Immune-mediated liver dysfunction after antiviral treatment in liver transplanted patients with hepatitis C: allo or autoimmune de novo hepatitis?

BACKGROUND: The recurrence of hepatitis C after liver transplantation is extremely frequent. Antiviral therapy combining pegylated-interferon with ribavirin is therefore increasingly used in these patients. It has been recently reported, however, that during antiviral treatment a hepatic immune-mediated liver dysfunction, similar to "de novo" autoimmune hepatitis, may develop in a few transplanted patients. PATIENTS AND METHODS: Three patients, treated with pegylated-interferon alpha-2a and ribavirin for recurrent hepatitis C after liver transplantation, developed an aggressive hepatitis with clinical, biochemical, and histological features similar to those of autoimmune hepatitis. RESULTS: In all three patients, a liver enzymes increase was evident after hepatitis C virus-RNA had become undetectable. Diagnosis of "de novo" autoimmune hepatitis was proposed, based on the presence of high-titre circulating autoantibodies and liver histology features. Following the introduction of a steroid therapy, clinical and biochemical parameters progressively improved. Hepatitis C virus infection, however, relapsed after a few months in all the patients. CONCLUSIONS: Following liver transplantation, antiviral therapy with pegylated-interferon alpha-2a and ribavirin for recurrent hepatitis C may be associated, in a few patients, with severe immune-mediated graft dysfunction similar to autoimmune hepatitis.

Gallstones, cholecystectomy and irritable bowel syndrome (IBS) MICOL population-based study.

BACKGROUND: Subjects with irritable bowel syndrome may undergo an excess of cholecystectomy. It is not known, however, whether the cholecystectomy rate parallels an increased risk of gallstones. AIM: Aim was to assess the prevalence and the incidence of gallstones and cholecystectomy in subjects with irritable bowel syndrome symptoms. SUBJECTS AND METHODS: In this population-based study, 29,139 subjects (63.2% of 46,139 randomly selected subjects, age 30-69 years) underwent a physical examination, an interview on gastrointestinal symptoms and an upper abdominal ultrasonography. An identical survey was carried out 7.8+/-1.0 (M+/-S.D.) years later on 8460 gallstone-free subjects at the first survey. Prevalence and incidence of gallstones and cholecystectomy were assessed in subjects with (1) irritable bowel syndrome; (2) abdominal pain and normal bowel; (3) altered bowel and no abdominal pain and (4) asymptomatic controls; univariate and multivariate regression logistic models were used for statistical analysis. RESULTS: Prevalence odds of gallstones and cholecystectomy were significantly higher in irritable bowel syndrome and abdominal pain and normal bowel than in controls. Irritable bowel syndrome and abdominal pain and normal bowel subjects were more aware of gallstones than controls (p<0.001), and the prevalence of gallstones in irritable bowel syndrome subjects unaware of their gallbladder status was not significantly different from the controls. The incidence of gallstone disease in irritable bowel syndrome, abdominal pain and normal bowel, and altered bowel and no abdominal pain subjects did not differ from the controls. The incidence of cholecystectomy was higher in irritable bowel syndrome and abdominal pain and normal bowel groups than in controls and altered bowel and no abdominal pain group. CONCLUSIONS: Irritable bowel syndrome subjects have an increased risk of cholecystectomy that is not due to an increased risk of gallstones, but rather to abdominal pain, awareness of having gallstones, and inappropriate surgical indications.

Outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is considered an optimal indication for liver transplantation (LT) because it may eliminate both the tumor and the underlying liver disease. The present study sought to compare cumulative survival, rate of HCC recurrence, and causes of death among patients with cirrhosis and HCC before and after the adoption of more restrictive criteria (Milan selection criteria) at the time of patient listing. Among 226 adult patients who received an elective liver transplantation between 1999 and 2005, 58 (27%) had a diagnosis of HCC at the time. The 38 patients who underwent transplantation for HCC in the period 1989 to 1998 were considered the "historical group." After LT (mean follow-up, 34 + 28 months), the cumulative survival rate was better among HCC versus non-HCC recipients (93% vs 71% at 1 year and 81% vs 67% at 3 years, respectively; P < .046), although the difference tended to attenuate after 5 years (66% vs 67%, respectively). Tumor recurrence (evaluated in patients surviving at least 3 months after LT) was observed in 10/31 in the historical group versus 4/53 among those who underwent transplantation after 1999. Among the causes of death, recurrence represented 50% in the old series and 23% in patients who underwent transplantation after 1999. Cumulative survival significantly improved among HCC patients who underwent transplantation after 1999 (93% vs 66% at 1 year and 81% vs 50% at 3 years; P < .00001). The 58 patients who underwent transplantation with a diagnosis of cirrhosis and concomitant HCC after 1999 showed even better survival than patients who underwent transplantation for end-stage liver disease without malignancy.

The anionic peptide fraction is present on the gallbladder apical epithelium and favours biliary cholesterol absorption.

BACKGROUND/AIMS: We investigated (a) in vitro and in vivo the changes of biliary mass of the anionic peptide fraction, apolipoproteinA-I, immunoglobulin-A, albumin and cholesterol over time in the excluded gallbladder and (b) in vivo the localization in the gallbladder epithelium of the anionic peptide fraction and cholesterol absorbed from bile. METHODS: Native bile was substituted with pig bile containing radiolabeled cholesterol in the in vitro isolated intra-arterially perfused pig gallbladder (n=9) and in vivo in anestethized pigs with excluded gallbladders (n=6). The amount of cholesterol (scintillation counting) and proteins (enzyme-linked immunosorbent assay) in gallbladder bile were measured over time. The localization of the anionic peptide fraction and cholesterol absorbed from bile in the gallbladder epithelium was studied in vivo by immunohistochemistry and fluoro-phospho-imager analysis. RESULTS: The rate of biliary cholesterol disappeared from bile was a function of the initial concentration and of the biliary mass changes over time of the anionic peptide fraction, but not of that of the other biliary proteins. The anionic peptide fraction colocalized with biliary cholesterol absorbed by the gallbladder on the apical side of gallbladder epithelial cells. CONCLUSIONS: These data indirectly suggest that biliary anionic peptide fraction could favour biliary cholesterol absorption by the gallbladder epithelium.

Bile salts regulate proliferation and apoptosis of liver cells by modulating the IGF1 system.

BACKGROUND: In different cell types, the insulin-like growth factor 1 and its receptor modulate growth, apoptosis and damage repair in cooperation with estrogen receptors. AIM: To evaluate the involvement of the insulin-like growth factor 1 system and estrogen receptors in bile salts modulation of apoptosis/proliferation of hepatocytes and cholangiocytes. Primary cultures of rat hepatocytes and cholangiocytes were exposed to glycochenodeoxycholate or tauro-CDC in the presence or absence of insulin-like growth factor 1 receptor blocking antibody (alphaIR3), small interfering RNA for insulin-like growth factor 1, 17beta-estradiol or estrogen receptor antagonist (ICI 182,780). Proliferation was evaluated by proliferating cell nuclear antigen Western blot and apoptosis by measuring caspase-3 activity or annexin-V. RESULTS: In hepatocytes, the insulin-like growth factor 1 receptor blocker enhanced glycochenodeoxycholate-induced apoptosis and caused tauro-CDC to promote apoptosis. 17Beta-estradiol or the estrogen receptor antagonist (ICI 182,780) did not influence the apoptotic effect of glycochenodeoxycholate. In cholangiocytes, both glycochenodeoxycholate and tauro-CDC induced proliferation at 100microM, while they induced apoptosis at 1mM with a more pronounced effect of glycochenodeoxycholate. Apoptosis induced by 1mM glycochenodeoxycholate or tauro-CDC in cholangiocytes was enhanced by blocking insulin-like growth factor 1 receptor or by silencing insulin-like growth factor 1. 17Beta-estradiol counteracts glycochenodeoxycholate-induced cholangiocyte apoptosis by enhancing insulin-like growth factor 1 secretion and activating the insulin-like growth factor 1 system. CONCLUSIONS: Modulation of the IGF1 system could represent a potential strategy for the management of bile salts-induced liver injury.

Management and outcomes of hepatic cirrhosis: Findings from the RING study.

BACKGROUND/AIM: Hepatic cirrhosis is a frequent reason for ordinary hospital admission (OA). The RING study collected hospital discharge files (HDF) from Italian hospital gastroenterology units (IGU). This caselist provides a broad picture of the patients admitted for this pathology. MATERIAL/METHODS: More than 50,000 HDF for OA were collected between 2001 and 2004 from 26 IGU. RESULTS: Eight thousand four hundred and eighty-seven HDF (16%) had a diagnosis of hepatic cirrhosis; Child-Pugh classes were 20.2% A, 34.8% B and 45.0% C. Patients' mean age was 63.7+/-12.1 years and 62.5% were male. A 61.1% of the cirrhosis cases had ascites, 29.9% portal-systemic encephalopathy, 29.2% hepatocellular carcinoma (HCC), 10% bleeding varices, 3.0% hepatorenal syndrome (HRS). Mortality for OA for cirrhosis was 5.7% versus 2.6% for other diagnoses. The proportion varied with the severity of the cirrhosis: 0% for Child A, 1.1% B, 10.5% C. Mortality was significantly associated with: Child-Pugh at admission (odds ratio: OR 9.2), HRS (OR 11.7), bleeding varices (OR 2.2), HCC (OR 1.8). CONCLUSIONS: Hepatic cirrhosis was found in 16% of the OA to IGU and mortality was double the rate for all the other pathologies in the same wards. Child-Pugh is a useful prognostic tool, higher classes implying a greater risk of death. HRS and bleeding varices were the complications with most influence on in-hospital mortality.

Predictive factors of outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma.

Studies to define the optimal upper limits of tumor size and number as predictors of outcome after orthotopic liver transplantation (OLT) have yielded conflicting results. We analyzed 72 patients with cirrhosis and hepatocellular carcinoma (HCC) who underwent OLT over a 12-year period in a single center. Predictive factors for survival and tumor recurrence, according to the Milan criteria, were also examined. Our cohort included 60 men and 12 women of mean age 54 +/- 8 years and mean follow-up of 40 +/- 39 months. Origin of cirrhosis was postviral in 70% and Child class B or C in two thirds of patients. HCC was multifocal in 61%; about one fifth of patients had micro- or macrovascular involvement or positive nodes upon histologic examination. The cumulative size of the lesions was <3 cm in 17 patients; >3 to < or =5 cm in 28 patients; >5 to < or =8 cm in 14 patients; and >8 cm in 13 patients. According to the number and size of tumor nodules, 49 patients met the Milan criteria. During follow-up 25 patients died, 13 due to tumor recurrence. The 1- and 2-year survivals were 90% and 85% for patients who met the Milan criteria versus 57% and 51% for patients exceeding those limits (P = .006). A cumulative tumor size >8 cm was predictive of survival and tumor recurrence upon multivariate analysis. The adoption of Milan criteria for selection of cirrhotic patients has improved survival and reduced the rate of tumor recurrence. The evaluation of cumulative tumor size might further improve patient selection.

Alpha-SMA expression in hepatic stellate cells and quantitative analysis of hepatic fibrosis in cirrhosis and in recurrent chronic hepatitis after liver transplantation.

BACKGROUND: The alpha isotype of actin expressed by hepatic stellate cells reflects their activation to myofibroblast-like cell and has been directly related to experimental liver fibrogenesis, and indirectly to human fibrosis in chronic liver disease. AIMS: To evaluate the changes in distribution and percentage of alpha-smooth muscle actin-positive hepatic stellate cells and the correlation with the degree of the fibrosis in cirrhotic livers, as well as in patients with recurrent HCV chronic hepatitis after liver transplantation. METHODS: Human liver biopsies were divided in four groups: (1) normal livers obtained from cadaveric liver donors (n=35), (2) cirrhosis post-HBV hepatitis (n=11), (3) cirrhosis post-HCV hepatitis (n=10), and (4) post-transplant recurrent HCV chronic hepatitis (n=13). Samples were stained with anti-alpha-smooth muscle actin antibody by immunoperoxidase method and semi-quantitatively evaluated. Liver fibrosis was assessed from specimens stained with Masson's trichrome and quantified by computer image analysis. RESULTS: The percentage of alpha-smooth muscle actin-positive hepatic stellate cells was significantly higher in the HBV cirrhosis, HCV cirrhosis and post-transplant HCV recurrent hepatitis groups (36.1+/-15.2, 23.8+/-19.7 and 27.8+/-16.4%, respectively) compared to the liver donor group (2.9+/-4.0%). The alpha-smooth muscle actin-positive hepatic stellate cells to fibrous tissue ratio were significantly higher in the post-transplant recurrent HCV hepatitis group (2.36+/-1.12) compared to both the donor livers and the HCV cirrhosis groups (0.74+/-1.09 and 1.03+/-0.91, respectively). The alpha-smooth muscle actin-positive hepatic stellate cell percentage and fibrosis correlated positively in the post-transplant recurrent HCV hepatitis group and negatively in the HCV cirrhosis group. No difference in the immunohistochemical and morphometrical variables was found between the HCV cirrhosis and HBV cirrhosis groups. CONCLUSIONS: These results indirectly confirm that, in vivo, alpha-smooth muscle actin expression is a reliable marker of hepatic stellate cells activation which precedes fibrous tissue deposition even in the setting of recurrent HCV chronic hepatitis after liver transplantation, and it could be useful to identify the earliest stages of hepatic fibrosis and monitoring the efficacy of the therapy. In the presence of advanced cirrhosis other factors, rather than alpha-smooth muscle actin-positive hepatic stellate cells, may sustain fibrosis deposition.

Malnutrition is not related to alterations in energy balance in patients with stable liver cirrhosis.

BACKGROUND AND AIMS: Little information are available on the relationship between energy balance and the alterations in nutritional status occurring in cirrhotic patients. The aim of the present study was to evaluate the daily energy balance in clinically stable cirrhotic patients with or without malnutrition. PATIENTS: Seventy-four consecutive cirrhotic patients and nine healthy controls were studied. METHODS: Basal energy expenditure was measured by indirect calorimetry and adjusted according to the patients' physical activity to estimate the daily energy expenditure. Food intake was evaluated based on a 3-day dietary diary. Nutritional status and body composition were assessed using skinfold anthropometry and dual energy X-ray absorptiometry, respectively. RESULTS: Thirty-two patients in the cirrhotic group were classified as severely malnourished according to anthropometric parameters. Two different patterns of soft-tissue loss were observed in the malnourished cirrhotic group: a significant reduction in fat mass and in fat-free mass was observed in males, whereas, females showed a significant reduction in fat mass only. Basal energy expenditure was similar in all groups, while the non-protein respiratory quotient was lower in cirrhotics notwithstanding their nutritional status. This suggests that lipids were the preferred oxidized fuel in the post-absorptive state in these patients. No difference in the estimated daily energy expenditure and energy intake was observed among groups. Lipid content of the diet was significantly lower in malnourished cirrhotics than in controls (33.1+/-1% vs 37.8+/-1%, P=0.02). CONCLUSIONS: Cirrhotic patients in stable clinical condition with malnutrition show a normal energy balance.

Helicobacter pylori diagnosis in patients with liver cirrhosis.

BACKGROUND: In cirrhotics, Helicobacter pylori infection is the major cause of peptic lesions, which are an important cause of upper intestinal haemorrhage in these patients. However, some diagnostic methods are not accurate for H. pylori detection in cirrhotics. AIMS: The study assessed the accuracy of different diagnostic methods for H. pylori detection in cirrhotics with and without gastroduodenal lesions. METHODS: The study population comprised of 53 cirrhotics. All patients underwent upper endoscopy: three biopsies were taken in the antrum and three in the gastric body. Four biopsies were used for Giemsa staining, while two were used for a rapid urease test. A blood sample was obtained for serology using Western blotting, and a [13C]urea breath test was performed in all patients. Histological assessment was regarded as the gold standard for diagnosis of H. pylori infection. RESULTS: H. pylori infection was detected at histological assessment in 28 (52.8%) patients. The [13C]urea breath test, rapid urease test, and serology were positive in 27 (51%) patients, 23 (43.4%) patients, and 34 (64.1%) patients, respectively. Sensitivity and specificity were 92.9 and 96% for the [13C]urea breath test, 78.6 and 96% for the rapid urease test, and 78.6 and 52% for serology. CONCLUSIONS: The [13C]urea breath test is very accurate in cirrhotics, whilst both serology and the rapid urease test give disappointing results.

Alfa and beta estrogen receptors and the biliary tree.

This manuscript summarizes recent data showing that estrogens and their receptors play an important role in modulating cholangiocyte proliferation. We have recently demonstrated that rat cholangiocytes express both estrogen receptors (ER)-alpha and -beta subtypes, while hepatocytes only express ER-alpha. ER and especially the ER-beta subtype, are overexpressed in cholangiocytes proliferating after bile duct ligation (BDL) in the rat, in association with enlarged bile duct mass and with enhanced estradiol serum levels. Cholangiocyte proliferation, during BDL, is impaired by estrogen antagonists (tamoxifen, ICI 182,780) which furthermore, induce the overexpression of Fas antigen and activate apoptosis of proliferating cholangiocytes. 17beta-estradiol stimulates, in vitro cholangiocyte proliferation, and this effect is individually blocked by tamoxifen or ICI 182,780. Cholangiocyte proliferation during BDL was associated with an enhanced protein expression of phosphorylated extracellular regulated kinases (ERK)1/2 which is, in contrast, negatively modulated by tamoxifen in association with its antiproliferative effect. This indicates a major involvement of the ERK system in the estrogen modulation of cholangiocyte proliferation.

Gastric epithelial cell proliferation in patients with liver cirrhosis.

An increased risk for gastric cancer in patients with liver cirrhosis has recently been reported. This study was performed in order to determine gastric epithelial cell proliferation in cirrhotic patients and to evaluate the role of congestive gastropathy (CG) and Helicobacter pylori infection in this process. Thirty-six cirrhotic patients and 18 controls were enrolled in the study. All patients underwent endoscopy and three biopsies were performed in the antrum and three in the gastric body. The presence of H. pylori infection was assessed by a rapid urease test and histology. The antral biopsies were used for gastric cell proliferation assessment by an immunohistochemical analysis (Ki-67). There was no significant difference in epithelial cell proliferation between cirrhotics and controls. Gastric proliferation values were higher in patients with H. pylori infection compared with uninfected patients, both in cirrhotic (P = 0.003) and in control groups (P = 0.06). Among the cirrhotic group, we found a progressive increase in gastric cell proliferation values related to the degree of CG, the highest values being observed in cirrhotic patients with severe CG. Moreover, cirrhotics with both severe CG and H. pylori infection had the highest proliferation values when compared with all other subgroups. In conclusion, this study found that: (1) CG significantly affects epithelial cell proliferation in gastric mucosa in cirrhotic patients, (2) H. pylori infection plays a similar role in gastric cell proliferation in both cirrhotic and non-cirrhotic patients, and (3) CG and H. pylori could act synergistically in this process.

Ascorbic acid and intestinal metaplasia in the stomach: a prospective, randomized study.

BACKGROUND: Intestinal type metaplasia plays a role in intestinal type gastric carcinoma development. Ascorbic acid demonstrates a protective effect against gastric carcinogenesis, due to its ability to inactivate oxygen free-radicals as well as its nitrite-scavenging effects. AIM: To assess whether long-term ascorbic acid administration following Helicobacter pylori eradication could affect intestinal metaplasia regression in the stomach. METHODS: Sixty-five patients were included in the study. The inclusion criterion was the presence of intestinal metaplasia on the gastric mucosa after H. pylori eradication. An upper gastrointestinal endoscopy was performed and 3 biopsy specimens were taken in the antrum, 3 in the gastric body, and 2 in the incisura angularis. Patients were randomized to receive 500 mg of ascorbic acid o.d., after lunch (32 patients) for 6 months or no treatment (33 patients). All patients underwent to endoscopic control at the end of the 6 months. RESULTS: H. pylori infection recurrence was detected in 6 (9.4%) patients (three from each group), and these patients were excluded from further analysis. We were unable to find evidence of intestinal metaplasia in any biopsied site of the gastric mucosa in 9/29 (31%) patients from the ascorbic acid group and in 1/29 (3.4%) of the patients from the control group (P=0.006). Moreover, a further six (20.7%) patients from the ascorbic acid group presenting chronic inactive pangastritis with widespread intestinal metaplasia at entry, showed less extensive antritis with intestinal metaplasia at control, whilst a similar finding was only seen in one patient from the control group (P=0.051). CONCLUSION: The administration of ascorbic acid significantly helps to resolve intestinal metaplasia of the gastric mucosa following H. pylori eradication, and its use as a chemoprevention treatment should be considered.

Clinical and histologic predictors of Helicobacter pylori infection recurrence.

Factors influencing Helicobacter pylori infection recurrence still have not been fully clarified. The aim of this study was to determine whether, after eradication of H. pylori, any clinical or histologic features could yield information on infection relapse. We enrolled in the study 72 patients successfully treated for H. pylori infection by either dual (n = 49) or triple (n = 23) therapy. H. pylori eradication was defined as a negative bacterial finding by rapid urease test and histologic assessment at least 4 weeks after cessation of therapy. Upon eradication, gastritis grading was performed and patients were asked to return for an endoscopic control 6-8 months later. The recurrence of H. pylori infection was observed in 12 of 72 (16.7%) patients. The infection recurrence rate resulted significantly higher in nonulcer dyspepsia patients (p = 0.01 ) and in women (p = 0.03), whereas infection relapse did not differ between patients treated with dual or triple therapy. There was a strong (p = 0.0001 ) relationship between the persistence of chronic active gastritis after H. pylori eradication and recurrence of infection, whereas gastritis grade and metaplasia were not related to recurrence. In conclusion, this study found that H. pylori infection recurrence after successful dual or triple therapy is fairly high and that gastroduodenal disease, gender, and gastritis activity seem to affect infection relapse.

A new highly effective short-term therapy schedule for Helicobacter pylori eradication.

BACKGROUND: Although triple therapy regimens suggested in the Current European guidelines give fairly good results, several studies have reported an unsatisfactory Helicobacter pylori eradication rate (< 80%). AIM: To evaluate the efficacy of a new short-term treatment sequence on H. pylori eradication. METHODS: A total of 52 patients with H. pylori infection and either non-ulcer dyspepsia (34 patients) or peptic ulcer (18 patients) were enrolled to receive a 10-day therapy: omeprazole 20 mg b.d. plus amoxycillin 1 g b.d. for the first 5 days, followed by omeprazole 20 mg b.d., clarithromycin 500 mg b.d. and tinidazole 500 mg b.d. for the remaining 5 days. H. pylori infection at entry was assessed by rapid urease test and histology on biopsies from the antrum and the corpus. Bacterial eradication was assessed by endoscopy (peptic ulcer patients) or 13C urea breath test (non-ulcer dyspepsia patients) 4-6 weeks after therapy had ended. RESULTS: All patients completed the study. H. pylori eradication was achieved in all but one patient, with an eradication rate of 98% (95% CI: 94.3-100) with intention-to-treat analysis. Patient compliance was good (consumption of prescribed drugs > 95%) for all but one patient, who took the triple therapy regimen for 4 days instead of 5 days. No major side-effects were reported but three (6%) patients complained of mild side-effects. CONCLUSIONS: The use of this 'five plus five' therapy schedule as an initial treatment for H. pylori deserves further investigation.

Impaired human gallbladder lipid absorption in cholesterol gallstone disease and its effect on cholesterol solubility in bile.

BACKGROUND & AIMS: The role of the gallbladder in gallstone pathogenesis is still unclear. We examined the effects of gallbladder mucosal lipid absorption on lipid composition and cholesterol crystallization in bile. METHODS: The in vitro-isolated, intra-arterially perfused gallbladder model was used (1) to compare the absorption rates of lipids from standard bile by gallbladders obtained from 7 patients with cholesterol gallstones and 6 controls; and (2) to measure the microscopic cholesterol crystal detection time in cholesterol-enriched pig bile before and after lipid absorption by the pig gallbladder. RESULTS: Control gallbladders, but not cholesterol gallstone gallbladders, significantly reduced cholesterol (P < 0.02) and phospholipid (P < 0.01) and increased bile salt (P < 0.01) molar percentages in bile over a 5-hour period by efficient and selective cholesterol and phospholipid absorption. A histomorphometric study of the epithelial cells showed significantly higher values for nuclear density (P < 0.01) and nuclear (P < 0.05) and cytoplasmic (P < 0.05) areas in the cholesterol gallstone than the control group. Sequential microscopy of cholesterol-enriched pig bile showed significantly shorter cholesterol filament (P < 0.01) and typical cholesterol plate (P < 0. 02) detection times before than after exposure of bile to the gallbladder lipid absorption. CONCLUSIONS: In cholesterol gallstone disease, the human gallbladder epithelium loses its capacity to selectively and efficiently absorb cholesterol and phospholipids from bile, even if it is hyperplastic and hypertrophic. This epithelial dysfunction eliminates the positive effect that the normal gallbladder exerts on cholesterol solubility in bile and might be a pathogenetic cofactor for cholesterol gallstone formation.

Cholelithiasis: genetic hypothesis.

In inbred mice gallstone susceptibility is determined by Lith (lithogenic) genes which promote cholesterol hypersecretion in bile as a response to a high-fat diet. At least three major classes of proteins can be considered as candidate genes: (a) enzymes involved in cholesterol metabolism regulation; (b) trans-membrane carrier proteins from hepatocyte into bile; (c) cytosolic transfer proteins which regulate intrahepatocyte trafficking. The main candidates are: Spgp, a transmembrane protein which produces bile salt transport. Its gene map in Lith 1 region (Chromosome 2) and its expression is increased in susceptible inbred strains of mice (C57L) of inbred mice. Cmoat is a carrier protein that promotes the secretion of conjugated substances in bile. Its gene map in Lith 2 region (Chromosome 19) and its expression is increased in susceptible inbred strains of mice fed on a lithogenic diet. HGMR is the enzyme that regulates de novo synthesis of cholesterol in the liver. Its activity increases in resistant strains fed on a lithogenic diet and unvaries in susceptible strains. Its gene does not reside in any Lith region, but one Lith gene could be responsible for its activity regulation. To date, the hypothesis of a genetic basis of cholelithiasis in men has only been investigated in one study, in which the association of cholelithiasis and a mutation in the C7AH gene was documented in a group of Mexican patients.

Relationship between antral lymphocyte density and basal gastrin levels in patients with Helicobacter pylori infection.

BACKGROUND: The mechanism by which Helicobacter pylori causes hypergastrinaemia is not completely understood. AIM: To evaluate whether antral lymphocyte density could play a role in this alteration. METHODS: A total of 12 patients with active duodenal ulcer and 10 with non-ulcer dyspepsia were enrolled upon detection of Helicobacter pylori infection at endoscopy Enrolled as controls were 7 matched dyspeptic patients without Helicobacter pylori infection. Biopsy specimens were collected for Helicobacter pylori and histological assessments, and for antral lymphocyte density assessment by a histomorphometric method. A blood sample was obtained from each patient to determine basal gastrin levels. All patients were controlled by a further endoscopy 4 weeks after the end of Helicobacter pylori treatment. RESULTS: Antral lymphocyte density (5,464 +/- 1,328 and 5,635 +/- 1,186 vs 2,267 +/- 557 lymphocytes/mm2; p<0.001 and p<0.001, respectively) and gastrin levels (66.7 +/- 14.1 and 60.4 +/- 21.7 vs 40.7 +/- 7.8 pg/dl; p=0.004 and p=0.02, respectively) were higher in duodenal ulcer and non-ulcer dyspepsia patients than in controls, while no significant differences emerged between duodenal ulcer and non-ulcer dyspepsia patients. There was a significant direct correlation between antral lymphocyte density and gastrin levels both in duodenal ulcer (r=0.77; p=0.003) and in non-ulcer dyspepsia (r=0.75; p=0.03) patients, while no correlation was found in controls [r=0.12; p=0.8). After treatment, this correlation persisted in 10 eradication failure patients (r=0.68; p=0.027), but disappeared in those successfully cured. CONCLUSIONS: These data suggest that lymphocyte density in the antral mucosa could play a role in the impaired gastrin production occurring in patients with Helicobacter pylori infection.