Search PubMed⌕ Search

Biomedical subjects

K J van Erpecum

Publications and source records attributed to K J van Erpecum.

At least 19 recordsLinked to original sources
PubMed2006

Indomethacin enhances bile salt detergent activity: relevance for NSAIDs-induced gastrointestinal mucosal injury.

Gastroduodenal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) is partly independent from cyclooxygenase inhibition, possibly related to increased intermixed micellar-vesicular (nonphospholipid-associated) bile salt concentrations thought to be responsible for bile salt cytotoxicity. We evaluated the effects of indomethacin on bile salt cytotoxicity with complementary in vitro and ex vivo systems. In the erythrocyte model, indomethacin alone did not induce hemolysis. In contrast, indomethacin enhanced and phospholipids decreased hemolysis induced by hydrophobic taurodeoxycholate (TDC). Hydrophilic tauroursodeoxycholate (TUDC) enhanced rather than decreased TDC-induced hemolysis in the presence of indomethacin. Indomethacin did not affect intermixed micellar-vesicular bile salt concentrations or compositions. Indomethacin also increased TDC-induced lactate dehydrogenase release in CaCo-2 cells and bile salt-induced rat colonic mucosal injury, and prevented potential protective effects of TUDC in these systems. Our data show that indomethacin enhances bile salt-induced cytotoxicity without affecting intermixed micellar-vesicular bile salt concentrations or compositions. These findings may be relevant for gastroduodenal injury during NSAID therapy.

Animals↗
PubMed2006

Indomethacin disrupts the protective effect of phosphatidylcholine against bile salt-induced ileal mucosa injury.

BACKGROUND: Indomethacin (Indo) exerts local toxic effects on small intestinal mucosa, possibly in association with hydrophobic bile salts. We investigated the potential toxic effects of Indo on ileal mucosa and the role of phosphatidylcholine (PC). MATERIALS AND METHODS: Transmucosal resistance and Na-fluorescein permeability of ileal mucosa segments from female Wistar rats were determined in Ussing chambers during a 30-min incubation with model systems containing: control-buffer, taurodeoxycholate (TDC), Indo, TDC-Indo, TDC-PC, or TDC-PC-Indo. Decrease of resistance and increase of permeability were considered as parameters for mucosal injury. After incubation in Ussing chambers, the histopathology was examined to quantify the extent of mucosal injury. Also, in CaCo-2 cells, LDH-release was determined as a measure of cytotoxicity, after incubation with various model systems. RESULTS: Decrease of resistance and increase of permeability were highest in systems containing TDC-Indo (P < 0.01). Phosphatidylcholine protected against the cytotoxic effects of TDC in absence of Indo only. Extent of mucosal injury by histological examination was also highest in systems containing TDC-Indo (P = 0.006). Again, PC exhibited protective effects in absence of Indo only. The LDH-release by CaCo2-cells was strongest in TDC-Indo systems (P < 0.001). CONCLUSIONS: Indomethacin disrupts protective effects of PC against bile salt-induced ileal mucosa injury. This finding is relevant for small intestinal injury induced by non-steroidal anti-inflammatory drugs.

Animals↗
PubMed2006

Hepatitis C: changing genotype distribution with important implications for patient management.

In The Netherlands an estimated 0.1 to 0.4% of the population are chronic hepatitis C (HCV) carriers (15,000 to 60,000 persons). HCV is characterised by genetic heterogeneity and six different genotypes have been identified. The distribution of HCV genotypes is relevant for the clinician, since there are important genotype-specific differences in response to interferon-alpha based treatment regimens. Between 1993 and 2005 a shift was observed in The Netherlands from a dominant prevalence of genotype 1 to a situation in which genotype non-1 is becoming more important.

Antiviral Agents↗
PubMed2004

Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease.

In the formation of cholesterol gallstones, cholesterol hypersecretion into bile causing cholesterol supersaturation and crystallization appears to be the primary factor, with disturbed gallbladder and intestinal motility as secondary factors. Although intestinal uptake mechanisms have not yet been fully elucidated, the HDL receptor scavenger receptor B1 (SRB1) may be involved. Since HDL-cholesterol, both from the intestine and peripheral sources, is the preferred type of cholesterol for biliary secretion, increased HDL transport to the liver can also cause cholesterol hypersecretion in bile. In the hepatocyte, bile formation is regulated by several transmembrane proteins, all belonging to the ABC family. A change in the activity in one of these proteins can have a profound impact on biliary lipid secretion. The bile salt export pump (BSEP or ABCB11) regulates the excretion of bile salts into bile and mutations cause severe cholestasis. The second ABC transporter, ABCB4 (MDR3) regulates the secretion in bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. These transporters also facilitate transport of sterols back into the intestinal lumen. Mutations in either of these genes cause sitosterolaemia with increased absorption of plant sterols and cholesterol. Until now, evidence for a genetic background of human gallstone disease is mostly indirect and based on ethnic differences. Only two single gene defects are associated with gallstones. One is an ABCB4 mutation which causes a deficiency in biliary PC secretion and the other is a CYP7A1 mutation, the rate-limiting enzyme in the synthesis of bile salts from cholesterol in the liver. Recently, several common DNA polymorphisms in the ABCG8 gene were discovered that are associated with variations in plasma sterols, which could also influence biliary cholesterol secretion, but there is still a paucity of human studies.

Bile↗
PubMed2004

Cholesterol saturation rather than phospholipid/bile salt ratio or protein content affects crystallization sequences in human gallbladder bile.

BACKGROUND: In model biles, cholesterol crystallization (an important factor in gallstone formation) mainly depends on phospholipid/bile salt ratios with characteristic sequences of plate-like (monohydrate) vs. non-plate-like (presumed anhydrous: arcs, needles, tubules, spirals) cholesterol crystals. We now investigate whether the same phenomenon occurs in human bile. METHODS: Appearances of plate-like and non-plate-like cholesterol crystals were determined in filtered bile of 80 cholesterol gallstone patients, and related to biliary lipid and pro-nucleating protein composition. RESULTS: Non-plate-like crystals appeared before plate-like crystals in 9 biles, on the same day in 24 biles, and after plate-like crystals in 31 biles. In 16 biles only plate-like crystals were observed. Crystal sequences did not depend on biliary lipid or protein composition. Cholesterol saturation indexes were higher in biles with than without non-plate-like crystals (150 +/- 6 vs. 125 +/- 12, P = 0.02). In contrast, phospholipid/(bile salt + phospholipid) ratios, bile salt species, phospholipid classes, concentrations of mucin, IgG, IgM, IgA, haptoglobin and alpha-1 acid glycoprotein did not differ. CONCLUSIONS: Cholesterol crystallization sequences in human bile depend on cholesterol saturation index rather than on phospholipid/bile salt ratio.

Bile↗
PubMed2003

Pathways of cholesterol crystallization in model bile and native bile.

Hypersecretion of hepatic cholesterol, chronic supersaturation of bile with cholesterol and rapid precipitation of cholesterol crystals in the gallbladder from cholesterol-enriched vesicles represent the primum movens in cholesterol gallstone formation. Physical-chemical factors and pathways leading to cholesterol crystallization can be investigated in artificial model biles and ex vivo in fresh human bile. Depending on modulatory factors (i.e., lipid concentration, bile salt or phospholipid species, humidity, mucins, etc.), cholesterol can precipitate in several forms (i.e., monohydrate, anhydrous) and habits (i.e., plate-like, needle-like, intermediate arcs, filaments, tubules, spirals). Careful analysis of biliary cholesterol crystals includes biochemical analysis of precipitated crystals, polarizing quantitative light microscopy, and turbidimetric methods. In this paper, recent concepts on cholesterol crystallization in artificial model biles as well as in human bile will be reviewed.

Bile↗
PubMed2003

Intestinal aspects of cholesterol gallstone formation.

Apart from biliary cholesterol supersaturation, crystallization-promoting proteins and impaired postprandial gallbladder motility, the intestine may be an important factor in the pathogenesis of cholesterol gallstones. Prolonged intestinal transit could increase gallstone risk by enhancing formation in the intestinal lumen of the secondary hydrophobic and pro-lithogenic bile salt deoxycholate. Furthermore, in normal subjects there is an intimate relationship between gallbladder and intestinal motility in the fasting (interdigestive) state. In gallstone patients we found disordered intestinal motility, absent gallbladder contraction and abnormal release of the hormone motilin in the interdigestive state. These disturbances could contribute to gallstone formation.

Cholecystolithiasis↗
PubMed2003

Sphingomyelin protects against apoptosis and hyperproliferation induced by deoxycholate: potential implications for colon cancer.

High fecal deoxycholate levels may promote colonic cancer. Phospholipids protect against bile salt-induced cytotoxicity. We therefore aimed to examine whether the dietary phospholipid sphingomyelin could decrease hyperproliferation induced by deoxycholate. In CaCo2 cells, hyperproliferation (by bromodeoxyuridine assay), phosphorylation state of cellular proteins, and apoptosis with concomitant caspase-3 activity were evaluated after incubation with 50-500 microM deoxycholate, with or without sphingomyelin. At 2 and 4 hr of incubation, deoxycholate induced dose-dependent apoptosis, with concomitant caspase-3 activation. At 16 hr, apoptosis had decreased markedly, but there was dose-dependent hyperproliferation (with changed phosphorylation status of cellular proteins) at this time point. Sphingomyelin dose-dependently reduced deoxycholate-induced apoptosis and hyperproliferation. In conclusion, sphingomyelin reduces deoxycholate-induced hyperproliferation and apoptosis. These findings may have implications for colonic cancer prevention by dietary modification.

Apoptosis↗
PubMed2003

Acute idiopathic pancreatitis: does it really exist or is it a myth?

BACKGROUND: Acute pancreatitis is a severe disease with considerable morbidity and mortality. Gallstones and alcohol abuse are the most frequent causes (75% of patients). Other well-known causes are: hyperlipidemia, hypercalcaemia, abdominal surgery and drugs. In 10%-40% of patients however, no cause is identified after initial diagnostic evaluation: acute idiopathic pancreatitis. Identifying a cause in these patients is important, since the recurrence rate is high. METHODS: A systematic review of the current literature was performed to identify possible causes, diagnoses and treatment options of acute idiopathic pancreatitis. Relevant literature was found via Pubmed. RESULTS: The presence of microlithiasis or biliary sludge is an important cause of acute 'idiopathic' pancreatitis (up to 80% of patients). Microlithiasis and sludge can be detected by transabdominal/endoscopic ultrasonography, ERCP or polarizing light microscopy of bile. Cholecystectomy is the treatment of choice, whereas endoscopic sphincterotomy and ursodeoxycholic acid maintenance therapy are effective alternatives. Sphincter of Oddi dysfunction can be identified as the cause of acute 'idiopathic' pancreatitis in up to 30% of patients. Manometry of Oddi's sphincter is the gold standard for its diagnosis. Endoscopic sphincterotomy prevents recurrence in most patients. Anatomic abnormalities such as major papilla stenosis, pancreas divisum, pancreatic duct strictures and tumours may also cause acute 'idiopathic' pancreatitis. Endoscopic sphincterotomy and surgery are effective treatments. Finally, genetic screening may reveal gene mutations as the cause of acute 'idiopathic' pancreatitis. CONCLUSIONS: Acute 'idiopathic' pancreatitis is a severe disease with a high recurrence rate. Extensive diagnostic investigations may lead to a cause in >90% of patients.

Acute Disease↗
PubMed2002

Intraduodenal conjugated bile salts exert negative feedback control on gall bladder emptying in the fasting state without affecting cholecystokinin release or antroduodenal motility.

BACKGROUND: Intraduodenal bile salts exert negative feedback control on postprandial gall bladder emptying. AIMS: We wished to examine whether a similar control mechanism occurs in the fasting state. METHODS: Intraduodenal bile salt depletion was achieved by 12 g of cholestyramine. Thereafter, in study A (seven subjects), the effects on gall bladder volume (by ultrasound) and antroduodenal motility of intraduodenal infusions of taurocholate egg yolk-phosphatidylcholine micelles were assessed. In study B (nine subjects), the effects on gall bladder volume of infusing mixed micelles composed of taurocholate (100 mM) and low (26 mM) or high (68 mM) amounts of egg yolk-phosphatidylcholine, or low amounts of dipalmitoylphosphatidylcholine were determined. RESULTS: Cholestyramine induced strong and prolonged gall bladder contraction without cholecystokinin release. In study A, micellar infusions increased gall bladder volume without affecting migrating motor complex cycle length. In study B, intraduodenal infusion induced strong increases in gall bladder volume in the case of taurocholate micelles containing low amounts of egg yolk-phosphatidylcholine, moderate increases in micelles containing low amounts of dipalmitoylphosphatidylcholine but no change in micelles containing high amounts of egg yolk-phosphatidylcholine, in all cases without altered plasma cholecystokinin levels. Phosphatidylcholine hydrolysis was significantly higher after infusion of egg yolk-phosphatidylcholine compared with infusion of dipalmitoylphosphatidylcholine containing micelles. Intermixed micellar-vesicular bile salt concentrations (responsible for detergent effects) were higher in egg yolk-phosphatidylcholine than in dipalmitoylphosphatidylcholine containing model biles and if lyso-phosphatidylcholine was included. CONCLUSIONS: Intraduodenal bile salts exert negative feedback on fasting gall bladder volume. The modulating effects of various phospholipids may relate to their effects on intermixed micellar-vesicular bile salt concentrations.

Adult↗
PubMed2001

Hydrophilic bile salts enhance differential distribution of sphingomyelin and phosphatidylcholine between micellar and vesicular phases: potential implications for their effects in vivo.

BACKGROUND/AIMS: The hepatocyte canalicular membrane outer leaflet contains both phosphatidylcholine (PC) and sphingomyelin (SM). Normally, PC is the exclusive phospholipid in bile. We examined effects of bile salt hydrophobicity on cytotoxicity and on differential SM and PC distribution between detergent-resistant aggregated vesicles (model for detergent-resistant canalicular membrane) and mixed micelles or small unilamellar vesicles (representing lipid phases in bile). METHODS: Aggregated vesicles were obtained by ultracentrifugation of cholesterol-supersaturated model systems containing SM, PC and various bile salts, micelles by ultrafiltration and unilamellar vesicles by dialysis of the supernatant. Erythrocyte hemolysis and lactate dehydrogenase release from CaCo-2 cells upon incubation with various micelles were quantified. RESULTS: Preferential SM distribution and lipid solubilization in aggregated vesicles increased in rank order taurodeoxycholate < taurocholate < tauroursodeoxycholate < taurohyodeoxycholate, with reciprocal PC enrichment in micelles and small unilamellar vesicles. Including small amounts of PC within taurohyodeoxycholate micelles increased cytotoxicity with more erythrocyte hemolysis and LDH release from CaCo-2 cells upon incubation, but decreased cytotoxicity in case of tauroursodeoxycholate micelles. CONCLUSIONS: Hydrophilic but not hydrophobic bile salts preserve integrity of pathophysiologically relevant phosphatidylcholine plus sphingomyelin-containing bilayers. Enhanced biliary phospholipid secretion during taurohyodeoxycholate but not during tauroursodeoxycholate therapy (Hepatology 25 (1997) 1306) may relate to different interactions of these bile salts with phospholipids.

Bile Acids and Salts↗
PubMed2001

Absence of apolipoprotein E4 genotype, good gallbladder motility and presence of solitary stones delay rather than prevent gallstone recurrence after extracorporeal shock wave lithotripsy.

BACKGROUND/AIMS: Extracorporeal shock wave lithotripsy (ESWL) with adjuvant bile salt dissolution therapy may be successful in selected gallstone patients, but the considerable risk of recurrence is a major drawback. Apolipoprotein E4 genotype and impaired gallbladder motility have been identified as major risk factors for recurrence during short-term follow up. We have now examined their relevance during long-term follow up. METHODS: Eighty-four cholesterol gallstone patients (55 solitary and 29 multiple (two to ten) stones) were followed prospectively up to 10 years after complete stone disappearance. Various potential risk factors for recurrence were evaluated. RESULTS: Gallstone recurrence was found in up to 80% of patients at 10 years follow-up. Absence of the apolipoprotein epsilon4 allele, initial solitary stones, good gallbladder emptying (i.e. minimal postprandial volume < or = 6 ml) and 2-year postdissolution ursodeoxycholic acid prophylaxis (in ten patients) all delayed but did not prevent recurrence. In contrast, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was identified as an independent protective factor, with greatly decreased recurrence (at 10 years: 58 vs 93% in non-NSAID users, P = 0.03). CONCLUSIONS: Non-apolipoprotein E4 genotype, presence of solitary stones and good gallbladder emptying delay rather than prevent recurrence after initially successful ESWL. Regular use of NSAIDs may prevent recurrence.

Adult↗
PubMed2001

Regulation of biliary cholesterol secretion is independent of hepatocyte canalicular membrane lipid composition: a study in the diosgenin-fed rat model.

BACKGROUND/AIMS: Phosphatidylcholine (PC) and sphingomyelin (SM) are the major phospholipids on the outer leaflet of the hepatocyte canalicular membrane. Since cholesterol preferentially associates with SM in detergent-resistant microdomains, we hypothesized that canalicular membrane lipid composition could modulate secretion of the sterol into bile. METHODS: Male Wistar rats were fed for 10 days with a control diet with or without the plant sterol diosgenin (1% w/w) to induce biliary cholesterol hypersecretion. Thereafter, lipid compositions and phospholipid molecular species were determined in fistula bile and highly enriched canalicular membrane fractions. RESULTS: Despite four-fold higher biliary cholesterol output in diosgenin-fed rats, no differences were observed between canalicular membranes of diosgenin and control groups with respect to cholesterol/phospholipid ratios (0.58 vs 0.62), phospholipid classes and acyl chain compositions of SMs (16:0 > 24:1 > 24:0 > 22:0 > 18:0 > 23:0 > 20:0 > 24:2), or PCs (mainly diacyl 16:0-18:2, 16:0-20:4, 18:0-20:4, and 18:0-18:2). In contrast to canalicular PCs, bile contained more hydrophilic species (mainly diacyl 16:0-18:2 and 16:0-20:4), without differences between both groups. In vitro resistance of purified canalicular membrane fractions against detergents such as Triton X-100 and taurocholate was also similar in both groups. CONCLUSIONS: Diosgenin-induced biliary cholesterol hypersecretion occurs in the absence of changes of canalicular membrane lipids. Our data therefore do not support a major role of canalicular membrane lipid composition in regulation of biliary cholesterol secretion.

Animals↗
PubMed2001

Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: soluble pronucleating proteins in gallbladder and hepatic biles.

BACKGROUND/AIMS: Gallstone susceptibility is high in C57L inbred mice (males > females) and low in AKR mice, related to variant lithogenic (Lith) genes. We examined the relationship between biliary crystallization-promoting proteins and gallstone susceptibility. METHODS: Biliary protein and lipid concentrations were determined at 0, 7,14, 21, 28 and 56 days on a lithogenic diet. RESULTS: Protein and soluble mucin concentrations in gallbladder biles increased markedly in males, but remained low in females of both strains and correlated with the cholesterol saturation index (CSI). In all groups, IgA and IgM concentrations decreased initially, but increased at later stages. There were no consistent changes in IgG concentrations, but aminopeptidase-N levels were higher in AKR than in C57L. During the lithogenic diet period, the CSI was > or = 2 in C57L males, approximately 1.5 in AKR males, and 1 in females of both strains. Taurodeoxycholate and taurochenodeoxycholate rose sharply in C57L, but remained low in AKR. CONCLUSIONS: Hydrophobic bile salts, cholesterol supersaturation, and possibly, high mucin concentrations are associated with gallstone formation. In vitro crystallization-promoting immunoglobulins and aminopeptidase-N do not appear to be major factors in murine gallstone pathogenesis, in line with the observation that genes encoding these proteins do not co-localize with any known Lith locus.

Animals↗
PubMed2001

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); gamma-glutamyl transpeptidase (gammaGT), 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%), gammaGT (-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.

Administration, Cutaneous↗
PubMed2001

Cholesterol crystallization in model biles: effects of bile salt and phospholipid species composition.

Cholesterol in human bile is solubilized in micelles by (relatively hydrophobic) bile salts and phosphatidylcholine (unsaturated acyl chains at sn-2 position). Hydrophilic tauroursodeoxycholate, dipalmitoyl phosphatidylcholine, and sphingomyelin all decrease cholesterol crystal-containing zones in the equilibrium ternary phase diagram (van Erpecum, K. J., and M. C. Carey. 1997. Biochim. Biophys. Acta. 1345: 269-282) and thus could be valuable in gallstone prevention. We have now compared crystallization in cholesterol-supersaturated model systems (3.6 g/dl, 37 degrees C) composed of various bile salts as well as egg yolk phosphatidylcholine (unsaturated acyl chains at sn-2 position), dipalmitoyl phosphatidylcholine, or sphingomyelin throughout the phase diagram. At low phospholipid contents [left two-phase (micelle plus crystal-containing) zone], tauroursodeoxycholate, dipalmitoyl phosphatidylcholine, and sphingomyelin all enhanced crystallization. At pathophysiologically relevant intermediate phospholipid contents [central three-phase (micelle plus vesicle plus crystal-containing) zone], tauroursodeoxycholate inhibited, but dipalmitoyl phosphatidylcholine and sphingomyelin enhanced, crystallization. Also, during 10 days of incubation, there was a strong decrease in vesicular cholesterol contents and vesicular cholesterol-to-phospholipid ratios (approximately 1 on day 10), coinciding with a strong increase in crystal mass. At high phospholipid contents [right two-phase (micelle plus vesicle-containing) zone], vesicles were always unsaturated and crystallization did not occur. Strategies aiming to increase amounts of hydrophilic bile salts may be preferable to increasing saturated phospholipids in bile, because the latter may enhance crystallization.

1,2-Dipalmitoylphosphatidylcholine↗