Riadh P. Jazrawi

Kinetics of hepatic bile acid handling in cholestatic liver disease: Effect of ursodeoxycholic acid

BACKGROUND/AIMS Ursodeoxycholic acid (UDCA) is clinically beneficial in chronic cholestatic liver disease, but the underlying mechanisms are unclear. It has been suggested that intrahepatic retention of endogenous hydrophobic bile acids contributes to cholestasis and that the hydrophilic bile acid UDCA reduces this retention; the aim of our study was to test these hypotheses. METHODS Twelve patients with primary biliary cirrhosis (PBC) and 5 with primary sclerosing cholangitis (PSC) were studied before and during UDCA (10 mg.kg-1.day-1) and compared with 11 healthy controls. Following intravenous 75Se labeled homocholic acid taurine (75SeHCAT) in the fasting state, abdominal gamma camera imaging was performed for 90 minutes. Initial hepatic uptake, transit time, net, and absolute excretory rates for 75SeHCAT were measured. RESULTS Mean initial hepatic uptake was not different between patients and controls (17.2% and 19.9% dose/minute, not significant). However, net and absolute excretory rates were significantly reduced in patients (1.4% vs. 3.7% dose/minute, P < 0.0001; and 2.35% vs. 3.96% dose/minute, P < 0.02, respectively), and hepatic transit time was prolonged (18.7 minutes vs. 11.6 minutes, P < 0.002). UDCA improved net and absolute hepatic excretory rates and transit time (1.43% to 1.96% dose/minute, P < 0.001; 2.35% to 3.15% dose/minute, P < 0.005 and 18.7 to 14.7 minutes, P < 0.001, respectively). However, UDCA did not alter initial hepatic uptake. CONCLUSIONS In PBC and PSC, there is a defect in hepatic bile acid excretion but not in uptake, implying bile acid retention. This retention is reduced by UDCA.

Postprandial Gallbladder Motor Function: Refilling and Turnover of Bile in Health and in Cholelithiasis

BACKGROUND & AIMS Impaired gallbladder emptying is implicated in gallstone disease. Ultrasonography and scintigraphy have shown conflicting results because the former is influenced by postprandial refilling, whereas the latter is not influenced by refilling. The aim of this study was to measure postprandial refilling and turnover of bile by combining the two techniques. METHODS Simultaneous scintigraphy and ultrasonography were used in 14 patients with gallstones and 11 healthy controls. Measurements were performed while the patients were fasting and at 10-minute intervals after a standard meal for 90 minutes, and the measurements were used to calculate postprandial refilling, turnover of bile (in milliliters), and turnover index. RESULTS Ultrasonography and scintigraphy provided different gallbladder emptying patterns. Compared with controls, patients with gallstones had impaired emptying by both scintigraphy (P < 0.0001) and ultrasonography (P < 0.01). Postprandial refilling and turnover were both reduced between 60 and 90 minutes (P < 0.05), and the turnover index was markedly reduced (1.8 vs. 3.5; P < 0.001). CONCLUSIONS Simultaneous scintigraphy and ultrasonography provide a new model of gallbladder motor function showing that refilling begins immediately postprandially. In healthy controls, the gallbladder postprandially handles up to six times its basal volume within a period of 90 minutes, but this turnover of bile is markedly reduced in cholelithiasis causing a reduced washout effect of the gallbladder contents, including cholesterol crystals.

Gallstone recurrence after medical dissolution: An overestimated threat?

We assessed gallstone recurrence rate in 42 patients diagnosed as having complete gallstone dissolution on bile acid therapy. By contrast with most previous studies, this diagnosis was based on ultrasound as well as on radiology, and only patients having their first gallstone recurrence were included in the study. Patients were followed for periods varying from 6 months to 7 years (median 30 months). Eleven patients had recurrences, giving an overall recurrence rate of 26%. A life analysis table was constructed by an actuarial method to compensate for the different lengths of follow-up in individual patients. Corrected recurrence rates by life table analysis were 15%, 21%, 25%, 36%, 45%, 45% and 45% at 1, 2, 3, 4, 5, 6 and 7 years respectively; for the same time intervals, cumulative recurrence rate overestimated the risk of gallstone recurrence (14%, 22%, 31%, 50%, 61%, 79% and 92%). We conclude that previous figures for recurrence rate have been an overestimate; but recurrence rate remains substantial over the first 5 years, and then levels off.

Ursodeoxycholic acid in chronic liver disease.

The hydrophilic bile acid ursodeoxycholic acid has recently been shown to reduce biochemical markers of both cholestasis and hepatocellular damage in patients with chronic liver diseases. The most compelling evidence available is for chronic cholestatic liver diseases, in particular primary biliary cirrhosis, primary sclerosing cholangitis, and cholestasis associated with cystic fibrosis. The effects may be less beneficial in patients with advanced liver disease from these conditions. Data from placebo controlled trials are now available in support of earlier uncontrolled observations, but it is not yet clear whether short term benefit results in an improvement in longterm prognosis. The mechanism of action of the compound seems to reside in its displacement of toxic hydrophobic bile acids from both the bile acid pool and hepatocellular membranes. There may be an independent effect on bile flow, which could be of particular importance in cystic fibrosis, and possibly an effect on the immune system. Ursodeoxycholic acid should now be regarded as occupying a central place in the medical management of chronic cholestatic liver diseases, in particular primary biliary cirrhosis, because it improves cholestasis and reduces hepatocellular damage and it is not toxic. Research should now be targeted on whether treatment with ursodeoxycholic acid, initiated early in cholestatic liver conditions, improves the long-term outcome.

Optimum bile acid treatment for rapid gall stone dissolution.

To determine the optimum bile acid regimen for rapid gall stone dissolution, 48 gall stone patients were divided into four groups of 12 according to stone diameter and were randomly allocated to receive one of four treatment regimens: bedtime or mealtime chenodeoxycholic acid (CDCA, 12 mg/kg/day) and bedtime or mealtime ursodeoxycholic acid (UDCA, 12 mg/kg/day). An additional 10 patients treated with a combination of CDCA plus UDCA (each 6 mg/kg/day) at bedtime were matched with the 10 patients on bedtime CDCA and the 10 on bedtime UDCA. The gall stone dissolution rates at six and 12 months were determined by standardised oral cholecystography and expressed as the percentage reduction in the gall stone volume after treatment. The gall stone dissolution rate at six months was higher for UDCA than CDCA treatment (median 78% v 48%, p less than 0.01), and for bedtime than mealtime administration (69% v 39%, p less than 0.02). Both differences were greater for stones less than 8 mm diameter. The dissolution rate was faster for combination therapy than for CDCA alone at both six (82% v 36%, p less than 0.05) and 12 months (100% v 54%, p less than 0.05), but was not different from UDCA alone. We conclude that bile acid treatment should be confined to patients with small gall stones and that bedtime administration of combined UDCA and CDCA is likely to provide the most effective and safe combination.

Serum intercellular adhesion molecule-1 in alcoholic liver disease and its relationship with histological disease severity

BACKGROUND Infiltration of the liver by leukocytes is a histological feature of alcoholic liver disease. Intercellular adhesion molecule-1 (ICAM-1) mediates the migration of lymphocytes from the circulation to target sites of inflammation. It has been demonstrated in the liver of alcoholic liver disease subjects and as a circulating soluble form (sICAM-1). The origin of sICAM-1 and its relationship to disease severity is unknown, although it has been postulated that it may arise from activated T lymphocytes and is an inflammatory marker. AIMS The aim of the study was to determine the relationship of sICAM-1 to clinical and histological severity of alcoholic liver disease and to serum T-cell (soluble interleukin-2 receptor (sIL-2R), beta 2-microglobulin) and monocyte (neopterin) immune activation markers. METHODS Serum from 48 outpatients with biopsy proven alcoholic liver disease (steatosis = 9, cirrhosis = 28, hepatitis +/- cirrhosis = 11), 31 with primary biliary cirrhosis and 27 normals was assayed for sICAM-1, sIL-2R, beta 2-microglobulin, and neopterin. RESULTS sICAM-1 was significantly elevated, p = 0.0001, in alcoholic liver disease and primary biliary cirrhosis patients compared to normals. Circulating sIL-2R (p = 0.0001) and beta 2-microgloblin (p = 0.0034) were significantly elevated in alcoholic liver disease compared to controls. There was a highly significant correlation between levels of sICAM-1 and histological grade of disease, Rs = 0.80 (p = 0.0001), but no significant correlation with clinical correlates of disease severity or circulating immune activation markers. CONCLUSIONS sICAM-1 is elevated in alcoholic liver disease, is a marker of histological severity of disease and does not appear to originate from activated T lymphocytes. Measurements of sICAM-1 may be useful in assessing histological severity of alcoholic liver disease.

Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones: a randomized multicentre trial

Combination therapy using ursodeoxycholic acid plus chenodeoxycholic acid has been advocated for dissolution of cholesterol gallstones because the two bile acids have complementary effects on biliary lipid metabolism and cholesterol solubilization.

Dissolution of Gallbladder Stones with Methyl tert-Butyl Ether and Stone Recurrence (A European Survey)

Since there are now several ways to treatsymptomatic gallstone disease, one is able to selecttreatment on the basis of the patients comfort, thepracticability, effectiveness, and side effects of the technique, and the relative costs. In order toassess the present status of contact dissolution withmethyl tert-butyl ether with regard to these aspects,the present enquiry reports the data of 21 European hospitals. Eight hundred three patients wereselected for contact litholysis of cholesterolgallbladder stones using methyl tert-butyl ether.Percutaneous transhepatic puncture of the gallbladderwas performed under x-ray or ultrasound guidance. Dissolutionrate, side effects, and treatment times of 268 patientsfrom one single center were compared to those of 535patients from the other 20 centers. Two hundred sixty-four patients were followed for fiveyears to assess stone recurrence. Physicians were askedhow they assessed the expenditure of the method, thediscomfort to the patients, and the staffing situation. Patients were asked to indicate theiracceptance on an analog scale. Puncture was successfulin 761 (94.8%) patients. Prophylactic administration ofantibiotics was not necessary. Stones were dissolved in 724 (95.1%) patients. In 315 (43.5%) sludgeremained in the gallbladder. The most severecomplication was bile leakage, which led 12 (1.6%)patients to have elective cholecystectomy. Toxicinjuries due to the ether were not reported.Methodrelated lethality amounted to 0%, 30-day-lethalityto 0.4%. Stone recurrence rate was about 40% in solitarystones and about 70% in multiple stones over five years. Patients with multiple stones developedrecurrent stones almost twice as often as those withsolitary stones. The probability of stone recurrence inpatients with sludge in the gallbladder after catheter removal was not statistically significantlydifferent from those without sludge. Seventy to 90% ofthe centers found the puncture to be simple and notdistressing for patients and the relation betweenexpenditure and therapeutic success to be acceptable. Theacceptance of contact litholysis by the patients wasexcellent. Contact litholysis when applied by anexperienced team provides real advantages in thetreatment of gallstone disease. The method is technicallysimple, well accepted by the patients, and can be easilyapplied in community hospitals. Contact litholysis maybe of particular value in patients who are not suitable for anesthesia orsurgery.

Prescribing habits in primary biliary cirrhosis : a national survey

BACKGROUND Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown aetiology. A number of drugs have been used in its treatment, but only ursodeoxycholic acid (UDCA) has been shown to improve survival. Our aims were to determine the current prescribing habits in PBC of all practising gastroenterologists in the UK. METHODS A postal questionnaire was sent to 454 gastroenterologists in 1996, followed by a second questionnaire a month later to the non-responders. RESULTS Of 454 doctors sent questionnaires, 379 (83%) replied. Of these, 58 were excluded from further analysis as they were not practising gastroenterologists. There are an estimated 4337 patients with PBC being seen by gastroenterologists in hospitals. Of these, only 1376 (32%) are being seen in liver units. Ninety-one per cent of gastroenterologists look after patients with PBC (median 10 patients, range 1-500). Ninety-five per cent of gastroenterologists prescribe UDCA but there is a large dose range (median 11.5 mg/kg/day, range 1.5-23.1). Of these, 93% also prescribe cholestyramine. Only 45 (14%) gastroenterologists prescribed other treatments for PBC (13 colchicine, 24 steroids, nine penicillamine, 13 immunosuppressants). Only 53 (17%) treat the symptoms/complications of PBC (37 fat-soluble vitamins, 15 calcium, six bisphosphonates, one hormone replacement therapy, 10 antihistamines, 10 rifampicin). CONCLUSIONS UDCA is being prescribed for PBC by the majority of practising gastroenterologists but over a wide dose range. Very few gastroenterologists are using preventive treatment for osteoporosis in this high-risk group. Other treatments, as yet unproven in trials, are being prescribed by a minority of gastroenterologists.

Use of a γ-labeled bile acid (75SeHCAT) as a test of ileal function: Methods of improving accuracy

Abstract The object of the present study was to improve the accuracy of measurements of ileal function obtained by abdominal scanning and fecal counting after oral administration of the γ-labeled bile acid 75 selenohomocholic acid-taurine ( 75 SeHCAT), as current techniques do not distinguish between retention of the bile acid within the enterohepatic circulation from retention within the colon, and are also affected by incomplete stool collection when using the fecal method. We have therefore introduced the following modifications: (a) simultaneous ingestion of 51 CrCl 3 as a nonabsorbable correction marker for both the abdominal scanning and fecal counting methods; and (b) the use of 75 SeHCAT counts over the gallbladder area on abdominal scanning, because these counts should be independent of colonic retention. We have studied 42 subjects, including 6 healthy controls, 6 ileal resection subjects, 15 ulcerative colitis patients, and 15 patients with unresected ileal Crohns disease. Colonic retention (0%–68% per day) caused a variable overestimate of 75 SeHCAT absorption. Corrected measurements of the fecal absorption index determined by a γ-counter and of the abdominal absorption coefficient determined by a γ-camera correlated well with each other (r = 0.92, p 51 CrCl 3 modification. The fecal absorption index could also be determined from the carmine-rich stool collection of a single day, and this also correlated well with the abdominal absorption coefficient (r = 0.81, p