No evidence for involvement of the interleukin-10 -592 promoter polymorphism in genetic susceptibility to primary biliary cirrhosis.

BACKGROUND/AIMS: Primary biliary cirrhosis is a chronic cholestatic liver disease with an autoimmune aetiology. Family studies, which have shown a significantly increased incidence of primary biliary cirrhosis in the close relatives of patients, suggest that genetic factors play a significant role in determining disease susceptibility. Several studies have previously identified loci which appear to play a role in determining this susceptibility, including the MHC class II allele HLA DR8, and the class III encoded C4A null allele (C4AQ0). Here, we have studied another candidate susceptibility locus in primary biliary cirrhosis, an apparently functional biallelic polymorphism at position -592 in the promoter region of the gene encoding the immuno-modulatory cytokine interleukin-10. Interleukin-10 plays an important role in the functional control, in vivo, of autoreactive Th-1 type CD4+ T-cells, with experimental manipulation of interleukin-10 leading to significant modulation of disease development in animal models of autoimmunity. METHODS: Interleukin-10 -592 genotypes were studied by polymerase chain reaction in 171 well-characterised, histologically-staged, primary biliary cirrhosis patients and 141 locally matched controls. RESULTS: Of 171 primary biliary cirrhosis patients, 99 were homozygous for the commoner allele (C/C), 68/171 (40%) were heterozygotes (A/C), whilst 4/171 (2%) were homozygous for the rarer allele (A/A). These genotype frequencies were not significantly different from those seen in controls (p=0.49, odds ratio 1.2 [0.8-1.91). CONCLUSIONS: These findings, in the first study of IL-10 as a candidate locus in a human autoimmune disease, suggest that IL-10 -592 is not a susceptibility locus in primary biliary cirrhosis.

A 3-year pilot study with 1,25-dihydroxyvitamin D, calcium, and calcitonin for severe osteodystrophy in primary biliary cirrhosis.

We carried out a 3-year pilot study of 59 consecutive women with osteoporosis of primary biliary cirrhosis (PBC), allocating them to two groups according to the severity of bone demineralization assessed by means of dual-photon absorptiometry (DPA) of the lumbar spine, Group A (36 patients; bone mineral density [BMD] > 0.800 g/cm2) received no treatment; group B (23 patients; BMD < 0.800 g/cm2) was treated as follows: oral 1,25-dihydroxyvitamin D (0.5 microgram twice a day for 5 days) followed by a 1-month course with oral calcium carbonate (1,500 mg/day) +carbocalcitonin (40 UMRC intramuscularly three times weekly). This treatment was repeated every 3 months. The following parameters were assessed at baseline and every 12 months: DPA, serum and urinary minerals, serum parathyroid hormone (PTH), osteocalcin (BGP), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D. During follow-up, 11 initially untreated patients whose BMD dropped below 0.800 g/cm2 were switched to the treatment group (8 after 12 months and 3 after 24 months). No significant changes were observed in either group for PTH, BGP, or vitamin D metabolites. Comparing patients who were always treated, those who were never treated, and those who switched to the treatment group (ever treated) in this 36-month period, the percentage of annual bone loss in the never-treated patients was significantly less (p < 0.002) than in the ever-treated patients, suggesting the presence of two subgroups in PBC patients; one with rapid bone loss and the other with slow bone loss. Moreover, in the ever-treated patients, ADFR (activate, depress, free, repeat) therapy resulted in an improvement in BMD (p < 0.05 compared with the value before therapy). We conclude that ADFR therapy is effective in the treatment of patients with PBC with severe osteodystrophy, despite no change in osteoblastic activity, although controlled, randomized studies are in order to confirm our data.

Chronic atrophic gastritis and Helicobacter pylori infection in primary biliary cirrhosis: a cross-sectional study with matching.

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by exocrine gland impairment. Up to now there have been no reports dealing with gastric mucosa involvement in this autoimmune condition, which is frequently associated with Sjögren's syndrome. The aim of this study was to investigate the morphologic, biochemical and immunological features of the gastric mucosa in PBC. METHODS: A cross-sectional study with matching was performed. Thirty-three PBC patients (30 F, 3 M, mean age 58 years; 17 with stage II-III, and 16 with stage IV disease) and 33 sex- and age-matched dyspeptic controls were included. Six biopsy specimens from the fundus (2), body (2) and antrum (2) were taken from all patients and controls. A serological assessment was performed for each subject, i.e. pepsinogen A (PGA), pepsinogen C (PGC), gastrin (G), and antibodies against Helicobacter pylori (anti-Hp IgG). RESULTS: Endoscopic gastritis was found in 22 PBC patients (66.6%). There was no difference between PBC patients and controls regarding the percentage of subjects with mild, moderate, severe or atrophic gastritis (AG). There was no difference in gastric mucosal involvement between PBC subjects with or without secondary Sjögren's syndrome. A discrepancy was observed in the data obtained with respect to Helicobacter pylori (H. pylori) infection. H. pylori colonization was significantly more frequent in controls than in PBC patients (79% vs 49%, p < 0.002), but anti-Hp IgG were detected in the same percentage in the two groups (90% vs 83% respectively). There was no difference between the two groups in the PGA, PGC, PGA/PGC ratio, or gastrin. Eight PBC patients had esophageal varices. CONCLUSIONS: PBC patients are not characterized by chronic atrophic gastritis. Even though they present chronic gastritis with the same prevalence as dyspeptic controls, and show signs of previous H. pylori infection as frequently as dyspeptic patients, they are actually much less frequently infected. The reasons for this observation are unclear.

Hepatitis C virus infection in pregnancy.

OBJECTIVES: To evaluate the clinical aspects of hepatitis C virus (HCV) liver disease in anti-HCV+ve mothers, both during pregnancy and six months after delivery, and to assess the outcome of pregnancy. SETTING: Obstetric department for high risk pregnancies of the University of Padova, Italy. PARTICIPANTS: Seventeen hundred consecutive pregnant women were studied. METHODS: Each woman underwent the following: 1. serological screening for hepatitis surface antigen (HBsAg), antibodies to HCV (anti-HCV), antibodies to human immunodeficiency virus type 1 (HIV1) within the first trimester of pregnancy; and 2. clinico-biochemical assessment in order to ascertain previous or active liver disease and risk factors for viral infections. RESULTS: Twenty-nine (1.7%) of the 1700 women were found anti-HCV positive. Eight of them had an associated positivity for HIV infection. HCV-RNA was positive in 64.2% of anti-HCV positive women. Liver function tests (included transaminases) were within the normal range in 27 mothers (both during and six months after delivery). Only 2/29 women had a slight increase in AST/ALT; liver biopsy in these cases was compatible with mild chronic active chronic active hepatitis. In all women the outcome of pregnancy was favourable (12/29 anti-HCV positive mothers underwent caesarean delivery for causes independent from HCV infection). CONCLUSIONS: A substantial proportion of anti-HCV positive pregnant mothers, even if asymptomatic, have circulating HCV-RNA. The pregnancy does not induce a deterioration of liver disease, and vice versa, HCV infection does not increase the risk of obstetric complications.

Different response to ursodeoxycholic acid (UDCA) in primary biliary cirrhosis according to severity of disease.

To evaluate the effect of ursodeoxycholic acid (UDCA) treatment according to the severity of primary biliary cirrhosis, a long-term prospective open trial in 54 consecutive PBC patients, 19 with histological stage I-II, 24 stage III, and 11 stage IV was carried out. UDCA was administered at a dosage of 250 mg twice a day. Clinical and biochemical assessment (AST, ALT, alkaline phosphatase, GGT, bilirubin) were done initially and every six months. Serum hyaluronate (HY) and type III procollagen amino propeptide (PIIIP) were also evaluated, as they are considered markers of fibrosis and prognosis. All patients were followed-up for at least two years (24-36 months); results were analyzed at 24 months after treatment. The composite pruritus score failed to show significant changes during UDCA treatment, while intensity score demonstrated a significant reduction from the 6th month. Patients with histological stage I-II disease had a significant decrease of liver enzymes (AST, ALT, alkaline phosphatase, GGT) after six months and maintained the levels up to 24 months. The patients with histological stage III disease showed a significant decrease of AST, ALT, alkaline phosphatase (but not GGT) up to month 18; subsequently AST and ALT serum levels increased, reaching values comparable to baseline by 24 months. In patients with histological stage IV disease no significant change in liver enzymes was observed during the follow-up. HY and PIIIP serum levels failed to show significant changes during UDCA treatment in the three groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Rehabilitation of patellofemoral joint disorders.

Patellofemoral dysfunction may be one of the most common and troublesome maladies to affect a patient. The correct identification of the underlying causes is paramount. Once identified, an effective rehabilitation program should be implemented. The program should include stretching and strengthening as well as several other therapeutic modalities. The most successful rehabilitation program is designed to address the specific needs of the patient.