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Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe liver fibrosis caused by iron overload after a long history of blood transfusion in a patient with chronic renal failure. Pertinent laboratory data were: serum (s)-Fe 148 microg/dl; unsaturated iron binding capacity (UIBC) 14 microg/dl; s-ferritin 9350 ng/ml; human leukocyte antigen (HLA) A2, A24, B39, B55, Cw1, Cw7. Computed tomography revealed a high density in the liver, and laparoscopy revealed a brown liver. Liver histology showed bridging fibrosis from portal tracts. A heavy iron deposit was seen in Kupffer cells as well as in hepatocytes surrounded by fibrosis around the portal tracts. Immunocytochemistry revealed alpha-smooth muscle actin in many stellate cells distributed along the fibrotic area, and electron microscopy revealed infiltrating myofibroblastic stellate cells coexisting with collagen fibers around degenerated hepatocytes containing iron deposits. The findings are consistent with the notion that stellate cells play an important role in liver fibrogenesis in both genetic and transfusional iron overload hemochromatosis.
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PMID:Activated hepatic stellate cells participate in liver fibrosis in a patient with transfusional iron overload. 977 45

The aim of this study was to investigate whether an iron chelator, deferoxamine (DFO) can prevent lipid peroxidation, resulting in reduced liver injury as well as reducing preneoplastic lesions induced by a choline-deficient L-amino acid-defined (CDAA) diet. CDAA diet administration resulted in an increased serum ALT level (367 +/- 58) after two weeks, but simultaneous DFO treatment for two weeks reduced this elevation of ALT as well as malondialdehyde (MDA) production in the liver. Feeding rats a CDAA diet for 12 weeks led to the development of severe liver fibrosis and preneoplastic lesions detected as enzyme-altered lesions. DFO treatment prevented the expression of activated stellate cells, resulting in the reduction of liver fibrosis as well as reducing the development of preneoplastic lesions. These results indicate that iron chelation can reduce the development of preneoplastic lesions in a CDAA diet model.
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PMID:Iron chelator deferoxamine reduces preneoplastic lesions in liver induced by choline-deficient L-amino acid-defined diet in rats. 1008 Jan 51

Steatosis is a frequent histological finding in chronic hepatitis C infection; however, the pathophysiology of steatosis and its role in disease progression have not been established. We studied 148 consecutive patients with untreated chronic hepatitis C to assess the effect of body mass index, diabetes mellitus, alcohol consumption, hepatic iron content, and viral load on steatosis and hepatic fibrosis. Ninety-one patients (61%) had steatosis: grade 1 (<30% hepatocytes involved) in 61 (41%), grade 2 (30%-70% hepatocytes involved) in 17 (11%), and grade 3 (>70% hepatocytes involved) in 13 (9%). After adjusting for potential confounding variables, a highly significant relationship was found primarily between steatosis and body mass index (P <.0001). The mean (+/-SD) body mass index of patients with no steatosis was 23.9 +/- 4.3 kg/m2, whereas for grade 1 steatosis it was 26.5 +/- 5.1 kg/m2, and for grade 2 and 3 steatosis combined the body mass index was 28.4 +/- 4. 9 kg/m2. Hepatic fibrosis was significantly associated with age (P =. 002). After adjusting for potential confounding variables, including age, hepatic fibrosis was also significantly associated with steatosis (P <.03). There was no significant association between hepatic iron content, alcohol intake, gender, and viral load and steatosis or fibrosis. These findings suggest that increasing body mass index has a role in the pathogenesis of steatosis in chronic hepatitis C and that steatosis may contribute to fibrosis. The association between body mass index and steatosis and fibrosis has important prognostic and therapeutic implications in the management of patients with chronic hepatitis C virus.
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PMID:Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. 1061 Mar 53

The aim of this study was to set up an in vitro model for studying the importance of an altered extra-cellular matrix composition and its importance for the resistance to oxidative stress, in hepatocytes from normal and iron loaded rats. Primary cultures of hepatocytes from iron loaded and normal rats were plated on a laminin rich extracellular matrix or on collagen type I, and incubated with tert-butyl hydroperoxide (TBH). Malon dialdehyde (MDA) and the activities of lactate dehydrogenase (LDH) in cell culture medium were analyzed. The protein synthesis, the concentrations of glutathione and the expression of manganese-superoxide dismutase and ferritin genes were measured. All hepatocytes contained lower concentrations of glutathione when plated on collagen than on EHS. Ferritin H and Mn-SOD gene expression showed no difference. The rate of lipid peroxidation in iron loaded hepatocytes exposed to TBH was higher on collagen than in those plated on EHS (0.95 +/- 0.28 microM MDA vs. 1.62 +/- 0.22 microM MDA, p < 0.05). Iron loaded cells were in general more susceptible to TBH than were normal hepatocytes (MDA, LDH, protein synthesis and glutathione content). Lipid peroxidation could be prevented by adding desferrioxamine. In conclusion, we show that the combination of iron overload and collagen matrix in rat hepatocytes leads to an increased susceptibility to oxidative stress. These findings may be of interest for the further studies on effects of iron overload and the altered matrix composition in liver fibrosis.
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PMID:Susceptibility of cultured rat hepatocytes to oxidative stress by peroxides and iron. The extracellular matrix affects the toxicity of tert-butyl hydroperoxide. 1022 73

Chronic hepatitis C is often associated with liver iron overload, which may affect the long-term prognosis and the response to antiviral treatment. The occurrence of hemochromatosis (HFE) mutations were studied to determine whether may contribute to the liver iron overload of chronic hepatitis C patients. The prevalence of two HFE mutations (C282Y and H63D) in 120 chronic hepatitis C patients was determined and the findings were correlated with clinical, histological and virological features. Hepatic iron was determined semiquantitatively by a histochemical hepatic iron index, defined as the ratio of a histochemical staining score to the patient's age, after correction for heterogeneous lobular iron distribution. Serum hepatitis C virus (HCV) RNA was measured by bDNA assay and typed by restriction fragment length polymorphism. Liver HCV RNA was measured by a semi-quantitative strand-specific reverse transcription-polymerase chain reaction (RT-PCR). Excess liver iron was stained in the liver of 36 patients (30%). Siderotic patients had the same geographic origin, serum and liver HCV RNA levels and H63D and C282Y mutations frequency as non-siderotic patients. However, siderotic patients were older (P = 0.015), more frequently males (P = 0.02), less frequently infected with HCV genotype 3 (P = 0.037) and had a higher liver fibrosis score (P = 0.008). The liver iron content did not correlate with the serum or liver HCV RNA titers. Ten of the 36 patients with liver siderosis had neither a history of excess alcohol intake, multiple transfusions, or HFE mutations. In conclusion, the pathogenesis of the liver iron overload in chronic hepatitis C patients cannot be fully explained by the occurrence of HFE mutations. The exact mechanism of iron accumulation in these patients therefore remains unexplained.
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PMID:Hemochromatosis gene mutations in chronic hepatitis C patients with and without liver siderosis. 1056 58

Nonalcoholic steatohepatitis (NASH) may present with increased hepatic fibrosis progressing to end-stage liver disease. No factors that determine increasing fibrosis and histologically advanced disease have been recognized, thus, liver biopsy is recommended in all patients for diagnosis and prognosis. Our aim was to identify independent predictors of severe hepatic fibrosis in patients with NASH. One hundred and forty-four patients were studied. All patients underwent liver biopsy. Clinical and biochemical variables were examined with univariate and multivariate analysis. Thirty-seven (26%) patients had no abnormal fibrosis, 53 (37%) had mild fibrosis, 15 (10%) had moderate fibrosis, 14 (10%) had bridging fibrosis, and 25 (17%) had cirrhosis. In multivariate analysis, older age (P =. 001), obesity (P =.002), diabetes mellitus (P =.009), and aspartate transaminase/alanine transaminase (AST/ALT) ratio greater than 1 (P =.03) were significant predictors of severe liver fibrosis (bridging/cirrhosis). Body mass index (P =.003) was the only independent predictor of the degree of fat infiltration. Increased transferrin saturation correlated positively with the severity of fibrosis (P =.02) in univariate analysis, and there was a trend for more female patients among those with more advanced fibrosis (P =. 09). However, iron studies or gender were not significant when controlled for age, obesity, diabetes, and AST/ALT ratio. In conclusion, older age, obesity, and presence of diabetes mellitus help identify those NASH patients who might have severe liver fibrosis. This is the subgroup of patients with NASH who would be expected to derive the most benefit from having a liver biopsy and considering investigational therapies.
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PMID:Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. 1057 11

A unique organic form of iron (dicyclopentadienyl iron; ferrocene) has been used to further elucidate specific hepatic histopathologic, biochemical, and molecular parameters associated with dietary iron overload. Male C57BL/6Ibg mice fed a diet containing 0.04-0.2% w/w ferrocene for 115 days displayed severe hepatic siderosis of hepatocytes accompanied by a 15-fold induction of nonheme iron content compared to control mice receiving a diet with normal amounts of iron. The ferrocene treatment led to significant increases in hepatocellular necrosis as measured by plasma alanine aminotransferase activity. Histological assessment of hepatic fibrosis revealed mild increases in collagen deposition localized with accumulations of hemosiderin primarily in centrilobular hepatocytes. Hepatic fibrosis was confirmed by measurement of hepatic hydroxyproline content that was increased 4-fold in ferrocene-fed animals compared to control animals not ingesting ferrocene. Hepatic siderosis was accompanied by significant increases in hepatic malondialdehyde content suggesting the ferrocene-induced iron burden initiated lipid peroxidation in vivo. Expression of the heavy-chain isoform of ferritin mRNA and protein measured in liver after ferrocene feeding was increased approximately 8- and 2-fold, respectively, compared to the appropriate controls. These results, using an organic form of iron fed to genetically well-characterized inbred mice, provide new additional insight into the specific molecular and biochemical events that occur in association with histopathologic changes initiated by iron-induced liver injury. These data support the hypothesis that peroxidation of cellular membrane lipids is an important mechanism involved in the toxicity of excess hepatic iron and possibly the initiation of liver fibrogenesis. The results presented here also provide novel in vivo evidence documenting the cellular modulation of ferritin in response to the toxic effects of hepatic iron overloading and iron-mediated oxidative stress.
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PMID:Characterization of hepatic iron overload following dietary administration of dicyclopentadienyl iron (Ferrocene) to mice: cellular, biochemical, and molecular aspects. 1064 Apr 49

Genetic hemochromatosis is an autosomal recessive disease, characterized by an increased iron absorption, leading to progressive iron overload. The fully expressed phenotype comprises fatigue, skin pigmentation, liver disease with hepatomegaly, cirrhosis and hepatocellular carcinoma, and diabetes. Arthralgias are frequent, cardiopathy or impotence may occur. This presentation is now unfrequent with earlier diagnosis, and patients are often asymptomatic--with only biochemical expression--or pauci-symptomatic (mild fatigue, arthralgias or increased transaminases). Transferrin saturation is always increased. Serum ferritin is proportional to iron burden. Diagnosis is now easy, since most patients are homozygote for the C282Y mutation of the HFE gene. Liver biopsy can be useful to quantify iron overload and assess liver fibrosis. The disease can be lethal due to liver disease, carcinoma or heart disease, but life expectancy goes to normal if patients are treated before the occurrence of cirrhosis. Treatment relies on regular venesections. Familial screening is essential.
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PMID:[Diagnosis and treatment of genetic hemochromatosis]. 1086 97

In the liver, the progressive accumulation of connective tissue, a complex and dynamic process termed fibrosis, represents a very frequent event following a repeated or chronic insult of sufficient intensity to trigger a "wound healing"-like reaction. The fibrotic process recognises the involvement of various cells and different factors in bringing about an excessive fibrogenesis with disruption of intercellular contacts and interactions and of extracellular matrix composition. However, Kupffer cells, together with recruited mononuclear cells, and hepatic stellate cells are by far the key-players in liver fibrosis. Their cross-talk is triggered and favoured by a series of chemical mediators, with a prominent role played by the transforming growth factor beta. Both expression and synthesis of this inflammatory and pro-fibrogenic cytokine are mainly modulated through redox-sensitive reactions. Further, involvement of reactive oxygen species and lipid peroxidation products can be clearly demonstrated in other fundamental events of hepatic fibrogenesis, like activation and effects of stellate cells, expression of metalloproteinases and of their specific inhibitors. The important outcome of such findings as regards the pathogenesis of liver fibrosis derives from the observation of a consistent and marked oxidative stress condition in many if not all chronic disease processes affecting hepatic tissue. Hence, reactive oxidant species likely contribute to both onset and progression of fibrosis as induced by alcohol, viruses, iron or copper overload, cholestasis, hepatic blood congestion.
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PMID:Pathogenesis of liver fibrosis: role of oxidative stress. 1097 99

Severe hemolytic anemia in Basenji dogs secondary to pyruvate kinase (PK) deficiency can be corrected by marrow allografts from healthy littermates after a conventional high-dose myeloablative conditioning regimen. The nonmyeloablative conditioning regimen used here, which consisted of a sublethal dose of 200 cGy total body irradiation before and immunosuppression with mycophenolate mofetil and cyclosporine after a dog leukocyte antigen (DLA)-identical littermate allograft, has been found to be effective in establishing stable mixed donor/host hematopoietic chimerism in normal dogs. We explored the feasibility of nonmyeloablative marrow allografts for the treatment of canine PK deficiency and studied the effect of stable allogeneic mixed hematopoietic chimerism on the natural course of the disease. Five affected dogs received transplants, of which 3 dogs had advanced liver cirrhosis and myelofibrosis. Both complications were presumed to be due to iron overload. All 5 dogs showed initial engraftment. Two rejected their grafts after 6 weeks but survived with completeautologous marrow recovery and return of the disease. One died from liver failure on day 27 with 60% donor engraftment. Two dogs have shown sustained mixed donor/host chimerism for more than a year with 85% and 12% donor hematopoietic cells, respectively. Overall clinical response correlated with the degree of donor chimerism. The dog with the low degree of chimerism achieved partial resolution of hemolysis, but the disease symptoms persisted as manifested by increasing iron overload resulting in progression of marrow and liver fibrosis. The dog with the high degree of donor chimerism achieved almost complete resolution of hemolysis with a decrease of marrow iron content and resolution of marrow fibrosis. These observations suggest that mixed hematopoietic chimerism can be relatively safely established in dogs with PK deficiency even in the presence of advanced liver cirrhosis. However, although effective in correcting or delaying the development of myelofibrosis, a low degree of mixed chimerism was not sufficient to prevent continued hemolysis of red blood cells of host origin. Complete donor chimerism appears necessary to achieve a long-term cure.
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PMID:Severe canine hereditary hemolytic anemia treated by nonmyeloablative marrow transplantation. 1121 93


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