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Objectives: The early life microbiome has been linked to inflammatory diseases in adulthood and a role for the microbiome in bile duct inflammation is supported by both human and murine studies. We utilized the NOD.c3c4 mouse model that develops a spontaneous immune-driven biliary disease with a known contribution of the microbiome to evaluate the temporal effects of the early life microbiome., Materials and Methods: Germ-free (GF) NOD.c3c4 mice were conventionalized into a specific pathogen free environment at birth (conventionally raised, CONV-R) or at weaning (germ-free raised, GF-R) and compared with age and gender-matched GF and conventional (CONV) NOD.c3c4 mice. At 9 weeks of age, liver pathology was assessed by conventional histology and flow cytometry immunophenotyping., Results: Neonatal exposure to microbes (CONV-R) increased biliary inflammation to similar levels as regular conventional NOD.c3c4 mice, while delayed exposure to microbes (GF-R) restrained the biliary inflammation. Neutrophil infiltration was increased in all conventionalized mice compared to GF. An immunophenotype in the liver similar to CONV was restored in both CONV-R and GF-R compared to GF mice displaying a proportional increase of B cells and reduction of T cells in the liver., Conclusions: Microbial exposure during early life has a temporal impact on biliary tract inflammation in the NOD.c3c4 mouse model suggesting that age-sensitive interaction with commensal microbes have long-lasting effects on biliary immunity that can be of importance for human cholangiopathies.

Research related to primary sclerosing cholangitis (PSC) has since 1980 been a major activity at the Oslo University Hospital Rikshospitalet. The purpose of this publication is to describe the development of this research, the impact of this research on the clinical handling of the patients, and finally to describe what we believe are the most urgent, remaining problems to be solved. During the early years, our research dealt primarily with clinical aspects of the disease. The concomitant inflammatory bowel disease (IBD) seen in most patients with PSC was a major interest and we also started looking into genetic associations of PSC. Prognosis, malignancy development and treatment with special emphasis on transplantation have later been dealt with. These activities has had impact on several aspects of PSC management; when and how to diagnose PSC and variant forms of PSC, how to handle IBD in PSC and how to deal with the increased rate of malignancy? The problems remaining to be solved are many. What is the role of the gut and the gut microbiota in the development of PSC? Do the PSC patients have an underlying disturbance in the bile homeostasis? And how does the characteristic type of fibrosis in PSC develop? The genetic studies have supported a role for the adaptive immune system in the disease development, but how should this be dealt with? Importantly, the development of malignancy in PSC is still not understood, and we lack appropriate medical treatment for our patients.

Aim and Background: The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013., Materials and Methods: The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report., Results: Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively., Conclusion: The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).

Objective: Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant., Material and Methods: In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis., Results: Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0-50) years at the time of Ltx and follow-up after Ltx was 5 (0-20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3-2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia., Conclusion: The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated.

Objective: Hepatitis C virus (HCV) cirrhosis is the most common indication for liver transplantation (LTX) world-wide. The prevalence of HCV infections is much lower in Norway than in most other countries from which data on HCV infection and liver transplantation have been published., Material and Methods: Patients with HCV infection referred for evaluation of a possible LTX between 1990 and 2005 were included in the study. Their clinical status, biochemical parameters and risk factors were recorded. All patients were followed until 1 January 2005 irrespective of transplantation status., Results: Fifty-one patients were included; 80% were males and 18% were non-Caucasians. Previous intravenous drug abuse (28%) and exposure to contaminated IgG products (15%) were the most common routes of infection. In 45/51 (88%) of the evaluated patients at least one risk factor for rapid progression of HCV disease was identified. Twenty-seven patients were accepted on the waiting list. The MELD (model for endstage liver disease) score for the accepted patients was significantly higher than that for the patients who were not listed because they were found to be too healthy (18.4 versus 12.1, p<0.01). Twenty-four patients (89% of those listed) received a liver allograft; their 1-, 3- and 5-year survival rates following LTX were 81%, 68% and 68%, respectively. Two patients needed a second transplantation., Conclusions: A low number of HCV-infected patients have so far been evaluated for LTX in Norway. The present study demonstrates that almost all of the HCV patients progressing to cirrhosis and being evaluated for LTX in Norway have additional risk factors for development of cirrhosis.

Objective: Primary sclerosing cholangitis (PSC) is currently thought to be an immune-mediated disease, where both host genes and environmental factors interact. Some of the immunoregulatory genes responsible for individual susceptibility to PSC have been identified. The co-stimulatory receptor gene cluster on chromosome 2q33 encodes both the positive T-cell regulators CD28 and ICOS, and the negative regulator CTLA4. The CTLA4 gene has been implicated in several immune-mediated diseases, but it is not known whether PSC is associated with any of these genes., Material and Methods: Polymerase chain reaction (PCR)-based genotyping was performed on 144 PSC patients and 285 controls. Two single nucleotide polymorphisms (SNPs) in the CTLA4 gene were investigated as well as six microsatellites covering approximately 262 kb of the flanking regions, including the ICOS and CD28 genes., Results: Overall, there were no statistically significant differences between PSC patients and controls in genotype and allele frequencies for the CTLA4 +49AG and CT60 SNPs or for the CD28-A, CD28-B, SARA43, SARA1, SARA31, and SARA47 microsatellite markers. Nor were any associations with clinical subgroups observed., Conclusions: There are no major effects of the CD28/CTLA4/ICOS gene region on susceptibility to PSC, but minor contributions (OR <1.8) cannot be excluded.

Background: Primary sclerosing cholangitis (PSC) is the most common indication for liver transplantation in the Nordic countries. Because these patients are difficult to evaluate with regard to timing of liver transplantation, it is important to establish predictors of post-transplant survival., Methods: Data from two groups of patients receiving liver allografts during 1982-2001 were recorded: (a) PSC patients and (b) comparison patients. Outcome following transplantation has been recorded for all patients. Regression analyses have been performed for PSC patients to analyse predictors of patient and graft survival., Results: A total of 245 PSC and 618 comparison patients received a first liver allograft in the period 1982 until the end of the study. The overall 1-, 3- and 5-year patient survival rates were 82%, 77% and 75%, and 80%, 77% and 74% in the PSC group and comparison group, respectively. Survival following transplantation has increased with time in both the PSC and the comparison group. Recent year of transplantation, no previous hepatobiliary surgery and a lower MELD score were predictors of survival following transplantation for PSC patients. PSC patients had a higher rate of re-transplantations (13% versus 8%, P = 0.01). Predictors of re-transplantation in PSC patients were an episode of early rejection and vascular thrombosis., Conclusion: In PSC patients, year of transplantation, previous hepatobiliary surgery and MELD score are predictors of survival following transplantation and these patients are more frequently in need of re-transplantation compared to the comparison group.

Background: A beneficial effect of corticosteroids in primary sclerosing cholangitis (PSC) has been suggested, but characteristics of responding patients and long-term outcome have not been assessed. In this retrospective study, we aimed to characterize PSC patients selected for corticosteroid treatment at our centre and to identify potential factors associated with response., Methods: We first compared groups of PSC patients treated (n = 47) and not treated (n = 88) with corticosteroids. Responding (n = 20) and non-responding (n = 27) patients were subsequently compared. Complete and partial responses were defined according to criteria established for autoimmune hepatitis. A third response category included improvement of symptoms and at least 50% reduction of transaminase and/or bilirubin levels during the first 6 months., Results: At diagnosis of PSC, patients treated with corticosteroids were significantly younger, had higher serum levels of alanine transaminases, and more histological features of autoimmune hepatitis compared to the non-treated group. Complete treatment response was obtained in three patients and partial response in two, together comprising 3.7% of all PSC patients in this study. Fifteen patients fulfilled criteria of the third response category. Response to treatment was associated with higher serum levels of alanine transaminases and bilirubin and lower levels of alkaline phosphatases at treatment start. Responders had better long-term survival than non-responders (hazard ratio 6.28; 95% confidence interval 1.62 to 24.4; P = 0.008)., Conclusions: A subgroup of PSC patients seems to respond favourably to corticosteroid treatment and may obtain improved long-term survival.

Background: Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation., Methods: A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A--chronic cholestatic liver disease (n = 28), and group B--chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-1-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals., Results: BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving cyclosporin A., Conclusion: Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Background: Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation., Methods: A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A-chronic cholestatic liver disease (n = 28), and group B-chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-l-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals., Results: BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving'cyclosporin A., Conclusion: Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Background: Primary sclerosing cholangitis (PSC) confers a high risk of cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected for early liver transplantation, it is a challenge to identify any predisposing factors. We compared the presentation and natural history of a large number of PSC patients with and without later CC development to identify features associated with risk of CC., Methods: Clinical and laboratory data from presentation and follow-up were collected from 394 PSC patients from five European countries. The cohort included 48 (12.2%) patients with CC., Results: CC was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus, abdominal pain and fatigue were significantly more frequent at diagnosis of PSC in the group that developed CC, but not after exclusion of cases diagnosed within the first year. Inflammatory bowel disease was diagnosed at least 1 year before PSC more often among patients with CC development than among those without (90% and 65%, respectively: P = 0.001). The duration of inflammatory bowel disease before diagnosis of PSC was significantly longer in patients who developed CC than in the remaining group (17.4 years and 9.0 years, respectively: P=0.009 in multivariate analysis)., Conclusions: A high proportion of CC cases is diagnosed within the first year after diagnosis of PSC. A long history of inflammatory bowel disease is a risk factor for CC development.

Background: An improvement of prognostic models in primary sclerosing cholangitis (PSC) is needed. In particular, inclusion of prognostic markers that are independent of the disease stage would be advantageous. We investigated whether HLA class II genes associated with PSC are also related to disease progression., Methods: The study included 265 PSC patients from five European countries with a median follow-up of 9.1 years. The end-points were death (n = 38) or liver transplantation (n = 52). Thirty patients developed cholangiocarcinoma during follow-up., Results: The DRB1*03,DQA1*0501, DQB1*02 (i.e. DR3,DQ2) heterozygous genotype was associated with an increased risk of death or liver transplantation (hazard ratio = 1.63; 95% confidence interval (CI) = 1.06-2.52). The presence of a DQ6 encoding haplotype (DQB1*0603 or DQB1*0602) in DR3,DQ2 negative individuals was associated with a reduced risk of death or liver transplantation (hazard ratio = 0.57; 95% CI = 0.36-0.88). There was a trend towards an increased risk of developing cholangiocarcinoma among DR4,DQ8 positive patients, but this did not reach significance (odds ratio = 2.27; 95% CI = 0.78-6.62)., Conclusion: The DR3,DQ2 heterozygous genotype is associated with a more rapid progression of PSC, whereas HLA-DQ6 is associated with a retarded disease progression. It is possible that the DR4,DQ8 haplotype is related to cholangiocarcinoma development.

Exertional heat stroke usually occurs in warm climates. Increased serum levels of liver enzymes is a common finding in this condition, whereas liver failure is a more rare event that carries a poor prognosis. Liver transplantation has been recommended as treatment in cases of severe liver failure, but no long-term survival after this procedure in exertional heat stroke has been described. We report the case of a 31-year-old man who had a heat stroke after running 5 km at 21 degrees C. He developed severe liver damage, with serum alanine aminotransferase (ALAT) activities increasing to 16,410 U/l (reference values, 10-50 U/l) after 48 h, concomitantly with a pronounced coagulation disturbance, with Normotest (NT) decreasing to 12% (international normalized ratio (INR) = 4.2) (reference values, 70%-130% for NT and 0.8-1.2 for INR). A liver biopsy on the 5th day after the incident showed extensive liver cell necrosis. The patient was referred to be considered for liver transplantation but recovered completely on conservative treatment. We conclude that exertional heat stroke is a diagnostic possibility also in temperate climates and that severe liver failure may ensue. The liver injury is reversible, and the indications for liver transplantation in this situation have not been clarified.

Background: Liver transplantation has become an established therapeutic option for patients with life-threatening liver disease. The aim of the present study was to analyse the results of and developments in liver transplantation in the Nordic countries during a 15-year period., Methods: Data on all patients receiving a liver allograft in the Nordic countries during 1982-98 and waiting list data for all patients listed for a liver transplantation after 1989 were obtained from the Nordic Liver Transplantation Registry., Results: A total of 1485 first liver transplantations were performed during 1982-98. The annual number of first liver transplantations increased steadily up to 1993, thereafter remaining around 150-170 per year. There are major differences between countries both in the number of transplants adjusted to populations performed per year, with more than twice as many performed in Sweden as in Norway, and in the relative distribution of patients in accordance with diagnosis. The number of patients more than 60 years old increased and comprised 13%-14% of the total patient population during 1996-98. Primary biliary cirrhosis, primary sclerosing cholangitis, acute hepatic failure, malignant liver disease, and alcoholic cirrhosis are the five most frequent diagnoses. The over-all 1-year patient survival probability has increased from 66% among patients receiving a transplant in 1982-89 to 83% in 1995-1998. The waiting time remains stable, with a median waiting time of 35 days during 1990-98. The mortality of patients while on the waiting list is 7.4% and is not increasing., Conclusion: Results of liver transplantation in the Nordic countries are very similar to those obtained in other countries. Waiting time and mortality remain low. There are, however, major differences between the countries both as to the number of transplantations performed and as to distribution of diagnoses.

Liver transplantation was performed in a patient with primary hypogammaglobulinaemia, chronic hepatitis C and hepatic failure. The immediate posttransplant period was uncomplicated. Owing to a stricture of the choledochojejunostomy the patient was reoperated with construction of a hepaticojejunostomy 11 months posttransplant. The patient remained hepatitis C virus (HCV) RNA-positive, with high and increasing levels of HCV. Liver biopsies demonstrated the recurrence of HCV. 14 months after the transplantation the patient developed severe diarrhoea caused by Cryptosporidium parvum. The infection did not respond to available therapeutic measures. He deteriorated with development of liver failure and died 18 months after the transplantation. The present case report illustrates the difficulties associated with organ transplantation in patients with primary hypogammaglobulinaemia.

Background: Many patients with chronic hepatitis C have long periods of normal or near-normal liver enzyme levels, even though histologic alterations have been confirmed. The recommendation today is not to treat this patient group., Methods: In a pilot study 23 hepatitis C virus (HCV) RNA-positive patients with alanine aminotransferase (ALAT) levels less than 1.5 times upper normal limits for at least 6 months on more than three occasions and with histologic liver abnormalities compatible with chronic hepatitis C were treated with 3 MU of interferon-alpha 2b three times a week for 6 months., Results: Nine patients (39%) became HCV RNA-negative in serum during treatment, but only two (8.7%) remained so after 6 months' follow-up. Significantly more patients with genotype other than type 1 became HCV RNA-negative than patients with genotype 1 during treatment (P = 0.005)., Conclusions: Patients with low-activity chronic hepatitis C have a response to interferon-alpha treatment similar to that of patients with increased ALAT levels. Genotype seems to influence the rate of response.

Background: Previous studies have suggested abnormal copper metabolism in patients with primary sclerosing cholangitis (PSC). In the present work the trace element metabolism was studied in a group of 32 patients with PSC., Methods: Hepatic copper and selenium concentrations were determined with a sensitive electrothermal atomic absorption technique. Serum concentrations of copper and zinc were determined by conventional atomic absorption., Results: For the patient group serum copper values (20.3 +/- 4.5 mumol/l) were higher than those for the control group (14 +/- 3 mumol/l), and average hepatic copper concentrations were greater by a factor of four. Serum selenium values were slightly lower, although the average hepatic selenium was significantly higher than in the healthy control group. Previous studies have discussed possible toxic effects of hepatocellular copper accumulation, which may be accompanied by formation of activated oxygen species and depletion of glutathione. In the present study, however, it could not be demonstrated that the concentration of the lipoperoxidation product, malonic dialdehyde, was higher than normal in blood. Furthermore, blood concentrations of glutathione and glutathione peroxidase were not abnormal., Conclusion: Although a protective effect of the raised selenium concentrations in the liver might be discussed, it is apparent that the copper accumulation in the liver cells described here did not induce detectable changes in the indices studied.

Background: Mid-gut carcinoid tumours often present with liver metastases, and survival has then been less than 2 years in earlier reports. We have evaluated the effects of interferon therapy on clinical response and survival, with or without hepatic artery embolization in these patients., Methods: In a prospective study 30 female and 12 male patients, aged 23 to 75 years, with mid-gut carcinoid tumours and liver metastases underwent surgery with removal of as much as possible of their primary tumour. If technically feasible, embolization of hepatic arteries was performed in the absence of contraindications. Seventeen patients were embolized, and all patients received interferon-alpha 2b treatment for 1 year. Response factors were computer tomography (CT) measurement of the largest liver metastasis and the 24-h urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA). After 12 months patients with objective response or stable disease either continued or withdrew from interferon therapy. Survival was estimated when all patients had been observed for at least 36 months., Results: Nine patients reduced the dose, and five withdrew from interferon treatment owing to side-effects the 1st year. Three patients died. Fifteen patients (39%) showed objective response 12 months after inclusion. Cumulative 5-year survival estimated from inclusion was 37.5% in all 42 patients but 71.4% in those who continued interferon therapy. The difference in survival between the interferon-treated and those who withdrew from interferon therapy at 12 months was significant when embolization was corrected for in a Cox model (p < 0.0125). The seemingly increased survival in embolized versus non-embolized patients did not reach statistical significance (p = 0.07)., Conclusion: Interferon induced an objective response in mid-gut carcinoid patients as judged by the 24-h urinary 5-HIAA excretion. Patients receiving continuous interferon therapy showed improved response and survival compared with patients who stopped the treatment. Regardless of medical therapy, more survivors and more responders, as evaluated from CT measurements, were found among the embolized patients than among the non-embolized. Embolization could, however, not be shown to have a significant effect on survival.

Background: Hepatic involvement in hereditary haemorrhagic telangiectasia (HHT) consisting of fibrosis, telangiectases, and cirrhosis, has been reported as a relatively frequent finding., Case: A 50-year-old man with HHT presented with monstrous ascites. Liver biopsy demonstrated multiple dilated sinusoids but not cirrhosis. There were no findings indicative of portal hypertension or malignant disease. Portal pressure, recorded in hepatic vein wedge position, was normal. Arteriography showed numerous hypervascular lesions throughout the liver. The clinical course has been stable for more than 2 years., Conclusion: No other reason for the monstrous ascites could be found. We thus hypothesize that this case of monstrous ascites is due to hepatic involvement in HHT, presenting as numerous vascular lesions throughout the liver.

Background: Duodenal and gastric content of mucosal enzymes in duodenal ulcer (DU) patients differs from that of controls. The purpose of this study has been to examine the effect of omeprazole and eradication of Helicobacter pylori on mucosal enzymes in DU patients., Methods: The enzyme activities of seven gastric and duodenal mucosal marker enzymes from the brush border, lysosomes, and mitochondria have been studied. In study I the measurements were made in 29 patients with an active DU before and after 14 days of omeprazole treatment. In study II 22 duodenal ulcer patients were given bismuth subnitrate, oxytetracycline, and metronidazole (triple therapy) for 2 weeks to eradicate H. pylori. Biopsy specimens were taken from the duodenum and the stomach for enzyme measurements and histologic assessment. In study II additional specimens were obtained from the prepyloric region for urease tests and culture of H. pylori., Results: The ulcer healing rates were more than 90% after both omeprazole and triple therapy. H. pylori was eradicated in 86% after triple therapy. The activities of the brush-border enzymes lactase, neutral-alpha-glucosidase, alkaline phosphatase, leucyl-beta-naphthylamidase, and gamma-glutamyltransferase (gamma-GT) increased significantly in the duodenal bulb and the descending duodenum during treatment with omeprazole. No changes in duodenal enzyme activity were detected after triple therapy, whereas a significant fall in gamma-GT and acid phosphatase activities was seen in the stomach. The mucosal DNA in the gastric antrum decreased both after treatment with omeprazole and after triple therapy., Conclusions: A similar decrease in mucosal DNA of the gastric antrum was demonstrated after both omeprazole and triple therapy with bismuth subnitrate, oxytetracycline, and metronidazole. Omeprazole also affects the content of duodenal mucosal enzymes, whereas triple therapy particularly affects the gastric mucosal enzyme activity.

Background: The aim of the present study was to describe the characteristics of patients with ulcerative colitis (UC) and hepatobiliary disease that does not satisfy the diagnostic cholangiographic criteria of primary sclerosing cholangitis (PSC) and to compare this group with PSC patients., Methods: Among 199 patients with UC admitted to our department during 1986-91, 64 patients had major hepatobiliary disease considered to be associated with the colitis. Biochemical tests, colonoscopy, endoscopic retrograde cholangiography (ERC), and liver biopsy were performed in these 64 patients and in 5 patients from our outpatient clinic., Results: PSC was diagnosed in 51 patients (group I; 80%). The other 13 patients (20%) and the additional 5 patients (n = 18; group II) all had normal extrahepatic bile ducts. Five patients in group II also had normal intrahepatic ducts, whereas 13 patients had intrahepatic abnormalities. The male to female ratio in group II was 2.0:1. All of them had extensive colitis. The clinical symptoms and the biochemical and histologic findings were quite similar in groups I and II., Conclusions: The patients in group II of this study constitute a major group with hepatobiliary lesions associated with UC, amounting to one-fourth the number of PSC patients. They have several similarities with classical PSC of the large bile ducts, and we suggest that they be classified as having small-duct PSC.

In a prospective study of 16,756 consecutive blood donors, we found 54 donors (0.3%) to be anti-hepatitis C virus (HCV)-positive by a first-generation enzyme-linked immunosorbent assay. After retesting, 18 donors were confirmed positive or indeterminate by a second-generation recombinant immunoblot assay. Sixteen of these donors were found positive by a second-generation enzyme-linked immunosorbent assay, and 15 of these were positive by HCV polymerase chain reaction with two primer sets. Nine donors (50%) had a history of drug abuse. In 15 donors found positive by a second-generation enzyme-linked immunoblot assay liver biopsy specimens were taken after at least 6 months' follow-up. In all except one hepatitis C RNA-negative donor, histologic abnormalities were observed, even when alanine aminotransferase (ALAT) levels were continuously normal or only moderately elevated. The abnormalities were less pronounced in these donors (n = 5) than in donors with ALAT levels increased more than twice the upper normal limit (p < 0.05). In conclusion, we found the proportion of previous drug abusers in anti-HCV-positive blood donors to be high. We confirm that the presence of anti-HCV (second generation) usually, and HCV-RNA always, seems to indicate ongoing infection--also when ALAT levels are normal. Our study further suggests that low-activity hepatitis, evaluated by ALAT levels, may indicate a milder disease.

The etiology and pathogenesis of the inflammatory and fibrotic bile duct lesions characteristic of primary sclerosing cholangitis (PSC) is unknown, but several lines of evidence support the contention that genetic and immunologic factors are involved. There is an association with human leukocyte antigens (HLA) with an increased frequency of DR3, DR6, and DR2 positive haplotypes. DRB3*0101(DR52a) is the most strongly associated allele in some studies, but the HLA gene conferring the primary HLA associated susceptibility to PSC remains to be established. There is an aberrant expression of HLA class II antigens (DR and DP) on bile duct epithelial cells, with the potential to present antigens to the surrounding T-lymphocytes. A defective suppressor T-cell function has been suggested in some studies. The patients may have elevated levels of circulating immune complexes, immunoglobulins, and non-organ-specific autoantibodies. Antibodies to perinuclear antigens (pANCA) are present in about 80% of cases. Increased metabolism of complement C3, reduced clearance of immune complexes, and increased concentration of biliary immune complexes have been found. The strong association between PSC and ulcerative colitis (UC) has not been explained. The detection of circulating IgG antibodies against a specific epitope shared by epithelial cells in the bile ducts and colon in about two-thirds of PSC patients may be of importance. Portal bacteremia secondary to a diseased bowel may possibly contribute to development of liver disease in UC. Viral infections and toxic and ischemic factors have also been implicated in the pathogenesis of PSC. In conclusion, PSC seems to occur in genetically predisposed individuals, mediated by immunologic mechanisms. The primary event triggering the disease development is, however, unknown.

Twenty patients with histologically verified carcinoid liver metastases underwent a total of 24 liver artery embolizations by means of interventional radiologic techniques. There were no deaths. The postembolization syndrome, consisting of fever, abdominal pain, nausea, and vomiting, occurred in all the patients. Severe complications were rare, the most serious being multiple hepatic abscesses with septicemia in one patient, septicemia in another, and mild acute pancreatitis in a third. All these three patients recovered without any sequels from the embolization, and none required surgical intervention. The hepatic abscesses were drained percutaneously, guided by ultrasound. Hepatic artery embolization seems justified in patients with disabling symptoms from the carcinoid syndrome, as long as alternative therapy with the same benefit but fewer complications is not available.

The activities of 11 marker enzymes from the gastric and duodenal mucosa were determined in 15 patients with active duodenal ulcer disease before therapy, after 4 weeks of therapy with the prostaglandin E1 analogue misoprostol, 400 micrograms twice daily, and after another 4 weeks without any therapy. Another 15 patients were given a high-dose liquid antacid regimen. The activities were measured in homogenized material obtained with forceps through an endoscope. The healing rates of the two groups at 4 weeks were 53% and 80%, respectively. No changes in mucosal inflammation were noted during therapy. During treatment with misoprostol the activities in the descending duodenum of the membrane enzymes alkaline phosphatase, leucyl-beta-naphthylamidase, gamma-glutamyltransferase, and 5'-nucleotidase increased towards the values seen in normal controls. Despite a higher healing rate, no changes in the enzyme activities occurred in the group given high-dose antacid therapy. Four weeks after cessation of therapy the enzyme activities in the misoprostol group were not significantly different from the pretreatment values. In the biopsy specimens from the duodenal bulb the activities of monoamine oxidase fell during treatment with misoprostol and were restored to the pretreatment activity when therapy was stopped. In the stomach mucosa the enzyme activities were largely unchanged during treatment with both misoprostol and antacids. These results indicate that misoprostol and antacids have different mechanisms of action but may also suggest that the demonstrated enzymic changes are unrelated to the healing process.

Thirty-six patients with histologically verified midgut carcinoid tumours and liver metastases were included in a prospective study with daily interferon therapy 5 x 10(6) IU s.c. for one or two years. All had the primary tumour removed at laparotomy, and whenever technically possible, an embolization of the hepatic arteries was performed prior to interferon start. Recombinant human alpha 2b interferon from Schering-Plough was employed. When interferon was given alone, 24% responded after one year, judged from a 50% reduction in excretion of 5-hydroxyindoleacetic acid in the urine. Three patients had died. Stable disease was found in 43%, while 19% progressed. Survival rate was 40% after 5 years from start of therapy. The median survival time from start of therapy was 3 years and 4 months. When embolization of the liver arteries had been performed prior to the start of interferon treatment, the response rate was 60% after one year, 20% had stable disease and 20% progressed. Survival rate was 75% up to 5 years of observation. We conclude that interferon is an effective treatment of malignant metastatic midgut carcinoid and that survival might be prolonged compared with historical controls. Embolization of the liver arteries seems to increase the response rate after one year. Kaplan-Meier plots suggest prolonged survival when interferon treatment is combined with embolization.

The frequency of hepatitic C virus (HCV) antibodies was determined in two different laboratories in stored sera from 128 consecutive patients with chronic liver disease and from 41 healthy blood donors. Repeated measurements were performed in most patients. At the first determination the frequency of HCV antibodies was 7% in primary sclerosing cholangitis, 42% in primary biliary cirrhosis, 40% in autoimmune chronic active hepatitis, and 27% in alcoholic liver disease. The reproducibility of the determinations was rather poor, with a within-assay variation of 9.9%, whereas the between-assay variation was 34% and 47% in the two laboratories. There was a significant difference in the results obtained in the controls, depending on the handling of the sera. Freezing and thawing and, possibly, protracted storing of sera had a major impact on the assay and may have invalidated the results obtained in many studies. A significant association between IgG levels and titers of HCV antibodies was found in the total group of patients (p less than 0.005), in autoimmune chronic active hepatitis (p less than 0.005), and in primary biliary cirrhosis (p less than 0.01). It may be questioned whether the assay really is specific for anti-HCV antibodies in these patients. Whether HCV has anything to do with the etiology and pathogenesis of chronic liver disease apart from NANB-hepatitis is still undetermined.

The activities of 11 marker enzymes from the gastric and duodenal mucosa were determined in 19 patients with active duodenal ulcer disease (DU) before therapy, after 4 weeks of therapy with ranitidine, 300 mg/day, and after another 4 weeks without treatment. The activities were measured in homogenized material obtained with forceps through an endoscope. The healing rate at 4 weeks was 68%. In the descending duodenum the activities of the membrane enzymes increased during the treatment period compared with pre-treatment activities. Although not as extensive as in the descending duodenum, an increase of membrane enzyme activities was also noted in the duodenal bulb during treatment. In the gastric mucosa only minor enzymic activity changes were seen. The altered enzyme activities in duodenum and stomach during treatment were independent of ulcer healing, smoking, antacids, and mucosal inflammation. Previously, significant differences in mucosal enzyme activities have been demonstrated between DU patients and controls. During ranitidine treatment the enzyme activities in the duodenal mucosa of the same DU patients tended to normalize, whereas they were mostly unchanged in the gastric mucosa. Four weeks after treatment the mucosal enzyme activities in the duodenum were as before treatment started, without occurrence of ulcer relapse. The altered enzymic activities of the duodenal mucosa in DU patients therefore seem to be largely independent of the presence of active ulcer.

Pi phenotype was determined in 335 patients with liver diseases and compared with the results in 2830 healthy blood donors. Eleven of 335 patients had phenotype MZ (3.3%, compared with 2.9% in healthy blood donors (NS]. None of 53 patients with autoimmune chronic active hepatitis had the MZ phenotype, but it was found in 2 of 18 patients (11.1%) with cryptogenic cirrhosis, 3 of 78 (3.8%) with alcoholic liver cirrhosis, 2 of 36 (5.6%) with primary sclerosing cholangitis, and 1 of 26 (3.9%) with primary biliary cirrhosis. Altogether, 3 of 335 patients were homozygous for Pi ZZ and had cirrhosis. One of them (a male) developed a hepatoma and died. We conclude that the reported association between Pi MZ phenotype and chronic non-B active hepatitis does not seem to include patients with autoimmune chronic active hepatitis, whereas the possibility of an association between cryptogenic cirrhosis and the MZ phenotype cannot be excluded.

In the period 1970 to 1987, 171 patients with small-intestinal mucosal atrophy have been hospitalized in our department. Of these, 132 patients fulfilled the diagnostic criteria of coeliac disease on the basis of histologic findings and clinical improvement on a gluten-free diet. Aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), and alkaline phosphatase (ALP) were chosen as markers of hepatic involvement. Elevation above the normal range in one or more of these tests was seen in 62 patients (47.0%, group I). In 70 patients (53.0%, group II) of similar age the levels of these variables were normal. In group I, 14 (10.6%) patients had an elevation of ALP only, leaving 48 (36.4%) patients with pathologic values for one or both transaminases. In group I, 32 patients had their ASAT, ALAT, and ALP reexamined after at least 6 months of gluten-free diet. Among the patients with increased values of one or both transaminases 18 patients were tested before and at least 6 months after start of gluten-free diet. The variables were significantly reduced in all patients. Liver biopsies were performed in 37 patients, and findings were normal in 5. In 25 patients the changes were classified as non-specific. Chronic active hepatitis was demonstrated in five patients. In one of these patients primary sclerosing cholangitis and ulcerative colitis were also diagnosed. Concomitant malignant disease was found in 22 patients, of whom 16 had malignant lymphoma. Malignant disease was seen more often in group I than group II (p less than 0.01). In conclusion, liver lesions were found in a great proportion of the patients with coeliac disease.(ABSTRACT TRUNCATED AT 250 WORDS)

In a series of 45 consecutive duodenal ulcer patients (DU) the activities of 10 marker enzymes from the brush border, basolateral membrane, mitochondria, and lysosomes were determined by analysis of homogenized material taken with biopsy forceps through an endoscope from the antral and body part of the stomach. They were compared with the enzyme activities determined in controls with similar types of gastritis but without any evidence of peptic ulcer disease. All the DU patients had gastritis in the antral mucosa. In the body part, about 30% had gastritis. In the antral mucosa of DU patients the activities of the membrane and lysosomal enzymes were mostly increased when compared with the controls. In the gastric body mucosa of DU patients the activities of the lysosomal enzymes were mostly increased, whereas most of the membrane enzymes showed unchanged activities when compared with the corresponding controls. Monoamine oxidase activities were decreased or unaltered in both regions in these patients. The finding of enzymatic changes in the gastric mucosa of DU patients gives further support to an altered mucosal metabolism in these patients.

To determine survival and the risk factors of death in primary biliary cirrhosis, data from 52 symptomatic and 13 asymptomatic patients were analyzed. The mean follow-up time was 6.3 years (range, 0.4-23 years). The average length of survival was 18 years for the symptomatic and 8.4 years for the asymptomatic patients. By a univariate analysis, ascites, presence of esophageal varices, gastrointestinal bleeding, jaundice, hepatomegaly and the logarithms of albumin and bilirubin were all associated with a poor prognosis. A multivariate analysis of the clinical features showed that the presence of bleeding from esophageal varices and the logarithm of bilirubin were the only predictors for poor prognosis. The survival of the symptomatic patients is longer than reported previously, while the life expectancy for the asymptomatic patients seems no better than for the symptomatic group.

Previous blind studies have shown an increased rate of healing of both duodenal and gastric ulcers following 4 weeks peroral administration of 50 mg trimipramine. The present study shows the effect of 50 mg trimipramine perorally on gastric secretion in relation to that of 25 mg of the drug and placebo. At regular intervals blood specimens were obtained for determination of the serum concentration of trimipramine. In 9 healthy young students it was found that the estimated stabilized values of volume and acid output following 50 mg trimipramine, 33 ml and 3.9 mmol/15 min, respectively, were significantly lower than those following the smallest dose, 37 ml and 4.6 mmol/15 min, respectively. On the other hand, no significant changes of gastric secretion were observed following the peroral administration of 25 mg trimipramine when compared to placebo. Following 50 mg trimipramine the output of pepsin was reduced by about 25%. The values of serum concentration of trimipramine were about 200 nmol/1 at 100 min after administration of 50 mg trimipramine and decreased gradually, whereas the values following the smaller dose were about half of those after the larger one. The results indicate that about 50 mg trimipramine is needed for obtaining a reduction of gastric secretions. Future studies may show whether 25 mg trimipramine, which does not suppress acid secretion when given perorally, is able to promote peptic ulcer healing.

In 1976 endoscopy with at least 20 biopsies and cytology were performed in 108 patients 20-25 years after partial gastrectomy (Billroth II). In one patient advanced carcinoma and in three cases severe dysplasia or carcinoma in situ, were found. At the follow-study in 1979, 7 patients had died of causes other than gastric carcinoma. A re-examination with endoscopy, biopsies and cytology were performed in fifty-eight patients. The present study did not show a progress of dysplasia in the gastric remnant during the three years of follow-up. The observations may suggest that re-examinations with gastroscopy and multiple biopsies every 3-5 years may be satisfactory in detecting carcinoma of the gastric remnant.

Thyrotropin-releasing hormone (TRH) has been shown to have a dose-dependent inhibiting effect on the pentagastrin-stimulated gastric acid secretion in man. We studied the effect of increasing doses of TRH on the gastric acid secretion stimulated by a submaximal histamine dose. The effect of a relatively high dose of TRH (500 micrograms/h) on the maximal histamine-stimulated acid secretion was examined. Furthermore, we studied the effect of two doses of TRH (40 micrograms/h and 500 micrograms/h) on the gastric acid output after insulin-induced hypoglycemia. A significant reduction of the submaximal histamine-stimulated gastric acid output was observed during infusion of 8 micrograms/h TRH (16%), 40 micrograms/h TRH (38%), and 200 micrograms/h TRH (42%) (percentage reduction compared with the control experiment). TRH, 1000 micrograms/h, had no significant effect. With regard to the acid output after maximal histamine stimulation, TRH 500 micrograms/h was without significant effect. After hypoglycemia the acid output was reduced by 30% during 40 micrograms/h TRH (p less than 0.05) and by 37% during 500 micrograms/h TRH (p less than 0.02). TRH had no effect on the acid concentration in any of the studies. The possible mechanisms by which TRH may interact with the acid regulation are discussed.

In the present study a comparison was made of the effect of increasing doses of trimipramine (0.05, 0.10, 0.20, 0.40 mg/kg/h), atropine (7, 14, 21, 28 microgram/kg/h), and cimetidine (0.3, 0.6, 1.2, 2.4 mg/kg/h) on the gastric secretion stimulated by 3 microgram/kg/h of histamine dihydrochloride as continuous infusion, each dose step lasting 30 min. In nine healthy individuals it was found that trimipramine had a stimulating effect on the volume and output of acid during one of eight 15-min periods. The largest dose of atropine caused a reduction of the volume and acid output by 68% and 77%, respectively, whereas cimetidine reduced the volume by 74% and the acid output by 89% during the last five 15-min periods, thus having the most pronounced effect. The study may suggest that the healing effect of trimipramine on peptid ulcer is not linked to the effect on submaximal histamine-stimulated secretion and that a different mechanism of action is probably present for the effect of trimipramine, compared with atropine and cimetidine, on the gastric secretion.

The influence of histamine, H1 and H2 agonists (2-AETD and dimaprit), and H1 and H2 antagonists (mepyramine and cimetidine) on the postprandial release of pancreatic polypeptide (PP) was assessed in five Labrador retrievers. Infusions of histamine, 0.25 mumol kg-1 h-1; 2AETD, 4 mumol kg-1 h-1; and dimaprit, 1 mumol kg-1 h-1, enhanced postprandial release (131-189% of control values). The response to 2-AETD and dimaprit was significantly different from control values (p less than 0.05). An increase was observed even when 50 mg mepyramine and 400 mg cimetidine were injected as intravenous boluses (131-139% of control values (p less than 0.05]. The action of the antagonists may be explained by partial agonism or histamine release induced by these agents. It is concluded that postprandial PP release is stimulated by H1 and H2 receptors.

Fasting, meal-stimulated, and insulin-hypoglycemia-stimulated serum gastrin levels were measured before and 3 and 12 months after gastric bypass surgery in nine obese patients. The basal gastrin concentration was unaffected by the operation. After a meal both serum gastrin and blood glucose levels were significantly increased before the operation (p less than 0.002), whereas there was no significant gastrin release in response to food 3 and 12 months after the operation. Insulin hypoglycemia did not elicit any gastrin response either before or after gastric bypass surgery, even though considerable hypoglycemia was obtained. It is concluded that this lack of gastrin release after food and insulin hypoglycemia postoperatively may in part explain the rare development of peptic ulcer in patients after extensive gastric exclusion.

The incidence of ulcerative colitis (UC) in the three counties that compose Western Norway was registered in a prospective study during the years 1984 and 1985. Both inpatients and outpatients were included. Five hundred and fifty general practitioners and 12 hospitals participated in the study. A total of 239 patients were diagnosed in this area with 807,000 inhabitants, giving a mean annual incidence of 14.8 per 100,000. For patients between 30 and 35 years of age the age-specific incidence rate was 31.2. The M/F sex ratio was 1.10. Familial occurrence of inflammatory bowel disease was found in 11% of the patients. Patients with rectal involvement only constituted 35% of the patients.

The effect of cholinergic, alpha-adrenergic, and beta-adrenergic blockade on human pancreatic polypeptide (HPP) release has been tested in six normal subjects before and after a meal. The response to food was abolished by atropine and significantly enhanced by phentolamine and propranolol. The increase induced by phentolamine occurred during the primary phase 0-60 min after food, and that caused by propranolol was observed during the secondary phase 60-120 min postprandially. A radioimmunoassay for HPP, evaluated by accepted criteria of reliability, is described. Various fractions of the 125I-BPP tracer peak have been evaluated. Those of the central portion proved to be superior to the others because of the constant immunoreactivity and the constant incubation damage during the observation period. Serum and plasma samples were subject to different conditions of preservation before analysis of HPP. It is concluded that preservation with aprotinin heparin, collection in chilled tubes, or instant centrifugation and freezing does not improve the stability of HPP after sampling. The present study confirms a positive correlation between age and fasting HPP concentrations (R = 0.15, p = 0.05), but no difference in HPP levels between men and women has been demonstrated.

The effect of dopamine, 0.006, 0.12, 1.2, and 2.4 mg X kg-1 X h1, and the dopamine antagonist sulpiride on postprandial pancreatic polypeptide (PP) release has been studied in dogs. Dopamine reduced PP release, the reduction ranging between 28% and 97% of the integrated PP response after food. The inhibition obtained with dopamine, 0.12 and 2.4 mg X kg-1 X h-1, could be partly reversed (p less than 0.05) by sulpiride, 7.5 mg X kg-1. The concomitant administration of phentolamine, 1.0 mg X kg-1, and propranolol, 0.5 mg X kg -1, partly reversed the inhibition obtained with dopamine, 2.4 mg X kg-1 X h-1 (p less than 0.05). In healthy volunteers basal PP concentration and postprandial PP release were diminished by dopamine, 0.12 mg X kg-1 X h-1 (p less than 0.02). Sulpiride in dogs and haloperidol in volunteers reduced PP release when given without concomitant administration of dopamine. It is concluded that dopamine inhibits postprandial PP release via both dopaminergic and adrenergic receptors.

To study possible pathogenetic mechanisms in hepatobiliary disease associated with ulcerative colitis (UC), we performed a metabolic investigation of component C3 of the most important effector of humoral immunity, the complement system. Purified and biologically active C3 was labelled with 125I and injected together with 131I-albumin into seven patients. All had hepatobiliary disease, and total colectomy had previously been performed for severe UC in all patients. The results were compared with those for 16 normal individuals. The fractional catabolic rates (FCR) were calculated by the metabolic clearance method and by analysis of the plasma radioactivity disappearance curve. An increase in the FCR of C3 was found in the patient group, indicating that humoral immune mechanisms may be of pathogenetic importance in hepatobiliary disease associated with UC. The increased FCR was compensated for by and increased synthesis rate of the protein.

A Levine tube was placed under radiological control in the stomach, and a thin polyethylene tube in the proximal jejunum of 6 healthy volunteers. The stomach and proximal part of jejunum were perfused for 2 hours with 1% acetylcholine, 20% meat extract (Bovril), and 15% liver extract (LE) alone and in combination with simultaneous infusion of different doses of exogenous pentagastrin intravenously. A significant increase in serum gastrin concentration was found with antral perfusion of LE only, whereas perfusion of the proximal jejunum did not change the basal level of the serum gastrin concentration. No change from control values was observed in gastric acid, and pepsin output on perfusing proximal jejunum with LE alone, or in combination with pentagastrin. Reflux to the stomach varied between 0-1.4%, as determined by addition of radioactive B12 to the perfusates. The experiments showed that gastrin was released from the antrum of the stomach by perfusion with 15 per cent LE, but not from the jejunum under the present experimental conditions. In the present experiments Bovril and acetylcholine perfusions did not cause significant responses from the antrum or from the proximal jejunum.

The incidence of Crohn's disease in western Norway was estimated in a prospective epidemiologic study during the years 1984 and 1985. The total population in the area was 807,000. Both inpatients and outpatients were included. Five hundred and fifty general practitioners and 12 hospitals participated in the study. A total of 86 patients were diagnosed, giving a mean annual incidence of 5.3 per 100,000. For patients between 15 and 19 years of age-specific incidence rate was 16.0 The M/F sex ratio was 0.9. In the same period 240 patients with ulcerative colitis were diagnosed (mean annual incidence, 14.8 per 100,000), giving a ratio of 2.8 between ulcerative colitis and Crohn's disease and an annual incidence of 20.1 per 100,000 for inflammatory bowel disease. Familial occurrence of IBD was found for 12% of the patients.