Gerard P. vanBerge-Henegouwen

Symptom perception in gastroesophageal reflux disease is dependent on spatiotemporal reflux characteristics

BACKGROUND/AIMS The mechanisms responsible for the development of symptoms in gastroesophageal reflux disease (GERD) are poorly understood. The aims of this study were to identify differences in spatiotemporal reflux characteristics (proximal extent and duration of reflux episodes, ascending velocity of the refluxate) between symptomatic and asymptomatic reflux episodes and to assess the influence of different pH sensor positions on the yield of symptom analysis. METHODS Esophageal pH was measured for 24 hours at 3, 6, 9, 12, and 15 cm above the lower esophageal sphincter (LES) in 18 symptomatic patients with GERD, and spatiotemporal reflux characteristics were assessed for symptomatic and asymptomatic reflux episodes. Additionally, the symptom-association probability (SAP) was calculated for each esophageal level. RESULTS The median episode duration (at 3 cm above the LES) was longer and the proximal extent was higher in symptomatic than in asymptomatic reflux episodes (P = 0.006 and P = 0.01). The ascending velocity of the refluxate was not significantly different. The SAP decreased significantly (P < 0.05) from distal to proximal, but no significant differences were found between distal and proximal esophageal levels for the proportion of patients with positive (> 95%) SAP values. CONCLUSIONS The perception of reflux symptoms depends on the duration of acid-exposure episodes and on the proximal extent of the refluxate. Small changes in pH-sensor position do not significantly influence the yield of symptom analysis.

Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type I diabetes mellitus.

BACKGROUND/AIMS Blood glucose concentration has been shown to be an important factor in gastric motility. However, the effect of hyperglycemia on gastric myoelectrical activity has not yet been studied in patients with diabetes. METHODS Surface electrogastrography was performed in eight patients with type I diabetes mellitus under normoglycemic and hyperglycemic conditions (glucose clamp technique) and in eight normoglycemic control subjects. RESULTS In the early postprandial state, the frequency of the normal pacemaker rhythm tended to be higher during hyperglycemia than during normoglycemia (3.10 +/- 0.27 vs. 2.92 +/- 0.19 cycle/min; P = 0.061). The frequency decrease that occurs immediately after a meal was found less frequently during hyperglycemia (in 25% vs. 75% of the patients; P = 0.046). Higher harmonics of the 3-cycle/min component, indicating an electrogastrographic waveform change, were found less often during hyperglycemia (in 13% vs. 63% of the patients; P = 0.039). Dysrhythmias (in particular, tachygastrias) were more prevalent during hyperglycemia (40.6% vs. 6.5% of the time; P = 0.028). No differences were found between normoglycemic patients and control subjects. CONCLUSIONS This study has shown that hyperglycemia is an important factor in the generation of gastric myoelectrical disturbances and tachygastrias in particular.

Homocysteine in inflammatory bowel disease: a risk factor for thromboembolic complications?

OBJECTIVE:Patients with inflammatory bowel disease (IBD) are at increased risk for thromboembolic events. Hyperhomocysteinemia, which is an established risk factor for arterial as well as venous thrombosis, may be more prevalent in IBD because of vitamin deficiencies.METHODS:In this retrospective study, we studied the concentrations of total homocysteine (tHcy), cobalamin, folate, and pyridoxine in 231 consecutive patients with IBD, of whom 16 patients had a history of venous thrombosis, and nine a history of arterial thrombosis. Age- and gender-matched healthy volunteers served as controls (n = 102).RESULTS:Homocysteine concentrations in patients were higher (12.3 μmol/L [range 4.6–51.3] vs 11.1 μmol/L [range 3.9–27.6], p = 0.001) and hyperhomocysteinemia tended to be more prevalent in patients than in the controls (11.1% vs 5%, p = 0.07). Folate, cobalamin, creatinine, and pyridoxine concentrations were correlated with tHcy. Folate deficiency was infrequently encountered in IBD patients (4.3%). The tHcy concentration in patients with a history of venous or arterial thrombosis was not higher than in patients without a history of thrombosis (12.7 μmol/L [range 4.6–40.1] and 15.2 μmol/L (range 10.5–26.8) vs 12.3 μmol/L [range 10.5–26.8], not significant). Hyperhomocysteinemia was found in 18.8% of the patients with venous thrombosis, 11.1% of the patients with arterial thrombosis, and 10.5% of the patients without thrombosis (not significant).CONCLUSIONS:Hyperhomocysteinemia is a common phenomenon in IBD and correlates with serum folate, cobalamin, creatinine, and pyridoxine concentrations. No correlation between tHcy and a history of venous or arterial thromboembolic complications is found. Hyperhomocysteinemia does not seem to be a major contributory factor in the development of venous or arterial thrombosis in IBD patients.

Small gallstones, preserved gallbladder motility, and fast crystallization are associated with pancreatitis†‡

Acute pancreatitis is a severe complication of gallstones with considerable mortality. We sought to explore the potential risk factors for biliary pancreatitis. We compared postprandial gallbladder motility (via ultrasonography) and, after subsequent cholecystectomy, numbers, sizes, and types of gallstones; gallbladder bile composition; and cholesterol crystallization in 21 gallstone patients with previous pancreatitis and 30 patients with uncomplicated symptomatic gallstones. Gallbladder motility was stronger in pancreatitis patients than in patients with uncomplicated symptomatic gallstones (minimum postprandial gallbladder volumes: 5.8 ± 1.0 vs. 8.1 ± 0.7 mL; P = .005). Pancreatitis patients had more often sludge (41% vs. 13%; P = .03) and smaller and more gallstones than patients with symptomatic gallstones (smallest stone diameters: 2 ± 1 vs. 8 ± 2 mm; P = .001). Also, crystallization occurred much faster in the bile of pancreatitis patients (1.0 ± 0.0 vs. 2.5 ± 0.4 days; P < .001), possibly because of higher mucin concentrations (3.3 ± 1.9 vs. 0.8 ± 0.2 mg/mL; P = .04). No significant differences were found in types of gallstones, relative biliary lipid contents, cholesterol saturation indexes, bile salt species composition, phospholipid classes, total protein or immunoglobulin (G, M, and A), haptoglobin, and α‐1 acid glycoprotein concentrations. In conclusion, patients with small gallbladder stones and/or preserved gallbladder motility are at increased risk of pancreatitis. The potential benefit of prophylactic cholecystectomy in this patient category has yet to be explored. (HEPATOLOGY 2005.)

Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR.

Acromegalic patients treated three times daily with subcutaneous injections of the somatostatin analogue octreotide frequently develop gallstones, due to suppressed cholecystokinin release and impaired gall‐bladder emptying.

Ursodeoxycholic acid therapy for primary sclerosing cholangitis: Results of a 2-year randomized controlled trial to evaluate single versus multiple daily doses

BACKGROUND/AIMS Ursodeoxycholic acid has been reported to be of potential benefit for primary sclerosing cholangitis but little is known about the long-term biochemical, histological and radiological efficacy or the optimum frequency of ursodeoxycholic acid administration. METHODS A 2-year multicentre randomised controlled trial was initiated to assess the effects of ursodeoxycholic acid (10 mg kg(-1).d(-1), given in either single or multiple daily doses, on symptoms, serum liver tests, cholangiographic and histological findings and the occurrence of treatment failure. Liver biopsies were taken and endoscopic retrograde cholangiography was performed at entry and after 2 years; follow-up examinations were at 3-month intervals. Treatment failure was defined as death, liver transplantation, 4-fold increase in serum bilirubin, variceal bleeding, de novo ascites or cholangitis. Actuarial survival was compared with predicted survival using the revised Mayo natural history model for primary sclerosing cholangitis. RESULTS Forty-eight patients were enrolled. In one case, ursodeoxycholic acid had to be discontinued because of gastro-intestinal complaints. No other side-effects were observed. After 2 years of follow-up, treatment was not associated with a beneficial effect on either symptoms or liver histology. Serum liver tests (alkaline phosphatase, y-glutamyl transferase, aspartate aminotransferase) improved significantly in both groups, while serum bilirubin (which was near normal at entry) and IgG remained stable. No major changes in radiographic bile duct appearance seemed to be present. After 2 years, actuarial survival was 91% (95 CI 83%-99%), which is comparable to the predicted 97% survival rate. Treatment failure occurred in 15% of cases. No significant differences in any of the study endpoints (symptoms, serum liver tests, cholangiographic findings, histology, disease progression) were found between the two groups. CONCLUSIONS Ursodeoxycholic acid is well tolerated in primary sclerosing cholangitis. Significant effects on biochemical parameters were found and symptoms, bilirubin and histology did not deteriorate. No advantage of a multiple daily dose over a single dose was observed.

Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy

Ursodeoxycholic acid (UDCA) and impaired gallbladder motility purportedly reduce biliary pain and acute cholecystitis in patients with gallstones. However, the effect of UDCA in this setting has not been studied prospectively. This issue is important, as in several countries (including the Netherlands) scheduling problems result in long waiting periods for elective cholecystectomy. We conducted a randomized, double‐blind, placebo‐controlled trial on effects of UDCA in 177 highly symptomatic patients with gallstones scheduled for cholecystectomy. Patients were stratified for colic number in the preceding year (<3: 32 patients; ≥3: 145 patients). Baseline postprandial gallbladder motility was measured by ultrasound in 126 consenting patients. Twenty‐three patients (26%) receiving UDCA and 29 (33%) receiving placebo remained colic‐free during the waiting period (89 ± 4; median [range]: 75[4–365] days) before cholecystectomy (P = .3). Number of colics, non‐severe biliary pain, and analgesics intake were comparable. A low number of prior colics was associated with a higher likelihood of remaining colic‐free (59% vs. 23%, P < .001), without effects on the risk of complications. In patients evaluated for gallbladder motility, 57% were weak and 43% were strong contractors (minimal gallbladder volume > respectively ≤ 6 mL). Likelihood to remain colic‐free was comparable in strong and weak contractors (31% vs. 33%). In weak contractors, UDCA decreased likelihood to remain colic‐free (21% vs. 47%, P = .02). In the placebo group, 3 preoperative and 2 post‐cholecystectomy complications occurred. In contrast, all 4 complications in the UDCA group occurred after cholecystectomy. In conclusion, UDCA does not reduce biliary symptoms in highly symptomatic patients. Early cholecystectomy is warranted in patients with symptomatic gallstones. (HEPATOLOGY 2006;43:1276–1283.)

The effect of acute oral erythromycin on gallbladder motility and on upper gastrointestinal symptoms in gastrectomized patients with and without gallstones: a randomized, placebo-controlled ultrasonographic study

OBJECTIVE:Gastrectomy might be a risk factor for cholelithiasis and gallbladder stasis might play a major role. We studied fasting and postprandial gallbladder motility with 600 mg oral erythromycin or placebo in gastrectomized patients (with and without gallstones) and controls.METHODS:Seventeen patients operated on for gastric cancer (subtotal gastrectomy: n = 10, total gastrectomy: n = 7) were compared with 20 sex- and body-size matched healthy controls. Subjects randomly received erythromycin or placebo 30 min before the ingestion of a standard 200 ml liquid test meal. Gallbladder volume was estimated by ultrasonography until 120 min after test meal. A visual analog scale monitored GI perception of appetite, satiety, nausea, abdominal fullness and epigastric pain.RESULTS:Gastrectomized patients had increased fasting gallbladder volume (35.9 ± 3.4 ml versus 21.0 ± 1.4 ml, p= 0.0005) with faster postmeal emptying (T/2 14.8 ± 1.1 min versus 23.5 ± 1.5 min, p= 0.00019) than controls. Six patients developed small and asymptomatic gallstones, which did not influence gallbladder motility. In these patients, fasting gallbladder volume increased with time after surgery (r =+ 0.82, p= 0.047). Perception of satiety, abdominal fullness, and epigastric pain after ingestion of the test meal were all significantly greater in patients than in controls. Erythromycin significantly enhanced gallbladder emptying during fasting (p= 0.001) and postprandially in both patients and controls (0.002< p < 0.017) and significantly reduced postmeal satiety and epigastric discomfort in gastrectomized patients.CONCLUSIONS:Increased fasting volume might be a form of stasis, predisposing patients to gallstone formation. Erythromycin improves fasting and postprandial gallbladder emptying and decreases upper GI symptoms in gastrectomized patients.

Small intestinal motor abnormalities in patients with functional dyspepsia demonstrated by ambulatory manometry.

AIMS/METHODS--In 30 patients with functional dyspepsia and in 20 healthy volunteers, ambulatory duodenojejunal manometry was performed to examine the interdigestive and postprandial small intestinal motility patterns in relation to symptoms. RESULTS--In the fasting state, the number of migrating motor complex cycles mean (SEM) was significantly lower in patients, especially in patients with dysmotility-like dyspepsia, than in control subjects (3.8 (0.4), 2.6 (0.5), and 5.3 (0.7) cycles, respectively; p < 0.05), due to a longer duration of phase II. Non-propagated and retrogradely propagated phase III activity was more prevalent in patients than in control subjects (48% v 15%; p = 0.020). During phase II and after dinner no differences were found in contraction incidence, mean amplitude or motility index. However, 1 1/2 hours after completing breakfast the motility index was higher in patients at all three recording levels (p < 0.05). Burst activity was more prevalent in patients than in control subjects (22% v 6% of the subjects; p = 0.003). In 41% of the patients the symptom index was > 75%. CONCLUSIONS--These results suggest that small intestinal motor abnormalities, especially during fasting, participate in the pathogenesis of symptoms in patients with functional dyspepsia. Ambulatory manometry of the small intestine is a valuable tool to demonstrate these abnormalities in outpatients pursuing their daily activities.

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.