Giovanni Galatola

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.

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.

A strong negative association between alcohol consumption and the risk of hepatocellular carcinoma in cirrhotic patients - A case-control study

We carried out a hospital-based, case-control study to assess the association of both the Hepatitis B Virus (HBV) infection and the lifetime daily alcohol intake with the risk of developing hepatocellular carcinoma (HCC) in patients with liver cirrhosis (LC). Cases were 62 consecutive inpatients of a Gastroenterology Division in whom a first diagnosis of HCC superimposed on LC was made. Two control groups were used: 310 patients without liver disease, matched 1:5 with cases and randomly selected from inpatients of the same hospital, and 97 consecutive asymptomatic inpatients in whom the first diagnosis of LC was made. Alcohol intake was quantified in all subjects by a standardized questionnaire. HBV infection was associated with HCC development in cirrhotics (odds ratio =6.8; 95% confidence interval =1.4−32.3), whereas we observed a trend towards a decreased HCC risk at increased alcohol intake values (odds ratio from 1 for lifetime abstainers to 0.2 for drinkers of 175 g/day or more). Our results suggest that alcohol intake is not a direct determinant of HCC, but its role is mediated by LC. Cirrhotics with high alcohol intake do not usually survive long enough to develop HCC.

Computer-aided detection for computed tomographic colonography screening: a prospective comparison of a double-reading paradigm with first-reader computer-aided detection against second-reader computer-aided detection.

ObjectivesThe objective of this study was to prospectively compare diagnostic performance and time efficiency of a double-reading paradigm in which a first-reader computer-aided detection (CAD) is followed by a fast 2-dimensional review (DR FR-CAD) with those of a double reading with second-reader CAD (SR CAD). Materials and MethodsThe local ethical committee approved this study. Consecutive immunological patients who have positive results for fecal immunological test who were scheduled for colonoscopy were enrolled for a 10-month period. Computed tomographic colonography studies were read with CAD (CAD COLON-1.20; im3D, Turin, Italy) by using both SR CAD (applied after unassisted interpretation primary 2-dimensional) and DR FR-CAD (CAD-prompts evaluation followed by a fast 2-dimensional review) in randomized order with the radiologist for each reading paradigm masked to the other reader’s results.Per-patient sensitivity and specificity of unassisted and CAD-assisted readings for detecting 6-mm adenomas or larger were calculated by using unblinding colonoscopy as reference standard. Reporting times were also calculated. Pairwise comparisons were performed. ResultsA total of 182 participants (median age, 65 years; range, 58–76) were included in the final analysis. Of these, 93 (51%) had at least 1 cancer or a 6-mm adenoma or larger. At the 6-mm threshold, sensitivity of unassisted reading (79.6%; 95% confidence interval [CI], 69.9–87.2) increased significantly with the use of both SR CAD (86.0%; 95% CI, 77.3%–92.3%) and DR FR-CAD (89.2%; 95% CI, 81.1%–94.7%), without differences between CAD readings (P = 0.500). No significant differences in specificity among the 3 paradigms were observed. Double reading with first-reader CAD required less reading time than that for SR CAD (378 vs 496; &Dgr;118 seconds; P < 0.001) and was 59 seconds longer than the unassisted reading (P = 0.058). ConclusionsWhen compared with unassisted reading, a double-reading paradigm in which first-reader CAD is followed by a fast 2-dimensional review improves the adenoma detection rate to the same level achieved by a second-reader CAD while decreasing reporting times.

Hepatic handling of a synthetic γ-labeled bile acid (75SeHCAT)

Abstract 75 Se-homocholic acid-taurine ( 75 SeHCAT) is the first available γ-labeled bile acid, and should therefore be handled more efficiently and specifically by the liver than previous hepatoscintigraphic agents. We have measured serum and hepatic kinetics for 75 SeHCAT, and compared them with those for the conventional hepatobiliary scintigraphic agent 99m Tc-hepatoiminodiacetic acid, and with serum kinetics for the corresponding natural bile acid, [ 14 C]cholic acid-taurine. We used a dynamic scintigraphic technique and serial blood sampling in 8 subjects. Initial hepatic uptake rate was identical to initial serum disappearance rate (14% dose/min) for 75 SeHCAT, but significantly lower for 99m Tchepatoiminodiacetic acid (6% vs. 14% dose/min, p 75 SeHCAT (13 min vs. 22 min, p 75 SeHCAT (14.3% and 1.5% dose/min) than for [ 14 C]cholic acid-taurine (21.3% and 2.8% dose/min, respectively), and plasma clearance was also lower (275 vs. 670 ml/min). In vitro, 75 SeHCAT was bound to serum proteins more completely than [ 14 C]cholic acid-taurine (90.4% vs. 86.5%, p 75 SeHCAT provides a hepatoscintigraphic agent that is handled more efficiently and specifically by the liver than the conventionally used agent 99m Tc-hepatoiminodiacetic acid. It is not cleared from the serum as rapidly as [ 14 C]cholic acid-taurine, probably due to its stronger protein binding. The clinical value of 75 SeHCAT in assessing liver disease should be investigated.

Serum interferon gamma in primary biliary cirrhosis: Effect of ursodeoxycholic acid and prednisone therapy alone and in combination

Background Interferon‐&ggr; may have immunopathogenic importance in primary biliary cirrhosis, stimulating aberrant expression on biliary epithelium of class II major histocompatibility molecules and inter‐cellular adhesion molecule‐1. Liver transcripts for interferon‐&ggr; are found in primary biliary cirrhosis. Its serum level is increased in pretransplantation stages and decreases after transplantation. Objectives (1) To verify whether serum interferon‐&ggr; levels are increased in non‐cirrhotic stages of primary biliary cirrhosis. (2) To evaluate the effect of ursodeoxycholic acid and prednisone alone and in combination on serum levels of interferon‐&ggr; and soluble inter‐cellular adhesion molecule‐1. Methods Nine non‐cirrhotic, anicteric patients with primary biliary cirrhosis (patient test group), 14 healthy, negative controls and 14 positive controls, with chronic hepatitis related to hepatitis C virus were studied in basal condition. Primary biliary cirrhosis patients were treated with ursodeoxycholic acid, prednisone and the association of the two drugs for three 4‐week periods, each period separated by a 4‐week wash‐out. Interferon‐&ggr; and soluble inter‐cellular adhesion molecule‐1 were measured in serum by commercially available immuno‐enzymatic kits. Results Median interferon‐&ggr; levels were increased in patients with primary biliary cirrhosis compared with healthy controls (44 vs 19 pg/ml; P < 0.01) but similar to those in chronic hepatitis patients (47 pg/ml). Serum soluble inter‐cellular adhesion molecule‐1 was significantly reduced by ursodeoxycholic acid, and an even greater reduction was obtained on addition of prednisone. No treatment affected interferon‐&ggr; levels. Conclusion Serum interferon‐&ggr; is increased in non‐cirrhotic patients with primary biliary cirrhosis, but this is not disease‐specific. Neither ursodeoxycholic acid, nor prednisone, nor the combination of the two drugs influenced this immunological pathway of primary biliary cirrhosis. Eur J Gastroenterol Hepatol 12:463‐468

Mangafodipir trisodium: review of its use as an injectable contrast medium for magnetic resonance imaging

Mangafodipir trisodium is a hepatobiliary contrast agent, taken up by the hepatocytes and largely excreted via the bile ducts. The agent increases the signal intensity of the normal liver, and to a lesser extent of the pancreas, adrenal glands, kidneys and myocardium, on T1-weighted imaging. The increase of the signal intensity on the T1 images allows better visualization of focal lesions, especially of those that are of non-hepatocitary origin such as metastases. For this reason the most important indication for the use of mangafodipir trisodium is in detecting liver metastases, especially when the information may influence therapeutic planning, which in many cases is surgical resection. New data show that this liver-specific contrast agent is accurate in detecting small lesions and in assessing the liver status following neoadjuvant chemotherapy, where other imaging techniques, such as CT and PET, fail. Other lesser indications for studies with mangafodipir trisodium are: in characterizing liver and pancreatic lesions; in identifying biliary leakage following bile duct and/or liver surgery; and possibly in the future in the assess- ment of the extent of myocardial damage.

Bile acid conjugation in early stage cholestatic liver disease before and during treatment with ursodeoxycholic acid

The efficiency of bile acid conjugation before and during therapy with 600 mg/day of ursodeoxycholic acid was measured in seven adult patients with early chronic cholestatic liver disease (6 with primary biliary cirrhosis; 1 with primary sclerosing cholangitis). Duodenal bile samples were obtained by aspiration and the proportion of unconjugated bile acids was determined using lipophilic anion exchange chromatography to separate bile acid classes, followed by analysis of individual bile acids by gas chromatography-mass spectrometry. The proportion of conjugated bile acids was determined by high-performance liquid chromatography. Use of a (99m)Tc-HIDA recovery marker permitted the absolute mass of unconjugated bile acids in the gallbladder to be calculated. Unconjugated bile acids comprised 0.4% of total biliary bile acids before and 0.2% during ursodeoxycholic acid therapy, indicating highly efficient conjugation of bile acids. During therapy, percentage unconjugated ursodeoxycholic acid significantly increased from (mean +/- S.D.) 13 +/- 13% to 54 +/- 12%; P < 0.002. When the unconjugated and conjugated fractions of bile acids were compared, there was an enrichment in unconjugated fraction for cholic acid and ursodeoxycholic acid and a depletion for chenodeoxycholic acid both in basal condition and during ursodeoxycholic acid therapy, suggesting that hydrophilic bile acids were conjugated less efficiently. During therapy, the conjugation efficiency significantly increased for cholic acid and ursodeoxycholic acid. The pretreatment mass of total unconjugated bile acids in the gallbladder was (mean +/- S.D.) 4.4 +/- 3.2 mumol, and was not significantly changed by ursodeoxycholic acid therapy (6.2 +/- 3.5 mumol). However, ursodeoxycholic acid therapy caused a significant increase in the mass of unconjugated ursodeoxycholic acid. It is concluded that endogenous bile acids and exogenous ursodeoxycholic acid when given at the usual dose are efficiently conjugated in patients with early cholestatic liver disease. Despite showing increased biliary unconjugated ursodeoxycholic acid during its oral administration, our data do not lend support to the occurrence of hypercholeresis due to cholehepatic shunting of bile acids.

Biliary lipid mass in the gallbladder in health and in cholesterol gallstone disease

Objectives: A high cholesterol saturation index of gallbladder bile is an essential prerequisite for cholesterol gallstone formation. This could be due to a high cholesterol mass, or to a low bile acid and/or phospholipid mass in gallbladder bile, or to a combination of these abnormalities. The conventional method of measuring the saturation index cannot distinguish between these alternatives. Our aim was to distinguish between these alternatives in patients with cholesterol gallstones by measuring biliary lipid masses, and to study the effect of gender and obesity within this gallstone population. Methods: We have developed a simple technique for the measurement of total biliary lipid masses in the gallbladder. This involves a combination of 99mTcHIDA cholescintigraphy and of nasoduodenal intubation with intravenous cholecystokinin infusion to obtain a bile sample. We validated this technique by comparing it with direct measurement of biliary lipid masses following cholecystectomy; we studied 19 male non-obese healthy controls and a total of 45 gallstone patients, who were further subdivided into male non-obese (n = 13), female non-obese (n = 17) and obese (n = 15) gallstone patients. Results: The validation studies showed close agreement for all three biliary lipids between our technique and the direct measurements. The male non-obese gallstone patients had a significantly higher saturation index than the male non-obese healthy controls. This was due to a reduction in bile acid mass (2.73 versus 4.79 mmol, P < 0.005), with no difference in the masses of phospholipid or cholesterol. There were no differences between male and female non-obese gallstone patients; and obese patients had a reduced phospholipid mass as well as a reduced bile acid mass. There was no increase in cholesterol mass within the gallbladder in any of the groups. Conclusions: We conclude that 99mTcHIDA scintigraphy together with nasoduodenal intubation provides a simple valid technique for measuring biliary lipid masses in the gallbladder; that the main defect in gallstone disease is a reduction in bile acid mass; that within the gallstone population, gender has no effect on biliary lipid masses, but that obese gallstone patients have a reduction in phospholipid mass also. There was no increase in cholesterol mass in the gallbladder in any of the gallstone groups, presumably because this was prevented by the low bile acid mass.

Anti-hcv antibodies in patients with chronic liver disease and different amounts of alcohol intake: a multivariate analysis

Objective To investigate the association between the mean daily alcohol intake and positivity for serum anti-hepatitis C virus antibodies in patients with chronic liver disease of varying severity. To test the hypothesis that alcohol intake and hepatitis C virus infection have an independent role in determining chronic liver disease. Design Retrospective study using a multivariate analysis model. Methods In 212 consecutive patients with chronic liver disease, serum anti-hepatitis C virus antibodies were detected using a second-generation test and recombinant immunoblotting assay. The lifetime mean daily alcohol intake was measured by a standardized questionnaire. Patients were subsequently divided according to the histological presence or absence of liver cirrhosis and stratified into progressive categories of alcohol intake. The dose-effect relationship between anti-hepatitis C virus status and mean daily alcohol intake was assessed by a model of unconditional logistic regression, where age, gender, degree of severity of liver disease and chronic hepatitis B virus infection were considered as covariates. Results There was a strong negative association between the mean daily alcohol intake and the presence of anti-hepatitis C virus antibodies, with odds ratio decreasing down to 0.01 for the category of highest alcohol intake; no association was found for the other variables considered. Conclusion Our data support the hypothesis that alcohol intake and infection with hepatitis viruses are independent determinants of chronic liver disease.