Mario Fracchia

Incidence of Barrett's adenocarcinoma in an Italian population : an endoscopic surveillance programme

Background: Barretts oesophagus is a premalignant condition leading to adenocarcinoma. The incidence of adenocarcinoma of the oesophagus and the gastro‐oesophageal junction is rapidly increasing in the USA, northern and central Europe. Data from southern Europe are still unavailable. Objective: To evaluate the incidence of oesophageal adenocarcinoma in a large cohort of Italian patients with Barretts oesophagus. Methods: A total of 344 patients (253 males and 91 females, age range 19‐75 years) with histologically proven Barretts oesophagus (length of metaplasia ≥3cm) were enrolled from November 1987 to June 1995. Endoscopic and histological examinations were scheduled at yearly intervals. Results: One hundred and eighty‐seven patients complied with the follow‐up. The mean duration of the follow‐up period was 36 months (total follow‐up 562 patient‐years; range 12‐90 months). Low grade dysplasia was found in five patients at the initial examination. During the surveillance period, dysplasia increased in frequency as well as in severity and was found exclusively in the intestinal type of Barretts oesophagus. In all, dysplastic changes were found in seven patients (five low grade and two high grade) and adenocarcinoma developed in three patients during the follow‐up. In a single case, both adenocarcinoma and specialized columnar epithelium developed without any evidence of dysplasia or intestinal metaplasia at the previous follow‐up examination. This prospective study shows an incidence of adenocarcinoma in Barretts oesophagus of 1/187 patientyears. When only patients with specialized columnar epithelium were considered, the risk of adenocarcinoma was 1/88 patient‐years. Conclusion: The present report shows that the incidence of adenocarcinoma in Italian Barretts oesophagus patients is in the range of that reported from other Western countries.

Offering people a choice for colorectal cancer screening

Objectives To assess the population coverage and diagnostic yield of offering an immunochemical faecal occult blood test (FIT) to non-responders to a flexible sigmoidoscopy (FS) invitation. Design A cohort study conducted in a population-based colorectal cancer (CRC) screening programme. In this programme, eligible men and women aged 58 (Turin; 43 748 subjects) or 60 (Verona; 19 970 subjects) are invited, with a personal letter signed by their general practitioner, to undergo an FS. Bowel preparation is limited to a single enema self-administered at home. Subjects in whom one distal polyp >5 mm (≥10 mm in Turin) or at least one adenoma (one advanced adenoma or more than two adenomas in Turin) is detected at FS are referred for colonoscopy. People who do not respond to the invitation to undergo an FS are invited to have an FIT (OC-Sensor; Eiken, Tokyo, Japan; single sample, cut-off 100 ng/ml). Attendance rate and neoplasia yield were analysed in four consecutive birth cohorts. Results Overall participation rate for the FS invitation was 39.3% in Verona and 29.9% in Turin. Of the eligible non-responders to the FS invitation, 19.3% (95% CI 18.9% to 19.7%) underwent an FIT. As a result, the proportion of people undergoing screening by FS or FIT was 55.2% in Verona and 39.3% in Turin, with no gender differences in either centre. FIT detected 8.3% of all advanced adenomas and 20.4% of all CRCs diagnosed at screening. Conclusions A strategy involving the sequential offer of FS and FIT is a feasible and efficient approach. FIT in people not attending for FS increases screening uptake and detection of advanced adenomas and CRCs.

Biliary lipid composition in cholesterol microlithiasis

BACKGROUND Little information is available on the pathogenesis of cholesterol microlithiasis, and it is not clear if biliary lipid composition in these patients is similar to changes seen in cholesterol gall stone patients. AIMS To measure biliary lipid composition in patients with cholesterol microlithiasis. PATIENTS Eleven patients with cholesterol microlithiasis, 20 cholesterol gall stone patients, and 17 healthy controls. METHODS Duodenal bile was collected in the fasting state during ceruletide infusion. Biliary cholesterol, phospholipids, and total bile acids were analysed by enzymatic assays, and conjugated bile acids by high pressure liquid chromatography. RESULTS Patients with microlithiasis had a cholesterol saturation index significantly higher than controls (mean value 1.30 (95% confidence interval 1.05–1.54)v 0.90 (0.72–1.08)) but similar to gall stone patients (1.51 (1.40–1.63)). This was due to a significant decrease in per cent phospholipid (10.0% (7.1–12.8)) compared with controls (21.4% (18.1–24.6)) and gall stone patients (24.9% (20.5–29.3)). Per cent cholesterol was similar in patients with microlithiasis and controls (5.3% (4.5–6.1) and 5.6 % (4.3–6.8), respectively) but was significantly increased in gall stone patients (10.9% (9.3–12.4)). Bile acid composition in patients with microlithiasis was similar to controls whereas in gall stone patients deoxycholic acid was significantly increased: 27.3% (24.8–29.7)v 19.0% (15.7–22.2) in controls and 20.6% (14.9–26.2) in patients with microlithiasis. CONCLUSION Patients with cholesterol microlithiasis have biliary cholesterol supersaturation, similarly to cholesterol gall stone patients. Whereas in the latter this is due to increased per cent cholesterol, in patients with microlithiasis this is caused by phospholipid deficiency, with normal per cent cholesterol and normal biliary bile acid composition.

Risk factors for the development of gallstone recurrence following medical dissolution

Objective To assess risk factors for gallstone recurrence following non‐surgical treatment. Design A prospective follow‐up of a multicentre cohort of post‐dissolution gallstone patients. Setting Six gastroenterology units in the UK and Italy. Participants One hundred and sixty‐three patients with confirmed gallstone dissolution following non‐surgical therapy (bile acids or lithotripsy plus bile acids), followed up by ultrasound scan and clinical assessment at 6‐monthly intervals for up to 6 years (median, 25 months; range, 6‐70 months). Outcome measures Subject‐related variables (sex, age, height, weight, body mass index), gallstone‐related variables (number, diameter, presence of symptoms, months to complete stone clearance), treatment modalities (bile acid therapy, extracorporeal shock wave lithotripsy) and follow‐up related variables (weight change, use of non‐steroidal anti‐inflammatory agents, statins, pregnancies and/or use of oestrogens) were assessed by univariate and multivariate analysis as putative risk factors for gallstone recurrence. Results Forty‐five gallstone recurrences were observed during the follow‐up period. Multiple primary gallstones and length of time to achieve gallstone dissolution were the only variables associated with a significant increase in the recurrence rate. Appearance of biliary sludge during follow‐up was also significantly related to development of gallstone recurrence. Use of statins or non‐steroidal antiinflammatory agents did not confer protection against recurrence. Conclusions Patients with primary single stones are the best candidates for non‐surgical treatment of gallstones, because of a low risk of gallstone recurrence. The positive association of recurrence with biliary sludge formation and time to dissolution of primary stones may provide indirect confirmation for the role of impaired gallbladder motility in the pathogenesis of this condition. Eur J Gastroenterol Hepatol 12:695‐700

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

BACKGROUND/AIMS Following 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. METHODS One 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). RESULTS Forty-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. CONCLUSIONS We 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.

Biliary lipid composition in idiopathic bile acid malabsorption

Background—Chronic diarrhoea is the clinical hallmark of patients presenting with idiopathic bile acid malabsorption. Its pathogenesis is unknown; colonic water secretion can be induced by dihydroxy bile acids, but it is not known whether enrichment of the bile acid pool with these bile acids occurs in such patients. Furthermore, bile acid malabsorption is known to affect biliary lipid composition, but no information is available for the idiopathic type. Aims—To verify: (a) whether diarrhoea in patients with idiopathic bile acid malabsorption is associated with enrichment of the bile acid pool with dihydroxy bile acids; and (b) whether supersaturation with cholesterol of duodenal bile occurs in such patients as a result of chronic bile acid depletion. Patients—Thirteen patients with idiopathic bile acid malabsorption diagnosed according to abnormal 75SeHCAT test and absence of other organic diseases, and 23 control subjects. Methods—Bile rich duodenal fluid was collected during intravenous ceruletide infusion in the fasting state. Biliary lipids were analysed by enzymatic assays and bile acids by high performance liquid chromatography. Results—Patients with idiopathic bile acid malabsorption had a cholesterol saturation index similar to controls. Bile acid composition showed only a decrease in percentage cholic acid (29 (2)% versus 36 (2)%; p<0.05); the dihydroxy:trihydroxy bile acid ratio was similar to controls. Conclusions—Patients with idiopathic bile acid malabsorption do not have an increased risk of forming cholesterol gallstones. The mechanism of diarrhoea does not seem to depend on an enrichment of the bile acid pool with dihydroxy bile acids.

Non-invasive evaluation of portal-systemic shunting in man by d-sorbitol bioavailability

Portal-systemic shunting is an important circulatory abnormality in patients with cirrhosis. This study explores the potential of the natural polyol D-sorbitol as test compound for non-invasive assessment of shunting. Ten normal subjects, 10 patients with cirrhosis and 12 cirrhotics with surgical portacaval shunts were studied after oral and intravenous administration of a 2 g dose of sorbitol. As measured by the H2 breath test, removal from the intestinal lumen was complete in both groups. Bioavailability of sorbitol, calculated as ratio of the areas under the plasma concentration/time curve after p.o. and i.v. administration, was zero in normal subjects, 0.29 +/- 0.15 in cirrhotic patients, and 0.38 +/- 0.11 in patients with portacaval shunts. Calculation of bioavailability on the basis of urinary outputs of sorbitol gave similar results. It is concluded that the bioavailability of sorbitol reflects portal-systemic shunting, although the relatively low figures suggest some degree of sorbitol metabolism by enterocytes.

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

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.

Computed tomography colonography in routine clinical practice

Objective To describe the experience of a radiology unit in using open access computed tomography (CT) colonography instead of double-contrast barium enema in patients who refused or had an incomplete first-attempt colonoscopy. Methods All consecutive patients who underwent CT colonography from December 1998 to August 2001 were recalled and evaluated. Patients in whom CT colonography showed intraluminal growths were sent for colonoscopy, performed using deep sedation if the first attempt failed. Results A total of 463 consecutive CT colonography examinations were performed: 304 patients were re-traceable and were evaluated. In 85 cases CT colonography reported the presence of intraluminal growth. Colonoscopy confirmed the presence of 74 of the 94 polyps, and of 43 of the 48 cancers found at CT colonography. Colonoscopy also diagnosed an additional two cancers in two patients with CT colonography findings of inflammatory changes, and an additional 26 polyps in 16 patients. On a per-lesion basis, the positive predictive value of CT colonography was 73%, 80% and 87% for polyps ⩽ 5 mm, 6–9 mm and ⩾ 10 mm, respectively, and was 90% for cancer. On a per-patient basis, the positive predictive value was 60%, 72% and 89% for lesions ⩽ 5 mm, 6–9 mm and ⩾ 10 mm, respectively, and was 93% for cancer. Conclusion CT colonography on an open access basis can be confidently used as a routine test instead of double-contrast barium enema when total colonoscopy cannot be performed.