Eosinophilic esophagitis: from the case report to the evidence.

Eosinophilic esophagitis (EE) is a rare disease characterized by esophageal symptoms and dense esophageal eosinophilic infiltrate, both of wich persist despite prolonged treatment with proton pump inhibitors. The pathogenesis is poorly understood, but there is an increasing body of clinical and basic evidence that EE is an immune-mediated disease triggered by both food and inhalant allergens. At present there is no consensus statement on the number of eosinophils requiredfor the diagnosis, but generally a number of 20 eosinophils per high power field is considered a significant cut-off point. Therapies considered to be effective in the treatment of EE include: specific elimination diets or elemental diets; either systemic or topical corticosteroids therapy; and therapy with a selective inhibitor of leukotriene D4 receptor.

Soluble apoptosis molecules in primary biliary cirrhosis: analysis and commitment of the Fas and tumour necrosis factor-related apoptosis-inducing ligand systems in comparison with chronic hepatitis C.

Apoptosis in the liver is generated mainly by the Fas system. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has been proposed recently as a new apoptotic inducer. In the liver environment hepatocytes and biliary epithelial cells express TRAIL receptors which are up-regulated by increased levels of bile acids and during viral hepatitis. As for FasL, a soluble form of TRAIL has been described. To explore the commitment and level of activation of these two apoptotic systems in patients affected by primary biliary cirrhosis (PBC) or chronic hepatitis C (CH-C), a comparative study was drawn. Thirty patients with PBC on ursodeoxycholic acid have been enrolled. This group was compared with 30 patients with CH-C and with 20 healthy subjects. Soluble Fas ligand (sFasL) and soluble TRAIL (sTRAIL) levels were evaluated by double determinant immune assay and enzyme-linked immunosorbent assay (ELISA), respectively. Soluble FasL molecules were higher in PBC compared to CH-C (P=0 x 009). Soluble FasL was not detected in controls. Soluble TRAIL was significantly higher in CH-C patients compared to PBC (P=0 x 0001). Soluble TRAIL levels were higher in PBC and in CH-C than in controls (P=0 x 015 and P<0 x 001, respectively). No correlation between sFasL and sTRAIL, stage of disease, liver histology in each disease and cytolysis was present. Our data show different levels of commitment of TRAIL and Fas apoptosis-inducing systems in CH-C and PBC. Thus a different prominent role of TRAIL and Fas systems in the pathogenesis of these two conditions can be speculated: the former by inducing the death of infected hepatocytes, the latter by mediating the disappearance of bile duct.

Chemokine receptor 5 and primary biliary cirrhosis: a two-centre genetic association study.

BACKGROUND: Chemokines and their receptors are important mediators of leucocyte trafficking and are suggested to be critical for establishment of inflammatory autoimmune processes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4+ T cells. We hypothesised that the CCR5delta(Delta)32 genotype, which impairs surface expression of CCR5 in heterozygotes and is linked to a functional polymorphism of CD45RA expressed on suppressor-inducer-like 'naive' CD4+ T cells, may modulate the inflammatory process in primary biliary cirrhosis (PBC). METHODS: CCR5Delta32 polymorphism was determined by PCR in 226 Caucasian PBC patients and 197 racially matched controls from two geographical areas, Newcastle, UK and Padua, Italy. (UK: 144 PBC, 105 controls, Italy: 82 PBC, 92 controls). RESULTS: When the two series were analysed separately, there were no significant differences in the genotype distribution comparing patients and controls (UK: wt/wt 72% vs 76%; wt/Delta32 28% vs 22%; Delta32/Delta32 0% vs 2%, P=0.24; Italy: wt/wt 72% vs 82%; wt/Delta32 27% vs 17%; Delta32/Delta32 0% vs 1%, P=0.14). However, when the data for the two series were pooled and reanalysed, we found an increase in the CCR5Delta32 mutation in PBC patients vs controls (28% vs 21%, OR=1.43, P=0.03), but there was no evidence that this Delta32 polymorphism is associated with less severe disease. CONCLUSIONS: Although this two-centre genetic association study is large compared with others performed in PBC, taken separately, each geographically based cohort of patients and controls is underpowered to detect a small effect of this functional polymorphism. This emphasises the need for far larger case-control collections to address which polymorphic markers or haplotypes might modify the pathogenesis and clinical course of PBC. We propose that multi-centre collaboration on an international scale in 'orphan' complex liver diseases such as (PBC) is supported by the International Association for the Study of the Liver and promoted via their journal with development of a brief format for web-based publication of studies.

Prevalence of coeliac disease in primary biliary cirrhosis and of antimitochondrial antibodies in adult coeliac disease patients in Italy.

BACKGROUND: Although an association between primary biliary cirrhosis and coeliac disease has recently been reported in Northern Europe, there are still conflicting data concerning this issue. AIM: To evaluate both the prevalence of coeliac disease in a series of primary biliary cirrhosis patients and that of antimitochondrial antibodies in a series of adult biopsy proven coeliac disease patients from Northern Italy. PATIENTS AND METHODS: A total of 87 primary biliary cirrhosis patients (79 female, 8 male) were screened for both IgA-transglutaminase antibodies and antiendomysium antibodies and, in those with either IgA-transglutaminase antibodies or antiendomysium antibodies positivity, upper endoscopy with distal duodenum biopsy was offered. In those who refused upper endoscopy, the intestinal permeability test with lactulose/mannitol excretion was performed. RESULTS: Antiendomysium antibodies positivity was detected in 3 subjects (3.4%), all of whom had serum IgA-transglutaminase antibodies above the normal range, and fulfilled the diagnosis of coeliac disease. Of 21 other patients with serum IgA-transglutaminase antibodies above the normal range, 17 underwent upper endoscopy which revealed normal duodenum architecture. The remaining 4 patients underwent the lactulose/mannitol excretion test which was within the normal range. Sera from 108 adult coeliac disease patients were tested for antimitochondrial antibodies and positivity was found in 4 patients (3.7%): all had normal liver biochemistry tests, whereas 2 of them also presented thyroid disease. Antibodies directed to the 74-kDa polypeptide of antimitochondrial antibodies were found in 3 out of 4 antimitochondrial antibodies+ve patients. CONCLUSIONS: These results suggest an association between primary biliary cirrhosis and coeliac disease similar to that observed in the Northern European series. In conclusion, screening for coeliac disease with antiendomysium antibodies in primary biliary cirrhosis is justified, and screening for antimitochondrial antibodies is advisable in adult coeliac disease patients.

Plasma antioxidant levels in chronic cholestatic liver diseases.

BACKGROUND: [corrected] A predictable consequence of cholestasis is malabsorption of fat-soluble factors, (vitamins A, D, E, K) and other free radical scavengers, such as carotenoids. It has been suggested that oxygen-derived free radicals may be involved in the pathogenesis of chronic liver damage. AIMS: (i) To evaluate retinol, alpha-tocopherol and carotenoid plasma levels in two groups of patients with chronic cholestatic liver disease (primary biliary cirrhosis and primary sclerosing cholangitis); (ii) to compare the respective plasma levels with those of the general population; (iii) to correlate the plasma levels with disease severity. METHODS: A total of 105 patients with chronic cholestasis were included in the study: 86 with primary biliary cirrhosis (81 female, five male, mean age 55.5 +/- 11 years), 19 with primary sclerosing cholangitis (seven female, 12 male, mean age 35 +/- 11 years; six patients had associated inflammatory bowel disease); 105 sex- and age-matched subjects from the general population in the same geographical area (88 female, 17 male, mean age 51.3.5 +/- 10 years) served as controls. Carotenoids (lutein zeaxanthin, lycopene, beta-carotene, alpha-carotene, beta-cryptoxanthin), retinol and alpha-tocopherol were assayed by high-pressure liquid chromatography. A food frequency questionnaire was administered to each subject to evaluate the quality and the quantity of dietary compounds. Data were processed by analysis of variance and linear regression analysis, as appropriate. RESULTS: Both primary biliary cirrhosis and primary sclerosing cholangitis patients had significantly lower levels of retinol, alpha-tocopherol, total carotenoids, lutein, zeaxanthin, lycopene, alpha- and beta-carotene than controls (P < 0.0001). Among the cholestatic patients, no significant difference in the concentration of antioxidants was observed between primary biliary cirrhosis and primary sclerosing cholangitis subjects. Anti-oxidant plasma levels were not affected by the severity of the histological stage in primary biliary cirrhosis, but a negative correlation was found between total carotenoids and both alkaline phosphatase (ALP) and gammaglutamyl transpeptidase (GGT) (P < 0.013 and P < 0.018, respectively). Within the primary sclerosing cholangitis group, no correlation was found between total carotenoids and cholestatic enzymes. Nutritional intake in cholestatic patients was comparable to controls, including fruit and vegetable intake. CONCLUSIONS: Although no clinical sign of deficiency is evident, plasma levels of antioxidants are low in cholestatic patients even in early stages of the disease. This is probably due to malabsorption of fat-soluble vitamins, as well as other mechanisms of hepatic release, suggesting the need for dietary supplementation.

Autosomal dominant benign recurrent intrahepatic cholestasis (BRIC) unlinked to 18q21 and 2q24.

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. On the basis of recent evidence of locus heterogeneity, we studied 19 subjects (7 affected members) of a BRIC family. Male-to-male transmission and the presence of affected females suggested autosomal dominant inheritance. Blood samples were collected after informed consent. Subjects were genotyped by using markers mapping to 18q and 2q24 region, respectively, where the genes FIC1 and FIC2 have been mapped. Segregation of haplotypes excluded the two regions in our family. These findings suggest further genetic heterogeneity of the origin of BRIC.

Chronic cholestasis associated with Turner's syndrome.

Liver abnormalities seem a very rare association in Turner's syndrome, only reported in a few anecdotal cases. We report the clinical and morphological findings in 3 patients who presented with cholestasis. One of them had a definite diagnosis of primary sclerosing cholangitis, in whom the natural history was complicated by the development of two distinct tumors. A review of the few cases described in the literature and our own case reports support the hypothesis that liver disease in Turner's syndrome may have a variety of expressions including cholestasis.

Oxygen-derived free radical production by peripheral blood neutrophils in chronic cholestatic liver diseases.

BACKGROUND/AIMS: Patients with chronic cholestasis, particularly those with associated cirrhosis, are susceptible to infectious complications. From animal models it has been postulated that cholestasis affects systemic polymorphonuclear leukocyte (PMNL) function by impeding chemotaxis, phagocytosis and superoxide release, which are necessary for an adequate immune response. The aim of this study was to evaluate neutrophil activity in the production of oxygen-derived free radicals in chronic cholestatic liver diseases. METHODOLOGY: The following groups were included in the study: 27 primary biliary cirrhosis (PBC) patients, 12 primary sclerosing cholangitis (PSC) patients, and 3 control groups (29 healthy subjects, 19 patients with HCV-related cirrhosis and 23 ulcerative colitis (UC) patients). Peripheral neutrophils were isolated from heparinized blood samples and PMNL activity was measured by free radical production, using a chemiluminometer, after stimulation with fMLP, PMA and Zymosan. The effect of liver disease severity and degree of cholestasis on PMNL function was also evaluated. RESULTS: Both PBC and PSC patients exhibited a normal PMNL activity compared to healthy subjects after the three stimuli used. In PBC patients only (but not in PSC patients), the histological stage of the disease seems to positively influence ROS production. Stage IV PBC patients showed a significantly higher PMNL activity compared to HCV-related cirrhotic patients. PSC patients failed to show any difference according to the association with UC. CONCLUSIONS: The increased susceptibility to bacterial infections in patients with chronic cholestatic liver disease is not related to an impaired PMNL activity. However, our findings may support the influence of biohumoral factors (cytokines?) on PMNL activation.

Primary sclerosing cholangitis (PSC): clinical, laboratory and survival analysis in children and adults.

BACKGROUND: Primary sclerosing cholangitis (PSC) is an uncommon disorder, rarely diagnosed in children, moreover, data on its natural history and survival are still lacking. AIM: The study was undertaken to compare clinical, laboratory and survival rates in two series of PSC: one in a pediatric group (group A) and the other in an adult population (group B). METHODS: Group A included 9 patients (5 males, 4 females, mean age 10 yrs, range 7-15); group B included 28 patients (19 males, 9 females, mean age 32 years, range 19-60). The mean follow-up was 5.2 years in group A and 6.9 years in group B (range 1-14 years). ERCP and colonoscopy were performed in each case. Survival was analyzed using the Kaplan-Meier method. RESULTS: At presentation children showed significantly higher levels of IgG and AST compared to adults (p<0.05); moreover, interface hepatitis occurred in 50% of children and in 14.2% in adults (p=ns). During follow-up the following major events occurred: oesophageal bleeding (n=2) in group A; progressive liver failure (n=6), cholangiocarcinoma (n=3), colonic cancer (n=1) in group B. Liver transplantation (OLTx) was performed in 4 adults (one died after a retransplantation). No deaths were observed in children. The Kaplan-Meier curve in adults shows a 65% rate of survival at 10 years. CONCLUSIONS: The present findings on PSC suggest a more severe activity of the disease in children than in adults at presentation; nonetheless, the prognosis seems to be better in children than in adults. The Mayo score prognostic index does not predict the development of liver/colonic cancer. A poor outcome (defined as death or being listed for OLTx) only occurred in adults.

Hepatic and extrahepatic malignancies in primary biliary cirrhosis.

Hepatocellular carcinoma (HCC) is rarely reported as a complication of primary biliary cirrhosis (PBC). However, data suggest that patients with PBC have an increased incidence of breast cancer when compared with the general population. Our aim was to analyze the incidence of malignancies in a large series of PBC patients from North-East Italy; to compare findings with those obtained in the general population of the same geographical area, as derived from the general cancer registry; and to study any possible adjunctive risk factor for malignancy. The overall sample included 175 patients (9 males, 166 females). The mean age at presentation was 50.8 years (range 23-77); 17 patients had histological stage I, 45 had stage II, 76 had stage III, and 37 had stage IV. The prevalence of gynecological diseases obtained from the past history of the females included 19.9% miscarriages, 12% hysterectomies, and 2.4% curettages. The follow-up period was 1,187 person/years (average 6.8 yrs per person as a mean). The comparison of the incidence of malignancies between the study group and the general population was obtained by the proportional incidence ratio (PIR), which is the ratio between the cases observed and the expected number of cases in the study group. Logistic regression analysis was performed utilizing the risk factors significantly associated with cancer development in the univariate analysis. Extrahepatic malignancies developed in eight cases (4.5%) and HCC in a further four cases (2.3%), all associated with cirrhosis. Two of the four patients with HCC had a superinfection with hepatitis C virus (HCV). Breast cancer developed only in two patients. The PIR for HCC was 26.27 (95% CI 6.8-46.5), whereas the PIR for breast cancer was 0.43. The logistic regression analysis indicated that a history of cigarette smoking and HCV-RNA positivity were independent variables for the development of HCC. HCC has a relatively high prevalence in PBC and HCV superinfection may play an important part in favoring HCC. The incidence of breast cancer is not significantly higher in PBC than in the general population of the same area.