Delayed diagnosis of glucagonoma syndrome.

The classical presentations of necrolytic migratory erythema associated with alpha cell pancreatic tumour have been well documented. In addition, the occurrence of extracutaneous hallmarks of this disease such as weight loss, diabetes, anaemia, stomatitis and diarrhoea have been described in various reports. Here we report three cases with glucagonoma syndrome. Early detection is important in view of the malignant course of the disease. However, diagnosis is sometimes complicated by the fact that some patients may fail to show the characteristic feature of glucagonoma syndrome.

The effect of a natural high-fibre diet on faecal and biliary bile acids, faecal pH and whole-gut transit time in man. A controlled study.

Dietary fibre possibly protects against colonic cancer by effects on bile acid metabolism. We investigated the effect of a natural high-fibre diet on secondary bile acid formation. Twelve healthy subjects on an habitual low-fibre diet (for 4 weeks) consumed a high-fibre menu for 10 weeks (experimental group). A control group of 10 subjects consumed their regular high-fibre diet during this period. Faecal and biliary acid composition, faecal weight, faecal pH and gut transit time were studied before and after 6 and 10 weeks of fibre addition. Changes in the experimental group were compared to changes in the control group. The concentration, but not the excretion, of the secondary faecal bile acids was reduced in the experimental group. Faecal weight increased, faecal pH dropped and gut transit time was not altered. The biliary deoxycholic acid content decreased and the cholic acid content increased after 6 weeks, but returned to baseline values after 10 weeks of fibre addition. This study shows that a natural high-fibre diet lowers secondary faecal bile acid concentration through an increase in stool weight. The 7 alpha-dehydroxylation of primary bile acids is probably not or only transiently inhibited.

Zinc uptake by blood cells of rats in zinc deficiency and inflammation.

In zinc deficiency, the function of leukocytes is impaired. However, the results of studies on the zinc concentration of blood cells in zinc deficiency are conflicting, probably in part because of technical and analytical problems. The aim of this study was to investigate, under standard conditions, the uptake of 65Zn-labeled zinc by blood cells, taken from zinc-deficient rats and from rats in which an inflammation is induced. In both conditions, the serum zinc concentration is reduced. In clinical practice, this makes it difficult to determine whether the decrease in serum zinc is the result of a real or an apparent zinc deficiency. In stress, like an inflammatory disease, the decrease of zinc reflects an apparent zinc deficiency because of redistribution of serum zinc into the liver and because of decrease in serum albumin concentration. Over 70% of the serum zinc is bound to albumin. Blood cells from zinc-deficient and control rats were isolated using a discontinuous Percoll gradient and incubated under nearly physiological conditions in a 65Zn-containing medium. A significant increase in the in vitro uptake of 65Zn-labeled zinc by the blood cells of zinc-deficient rats was seen: erythrocytes 1.3, mononuclear cells 2.0, and polymorphonuclear cells 2.6 times the control values. During inflammation, no change in 65Zn-labeled zinc uptake by erythrocytes and mononuclear cells was demonstrated after 2 d, although the serum zinc and albumin concentrations were decreased, but a small but significant increase in zinc uptake by polymorphonuclear cells was observed. This study of 65Zn uptake in vitro under standard conditions may prove of value for distinguishing in patients real zinc deficiency from apparent zinc deficiency owing to, e.g., stress, although additional experiments should be performed.

Disposition of mesalazine from mesalazine-delivering drugs in patients with inflammatory bowel disease, with and without diarrhoea.

The disposition of mesalazine from the azo compounds sulphasalazine and olsalazine (Dipentum) and from the slow-release mesalazine drugs Pentasa, Asacol, and Salofalk was studied in 20 patients with inflammatory bowel disease. Ten of them had diarrhoea, and 10 had normal stools. On the last 2 days of a 7-day maintenance treatment with each of the study drugs urine and faeces were collected for determination of mesalazine, acetyl-mesalazine, and unsplit azo compound. In patients with and without diarrhoea the urinary and the faecal excretion of acetyl-mesalazine was lowest during treatment with olsalazine. The proportion of acetyl-mesalazine in faeces was highest during treatment with Pentasa in both groups. The presence of diarrhoea was associated with a decrease in the proportion of acetyl-mesalazine in faeces during treatment with all drugs, not significant only for Pentasa. The proportion of unsplit azo compound in faeces increased in the case of diarrhoea to almost 50%. It is concluded that in patients with inflammatory bowel disease diarrhoea substantially influences the disposition from all these drugs except Pentasa.

Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: a prospective, double-blind, randomized multicenter study. The Ulcerative Colitis Multicenter Study Group.

Forty-nine patients with ulcerative colitis in remission were entered into a prospective, double-blind, multicenter trial comparing the relapse-preventing effect and safety of 4 g sulfasalazine and 2 g olsalazine daily during 48 wk. Of the 46 evaluable patients, 23 were assigned to sulfasalazine and 23 to olsalazine. Seven of 23 patients (30.4%) relapsed on sulfasalazine and six of 23 patients (26.1%) on olsalazine (95% confidence interval of the difference -22.0% to 30.3%). The relapse-free survival curves did not differ significantly at any time during the trial period. In both treatment groups, three patients dropped out because of adverse effects. Four patients on sulfasalazine and six patients on olsalazine experienced minor adverse effects. One patient on sulfasalazine had mild leukopenia, and four patients on sulfasalazine and one patient on olsalazine had decreased levels of haptoglobin. Thus, sulfasalazine and olsalazine are equally effective in maintaining remission of ulcerative colitis and are accompanied by a similar incidence of adverse effects.

Bacterial acetylation of 5-aminosalicylic acid in faecal suspensions cultured under aerobic and anaerobic conditions.

After oral administration of 5-aminosalicylic acid a substantial proportion of the acetylated form is excreted in the faeces. We have studied the role of the faecal microflora in acetylating 5-aminosalicylic acid. In faeces incubated under both aerobic and anaerobic conditions there was acetylation of 5-aminosalicylic acid. Of the anaerobic bacteria isolated from a 10(8) faecal dilution 44% were able to acetylate 5-aminosalicylic acid. We conclude that the normal faecal microflora contribute to the acetylation of 5-aminosalicylic acid.

Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease. A double-blind, randomized, multicenter trial.

OBJECTIVE: To determine whether sulphasalazine plus prednisone is more effective than sulphasalazine alone in treating active Crohn disease. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Multicenter trial in one university hospital and nine general hospitals. PATIENTS: Patients with active Crohn disease and a Van Hees Activity Index of 140 or more. Of 71 patients who were randomly assigned, 60 completed treatment and were analyzed. INTERVENTIONS: For 16 weeks, 30 patients received sulphasalazine, 6 g/d (or 4 g/d if adverse effects occurred) and prednisone, 30 mg/d initially. Prednisone therapy was tapered in increments of 5 mg/2 wk to 10 mg/d after 8 weeks. Thirty other patients received sulphasalazine and a placebo. MEASUREMENTS AND MAIN RESULTS: In the first 6 weeks of treatment, the Van Hees Activity Index decreased to a median of 70% (interquartile range, 57% to 81%) of the initial value in patients treated with sulphasalazine and prednisone and to a median of 87% (interquartile range, 70% to 94%) in patients treated with sulphasalazine alone (P = 0.001). In the last 4 weeks of treatment, the corresponding figures were 63% (interquartile range, 40% to 75%) and 70% (interquartile range, 54% to 90%) (P = 0.10). The Crohn's Disease Activity Index decreased in the first 6 weeks to a median of 65% (interquartile range, 57% to 86%) in patients receiving sulphasalazine and prednisone and to a median of 75% (interquartile range, 58% to 101%) in patients receiving sulphasalazine alone (P = 0.13). In the last 4 weeks of treatment, the corresponding figures were 65% (interquartile range, 42% to 90%) and 76% (interquartile range, 49% to 110%) (P = 0.19). CONCLUSIONS: The use of prednisone in addition to sulphasalazine in patients with active Crohn disease results in a significantly faster initial improvement, but not in a significantly better result after 16 weeks of treatment, when disease activity is measured by the Van Hees Activity Index.

[Extracardial manifestations in constrictive pericarditis]. / De extracardiale verschijnselen bij pericarditis constrictiva.

Constrictive pericarditis is a slowly progressive disabling disease. The diagnosis is easily overlooked because of the striking extracardial signs and symptoms such as abdominal discomfort, general fatigue, cachexia, ascites and oedema. We describe 7 patients with these symptoms in whom the diagnosis was missed during 0.5-17 years. The decisive clue for correct diagnosis appeared to be the raised central venous pressure. This proves the importance of an accurate physical examination. Other findings were: ascites (7/7), hepatomegaly (7/7), oedema (6/7), narrow pulse pressure (less than or equal to 35 mmHg) (5/7), ECG abnormalities (7/7) and pericardial calcifications on the chest X-ray (5/7). In addition we found slightly raised liver enzymes and a protein-losing enteropathy leading to low serum protein levels. These abnormalities are all explained by the alterations in haemodynamics and lymph flow. The only curative therapy is surgical decortication of the heart.

[Mega-dosages vitamin D: progressive medicine?]. / Megadoses vitamine D: progressieve geneeskunde?

Although the risk of vitamin intoxication is well recognised, massive doses of these preparations continue to be prescribed, especially in the so-called 'alternative' medical sector. We describe a patient with hypervitaminosis D due to administration of megadoses of vitamin D in the absence of an obvious indication. Mode of action and symptoms of vitamin D intoxication are discussed. It is emphasized that vitamin preparations should only be used when strictly indicated and that close clinical and biochemical supervision is necessary.

[The course of illness in ulcerative colitis]. / Het ziektebeloop bij colitis ulcerosa.

The data of 301 ulcerative proctitis/colitis patients, with a mean follow-up of 10 (1/2-26) years were analysed retrospectively. In 84 patients (28%) the diagnosis was made in this hospital (non-selected group), the other 217 patients were referred from other hospitals with an established diagnosis of ulcerative colitis. At any time after the fifth year of illness approximately 55% of the non-selected patients were free of symptoms, for the referred patients this proportion was 30%. In one half of the cases the inflammation started as a proctitis, almost 60% of these progressed to colitis later. Fourteen patients (5%) had a toxic megacolon, and a colon carcinoma developed in 9 patients (3%) on average 13 years after the first symptoms of colitis. We recorded 9 colitis-related deaths. Fifty patients (17%) underwent a colectomy, mostly because of failure of conservative therapy.

Disposition of 5-aminosalicylic acid from 5-aminosalicylic acid-delivering drugs during accelerated intestinal transit in healthy volunteers.

In eight healthy volunteers accelerated intestinal transit time was induced with bisacodyl, and urinary and faecal excretion of sulphasalazine, olsalazine, 5-aminosalicylic acid (5-ASA), and acetyl-5-ASA was studied after a single oral dose of 3.3 mmol sulphasalazine, olsalazine, Pentasa, and Salofalk and 2.6 mmol of Asacol. The faecal and urinary excretion of acetyl-5-ASA was lowest after intake of sulphasalazine and olsalazine and highest after intake of Pentasa and Salofalk. The figures for Asacol were intermediate. This indicates insufficient release of 5-ASA from sulphasalazine and olsalazine. When the results of this study are compared with those of a previous study without accelerated transit time, the disposition of 5-ASA from all the 5-ASA-delivering drugs is influenced unfavourably by an accelerated gut transit but most pronounced in the case of sulphasalazine, olsalazine, and Asacol. The impaired release from the azo compounds sulphasalazine and olsalazine is a result of far less complete splitting of the diazo bond.

[Achlorhydria and stomach carcinoma]. / Achloorhydrie en maagcarcinoom.

Patients with achlorhydria are suspected to have an increased risk of developing gastric adenocarcinoma. However, in the literature the reported risk varies considerably. In The Netherlands no such data are available. The risk of developing gastric adenocarcinoma was investigated in 129 achlorhydric patients. During a mean observation period of 12.3 yrs gastric adenocarcinoma was diagnosed in six patients. The expected incidence was 1,275, calculated by making use of age, sex and calendar specific incidence and mortality rates of gastric cancer in the Dutch population. The relative risk to develop gastric cancer was 4.7 (95% confidence limits: 1.7-10.2; p less than 0.05). Despite a significantly increased risk, screening of achlorhydric patients for gastric cancer is not advised.

Unconjugated serum bile acids as a marker of small intestinal bacterial overgrowth.

Non-invasive methods to detect small intestinal bacterial overgrowth often lack specificity in patients who have undergone an ileal resection or have an accelerated intestinal transit. Since elevated serum unconjugated bile acid levels have been found in patients with clinical signs of bacterial overgrowth, we studied the clinical value of unconjugated serum bile acids as a marker of small intestinal bacterial overgrowth. Patients with culture-proven bacterial overgrowth had significantly elevated fasting unconjugated serum bile acid levels (median and range: 4.5; 1.4-21.5 mumol l-1) as compared to healthy subjects (0.9; 0.3-1.7 mumol l-1, P less than 0.005), to persons with an accelerated intestinal transit (1.0; 0.3-1.9 mumol l-1, P less than 0.005) and to persons who have undergone an ileal resection (2.1; 0.7-3.6 mumol l-1, P less than 0.005). The same was true 30 and 60 min after ingestion of a Lundh meal. Serum unconjugated bile acid levels above 4 mumol l-1 were found in eight of 10 patients with culture-proven small intestinal bacterial overgrowth whereas serum levels above 4 mumol l-1 were found in none of the patients from the three control groups. These results suggest that determination of unconjugated serum bile acids is of clinical value in the evaluation of patients suspected of small intestine bacterial overgrowth.

Glutathione S-transferase, cytochrome P450, and uridine 5'-diphosphate-glucuronosyltransferase in human small intestine and liver.

In humans, data on biotransformation enzymes in the intestine, and to a lesser extent in the liver, are rather scarce. Much knowledge about these enzymes is, therefore, obtained from animal studies. We were able to examine both small intestinal and hepatic tissue from a kidney donor and performed a systematic study on enzyme contents and distribution in these organs. In the small intestine the longitudinal distribution of cytochrome P450, glutathione S-transferase, and bilirubin uridine 5'-diphosphate (UDP)-glucuronosyltransferase declined from duodenum to ileum. Activity of 4-nitrophenol- and 4-methylumbelliferone UDP-glucuronosyltransferase increased or remained constant, respectively. Total and specific activity of most enzymes was much higher in the liver, except for bilirubin UDP-glucuronosyltransferase and glutathione S-transferase, where the small intestine contained 28.6% and 7.4% of total hepatic activity, respectively. The relatively great amount of bilirubin UDP-glucuronosyltransferase activity in the small intestinal mucosa of this patient, who probably suffered from Gilbert's syndrome, could indicate that under pathological conditions intestinal metabolism may contribute significantly to the clearance of bilirubin. With a monoclonal antibody, UDP-glucuronosyltransferase isoforms were immunodetectable in microsomes. In the liver, two bands, one of 57 kilodaltons and one in between 53 and 54 kilodaltons, were seen. In the proximal small intestine two isoforms (53 and 54 kilodaltons) were detected. However, in the distal small intestine where bilirubin UDP-glucuronosyltransferase activity was low, only one isoform (54 kilodaltons) was seen. This may indicate that bilirubin UDP-glucuronosyltransferase activity is correlated with the 53-kilodalton isoform. The presence of multiple UDP-glucuronosyltransferase isoforms in humans, similar to that described before in the rat, is further established by this study.

Human intestinal glutathione S-transferases.

Cytosolic glutathione S-transferases were purified from the epithelial cells of human small and large intestine. These preparations were characterized with regard to specific activities, subunit and isoenzyme composition. Isoenzyme composition and specific activity showed little variation from proximal to distal small intestine. Specific activities of hepatic and intestinal enzymes from the same patient were comparable. Hepatic enzymes were mainly composed of 25 kDa subunits. Transferases from small intestine contained 24 and 25 kDa subunits, in variable amounts. Colon enzymes were composed of 24 kDa subunits. In most preparations, however, minor amounts of 27 and 27.5 kDa subunits were detectable. Separation into isoforms by isoelectric focusing revealed striking differences: glutathione S-transferases from liver were mainly basic or neutral, enzymes from small intestine were basic, neutral and acidic, whereas large intestine contained acidic isoforms only. The intestinal acidic transferase most probably was identical with glutathione S-transferase Pi, isolated from human placenta. In the hepatic preparation, this isoform was hardly detectable. The specific activity of glutathione S-transferase showed a sharp fall from small to large intestine. In proximal and distal colon, activity seemed to be about equal. In the ascending colon there might be a relationship between specific activity of glutathione S-transferases and age of the patient, activity decreasing with increasing age.

Stability of disodium azodisalicylate (olsalazine) and metabolites in urine and faeces stored at different temperatures.

METHODS: The stability of disodium azodisalicylate, 5-aminosalicylic acid and acetyl-5-aminosalicylic acid dissolved in distilled water and in urine or mixed with faeces to which HgCl2 was added, was studied at -20 degrees C, 4 degrees C and room temperature. RESULTS: In water, no marked differences were found between the three storage regimens. In urine, disodium azodisalicylate and acetyl-5-aminosalicylic acid were stable, while the 5-ASA concentration decreased when stored at 4 degrees C and room temperature. In faeces stored during seven days, a marked decrease in 5-aminosalicylic acid concentration to about zero was found when it was kept at 4 degrees C and room temperature. No marked change in the concentration of disodium azodisalicylate and 5-aminosalicylic acid added to the faeces-HgCl2-mixtures appeared.

Inhibition of secondary bile acid formation in the large intestine by lactulose in healthy subjects of two different age groups.

Secondary bile acids have been implicated in colonic carcinogenesis. Transformation of primary into secondary bile acids (7 alpha-dehydroxylation) in the large bowel is a pH-dependent process. Inhibition of this reaction could be achieved by lowering colonic pH. We, therefore, studied the effects of lactulose (a non-absorbable disaccharide), which is capable of acidifying colonic contents, on secondary bile acid metabolism. Because this metabolism is age dependent, lactulose was given (0.3 g kg-1 twice daily for 12 weeks) to nine middle-aged (age 31-54 years; mean 45.7) and ten elderly subjects (age 56-81 years; mean 66.4). Twice before, and after 6 and 12 weeks' lactulose administration, biliary and faecal bile acids, whole gut transit time, faecal weight and dry weight, and faecal pH were recorded. The concentration of (iso)lithocholic and deoxycholic acid in faeces was higher in elderly subjects (P less than 0.05) but the excretion was comparable. After lactulose the concentration and excretion of the major secondary bile acids decreased. The primary bile acid fraction rose from 5% before, to more than 20% after, lactulose (P less than 0.05). Faecal weight increased and faecal dry weight decreased, resulting in a higher faecal water output during lactulose. Whole gut transit time did not change. The faecal pH dropped after 6 (P less than 0.05) and further after 12 weeks' lactulose (P less than 0.05). The percentage deoxycholic acid in bile was higher, and cholic acid lower, in elderly subjects (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of the dumping syndrome with the somatostatin analogue SMS 201-995.

In six patients suffering from severe early dumping and six patients with late dumping after peptic ulcer surgery, the effect of the somatostatin analogue SMS 201-995 was compared with placebo. In early dumpers subcutaneous administration of 50 micrograms SMS 201-995 prior to meal ingestion induced a strong improvement of dumping symptoms as reflected by a decrease of the Sigstad dumping score from 12 +/- 2 during placebo to 5 +/- 2 (p less than 0.05). Furthermore, the postprandial increase of pulse rate was abolished; maximum pulse rate decreased from 85 +/- 7 beats/min to 67 +/- 7 beats/min (p less than 0.05). SMS 201-995 did not significantly affect postprandial changes in packed cell volume. In late dumpers 50 micrograms SMS 201-995 reduced peak plasma insulin after oral glucose from 173 +/- 16 mU/L during placebo to 35 +/- 9 mU/L during SMS 201-995 (p less than 0.05) and increased individual plasma glucose nadirs from 1.9 +/- 0.3 mmol/L to 7.5 +/- 3.3 mmol/L (p less than 0.01). Both in early and late dumpers SMS 201-995 improved postprandial expiratory breath hydrogen excretion indicating slowing of gastrointestinal hurry. SMS 201-995 is a powerful therapeutic agent for the management of patients suffering from the dumping syndrome after gastric surgery.