A. Lanzini

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.

Intestinal absorption of the bile acid analogue 75Se-homocholic acid-taurine is increased in primary biliary cirrhosis, and reverts to normal during ursodeoxycholic acid administration.

Background: Whether ileal absorption of bile acid is up or downregulated in chronic cholestasis is still debated, and most evidence has come from animal studies. Aims: To compare ileal bile acid absorption in patients with primary biliary cirrhosis (PBC) and in healthy control subjects, and to assess the effect of ursodeoxycholic acid (UDCA). Patients: We studied 14 PBC patients before and during (n=11) UDCA administration, 14 healthy control subjects, and 14 Crohn’s disease patients (as disease controls). Methods: We used cholescintigraphy to measure retention in the enterohepatic circulation over five successive days of the bile acid analogue 75Se-homocholic acid-taurine (75SeHCAT) as an index of ileal bile acid absorption. Results were expressed as 75SeHCAT fractional turnover rate (FTR) and t½12. Results:75SeHCAT FTR was 0.19 (0.11)/day, 0.34 (0.11)/day (p<0.001), and 0.83 (0.32)/day in PBC patients, healthy controls (p<0.0001), and Crohn’s patients (p<0.001), respectively, which increased to 0.36 (0.16)/day in PBC patients during UDCA treatment (p<0.005). 75SeHCAT t½12 was 4.8 (2.1) days in PBC patients, 2.2 (0.5) days (p<0.001) in healthy controls, and 1.0 (0.5) days (p<0.001) in Crohn’s disease patients. 75SeHCAT t½12 decreased to 2.2 (0.93) days (p< 0.001) in PBC patients during UDCA treatment. Conclusions: Our results support the concept that ileal bile acid absorption is upregulated in PBC patients, and that this effect may contribute towards damaging the cholestatic liver. This upregulation of bile acid absorption is abolished by UDCA.

Effect of ursodeoxycholic acid on biliary lipid coupling and on cholesterol absorption during fasting and eating in subjects with cholesterol gallstones

The aim of this study was to determine the effect of chronic ursodeoxycholic acid administration on coupling of bile acids with cholesterol and phospholipid in hepatic bile, and on cholesterol absorption in the duodenum. A range of bile acid secretion rates was obtained during an evening meal and an overnight fast. Duodenal perfusion of polyethylene glycol as a nonabsorbable recovery marker and of [3H]cholesterol and [14C]lecithin as absorbable recovery markers was combined with continuous intravenous infusion of indocyanine green as a hepatic bile marker. Six subjects with gallstones were studied before and during chronic administration of ursodeoxycholic acid (675 mg/day). Duplicate pretreatment studies revealed good reproducibility for biliary lipid coupling and cholesterol absorption. During ursodeoxycholic acid administration there was a significant alteration not only in bile acid/cholesterol coupling (p less than 0.001), but also in bile acid/phospholipid coupling (p less than 0.001). Mean cholesterol absorption decreased from 25% to 15% (p less than 0.001) during ursodeoxycholic acid administration. These effects of chronic ursodeoxycholic acid administration on biliary lipid coupling are similar to those reported for acute administration, and are thus consistent with an effect caused by bile acid lipid-solubilizing capacity.

A randomised, open label, controlled trial on the effect of interferon plus amantadine compared with interferon alone for treatment of chronic hepatitis C

BACKGROUND: Combination of the antiviral drug amantadine with interferon (IFN) may be more effective than IFN monotherapy for treatment of chronic hepatitis C. METHODS: We randomised 93 patients with chronic hepatitis C to IFNIFN 6 MU 3 times/week for 24 weeks, followed by IFN 3 MU 3 times/week for further 24 weeks given in combination with amantadine 100 mg t.i.d. (regimen A, n=48) or as monotherapy (regimen B, n=45). Control liver biopsies were obtained 6 months post treatment. RESULTS: At the end of the trial a similar proportion of patients had normal serum ALT levels (35% for regimen A, and 44% for regimen B) as measured by intention to treat criteria. Sustained biochemical response at 6 months post treatment was 15 and 20%, and sustained virological response was 10 and 20% for regimen A and B, respectively. The effect on liver histology was also similar: the inflammatory components of the Knodell score decreased by 1.3+/-0.6 points for regimen A and by 1.6+/-0.6 for regimen B, and score for fibrosis remained unchanged with both regimens. CONCLUSIONS: Combination of IFN therapy with amantadine does not enhance the effect of IFN as shown by biochemical, virological and histological criteria.

Maintenance of hepatic bile acid secretion rate during overnight fasting by bedtime bile acid administration

We have tested the hypothesis that the greater clinical efficacy of bedtime administration of bile acid in gallstone dissolution is due to prevention of the reduction in hepatic bile acid secretion that normally accompanies overnight interruption of the enterohepatic circulation, thus also reducing the secretion of supersaturated hepatic bile. We measured the hepatic bile acid secretion rate by combining duodenal perfusion of a nonabsorbable recovery marker (polyethylene glycol) with continuous intravenous infusion of a hepatic bile marker (indocyanine green). We studied 6 subjects with gallstones before and during administration of ursodeoxycholic acid (UDCA, 675 mg) at bedtime. Duplicate pretreatment studies revealed good reproducibility. Mean values for hepatic bile acid secretion rate were uninfluenced by chronic UDCA administration before the acute bedtime dose, but during the 4-h period after acute administration of UDCA the total bile acids secreted increased by a mean value of 2.2 mmol (p less than 0.01). Before treatment, nine of the 78 hourly samples were secreted at a hepatic bile acid secretion rate of less than 5 mumol/kg.h in the 6 patients studied, compared with only one hourly sample during UDCA administration. Super-saturated hepatic bile was secreted for a mean of 9.5 h before treatment, and for 1.2 h during UDCA treatment (p less than 0.005). We conclude that if UDCA is administered at bedtime, this maintains the hepatic bile acid secretion rate overnight, thus reducing secretion of supersaturated hepatic bile, in addition to the well-established effect of UDCA on cholesterol secretion.

Prospective, multicenter study on value of computerized tomography (CT) in gallstone disease in predicting response to bile acid therapy

The aim of the study was to assess the value of quantitative attenuation values (Hounsfield units) and of gallstone pattern by computerized tomography in predicting response to bile acid therapy. We carried out a prospective study in a multicenter setting on 90 consecutive outpatients with radiolucent gallstones. All received bile acid therapy (UDCA 10 mg/kg/day or UDCA+CDCA 5 mg/kg/day of each) up to two years. Hounsfield units for gallstones were recorded using standardized criteria and six categories of patterns were defined: hypodense, isodense, homogenously dense, laminated, rimmed and speckled. We assessed gallstone dissolution rate (percent reduction in volume), response to therapy (>25% reduction in volume), and final outcome of therapy. Eighty-one percent of patients with hypodense/isodense and all four patients with speckled stone pattern responded to therapy, whereas none of the 10 patients with laminated/rimmed and only 45% of patients with homogenously dense stone pattern did. Complete dissolution was achieved by 68%, 50%, 35%, 0% of the hypodense/isodense, speckled, homeogenously dense, rimmed/laminated gallstones, respectively. The use of Hounsfield units did not show an advantage over gallstone pattern for predicting either response or final outcome to bile acid therapy. We conclude that computerized tomography analysis of gallstones is of value in predicting response to bile acid therapy and that gallstone pattern alone predicts response in most cases without the need for quantitative assessment.

Assessment of the motor functions of the gallbladder

We describe the advantages and limitations of the different methods available for assessment of gallbladder motor function in man, and review the evidence for the presence of an abnormality of gallbladder motor function in patients with cholesterol gallstones

Efficacy and tolerability of combination therapy with interferon-alfa plus ribavirin in patients with chronic hepatitis C virus infection: A single-center study in relapsers and nonresponders to previous treatment with high-dose interferon-alfa monotherapy

BACKGROUND In chronic hepatitis C virus (HCV) infection, interferon (IFN) monotherapy usually is carried out at doses of 3 to 6 million units (MU) 3 times per week, but treatment efficacy is low. OBJECTIVE The aim of our study was to assess the efficacy and tolerability of IFN-alfa2b in combination with ribavirin in relapsers and nonresponders to high-dose IFN treatment (5 to 6 MU 3 times per week). We measured the biochemical and virologic responses to treatment and the risk for relapse during the 24 weeks following the end of treatment. METHODS Patients with chronic HCV infection (relapsers and nonresponders to a previous treatment with high-dose IFN) received IFN-alfa2b, 3 MU 3 times per week, and ribavirin, 1000 or 1200 mg/d for 24 or 48 weeks. The patients were then followed up for an additional 24 weeks. Sustained response was defined as normal serum alanine aminotransferase (ALT) level and undetectable HCV RNA 24 weeks after treatment was stopped. RESULTS Forty-three patients (32 men, 11 women; mean [SD] age, 45 [2] years; 10 relapsers, 33 nonresponders) were included in the study. Four patients were withdrawn from the study at week 4 of treatment because of treatment-related adverse events, and 1 dropped out. At the end of the treatment period, normalization of serum ALT levels and undetectable HCV RNA levels were seen in 58.1% and 30.2% of patients, respectively. No significant difference in virologic response at the end of treatment was found between nonresponders (10/33 [30.3%]) to previous IFN therapy and relapsers (3/10 [30.0%]). At the end of follow-up, 3 (7.0%) treated patients had sustained response (2 nonresponders to the first IFN course and 1 relapser). All of the patients with sustained response were treated for 24 weeks. CONCLUSION Based on the results of our study, combination therapy with IFN-alfa and ribavirin may be of value in a limited number of patients with chronic HCV infection who do not respond to, or relapse after, a first course of treatment with high-dose IFN monotherapy.

Quantification of Temocillin Biliary Excretion and Gallbladder Bile Concentration in Healthy Subjects

SummaryThe techniques of duodenal perfusion with polyethylene glycol as a nonabsorbable marker, and cholescintiscan using 99Tc HIDA as a gallbladder bile marker, were used to measure the total duodenal output and gallbladder bile concentration of temocillin after administration of an intravenous bolus injection to each of 6 healthy subjects. We carried out 8 studies, 3 with 0.5g temocillin and 5 with 1g temocillin. The plasma half-life of temocillin was 177 (± 25) minutes [mean (± SD)] and 196 (± 29) minutes with the 0.5g and 1g doses, respectively. Urinary excretion accounted for 38% of the total dose given during the study period of 6 hours, and total biliary excretion was recorded as 2.2% of the given dose for both doses. The mean concentration of temocillin in gallbladder bile was 314.7 (± 273.2) mg/L after the 0.5g dose and 474.5 (± 307.3) mg/L after 1g dose. It was concluded that temocillin is highly concentrated in the normal gallbladder in man.