Diagnostic value of endoscopic markers for celiac disease in adults: a multicentre prospective Italian study.

AIM: Some endoscopic features of duodenal mucosa are marker of mucosal injury, the most common cause being celiac disease (CD). The aim of this study was to prospectively assess the diagnostic value of the endoscopic markers for the diagnosis of CD in the adult population undergoing routine upper endoscopy. METHODS: This was a prospective multicenter study conducted at 37 Italian endoscopic centers. A total of 509 consecutive patients submitted to routine upper endoscopy who presented one or more of following endoscopic markers were included: 1) mucosal mosaic pattern in the bulb and/or descending duodenum (DD); 2) nodularity in the bulb and/or DD; 3) scalloping of Kerkring's folds; 4) reduction in the number or absence of folds in the DD. 4 biopsies samples were taken from descending duodenum. In patients with histological findings consistent with CD, according to Oberhuber classification, sierologic test (EMA, tTGA) were performed for confirm the diagnosis. RESULTS: At endoscopy, 249 patients showed an isolated marker; 260 subjects showed a coexistence of more than one marker; 369 patients (72.5%) presented mucosal lesions at histological examination and in 347 of these patients the diagnosis of CD was confirmed by serologic markers (94.0%). For 10 patients the diagnosis remained uncertain because of negative sierology and exclusion of other other cause of mucosal lesions. The diagnosis of CD was made in 61.3% patients who showed the mosaic pattern, in 65.7% of patients with nodular mucosa, in 64.4% of patients with scalloping of folds, in 40.2% of patients with reduction of folds, and in 61.5% of patients with loss of folds and in 83.6% of patients who showed the coexistence of more than one marker. The endoscopic markers overall had a PPV of 68% for the diagnosis of CD; the markers that singularly have demonstrated a higher correlation with CD are: mosaic mucosa of DD (PPV 65.0%), nodular mucosa of the bulb and DD (PPV 75.5%), and scalloping of folds (PPV 64.4%). CONCLUSION: The study confirms the important role of endoscopy in the diagnostic process of CD not only for the bioptic sampling in patients with clinical suspicion of CD, but especially for the opportunity to evaluate alterations of the duodenal mucosa suggestive of CD in the general population and, consequently, to identify those patients who should undergo a duodenal biopsy.

Proteins specifically hyperexpressed in a coeliac disease patient with aberrant T cells.

An aberrant T cell population is the basis for diagnosis of refractory coeliac disease and determines the risk of enteropathy-associated T cell lymphoma. This disease is serious with a poor survival. Pathogenetic mechanisms sustaining aberrant T cell proliferation remain unknown. Recently, alemtuzumab has been proposed as a promising new approach to treat these patients. Only few single cases have been tested at present; nevertheless, in all the cases a clinical improvement was observed. However, whether intraepithelial lymphocytes have been targeted effectively by alemtuzumab is still debated. This study reports, using two-dimensional difference gel electrophoresis (2D DIGE), hyperexpressed proteins associated specifically with aberrant T cells found in a patient with coeliac disease by comparison of the protein expression of this sample with that of patients with coeliac disease and polyclonal T cells or with control subjects. The data demonstrated a significantly higher expression of IgM, apolipoprotein C-III and Charcot-Leyden crystal proteins in a duodenal biopsy specimen of the patient with clonal T cells compared with that of other patients. These preliminary results allow hypothesizing different clinical effects of alemtuzumab in patients with coeliac disease and aberrant T cell proliferation, because as well as the probable effect on T cells, alemtuzumab could exert its effect by acting on inflammatory associated CD52(+) IgM(+) B cells and eosinophil cells, known to produce IgM and Charcot-Leyden crystal proteins, that we demonstrated to be altered in this patient. The results also emphasize the possible association of apolipoprotein with aberrant T cell proliferation.

Bovine lactoferrin for Helicobacter pylori eradication: an open, randomized, multicentre study.

BACKGROUND: Cure rates for eradication of Helicobacter pylori appear to be decreasing, thus more effective therapies must be identified. AIM: To evaluate the efficacy of bovine lactoferrin in the treatment of H. pylori infection. METHODS: In a multicentered prospective study, 402 (mean age 52.4, range 19-84 years) H. pylori-positive patients were assigned to one of three regimens: group A - esomeprazole 20 mg b.d., clarithromycin 500 mg b.d. and tinidazole 500 mg b.d. for 7 days; group B - lactoferrin 200 mg b.d. for 7 days followed by the same schedule of group A; group C - esomeprazole 20 mg b.d., clarithromycin 500 mg b.d. and tinidazole 500 mg b.d. plus lactoferrin 200 mg b.d. for 7 days. RESULTS: Of the 402 patients, 389 completed the study. Six patients were discontinued due to side effects, one patient in group B died and six patients were lost to follow up. The eradication rate (intention-to-treat analysis) was 77% in group A (105/136), 73% in group B (97/132) and 90% in group C (120/134) (chi(2)-test P < 0.01). The incidence of side effects was 9.5% in group A, 9% in group B and 8.2% in group C (chi(2)-test P = 0.1). CONCLUSION: This study demonstrates that bovine lactoferrin is an effective adjuvant to 7-day triple therapy for eradication of H. pylori infection.

Prevalence of intestinal metaplasia in the distal oesophagus, oesophagogastric junction and gastric cardia in symptomatic patients in north-east Italy: a prospective, descriptive survey. The Italian Ulcer Study Group "GISU".

BACKGROUND: Incidence of adenocarcinoma of distal oesophagus and gastric cardia, probably arising from areas of intestinal metaplasia, has been increasing rapidly. AIMS: To define prevalence of intestinal metaplasia of distal oesophagus, oesophagogastric junction and gastric cardia and to evaluate potential associated factors, by means of a prospective multicentre study including University and teaching hospitals, and primary and tertiary care centres. PATIENTS: Each of 24 institutions involved in study enrolled 10 consecutive patients undergoing first-time routine endoscopy for dyspeptic symptoms. METHODS: Patients answered symptom questionnaires and underwent gastroscopy Three biopsies were taken from distal oesophagus, oesophago-gastric junction and gastric cardia, and were stained with haematoxylin and eosin. Specimens were also evaluated for Helicobacter pylori infection. RESULTS: A total of 240 patients (124 male, 116 female; median age 56 years, range 20-90) were enrolled in study. Intestinal metaplasia affected distal oesophagus in 5, oesophago-gastric junction in 19 and gastric cardia in 10 patients. Low-grade dysplasia was found at distal oesophagus and/or oesophago-gastric junction of 3/24 patients with intestinal metaplasia vs 2/216 without intestinal metaplasia (p<0.05). A significant association was found between symptoms and presence of intestinal metaplasia, regardless of location, and between Helicobacter pylori infection and intestinal metaplasia at oesophago-gastric junction. CONCLUSIONS: Intestinal metaplasia of distal oesophagus, oesophagogastric-junction and gastric cardia is found in a significant proportion of symptomatic patients undergoing gastroscopy and is associated with dysplasia in many cases. Although prevalence of dysplasia seems to decrease when specialized columnar epithelium is found in short segment, or even focally in oesophago-gastric junction, these small foci of intestinal metaplastic cells may represent source of most adenocarcinomas of cardia.

Cure of Helicobacter pylori-positive active duodenal ulcer patients: a double-blind, multicentre, 12-month study comparing a two-week dual vs a one-week triple therapy. GISU (Interdisciplinary Group for Ulcer Study).

AIMS: To compare a two-week dual therapy to a one-week triple therapy for the healing of duodenal ulcer and the eradication of the Helicobacter pylori infection. PATIENTS AND METHODS: A total of 165 patients with active duodenal ulcer were enrolled in the study. At entry, endoscopy, clinical examination and laboratory tests were performed. Histology and the rapid urease test were used to diagnose Helicobacter pylori infection. Patients received either lansoprazole 30 mg plus amoxycillin 1 g bid for two weeks (two-week, dual therapy) or lansoprazole 30 mg plus amoxycillin 1 g plus tinidazole 500 mg bid for one week plus lansoprazole qd for an additional week (one-week, triple therapy). Two and twelve months after cessation of therapy, endoscopy and clinical assessments were repeated. RESULTS: Duodenal ulcer healing and Helicobacter pylori eradication were both significantly greater (p<0.0001) in the triple therapy group (healing: 98.6%; Helicobacter pylori cure rate: 72.6%) than in the dual therapy group (healing: 77.3%; Helicobacter pylori cure rate: 33.3%). Ulcers healed more frequently in Helicobacter pyloricured than in Helicobacter pylori-not cured patients (94.9% vs. 77.2%; p<0.0022). After one year, Helicobacter pylori eradication was re-confirmed in 46/58 patients previously treated with the triple therapy and in 10/40 patients treated with the dual therapy [p<0.0001]. Only three duodenal ulcer relapses were observed throughout follow-up: all were in Helicobacter pylori-not cured patients. CONCLUSIONS: Triple therapy was more effective than dual both in curing Helicobacter pylori infection and healing active duodenal ulcers. The speed of ulcer healing obtained after only 7 days of antibiotics and 14 days of proton pump inhibitors confirmed that longer periods of anti ulcer therapy were not necessary. Helicobacter pylori -not cured patients had more slowly healing ulcers which were more apt to relapse when left untreated.

Reversal of ethinylestradiol-induced cholestasis by epomediol in rat. The role of liver plasma-membrane fluidity.

Epomediol (EPO) is a synthetic terpenoid compound shown to be active in increasing bile flow and some enzymatic activities of liver plasma membranes in the rat. The possible effect of EPO treatment in the ethinyl-estradiol (EE) induced cholestasis in the rat was investigated by measuring the hepatic transport of sulfobromophthalein (BSP) (plasma clearance and biliary secretion) and bile flow. Liver plasma membrane fluidity was also determined by the steady state fluorescence polarization (P) of diphenylhexatriene (DPH). EE administration (5 mg/kg s.c. for 5 days) was followed by a significant, comparable reduction (P less than 0.001) in BSP plasma clearance and biliary excretion and in bile flow. Intraperitoneal administration of EPO (100 mg/kg) to EE-treated rats restored both parameters of BSP transport, as well as bile flow, to control values. Liver plasma membrane fluidity was markedly (P less than 0.01) decreased by EE administration with a concomitant reduction (P less than 0.01) in Na+/K+-ATPase activity. EPO administration significantly increased membrane fluidity to values higher either to cholestatic (P less than 0.05) or control (P less than 0.05) animals. On the contrary, EPO did not influence Na+/K+-ATPase activity in either EE-treated or control animals. These data indicate that EPO fully reverses the impairments of BSP transport and bile flow induced by EE, possibly by reversing the decrease in liver plasma membrane fluidity induced by the synthetic estrogen. On the contrary, the EE-mediated decrease in Na+/K+-ATPase activity was not reversed by EPO.

Sex steroid modulation of the hepatic uptake of organic anions in rat.

To investigate the role of sex steroids in the sex-related difference in the hepatic uptake of organic anions, sulphobromophthalein (bromsulphalein, BSP) transport was measured in hepatocytes isolated from rats either deprived of hormonal influence by castration at prepubertal age or after hormonal substitution. In control animals, the kinetics of BSP uptake showed the presence of two components: one saturable (0-3 microM), with high affinity and low capacity, and the other linear (9-30 microM), probably related to the non-specific component of BSP uptake. Sex difference was detected only in the saturable portion of the uptake process as the apparent Km was significantly lower in females than in males (3.8 +/- 0.7 vs. 6.1 +/- 1.8 microM, mean +/- S.D. of six animals, P less than 0.01). In contrast, no difference was observed in Vmax (2.3 +/- 0.3 vs. 2.2 +/- 0.7 nmol BSP.(mg protein)-1.min-1). Castration was associated with the disappearance of the saturable uptake site and abolished the sex difference. Progesterone treatment of castrated males failed to restore the saturable kinetics of BSP uptake. In contrast, administration of oestradiol to castrated males or testosterone to castrated females did restore the saturable kinetics of the high-affinity BSP uptake. Km and Vmax were comparable to those of adult females and males, respectively, with the exception of testosterone which induced a Vmax value higher than that observed in the other groups of animals. These data suggest that the influence of oestrogen and testosterone is necessary for the expression of the high-affinity, low-capacity carrier-mediated process of hepatic BSP uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum free fatty acids and bilirubin concentration during fasting in patients with Gilbert's syndrome and normal controls.

The increments in serum concentrations of unconjugated bilirubin and free fatty acids (FFA) were measured 24 and 48 h after reduction of the caloric intake (400 cal/day) in 17 patients with Gilbert's syndrome (GS) and in 12 healthy control subjects. In males, both normal and with GS, the rise in serum bilirubin was statistically higher (p less than 0.01) as compared to females. On the contrary, no sex difference was found in FFA concentrations. A linear correlation (p less than 0.01) between bilirubin and FFA serum levels was present in normal males and in patients with Gilbert's syndrome of both sexes. Because bilirubin and FFA partly share a common, bilitranslocase-mediated, hepatic uptake mechanism, data reported support the hypothesis that a bilitranslocase function may be one of the metabolic defects in Gilbert's syndrome.

Dose dependence of nicotinic acid-induced hyperbilirubinemia and its dissociation from hemolysis in Gilbert's syndrome.

The serum increments in unconjugated bilirubin and total iron were determined after intravenous administration of 5.90 mumol/kg body weight of nicotinic acid (NA) in 26 patients with Gilbert's syndrome (GS), seven patients with hemolytic anemia, and 13 healthy volunteers. The hyperbilirubinemic response, expressed as the area under time concentration curve of unconjugated bilirubin (AUCBR, milligrams per deciliter per 240 minutes) was significantly higher (P less than 0.01) in patients with GS than in controls and patients with hemolytic anemia, in whom no difference was observed. In contrast, comparable values of the hypersideremic effect (AUCFe, milligrams per deciliter per 240 minutes) were noticed among the three groups. In seven consecutive patients with GS, seven with hemolytic anemia, and four healthy volunteers, AUCBR, AUCFe, and the NA plasma half-life of the first fast slope of the curve were determined at three different doses of the drug (1.18, 2.95, and 5.90 mumol NA per kilogram body weight). A significant, dose-dependent increase in AUCBR was present in patients with GS, whereas it remained constant both in controls and in patients with hemolytic anemia. The NA plasma half-life was also significantly prolonged in GS with each of the three doses, but remained unchanged in the other two groups. In patients with GS, a linear correlation (r = 0.891, P less than 0.001) was present between AUCBR and NA plasma half-life. In contrast, the AUCFe value remained constant at the different doses used in the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Sex differences in the hepatic uptake of sulphobromophthalein in the rat.

Sex difference in the hepatic uptake of sulphobromophthalein (BSP) was investigated in male and female rats in three different experimental models. In the intact animal the BSP plasma disappearance rate was significantly higher (P less than 0.01) in females than in males when 0.15 or 1.5 mumol/kg body wt. was injected. Comparable values were found at the highest BSP dose (15 mumol/kg body wt.) used. In the perfused liver, the first-pass hepatic extraction and the uptake velocity were significantly higher (P less than 0.001) in female rats at low BSP doses (0.3-750 mumol/g of liver) whereas identical values were found at higher concentrations. In hepatocytes isolated by collagenase perfusion, the BSP uptake occurs via two different uptake sites in both sexes. The Km of the high affinity sites was lower in females than in males (3.67 +/- 0.58 vs 7.24 +/- 0.68 mumol/l, P less than 0.001) whereas Vmax. showed comparable values (2.70 +/- 0.36 vs 2.47 +/- 0.45 nmol of BSP/mg of protein, NS). In contrast, no difference was found in the kinetic parameters of the low affinity sites (Km 50.6 +/- 31.1 vs 61.0 +/- 17.5 mumol/l; Vmax. 21.9 +/- 13.2 vs 25.0 +/- 3.6 nmol of BSP/mg of protein, mean +/- SD, NS, females and males respectively). Taken together these data show that low doses of BSP are taken up by the liver more efficiently in female than in male rats and are consistent with a sex-related difference in the affinity but not in the number of the BSP high affinity uptake sites.

Comparison of nicotinic acid- and caloric restriction-induced hyperbilirubinaemia in the diagnosis of Gilbert's syndrome.

The diagnostic value of the nicotinic acid (NA)-induced hyperbilirubinaemia was compared with that resulting from caloric restriction in 40 patients with Gilbert's syndrome (GS) and 20 controls. Both tests resulted in a significant higher level of serum bilirubin in GS than in controls (P less than 0.001). When the serum bilirubin level 240 min after NA administration (5.9 mumol/kg i.v.) was higher than 18 mumoles/l, this test had a specificity and sensitivity of 100%, both in males and females with the syndrome. The discriminatory value of the test was lower when either the area under the time concentration curve or the maximal increment of serum unconjugated bilirubin were used. Reduction in caloric intake (400 calories/day) showed a lower specificity and sensitivity than the NA test, particularly in females. An increment of bilirubin at 24 h greater than 15 mumoles/l was more diagnostic than an increase by 100% or more over the pre-diet value. The efficacy was not improved by prolonging the test for additional 24 h. From these data we conclude that NA-induced hyperbilirubinaemia and, in particular the concentration of the pigment 240 min after drug administration, is more efficient than fasting-induced hyperbilirubinaemia in the diagnosis of the Gilbert's syndrome both in males and in females.