Niels G. Venneman

Nasobiliary drainage induces long‐lasting remission in benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by episodic cholestasis and pruritus without anatomical obstruction. Effective medical treatment is not available. We report complete and long‐lasting disappearance of pruritus and normalization of serum bile salt concentrations in cholestatic BRIC patients within 24 hours after endoscopic nasobiliary drainage (NBD). Relative amounts of phospholipids and bile salts in bile collected during NBD appeared to be normal, but phospholipids other than phosphatidylcholine (especially sphingomyelin) were increased. In conclusion, we propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic BRIC patients. (HEPATOLOGY 2006;43:51–53.)

Small Gallstones Are Associated with Increased Risk of Acute Pancreatitis: Potential Benefits of Prophylactic Cholecystectomy?

OBJECTIVES:Pancreatitis is a severe complication of gallstone disease with considerable mortality. Small gallstones may increase the risk of pancreatitis. Our aims were to evaluate potential association of small stones with pancreatitis and potential beneficial effects of prophylactic cholecystectomy.METHODS:Stone characteristics were determined in patients with biliary pancreatitis (115), obstructive jaundice due to gallstones (103), acute cholecystitis (79), or uncomplicated gallstone disease (231). Sizes and numbers of gallbladder and bile duct stones were determined by ultrasonography and endoscopic retrograde cholangiopancreatography, respectively. Effects of prophylactic cholecystectomy were assessed by decision analyses with a Markov model and Monte Carlo simulations.RESULTS:Patients with pancreatitis or obstructive jaundice had more and smaller gallbladder stones than those with acute cholecystitis or uncomplicated disease (diameters of smallest stones: 3 ± 1, 4 ± 1, 8 ± 1, and 9 ± 1 mm, respectively, p < 0.01). Bile duct stones were smaller in case of pancreatitis than in obstructive jaundice (diameters of smallest stones: 4 ± 1 vs 8 ± 1, p < 0.01). Multivariate analysis identified old age and small stones as independent risk factors for pancreatitis. Decision analysis in a representative group of patients with small (≤5 mm) gallstones (5,000 patients, 67% females, 45 yr old, 10-yr follow-up) indicates that life-years may be gained or lost by cholecystectomy, depending on incidence and mortality of pancreatitis.CONCLUSIONS:Small gallstones are associated with pancreatitis. Prophylactic cholecystectomy may lead to gain or loss of life-years in patients with small stones, depending on incidence and mortality of pancreatitis.

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.)

Pathogenesis of Gallstones

Cholesterol gallstone formation is a complex process and involves phase separation of cholesterol crystals from supersaturated bile. In most cases, cholesterol hypersecretion is considered the primary event in gallstone formation. The sterol is transported through the hepatocytic canalicular membrane by ABCG5-G8. Expression of this transport protein is regulated by transcription factor Liver X Receptor-alpha, which may be responsible for biliary hypersecretion. Hydrophobic bile salt pool, bile concentration, excess pronucleating mucin, and impaired gallbladder and intestinal motility are secondary phenomena in most cases but nevertheless may contribute to gallstone formation.

New strategies for the treatment of gallstone disease.

Background : Symptomatic gallstones are generally accepted as being the indication for cholecystectomy. Generally, severe abdominal pain in epigastrium and in the right upper abdominal quadrant, and lasting for more than 15 min, is thought to be caused by gallstones. However, many patients with other abdominal complaints undergo cholecystectomy and are satisfied with the outcome of surgery. Possible ways to improve the results of cholecystectomy are discussed. Methods : Review of previous work by the authors. Results : The introduction of laparoscopic cholecystectomy has even led to an increase in cholecystectomies; in a higher complication rate; and in increased costs of the treatment of gallstone disease. Because of faster recovery, 70% of symptomatic gallstone patients are able and willing to undergo laparoscopic cholecystectomy in day care. Cholecystectomy after sphincterotomy and stone extraction in patients who have stones in the gallbladder was demonstrated to prevent gallstone-related symptoms in at least 40% of patients. If the gallbladder had to be removed later for symptomatic disease, however, this did not result in a higher rate of conversions and complications. Because of shortage in operation capacity in The Netherlands, there is a considerable delay between the diagnosis of symptomatic stones and cholecystectomy. Better selection of patients for cholecystectomy will not only improve the results of cholecystectomy, it will also reduce the number of cholecystectomies and patients on waiting lists. Delay of cholecystectomy is associated with more complications, longer operative times, higher conversion rates to open cholecystectomy and prolonged hospitalization. The efficacy of the bile salt ursodeoxycholic acid in preventing gallstone-related pain attacks and complications in patients with contraindications for operation or waiting to undergo cholecystectomy should be investigated further, since two retrospective studies have demonstrated favourable outcomes for this strategy. Conclusion : The results of cholecystectomy are likely to be improved by better selection of patients, prevention of delay of the procedure and possibly treatment with ursodeoxycholic acid.

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.

Reassessment of the predictive value of the Forrest classification for peptic ulcer rebleeding and mortality: can classification be simplified?

BACKGROUND AND STUDY AIMS This study aimed to reassess whether the Forrest classification is still useful for the prediction of rebleeding and mortality in peptic ulcer bleedings and, based on this, whether the classification could be simplified. PATIENTS AND METHODS Prospective registry data on peptic ulcer bleedings were collected and categorized according to the Forrest classification. The primary outcomes were 30-day rebleeding and all-cause mortality rates. Receiver operating characteristic curves were used to test whether simplification of the Forrest classification into high risk (Forrest Ia), increased risk (Forrest Ib-IIc), and low risk (Forrest III) classes could be an alternative to the original classification. RESULTS In total, 397 patients were included, with 18 bleedings (4.5%) being classified as Forrest Ia, 73 (18.4%) as Forrest Ib, 86 (21.7%) as Forrest IIa, 32 (8.1%) as Forrest IIb, 59 (14.9%) as Forrest IIc, and 129 (32.5%) as Forrest III. Rebleeding occurred in 74 patients (18.6%). Rebleeding rates were highest in Forrest Ia peptic ulcers (59%). The odds ratios for rebleeding among Forrest Ib-IIc ulcers were similar. In subgroup analysis, predicting rebleeding using the Forrest classification was more reliable for gastric ulcers than for duodenal ulcers. The simplified Forrest classification had similar test characteristics to the original Forrest classification. CONCLUSION The Forrest classification still has predictive value for rebleeding of peptic ulcers, especially for gastric ulcers; however, it does not predict mortality. Based on these results, a simplified Forrest classification is proposed. However, further studies are needed to validate these findings.

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

Abstract 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 e 4 allele, initial solitary stones, good gallbladder emptying (i.e. minimal postprandial volume ≤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.

Review article: agents affecting gall-bladder motility - role in treatment and prevention of gallstones

Various agents may either enhance or impair post‐prandial gall‐bladder motility, and they are identified in this review. When studying the impact of medication on gall‐bladder motility, the effects on interdigestive gall‐bladder and intestinal motility should also be taken into account. Patients at high risk of gallstone disease, and patients who are treated chronically with gall‐bladder motility inhibiting drugs, may benefit from improved gall‐bladder motility using a prokinetic agent. However, there are no long‐term studies to prove that such a strategy prevents gallstone formation.