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Cholangiocytes function as antigen-presenting cells with CD1d-dependent activation of natural killer T (NKT) cells in vitro. NKT cells may act both pro- and anti-inflammatory in liver immunopathology. We explored this immune pathway and the antigen-presenting potential of NKT cells in the bile ducts by challenging wild-type and Cd1d−/−mice with intrabiliary injection of the NKT cell activating agent oxazolone. Pharmacological blocking of CD1d-mediated activation was performed with a monoclonal antibody. Intrabiliary oxazolone injection in wild-type mice caused acute cholangitis with significant weight loss, elevated serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin, increased histologic grade of cholangitis and number of T cells, macrophages, neutrophils and myofibroblasts per portal tract after 7 days. NKT cells were activated after intrabiliary injection of oxazolone with upregulation of activation markers. Cd1d−/−and wild-type mice pretreated with antibody blocking of CD1d were protected from disease. These findings implicate that cells in the bile ducts function as antigen-presenting cells in vivo and activate NKT cells in a CD1d-restricted manner. The elucidation of this biliary immune pathway opens up for potentially new therapeutic approaches for cholangiopathies.

Cholangiocytes function as antigen-presenting cells with CD1d-dependent activation of natural killer T (NKT) cells in vitro. NKT cells may act both pro- and anti-inflammatory in liver immunopathology. We explored this immune pathway and the antigen-presenting potential of NKT cells in the bile ducts by challenging wild-type and Cd1d−/−mice with intrabiliary injection of the NKT cell activating agent oxazolone. Pharmacological blocking of CD1d-mediated activation was performed with a monoclonal antibody. Intrabiliary oxazolone injection in wild-type mice caused acute cholangitis with significant weight loss, elevated serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin, increased histologic grade of cholangitis and number of T cells, macrophages, neutrophils and myofibroblasts per portal tract after 7 days. NKT cells were activated after intrabiliary injection of oxazolone with upregulation of activation markers. Cd1d−/−and wild-type mice pretreated with antibody blocking of CD1d were protected from disease. These findings implicate that cells in the bile ducts function as antigen-presenting cells in vivo and activate NKT cells in a CD1d-restricted manner. The elucidation of this biliary immune pathway opens up for potentially new therapeutic approaches for cholangiopathies.

AbstractLiver transplantation was previously only offered to patients under 60 years of age. We have analyzed the outcome after acceptance on the waiting list and after liver transplantation of patients over 60 years old. A total of 150 patients over 60 years old were listed for a first liver transplantation during 1990‐1998. The annual number increased throughout the period. Primary biliary cirrhosis, primary sclerosing cholangitis, and acute hepatic failure were the most frequent diagnoses. A total of 119 patients received a first liver allograft. The patient 1‐year survival was 75 % and 3‐year survival 62%, which was not significantly lower (P= 0.21) than that of the younger patients. When correcting for year of transplantation, the survival was, however, moderately but significantly lower than among the younger patients. Survival among those > 65 years (n= 38) did not differ from that of patients 60‐65 years of age (n= 81). We conclude that an increasing number of patients over 60 years old can be listed for liver transplantation and receive a liver allograft with highly satisfying results.

Orthotopic liver transplantation was performed on a 23-year-old female with hereditary tyrosinaemia. The disorder was diagnosed at 7 years of age due to severe rickets, and the patient was treated with a diet restricted in phenylalanine and tyrosine. Nineteen months before the transplantation she had an acute episode of diffuse gastrointestinal bleeding due to portal hypertension. Three subsequent bleeding episodes with accompanying ascites and signs of encephalopathy were considered life-threatening. Nine months after the liver transplantation the patient is well, but serum transaminases are slightly elevated. Without dietary restrictions serum tyrosine and inorganic phosphate are normalized, no succinylacetone can be detected in serum, and urinary excretion ofp-hydroxyphenyllactate andp-hydroxyphenylpyruvate is normal. Excretion of amino acids, glucose andß2-microglobulin decreased significantly after the transplantation but is still elevated. The succinylacetone concentration in urine is about 20% of the preoperative level. After an oral tyrosine load, succinylacetone excretion increased sevenfold but no deterioration of the renal tubular function was observed and no tyrosine metabolites were detectable in serum. The findings indicate that the defective tyrosine metabolism occurs in the kidneys, but does not produce tubular dysfunction. The residual tubular dysfunction of the patient is probably due to irreversible damage of the tubular epithelium.

Duplex Doppler sonography (DDS) and angiography were performed in a prospective study comprising 22 adult patients with hepatic failure. The ability of the 2 methods to visualize the different splanchnic vessels was compared, as well as any abnormality in the liver parenchyma and vessels. The purpose of the study was to decide if DDS could replace angiography in the pretransplantation work-up in these patients. The portal vein was correctly identified as open in 20 patients using DDS and in 21 patients at angiography. Portal vein thrombosis in one patient was correctly diagnosed by both methods. The identification of other vascular structures in the upper part of the abdomen, e.g., liver arteries and splenic vein, was demonstrated in 14 and 16 patients respectively at DDS. Hepatoma in one patient was correctly identified by both methods, as well as the presence of ascites. Splenic artery aneurysms were found in 4 patients at angiography, and in none of these was DDS able to show this abnormality. We conclude that abdominal angiography still seems superior to DDS in the evaluation of patients with hepatic failure prior to orthotopic liver transplantation, especially to demonstrate possible splenic artery aneurysms and detailed mapping of the hepatic arteries.

Three experiments were carried out in each of 6 healthy students on separate days, in a randomized order. Intravenous saline infusions were given for one hour basally in each experiment. During the second hour either pentagastrin, pentagastrin and somatostatin, or somatostatin alone were given. Gastric juice was collected continuously during all experiments. Somatostatin decreased the volume of gastric secretion and the concentrations of acid and pepsin, and output of acid, pepsin, and intrinsic factor (IF). The plasma gastrin concentration was not changed by somatostatin. A rebound effect was seen on pepsin and IF outputs after cessation of somatostatin, and on blood sugar concentration. The present study suggests that somatostatin acts on gastric secretion either directly or by mechanisms other than by inhibition of gastrin. The rebound of pepsin and IF indicates a release-inhibiting action on these substances similar to the effect of somatostatin on the release of some hormones.

Duplex Doppler sonography (DDS) and angiography were performed in a prospective study comprising 22 adult patients with hepatic failure. The ability of the 2 methods to visualize the different splanchnic vessels was compared, as well as any abnormality in the liver parenchyma and vessels. The purpose of the study was to decide if DDS could replace angiography in the pretransplantation work-up in these patients. The portal vein was correctly identified as open in 20 patients using DDS and in 21 patients at angiography. Portal vein thrombosis in one patient was correctly diagnosed by both methods. The identification of other vascular structures in the upper part of the abdomen, e.g., liver arteries and splenic vein, was demonstrated in 14 and 16 patients respectively at DDS. Hepatoma in one patient was correctly identified by both methods, as well as the presence of ascites. Splenic artery aneurysms were found in 4 patients at angiography, and in none of these was DDS able to show this abnormality. We conclude that abdominal angiography still seems superior to DDS in the evaluation of patients with hepatic failure prior to orthotopic liver transplantation, especially to demonstrate possible splenic artery aneurysms and detailed mapping of the hepatic arteries.

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 aminotranferase (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<0.01). In conclusion, liver lesions were found in a great proportion of the patients with coeliac disease. The liver lesions were mainly classified as non-specific and improved with gluten-free diet. More severe liver lesions, as found in seven patients, showed no dietary response.

Orthotopic liver transplantation was performed on a 23-year-old female with hereditary tyrosinaemia. The disorder was diagnosed at 7 years of age due to severe rickets, and the patient was treated with a diet restricted in phenylalanine and tyrosine. Nineteen months before the transplantation she had an acute episode of diffuse gastrointestinal bleeding due to portal hypertension. Three subsequent bleeding episodes with accompanying ascites and signs of encephalopathy were considered life-threatening.

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.

Flow cytometric DNA studies were performed on cell suspensions of biopsy specimens from gastric tumors and neutral gastric mucosa in 18 patients with gastric cancer and 9 patients with gastric polyps. In cancer, aneuploidy was found in two tumors in the antral and five in the body part of the stomach (39%). The mean DNA index for aneuploid cancers was 1.57. In patients with aneuploid carcinomas three biopsy specimens from uninvolved mucosa also showed aneuploidy. In diploid carcinomas in the antral part of the stomach, the proliferative index (PI) was increased when compared with that of antral mucosa in controls (p < 0.05). Increased PI was found in uninvolved mucosa in aneuploid carcinomas of the body part of the stomach when compared with that in diploid carcinomas (p < 0.001). In uninvolved body mucosa in aneuploid carcinomas of the body part significantly reduced levels of acid-β-glucuronidase (p < 0.0001) were found when compared with diploid carcinomas. No polyps showed aneuploidy. and the PI in biopsy specimens from patients with gastric polyps did not differ from that in controls.

The cellular DNA distribution pattern in biopsy specimens from all main segments and neoplastic lesions of the large bowel, obtained from 16 patients with ulcerative colitis, 22 with adenomas, 17 with carcinoma, and 20 controls, has been studied by the flow cytometry technique. Aneuploid cell populations were demonstrated in three patients with ulcerative colitis (19%), in six with tubular adenomas (27%), and in nine with carcinoma (53%). Aneuploid cells were found in all cases of poorly differentiated adenocarcinomas. The fractional number of cells with a DNA content corresponding to the DNA synthetic and G2M phases of the cell cycle was defined as the 'proliferative index' (PI). In controls PI and its complementary G1 cell fraction varied significantly (p < 0.005) between the segments, on the basis of analysis of variance. When compared two by two, PI was significantly higher in the sigmoid colon (p < 0.01) and rectum (p < 0.0s) than in the ascending part. The PI of uninvolved mucosa from adenoma patients with diploid histograms was significantly higher than that in controls (p<0.01). ulcerative colitis (p<0.05), and cancer patients (p < 0.05), when dependence on segment was taken into account.

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 μg 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-β-naphthylamidase, γ-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.

Until December 1988, 38 patients with primary biliary cirrhosis (PBC) had been transplanted in the Nordic countries. The observed survival probability in accordance with Kaplan-Meier analysis was around 75% 2-3 months after surgery, with few deaths during the next 3 years. The observed survival curve was compared with the expected survival calculated from the experience of a recent English PBC transplant series; the patterns are very similar. Secondly, the observed survival was compared with the expected survival curve, calculated from the survival experience of an international trial of medical treatment - that is, the expected survival had the patients not been transplanted; after the first 2-3 months the observed survival stayed better than the expected survival. Finally, the merits of transplantation for each particular patient was evaluated by means of the ratio of probability of survival when transplanted to probability of survival when medically treated 3, 6. and 8 months after surgery. The ratio increased with time, indicating a relative increase in the benefit of transplantation with time after surgery.

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, 300mg/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.

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 < 0.005), in autoimmune chronic active hepatitis (p < 0.005), and in primary biliary cirrhosis (p < 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.

Biopsy specimens from 29 adenomas, 17 adenocarcinomas, and 6 synchronous adenomas in cancer patients and from uninvolved mucosa of all main segments of the large bowel were examined histologically and assayed for a series of organelle marker enzymes. Six enzymes - lactase, sucrase, alkaline phosphatase, 5'-nucleotidase, acid phosphatase, and N-acetyl-β-D-glucosaminidase - showed less activity in adenomas than in adjacent uninvolved mucosa and in specimens from controls. Cancer tissue had higher γ-glutamyltransferase and lower lactase, alkaline and acid phosphatases, and N-acetyl-β-d-glucosaminidase activities than specimens from uninvolved mucosa in cancer patients and control patients. Enhanced alkaline phosphatase and N-acetyl-β-d-glucosaminidase activities were seen in uninvolved mucosa of cancer patients as compared with those of adenoma and control patients. Evidence has been found for multienzyme analysis to identify adenomas with signs of malignant transformation and carcinomas with poor prognosis.

The effects of a small dose of somatostatin (0.025 mg/h) on the pancreatic secretion of bicarbonate, amylase, and chymotrypsin during stepwise increasing doses of secretin was examined in six healthy volunteers. The secretion of bicarbonate, amylase, and chymotrypsin in response to secretin was significantly reduced by somatostatin. Both output and concentration of pancreatic enzymes were reduced, whereas the concentration of bicarbonate remained unchanged. The pattern of inhibition suggests that somatostatin is a competitive inhibitor of secretin in the stimulation of pancreatic secretion of bicarbonate, which supports the hypothesis of a direct effect of somatostatin on the exocrine secretory cells of the pancreas. The pattern of inhibition of amylase and chymotrypsin secretion is different and difficult to interpret from the present study, but somatostatin may inhibit also the secretin stimulated pancreatic secretion of enzymes completely, as the inhibitory effect seemed to decline when larger doses of secretin were applied.

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-α2b 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 signifiance (p = 0.07).Conclusion: Interferon induced an objective response in mid-gut carcinoid patients as judged by the 24-h urinary S-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 (JT 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.

Boberg KM, Schrumpf E, Fausa O, Elgjo K, Kolmannskog F, Haaland T, Holter E. Hepatobiliary disease in ulcerative colitis. An analysis of 18 patients with hepatobiliary lesions classified as small-duct primary sclerosing cholangitis. Scand J Gastroenterol 1994;29:744-752.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 equals; 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 symtoms 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.

Nordøy I, Schrumpf E, Elgjo K, Flesland ø, Andersen Glende J, ørjasaeter H, Siebke J-C Liver disease in anti-hepatitis C virus-positive Norwegian blood donors. Scand J Gastroenterol 1994;29:77-81.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.

Vetvik K, Schrumpf E, Mowinckel P, Aase S, Andersen K-J. Effects of omeprazole and eradication of Helicobacter pylori on gastric and duodenal mucosal enzyme activities and DNA in duodenal ulcer patients. Scand J Gastroenterol 1994;29:995-1000.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 patientsMethods: 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-α-glucosidase, alkaline phosphatase, leucyl-β-naphthylami-dase, and γ-glutamyltransferase (γ-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 γ-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.

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.

Nineteen patients with histologically verified midgut carcinoid tumours and liver metastases were included in a prospective study with daily recombinant human 2b interferon injections of 5 million IU subcutaneously for 1 year. All had as much as possible of the primary tumour removed at laparotomy. Whenever technically possible (in seven cases), an embolization of the hepatic arteries was performed before interferon start. The response rate of the combined embolization and interferon treatment (n = 7) was 86% after 1 year, as judged from either a 50% reduction in excretion of 5-hydroxy-3-indoleacetic acid in the urine or a 50% reduction in the area of the largest liver metastasis as evaluated by computed tomography. All patients experienced an improvement in diarrhoea and/or flushing. When interferon was given alone (n = 12), 40% responded on the basis of objective criteria (50% after 6 months), whereas an improvement in either diarrhoea or flushing was experienced by 70% (75% after 6 months). In this group one patient had died and one had decided to withdraw after 6 months, at which time both were responders. We conclude that interferon seems to be an effective treatment of malignant metastatic midgut carcinoid tumours and that embolization of the liver arteries seems to increase the response rate, as judged after 1 year.

The distribution of a series of marker enzymes in the gastric mucosa was studied by analysis of homogenized biopsy specimens from the lesser and greater curvature of the body and antrum, respectively, obtained from 11 control patients. The activities varied significantly between the regions for the membrane enzymes lactase (p < 0.0001), neutral-β-glucosidase (p < 0.005), alkaline phosphatase (p < 0.01), leucyl-β-naphthylamidase (p < 0.005), and β-nucleotidase (p < 0.0001) and the lysosomal enzymes iV-acetyl-β-D-glucosaminidase (p < 0.0001) and acid β-glucuronidase (p < 0.0001), using analysis of variance modified for repeated measurements. When paired comparisons between regions were evaluated, the enzyme activities of the antral regions were significantly higher than those of the body stomach. The activities of y-glutamyltransferase, acid phosphatase, and the mitochondrial enzyme monoamine oxidase did not alter between regions, nor did the protein to DNA ratio. The demonstrated biochemical distinction between antrum and body of the stomach may be explained by different physiological and histological properties of the two parts.

Elevated serum levels of gastrin, pancreatic polypeptide, and glucagon were found in 10 uraemic patients, whereas gastric inhibitory polypeptide and somatostatin levels were normal. After renal transplantation there was a significant reduction in serum gastrin (median, 5pmol/l; p = 0.05, n = 9), pancreatic polypeptide (145pmol/l; p < 0.01, n = 9), GIP (9.5 pmol/l;p = 0.02, n = 7), and glucagon (92pg/l;p < 0.02, n = 9), whereas no alteration was seen in the somatostatin level. Meal stimulation produced consistent increases in serum levels of all hormones, and the response appeared to be unchanged after renal transplantation.

The distribution of a series of mucosal enzymes along the large bowel was studied by analysis of homogenized biopsy specimens from five different segments, obtained from 20 control patients. The activities varied significantly between the segments for the membrane enzymes lactase (p < 0.005), alkaline phosphatase (p < 0.0005), leucyl-0-naphthylamidase (p < 0.0001), and 5'-nucleotidase (p < 0.001) and the mitochondrial enzyme monoamine oxidase (p < 0.0005) when tested by analysis of variance modified for repeated measurements. When paired comparisons between segments were evaluated, the enzyme activities of the proximal large bowel were significantly higher than those of distal segments. The levels of sucrase, neutral-α-glucosidase, γ-glutamyltransferase, and lysosomal enzymes remained unchanged throughout the large intestine, as did the protein to DNA ratio. The results are compatible with the theory that different segments of the large bowel have different functions.

In a 5-year period 48 (14) of 336 patients with ulcerative colitis were found to have hepatobiliary disease. The bile ducts were examined in 35 of these patients, and optimal visualization of both intra- and extra-hepatic bile ducts was obtained in 26. Duct changes compatible with sclerosing cholangitis were found in 14 patients. This finding of sclerosing cholangitis in 4 of all patients admitted with ulcerative colitis by far exceeds previous estimations on the incidence of sclerosing cholangitis in ulcerative colitis. The entire colon was usually affected, and the symptoms of the bowel disease were most often mild or moderate. The age at the onset of the colitis was usually below 20 years in patients with combined ulcerative colitis and hepatobiliary disease. In most patients the hepatobiliary disease gave no symptoms. Biochemical data and the histological findings in the liver biopsies did not distinguish between patients with hepatobiliary disease with and without sclerosing cholangitis. Our follow-up study has so far shown that most patients with sclerosing cholangitis remain asymptomatic for a considerable period of time.

The stomachs of 8 healthy volunteers were intubated with a Levine tube under radiological control. In addition, a thin polyethylene tube was placed in the proximal duodenum. After a 1-hour period with no perfusion, the duodenum was perfused for two hours with 15 liver extract (LE) (pH 4.5-5.5; 1027 mosm/kg water) at a rate of 100 ml/hour either alone or in combination with intravenous infusion of different doses of exogenous pentagastrin. All subjects were also tested with the tubes in place for 3 hours, but with no perfusion or pentagastrin. Reflux to the stomach was monitored by addition of radio-activeB12to the perfusates. Plasma gastrin, gastric acid, and pepsin were measured in 15-minute periods. During perfusion of the proximal duodenum, where reflux of the perfusates was less than 4, only a slight and inconstant change in plasma gastrin was seen. Gastric acid and pepsin outputs were increased to approx. 18 and 25 of the maximal pentagastrin stimulation respectively. Whereas 15 LE was shown to release gastrin by antral perfusion however, such release was not found by duodenal perfusion, except where reflux to the antrum was seen. The results suggest that intestinal stimulation of gastric secretion exists, but has not been found to be gastrin dependent in the present investigation.

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 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 μg/kg/h), and cimetidine (0.3,0.6,1.2,2.4 mg/kg/h) on the gastric secretion stimulated by 3 μg/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 peptic 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.

A patient with congenital cystic dilatation of the bile duct (Caroli's disease) is described. The diagnosis was obtained after endoscopic retrograde cholangiography. Owing to monolobar localization of the disease, the patient was successfully treated with partial resection. This patient is the third who has been reported as having this procedure as primary treatment.

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 < 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.

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-α2b 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 μmol/1) were higher than those for the control group (14 ± 3 μmol/1), 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: Recombinant interferon remains the cornerstone of treatment of chronic hepatitis C virus (HCV) infection. Still, evaluation of treatment on the basis of response indicators and long-term effect of the treatment raises several questions. Methods: Seventy-four patients with chronic HCV infection were randomized to a high (3 MIU, 3/7 days) or low (1 MIU, 3/7 days) dose of recombinant interferon-alpha-2b for 48 weeks after a 4-week course of 3 MIU, 3/7 days. Response to treatment was assessed by means of liver enzymes (transaminases), HCV RNA, and liver histology. Results: The higher maintenance dose was associated with a significantly higher rate of sustained alanine aminotransferase (ALAT) response (45% versus 19%) and with a significantly better chance of becoming HCV RNA-negative during therapy (47% versus 23%). In the high maintenance dose group 14 of the 29 (48%) patients with available HCV RNA data were negative at the 3-month follow-up, compared with 4 of 27 (15%) in the low maintenance dose group. Significantly more patients had improved liver biopsy findings after interferon in the high maintenance dose group (79%) than in the low maintenance dose group (36%). There was a close correlation between ALAT response and HCV RNA response. Of 17 patients who were HCV RNA-negative 3 months after the end of treatment, 10 remained HCV RNA-negative 2-4 years later. Conclusion: The study demonstrates a higher response rate as assessed by biochemistry, HCV RNA, and liver histology in the higher dose group.

Two hundred patients with different liver diseases were observed during a period of 6-8 years. The diagnosis at the first hospitalization was based on morphological criteria (and, in some cases, additional clinical information). In 162 of the cases an initial 'specific:' diagnosis could be made. By the time of the follow-up study the diagnosis was confirmed in 739r of them. In 22 of 38 patients who were initially unclassifiable. the diagnosis was made definite by the follow-up study. Eighty-five patients were hospitalized for re-examination 6-8 years after the initial study. Several of the liver diseases initially had quite typical patterns of clinical chemical data. Allocation by discriminant analysis was therefore in good agreement with the morphological classification. The follow-up study showed that several patients with initially atypical patterns of clinical chemical results had their diagnosis changed. In 35 patients with the final diagnosis of chronic active hepatitis (CAH) or primary biliary cirrhosis (PBC), laboratory data from the last hospitalization were used for discriminant analysis with teaching data from the initial study. Ninety-seven per cent were correctly allocated, and we conclude that these patients retain recognizable patterns of laboratory results for several years, even when given immunosuppressive treatment. The potential clinical usefulness of discriminant analysis of laboratory data for differential diagnosis was evaluated by a prospective study of 65 patients with the morphological diagnosis of CAH or PBC. Correspondence with the morphological classification system was found in almost 90% of the cases.

A series of variables involved in glucose handling were monitored before and after gastric bypass operation for morbid obesity. Blood glucose, insulin, C-peptide, gastric inhibitory polypeptide (GIP), pancreatic polypeptide (PP), and gastrin were measured basally and after an oral glucose load. Blood glucose, insulin, C-peptide, and PP were also measured after an intravenous glucose load. Adrenocortical function was evaluated by measuring plasma cortisol and urinary excretion of 17-hydroxy-corticosteroids and 17-ketosteroids. Nine subjects were examined before and 3 and 12 months after operation. Glucose tolerance improved postoperatively concomitant with decreased basal levels of C-peptide and insulin, increased hepatic insulin extraction, and evidence of reduced adrenocortical function. Parallel with reduced insulin resistance, support for an increase in both insulin secretion and removal was obtained postoperatively. It is concluded that the considerable endocrine abnormalities seen in morbid obesity can be normalized after gastric bypass operation and weight reduction.

Biopsy specimens from the antral and body part of the stomach were studied for a range of marker enzymes in 11 patients with superficial gastritis, 9 patients with atrophic gastritis, and 31 Billroth-II-resected patients and compared with activities found in controls with normal gastric mucosa. Li the antral part of the stomach increased y-glutamyitransferase activity was found in superficial (p < 0.01) and atrophic gastritis (p < 0.05), whereas monoamine oxidase activity was decreased in superficial (p < 0.01) and atrophic gastritis (p < 0.05). In the body part, increased activity of y-glutamyltransferase (p < 0.01) and acid-β-glucuronidase (p < 0.01) was found in superficial gastritis. In atrophic gastritis increased activities for lactase (p<0.01), alkaline phosphatase (p<0.05), leucyl-β-naphthylamidase (p<0.05), γ-glutamyltransferase (p < 0.01), 5'-nucleotidase (p < 0.01), N-acetyl-β-D-glucos-aminidase (p < 0.05), and acid-β-glucuronidase (p < 0.01) were found. Specimens from the gastric remnant showed an enzyme activity pattern similar to that seen in the body in atrophic gastritis, apart from a significantly decreased monoamine oxidase activity (p < 0.004). Specimens with dysplasia in the gastric remnant showed decreased monoamine oxidase activity when compared with specimens without dysplasia (p < 0.01).

Enzyme activities and the protein to DNA ratio in gastric biopsy specimens from patients with gastric cancer and polyps have been measured and compared with values from controls. In uninvolved mucosa in antral gastric cancer increased activities were found for several membrane and lysosomal enzymes, whereas the monoamine oxidase (MAO) activity was decreased (p < 0.0005). In cancer tissue the MAO was also decreased (p < 0.0003). In uninvolved mucosa in gastric cancer of the body, most membrane and lysosomal enzyme activities were increased. In the cancer tissue itself an increase in membrane enzyme activities was found for several enzymes. whereas the MAO activity was decreased (p < 0.0001). Differences between activities in specimens from the gastric mucosa in patients with gastric polyps and those in controls were less pronounced than between gastric cancer and controls. A discriminant analysis, using the enzymes most sensitive to establish correct diagnosis, could identify normal gastric mucosa in 85-95%, atrophic gastritis in 56-63%, and uninvolved mucosa in gastric cancer in 66-78%.

During the 10-year period from 1 January 1975 to 31 December 1984, primary sclerosing cholangitis (PSC) was diagnosed in 45 patients. Twelve of the patients have died (26.7%), 10 of them of causes related to PSC. Inflammatory bowel disease was found in all patients; ulcerative colitis was found in 37, Crohn's disease in 6, and unclassified colitis in 2 patients. Of the patients alive, 27 were submitted to a follow-up study in 1985. At the follow-up examination no general progression of the liver disease, as measured on the basis of clinical examination and levels of transaminases, alkaline phosphatases, and bilirubin, was found. Cholangiographic evaluation in 24 patients showed that the stage of ductal changes progressed from mild to moderate in 3 patients; in the other patients the stage was not altered. Morphologic examination of liver biopsy specimens in patients with a benign clinical course usually showed portal inflammation, fibrosis, and minor signs of piecemeal necrosis, whereas widespread piecemeal necrosis was found in patients who deteriorated and died. The 50% survival since diagnosis of liver disease was calculated to be 17 years in patients with PSC and 50 years in a comparable group among the general population. The estimated survival curve in PSC was displaced to the left, indicating a reduced life expectancy of about 30 years.

Flow cytometric measurements of cellular DNA have been performed on biopsy specimens obtained by gastroscopy in patients with normal gastric mucosa (controls), superficial and atrophic gastritis, and resected stomachs. Aneuploidy was found in two biopsy specimens from a patient with superficial gastritis and in one specimen from a resected stomach. The fractional number of cells with a DNA content corresponding to the DNA synthetic and (G: + M) phases of the cell cycle was defined as the 'proliferative index' (PI). No difference between the antral and body part of the stomach was found for the PI in controls or between controls and superficial and atrophic gastritis. PI was weakly but significantly correlated to a selection of mucosal enzymes. In resected stomachs increased PI was found when compared with that in the body part of the stomach in controls (p < 0.01). Biopsy specimens with intestinal metaplasia (p < 0.01) or atrophy (p < 0.05) in the resected stomach showed significantly higher PI when compared with specimens with such findings from the body part of the stomach in atrophic gastritis.