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Background: Treatment guidelines recommend a stepwise approach to primary biliary cholangitis: all patients begin treatment with ursodeoxycholic acid (UDCA) monotherapy and those with an inadequate biochemical response after 12 months are subsequently considered for second-line therapies. However, as a result, patients at the highest risk can wait the longest for effective treatment. We determined whether UDCA response can be accurately predicted using pretreatment clinical parameters. Methods: We did logistic regression analysis of pretreatment variables in a discovery cohort of patients in the UK with primary biliary cholangitis to derive the best-fitting model of UDCA response, defined as alkaline phosphatase less than 1·67 times the upper limit of normal (ULN), measured after 12 months of treatment with UDCA. We validated the model in an external cohort of patients with primary biliary cholangitis and treated with UDCA in Italy. Additionally, we assessed correlations between model predictions and key histological features, such as biliary injury and fibrosis, on liver biopsy samples. Findings: 2703 participants diagnosed with primary biliary cholangitis between Jan 1, 1998, and May 31, 2015, were included in the UK-PBC cohort for derivation of the model. The following pretreatment parameters were associated with lower probability of UDCA response: higher alkaline phosphatase concentration (p

Individuals from hereditary pancreatitis (HP) and familial pancreatic cancer (FPC) kindreds are at increased risk of developing pancreatic cancer. Premalignant molecular changes may be detected in pancreatic juice collected by endoscopic retrograde cholangiopancreatography (ERCP). The objective was to determine the risk of post-ERCP pancreatitis (PEP).A prospective study (1999-2013) was undertaken of 80 ERCPs (24 in HP and 56 in FPC) from 60 individuals and the impact of PEP prophylaxis using a self-expelling pancreatic stent and 50 mg diclofenac per rectum from 2008.There was no PEP in the HP cohort and 13 (23.2%) PEP from 56 procedures in the FPC cohort (P = 0.0077). Up to 2008 PEP had occurred in 7 (43.8%) of 16 procedures in FPC individuals versus none of 18 procedures in HP individuals (P = 0.0021). After the introduction of prophylaxis, the incidence of PEP fell to 6 (15.0%) of 40 procedures in FPC individuals (P = 0.0347).The odds ratio (95% confidence interval) was 0.23 (0.06-0.84) in favor of prophylaxis (0.035).Individuals with HP are at minimal risk for PEP. Although the risk of PEP in individuals with FPC can be reduced by using prophylactic self-expelling stents and diclofenac, it remains too high for routine screening.

Study background and aims: Predicting outcome at endoscopic retrograde cholangiopancreatography (ERCP) remains difficult. Our aim was to identify the risk factors for failed ERCP. Patients and methods: A prospective multicenter study of ERCP was performed in 66 hospitals across England. Data on 4561 patients were collected using a structured questionnaire completed at the time of ERCP. Results: In total 3209 patients had not had an ERCP prior to the study period. Considering their first ever ERCP, 2683 (84 %) were successfully cannulated, 2241(70 %) had all intended therapy completed, 360 (11 %) had some intended therapy completed, and 608 (19 %) were considered to have had a failed procedure. For first ever ERCP, factors associated with incomplete procedure (odds ratio and 95 % confidence interval) were: Billroth surgery (9.2, 3.2 – 26.7), precutting (2.0, 1.6 – 2.7), common bile duct (CBD) stone size and number (3.2, 2.1 – 4.8 for multiple, large stones), interventions in the pancreatic duct (3.4, 1.6 – 7.0), and CBD stenting (2.8, 2.2 – 3.5). Analysis of the 1352 patients who had undergone an ERCP prior to the study period indicated previous failed ERCP was also predictive of incomplete therapy (1.5, 1.1 – 2.1). The modified Schutz score correlated with ERCP completion, as did the Morriston score, even when modified to include only variables measurable before the procedure. Conclusion: This study confirms that patient- and procedure-based variables are key predictors of technical success and validates current methods of rating ERCP difficulty. Of note, a correlation between outcome and institutional factors, such as unit and endoscopist caseload, was not demonstrated.

Acute pancreatitis is a disease caused by gallstones in 40-60% of patients. Identification of these patients is extremely important, since there are specific therapeutic interventions by endoscopic sphincterotomy and/or cholecystectomy. The combination of trans-abdominal ultrasound (stones in the gallbladder and/or main bile duct) and elevated serum alanine transaminase (circa60 IU/l within 48 h of presentation) indicates gallstones as the cause in the majority of patients with acute pancreatitis. In the presence of a severe attack this is a strong indication for intervention by endoscopic sphincterotomy. The presence of a significant main bile duct dilatation is also strongly indicative of gallstones and should prompt the use of endoluminal ultrasonography:8 mm diameter with gallbladder in situ, or10 mm following cholecystectomy if aged70 years and12 mm, respectively, ifor = 70 years. In mild pancreatitis surgically fit patients should be treated by cholecystectomy, and intra-operative cholangiography, as pre-operative biliary imaging is not efficient in this setting. Patients who are not fit for cholecystectomy should undergo prophylactic endoscopic sphincterotomy to prevent further attacks. In the post-acute-phase, pancreatitis patients in whom the aetiology is uncertain should undergo endoluminal ultrasonography. Thisis the most sensitive method for the detection of cholelithiasis and choledocholithiasis and may reveal alternative aetiological factors such as a small ampullary or pancreatic cancer. A number of recent studies have shown that bile crystal analysis, a marker for microlithiasis, increases the yield of positive results over and above endoluminal ultrasonography, and should be considered as part of the modern investigative algorithm.

Background: Three-session days were introduced in our endoscopy unit to accommodate the increased demand resulting from the introduction of the National Health Service Bowel Cancer Screening Programme (BCSP). Cecal intubation rate (CIR) and adenoma detection rate (ADR) may decline with time during a standard working day, but data are lacking for an extended three-session day. We assessed colonoscopy performance in an extended three-session day. Methods: Colonoscopies performed during the year 2011 were retrospectively analyzed. The CIR and ADR were analyzed according to the time of day when procedures were done: morning (AM), afternoon (PM), or evening (EVE). Because of an expected higher incidence of adenomas in the BCSP patients, ADR was analyzed according to indication (BCSP or non-BCSP). Results: Of the 2574 colonoscopies, 1328 (51.7 %) were in male patients and 1239 (48.3 %) in female patients with a median age of 63 years (interquartile range [IQR], 51 – 70). Of the 2574 colonoscopies, 1091 (42.4 %) were performed in AM lists, 994 (38.6 %) in PM lists, and 489 (19 %) in EVE lists. Time of day did not affect the CIRs for the AM, PM, and EVE lists (90.5 %, 90.1 %, and 89.9 %, respectively; χ 2 [2, N = 2540] = 0.15, P = 0.927). The CIR was reduced in female patients and those with poor bowel preparation (P 0.05). The ADR was significantly higher in patients older than 60 years and in men (P

Prisons are an important setting to address prevention, testing and treatment of hepatitis C virus (HCV) and other blood-borne viruses. This audit examined current practice against national standards in a representative sample of prisons in England.The audit tool was developed based on best practice guidelines and piloted in one prison. In December 2012, the audit was conducted in a further 20 prisons, which were chosen to represent different types, sizes and geographical spread across England.Testing for HCV was offered in the majority of prisons audited (20 of 21), but only two-thirds had a written policy on testing and treatment; less than a third had a steering group to oversee the process. The nature of services varied greatly. There were inconsistencies across data sources on testing.This audit found that while there were many areas of good practice, the quality and content of hepatitis C service provision varied. It highlighted the need to provide appropriate guidance for prisons in delivering a high-quality service, ensuring that relevant training is available for different staff and that adequate psychosocial support is provided to patients.

Liver disease in the UK stands out as the one glaring exception to the vast improvements made during the past 30 years in health and life expectancy for chronic disorders such as stroke, heart disease, and many cancers. Mortality rates have increased 400% since 1970, and in people younger than 65 years have risen by almost fi ve-times. Liver disease constitutes the third commonest cause of premature death in the UK and the rate of increase of liver disease is substantially higher in the UK than other countries in western Europe. More than 1 million admissions to hospital per year are the result of alcohol-related disorders, and both the number of admissions and the increase in mortality closely parallel the rise in alcohol consumption in the UK during the past three decades. The new epidemic of obesity is equally preventable. Of the 25% of the population now categorised as obese, most will have non-alcoholic fatty liver disease many (up to 1 in 20 of the UK population) will have ongoing infl ammation and scarring that fi nally leads to cirrhosis. Of those patients with cirrhosis, 5-10% will get liver cancer. This increasing burden of liver disease is added to by chronic viral hepatitis; annual deaths from hepatitis C have almost quadrupled since 1996 and about 75% of people infected are estimated to be still unrecognised. The same applies to chronic hepatitis B infection, in which progression to cirrhosis and liver cancer also happens. The number of silently infected individuals in the UK is increasing every year as a result of immigration from countries with a high prevalence of hepatitis B and hepatitis C infections. Costs to the UK's National Health Service are equally staggering, with estimates of £3.5 billion per year for alcohol-related health problems and £5.5 billion per year for the consequences of obesity. Obesity costs are almost certainly an underestimate now that the disorder is recognised as an important factor in several common cancers, including breast cancer and colon cancer.1 Obesity is a factor in metabolic disorders-the basis of diabetes, hypertension, cardiac diseases, and strokes. Furthermore, the poorest and most susceptible in society have the highest incidence of liver disorders, making liver disease a major issue for health inequalities. Of particular concern is the 2013 National Confi dential Enquiry into Patient Outcome and Death (NCEPOD) report,2 which showed that the care of patients acutely sick with liver disease dying in hospital was judged to be good in less than half of patients; other unacceptable fi ndings were the inadequate facilities and lack of expertise of those caring for patients. Also, it is increasingly evident that defi ciencies exist in primary care, which has crucial opportunities for early diagnosis and prevention of progressive disease. The aim of this Commission is to provide the strongest evidence base through involvement of experts from a wide cross-section of disciplines, making fi rm recommendations to reduce the unacceptable premature mortality and dsease burden from avoidable causes and to improve the standard of care for patients with liver disease in hospital. From the substantial number of recommendations given in our Commission, we selected those that will have the greatest eff ect and that need urgent implementation. Although the recommendations are based mostly on data from England, they have wider application to the UK as a whole, and are in accord with the present strategy for health-care policy by the Scottish Health Boards, the Health Department of Wales, and the Department of Health and Social Services in Northern Ireland. Our ten key recommendations are based on the strong evidence base and are in line with reports in 2014 of several other enquiries, including from the 2014 All Party Parliamentary Group on Hepatology3 and the All Party Parliamentary Group on alochol misuse. Results showing the value of a minimum unit price policy in targeting heavy drinkers were published in The Lancet in May, 2014, and the European Observatory on Health Polcy, together with the Department of Health and NHS England, has drawn attention to four areas of premature mortality, including liver disease, in which the UK lags behind other European countries. Such stark contrasts with our European neighbours are unacceptable and in this Commission we give clear, evidence-based policy proposals for the UK Government to use in closing the gap in liver disease.

This review analyses the current state of knowledge and understanding concerning the optimum treatment and therapeutic management of patients who suffer from pancreatic cancer. It outlines recent advances in scientific understanding and assesses their potential future value to clinicians in confronting this disease. Despite a significant expansion in scientific knowledge relating to factors underlying the early development of pancreatic carcinoma, the clinician continues to be restricted to a severely limited therapeutic armoury for this disease. Local therapies (surgery and radiation) are inevitably of limited value in the face of a disease that is normally encountered at a stage where metastasis is already highly developed. Despite such limitations, however, surgery performed in specialist units may be of value for 10-20% of patients, with a 5-year survival rate in such units of between 10 and 24%. This may be improved even further by appropriate use of adjuvant treatment. The advanced stage of the disease when normally encountered emphasizes the potential value of systemic treatment in this therapeutic area. Unfortunately systemic treatment (chemotherapy) has been found to be ineffective to date in significantly extending survival, with a low rate and duration of remission being identified in most trials. The challenge for both the health service and the pharmaceutical industry is to harness recent and future developments in scientific knowledge to the practical benefit of clinicians. Where cure is possible it should be vigorously pursued; where it is not, in this field above all others, clinicians have a duty of care. To achieve this it is necessary to abandon the therapeutic nihilism that has characterized the attitudes of clinicians towards this disease in the past. It is time that such nihilism was replaced by a recognition of the challenges and the opportunities available to clinicians in enhancing the quantity and quality of life available to patients. The dictum of 'curing whenever possible but caring always' should be the future therapeutic philosophy used to guide clinicians in this important and rapidly changing therapeutic area.

1.The aim of this study was to devise a method of segregating crypt and villus cell subpopulations from endoscopic human small intestinal biopsies which might be used to examine changes associated with functional differentiation at the molecular level. 2.Routine endoscopic biopsies from the human small intestine were subjected to a modified protocol of mechanical disruption and chelation to yield subpopulations of different cell types. The purity and character of the cell populations isolated was assessed by measuring enzyme activity and thymidine incorporation and by histology. A guanidinium isothiocyanate method was adapted for small samples to extract RNA from the isolated subpopulations, and probes for RNA with a known predilection for crypt and villus cells were used to further investigate the application and usefulness of the technique. 3.Sequential histological examination during the segregation protocol demonstrated that different cell types were removed serially from the biopsy samples. Cell-type enrichment of the segregated subpopulations was demonstrated by differential alkaline phosphatase activity and by differences in thymidine incorporation in the samples isolated. Sufficient quantities of RNA could be extracted from the segregated subpopulations for Northern blot analysis and the differential expression of mRNA for sucrase-isomaltase and transferrin receptor was demonstrated in the villus and crypt subpopulations respectively. 4.Messenger RNA can be successfully extracted from different cell types segregated from routine human endoscopic small intestinal biopsies. This technique should prove useful for investigating the mechanisms regulating the functional differentiation of epithelial cells in the small intestine and the regulatory mechanisms governing absorption of macromolecules.

Background and Study Aims: Treatment options for un-resectable hepatic hilar strictures include percutaneous or endoscopic stent insertion, using either standard Teflon or self-expanding metal endoprostheses. The use of Teflon stents is complicated by stent migration and high occlusion rates. Published series of endoscopically placed metal stents have not concentrated on their use in the treatment of high-grade hilar strictures (Bismuth grades II and III). We therefore undertook a prospective and open pilot study to evaluate the efficacy of endoscopically placed metal endoprostheses in the palliation of jaundice due to high-grade hilar strictures. Patients and Methods: Self-expanding metal stents were placed endoscopically in 17 patients (nine women, eight men; median age 64 years, range 33-77). Of the 17 malignancies 11 patients (65%) had a diagnosis of cholan-giocarcinoma, and 12 (71%) had Bismuth grade III strictures. Results: The stents were inserted successfully in all 17 patients. Adequate drainage, as demonstrated by a significant reduction in bilirubin, was achieved in 15 (88 %); the two patients in whom drainage failed had extensive intrahepatic disease. Early complications (cholangitis) developed in one patient (6%), and there were seven late complications (41 %) in five patients (four occluded stents and three cases of duodenal compression). The stent patency appeared to be prolonged (median stent patency 12 months, range 1.5-24 months, in patients surviving five months or more). The median survival was ten months (range 1-48 months) after stent insertion. All of the patients died during follow-up. Conclusions: These results suggest that endoscopically placed metal stents offer effective palliation for high-grade hilar malignancies, although controlled trials comparing the use of metal and Teflon endoprostheses in this patient group are required.

OBJECTIVE The human pituitary gland is affected selectively by conditions associated with iron deposition, but the mechanisms for this are unknown. In this study we have determined whether the transferrin receptor, which mediates iron uptake by cells, could be detected immunocytochemically in human pituitary adenomas in vitro. PATIENTS Data were derived from 35 patients undergoing transsphenoidal surgery and included 13 with clinically non-functioning adenomas, 15 with acromegaly, 4 prolactinomas, 2 patients with Cushing’s disease and one patient with Nelson’s syndrome. MEASUREMENTS Transferrin receptor immunopositivity was determined for each adenoma in dispersed cell culture using a specific monoclonal antibody. RESULTS Eight of 13 clinically functionless adenomas showed immunopositive transferrin receptor expression, whilst adenomas from 15 patients with acromegaly, 4 prolactinomas, 2 Cushing’s syndrome and one patient with Nelson’s syndrome were negative. The eight transferrin receptor positive tumours were gonadotrophinomas and accounted for eight of the nine tumours which secreted and immunostained for FSH; all eight also secreted and immunostained for LH. CONCLUSIONS These findings may reflect a special requirement for iron by gonadotrophin secreting cells in comparison to other pituitary cell types and this could underlie the reasons why in the normal pituitary these cells are especially susceptible to malfunction in iron overload syndromes such as genetic haemochromatosis and β-thalassaemia.

Tissue iron loading in hypotransferrinaemic (hpx/hpx) mice was investigated as a model for genetic (primary) haemochromatosis. Iron loading of liver preceded that in the pancreas and heart. One-year-old hpx/hpx mice showed iron staining in exocrine pancreas, liver parenchymal cells, and cardiac and intestinal smooth muscle cells. Iron-loaded macrophages were observed in all these tissues. Islets of Langerhans, biliary epithelial cells, and spleen were iron-free. The pancreas was fibrotic with massive macrophage infiltration and loss of secretory epithelium. Liver showed evidence of chronic inflammatory infiltration with increased collagen fibres in the parenchymal region but no cirrhosis. Serum aspartate aminotransferase activity and plasma glucose were increased in hpx/hpx compared with wild-type mice. Heavy iron loading with haemosiderin deposition in the liver could be demonstrated in hpx/hpx mice from 6 weeks of age. Heterozygous hypotransferrinaemic mice showed minor increases in liver iron stores at 6-12 weeks, but not at 1 year of age. Serum ferritin levels in heterozygous mice were also increased at 6-8 weeks of age. It was concluded that 1-year-old hpx/hpx mice showed evidence of liver and pancreatic damage secondary to tissue iron overload. The iron loading pattern and tissue damage showed some features which were distinct from those observed in haemochromatosis.

Background: Effective treatment for primary biliary cirrhosis (PBC) resulting in slower progression and improved survival remains elusive. Cyclosporin A (CyA), which has been so effective in preventing human allograft rejection, has shown promise in small numbers of patients in early studies. Methods: Three hundred forty-nine patients with PBC were randomized to receive CyA, 3 mg · kg−1 · day−1, or placebo in a multicenter study with follow-up for 6 years. The end point was death or liver transplantation. Results: Cox multivariate analysis showed time from entry to death or transplantation was significantly prolonged (by up to 50%) in the CyA-treated group. Liver-related mortality was also significantly lower. However, a univariate analysis of survival showed no statistical differences between the two groups. Biochemical liver indices deteriorated more slowly in the CyA-treated group, but serum creatinine concentration was elevated >150 (μmol/L in 9%, necessitating permanent discontinuation in half of these. A reduction in the dose of CyA was required in 11% because of hypertension. Conclusions: CyA has some therapeutic potential in primary biliary cirrhosis, providing blood pressure and renal function are closely monitored.

Clinicians use fibrosis in a liver biopsy to predict clinical outcomes of chronic liver disease. The performance of non-invasive tests has been evaluated against histological assessment of fibrosis but use of clinical outcomes as the reference standard would be ideal. The enhanced liver fibrosis (ELF) test was derived and validated in a large cohort of patients and shown to have high diagnostic accuracy (area under the curve (AUC)=0.80 95% CI 0.76 to 0.85) in identification of significant fibrosis on biopsy.To evaluate ELF performance in predicting clinical outcomes by following up the original ELF cohort.Patients recruited to the ELF study at seven English centres were followed up for liver morbidity and mortality by examination of clinical data. Defaulting/discharged patients were followed up by family practitioner questionnaires. Primary outcome measure was liver-related morbidity/liver-related death.457 patients were followed up (median 7 years), with ascertainment of clinical status in 92%. There were 61 liver-related outcomes (39 deaths). Survival analysis showed that the ELF score predicts liver outcomes, with people having the highest ELF scores being significantly more likely to have clinical outcomes than those in lower-score groups. A Cox proportional hazards model showed fully adjusted HRs of 75 (ELF score 12.52-16.67), 20 (10.426-12.51) and 5 (8.34-10.425) compared with patients with ELF8.34. A unit change in ELF is associated with a doubling of risk of liver-related outcome.An ELF test can predict clinical outcomes in patients with chronic liver disease and may be a useful prognostic tool in clinical practice.

Endoscopic placement of a biliary endoprosthesis has been proposed for the management of choledocholithiasis when stone extraction is difficult or considered hazardous. Over a two year period this approach was used in 40 such patients. There were 24 women and 16 men with a median age of 76 years. In seven patients with severe cholangitis no attempt was made to extract the stones. Twenty three (57.5%) patients underwent a sphincterotomy and four (10%) needle knife papillotomy. The endoprosthesis insertion was considered a temporary measure in 13 (32.5%) patients and definitive treatment in 27 (67.5%). Bile duct drainage was established in all patients. Early complications occurred in six patients (15%), but were without sequelae. Late complications developed in eight (20%) of the patients and included biliary colic (four), cholangitis (three), and cholecystitis (one). Two patients (one cholangitis and one cholecystitis) died as a consequence of the complication. Only patients without a sphincterotomy developed cholangitis. A total of eight patients (20%) underwent surgery (one as an emergency) and nine a repeat endoscopic retrograde cholangio pancreatography (two as an emergency) to clear the duct. The remaining 23 patients are asymptomatic at a median of 13 months (range five to 24 months). Biliary endoprosthesis insertion for choledocholithiasis is an important alternative means of establishing drainage in selected cases, and is probably the optimum method of management for the elderly and or debilitated patients with previous cholecystectomy. Caution must be exercised, however, in patients with an in situ gall bladder.

An iron-loaded liver from a 20-year-old man with occult haemochromatosis was inadvertently transplanted into a 64-year-old lady with primary biliary cirrhosis. Increased hepatic iron storage was observed in biopsy specimens undertaken at 18, 30 and 36 months after transplantation. Serum iron levels and transferrin iron saturation increased and remained elevated 4 years after surgery. Ferritin levels were also consistently increased. Iron absorption test, performed at 4 years after transplant, was increased at 38%. Our data suggest that an intrahepatic defect in haemochromatosis cannot be excluded, and casts some doubt on the assertion that a precirrhotic haemochromatotic liver can be transplanted without sequelae.

Summary. Iron absorption rates by homozygous and wildtype mice from a hypotransferrinaemic mouse colony were examined with in vivo tied-off duodenal segments and in vitro incubated duodenal fragments. Enhanced initial rates of mucosal uptake and carcass transfer by homozygotes. compared to wild-types, were observed. The changes in vivo and in in vitro uptake kinetics resemble changes seen in iron deficient or hypoxic mice, suggesting that the liver iron loading shown by homozygotes is due to a failure of the normal mechanism for regulation of iron absorption. In vivo mucosal uptake and carcass transfer of radioiron showed an inverse correlation with liver non-haem iron content in homozygous hypotransferrinaemic mice, suggesting that some degree of control of absorption, albeit at markedly reduced sensitivity. can operate in these mice. No correlation between haemoglobin level and iron absorption was observed in homozygous hypotransferrinaemic mice, suggesting that this regulator of iron absorption does not function in these mice. The precise pathogenic mechanism of the enhanced iron absorption in hypotransferrinaemia remains to be determined. Mucosal transferrin levels were found to parallel serum transferrin levels in homozygotes. heterozygotes and wild-type mice. This supports previous suggestions that mucosal transferrin is derived from plasma transferrin and that the enhancement of iron absorption, by physiological mechanisms, does not require the presence of mucosal transferrin.

The last 30 years have seen major developments in the management of gallstone-related disease, which in the United States alone costs over 6 billion dollars per annum to treat. Endoscopic retrograde cholangiopancreatography (ERCP) has become a widely available and routine procedure, whilst open cholecystectomy has largely been replaced by a laparoscopic approach, which may or may not include laparoscopic exploration of the common bile duct (LCBDE). In addition, new imaging techniques such as magnetic resonance cholangiography (MR) and endoscopic ultrasound (EUS) offer the opportunity to accurately visualise the biliary system without instrumentation of the ducts. As a consequence clinicians are now faced with a number of potentially valid options for managing patients with suspected CBDS. It is with this in mind that the following guidelines have been written.

In genetic hemochromatosis, metabolic studies have demonstrated inappropriately increased iron absorption by cells of the duodenal mucosa. It is not clear whether this reflects an intrinsic abnormality of iron homeostasis at this site or is a consequence of a more generalized defect in cellular iron metabolism particularly involving the liver. We have previously used the expression of iron-related proteins as markers of iron homeostasis and have demonstrated normal regulation of the transferrin receptor and ferritin in the liver in this condition. In the present study we used immunohistochemical techniques to study transferrin-receptor expression in the gastrointestinal epithelium in normal subjects and patients with iron overload. In untreated genetic hemochromatosis and normal subjects, villus epithelial cells expressed receptor in the basolateral, subnuclear region. In contrast, in patients with secondary iron overload, receptor staining was absent in villus epithelial cells. The cells in the duodenal crypts showed intense staining for the transferrin receptor in all subjects investigated, a finding consistent with the known behavior of this receptor in proliferating cells. Given that body iron stores in both types of iron overload were comparable, these findings indicating a failure of down-regulation of the villus enterocyte transferrin receptor in genetic hemochromatosis may reflect the presence of a regulatory defect associated with the inability to control iron absorption in this condition.

BACKGROUND AND STUDY AIMS: Analyses of endoscopic retrograde cholangiopancreatography (ERCP) complication are often constrained by the number of endpoints observed. This large-scale study aimed to identify the principal risk factors for ERCP complication. PATIENTS AND METHODS: This was a prospective multicenter study of ERCP complications, based in five English regions. An exploratory univariable analysis of patients’ first recorded procedures identified potentially important patient- and procedure-related factors. For overall complications and pancreatitis, variables significant in univariable analysis were included in multiple regression. RESULTS: A total of 66 centers collected data on 5264 ERCPs, performed on 4561 patients. A therapeutic intervention was attempted in 3447/4561 (76 %) of patients as part of their first recorded ERCP. Following first recorded ERCP, 230 patients (5.0 %) suffered ≥ 1 complication: pancreatitis in 74 (1.6 %), cholangitis in 48 (1.0 %), hemorrhage in 40 (0.9 %), perforation in 20 (0.4 %), and miscellaneous in 54 (1.2 %). Significant factors from multiple regression were included in a multi-level analysis, which incorporated variables measured at the level of the endoscopist and hospital. For overall complication, risk factors ( P value, odds ratio [OR], 95 % confidence interval [CI]) were: cannulation attempts > 1 ( P = 0.094, OR 1.32, 95 % CI 0.95 - 1.83), precut ( P = 0.033, OR 1.55, 95 % CI 1.04 - 2.32), and suspected sphincter of Oddi dysfunction ( P = 0.121, OR 1.97, 95 % CI 0.84 - 4.64). For pancreatitis, risk factors ( Pvalue, OR, and 95 % CI) were: cannulation attempts > 1 ( P = 0.0001, OR 3.14, 95 % CI 1.74 - 5.67), female sex ( P < 0.001, OR 2.22, 95 % CI 1.43 - 3.45), age ( P < 0.002, OR 1.09 per 5 year decrease, 95 % CI 1.03 - 1.15), and performance in a district (as opposed to university) hospital ( P = 0.034, OR 2.41, 95 % CI 1.08 - 5.41). CONCLUSION: Careful patient selection combined with skilled cannulation minimizes complications. Higher-risk procedures should be performed in specialist centers.

Objective: To examine endoscopic retrograde cholangio-pancreatography (ERCP) services and training in the UK. Design: Prospective multicentre survey. Setting: Five regions of England. Participants: Hospitals with an ERCP unit. Outcome measures: Adherence to published guidelines, technical success rates, complications and mortality. Results: Organisation questionnaires were returned by 76 of 81 (94%) units. Personal questionnaires were returned by 190 of 213 (89%) ERCP endoscopists and 74 of 91 (81%) ERCP trainees, of whom 45 (61%) reported participation in 5 mg of midalozam. Prothrombin time was recorded in 4539 of 5264 (86%) procedures. Antibiotics were given in 1021 of 1412 (72%) cases, where indicated. Patients’ American Society of Anesthesiology (ASA) scores were 3–5 in 670 of 5264 (12.7%) ERCPs, and 4932 of 5264 (94%) ERCPs were scheduled with therapeutic intent. In total, 140 of 182 (77%) trained endoscopists demonstrated a cannulation rate ⩾80%. The recorded cannulation rate among senior trainees (with an experience of >200 ERCPs) was 222/338 (66%). Completion of intended treatment was done in 3707 of 5264 (70.4%) ERCPs; 268 of 5264 (5.1%) procedures resulted in a complication. Procedure-related mortality was 21/5264 (0.4%). Mortality correlated with ASA score. Conclusion: Most ERCPs in the UK are performed on low-risk patients with therapeutic intent. Complication rates compare favourably with those reported internationally. However, quality suffers because there are too many trainees in too many low-volume ERCP centres.

1. The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3, controls calcium absorption in the human duodenum, an effect that is mediated by mucosal vitamin D receptor expression. Functional vitamin D receptor signalling in the human colon is suggested by the reduced colonic mucosal cell proliferation seen in response to 1,25-dihydroxyvitamin D3. Thus 1,25-dihydroxyvitamin D3 might be expected to reduce cell proliferation in the small-bowel epithelium. 2. We have used an organ-culture system combined with the metaphase arrest technique to study the effects of 1,25-dihydroxyvitamin D3 on human duodenal mucosal proliferation. To validate our technique, multiple human mucosal explants were established in organ culture and vincristine (0.6μg/ml) was added at 10 h. Explants were removed sequentially from 10 to 15 h and metaphase arrest figures were demonstrated by using the Feulgen reaction. The mean number of metaphase arrest figures was plotted against time in culture to show a linear accumulation of metaphases between 11 and 15 h (correlation coefficient = 0.93, r2 = 0.87, P < 0.0001). The mean crypt cell production rate was 2.01 (0.27) cells/h per crypt. 3. Paired normal duodenal mucosal biopsies from six patients were then established in organ culture with or without 10−10 mol/l (100 pmol/l) 1,25-dihydroxyvitamin D3. The crypt cell production rate was determined between 12 and 15 h after vincristine-induced metaphase arrest. 1,25-Dihydroxyvitamin D3 reduced the median crypt cell production rate from 2.42 (1.15–4.82) to 1.41 (0.03–2.05) cells/h per crypt (P < 0.05). Thus, vitamin D3 reduces human duodenal epithelial cell proliferation.

Objectives Transjugular intrahepatic portosystemic stent shunt (TIPSS) is now widely used in the treatment of uncontrolled and recurrent variceal haemorrhage. This study reports the outcome and long-term follow-up of 125 patients who were referred to a single centre for TIPSS. Methods One hundred and twenty-five patients were referred to undergo TIPSS. All but 10 had variceal haemorrhage. The 10 patients referred with refractory ascites were excluded from the analysis. Our follow-up protocol was to assess shunt patency only if bleeding recurred or there was a clinical indication. The mean age was 51.5 years (range 18-87 years) and 64 patients (56%) were male. The commonest aetiology for chronic liver disease was alcohol (80%). At referral, 19 patients (16%) were Child-Pugh class A, 26 patients (23%) were Child-Pugh class B and 70 patients (61%) were Child-Pugh class C. The mean follow-up period was 20.4 months (range 0-95 months). Results TIPSS was successfully placed in 108 of 115 patients (94%). The thirty-day mortality was 30%. One-year and 2-year overall cumulative survival was 52% (survival ratio, 0.525; 95% confidence interval, 0.432-0.619) and 43% (survival ratio, 0.436; 95% confidence interval, 0.340-0.532), respectively. Conclusion TIPSS is effective in the treatment of uncontrolled or recurrent variceal bleeding. In comparison with previously published studies, our study suggests no value in regular or routine shunt surveillance to reduce rebleeding episodes or mortality, but this needs to be further assessed in prospective randomized studies.

The outcome of pancreatic resection for chronic pancreatitis in patients with preoperative opioid use is not well described.During 1997 to 2003, 112 of 231 patients referred with chronic pancreatitis underwent pancreatic resection. The outcome of patients who had preoperative opioid use (N=46) was compared with those without (N=66).Patients who used opioids presented at a younger age and had a younger age of symptom onset, longer symptom duration, more hospitalizations, a higher frequency of diabetes mellitus, a higher pain score, and more restriction in daily activity (all P.05). Twenty-one (46%) patients with opioid use had a total pancreatectomy compared with 9 (14%) without opioid use (P=.0002); the 21 patients also had a higher frequency of postoperative bleeding and early reoperation (8 vs 2, P.02; 11 vs 3, P=.003, respectively). Mortality and overall morbidity was not significantly different between the 2 groups (4 vs 1, 27 vs 34, respectively). Pain scores improved postoperatively in both groups (P=.001) and was not significantly different between the groups from 12 months onward (median follow-up of 12 months, range, 3-60 months). Twenty percent of patients who used preoperative opioids however reverted to morphine use compared with 6% of patients who had not used opioids.Patients who used opioids had more advanced disease than patients without opioid use, accounting for part of the postoperative morbidity. Although long-term pain relief was comparable between the 2 groups, maintaining opioid withdrawal was more problematic in those with preoperative opioid use. Earlier referral for resection may be warranted in this group of patients.

SurgeryIntroductionThe incidence and prevalence of chronic pancreatitisappear to be increasing [1–4]. Pancreatic pseudocyst is acommon complication of chronic as well as acute pancre-atitis that is unrelated to the underlying aetiology. Ad-vances in radiological techniques have in part led to anincrease in the diagnosis of pseudocyst and better charac-terization of associated complications. There is now a bet-ter understanding of the natural history of pseudocysts inrelation to the underlying disease. The introduction ofnew treatment modalities has also increased the optionsfor surgical management. Thus with better knowledge ofthe disease and with technical advances the indications,timing and methods to treat pancreatic pseudocysts haveundergone a marked evolutionary change.DefinitionA pancreatic pseudocyst is a localised collection ofpancreatic-enzyme-rich fluid, originating in or adjacent tothe pancreas and enclosed in a wall of granulation and/orfibrous tissue lacking an epithelial lining [5]. The princi-ple mechanism leading to pseudocyst formation is be-lieved to involve disruption of the main pancreatic ductand/or peripheral ductules causing leakage and activationof pancreatic enzymes, which in turn leads to localisedautodigestion and necrosis of pancreatic parenchyma.This evokes an inflammatory response with the formationof a distinct pseudocyst wall composed of granulation tis-sue and blood vessels that organizes with more connectivetissue and fibrosis [6–11].On-table pancreatography [12] and endoscopic retro-grade cholangiopancreatography (ERCP) have demon-strated a communication between the pseudocyst and thepancreatic ductal system in up to 80% of the patients [13,14], and peripheral or main pancreatic duct disruption isknown to be an early event in acute pancreatitis [15].Rarely disruption of a retention cyst [16] or trauma thatdisrupts the pancreatic ductal system may also lead to apseudocyst [17–19].

The prevalence of pancreatic cancer in the general population is too low--even in high-prevalence areas such as Northern Europe and North America (8-12 per 10(5) population)--relative to the diagnostic accuracy of present detection methods to permit primary screening in the asymptomatic adult population. The recognition that the lifetime risk of developing pancreatic cancer for patients with hereditary pancreatitis (HP) is extremely high (20% by the age of 60 years and 40% by the age of 70 years) poses considerable challenges and opportunities for secondary screening in those patients without any clinical features of pancreatic cancer. Even for secondary screening, the detection of cancer at a biological stage that would be amenable to cure by surgery (total pancreatectomy) still requires diagnostic modalities with a very high sensitivity and specificity. Conventional radiological imaging methods such as endoluminal ultrasound and endoscopic retrograde pancreatography, which have proved to be valuable in the early detection of early neoplastic lesions in patients with familial pancreatic cancer, may well be applicable to patients with HP but only in those without gross morphological features of chronic pancreatitis (other than parenchymal atrophy). Unfortunately, most cases of HP also have associated gross features of chronic pancreatitis that are likely to seriously undermine the diagnostic value of these conventional imaging modalities. Pre-malignant molecular changes can be detected in the pancreatic juice of patients. Thus, the application of molecular screening in patients with HP is potentially the most powerful method of detection of early pancreatic cancer. Although mutant (mt) K-ras can be detected in the pancreatic juice of most patients with pancreatic cancer, it is also present in patients with non-inherited chronic pancreatitis who do not progress to pancreatic cancer (at least in the short to medium term), as well as increasingly in the older population without pancreatic disease. Nevertheless, the presence of mt-K-ras may identify a genuinely higher-risk group, enabling additional diagnostic imaging and molecular resources to be focussed on such a group. What is clear is that prospective multi-centre studies, such as that being pursued by the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC), are essential for the development of an effective secondary screening programme for these patients.

Editor—We were interested to read Terence English's personal paper about extending nurses' professional roles.1 We set up the first course to train nurses in endoscopy and to insert percutaneous endoscopic gastrostomy feeding tubes that was approved by the English National Board,2 and we therefore have first hand experience of many of the issues he addressed. It may be important to make a distinction for …

BACKGROUND: The treatment for endstage cystic fibrosis is, where appropriate, double-lung, heart-lung or, occasionally, heart-lung-liver transplantation. Optimising the timing of transplantation depends upon an accurate prediction of survival, but while current criteria give some guidance to this, they are not based upon statistically derived prognostic models. METHODS: Data collected prospectively on 403 patients with cystic fibrosis, recruited between 1969 and 1987 (cohort A), were analysed by log rank and univariate Cox regression analysis to determine variables that accurately predict survival. The significant variables were then subject to time dependent multivariate Cox regression analysis to generate a prognostic model. The model was validated, within the study population, using split sample testing, and was subsequently validated in a further cohort of patients recruited since October 1988 (cohort B). RESULTS: One hundred and eighty eight (50.4%) of the study cohort died within the study period. Percentage predicted forced expiratory volume in one second (FEV1), percentage predicted forced vital capacity (FVC), short stature, high white cell count (WBC), and chronic liver disease (as evidenced by the presence of hepatomegaly) were negatively correlated with survival. These variables, when combined into a prognostic index, accurately predicted one year survival in the study population and in the cohort recruited since 1988. CONCLUSION: This prognostic index may prove valuable in predicting prognosis in other cohorts with cystic fibrosis and thereby improve the timing of transplantation.

Background This audit follows a survey of hepatitis C services in prisons in England published in 2012 by the Health Protection Agency (HPA) and the Department of Health (DoH). This survey revealed variation in the quality of hepatitis C services delivered in prisons, which required further examination. An audit instrument was developed in December, 2012, on the basis of the best practice guidance in the survey as well as existing national guidance to examine key areas of service provision. The aim of the audit was to identify best practice guidance that was being followed and provide evidence and intelligence for commissioners and service providers as a driver to improve the care received by patients. Methods The audit was done before April, 2013, by the DoH as well as the HPA (a predecessor organisation of Public Health England [PHE] that was formed in April, 2013). A sampling frame based on those adult prisons covered by the HPA's sentinel surveillance study for hepatitis C was used to select 21 prisons for audit. Prisons were then selected to ensure representation of the institutions identified in the whole estate by security category, population size, and geographical distribution in England. The sampling strategy was as follows: four category B (at least one of each size); seven category C or D (at least two of each size); one female (any size); one high security (any size); and eight local prisons (only large and medium in sample frame). A letter was sent by the National Offender Management Service, the HPA, and DoH to prison governors and health-care managers. Completion of the audit was not mandatory. Findings Only one prison did not respond (95% response rate) and we used another prison from the same region and of the same category to replace it. Six (29%) of 21 prisons had a steering group to oversee the testing, treatment, and care strategy in prisons. 13 (62%) had a written hepatitis C policy or equivalent document. 11 (52%) had blood-borne virus information available in the induction programme for new prisoners. Disinfectant tablets were available in 17 prisons (81%). 13 prisons (62%) stated that blood samples were automatically tested by PCR. 16 (76%) had documented guidelines requiring a pretest discussion and 15 (71%) a post-test discussion. The most common service delivery model was hospital outpatient (11 of 21 [52%]), followed by hospital in-reach (nine of 21 [43%]) and general practitioner led (one of 21 [5%]). 18 prisons (86%) reported that they always or sometimes place prisoners on medical hold. 17 prisons (81%) had training in blood-borne viruses for health-care staff; ten (48%) had training for prison officers; and 12 (57%) had training for drug workers. There are limitations to the audit because it is based on self-reporting from the prison. Also, the audit represents 17% of the total number of adult prisons in England. Interpretation The audit highlighted areas of good practice as well as areas of concern; the findings are now being used to drive an improvement in the commissioning and service delivery of hepatitis C services nationally. The audit showed a scarcity of provision for in-reach hospital services. A set of 12 recommendations were made, which included the need for PHE and National Health Service England to coproduce a high-level service specification in relation to hepatitis C to ensure that all prisons and detention centres are consistently delivering good quality and accessible care in line with the good practice described in the audit. This recommendation has already started to be addressed nationally. Funding None.

Introduction Traditionally plastic stents (PS) are inserted at the index ERCP to treat obstructive jaundice from malignant distal biliary strictures. However, with the development of fully covered metal stents (C-SEMS), this approach is now debated and practise at the Royal Liverpool Hospital (RLH) has now changed towards preference for C-SEMS in this clinical scenario. This of course has cost implications as C- SEMS are 15–20 times more expensive than plastic stents. The aim of this study is to determine the benefit of C-SEMS over PS placement, to answer the question which stent should be inserted at the index ERCP if a patient presents with malignant obstructive jaundice Methods A retrospective audit was performed of patients undergoing ERCP with placement of plastic or SEMS for obstructive jaundice due to malignant distal biliary strictures at the RLH between March 2007 and December 2012. Clinical history, course and outcomes from MDT documents, electronic patient records and the endoscopy database were recorded on a standardised proforma. Only PS and C-SEMS insertion at the index ERCP were included. Results Of 147 patients identified, 72 were excluded (bare metal stents or partially covered metal stents placed). This left 43 in PS group and 32 in C-SEMS group. 21 patients underwent surgical resection; 17 within PS and 4 within C-SEMS. Of these no patient with C-SEMS but 3 (18%) patients with plastic stents required re-intervention prior to surgery due to stent dysfunction. In the remaining palliative patients (PS: n = 26 and C-SEMS: n = 28), 19 with plastic stents (73%) and 3 patients with SEMS (7%) required endoscopic re-intervention due to stent dysfunction (p Conclusion Placement of a fully covered SEMS (C-SEMS) at index ERCP offered a definitive procedure in majority of patients compared to plastic stent (PS) which was just over half. Whilst C-SEMS significant more expensive than PS, this increased cost may be potentially be offset by the reduction in the need for repeat ERCP intervention and subsequent stent insertions. A full cost analysis is currently being undertaken. Disclosure of Interest None Declared

s / Pancreatology 13 (2013) e1–e94 e60 months (19.3-38.6) in localized disease; 11 months (10.2-11.7) in regional stage and 3 months (2.8-3.1) in distant stage disease. Younger age, localized disease, curative intent surgery, radiotherapy, more recent year of diagnosis (2002-2008 vs 1988-1994) [but not gender, race, geographic location] were associated with increased survival. Conclusions: Although there has been a decrease in the age-adjusted incidence rate and mortality from PMC in recent years, most patients are diagnosed at an advanced stage, and this tumor has a poor prognosis. Efforts to recognize malignancy in mucinous pancreatic cysts and earlier diagnosis are warranted.

Nigel B. Jamieson , Nigel I.J. Chan , Alan K. Foulis , Euan J. Dickson , Colin J. McKay , C. Ross Carter . West of Scotland Pancreatic Unit, College of Medical, Veterinary and Life of Sciences, University of Glasgow, UK University Department of Surgery, Academic Unit of Surgery, College of Medical, Veterinary and Life of Sciences, University of Glasgow, UK Department of Pathology, Glasgow Royal Infirmary, Alexandra Parade, Glasgow, G31 2ER, UK

The value of an endoprosthesis for long-term management of bileduct stones has not been formally established. The main theoretical advantage of endoprosthesis insertion (BE) over conventional endoscopic duct clearance (DC) is the prevention of stone impaction, with obstruction and consequent cholangitis or pancreatitis. In a randomised study we compared the results of these two methods in patients with symptomatic bileduct stones who were at high risk because of old age (70 yr) or serious debilitating disease.43 high-risk patients were randomised to BE with a 7F double-pigtail endoprosthesis and0.75 cm sphincterotomy, and 43 to DC with standard 1.25-1.50 cm sphincterotomy and stone extraction by balloon or basket, with or without mechanical lithotripsy. The principal endpoint was the rate of biliary related complications.In the BE group biliary drainage was achieved in the first session in all but one patient (who required 2 sessions). In the DC group, 24 patients had duct clearance at the first attempt and 35 (81%) after a median of 2 sessions (range 2-4); eight of this group had an endoprosthesis inserted to maintain long-term drainage. At 72 h the complication rates were 7% in the BE group and 16% in the DC group (p = 0.18). However, the long-term complication rate for BE was higher: by Kaplan-Meier analysis, at a median of 20 months the proportions free of biliary complications were 64% BE and 86% DC (p = 0.03, log-rank test).For immediate bileduct drainage, endoprosthesis insertion proved a safe and effective alternative to duct clearance. Because of the risk of subsequent cholangitis, its use as a definitive treatment should be confined to highly selected cases.

Introduction Patients who have a high risk of developing pancreatic cancer (FPC) may have pre-malignant molecular changes and have been enrolled in a EUROPAC Study to conduct diagnostic ERCP for the collection of pancreatic juice. 1 2 These otherwise healthy patients have been identified as a higher risk group for ERCP-induced pancreatitis. 3 To reduce the incidence of post-ERCP pancreatitis a self-expelling plastic stent is routinely inserted into the pancreatic duct after ERCP. Stents have been shown to reduce pancreatitis in small cohorts but previous spontaneous intraluminal migration has been quoted at 67% for pancreatic stents. 4 5 Methods Prospective observational study of 24 patients who underwent ERCP and secretin stimulated collection of pancreatic juice as part of the EUROPAC study. No pancreatic or biliary disease was present. In all patients a plastic stent was inserted (3 cm 5 Fr Zimmon, Cook Medical © ) to avoid post-ERCP pancreatitis. Plain abdominal x-ray was requested at 6 weeks post-ERCP to assess expulsion of the stent. Complications were recorded. Results Of the 24 participants 16 were female. Abdominal x-rays were obtained in all patients at a median of 6 weeks (5–12 weeks) post-ERCP. Stents were retained in 2 (8.3%) patients. Spontaneous stent self-expulsion rate was therefore 91.7%. There were no other compliations. Hyperamylaseaemia occurred in 2 (8.3%) patients—unrelated to stent retention. Prior to routine stent insertion pancreatitis occurred in seven patients (46%), thus we have shown a reduction in ERCP-induced pancreatitis (p=0.003). Conclusion In the absence of pancreatic and biliary disease stents will self-expel by 12 weeks. We have also shown that the deployment of small pancreatic stents is safe and well tolerated. Comparison with ERCP performed prior to routine stent placement has shown a significant reduction in the rate of pancreatitis. Both retained stents were removed without complication by a standard OGD. Competing interests None declared. References 1. Greenhalf W , et al. Screening of high-risk families for pancreatic cancer. Pancreatology 2009; 9 :215–22. 2. Grocock CJ , et al. Familial pancreatic cancer: a review and latest advances. Adv Med Sci 2007; 52 :37–49. 3. Williams EJ , et al. Risk factors for complication following ERCP: results of a large scale, prospective, multicentre study. Endoscopy 2007; 39 :793–801. 4. Singh P , et al. Does prophylactic pancreatic stent placement reduce the risk of post-ERCP acute pancreatitis? A meta-analysis of controlled trials. Gastrointest Endosc 2004; 60 :544–50. 5. Chahal P , et al. Pancreatic stent prophylaxis of post endoscopic retrograde cholangiopancreatography pancreatitis: spontaneous migration rates and clinical outcomes. Minerva Gastroenterol Dietol 2007; 53 :225–30.

A 74-year-old Caucasian female presented with a 12 month history of non-bloody, culture-negative diarrhoea associated with weight loss of 10 kg. She denied any extragastrointestinal manifestations. She had previously undergone orthotopic liver transplantation for primary biliary cirrhosis 12 years ago. Her immunosuppression was mycophenolate mofetil 500 mg twice daily for the past 2 years. She had previously been on ciclosporin but this was discontinued due to renal impairment. Baseline bloods revealed: haemoglobin 9.6 g/dl (mean corpuscular volume (MCV) 85 fl), C-reactive protein 76 mg/l and normal renal and liver biochemistry. She was euthyroid, and coeliac serology was negative. Colonoscopy demonstrated moderate, patchy mucosal inflammation predominantly affecting the proximal colon (figure 1). Multiple biopsies were obtained. Figure 1 Ascending colon. What is the diagnosis? What is the best management? See page 1302 for the answers From the questions on page …

The insertion of percutaneous endoscopic gastrostomy has been well documented. The possible benefits for patient nutrition and nursing practice have, however, not been assessed. We report a study of enteral feeding by percutaneous endoscopic gastrostomy in 30 patients, the majority with a persistent vegetative state. All patients had previously been fed through a nasogastric tube using manual administration and a dietitian assessed protein calorie intake. Based upon body mass index (weight/height2), midarm circumference and triceps skinfold thickness, 20 (67%) were malnourished, with 10 patients having a body mass index less than 17 (severe malnutrition); attributed to high rates of both tube displacement and feed regurgitation. Patients were observed over six to 12 months after percutaneous endoscopic gastrostomy insertion combined with overnight continuous pump feeding. All patients attained a body mass index greater than 17, and 17 (56%) of the total number achieved the normal range with no change in protein-calorie intake (pre: 2110 kcal, post: 1880 kcal). Complications of percutaneous endoscopic gastrostomy in the study group included peritonitis (one), tube site infection (two) and displacement (two); all without serious sequelae. As part of an integrated approach percutaneous endoscopic gastrostomy proved a safe and efficient method of enteral feeding and justifies wider consideration in the United Kingdom.

The liver may be involved in generalized immunoinflammatory reactions or may become the target for an organ-specific immune attack. Specific cell types (e.g., epithelial cells, hepatocytes) may be preferentially affected during such a reaction, giving rise to a number of clinical syndromes. The etiologic agents and pathogenetic mechanisms are still incompletely understood, but nevertheless have allowed clinical trials of immunotherapy to be conducted. In this chapter we discuss the possible immunopathogenetic mechanisms resulting in different patterns of liver disease, the rationale behind specific therapeutic regimens, and the difficulties in assessing these. We also review the data from reported therapeutic trials.

Six jaundiced patients with primary sclerosing cholangitis and a dominant biliary stricture were managed by endoscopic placement of endoprostheses. Five showed considerable improvement within weeks of stenting: their serum bilirubin concentration fell from mean (range) 266 mumol/l (63-681) to 65 mumol/l (10-280) after one month. One patient required a liver transplant at five months because of continued deterioration in hepatic function. Follow up of 12-49 months in the remaining five patients shows sustained biochemical improvement, with repeat cholangiograms indicating doubling of the minimum calibre of the extrahepatic bile duct in four patients and considerable shortening of stricture length in three. Three patients developed sepsis at the time of the initial endoprosthesis insertion: surgical drainage was necessary in one. Endoscopic methods of improving biliary-enteric drainage in jaundiced patients with primary sclerosing cholangitis may be preferable to surgical and percutaneous methods, which may complicate subsequent liver transplantation.

SUMMARY Reduced suppressor cell number and function have been described in a number of autoimmune diseases and this may contribute to pathogenesis. Suppressor cell function depends upon the interaction of the CD8 antigen expressed on suppressor cells with other limbs of the immune system. Recently, soluble membrane antigens including CD8 have been identified in serum and it is possible that the loss of such antigens from viable cells could result in functional deficit. In order to examine whether the decreased suppressor cell function reported in autoimmune type of chronic liver disease is associated with soluble serum CDS levels, sera from 23 patients with primary biliary cirrhosis (PBC). 12 with autoimmune chronic active hepatitis (AI-CAH) and 21 healthy controls were tested using a commercially available enzyme immunoassay. The proportion of cells expressing the CDS antigen and the intensity of its display were also determined using an immunofluorescent technique and an ELISA, respectively, for 12 PBC and 10 healthy controls. The soluble serum CDS levels were significantly higher in PBC (mean U/ml.s.d., 777.331). and AI-CAH (575±291) than controls (322±115) (P < 0.001 and P = 0004, respectively). While the intensity of CDS antigen expression on suppressor/cytotoxic populations was not significantly different in PBC (347±125 per 104 cells) compared with controls (441 ±206). the mean proportion of CDS positive cells was significantly less in PBC (14.1±6.8%) than controls (20.4±7%) (P < 0.05). These data suggest that the apparent reduction in suppressor cell number found for patients with PBC and AI-CAH may be a consequence of the shedding or secretion of CDS antigen from cell membrane of CDS positive lymphocyte. It is also possible that the loss of this antigen is responsible for the reduced suppressor cell function seen in these conditions.

Circulating osteocalcin, a non-collagen bone protein is considered a useful indirect index of turnover. Osteocalcin levels were measured by radioimmunoassay in 57 female patients with primary biliary cirrhosis (PBC) from two centres, 52 normal female controls, 11 female patients following liver transplantation for PBC and seven female patients with PBC treated with Ciclosporin. Serum levels were significantly less in the PBC group (median 10 ng/ml) compared to normals (median 15 ng/ml: p less than 0.001). Patients with PBC treated with Ciclosporin had significantly higher levels than untreated patients (median 23 ng/ml: p less than 0.001). Levels also increased significantly following transplantation when all patients were receiving Ciclosporin (median 40 ng/ml: p less than 0.001). The results suggest that the abnormal bone metabolism of PBC is significantly altered by Ciclosporin and liver transplantation.