Gerard P. van Berge Henegouwen

Different Hepatobiliary Effects of Oral and Transdermal Estradiol in Postmenopausal Women

Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However, oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects, 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy, Arnhem, The Netherlands), 100 micrograms/day for 4 weeks, and after 1 month without therapy, with oral estradiol (Progynova; Schering, Weesp, The Netherlands), 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary, the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean +/- SEM, 1.25 +/- 0.06 before and 1.22 +/- 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 +/- 0.09 before and 1.36 +/- 0.09 during oral treatment). However, the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (greater than 0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index, a decrease in relative percentage chenodeoxycholic acid in bile, and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary, oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.

Social position of adolescents with chronic digestive disorders

Objective To investigate the consequences of having a chronic digestive disorder on the social position of adolescents. Methods Five diagnostic groups, including inflammatory bowel disease (IBD), chronic liver diseases, congenital digestive disorders, coeliac disease and food allergy (total n = 758, ages 12–25 years), were each compared with a population-based control group in a multicentre study using a cross-sectional design. Social position was assessed by a mailed questionnaire measuring 24 aspects, categorized as education, leisure activities, friendship, labour participation, financial situation, partnership and sexuality. Results Eight aspects of social position were found to be affected negatively by one or more chronic digestive diseases: absence from school due to illness, going out, having a paid job, needing re-education in order to get a job, getting benefits as main income source, encountering bottlenecks in establishing financial commitments, having self-confidence in making a pass at someone, and restrictions in making love. Adolescents with chronic liver disease and IBD were found to experience more restrictions in social position. Adolescents with food allergy and congenital digestive disorders appear to experience some restrictions, but to a lesser degree, and adolescents with coeliac disease do not appear to have any problems regarding social position compared with controls. Conclusion The social position of adolescents is affected negatively by having a chronic digestive disease, in particular chronic liver disease and IBD. Negative consequences occur in education, leisure activities, labour participation, financial situation, partnership and sexuality.

No beneficial effects of transdermal nicotine in patients with primary sclerosing cholangitis: results of a randomized double-blind placebo-controlled cross-over study

Background/aims Smoking is associated with a decreased risk of primary sclerosing cholangitis. We aimed to explore the therapeutic efficacy of and tolerance for transdermal nicotine treatment in this disease. Methods Twelve patients (11 males; 37 + 6 years; six with ulcerative colitis) who did not achieve complete biochemical remission on ursodeoxycholic acid (14 mg/kg/day) were treated in a randomized cross-over trial with transdermal nicotine (15 mg/day) or a placebo, each for 8 weeks (4-week washout period between treatments). Results One patient developed de novo ulcerative colitis and two did not complete the entire protocol because of intercurrent bacterial cholangitis. Baseline values [mean (range)] were: bilirubin, 1.3 (0.5–2.6); alkaline phosphatase (APh), 2.5 (1.4–4.7); γ-glutamyl transpeptidase (γGT), 7.7 (0.7–38); aspartate aminotransferase (AST), 1.9 (0.5–3.2); alanine aminotransferase (ALT), 2.4 (0.4–7.3); and bile salts, 10.9 (2.1–39) times the upper limit of normal. No significant effect on pruritus or fatigue was noted during either period, but a small increase in bodyweight was observed during placebo treatment. No significant differences were observed between the two treatment modalities after 8 weeks in bilirubin (nicotine versus placebo, +13% versus −6% change from baseline), APh (−3% versus −17%), γGT (−11% versus −13%), AST (+2% versus −10%), ALT (−1% versus −11%) or bile salts (+36% versus −3%). Conclusion Transdermal nicotine does not seem to have a clear short-term beneficial effect in primary sclerosing cholangitis treated with ursodeoxycholic acid.

Successful dissolution of cholesterol gallstone during treatment with pravastatin

This case report describes a 51-year-old hypercholesterolemic male patient who had a large solitary cholesterol gallstone. The patient was treated with the 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin, 40 mg/day. After 3 months of therapy, serum cholesterol level normalized (7.7 mmol/L before and 5.2 mmol/L during treatment), and biliary cholesterol saturation index decreased from 1.3 before to 0.8 during treatment. Repeatedly performed ultrasonography showed complete gallstone dissolution. Pravastatin may be valuable in the nonsurgical treatment of cholesterol gallstone disease particularly when there is an additional indication for HMG-CoA reductase inhibitors because of hypercholesterolemia.

A bioluminescence assay for total 3α-hydroxy bile acids in serum using immobilized enzymes

Abstract A bioluminescence assay for bile acids was developed using a co-immobilized 3α-hydroxysteroid dehydrogenase, diaphorase, and bacterial luciferase. The assay was specific for bile acids containing a free 3α-hydroxyl group, as well as androsterone. Light output was linear over a bile acid concentration range of 1–20000 pmol. Intra-assay precision was 6.2–8.2% and the recovery of added standards was 92–110%. Comparison of results using the bioluminescence assay with those using gas liquid chromatography revealed an excellent correlation ( r = 0.99, n = 31). Since the bioluminescence assay is rapid, sensitive, specific, and uses inexpensive reagents, it appears to be an ideal method for the measurement of total bile acids in serum.

Chemiluminescence in inflammatory bowel disease patients: a parameter of inflammatory activity

BACKGROUNDnReactive oxygen species (ROS) are produced in excess in the inflamed mucosa and peripheral blood of patients with inflammatory bowel disease. These species have emerged as a common pathway of tissue injury in a wide variety of inflammatory and other disease processes. The present study was conducted to assess ROS production and to correlate this with parameters of inflammatory activity.nnnMETHODSnIn 25 patients with Crohns disease (CD), 20 patients with ulcerative colitis (UC) and 65 age- and sex-matched healthy volunteers ROS production was measured using the whole blood luminol enhanced chemiluminescence assay (LECA). Disease activity was assessed using the Crohns disease activity index and the Ulcerative Colitis Symptoms Score (UCSS) for CD and UC, respectively. Furthermore, the effect of various scavengers, enzymes and enzyme inhibitors on LECA was studied to assess the contribution of different ROS.nnnRESULTSnLECA was significantly higher in CD and UC patients compared with healthy controls (7.1+/-4.7 and 9.8+/-6 vs. 5.2+/-2.8 x 10(3) counts per minute (cpm), p<0.05 and <0.001). In CD, relative LECA (patient/control) was correlated with the Crohns disease activity index and C-reactive protein (CRP) (r=0.54, p=0.001 and r=0.51, p=0.01). In UC, CRP but not LECA was correlated with the Ulcerative Colitis Symptoms Score (C-reactive protein: r=0.42, p=0.01). Addition of azide, superoxide dismutase, deferoxamine and dimethylthiourea resulted in a decrease of LECA values.nnnCONCLUSIONnWhole blood LECA is increased in patients with CD and UC. This parameter is correlated with disease activity in CD. The observed chemiluminescence is probably due to generation of superoxide and the hydroxyl radical.

Disease characteristics as determinants of the labour market position of adolescents and young adults with chronic digestive disorders.

Background Job prospects can be problematic for young patients with chronic digestive disorders. Objectives To compare the employment status and disease burden in young adult patients with several chronic digestive disorders with healthy controls, and to determine whether labour participation depends on disease characteristics, such as type of diagnosis and burden of disease. Participants In total 622 patients categorized into five diagnostic groups — inflammatory bowel disease (IBD) (n=274), chronic liver diseases (n=78), congenital digestive disorders (n=104), food allergy (n=77), celiac disease (n=89) — and a population-based control group (n=248), age 15–24 years. Methods Labour participation and burden of disease (i.e. consequences of the disease in daily life) were assessed by a postal questionnaire. Multivariate statistics were computed to investigate the relationship between disease characteristics and labour participation. Results Patients with IBD or chronic liver diseases were found to have limited job prospects. Patients with chronic liver diseases, IBD and food allergy reported more disease burden regarding several indicators compared with controls. Logistic regression analyses including background characteristics revealed socio-economic status (educational level of parents) and nocturnal toilet use as important determinants of employment. In addition, gender and medication intake were found to be most determinative for a full-time position. Conclusions The possible impact of IBD and chronic liver diseases on the labour participation of young adults should be recognized and deserves extra attention from gastroenterologists so that young patients can be supported to increase their job opportunities.

Coping in adolescents and young adults with chronic digestive disorders: impact on school and leisure activities.

Coping strategies were compared across adolescents and young adults with several chronic digestive disorders and healthy peers, and across age groups. Subsequently, the impact of coping on performance in school and leisure activities was investigated. Participants were adolescents and young adults (age 12 to 25 years) suffering from inflammatory bowel diseases (IBD), chronic liver diseases, congenital diseases, coeliac disease or food allergy (total nu2009=u2009521) and healthy controls (nu2009=u2009274). For comparison reasons, a generic coping measuring instrument was employed: the shortened version of the Coping Inventory for Stressful Situations (CISS-21). The CISS-21 assesses three meta coping strategies: task-oriented, emotion-oriented and avoidance coping. Comparisons between several groups only revealed less use of coping strategies in the youngest adolescents. No differences were found among diagnostic groups, nor between diagnostic groups and control group. Coping was found to be related to school and leisure activities of adolescents and young adults with chronic digestive disorders.

Micellar lipid composition profoundly affects LXR-dependent cholesterol transport across CaCo2 cells

Intraluminal phospholipids affect micellar solubilization and absorption of cholesterol. We here study cholesterol transport from taurocholate–phospholipid–cholesterol micelles to CaCo2 cells, and associated effects on ABC‐A1 mediated cholesterol efflux. Micellar incorporation of egg‐yolk‐phosphatidylcholine markedly increased apical retention of the sterol with decreased expression of ABC‐A1, an effect that is prevented by synthetic liver X receptor (LXR) or retinoid X receptor (RXR) agonists. On the other hand, incorporation of lyso‐phosphatidylcholine (LysoPC) increased ABC‐A1–HDL‐dependent basolateral cholesterol efflux, an effect that is abated when LXR is silenced. Thus, the modulation of cholesterol metabolism via intraluminal phospholipids is related to the activity of the oxysterol nuclear receptor LXR.

Quantifying vesicle/mixed micelle partitioning of phosphatidylcholine in model bile by using radiolabeled phosphatidylcholine species

Phospholipid in vesicles and mixed micelles of (model) bile has been traced or quantitated (or both) by adding radioactively labeled phosphatidylcholine species. The question is whether these labeled species mix homogeneously with the phosphatidylcholine species mixture present, such that the label distribution reflects the already established mass partitioning of species. In this study, model bile containing egg yolk phosphatidylcholine was incubated with radioactive phosphatidylcholine species. Vesicle and mixed micelle fractions were separated by gel filtration. Radiochemical analysis of the species distribution confirmed chemical analysis: 1,2-di(14C)palmitoyl-phosphatidylcholine was enriched in the vesicles, the 1-palmitoyl-2-(14C)oleoyl species evenly distributed, and the 1-palmitoyl-2-(14C)linoleoyl species more expressed in mixed micelles. This indicates that the distribution of an added radioactive phosphatidylcholine species represents the vesicle/mixed micelle distribution of that particular phosphatidylcholine species. Consequently, the label distribution of a particular added radioactive phosphatidylcholine species can be used to calculate the vesicle/mixed micelle partitioning of total phosphatidylcholine only after it has been established that the radioactive species reaches the same partitioning as total phosphatidylcholine.