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)

When compared to values obtained in 17 normal weight normolipidemic control subjects (41.63 +/- 2.73 ml X min-1) antipyrine clearance determined in the saliva was found to be obviously decreased in the 10 patients with liver cirrhosis (21.88 +/- 0.79) and significantly increased in the 17 subjects with type IV hyperlipoproteinemia (59.91 +/- 4.59). Antipyrine clearance was positively correlated with both serum triglyceride concentration (r = 0.574; p less than 0.001) and serum cholinesterase activity (r = 0.705; p less than 0.001) and these correlations persisted even after the exclusion of cirrhotic patients. It is suggested that the accelerated hepatic secretion of very low density lipoproteins and of many export proteins and enzymes noted in most hypertriglyceridemic subjects is accompanied by an enhanced activity of liver microsomal enzymes involved in drug metabolism.
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PMID:Increased values of antipyrine clearance in type IV hyperlipoproteinemia. 377 12

This chapter has dealt with five photocutaneous forms of human porphyria. The forms are a diverse group of disorders with many different hematologic, hepatologic, and neurologic manifestations. In essence, most photocutaneous porphyrias occurring in childhood will relate to congenital erythropoietic porphyria or protoporphyria. The nature of the skin lesions and a study of the heme precursor profile in red cells, plasma, urine, and feces should easily distinguish these two conditions. CEP is a disease wherein photomutilation is a dominant concern and aggressive new approaches of therapy also have been discussed. In protoporphyria, the dermatologic problem is less severe and the dermatologist should be aware that a subset of patients could develop active liver disease that may lead to fatal cirrhosis. Novel approaches of therapy have been briefly alluded to. With regard to postpubertal photocutaneous porphyria, the classic porphyria cutanea tarda syndrome is associated with liver disease, usually alcoholic with siderosis, and the treatment by phlebotomy to reduce hepatic iron is highly effective. The potential danger of liver carcinoma has been discussed. In subsets of porphyria cutanea tarda, this can be an endemic disease relating to environmental factors, ie, ingestion of polyhalogenated hydrocarbons. The biochemical diagnosis can be attained by fairly straight-forward solvent extraction analyses of urine and feces, showing the dominance of uroporphyrin excretion in the urine and coproporphyrin in the feces. Chromatographic techniques in plasma, bile, and feces reveal a PCT-specific porphyrin: isocoproporphyrin. Rare subtypes with hematologic manifestations, ie, hepatoerythropoietic porphyria and CEP, indicate the wide spectra of disorders that might be associated with a spontaneous deficiency of uroporphyrinogen decarboxylase activity. These latter syndromes are, however, rare. Two hereditary hepatic porphyrias, ie, autosomal dominantly inherited VP and HCP, have been briefly discussed. The hepatic lesion is metabolic, not morphologic, and its expression by the liver relates to its adaptive response to induction of microsomal hemoproteins by a variety of exogeneous and endogeneous compounds, eg, drugs and hormones. Photocutaneous lesions of HCP and VP are identical to PCT, the latter having no neurologic sequelae. In the former two, however, exposure of persons to drugs, such as the hydantoins and barbiturates, can lead to potentially fatal acute porphyric attacks.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hematologic and hepatic manifestations of the cutaneous porphyrias. 391 35

The possibility of a relationship between hepatic and renal cytochrome P-450 contents was assessed in rats with liver disease. In rats killed 3 days after two-thirds hepatectomy (a model for hepatocellular insufficiency), the total microsomal cytochrome P-450 content of the whole liver was decreased by 60% as compared to that in control rats; renal cytochrome P-450 was increased by 30% while the 7-ethoxycoumarin deethylase activity of kidney microsomes was increased by 80%. In rats killed 7 days after bile duct ligation (a model for cholestasis) or 35 days after bile duct ligation (a model for biliary cirrhosis), hepatic cytochrome P-450 was decreased by 60% and 45%, respectively, while renal cytochrome P-450 content was increased by 50% and 150%, respectively. In contrast, in rats killed 15 days after the last dose of carbon tetrachloride, 1.3 ml/kg twice weekly for 3 months (a model for post-necrotic cirrhosis), both hepatic and renal cytochrome P-450 contents remained unchanged. Phenobarbital (80 mg/kg daily for 3 days) was a poor inducer of renal cytochrome P-450 in sham-operated rats but became a potent inducer of renal cytochrome P-450 in rats with two-thirds hepatectomy. We conclude that renal cytochrome P-450 is increased in three models in which hepatic cytochrome P-450 contents are decreased (two-thirds hepatectomy, cholestasis and biliary cirrhosis), but remains unchanged in a model of severe liver pathology, in which hepatic cytochrome P-450 content is not modified (late, post-necrotic cirrhosis). The hypothetical role of endogenous inducer(s) is discussed.
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PMID:Regulation of renal cytochrome P-450. Effects of two-thirds hepatectomy, cholestasis, biliary cirrhosis and post-necrotic cirrhosis on hepatic and renal microsomal enzymes. 391 37

Both cimetidine therapy and cirrhosis individually interfere with normal elimination of various drugs. Cimetidine is often prescribed in patients with cirrhosis but there is incomplete data on its effect on drug elimination in cirrhotics. The purpose of this study was to address this issue. Eight stable cirrhotics were studied prior to and following 7 days of cimetidine administration, (300 mg orally q.i.d.). Chlordiazepoxide (Librium), which is eliminated by the liver after demethylation, and indocyanine green, which is removed by the liver without biotransformation, were used as probes. Consistent with the concept that cimetidine interferes with drug metabolism by inhibiting microsomal oxidation, chlordiazepoxide clearance in the cirrhotics was inhibited by cimetidine (p less than 0.05), but indocyanine green clearance was unaffected. As shown by us previously (Roberts, R. K. et al., Gastroenterology 1978; 75:479-485), untreated cirrhotics had substantially lower chlordiazepoxide clearance than did controls. The inhibitory effect of cimetidine on chlordiazepoxide clearance was less in cirrhotics than in controls (p less than 0.05). In all subjects, there was excellent correlation between initial clearance and magnitude of depression in clearance after cimetidine, i.e., the larger the initial clearance, the larger the change (r = 0.97, p less than 0.0001). Forty-eight hours after stopping cimetidine, chlordiazepoxide clearance returned to baseline in cirrhotics and controls. Our data demonstrate that cimetidine and cirrhosis may act additively to impair drug metabolism. This effect of cimetidine on chlordiazepoxide clearance is smaller in cirrhotics than in controls, but, because of impaired initial drug elimination in cirrhosis, it may result in adverse clinical effects.
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PMID:The effect of cimetidine on hepatic drug elimination in cirrhosis. 397 62

The relationship between hepatic glycerolipids and microsomal drug-metabolizing enzymes was studied in liver biopsies from 41 subjects. The series included obese, diabetic, epileptic and chronic alcoholic patients, all of whom were hospitalized for suspected hepatic ailments (fatty liver, hepatitis or cirrhosis). Therapy with enzyme-inducing anticonvulsants was associated with high phospholipid and cytochrome P-450 and low triacylglycerol concentration in the liver. In patients with fatty liver or cirrhosis low phospholipid and cytochrome P-450 and high triacylglycerol concentrations were observed. There was a significant correlation (r (Pearson's product moment correlation coefficient) = 0.91) between the hepatic phospholipid and cytochrome P-450 concentration. The cytochrome P-450 concentration was inversely related (r = -0.74) to the triacylglycerol concentration. The positive correlation between hepatic phospholipids and drug-metabolizing enzymes could be interpreted as indicating that in human liver phospholipid and cytochrome P-450 synthesis share common regulators, or that phospholipids are necessary for the maximum rate of cytochrome P-450 synthesis.
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PMID:Relationship between lipid composition and drug metabolizing capacity of human liver. 398 78

Cytochrome P450 levels are often low in the cirrhotic liver but the reason for this has not been established. Because changes in heme metabolism may reduce hepatic levels of cytochrome P450, the relationship of heme turnover to cytochrome P450 levels has been examined in rats with cirrhosis. Cirrhosis was produced by repeated carbon tetrachloride inhalation. In animals with cirrhosis, hepatic microsomal cytochrome P450 content was significantly less (32%) than in controls. Heme synthesis was assessed by measuring the activity of mitochondrial delta-amino-levulinic acid synthetase and also by determining the incorporation (within 30 min) of radiolabeled delta-aminolevulinic acid into the microsomal heme fraction. Both these parameters were normal in rats with CCl4-induced cirrhosis. In addition, the activity of microsomal heme oxygenase, the rate-limiting enzyme in catabolism of heme to bilirubin, was not altered. Cytochrome P450 heme degradation was then determined directly by injecting radiolabeled delta-aminolevulinic acid and measuring radioactivity in CO-binding particles (microsomes incubated with protease to remove cytochrome b5) prepared at various times thereafter. By this method, the degradation rate of cytochrome P450 heme did not differ between rats with cirrhosis and controls. Finally, the availability of hepatic heme for formation of hemoproteins was deemed to be satisfactory in cirrhotic liver because tryptophan pyrrolase saturation was comparable with controls, and also because heme administered in vivo did not enhance hepatic clearance of the cytochrome P450 substrate antipyrine. The failure to find defective heme biosynthesis or accelerated heme breakdown and the evidence that heme is available in amounts that do not restrict hemoprotein formation indicate that aberrant heme metabolism is not the cause of low cytochrome P450 levels in this rat model of cirrhosis.
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PMID:Hepatic heme metabolism and cytochrome P450 in cirrhotic rat liver. 400 1

Alcohol is the most significant liver poison. Its degradation takes above all place by the alcohol dehydrogenase and the microsomal alcohol-oxidizing system. In the first step of degradation acetaldehyde develops which in enrichment evokes immediately toxic defects on the mitochondrias of the cells of the liver parenchyma and thus introduces a vicious circle. Furthermore, an increased affection of pharmacometabolites as a sequel of the alcohol-conditioned enzyme induction may lead to a defect. Alcohol influences intermediary metabolic functions: the gluconeogenesis is inhibited, multi-layer disturbances in the lipid metabolism lead to fatty degeneration of the liver. A hyperuricaemia results from overproduction in the liver as well as from decreased renal excretion. The proline formation is increased. Distinct increase of the gamma-GT-activity is an early and relatively specific indicator of the alcoholic liver defect. Morphologic and clinical manifestations are fatty degeneration of the liver, hepatitis based on fatty degeneration of the liver and cirrhosis. Apart from dose and duration of the alcohol intake additional factors require consideration. The author adopts a definite attitude to etiopathogeneis and therapeutic possibilities.
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PMID:[Alcohol and the liver]. 611 57

Antibodies to a liver-specific lipoprotein complex (LSP) were determined by radioimmunoassay in the sera of 65 children with possible chronic liver disease. Thirteen had "autoimmune" chronic active hepatitis (CAH), 21 alpha 1-antitrypsin deficiency PiZ (alpha 1-ATD), all having significant liver disease, while 10 of 31 children with cystic fibrosis (CF) had abnormal biochemical tests of liver function, six having cirrhosis. Sera from 12 (92%) of 13 untreated CAH patients contained detectable anti-LSP antibodies, the highest titres occurring in those with anti-liver/kidney microsomal or smooth muscle antibodies. Titre of anti-LSP antibodies correlated with piecemeal necrosis of periportal hepatocytes in liver biopsies, but not with standard biochemical tests of liver function or serum immunoglobulin concentrations. The incidence of LSP antibodies fell as liver damage improved with immunosuppressant therapy, being positive in 18 of 26 sera from children in whom the transaminases were still above normal, but positive in only two of 20 in whom transaminase values were within the normal range (chi 2 = 16, p less than 0.001). Sera from two of 31 patients (6%) with CF contained anti-LSP antibodies as did sera from six of 21 patients with alpha 1-ATD. Antibody concentrations were lower than in CAH, and in alpha 1-ATD the presence of anti-LSP could not be correlated with the presence or absence of piecemeal necrosis on liver biopsy. Our data suggest that autoimmune mechanisms involving antibody to hepatocyte membrane components have a role in the pathogenesis of chronic liver disease in autoimmune CAH in children as in adults.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Antibodies to liver-specific lipoprotein in children with chronic liver disease due to "autoimmune" chronic active hepatitis, cystic fibrosis, and alpha 1-antitrypsin deficiency. 633 53

Ther are several main mechanisms that allow us to understand a number of the hepatic and metabolic effects of ethanol. Ethanol is oxidized in the liver to two products (hydrogen and acetaldehyde), to which many of the effects of ethanol can be attributed. The hydrogen generated alters the redox state, and though this effect is attenuated after chronic ethanol consumption, it may still be sufficient to explain alterations in lipid metabolism, possibly increased collagen deposition, and, under special circumstances, depression of protein synthesis. Acetaldehyde impairs microtubules, decreases protein secretion, and causes protein retention and ballooning of the hepatocyte. Acetaldehyde exerts toxicity also with regard to other key cellular functions, particularly in the mitochondria, and it may promote peroxidation of the cellular membranes. It is noteworthy that after chronic consumption of ethanol, there is increased acetaldehyde, in part because of decreased disposition in the mitochondria and partly because of induction of an alternative pathway of ethanol metabolism, namely the microsomal ethanol-oxidizing system. Indeed, this MEOS increases in activity after chronic ethanol consumption, with cross induction and acceleration of the metabolism of other drugs and increased lipoprotein production with hyperlipemia. There is also increased microsomal activation of hepatotoxic compounds (including drugs and possibly vitamin A). Fibrosis and cirrhosis can develop despite an associated adequate diet and even in the absence of alcoholic hepatitis. They are preceded by myofibroblasts and fibroblast proliferation. What eventually causes the increased number of myofibroblasts and promotes fibrosis is unclear, nor do we know the relative role of hepatocytes or mesenchymal cells in the process of fibroplasis. Possibly selective roles in this process of specific nutritional factors remain to be elucidated.
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PMID:Alcohol, protein nutrition, and liver injury. 634 74

The sera of 131 patients with anti-liver-kidney microsome antibodies (anti-LKM) detected between 1973 and 1979 in two different laboratories were re-examined. (1) Eighty-six anti-LKM corresponded to the description given by Rizzetto, Swana & Doniach (1973), with a pattern of fluorescence predominating on the 3rd portion of the proximal tubules (P3). This group comprised 45 cases of idiopathic chronic hepatitis or idiopathic cirrhosis and one case of halothane-induced hepatitis. (2) Forty-five anti-LKM gave a different pattern on male mouse liver and male rat kidney: (a) fluorescence was greater on centrolobular than on periportal hepatocytes; (b) the first and second portions of proximal tubules (P1 and P2) predominated over P3; (c) P1 fluorescence was equally intense as P2 and (d) P3 cells were heterogeneous with one cell out of 20 more positive than the rest. Absorption tests confirmed that the corresponding antigen was also present in the liver microsomal fraction. A retrospective clinical study discovered tienilic acid-induced hepatitis in all cases. We suggest naming this new antibody 'anti-LKM2'.
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PMID:A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. 636 59


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