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)

Hepatic fibrosis and cirrhosis are common findings in humans with hemochromatosis. In this study we investigated the molecular pathways of iron-induced hepatic fibrosis and evaluated the anti-fibrogenic effect of vitamin E. Male gerbils were treated with iron-dextran and fed a standard diet or a alpha-tocopherol enriched diet (250 mg/Kg diet). In gerbils on the standard diet at 6 wk after dosing with iron, in situ hybridization analysis documented a dramatic increase of signal for collagen mRNA around iron foci onto liver fat storing cells (FSC), as identified by immunocytochemistry with desmin antibody. After 4 mo, micronodular cirrhosis developed in these animals, with nonparenchymal cells surrounding hepatocyte nodules and expressing high level of TGF beta mRNA. In this group, in vivo labeling with [3H]-thymidine showed a marked proliferation of nonparenchymal cells, including FSC. In iron-dosed gerbils on the vitamin E-enriched diet for 4 mo, in spite of a severe liver iron burden, a normal lobular architecture was found, with a dramatic decrease of collagen mRNA accumulation and collagen deposition. At the molecular level, a total suppression of nonparenchymal cell proliferation was appreciable, although expression of collagen and TGF beta mRNAs was still present into microscopic iron-filled nonparenchymal cell aggregates scattered throughout the hepatic lobule. In conclusion, our study shows that anti-oxidant treatment during experimental hepatic fibrosis arrests fibrogenesis and completely prevents iron induced hepatic cirrhosis mainly through inhibition of nonparenchymal cell proliferation induced by iron.
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PMID:Molecular and cellular aspects of iron-induced hepatic cirrhosis in rodents. 770 89

Following the pioneer report of Di Luzio (Physiologist 6, 169-173, 1963) concerning the prevention of the acute ethanol-induced fatty liver by antioxidants, many observations have shown that ethanol-induced liver injury may be linked, at least partly, to an oxidative stress resulting from increased free radical production and/or decreased antioxidant defence. The disturbances induced in the major hepatic enzymatic and non-enzymatic antioxidant systems following experimental acute and chronic ethanol administration are reviewed, emphasizing the important role of dietary alpha-tocopherol in modifying the induction of oxidative stress and its usual expression as increased lipid peroxidation. Adaptative increases in some elements of the hepatic antioxidant defence partly counteract the enhanced generation of prooxidant free radicals following chronic ethanol intake. By contrast, lipid peroxidation is favoured when ethanol is administered together with a fat-rich diet and/or various xenobiotics. Chronic ethanol feeding has also been reported to potentiate the oxidative stress resulting from an acute ethanol load. By generating potent chemoattractants for human neutrophils and/or by stimulating the expression of genes involved in collagen biosynthesis, liver lipid peroxidation may play an important role in the progression of steatosis to hepatitis and cirrhosis. Oxidative stress has been shown not to be restricted to the liver, but also to affect, under some experimental conditions of ethanol administration, extrahepatic tissues, such as the central nervous system, the heart and the testes. This stress can be partly prevented by vitamin E supplementation. Ethanol-induced antioxidant disturbances have also been reported in clinical studies in blood and liver biopsies. Pharmacological antioxidants could have beneficial effects in reducing the incidence of ethanol-induced changes in cellular lipids, proteins and nucleic acids. The antioxidants considered could act by reducing free radical production (e.g. chelators of redox-active iron derivatives), trapping free radicals themselves, interrupting the peroxidation process or reinforcing the natural antioxidant defence.
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PMID:Alcohol and antioxidant systems. 781 35

The RRR-alpha-tocopherol (vitamin E) content in plasma from 46 patients with liver diseases and 23 healthy controls was determined by high performance liquid chromatography and electrochemical detection. Patients were divided into three groups: alcoholic liver diseases (n = 17; group A), hemochromatosis (n = 17; group B) and Wilson's disease (n = 12; group C). Lipid-standardized alpha-tocopherol levels were determined to neutralize differences due to hyperlipemia. The ratio of serum vitamin E to serum lipids (cholesterol, triglycerides, phospholipids) was highest in healthy controls and in patients in group A with cirrhosis and normal transaminases and bilirubin. Patients in group A with acute or chronic ethanol intoxication and high bilirubin levels had a 37% lower lipid-standardized vitamin E level than controls. Patients in group B with hemochromatosis, showing high serum iron (> 180 micrograms/dl), a low free iron binding capacity (< 8 mumol/l) and high ferritin-levels (< 450 micrograms/l), had a 34% lower vitamin E/lipid ratio than healthy controls. No significant lowering of the vitamin E/lipid ratio was observed in the other patients in group B. A significant decrease (37%) in the vitamin E/lipid ratio was only detectable in patients with Wilson's disease (group C) showing high free serum copper (> 10 micrograms/dl). The data support a role for free radicals in the pathogenesis of active liver diseases.
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PMID:Low vitamin E content in plasma of patients with alcoholic liver disease, hemochromatosis and Wilson's disease. 781 21

Nutritional assessment and adequacy of spontaneous dietary intake was evaluated in thirty-seven clinically stable hospitalized patients with alcoholic liver cirrhosis. About two-thirds of the patients had ascites or oedema, or both, and, therefore, body weight could not be used for assessment of nutritional status. Lean body mass (LBM; measured by three consecutive 24 h creatinine excretions) was 62 (range 40-95)% of reference values, mid-arm-muscle area (MAMA) was 70 (range 43-115)% and triceps skinfold (TSF) was 45 (range 20-113)% of reference values (all median values). In patients without ascites or oedema, or both, there was a rectilinear correlation between body weight and LBM and between body weight and MAMA (r 0.93 and 0.85 respectively). In patients with ascites or oedema, or both, the correlation between body weight and LBM was poor as could be expected. We suggest that LBM is a useful measure of nutritional status when body weight is unreliable because of ascites or oedema, or both. Energy balance for the group was calculated from energy intake recorded by a 24 h dietary recall and energy expenditure calculated by the factorial method. Median intake was 102 (range 34-176)% of expenditure. N loss was calculated from the average of three 24 h urea excretions. Protein intake was calculated from the 24 h dietary recall. The N balance was positive in the patients as a group (median intake was 120 (range 26-183)% of output). The most malnourished patients tended to have the most positive N balance which was due to a significantly lower N excretion. The protein requirement for N balance was 0.83 (SE 0.05) g/kg per d and only at an intake above 1.20 g/kg per d were all patients in positive N balance. The median intakes of thiamin, folacin, vitamin D, vitamin E, Mg, and Zn were judged to be insufficient. It is concluded that impaired nutritional status is common among patients with liver cirrhosis, even in a stable clinical condition. It is suggested that nutritional status in these patients is evaluated by dietary recalls, in combination with measurement of body weight in patients without ascites or oedema, or both, or in combination with determination of LBM by three 24 h creatinine excretions in patients with ascites or oedema, or both. Criteria for selection of patients that might benefit from nutritional therapy are discussed.
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PMID:Nutritional assessment and adequacy of dietary intake in hospitalized patients with alcoholic liver cirrhosis. 832 43

Chronic ethanol consumption is associated with increased incidence of a variety of illnesses, including cancer. Studies have shown that ethanol consumption may result in increased oxidative stress with formation of lipid peroxides and free radicals. The susceptibility of a given tissue to peroxidation is, however, a function of the overall balance between prooxidants and antioxidant defence systems. The latter involve both intracellular and extracellular protective factors were nutrients play an important role. Impaired nutritional status of different vitamins and trace elements have been reported in alcoholics. Reduced levels of vitamin E have been found in serum of alcoholics with and without liver disease and in liver biopsies from alcoholics with cirrhosis. These findings may be due to the increased oxidative stress as reported in experimental animals, and may be of importance since vitamin E is the major, if not the only, lipid-soluble free radical scavenger in some tissues. Reduced antioxidant capacity has been found in several tissues and may promote the generation of free radicals and lipid peroxides which may damage cells directly, induce inflammation and accelerate collagen synthesis. These events may progress to tissue damage and disease. The importance of radicals in cancer initiation and promotion is presently of great interest. The role of lipid peroxides and free radicals in alcohol-related disease and cancer remains unresolved. Further research is required to establish the role of these reactive species in the pathogenesis of alcohol-related disease, and to evaluate the role of nutrition in favour of the antioxidant defence mechanisms.
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PMID:Antioxidant status and alcohol-related diseases. 847 Oct 81

The high incidence of hepatocellular carcinoma (HCC) in cirrhosis, where previous studies have indicated a severe reduction in several antioxidant vitamin factors, prompted us to compare plasma liposoluble vitamins with tocopherol content in healthy and neoplastic liver tissue in humans. This, with a view to a more positive preventive dietary approach, given the conflicting results obtained by liposoluble vitamin dietary supplementation in different malignancies. Eleven patients with cirrhosis, 18 patients affected by cirrhosis with HCC, and 10 patients with liver metastases (LM) from digestive tract adenocarcinomas were compared with controls who had undergone perlaparoscopic cholecistectomy. Plasma alpha- and beta-carotene, retinol and tocopherol, together with liver tocopherol, from both nonmalignant portions and malignant nodules of the same organ, were determined by high-performance liquid chromatography following a well-assessed technique. The results confirm a trend towards a reduction in circulating carotenoids and tocopherol in cirrhosis and in patients affected by cirrhosis with HCC. Tocopherol content in liver tissue is significantly decreased in cirrhosis (0.26 + 0.03 micromol/g prot., mean + SEM, P < .001) and in cirrhotic areas of the HCC group (0.31 + 0.02, P < .002), with respect to its content in liver specimens of healthy controls (0.46 + 0.03) and in healthy areas of the same organ in patients with LM (0.41 + 0.03). Tocopherol concentration is further reduced by 50% in malignant liver nodules of HCC, with respect to surrounding cirrhotic tissue, whereas in metastatic liver nodules from digestive neoplasms the tocopherol content is almost twice that of healthy surrounding areas. This unpredictable tocopherol behavior in liver specimens, of secondary as opposed to primary malignancies of the liver, affords further insight into the conflicting effects of liposoluble vitamins employed in the chemopreventive treatment of different malignant diseases, where hepatic tocopherol concentration show opposite trends: halved in primary HCC and doubled in LM of digestive adenocarcinomas, with respect to healthy controls.
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PMID:Hepatic tocopherol content in primary hepatocellular carcinoma and liver metastases. 921 53

No published reports compare hepatic alpha-tocopherol (adjusted for hepatic lipid content) with indicators of blood alpha-tocopherol in adult patients with various liver diseases. alpha-Tocopherol was simultaneously measured in liver biopsy tissues and blood from 66 subjects (9 comparison patients hospitalized for biliary tract surgery, 13 with chronic persistent hepatitis, 9 with chronic aggressive hepatitis, 10 with acute hepatitis, 10 with cirrhosis, 7 with both cirrhosis and hepatic cell carcinoma, and 8 with fatty liver). Hepatic, erythrocyte, and plasma alpha-tocopherol concentrations were measured, as were hepatic and serum lipids. The ratios of alpha-tocopherol to total lipid concentrations (Toc/TL ratios) in plasma and liver were calculated. In both comparison patients and patients with chronic persistent hepatitis and fatty liver, hepatic alpha-tocopherol concentrations were strongly correlated with hepatic triglyceride and total lipid concentrations (r = .72, P < .001; and r = .75, P < .001, respectively); the relationships (slopes) when hepatic alpha-tocopherol concentrations were compared with hepatic triglyceride and total lipid concentrations were similar in these patients and in all subjects. No strong correlations were found between hepatic and blood alpha-tocopherol parameters in all subjects. These results suggest that hepatic alpha-tocopherol is present at similar concentrations in triglycerides as well as total cholesterol and phospholipids and that neither plasma Toc/TL ratios nor erythrocyte alpha-tocopherol concentrations are useful indicators of hepatic vitamin E status. The hepatic Toc/TL ratio may be useful to assess total hepatic vitamin E status.
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PMID:Assessment of hepatic vitamin E status in adult patients with liver disease. 925 50

The structural elucidation and mechanism of action of a potential component, LLU-alpha, of what is possibly a multifactorial complex known as "natriuretic hormone" was recently reported [Wechter, W.J. et al. (1996a) Proc. Natl. Acad. Sci. U.S.A. 93: 6002-6007]. "Natriuretic hormone," a long-sought factor, is believed to regulate extracellular fluid volume and consequently be pathomimetic for hypertension, cirrhosis, congestive heart failure and other volume expanded states. The studies reported herein further characterize LLU-alpha. The precursor of the endogenous LLU-alpha was demonstrated to be gamma-tocopherol by radiolabeling studies. The pharmacokinetics of infused rac-LLU-alpha proved to be biphasic (half-lives: 12 min and 6 h). Specificity of the inhibition of the 70 pS potassium channel of the thick ascending limb of the loop of Henle was examined with the natural S-enantiomer being the most potent known inhibitor whereas the analogous alpha-tocopherol metabolite, rac-5-Me-LLU-alpha, showed no inhibition. Rac-LLU-alpha does not inhibit two isozymes of the Na+/K+-ATPase. LLU-alpha is natriuretic acting via inhibition of the 70 pS potassium channel and not Na+/K+-ATPase, the assumed mechanism of action of the "natriuretic hormone." LLU-alpha, a metabolite of a vitamin, if it were found to play a role in the regulation of extracellular fluid volume, would be the second example of a vitamin acting as a precursor for a hormone. Of considerable interest is the fact that this manuscript reports the first biological activity of gamma-tocopherol, a member of the vitamin E complex.
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PMID:Endogenous natriuretic factors 7: biospecificity of a natriuretic gamma-tocopherol metabolite LLU-alpha. 926 27

Recent studies demonstrated the role of antioxidants in preventing organ damage caused by free radicals. The present study was conducted to find out the modulatory effect of some antioxidants on lipid patterns in experimentally-induced liver damage. Rats chronically intoxicated with carbon tetrachloride (CCl4) were used as a model of liver injury terminating with fibrosis or cirrhosis. One hundred and sixty six albino rats were classified into five groups: one served as a control group; the second was subjected to oral administration of CCl4 (200 microL/100 g body weight) twice a week; the other three groups, in addition to CCl4, received oral doses of silymarin (30 mg/kg), vitamin E (200 IU/kg) and vitamin C (50 mg/kg) respectively. At the end of the experiment, the animals were killed, blood was collected and liver was taken for histopathological examination. Liver function tests, disturbed by CCl4 were significantly modulated by antioxidants, and histopathological examination showed that antioxidants ameliorated the necrotic and fibrotic changes caused by CCl4. Treatment with antioxidants was also shown to modulate the toxic effect of CCl4 on the lipid profile and malondialdehyde content. Administration of antioxidants could play an important role in prophylaxis against lipid peroxidation and consequently liver fibrosis caused by free radicals.
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PMID:Biochemical effect of antioxidants on lipids and liver function in experimentally-induced liver damage. 936 4

Neonatal haemochromatosis is a disorder which affects foetuses and newborns. It is characterized by hepatocellular insufficiency, often appearing on the first day of life in the form of coagulopathy, hypoalbuminemia, hypoglycemia and jaundice. While spontaneous recovery has been reported, most of these infants die, and the diagnosis was previously often made during autopsy. With the help of MRI and salivary gland biopsies, plus increasing awareness of this disorder, the diagnosis is now often made quite early, and successful liver transplantations have been reported. Recently, there have also been encouraging preliminary reports of successful intervention with antioxidant and chelation pharmacotherapy, using a combination of selenium, vitamin E, N-acetylcysteine, deferoxamine, and prostaglandin E. We describe two patients with neonatal haemochromatosis who were both treated with this new "cocktail", one of whom died at five days of age, while the other survived, but needed a liver transplant at 2 1/2 months of age. The pathology of this condition is characterized by hepatic cirrhosis with giant cell transformation, and by siderosis of extrahepatic tissues. The prognosis is poor, and our experience with antioxidant treatment has been disappointing. Liver transplantation is a therapeutic option, but its use is limited by the scarcity of donor organs and the small size of many of the patients.
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PMID:[Neonatal hemochromatosis]. 954 1


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