Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several studies suggest that UDCA treatment has beneficial effects in chronic cholestatic diseases. We designed a controlled trial to assess the efficacy and tolerance of UCDA in primary biliary cirrhosis (PBC): 73 patients received UDCA (13-15 mg/kg per day) and 73 a placebo. One side-effect required interruption of therapy in each group. The relative risk of treatment failure (doubling of the bilirubin level or occurrence of a severe complication of cirrhosis) was 3 times higher in the placebo group. Pruritus resolved in 40% of the patients of UDCA group vs 19% in placebo group. Biological and histological parameters significantly improved in the patients receiving UDCA. Unexpectedly, immune parameters, including IgM levels and anti-mitochondrial antibody titers, also improved. The Mayo risk score was significantly different between the two groups at one and two years, suggesting that UDCA could prolong survival in PBC. Recent studies suggest that UDCA could have immunoregulating properties. Abnormal MHC class I expression by hepatocytes, observed in PBC, was dramatically reduced by UDCA treatment. Cholestasis itself induces hepatic MHC expression: hepatocyte MHC class I expression was present in 6/6 cholestatic patients vs 0/8 control subjects. Experimental cholestasis in the rat induced MHC class I expression. Cyclosporin or corticosteroids had no effect on this overexpression, suggesting that an immune mechanism is not involved in this phenomenon. To assess the effect of bile acids on MHC expression, human hepatocytes were incubated with bile acids. Chenodeoxycholic acid (CDCA) (an endogenous bile acid) but not UDCA induced a dose-dependent MHC class I hyperexpression. UDCA suppressed the CDCA-induced MHC hyperexpression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ursodeoxycholic acid (UDCA) in the treatment of chronic cholestatic diseases. 178 27

Graft-versus-host disease (GVHD) across minor histocompatibility antigens was developed in mice and the bile duct lesions were surveyed for up to 7.5 months after spleen and bone marrow cell transplantation. Lymphoid cell infiltration was evident by day 3, reached maximum at 2 weeks, then reduced gradually and persisted during the observation period. Fibrous expansion of the portal tracts paralleled with the time after transplantation, but none of the cases progressed into liver cirrhosis. The infiltrates abutted the interlobular and septal bile ducts and distorted their appearance with a frequent infiltration of mononuclear lymphoid cells into the duct epithelial layer. The duct epithelium showed a variety of degenerative and hyperplastic changes, including nuclear enlargement with anisonucleosis, nuclear pyknosis, cytoplasmic and nuclear darkness, cytoplasmic vacuolization, focal epithelial dropout, formation of apoptotic bodies, and micropapillary infolding. Disappearance of the bile ducts and formation of granuloma around the bile ducts were not seen. Immunocytochemical study revealed the exclusive preponderance of helper/inducer T cells in the portal infiltrates and marked expression of I-A antigen on the bile duct epithelium in GVHD mice. These results suggest that immunological mechanisms by helper/inducer T cells against minor histocompatibility antigen on bile duct epithelium in association with class II molecules of MHC are important in the pathogenesis of the bile duct lesions. A putative role of such lymphocytes is discussed.
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PMID:Histological changes of bile duct in experimental graft-versus-host disease across minor histocompatibility barriers. I. Light microscopic and immunocytochemical observations. 330 87

Pigs usually reject MHC incompatible liver allografts less aggressively than skin or kidney allografts. Orthotopic liver allografts can survive undefinitely without any immunosuppression. The liver is considered to be an immunologically privileged organ. Despite this phenomenon, morphological changes and deranged liver function due to rejection reaction are regularly seen; their intensity depends on the histocompatibility antigen disparity between donor and recipient. In long-term survivors the continuous exposure of the recipient's immune system to the liver allograft results in an increasing fibrosis which can turn into liver cirrhosis being considered as the result of chronic rejection. The cholestasis represents a remarkable feature, which is mainly due to perfusion, infection and immunological reaction.
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PMID:[The allogeneic liver transplantation. I. Morphological and functional patterns in pig liver allografts (author's transl)]. 701 36

Inflammation of the bile ducts was studied in liver biopsies from patients with chronic hepatitis C to determine whether the frequency of inflamed bile ducts changes with therapy and correlates with other histological variables and expression of class I and II MHC antigens on ductal epithelium. Twenty patients treated at UMMC between 1991 and 1994 underwent needle biopsies of the liver before and after therapy with interferon alpha 2B (IFN). A complete response to therapy was defined as a return to normal serum alanine aminotransferase levels occurring and persisting during therapy. The number of inflamed bile ducts/total ducts (%IBDs), presence of piecemeal necrosis and lymphoid aggregates, and grade of inflammation were assessed in each high-power field in all areas with bile ducts. The frequencies of these variables were compared in cirrhotics and non-cirrhotics and in patients with complete or incomplete responses to IFN. Frozen sections of biopsies from 5 patients were immunostained using antibodies to HLA-DR and B-2 microglobulin, and positive staining was noted on bile ducts. Before therapy, the %IBD was slightly greater in patients with cirrhosis. After IFN, both %IBD and serum alkaline phosphatase levels decreased in non-cirrhotics who responded to IFN. The change in frequency of IBD with IFN paralleled the changes in the other histological features. No correlation was noted between bile duct inflammation and expression of class I and II antigens. The conclusion is that inflammation of the bile ducts occurs frequently in chronic hepatitis C, correlates with other features of inflammation in the triads, and decreases in response to IFN therapy.
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PMID:Effect of interferon therapy on bile duct inflammation in hepatitis C. 876 34

HHC is the most common inherited metabolic disease among the white population worldwide, with a gene frequency of about 10% and a frequency of homozygosity of about 1 of 250. Many patients harbor a common haplotype of informative markers on chromosome 6p2l.23, suggesting a strong founder effect exerted by a common Celtic ancestor. With the advent of screening tests (serum Tf saturation, fe), many subjects with HHC are being identified before development of cirrhosis or diabetes mellitus, and early detection is important because prompt and vigorous iron reduction prevents development of such complications and assures normal life expectancy. The HIC can be estimated as accurately by specialized magnetic resonance imaging or susceptometric measurements as by chemical measurements on liver biopsy specimens. However, biopsy specimens retain value for showing fibrosis/cirrhosis and dysplastic hepatocytes, both of which increase risks of HCC development. There is growing evidence that iron in the liver plays an important role in non-HHC diseases, such as alcoholic liver disease, chronic viral hepatitis, and porphyria cutanea tarda. The complicated, manifold roles of iron in pathogenesis of the latter disorder include enhancement of production and irreversible oxidation of uroporphyrinogen, as well as formation of an inhibitor targeted specifically at hepatic uroporphyrinogen decarboxylase. The nature of the gene and gene product that are abnormal in HHC remain elusive, despite the intense efforts of several investigative groups. The search has been hampered by a dearth of informative markers in HHC patients in the relevant region of chromosome 6p. Note added in proof: The cloning of a candidate gene, the mutation of which may perhaps cause HLA-linked hemochromatosis, has just been reported (Feder et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature (Genetics) 1996;399-408). These workers identified a 250-kb region move than three megabases telomeric of the MHC that was identical in 85% of chromosomes of HHC patients. Within this region, they identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations one of which is predicted to inactivate this class of proteins. 83% of 178 patients were homozygous for this mutation (Cys 282Tyr). This variant was also found on 3.2% of control chromosomes, as would be expected for such a common disorder. Functional studies are awaited with great interest.
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PMID:An update on iron metabolism: summary of the Fifth International Conference on Disorders of Iron Metabolism. 878 49

The immune response in liver cirrhosis and hepatocellular carcinoma is receiving renewed attention in consideration of the possible treatment with biological response modifiers. The aim of this study was to evaluate whether cirrhosis and hepatocellular carcinoma induce any modification in peripheral lymphocyte subsets. Lymphocytes were evaluated (number/percentage) in 61 patients with hepatocellular carcinoma, 35 with cirrhosis and 24 healthy controls. Using flow cytometry, 10 lymphocyte subpopulations were assayed, plus the CD4/CD8 ratio. Results demonstrated no change in the number of lymphocytes; cirrhosis and hepatocellular carcinoma patients had significantly more HLA-DR+ (p = 0.001) and CD3+/HLA-DR+ (activated T) (p = 0.002) and fewer CD3+ (mature T) (p = 0.02) cell than controls; hepatocellular carcinoma patients had significantly more CD3+/CD56+/CD16- (cytotoxic non-MHC restricted T cells) and CD25+ (IL-2 receptor positive cells). If the percentages of all cells with cytotoxic-T activity were pooled, a significant increase (p = 0.03) was seen in hepatocellular carcinoma patients. In conclusion, in contrast to previous data, hepatocellular carcinoma patients reveal an increased number of cytotoxic non-MHC restricted T cells.
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PMID:Activation of cytotoxic and natural killer T-cell system in patients with hepatocellular carcinoma and cirrhosis. 913 93

Genetic haemochromatosis (GH) is one of the most common hereditary diseases, with a prevalence of 1-5/1000 in the Western world. In 90 per cent of cases a mutation is found in an MHC-class-like gene designated HFE, involving a substitution at position 282 of the HFE protein and resulting in defective binding of beta(2)-microglobulin. Animals with beta(2)-microglobulin deficiency develop iron overload, indicating this protein to be involved in the regulation of iron metabolism. Hepatic iron overload results in increased production of oxygen free radicals and peroxidation of membrane lipids, thus causing damage to lysosomes, mitochondria and the endoplasmic reticulum. These cellular events may progress to cell death, fibrogenesis, and the development of liver cirrhosis which is associated with a 200-fold increase in risk of hepatocellular carcinoma. In addition to the risk of diabetes, arthralgia, cardiac arrhythmia, pituitary insufficiency and hypogonadism, iron excess is also associated with aggravation of the cytotoxic effects exerted on hepatocytes by other agents such as alcohol or hepatotrophic viruses. The treatment of iron overload in GH consists of weekly venesection until the serum ferritin level is normalized, followed by maintenance therapy. Survival rates are normal if the disease is detected and treated before complications have developed.
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PMID:[Defective iron metabolism in genetic hemochromatosis. The mechanisms remain unknown in spite of genetic advances]. 972 62

Primary, hereditary or genetic haemochromatosis is one of the most common inherited disorders in a Caucasian populations with a disease frequency of 1:300-400 and a carrier frequency of approximately 10%. The basic genetic defect remains unknown, although the haemochromatosis gene has now been cloned and is known to be a member of the MHC non-classical class I family. Many factors--environmental, genetic and non-genetic in nature--influence the degree of iron loading in affected individuals. In particular, pathological and physiological blood loss influence iron stores in haemochromatosis. The iron concentration in the liver is an important determinant of survival because a hepatic iron concentration in excess of 400 mumol/g dry weight is usually associated with cirrhosis. Patients with cirrhosis secondary to haemochromatosis are at risk of hepatocellular carcinoma. The combination of improved awareness of the disease and the appropriate use of genetic testing for the common C282Y mutation should lead to earlier diagnosis and therapy.
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PMID:Haemochromatosis. 989 69

The hepatitis B virus (HBV) is a coated, incompletely double-stranded DNA virus with some outstanding features. (1) All three coat proteins of HBV contain HBsAg, which is highly immunogenic inducing anti-HBs. These antibodies are protective for HBV outer cells (humoural immunity). Structural viral proteins induce specific T-lymphocytes, which are able to eliminate HBV-infected cells (cytotoxic T-cells; cellular immunity). (2) Intracellular HBV primarily causes little or no damage (non-cytopathogenic), which is an excellent strategy of viral survival. However, viral oligo-peptides of 8-15 amino acids are loaded on host cell MHC-class 1 molecules and are transported to the cell surface. Thus, HBV-specific T-lymphocytes are able to detect infected cells and destroy them, an ingenious defence strategy. However, this cell deletion triggered by inflammation cells may result in acute hepatitis. If HBV is not eliminated, a delicate balance between viral replication and immunodefence prevails which may lead to chronic hepatitis and liver cirrhosis. (3) In chronically infected cells HBV may become partly cytopathogenic--a process still poorly understood--and the viral DNA may integrate into the host cell DNA (through a viral transcriptase). If integration leads to activation of crucial host genes a hepatocellular carcinoma results. These outstanding features are responsible for the highly variable course of HBV infection and its final outcome, e.g. when the load of HBV-infected cells is still low at the time when an efficient immune defence starts, the infection is self-limited and asymptomatic, and immunity results. When there is no immune defence or a defective immune defence (immune tolerance of new-borns or immunosuppressed individuals) the HBV infection very often becomes chronic. In these cases, no acute hepatitis occurs, but hepatocellular carcinoma may result. Treatment with Interferon has become accepted, resulting in up to 30 to 40% of cases in the elimination of the virus. However, treatment is laborious and expensive, and the mechanism of action is still poorly understood (anti-viral and/or immune-modulating).
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PMID:Hepatitis B: virus, pathogenesis and treatment. 991 26

Hereditary haemochromatosis (HHC) is a common inherited disorder of iron metabolism characterised by progressive iron loading of parenchymal cells of the liver, pancreas, heart and other organs ultimately leading to cirrhosis and organ failure. Despite HLA studies which localised the defective gene to the short arm of chromosome 6, the haemochromatosis gene remained elusive until 1996, when the gene was identified by a massive positional cloning effort. The haemochromatosis gene (HFE) encodes a novel nonclassical MHC class-1-like molecule. Two missense mutations have been identified in patients with HHC, a G to A at nucleotide 845, resulting in a substitution of tyrosine for cysteine at amino acid 282 (referred to as the C282Y mutation) and a C to G at nucleotide 187, resulting in a substitution of aspartate for histidine at amino acid 63 (H63D). An average of 85-90% of patients with typical clinical features of HHC are homozygous for the C282Y mutation. H63D is not associated with the same degree of iron loading as C282Y. Clinical expression is variable depending on environmental (dietary) iron, physiological and pathological blood loss and as yet unidentified modifying genetic factors. One recent Australian study indicates that only about 50% of homozygous subjects are fully expressing and symptomatic and that about 30% show no clinical or biochemical expression. Genetic tests for identifying mutations in the HFE gene provide precise means for diagnosis, family testing and population screening and have led to re-evaluation of the indications for liver biopsy in this disease. At the present time, however, the most practical and cost-effective method of screening is for phenotypic expression by transferrin saturation or unsaturated iron binding capacity measurement. In the future, population screening by genotype should be feasible once the relevant technical, legal and ethical issues are resolved.
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PMID:Haemochromatosis in the new millennium. 1072 94


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