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)

In vitro models have shown that metabolites of ethanol (acetaldehyde and lactate) stimulate collagen synthesis, thereby, suggesting that they may be important as fibrogenic mediators. The relevance of these findings for fibrogenesis in the human liver in vivo, however, has not as yet been demonstrated. Serum markers for collagen (PIIINP, using radioimmunoassays employing polyclonal antibodies and Fab-fragments (PIIINP-Fab), respectively) and basement membrane (laminin) metabolism were therefore investigated in 25 alcoholic cirrhotics (Pugh-Score: 6.7 +/- 1.9 S.D.) and in 19 comparable nonalcoholic cirrhotics (Pugh-Score: 6.3 +/- 1.5, n.s.) with only slight evidence for inflammation: GOT 28 +/- 22 vs. 24 +/- 21 U/l; GPT 24 +/- 23 vs. 31 +/- 28 U/l; gamma-globulins 24 +/- 8 vs. 22 +/- 5%, respectively (all n.s.). Severity of the disease was assessed by quantitative liver function tests. Levels of PIIINP, PIIINP-Fab and laminin measured by RIA were 21 +/- 19 micrograms/l, 90 +/- 42 micrograms/l and 2.5 +/- 0.8 U/ml in alcoholic cirrhosis and 10 +/- 6 micrograms/l, 61 +/- 10 micrograms/l and 1.9 +/- 0.4 U/ml in nonalcoholic cirrhosis, respectively (all p less than 0.01). Differences on PIIINP and PIIINP-Fab remained significant even after accurate matching for galactose elimination capacity, aminopyrine breath test and hepatic sorbitol clearance. Laminin levels were higher in alcoholic cirrhosis only after matching for the hepatic sorbitol clearance (p less than 0.01). The higher levels of serum markers for collagen and basement membrane metabolism in alcoholic vs. nonalcoholic patients with cirrhosis at equal severity of the disease and with only minimal signs of inflammation may be the clinical reflection of a specific fibrogenic effect of ethanol metabolites.
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PMID:Higher levels of serum aminoterminal type III procollagen peptide, and laminin in alcoholic than in nonalcoholic cirrhosis of equal severity. 173 19

To clarify the pathogenetic role of acetaldehyde in the development of alcoholic liver disease, genotyping of aldehyde dehydrogenase-2 genes was performed and the clinical features of the alcoholic liver disease patients with different genotypes were compared. Genotyping of aldehyde dehydrogenase-2 was performed in 47 patients with alcoholic liver disease using the polymerase chain reaction and slot-blot hybridization. Of the 47 patients with alcoholic liver disease, 40 were homozygous for the normal aldehyde dehydrogenase-2 gene and the remaining seven cases were heterozygous for the normal and mutant aldehyde dehydrogenase-2 genes. No homozygote was found for the mutant aldehyde dehydrogenase-2 genes. Daily alcohol intake was less than 100 gm in all heterozygotes without relation to the type of alcoholic liver disease. On the other hand, all but four patients homozygotic for the normal aldehyde dehydrogenase-2 gene drank more than 100 gm alcohol/day. The mean daily alcohol intake in the heterozygotes was significantly lower than that in the normal homozygotes. The incidence of alcoholic fibrosis tended to be lower in the heterozygotes than in the normal homozygotes (14.2% vs. 52.5%). On the other hand, the incidence of alcoholic hepatitis and/or cirrhosis tended to be higher in the heterozygotes than in the normal homozygotes. These results indicate that alcoholic liver disease develops even with moderate amounts of alcohol intake in heterozygotes of the aldehyde dehydrogenase-2 genes, in which acetaldehyde metabolism in the liver is impaired and liver damage in the heterozygotes is more severe than that in the normal homozygotes, suggesting that habitual drinkers who are heterozygotes of the aldehyde dehydrogenase-2 genes may be at high risk for alcoholic liver disease.
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PMID:Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes. 205 Mar 24

Alcoholic liver disease includes steatosis, alcoholic hepatitis and cirrhosis. Other liver diseases of genetic origin, but with a curious association with alcohol intake, are hemochromatosis and porphyria cutanea tarda. The attribution of chronic hepatitis to alcohol intake remains speculative, and the association may reflect hepatitis C infection. Hepatic injury attributed to alcohol includes the changes reported in the fetal alcohol syndrome. Steatosis, the characteristic consequence of excess alcohol intake, is usually macrovesicular and rarely microvesicular. Acute intrahepatic cholestasis, which in rare instances accompanies steatosis, must be distinguished from other causes of intrahepatic cholestasis (e.g., drug-induced) and from mechanical obstruction of the intrahepatic bile ducts (e.g., pancreatitis, choledocholithiasis) before being accepted. Alcoholic hepatitis (steatonecrosis) is characterized by a constellation of lesions: steatosis, Mallory bodies (with or without a neutrophilic inflammatory response), megamitochondria, occlusive lesions of terminal hepatic venules, and a lattice-like pattern of pericellular fibrosis. All these lesions mainly affect zone 3 of the hepatic acinus. Other changes, observed at the ultrastructural level, are of importance in progression of the disease. They include widespread cytoplasmic shedding, and capillarization and defenestration of sinusoids. Progressive fibrosis complicating alcoholic hepatitis eventually leads to cirrhosis that is typically micronodular but can evolve to a mixed or macronodular pattern. Hepatocellular carcinoma occurs in 5 to 15% of patients with alcoholic liver disease. The clinical syndrome of alcoholic liver disease is the result of three factors--parenchymal insufficiency, portal hypertension and the clinical consequences of extrahepatic damage produced by alcohol. At the several phases of the life history of alcoholic liver disease, the individual factors play a different role. The clinical manifestations of alcoholic steatosis are mainly extrahepatic in origin. Those of alcoholic hepatitis reflect mainly parenchymal insufficiency and those of cirrhosis are mainly those of portal hypertension. Alcoholic liver injury appears to be generated by the effects of ethanol metabolism and the toxic effects of acetaldehyde, perhaps the immune responses to alcohol- or acetaldehyde-altered proteins, and questionably enhanced by viral hepatitis. Alcoholic hepatitis may be mimicked histologically, and to a varying degree clinically, by a number of conditions (obesity, diabetes, several drug-induced injuries, jejunoileal bypass, and related "shortcircuiting" of the bowel). Perhaps the most important facet of the hepatotoxicity of alcohol is its enhancement of the effects of a number of other hepatotoxic agents, among which acetaminophen is the prime example.
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PMID:Alcoholic liver disease: pathologic, pathogenetic and clinical aspects. 205 45

Significance of the antibody to alcohol altered hepatocyte plasma membrane (AAHM) was studied in various types of alcoholic liver diseases (ALD). AAHM was detected in the sera that were collected within 3 months of alcohol abstinence from patients with various types of ALD, with higher frequency in alcoholic hepatitis and cirrhosis. Serum acetaldehyde, gamma-globulin fraction, immunoglobulin A and G were higher in patients positive for AAHM, though the levels of GOT, GPT, mGOT were indifferent of the existence of AAHM. Histologically, hepatocyte ballooning and pericellular fibrosis were frequently seen in patients positive for AAHM, but close relationship between the extent of necrosis and existence of AAHM was not observed. These findings suggest that the occurrence of AAHM is closely related with the functional and morphological changes of the hepatocyte induced by acetaldehyde but not with hepatocyte necrosis.
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PMID:[Study of the antibody to alcohol altered hepatocyte plasma membrane in alcoholic patients]. 222 84

Alcoholic hepatitis is a necrotizing, often inflammatory, process that is an important precursor to the development of cirrhosis. Acetaldehyde, which is derived from alcohol by the action of alcohol dehydrogenase, is apparently the most important factor leading to alcohol-induced liver injury. Other factors of importance in determining the appearance and rate of progression of liver diseases in patients who are chronic alcoholics include sex, nutritional status, and various immunologic reactions. In addition, there is an incompletely understood genetic predisposition to the development of alcoholic hepatitis. Several histologic features found in patients with alcoholic hepatitis have been evaluated in efforts to determine which are of prognostic value. The predominance of the alcohol-induced injury in zone III of the hepatic lobule; deposition of collagen, IgA, and fibronectin in the space of Disse; defenestration of endothelial cells; and transformation of lipocytes and myofibroblasts to fibroblasts have been investigated. Prolongation of the prothrombin time and marked elevation of serum bilirubin levels are indicators of a subgroup of patients with alcoholic hepatitis who have a poor prognosis, especially if there is also evidence of hepatic encephalopathy. Supportive care and abstinence from alcohol are the foundations of therapy. Corticosteroid therapy appears to decrease the number of early deaths in patients with severe alcoholic hepatitis. Other experimental approaches to therapy include the use of propylthiouracil, anabolic-androgenic steroids, and insulin and glucagon.
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PMID:Alcoholic hepatitis: pathogenesis and approaches to treatment. 223 74

We describe three patients with cholesteryl ester storage disease. Diagnosis was confirmed by demonstrating a deficiency in lysosomal acid cholesteryl hydrolase activity in cultured skin fibroblasts from each of these patients. All had hepatomegaly, elevated serum aminotransferase activities and hyperlipoproteinemia. Histological examination of liver biopsy specimens before treatment revealed accumulation of fat within hepatocytes, bile duct epithelium and endothelial and Kupffer cells. Cholesterol crystals were recognized by their birefringence in frozen sections. A striking feature was the presence of markedly hypertrophied Kupffer cells and portal macrophages with foamy, tan-colored cytoplasm that stained readily with the periodic acid-Schiff reagent and aldehyde fuchsin. Periportal fibrosis was noted in all cases; incomplete cirrhosis was present in one case. Distinctive and hitherto undescribed lysosomal accumulations of triglyceride and cholesterol crystals were noted. The patients were treated with lovastatin, a cholesterol-lowering agent, for at least 12 mo. No significant changes were seen in serum lipoprotein concentrations or liver histopathology after therapy. Thus lovastatin did not have an obviously beneficial effect on abnormal lipid metabolism in these patients.
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PMID:Cholesteryl ester storage disease: hepatopathology and effects of therapy with lovastatin. 234 51

The so-called novel inclusion body (NIB) is an intrahepatocytic structure which is frequently observed in human cirrhotic liver. It resembles very much to, but definitely differs from Hepatitis B surface antigen (HBsAg) morphologically. The age distribution of liver cirrhosis cases positive for NIB is similar to that positive for HBsAg, except for an existence of a time lag in mean age. One of the best staining methods to demonstrate NIB, for example, is to exhibit it as a reddish body stained by Luna, with a contrast of HBsAg counterstained purple in color by aldehyde fuchsin after thiosulfation. Electron microscopy of the liver obtained from a patient, negative for both HBsAg and Hepatitis B e antigen (HBeAg) but positive for Hepatitis B core antibody (HBcAb) and Hepatitis B surface antigen antibody (HBsAb) clinically, revealed some unfamiliar, tubular and cisternal arrays showing a network pattern and ring-shaped structure at the site exactly corresponding to NIB localization. These are considered to have been induced from the endoplasmic reticulum by an unknown agent, for which non A non B hepatitis virus (NANBV) is rationally postulated as one of the possibilities. A close relation between NIB and NANBV is highly suspected because of much similarities in histology, histochemistry, age distribution, and electron microscopy. The true nature of NANBV should be rescrutinized, especially in relation with Hepatitis B virus infection, since NIB is quite often observed also in cirrhotic liver positive for HBsAg.
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PMID:A study on so-called novel inclusion body in human hepatocyte. 241 47

The effects of acute ethanol challenge on serum glycoprotein concentrations in man were studied. Serum levels of haptoglobin, alpha-2-macroglobulin and pre-albumin were measured fasting and 6 hr after oral ethanol 0.75 g/kg body weight in 8 healthy controls, 13 patients with alcoholic liver disease and 13 with non-alcoholic-related liver damage, both patient groups being further subdivided into those with and without cirrhosis. Basal levels of haptoglobin were significantly higher in non-cirrhotic alcoholics than controls and pre-albumin levels were lower in non-alcohol-related cirrhotic liver disease. In response to ethanol challenge, no consistent change was observed in any group, nor was there any significant difference between groups. There was, however, a significant correlation (r = 0.53, P less than 0.005) between the percentage changes in haptoglobin and alpha-2-macroglobulin. In 16 subjects (2 controls, 8 alcoholics and 6 non-alcoholics) blood levels of ethanol and acetaldehyde were measured serially: there was no relationship between the peak or mean concentration and the glycoprotein response. This study does not substantiate other reports which claimed to be able to predict the severity and reversibility of alcoholic liver disease on the basis of the serum glycoprotein response to ethanol: ethanol challenge with measurement of serum glycoproteins cannot substitute for proper histological assessment.
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PMID:Effect of ethanol challenge on serum glycoproteins in alcoholic and non-alcoholic liver disease. 244 17

Acetaldehyde, a product of ethanol oxidation which forms adducts with proteins, has been incriminated in the pathogenesis of alcoholic liver injury. High serum antibody titers against acetaldehyde-protein adducts have been found not only in alcoholics but also in patients with nonalcoholic liver disease, suggesting a contribution of acetaldehyde derived from sources other than exogenous ethanol. To investigate the effect of liver injury on the removal and the production of acetaldehyde, we produced fibrosis and cirrhosis (by chronic administration of carbon tetrachloride) and fatty liver (with very small doses of dimethylnitrosamine) in rats. Endogenous blood acetaldehyde levels increased by 38% in rats with severe liver injury (p less than 0.005), but not significantly in rats with fatty liver. However, an i.v. load of threonine (a physiological source of acetaldehyde), in amounts equivalent to the daily intake of this amino acid, increased blood and hepatic acetaldehyde levels in the rats with both types of liver injury more than in controls. Threonine dehydrogenase and dehydratase activities, involved in the major pathways for threonine degradation in mitochondria and cytosol, respectively, were markedly decreased in rats with liver injury with a resulting increase in hepatic threonine concentration. Moreover, the threonine aldolase activity, which splits threonine into glycine and acetaldehyde, remained unaffected or even slightly increased. Liver injury was also associated with impaired mitochondrial functions, including a 10 to 23% decrease in acetaldehyde oxidation (depending upon the severity of the lesions). As a consequence, administration of ethanol (an exogenous source of acetaldehyde) resulted in striking elevations in the levels of acetaldehyde in carbon tetrachloride-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High levels of acetaldehyde in nonalcoholic liver injury after threonine or ethanol administration. 251 Nov 35

The authors describe the correlations between chronic alcoholism and cirrhosis known not only from clinical observations but also from retrospective assessment of liver biopsy. However, the mechanism of hepatocellular injury by ethanol remains still unclear. It seems that three hypotheses prevail presently: 1) acetaldehyde which is a product of ethanol oxidation in the liver forms with certain biogenic amines alkaloids of the type of salsolinol causing cirrhosis, 2) ethanol or/and acetaldehyde catalyse the development of free radicals which may induce liver damage through lipid peroxides etc, 3) acetaldehyde formed during ethanol oxidation is released into blood or tissue fluids where it binds to albumins with formation of cytotoxic complexes leading to cirrhosis.
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PMID:[Various biochemical mechanisms of alcoholic liver cirrhosis]. 261 99


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