Tim C. Northfield

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

BACKGROUND/AIMSnUrsodeoxycholic 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.nnnMETHODSnTwelve 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.nnnRESULTSnMean 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.nnnCONCLUSIONSnIn 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 & AIMSnImpaired 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.nnnMETHODSnSimultaneous 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.nnnRESULTSnUltrasonography 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).nnnCONCLUSIONSnSimultaneous 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.

Faecal markers in the assessment of activity in inflammatory bowel disease

The fundamental pathological process behind ulcerative colitis and Crohns disease is intestinal inflammation. As the precise cause of this is not yet completely understood, current treatment strategies are aimed at reducing or eliminating the inflammation. Endoscopic examination and histological analysis of biopsy specimens remain the `gold standard methods for detecting and quantifying bowel inflammation; however, these techniques are costly, invasive, and repeated examinations are unpopular with patients. Disease activity questionnaires and laboratory `inflammatory markers, although widely used, show an unreliable correlation with endoscopy and histology. New markers need to be developed to detect and quantify bowel inflammation. These would be of use diagnostically and also an aid to pharmacological treatment.

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.

Direct measurement of first-pass ileal clearance of a bile acid in humans

The purpose of this study was to develop and validate a method of directly measuring ileal bile acid absorption efficiency during a single enterohepatic cycle (first-pass ileal clearance). This has become feasible for the first time because of the availability of the synthetic gamma-labeled bile acid 75Selena-homocholic acid-taurine (75SeHCAT). Together with the corresponding natural bile acid cholic acid-taurine (labeled with 14C), SeHCAT was infused distal to an occluding balloon situated beyond the ampulla of Vater in six healthy subjects. Completion of a single enterohepatic cycle was assessed by obtaining a plateau for 75SeHCAT activity proximal to the occluding balloon, which prevented further cycles. Unabsorbed 75SeHCAT was collected after total gut washout, which was administered distal to the occluding balloon. 75SeHCAT activity in the rectal effluent measured by gamma counter was compared with that of absorbed 75SeHCAT level measured by gamma camera and was used to calculate first-pass ileal clearance. This was very efficient (mean value, 96%) and showed very little variation in the six subjects studied (range, 95%-97%). A parallel time-activity course in hepatic bile for 14C and 75Se during a single enterohepatic cycle, together with a ratio of unity for 14C/75Se in samples obtained at different time intervals, suggests that 75SeHCAT is handled by the ileum like the natural bile acid cholic acid-taurine. Extrapolation of 75SeHCAT first-pass ileal clearance to that of the natural bile acid therefore seems justifiable. In a subsidiary experiment, ileal absorption efficiency per day for 75SeHCAT was also measured by scanning the gallbladder area on 5 successive days after the measurement of first-pass ileal clearance. In contrast with absorption efficiency per cycle, absorption efficiency per day varied widely (49%-86%), implying a possible wide variation in recycling frequency per day.

Soluble E-selectin and vascular cell adhesion molecule-1 (VCAM-1) in primary biliary cirrhosis

BACKGROUND/AIMSnE-selectin and vascular cell adhesion molecule-1, important in leucocyte adhesion, have recently been detected in soluble form in the circulation. However, their clinical significance remains unclear. Our aims were to determine whether the levels of these molecules are increased in primary biliary cirrhosis, and to relate these to histological disease stage, biochemical measures of liver damage and to lymphocyte activation.nnnMETHODSnWe studied 42 patients with primary biliary cirrhosis, nine with primary sclerosing cholangitis, 14 with alcoholic liver disease and 17 healthy subjects. Circulating E-selectin and vascular cell adhesion molecule-1 levels were measured by enzyme-linked immunosorbent assay. In subgroups of patients with primary biliary cirrhosis, hepatic bile acid uptake and excretory rates and T-cell activation were also determined.nnnRESULTSnSoluble E-selectin and vascular cell adhesion molecule-1 levels were significantly elevated in primary biliary cirrhosis compared to healthy controls. However, there was no difference between primary biliary cirrhosis and other liver disease groups. In primary biliary cirrhosis, both adhesion molecules correlated with disease stage, but differed in their relationships with specific liver function tests. They did not correlate with either hepatic bile acid uptake or excretion, or lymphocyte activation.nnnCONCLUSIONSnWe conclude that soluble E-selectin and vascular cell adhesion molecule-1 are elevated in chronic liver diseases. In primary biliary cirrhosis, they reflect the stage of disease and may reflect the degree of leucocyte adhesion and migration.

Bile Acids in Health and Disease

1 Overview: the enterohepatic circulation of bile acids - a topic in molecular physiology.- Section A Biliary Chemistry And Physiology.- 2 Hepatic bile acid transport and secretion.- 3 Hepatic biliary lipid synthesis and transport.- 4 Biliary lipid secretion and its control.- 5 Lipid solubilisation in bile.- 6 Gallbladder motor function.- Section B Pathogenesis Of Cholesterol Gallstone Disease.- 7 The secretory defect.- 8 The physico-chemical defect.- 9 The motility defect.- Section C Gallstone Prevention.- 10 Clues from epidemiology.- 11 Post-dissolution trials.- Section D Non-Surgical Treatment Of Gallstones.- 12 Cheno- versus ursodeoxycholic acid.- 13 Cheno- plus ursodeoxycholic acid.- 14 Methyl tert-butyl ether.- 15 Lithotripsy.- 16 Overall strategy.- Section E Lipid Digestion And Bile Acid Absorption.- 17 Fat digestion and solubilisation.- 18 Bile acid absorption.- Section F Lipid Maldigestion And Bile Acid Malabsorption.- 19 Fat digestion and solubilisation in disease.- 20 Bile acid malabsorption, diarrhoea and steatorrhoea.- 21 Bile acids in irritable bowel syndrome.- Section G Diagnosis Of Bile Acid Malabsorption - Role Of 75SeHCAT.- 22 75SeHCAT: an overview of its physiological properties and clinical value.- 23 Whole body and abdominal retention of75SeHCAT.- 24 Gallbladder retention of 75SeHCAT.

Repeated bile acid therapy for the long-term management of cholesterol gallstones.

BACKGROUND/AIMSnFollowing non-surgical treatment, cholesterol gallstones recur in a high proportion of patients, and recurrence cannot be predicted nor effectively prevented. Our aim was to test prospectively the viability and the efficacy of repeated bile acid therapy, in which recurrent stones are diagnosed at an early stage by regular ultrasound monitoring and promptly retreated, as a strategy for the management of these patients in clinical practice.nnnMETHODSnOne hundred and seventy-two consecutive patients were recruited upon achieving complete gallstone dissolution using non-surgical therapy (bile acids or lithotripsy plus bile acids), and followed up at 6-monthly intervals by ultrasound scan. Gallstone recurrence was promptly treated by a combination of ursodeoxycholic acid plus chenodeoxycholic acid (5 mg/kg per day each) for a period of 2 years, or less if complete redissolution was achieved. Median follow-up period was 34 months (range 6-70).nnnRESULTSnForty-five patients had gallstone recurrence; of these, 39 underwent one or more repeated courses of bile acid therapy (follow-up data available in 27). Gallstone recurrence rate was 15% at 1 year and 47% at 5 years. Average annual redissolution rate of recurrent gallstones (intention to treat) was 41%. The proportion of gallstone-free patients in the whole population was 88%, 84%, 77%, 78%, 75% at 1-5 years, respectively, and rose to > 90% at 3 years onwards in patients with single primary stones.nnnCONCLUSIONSnWe conclude that repeated bile acid therapy maintains the majority of patients gallstone free, and is therefore an effective long-term management strategy, especially in patients with primary single gallstones.

Pharmacological treatment of gallstones : practical guidelines

SummaryLaparoscopic cholecystectomy is the treatment of choice for symptomatic cholelithiasis. Medical treatment is indicated for patients who are not fit or are afraid of surgery. For any form of medical treatment to be effective gallstones must be cholesterol rich, thus radiolucent, and the cystic duct must be patent, as indicated by gallbladder opacification on oral cholecystography. Three forms of medical treatment are currently available for clinical use — oral bile acids, bile acids as adjuncts to lithotripsy and contact dissolution using methyltertbutylether.The choice of treatment depends mainly on gallstone size. Gallstones <6mm in diameter are best treated with oral bile acids, chenodeoxycholic acid 15 mg/kg/day or ursodeoxycholic acid 10 mg/kg/day given alone or in combination (5 mg/kg/day each). Careful patient selection and bedtime administration of the whole daily bile acid dose enhance treatment, and may achieve up to 75% complete dissolution annually. Single stones <30mm in diameter or multiple stones (n < 3) are best treated with lithotripsy combined with oral bile acid for dissolution of fragments. Annual dissolution rates are about 80 and 40% for single and multiple stones, respectively.Stones of any size and number can be dissolved by direct contact dissolution using methyltertbutylether. Dissolution has been reported to be complete in almost 100% of stones, but debris is frequently left behind in the gallbladder. Following dissolution using any form of treatment, gallstones recur in about 50% of patients, and cannot be reliably prevented by low dose bile acid or dietary manipulations. Failing prevention, early detection and retreatment of recurrent stones is the best alternative option as a long term strategy.