Thiopurine methyltransferase genotype distribution in patients with Crohn's disease.

BACKGROUND: Inter-individual response to azathioprine is partly due to inter-individual variation in the thiopurine methyltransferase (TPMT) activity. The TPMT genotype, which reflects the TPMT activity, has previously been studied in healthy Caucasians, with the most common variant allele being TPMT*3A. TPMT genotyping in adult patients with Crohn's disease has never been performed systematically. AIM: To determine the TPMT genotype distribution in adult patients with Crohn's disease. METHODS: One hundred and twenty randomly selected Danish patients (64 females and 56 males) with azathioprine-dependent Crohn's disease were included, and a polymerase chain reaction assay was used for TPMT genotyping. The patients were genotyped for the low-level genotype G460-->A and A719-->G transitions. RESULTS: One hundred and nine patients (90.3%; 95% confidence interval, 84.1-95.3) had a wild-type/ wild-type genotype, whereas 10 patients (8.3%; 95% confidence interval, 4.1-14.8) had one non-functional mutant allele and one patient (0.8%; 95% confidence interval, 0.02-4.6) had two non-functional mutant alleles. Only the TPMT*3A variant allele was found. CONCLUSIONS: The study showed a TPMT genotype distribution amongst adult Danish patients with Crohn's disease which was similar to the distribution of TPMT variant alleles normally found in healthy Caucasians.

Corticosteroids for maintaining remission of Crohn's disease.

OBJECTIVES: To evaluate the effectiveness and safety of conventional systemic corticosteroid therapy in maintaining clinical remission in Crohn's disease. SEARCH STRATEGY: A computer-assisted search of the on-line bibliographic database MEDLINE of studies published in English, French, Spanish, Italian and German between 1966 and February, 2001. Manual searches of the reference lists from the potentially relevant studies were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Proceedings from major gastrointestinal meetings were also manually searched from 1985 to 2000 in order to identify unpublished studies. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. SELECTION CRITERIA: Randomized double-blind placebo-controlled trials involving patients of any age with Crohn's disease in clinical remission as defined by a CDAI < 150 or by the presence of no symptoms or only mild symptoms at the time of entry into the trial. The experimental treatment consisted of oral conventional corticosteroid therapy (excluding budesonide, fluticasone, etc). Clinical disease relapse was used as the outcome measure of interest. DATA COLLECTION AND ANALYSIS: Eligible studies were selected by 4 reviewers and data were extracted onto standardized data extraction forms. Disagreements in eligibility or data extraction were resolved by consensus. Data were converted into individual 2x2 tables for each study. The presence of significant heterogeneity among studies was tested using the chi-square test. The 2x2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel (the 'odds ratio' in MetaView). A fixed effects model was used for the pooling of data. MAIN RESULTS: Four studies were initially judged as being eligible for inclusion. After obtaining additional information on one of the studies it was excluded because it was not double-blind. The total number of subjects included in the analysis at the time points of 6, 12 and 24 months were 142, 131 and 95 for the corticosteroid group and 161, 138 and 87 for the control group. The odds ratios for relapse on active treatment and the corresponding 95% confidence intervals were 0.71 (0.39, 1.31), 0.82 (0.47, 1.43) and 0.72 (0.38, 1.35) at 6, 12 and 24 months. REVIEWER'S CONCLUSIONS: The use of conventional systemic corticosteroids in patients with clinically quiescent Crohn's disease does not appear to reduce the risk of relapse over a 24 month period of follow-up. This review updates the existing review of corticosteroids for maintaining remission of Crohn's disease which was published in the Cochrane Library (Issue 2, 2001).

Corticosteroids for maintaining remission of Crohn's disease.

OBJECTIVES: To evaluate the effectiveness and safety of conventional systemic corticosteroid therapy in maintaining clinical remission in Crohn's disease. SEARCH STRATEGY: A computer-assisted search of the on-line bibliographic database MEDLINE of studies published in English, French, Spanish, Italian and German between 1966 and May, 1998. Manual searches of the reference lists from the potentially relevant studies were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Proceedings from major gastrointestinal meetings were also manually searched from 1985 to 1997 in order to identify unpublished studies. The Cochrane Controlled Trials Register and the Inflammatory Bowel Disease Review Group Trials Register were also searched. SELECTION CRITERIA: Randomized double-blind placebo-controlled trials involving patients of any age with Crohn's disease in clinical remission as defined by a CDAI < 150 or by the presence of no symptoms or only mild symptoms at the time of entry into the trial. The experimental treatment consisted of oral conventional corticosteroid therapy (excluding budesonide, fluticasone, etc). Clinical disease relapse was used as the outcome measure of interest. DATA COLLECTION AND ANALYSIS: Eligible studies were selected by 4 reviewers and data were extracted onto standardized data extraction forms. Disagreements in eligibility or data extraction were resolved by consensus. Data were converted into individual 2x2 tables for each study. The presence of significant heterogeneity among studies was tested using the chi-square test. The 2x2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel (the 'odds ratio' in MetaView). A fixed effects model was used for the pooling of data. MAIN RESULTS: Four studies were initially judged as being eligible for inclusion. After obtaining additional information on one of the studies it was excluded because it was not double-blind. The total number of subjects included in the analysis at the time points of 6, 12 and 24 months were 142, 131 and 95 for the corticosteroid group and 161, 138 and 87 for the control group. The odds ratios for relapse on active treatment and the corresponding 95% confidence intervals were 0.71 (0.39, 1.31), 0.82 (0.47, 1.43) and 0.72 (0.38, 1.35) at 6, 12 and 24 months. The numbers needed to treat with corticosteroids to prevent one additional relapse were 24, 35, 15 respectively. REVIEWER'S CONCLUSIONS: The use of conventional systemic corticosteroids in patients with clinically quiescent Crohn's disease does not appear to reduce the risk of relapse over a 24 month period of follow-up.

Corticosteroids for maintenance of remission in Crohn's disease.

BACKGROUND: The efficacy of corticosteroids in the setting of maintenance therapy for Crohn's disease has never been clearly demonstrated. It would be important to determine, based upon the currently available data from controlled trials, if the use of chronic corticosteroid therapy is of benefit in patients with quiescent Crohn's disease or if there is an identifiable subgroup of Crohn's disease patients, such as those in whom therapy cannot be successfully tapered, who might benefit from such treatment. OBJECTIVES: To evaluate the effectiveness and safety of conventional systemic corticosteroid therapy in maintaining clinical remission in Crohn's disease. SEARCH STRATEGY: A computer-assisted search of the on-line bibliographic database MEDLINE of studies published in English, French, Spanish, Italian and German between 1966 and July, 2003. Manual searches of the reference lists from the potentially relevant studies were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Proceedings from major gastrointestinal meetings were also manually searched from 1985 to 2003 in order to identify unpublished studies. The Cochrane Central Register of Controlled Trials and the Inflammatory Bowel Disease Review Group Specialized Trials Register were also searched. SELECTION CRITERIA: Randomized double-blind placebo-controlled trials involving patients of any age with Crohn's disease in clinical remission as defined by a CDAI < 150 or by the presence of no symptoms or only mild symptoms at the time of entry into the trial. The experimental treatment consisted of oral conventional corticosteroid therapy (excluding budesonide, fluticasone, etc). Clinical disease relapse was used as the outcome measure of interest. DATA COLLECTION AND ANALYSIS: Eligible studies were selected by 4 reviewers and data were extracted onto standardized data extraction forms. Disagreements in eligibility or data extraction were resolved by consensus. Data were converted into individual 2x2 tables for each study. The presence of significant heterogeneity among studies was tested using the chi-square test. The 2x2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel (the 'odds ratio' in MetaView). A fixed effects model was used for the pooling of data. MAIN RESULTS: Four studies were initially judged as being eligible for inclusion. After obtaining additional information on one of the studies it was excluded because it was not double-blind. The total number of subjects included in the analysis at the time points of 6, 12 and 24 months were 142, 131 and 95 for the corticosteroid group and 161, 138 and 87 for the control group. The odds ratios for relapse on active treatment and the corresponding 95% confidence intervals were 0.71 (0.39, 1.31), 0.82 (0.47, 1.43) and 0.72 (0.38, 1.35) at 6, 12 and 24 months. REVIEWER'S CONCLUSIONS: The use of conventional systemic corticosteroids in patients with clinically quiescent Crohn's disease does not appear to reduce the risk of relapse over a 24 month period of follow-up. This review updates the existing review of corticosteroids for maintaining remission of Crohn's disease which was published in the Cochrane Library (Issue 2, 2003).

[Informed consent in connection with autopsy and sending out discharge notes. A questionnaire study]. / Informeret samtykke i forbindelse med obduktion og udsendelse af epikrise. En spørgeskemaundersøgelse.

The purpose of this study was to illustrate the attitude towards informed consent in connection with performing an autopsy and sending out discharge notes amongst a group of patients, doctors and nurses. A questionnaire was given to four different groups consisting of 75 patients, 20 nursing staff, 20 hospital doctors and 20 family doctors. The attitudes amongst the two groups of doctors were generally close to the attitudes amongst patients. The majority of doctors and patients in contrary to the nursing staff found it unnecessary to obtain informed consent before sending out discharge notes. More than half of all of the groups thought that patients should take part in the decision of performing autopsy, but still the family should be asked as well.

[Collagenous colitis]. / Kollagen colitis.

Collagenous colitis was first described in 1976 by Lindström as an unusual cause of persistent, watery diarrhea. He noted a large subepithelial band of collagen deposited in the rectum and the colon. Collagenous colitis occurs predominantly in females and is more frequent in the elderly. Radiographic examination of the colon is unremarkable, and the patients show no signs of malabsorption. The diagnosis requires biopsy specimens from the colon, as the disease is focal and less frequently affects the rectum. Biopsies taken only from the rectum cannot exclude the diagnosis. For the time being there is no consensus as to the treatment of the disease. We describe two patients with collagenous colitis successfully treated with prednisolone. The diagnostic importance of total colonoscopy with multiple biopsies in a normal-appearing colon in patients with unexplained chronic watery diarrhea is stressed.

[Increased urea synthesis in patients with active inflammatory bowel disease]. / Accelereret urinstofsyntese hos patienter med aktiv inflammatorisk tarmsygdom.

Patients with active inflammatory bowel disease are often reported to be in negative nitrogen balance. Therefore, we examined basal and amino acid stimulated urea synthesis in 11 patients with active inflammatory bowel disease and in 10 patients with non-active disease. A primed continuous infusion of an amino acid mixture was given from t = 1 h to t = 5 h; during the first and the last two hours no amino acid infusion was given. Urea nitrogen synthesis rate was quantified independently of changes in blood amino acid concentration by means of the functional hepatic nitrogen clearance, i.e. the linear slope of the regression of urea nitrogen synthesis rate on blood amino acid concentration. Basal and amino acid stimulated urea nitrogen synthesis rate as well as functional hepatic nitrogen clearance were elevated twofold in the patients with active disease. No differences between the two groups were observed as regards basal or stimulated plasma glucagon, cortisol, catecholamines and serum levels of interleukin-1 alpha, interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6. The results show that liver function related to conversion of amino-nitrogen to urea is increased and may contribute to the less efficient nitrogen economy in patients with active inflammatory bowel disease.

[Reliability of death certificates. The reproducibility of the recorded causes of death in patients admitted to departments of internal medicine]. / Pålideligheden af dødsattester. Reproducerbarheden ved udfyldelsen af dødsattestens diagnoser på patienter indlagt på medicinsk afdeling.

The aim of the study was to assess the reproducibility when different doctors fill in diagnoses on death certificates. Records from 40 patients who had died in 1994 during admission to a medical hospital department in Denmark were selected at random. Ten doctors filled in a death certificate for each patient (without knowledge of autopsy findings and results of examinations received after the patient's death). The agreement between the diagnoses was assessed using a rating scale with seven categories. Afterwards the 400 death certificates were mixed and coded by the Medicostatistical Section of the Danish National Board of Health. The diagnoses made by the ten doctors showed insignificant discrepancies in ten cases, larger discrepancies were found in eight cases and large discrepancies in 19 cases. In three cases the patient had died suddenly and little information was available. The coding was standardized at the Danish National Board of Health, but their diagnoses reflected the discrepancies between the doctors' diagnoses. In conclusion, the reproducibility of diagnoses on death certificates is so poor that information from the Registry of Causes of Death is of little use of administrative or scientific purposes.

[Penicillin treatment of non-nosocomial pneumonia in Danish medical departments. A questionnaire]. / Penicillinbehandling af ekstranosokomielt erhvervet pneumoni på medicinske afdelinger i Danmark. En spørgeskemaundersøgelse.

This study describes the most common penicillin-regime for hospitalized patients with community-acquired pneumonia in Denmark. One hundred and seventy-one consultant physicians received an anonymous questionnaire, 85% were returned and 75% were evaluated. The most common regime is a treatment duration of six to ten days with 3-6 million IU of penicillin daily given in three doses. The most common route of administration is intravenously until the patient's body temperature drops. Then the same dose is given orally. Variations in strategy were revealed and call for further investigations to establish and maintain restrictive antibiotic regimes.

[Attitude of Danish patients and physicians to information on cancer. A questionnaire study]. / Danske patienters og laegers holdning til information ved kraeftsygdom. En spørgeskemaundersøgelse.

This survey reports the attitude towards information of cancer patients as regards diagnosis and prognosis among gastroenterologists and patients (not suffering from cancer). The questions were based on a case history (a patient with colonic cancer). Most doctors informed their patients openly, and most patients expected that. Younger doctors in particular were more restrictive than patients as regards information of the spouse.

[Prevention of duodenal ulcer recurrence with penicillin]. / Forebyggelse af recidiv af ulcus duodeni med penicillin.

The aim of this study was to test the hypothesis that infection with Helicobacter pylori is essential for recurrence of duodenal ulcer. We performed a randomized controlled trial of the relapse rate of duodenal ulcer during 12 weeks treatment with penicillin V or placebo in 170 out-patients from five centres. The relapse rate was 9% during treatment with penicillin and 50% with placebo, P < 0.0001. It is concluded that infection with penicillin-sensitive bacteria, i.e. H. pylori, plays an important role for recurrence of duodenal ulcer disease. Penicillin V suppresses this infection but does not eradicate it.

[National surveillance of Helicobacter pylori eradication in Denmark. Results based on registration of 34.582 drug prescriptions]. / National overvågning af Helicobacter pylori-eradikationsterapi i Danmark. Resultater fra registreringen af 34.582 receptudskrivninger.

We wanted to characterize the use of H. pylori eradication therapy in Denmark (inhabitants 5,227,862). All H. pylori eradication treatments from a nation wide database covering all drug prescriptions in the period January 1994-June 1996 were identified. We found 28,784 out-patients having a prescription with drugs for H. pylori eradication, accounting for 34,582 prescriptions in total. The incidence of new consumers was 220 per 10(5) inhabitants per year, with a maximum at 70-79 years of age. Eighty-six percent of the patients had only one treatment course. Forty-five percent had an anti-ulcer drug prescribed 1-12 months after the H. pylori eradication therapy. Consumption of antibiotics used for H. pylori eradication accounted for 1.4% of the total consumption of antibiotics. In conclusion, the incidence of H. pylori eradication therapy was fairly stable but with changes in the pattern of drug regimens used. Anti-ulcer drugs were often given after H. pylori eradication therapy, suggesting an inappropriate use of eradication treatment.

Gastroenterology in the last decennia and initiatives in medical ethics: coincidence or linkage?

A quarter of a century ago ethics was an esoteric term, known to theologians and philosophers, but unknown as a discipline to the majority of doctors. Since then, however, ethics has become a substantial part of clinical medicine and health research. Ethics as an area of interest for Danish gastroenterologists appeared from several foci in the early days. One angle was an almost revival-like interest in research methodology and its ethical dimensions. Other angles were derived from Danish gastroenterologists' experiences transferred from other disciplines before the birth of Danish gastroenterology. From the time of these early incentives Danish gastroenterologists have constituted a platform for the implementation of the basic principles, lying behind medical ethics, now in collaboration with other parts of the medical profession. The topics are reflected in a number of publications and in the various practical diversions. An interest in information of patients appeared at an early stage. Publication ethics as a subdiscipline involved Danish gastroenterologists and has led to contributions within the framework of the International Group of Medical Journal Editors. Research ethics, a central topic throughout all years, has led to such important initiatives as the Second Helsinki Declaration and the establishment of a national control system for medical research in man. A further ramification of ethics is scientific dishonesty and good clinical practice. Here a recent initiative has led to the establishment of a national Committee on Scientific Dishonesty. Under the auspices of the OMGE (Organisation Mondiale de Gastroentérologie) Danish gastroenterologists have investigated transnational and transcultural differences in gastroenterologists' attitudes to information of patients and relatives and have unmasked considerable and important differences throughout the world. Medical ethics has, together with scientific methodology, to some extent reunited the sub-specialized fragments of the mother disciplines medicine and surgery and in this way has acted as partes pro toto.

Genetic polymorphisms of tumour necrosis factor receptor superfamily 1b and fas ligand are associated with clinical efficacy and/or acute severe infusion reactions to infliximab in Crohn's disease.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in TNF receptor superfamily (TNFRSF) 1A and 1B, and Fas ligand (FASLG) genes, have been associated with responsiveness to infliximab (IFX) in Crohn's disease. AIM: To investigate if SNPs in TNFRSF1A and 1B, and FAS (TNFRSF6) and FASLG (TNFSF6), associated with short- or long-term clinical and biological efficacy and with acute severe infusion reactions. METHODS: Observational, retrospective and explorative cohort study of IFX-treated Caucasian patients with Crohn's disease classified as primary nonresponders (n = 21), response failures on maintenance therapy (n = 37), maintained remission (n = 47) and occurrence of acute severe infusion reactions (n = 20). RESULTS: During IFX maintenance therapy, minor allele carriage of TNFRSF1B, rs976881 is associated with loss of response [OR 3.3 (1.2-9.1), P = 0.014]. Minor allele homozygosity increased the risk substantially (OR estimated 19, P = 0.006), and furthermore associated with a mean CRP increase of 17 mg/L as compared to a mean decrease of 17 mg/L in all others (P = 0.036). In contrast, minor allele carriage of TNFRSF1B, rs1061622 is associated with beneficial response to IFX induction [OR 4.2 (1.2-18.2), P = 0.014], and with persistence of remission during maintenance therapy [OR 5.5 (1.5-25.5), P = 0.007]. Carriage of the minor allele of FASLG, rs76110 increased risk of severe infusion reactions [OR 4.0 (1.1-22.4), P = 0.041]; minor allele carriage of TNFRSF1B, rs652625 decreased the risk (OR estimated 0.2, P = 0.043 ). CONCLUSIONS: The TNFRSF1B polymorphisms may contribute to predict efficacy of infliximab. Moreover, FASLG and TNFRSF1B polymorphisms may confer genetic susceptibility to severe infusion reactions. These findings could potentially aid clinical decisions if confirmed in larger studies.

Randomised clinical trial: certolizumab pegol for fistulas in Crohn's disease - subgroup results from a placebo-controlled study.

BACKGROUND: Treatment options for fistulizing Crohn's disease (CD) are limited. AIM: To examine whether fistula closure is maintained at week 26 following treatment with certolizumab pegol. METHODS: Patients with draining fistulas at baseline from PRECiSE 2 (n = 108) received open-label induction with certolizumab pegol 400 mg at weeks 0 (baseline), 2 and 4. Response was defined as ≥100-point decrease from baseline in the Crohn's Disease Activity Index. Nonresponders (50/108) were excluded. At week 6, responders with draining fistulas (N = 58) were randomised to certolizumab pegol 400 mg (n = 28) or placebo (n = 30) every 4 weeks across weeks 8-24. Fistula closure was evaluated throughout the study, with a final assessment at week 26. RESULTS: The majority of patients (55/58) had perianal fistula. At week 26, 36% of patients in the certolizumab pegol group had 100% fistula closure compared with 17% of patients receiving placebo (P = 0.038). Protocol-defined fistula closure (≥50% closure at two consecutive post-baseline visits ≥3 weeks apart) was not statistically significant (P = 0.069) with 54% and 43% of patients treated with certolizumab pegol and placebo achieving this end point, respectively. CONCLUSION: Continuous treatment with certolizumab pegol improves the likelihood of sustained perianal fistula closure compared with placebo.

Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease.

BACKGROUND: Infliximab (IFX) elicits acute severe infusion reactions in about 5% of patients with inflammatory bowel disease (IBD). AIM: To investigate the role of anti-IFX antibodies (Ab) and other risk factors. METHODS: The study included all IBD patients treated with IFX at a Danish university hospital until 2010 either continuously (IFX every 4-12 weeks) or episodically (reinitiation after >12 weeks). Anti-IFX Ab were measured using radioimmunoassay. RESULTS: Twenty-five (8%) of 315 patients experienced acute severe infusion reactions. Univariate analysis showed that patients who reacted were younger at the time of diagnosis (19 vs. 26 years, P=0.013) and at first IFX infusion (28 vs. 35 years, P=0.012). Furthermore, they more often received episodic therapy (72% vs. 31%, P<0.001) and logistic regression revealed this as the only significant predictor of reactions (OR 5 [2-13]; P<0.001). IFX reinitiation after 6 months intermission further increased the risk (OR 8 [3-20], P<0.001). Most reactions (n=14, 88%) occurred at 2nd infusion in the 2nd treatment series (P=0.006). Anti-IFX IgG Ab were highly positive in 19 of 20 patients (95%) shortly after the reactions (median 84 U/mL). Anti-IFX IgG Ab measured prior to the retreatment series were negative in 7 of 11 patients tested (64%). Anti-IFX IgE Ab were negative in all patients with reactions. CONCLUSIONS: Acute severe infusion reactions were strongly associated with development of anti-IFX IgG Ab, but not with anti-IFX IgE Ab. The risk was particularly high at the 2nd infusion in retreatment series. Negative anti-IFX Ab before reinitiation did not rule out reactions.

Importance of perfusate hematocrit for insulin- and glucagon-induced choleresis in the perfused rat liver.

Insulin and glucagon stimulate bile production in the intact rat without affecting the biliary excretion rate of bile acids. This effect was not demonstrable in rat liver perfused with human erythrocytes suspended in a Krebs-Henseleit-bicarbonate buffer at a hematocrit of about 18%. The present experiments demonstrate that the choleretic effect of insulin and glucagon observed in the intact rat is reproducible in perfused rat liver if the hematocrit of the perfusate is raised to about 35%. An increase in perfusate hematocrit is also accompanied by a 65% rise in hepatic oxygen consumption and a 27% rise in the basic production of bile, due to an increase in bile acid-independent bile formation. The mechanism by which these changes in perfusate hematocrit influence the function of the perfused liver is obscure. The difference in oxygen content of the perfusates appears to be without importance. Judged from lactate-pyruvate and beta-hydroxybutyrate-acetoacetate ratios of perfusate as well as electron microscopy, maldistribution of perfusate flow and local hypoxia were not evident in perfusions with low hematocrit. A part of the increase in hepatic oxygen consumption seen with a rise in perfusate hematocrit can, however, be explained by an increase in lactate supply from erythrocyte glycolysis. The results stress the importance of perfusate hematocrit for optimal bile production of the perfused rat liver.

Interaction of insulin, glucagon, and DBcAMP on bile acid-independent bile production in the rat.

In experiments on fasted, pentobarbital-anesthetized rats the effect of insulin (1 U X kg-1, followed by 0.05 U X kg-1 X min-1), glucagon (0.5 micrograms X kg-1 X min-1), and dibutyrylic cyclic AMP (DBcAMP) (0.5 mumol X kg-1 X min-1) on bile flow and composit8ion was examined. Infusion of these substances resulted in maximal increases only in the bile acid-independent bile formation, and insulin appeared to be a more powerful stimulant of bile production than glucagon or DBcAMP. When bile production was first stimulated maximally with glucagon or DBcAMP, supplementary infusion of insulin increased bile production significantly. When administration of glucagon or DBcAMP supplemented maximal infusion of insulin, only DBcAMP resulted in a further increase in bile production. Bile production was, however, increased by supplementary glucagon infusion, when a submaximal dosage of insulin was given. No additive effect of glucagon and DBcAMP on bile secretion was observed. The results suggest that glucagon induces choleresis in rats via liberation of cAMP and that the mechanisms of glucagon choleresis differ at least partly from those involved in insulin choleresis. The results are compatible with an insulin-produced inhibition of the adenylate cyclase and activation of the phosphodiesterase in the liver. In accordance with present knowledge of the biological effects of insulin and glucagon the choleretic response to both hormones may be secondary to stimulation of Na-K-ATPase located to the hepatocellular membrane.