μM EPA (p LPON Although incubation with 250 μM EPA reduced triglyceride content in the LPON model when quantified with oil red staining (60 308 vs 79 219 pixels in 250 μM EPA vs untreated cells; p Conclusion These results suggest that EPA is effective at reducing triglyceride accumulation in untreated hepatocytes but is not effective in either oleate or LPON models of cellular steatosis. It is therefore possible that the presence of steatosis and mitochondrial dysfunction in NAFLD may limit the efficacy of EPA as a treatment. Competing interests None declared.

Primary graft dysfunction occurs in up to 10% of liver transplant recipients and is the major reason for early mortality and retransplantation. The conventionally used markers of early graft function--i.e., correction of acidosis, glucose requirement, consumption of potassium, serum alanine transaminase (ALT), prothrombin time (PT), bile flow, resolution of encephalopathy and haemodynamic instability can be very misleading as they are dependent on numerous other factors. The aim of this study was to assess the use of indocyanine green clearance (ICG) as a measure of graft function. Peripheral ICG clearance was measured 18-24 hr after liver transplantation in twenty-three consecutive patients (24 transplants). Doppler ultrasonography confirmed normal hepatic arterial blood flow. Correlations between ICG clearance and other markers of graft function and outcome were sought. The mean ICG clearance was 406 mls/min (SD 137.5). A threshold value of 200 ml/min reliably predicted outcome. Significant correlations were found between ICG clearance and times to normalization of PT (P0.02) and to the correction of acidosis (P0.05). No correlation was found with ALT, PT, bile flow, glucose requirement, or consumption of potassium. ICG clearance measured on the day after liver transplantation accurately reflects graft function and may be used to predict graft survival and final outcome.

SUMMARY Background: Propranolol has been shown to be effective in both primary and secondary treatment of variceal haemorrhage; most primary prevention trials have only included patients with large oesophageal varices. Aim of the study: The aim of this study was to look at the effect of propranolol in the primary prevention of variceal bleeding and its long-term effects on mortality in unselected patients with chronic liver disease. Methodology: Three hundred and nineteen patients were included in a double-blind parallel group study in three centres to receive propranolol 160 mg long-acting (LA) or placebo. Patients were followed up for a minimum of one year. Results: There were eleven episodes of variceal bleeding and 38 deaths with no statistically significant difference in bleeding rates between the two treatment groups. Child's group and history of ascites were the most important prognostic factors determining the likelihood of early death and variceal bleeding respectively. Conclusions: In this study we failed to demonstrate a significant effect of propranolol on first variceal bleeding or in prolonging survival in unselected patients with chronic liver disease. Our results, however, might have been influenced by the low event rate observed in these unselected group of patients and suggest that careful selection of patients who are most likely to benefit from propranolol is important.

Morphology, Metabolomics and Phenotypic Expression of 2D to 3D Transitional Co-Cultures of Hepatic C3A Cells with Endothelial Progenitors Leonard J Nelson1 Karl Burgess3 Olga Tura2, Maria Navarro1, Kay Samuel2, Peter C Hayes1, Marc L Turner2, John N Plevris1 Laboratory Department of Hepatology, Royal Infirmary of Edinburgh; and 2MRC Centre for Regenerative Medicine, University of Edinburgh; 2Scottish National Blood Transfusion Service, Edinburgh, UK; 3ScotMet, University of Glasgow.

Gall bladder bile is more acid that hepatic bile and this has been attributed to bicarbonate absorption by the gall bladder epithelium. The aim of this study was to investigate in vitro the acid base changes that occur across the human gall bladder mucosa. Fresh gall bladder tissue was obtained at cholecystectomy and placed in an Ussing Chamber and perfused with Ringer-Krebs glucose bicarbonate solution. The viability of the gall bladder was assessed by measuring the potential differences across the epithelium and by the morphology of the epithelial cells at the end of the experiments. Aliquots from the solutions were taken at two, 45 and 70 minutes and pCO2, hydrogen ion and bicarbonate concentrations were measured. In the mucosal side of the chamber a consistent and significant decrease was observed from two minutes to 70 minutes in bicarbonate concentration while pCO2 and hydrogen ion concentrations significantly increased. The degree of inflammation correlated well with the ability for acidification, the more inflamed the tissue the less its ability to acidify. When the gall bladder was exposed to amiloride or sodium free solution acidification was abolished in the mucosal side. When tissue metabolism was irreversibly inhibited by exposure to formaldehyde, hydrogen ion concentration and pCO2 were significantly decreased in the mucosal side of the chamber compared with the viable gall bladder. The human gall bladder is capable of secreting acid and this may be an important mechanism for preventing calcium precipitation and gall stone formation.

Chronic liver disease is frequently associated with a hyperdynamic circulation, with warm hands and capillary pulsations. In our experience, however, a significant number of patients with alcoholic liver disease complain of cold hands. In this study, we have investigated the presence of the subjective feeling of hand temperature in 114 patients with alcoholic liver disease compared with 96 healthy controls, and studied possible correlations of this subjective feeling with the severity of liver disease. Significantly more patients with alcoholic liver disease complained of cold hands than did normals, and these differences were more prominent in the male group. The awareness of cold hands appears to be commoner in an intermediate group of patients, between those with noncirrhotic liver disease without varices and those with cirrhosis with varices. A similar pattern of awareness of hand temperature was found when patients were staged according to the severity of their liver disease. We conclude that a staging can be made; at an early stage of liver disease, patients tend to have warm hands, subsequently develop cold hands, and at a later stage, their hands become warm again.

Chronic liver disease is frequently associated with a hyperdynamic circulation, with warm hands and capillary pulsations. In our experience, however, a significant number of patients with alcoholic liver disease complain of cold hands. In this study, we have investigated the presence of the subjective feeling of hand temperature in 114 patients with alcoholic liver disease compared with 96 healthy controls, and studied possible correlations of this subjective feeling with the severity of liver disease. Significantly more patients with alcoholic liver disease complained of cold hands than did normals, and these differences were more prominent in the male group. The awareness of cold hands appears to be commoner in an intermediate group of patients, between those with noncirrhotic liver disease without varices and those with cirrhosis with varices. A similar pattern of awareness of hand temperature was found when patients were staged according to the severity of their liver disease. We conclude that a staging can be made; at an early stage of liver disease, patients tend to have warm hands, subsequently develop cold hands, and at a later stage, their hands become warm again.

The pharmacokinetic and pharmacodynamic profiles of two angiotensin-converting enzyme (ACE) inhibitors, enalapril (a prodrug) and lisinopril (directly acting), were compared in eight patients with hepatic cirrhosis and 10 healthy controls. The pharmacokinetics of both drugs were affected in patients with hepatic cirrhosis. The percentage urinary recovery of the parent (inactive) drug enalapril was higher in patients with cirrhosis than controls. Serum concentrations of both drugs showed considerable variation in cirrhotic patients, but the variance ratio between patients with cirrhosis and controls was greater for enalapril than lisinopril. Peak serum concentrations of both ACE inhibitors were higher in patients with cirrhosis than in controls, which may be due to increased drug absorption. The time to peak drug concentration was longer for lisinopril than enalapril.