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The pathogenesis of hepatitis B virus (HBV) infection is variable and can result in the development of acute and chronic hepatitis, cirrhosis and primary hepatocellular carcinoma (PHC). In this review, the relationship between the patterns of virus gene expression, host immunological responses, and liver pathology in chronic infection will be discussed. Available evidence suggests that the virus is not directly cytopathic to liver cells and that the pathologic sequelae to infection are mediated by both humoral and cellular immune responses against one or more virus gene products. In addition, chronic liver disease might also be mediated by autoaggressive immune responses that may be stimulated by the direct action of virus gene products upon host gene expression, by the lysis of infected hepatocytes by virus specific host immune responses, or by both. Given the complex and variable outcome of HBV infection, the lack of adequate treatment for chronic liver disease, and the fact that long-term infection dramatically increases the risk of developing PHC, the future provides challenges for devising new models to study, understand and successfully manipulate the pathogenesis of chronic HBV infection.
Mol Biol Med 1989 Oct
PMID:Hepatitis B virus gene products as immunological targets in chronic infection. 269 58

The purpose of this study was to compare the serological analysis for hepatitis C infection using the recombinant immunoblot assay (RIBA) to the direct in situ localization of the hepatitis C viral genome using the reverse transcriptase (RT) in situ PCR technique. Concurrent sera and liver biopsies from 42 patients with clinical and histologic evidence of chronic liver disease were studied. Antibodies against hepatitis C specific antigens were demonstrated by RIBA in the sera of 39/42 (92%), and PCR amplified viral cDNA was detected in the biopsies of 21 (54%) of the 39 seropositive patients. The detection rate using standard in situ hybridization for the tissues known to be viral positive with RT in situ PCR was 9/21 (42%). It is concluded that approximately one-half of patients with chronic hepatitis and serologic evidence of hepatitis C infection will not have virus detectable in their liver biopsy even with a highly sensitive PCR-based technique.
Diagn Mol Pathol 1995 Jun
PMID:Comparison of serologic analysis and in situ localization of PCR-amplified cDNA for the diagnosis of hepatitis C infection. 755

Primary Biliary Cirrhosis (PBC) is a chronic liver disease of unknown aetiology. The main characteristic feature of the disease is the presence of circulating antimitochondrial antibodies (AMA) to components (collectively named M2) of the mitochondrial 2-oxo-acid multienzyme complexes; pyruvate, oxoglutarate and branched chain oxo-acid dehydrogenase complexes. As these enzymes are phylogenetically conserved, AMA also exhibit reactivity against a range of microorganisms. PBC patients have an increased incidence of recurrent urinary tract infection (UTI) compared to other chronic liver disease controls. Interestingly, we have recently detected low titre AMA in patients with a history of recurrent UTI but normal liver function using crude bovine heart mitochondrial preparations and immunoblotting techniques. Here we confirm these findings using purified M2 antigens and ELISA. We found that 52% of "normal" subjects with a history of recurrent UTI had AMA specifically to M2 antigens. The percentage was significantly higher than that found for chronic liver disease (19%, p < 0.01) and normal controls (4%, p < 0.001). These results support our hypothesis for molecular mimicry in PBC. We propose that a bacterial trigger, possibly resulting from recurrent UTIs, is responsible for initiating an autoimmune response in a predisposed host because of a cross-reactivity between mitochondrial and bacterial antigens.
Biochem Mol Biol Int 1995 Mar
PMID:Detection of M2 antibodies in patients with recurrent urinary tract infection using an ELISA and purified PBC specific antigens. Evidence for a molecular mimicry mechanism in the pathogenesis of primary biliary cirrhosis? 777 84

In order to evaluate the pathogenetic role of iron in Porphyria cutanea tarda (PCT), the metabolism of iron was studied in 440 patient with PCT and associated chronic liver disease (CLD) and in 91 nonporphyric CLD patients (used as a control group). The parameters considered were the following: serum iron, ferritin, Total Iron Binding Capacity (TIBC) and percent saturation of transferrin. The statistical analysis showed that the differences between the means, in the two groups, were not significant in any of the parameters examined. To investigate the possible relationships between iron metabolism and other chemico-clinical parameters concerning the porphyric disease, the associated hepatic disease and hemometry, we studied the correlations between iron parameters and total urinary and serum porphyrins, serum copper, serum albumin, hemoglobin, red blood cells, ALT, AST, CHE and GLDH. This investigation was only possible in the last 99 cases. In addition to the obvious correlations between the parameters concerning iron metabolism, the highly significant (p < 0.001) correlation between ferritin and enzyme activities which indicate cytolysis (ALT, AST, GLDH) is extremely interesting. The results seem to point to the tentative conclusion that the alterations of iron metabolism are more related to the hepatocellular necrosis than to the metabolism of porphyrins.
Cell Mol Biol (Noisy-le-grand) 1997 Feb
PMID:Iron and porphyria cutanea tarda. 907 91

Plasma collagen-binding vitronectin was assayed in 62 patients with chronic liver disease and 14 healthy control subjects. It was measured by an enzyme immunoassay using type I collagen and monoclonal antibody to vitronectin before and after treatment with heparin or dextran sulfate in vitro. The pretreatment level of plasma collagen-binding vitronectin (mean +/- S.E.M.) was 5.5 +/- 0.5 micrograms/ml in the controls, 8.2 +/- 0.3 micrograms/ml in chronic persistent hepatitis, 8.3 +/- 0.7 micrograms/ml in chronic active hepatitis, 7.9 +/- 0.7 micrograms/ml in liver cirrhosis, and 8.2 +/- 0.5 micrograms/ml in hepatocellular carcinoma with cirrhosis. After treatment with heparin, the percent collagen-binding vitronectin to total vitronectin was 20.6 +/- 2.0% in the controls, 24.7 +/- 4.1% in chronic persistent hepatitis, 28.6 +/- 2.5% in chronic active hepatitis, 42.6 +/- 4.5% in liver cirrhosis, and 31.8 +/- 2.3% in hepatocellular carcinoma. All percents were significantly increased compared to the pretreatment percent. The same pattern was also found after dextran sulfate treatment. Compared to that in the pretreatment state, the collagen-binding vitronectin after these treatments was more closely correlated with the serum levels of 7S collagen and hyaluronic acid. These results suggest that the collagen-binding activity of vitronectin may play an important role in the progression of liver disease and/or fibrosis through its activation with some glycosaminoglycans.
Res Commun Mol Pathol Pharmacol 1997 Sep
PMID:Plasma collagen-binding vitronectin activated by heparin and dextran sulfate in chronic liver disease. 938 91

Hyaluronate in tissue and lymph is known to be heterogenous and to show a wide range of molecular weights (10(4) to 10(7) Da). Serum hyaluronate concentrations are increased under various pathophysiological conditions such as liver disease, post-gastrectomy, and after the ingestion of food. To clarify whether the chromatographic patterns of hyaluronate in serum from patients with chronic liver disease are different under these conditions, we subjected sera to chromatography using a Sephacryl S 400 HR column. The chromatograms revealed that the hyaluronate in serum was eluted as a single peak at the position corresponding to the molecular weight of blue dextran, the molecular weight being more than 2 x 10(6) Da. The patterns of the chromatogram were similar among the patients with liver disease and the healthy subject although the heights of the peaks were different. Ingestion of food and a history of gastrectomy for gastric cancer did not influence the elution patterns of serum hyaluronate. These results indicate that hyaluronate in serum has molecular weight of more than 2 x 10(6) Da, and that its elution patterns are not influenced by pathophysiological factors, such as the severity of liver disease, or history of gastrectomy or by food intake in patients with chronic liver disease.
Res Commun Mol Pathol Pharmacol 1998 Feb
PMID:Molecular weight of hyaluronate in the serum of patients with chronic liver disease. 958 94

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide and the leading indication for liver transplantation. The hallmark of the disease is its propensity to evolve into chronicity, probably because viral heterogeneity allows the virus to escape immune-mediated neutralization. Treatment with interferon alpha (IFN-alpha) has been disappointing, but higher and more frequent doses, and combination therapies, including nucleoside analogs, might lead to improved suppression of HCV RNA levels. Molecular analysis of HCV before and during treatment has indicated that high viral RNA levels and the presence of HCV genotype 1 are independent predictors of poor treatment outcome. New antiviral agents in development include inhibitors of HCV replicative enzymes, such as protease, helicase and polymerase, as well as several genetic approaches, such as ribozymes and antisense oligonucleotides. The main hindrance to drug development for hepatitis C is the lack of a small animal model or a productive tissue culture system for assessing drug action.
Mol Med Today 1999 Sep
PMID:Hepatitis C virus: current understanding and prospects for future therapies. 1046 51

The possible role of iron in facilitating the development of liver cancer is still debated. The aims of this study were to define the prevalence of the mutations 845G --> A and 187C --> G (C282Y and H63D) in the HFE gene associated with hereditary hemochromatosis in Italian patients with hepatocellular carcinoma occurring in cirrhosis and to analyze the interaction between these mutations and other established risk factors for hepatocellular carcinoma. The HFE gene mutations, performed by polymerase chain reaction, were analyzed in 81 patients (63 males, 18 females) with hepatocellular carcinoma. None of the patients had a phenotype compatible with homozygous hereditary hemochromatosis. Interaction between HFE mutations and exogenous risk factors was analyzed by collecting information on alcohol consumption, hepatitis B and C virus infections, and iron status at the time of diagnosis of chronic liver disease. This analysis was performed only in males to rule out gender influence on patients' iron status by using the case-only approach specifically designed to estimate departure from multiplicative risk ratios under the assumption of independence between genotype and environmental exposure. The prevalence of the C282Y mutation was significantly higher in patients with hepatocellular carcinoma than in normal controls (8.6% vs 1.6%, P < 0.03). At univariate analysis, iron overload was significantly associated with both HFE mutations (P < 0.0001), whereas ongoing hepatitis B virus infection was associated with the C282Y mutation (P < 0.05). By multivariate analysis, a trend for an increased risk of being positive for hepatitis virus markers (OR 2.9, CI 95% 0.9-9.5) and of having been alcohol abusers (OR 3, CI 95% 0.7-14) was observed in patients heterozygous for the HFE mutations. These data indicate that the prevalence of the main mutation associated with hereditary hemochromatosis is significantly higher in cirrhotic Italian patients with hepatocellular carcinoma compared to a normal population and suggest that heterozygotes for HFE mutations exposed to hepatitis virus infections or who had been alcohol abusers could have an increased risk of developing cirrhosis and later liver cancer than people without the mutations exposed to the same risk factors.
Blood Cells Mol Dis
PMID:Mutations in the HFE gene and their interaction with exogenous risk factors in hepatocellular carcinoma. 1150 61

TT viruses have recently been reported in serum samples from varying percentages of human blood donors and in patients with chronic liver disease. However, no association with human pathology has yet been reported. In a pilot study we analysed 162 biopsy specimens from various human cancers and from colon polyps for the presence of TT virus related sequences by polymerase chain reaction using three sets of nested primers for TT virus detection. All gels were subjected to Southern blot hybridisation, and DNA from hybridising bands was cloned and sequenced. A total of 54.3% of tumour specimens contained identifiable TT virus related sequences. Specimens from hypopharynx, larynx, endometrial, ovarian and bladder cancers were 14-35% positive and gastrointestinal cancers (oesophagus, stomach, colon, rectum) and colon polyps 57-100% positive. Lung cancers (68.4%), mammary cancers (50%), multiple myelomas (85.7%) and human leukaemias (53.3%) also revealed a high prevalence of TT virus related sequences. Since normal control tissues were not available for the tumour biopsy specimens tested, these data do not permit conclusions concerning a possible causal relationship between the virus infections and carcinogenesis. Another aspect, however, deserves attention: the heterogeneity of TT virus clones obtained from the specimens tested here was striking: 66 novel sequences, probably belonging to new types were identified. Only 16 clones corresponded by more than 97% of their sequences to established prototypes. Even individual tumours commonly contained sequences substantially diverging in nucleic acid composition. Up to five different types were identified within an individual tumour. The high variability of these virus types suggests that additional primer combinations within the highly conserved region of the genome would detect a still higher rate of positive tumours.
J Mol Med (Berl) 2002 Jan
PMID:Heterogeneity of TT virus related sequences isolated from human tumour biopsy specimens. 1186 24

Mutations in the Wilson disease gene ATP7B, a P-type ATPase, are responsible for copper accumulation in the liver and other organs leading to Wilson disease (WD, OMIM 277900). Clinical manifestations of Wilson disease (WD) include chronic liver disease, acute hepatic failure or neuropsychiatric diseases. Since potent medical treatments are available to prevent disabling residual symptoms, early diagnosis is crucial. To demonstrate the clinical course and genetic findings, a male patient with a novel mutation in the ATP7B gene, a 10 base pair insertion in exon 6 (1927ins 10), and a second missense mutation in exon 13 (P992L) is reported. The patient presented with signs of chronic liver disease at the age of 10 years. Clinical findings included hepatomegaly, elevated liver enzymes and coagulopathy. A combination treatment with the copper chelating agent D-penicillamine and zinc acetate was started leading to normalization of liver function and no appearance of neurological signs or Kayser-Fleischer ring after 7 years follow-up. Truncating mutations of the ATP7B gene (insertions, deletions, nonsense mutations) leading to gross loss of C-terminal parts of the protein, thereby probably completely destroying the protein function, may correlate with a hepatic phenotype and early onset as seen in the patient presented.
Cell Mol Biol (Noisy-le-grand) 2001
PMID:Disturbed copper transport in humans. Part 2: mutations of the ATP7B gene lead to Wilson disease (WD). 1193 61


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