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)

Since ethanol metabolism predominantly takes place in the liver it is not surprising that hepatic intermediary metabolism is strikingly influenced. Alcohol is metabolized via three enzyme systems: alcohol dehydrogenase (ADH), microsome ethanol oxidizing system (MEOS) and catalase. The ADH reaction produces reducing equivalents as NADH which results in various metabolic disorders such as hyperproteinemia IV and V, hypoglycaemia, lactacidosis, hyperuricaemia, and certain forms of porphyria. The metabolism of hormones is also disturbed. Alcohol fatty liver is a direct consequence of NADH production. Alcoholic liver disease comprises of fatty liver, alcoholic hepatitis and cirrhosis. Risk factors of alcoholic liver disease are the amount of alcohol consumed, drinking pattern, female gender and certain genetic predispositions. Alcoholic hepatitis is characterized by a typical clinical and laboratory feature, and specific heaptic morphology. Poor prognostic factors are continuous alcohol consumption, cholestatis and perivenular fibrosis. Alcoholic cirrhosis has similar complications as cirrhosis of other etiology. Therapy includes abstinence, antioxidative drugs, steroids, and S-adenosylmethionine. Liver transplantation is of long-term benefit.
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PMID:[Alcohol and the liver]. 1080 81

Disorders of the serum sodium concentration (hypo- and hypernatremia) are amongst the most frequent electrolyte disorders in clinical medicine. They are attributable to disturbance of to water metabolism. Hyponatremia is almost always a condition of water excess while hypernatremia is due water deficiency. Physiological normonatremia (normal plasma osmolality) is maintained by an integrated system involving regulated water intake via thirst and control of water excretion via antidiuretic hormone secretion. Therefore hypo- and hypernatremia should be analyzed in terms of dysregulated ADH secretion, fluid intake and renal water excretion. Hyponatremia is usually a disorder of vasopressin excess, due to 'non-osmotic' vasopressin release. The latter may occur in two different settings: (I) SIADH, (II) baroreceptor mediated vasopressin secretion (cardiac failure, liver cirrhosis). This entities are easy to distinguish in clinical practice. SIADH is associated with striking lower plasma concentrations of urate, creatinine and urea. In SIADH the blood pressure is normal and there is no edema. In contrast in the hyponatremia of liver cirrhosis and heart failure the plasma measurements indicated are usually slightly elevated, the blood pressure is low and there is edema. The typical patient with hypernatremia is old and has no thirst sensation. Hypo- or hypernatremia may cause major neurologic symptoms. These symptoms are more related to the rate of change in the serum sodium concentration than to the absolute level of a hypo- or hypernatremia reached. The traditional treatment for hyponatremia used to be water restriction. However V2-Vasopressin-Antagonists may provide a better treatment modality in the future. Hypernatremia is treated by slow rehydratation.
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PMID:[Hyponatremia--with comments on hypernatremia]. 1089 27

An 11-year-old boy was diagnosed as having acute lymphoblastic leukemia (ALL, L1) in 1987 and underwent treatment with an ALL high-risk protocol (prednisolone, vincristine (VCR), daunorubicin, 1-asparaginase), which resulted in complete remission. In 1990 he developed chronic hepatitis C and received interferon therapy. In December 1994, ALL recurred, and the patient was treated with VCR. He subsequently developed severe hemolysis (Hb 12.5 g/dl-->6.8 g/dl) with increases of indirect bilirubin, AST, and LDH. Furthermore, symptoms resembling a syndrome of inappropriate secretion of ADH (SIADH) and DIC developed. Upon incubation of the patient's red blood cells with VCR in vitro, extreme deformity of the cells was observed. These findings suggested that splenomegaly, due to liver cirrhosis which had developed rapidly from chronic hepatitis C while the patient was in an immunosuppressed state induced by anticancer drugs, had trapped the deformed red blood cells and resulted in severe hemolysis. The patient died on the 165th day after admission due to liver failure.
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PMID:[Severe hemolysis and SIADH-like symptoms induced by vincristine in an ALL patient with liver cirrhosis]. 1119 45

VPA-985 is an orally active, competitive vasopressin V(2) receptor antagonist that in normal human beings increases water excretion without affecting solute excretion. Whether solute excretion is affected in patients with hyponatremia resulting from inappropriate secretion of antidiuretic hormone (SIADH) or from cirrhosis treated with VPA-985 is unknown. Six hyponatremic patients with SIADH and 5 hyponatremic patients with cirrhosis with ascitis (CWAs) were treated with 50 or 100 mg VPA-985 twice daily. Evolution of creatinine, urea, uric acid, sodium, potassium, and osmotic clearance were determined. Volume hormones (plasma renin [PR], aldosterone, antidiuretic hormone [ADH], atrial natriuretic factor [ANF]) were also determined before and after treatment. In patients with SIADH, serum sodium concentration (SNa) was generally corrected in 1 day (SNa: 126 +/- 4.5 mmol/L at t = 0 hours and 133 +/- 5.6 mmol/L at t = 24 hours) and associated with a decrease in sodium excretion (from 82 +/- 22 mmol/24 hours to 45 +/- 21 mmol/24 hours; P < 0.05) without modification in potassium excretion. Despite an increase in diuresis (from 0.84 +/- 0.2 ml/min to 1.46 +/- 0.4 ml/min) urea and uric acid clearances decreased. Urine osmolality decreased from 414 +/- 148 mOsm/kg H(2)O to 209 +/- 55 mOsm/kg H(2)O. Volume hormones did not change. In the CWAs the rise of SNa was more progressive (SNa: 126 +/- 2.8 mmol/L at t = H0 to 133 +/- 4.9 mmol/L at t = 48 hours) and parallel to an augmentation in sodium excretion (from 23 +/- 18 mmol/24 hours to 65 6 60 mmol/24 hours the second day of VPA administration). The higher sodium excretion was also connected with a progression in potassium excretion (from 22 6 7 mmol/24 hours to 36 +/- 18 mmol/24 hours). The increase in diuresis under VPA from 0.42 +/- 0.2 mL/min to 1.7 +/- 0.9 mL/min resulted in a higher urea clearance. Urine osmolality decreased from 509 +/- 142 mOsm/kg H(2)O before VPA to 194 +/- 106 mOsm/kg H(2)O after VPA. ADH increased in CWAs treated with VPA, from 1.9 +/- 1.2 pg/mL to 5.3 +/- 2.8 pg/mL (P <.05) while other volume hormones did not change. VPA-985 is a highly effective drug in the short-term management of hyponatremic patients with SIADH or CWAs. SNa correction is associated with urinary sodium retention in SIADH, whereas in CWAs a mild increase in sodium excretion is observed.
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PMID:Difference in solute excretion during correction of hyponatremic patients with cirrhosis or syndrome of inappropriate secretion of antidiuretic hormone by oral vasopressin V2 receptor antagonist VPA-985. 1175 87

Possible molecular mechanisms underlying changes in catalytical properties of alcohol dehydrogenase (ADH) and lactate dehydrogenase (LDH) were studied at toxic hepatitis. The development of toxic hepatitis is accompanied by significant changes in the activity of ADH and LDH assayed in subcellular fractions and kinetic characteristics of these enzymes. This can result in an increase cellular level of acetylaldehyde and lactate which promotes the development of liver cirrhosis.
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PMID:[Molecular mechanisms of metabolic adaptation in pathological changed liver during toxic hepatitis ]. 1155 17

Alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P-4502E1 (CYP2E1), and then to acetate by aldehyde dehydrogenase (ALDH). Polymorphisms of these ethanol-metabolizing enzymes may be associated with inter-individual difference in alcohol metabolism and susceptibility to alcoholic liver disease. We determined genotype and allele frequencies of ALDH2, CYP2E1, ADH2, and ADH3 in male Korean patients with alcoholic cirrhosis (n=56), alcoholics without evidence of liver disease (n=52), and nondrinkers (n=64) by using PCR or PCR-directed mutagenesis followed by restriction enzyme digestion. The prevalences of heterozygous ALDH2*1/*2 plus homozygous ALDH2*2/*2 in patients with alcoholic cirrhosis (7.1%) and alcoholics without evidence of liver disease (3.8%) were significantly lower than that in nondrinkers (45.3%). The c2 allele frequencies of the CYP2E1 in alcoholic cirrhosis, alcoholics without evidence of liver disease, and nondrinkers were 0.21, 0.20, and 0.20, respectively. Allele frequencies of ADH2*2 in the three groups were 0.78, 0.74, and 0.77 and those of ADH3*1 were 0.94, 0.98, and 0.95. Therefore, we confirmed the observation that the ALDH2*2 gene protects against the development of alcoholism. However, the development of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.
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PMID:Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population. 1174 56

Even though the number of alcohol-dependent women is only about 1/3 of the number of alcoholic men, the alcoholism in women, by its clinical features and its course, is the source of therapeutic and economic stakes, particularly in young women among whom an increase of alcohol consumption related problems is reported. Another specificity of the female alcoholism is the lack of care seeking, whereas women have tendency globally to solicit more often care structures than men. Women represent only 1/4 of the overall treated alcoholic patients. The main explanation for this phenomenon is the pejorative social and moral connotation of the female alcoholism, with frequent feelings of shame and deep guilt, that also account for the frequency of hidden and lonely alcohol intakes. The female alcoholism is essentially characterized by an increased vulnerability to the toxic effects of the alcohol, whereas the pathological consumption starts later and with smaller daily amounts. Most studies have revealed a higher vulnerability in women to somatic complications directly attributable to the alcohol organs toxicity, such as hepatic cirrhosis and cardiovascular complications (high blood pressure, non obstructive cardiomyopathy). The reported brain morphological abnormalities could also occur more precociously in alcoholic women than in men. A decreased corpus callosum size among alcoholic women, but not in alcoholic men, was thus found in a recent study, compared with healthy controls. Among the different hypothesis proposed to explain this increased alcohol toxicity, the most incriminated is higher alcohol blood rates for the same ingested amount, mainly of the fact of a lower size with a weaker proportion of the bodily total water, but also of weaker concentrations of gastro-intestinal tract ADH, or of a longer metabolism during some menstrual phases. Indeed, some experimental studies on animal showed that the alcohol toxic effects may occur only from a threshold of alcohol blood rate. More recent studies suggest that the explanation to keep is more related to the lower gastric metabolism in women (lower ADH activity), than the difference of gastric volume or alcohol hepatic oxidation. Regarding to comorbidity, in the Epidemiologic Catchment Area survey, 65% of women, versus 44% of men, with abuse and/or dependence to alcohol had at least one another life-time psychiatric disorder (mainly depression and anxiety disorders), compared to 36% of the overall women of the studied sample. On the other hand, the alcohol dependence is, more often than in men, secondary to other psychiatric disorders, essentially depressive episodes, but less associated to antisocial behaviours. Among the different etiopathogenic factors involved in the alcohol dependence occurrence, genetic factors seem to have a determinant impact. According to the previous family, separation/adoption and twins studies performed, genetic factors could explain 50 to 60% of the alcoholism vulnerability in both men and women. In this context, and whereas we assist to the development of etiopathogenic models with new therapeutic perspectives in alcohol dependence, it seems necessary not to neglect female alcoholism specificities.
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PMID:[Clinical and biological specificities of female alcoholism]. 1250 62

Although the molecular basis for the pathophysiology of nonalcoholic steatohepatitis (NASH) is poorly understood, insulin resistance and mitochondrial dysfunction are physiologic hallmarks of this condition. We sought evidence of a transcriptional or pretranscriptional basis for insulin resistance and mitochondrial dysfunction through measurement of hepatic gene expression (messenger RNA [mRNA]) using high-density synthetic oligonucleotide microarray analysis (Hu6800 GeneChip, Affymetrix, CA). Global hepatic gene expression was determined in snap-frozen liver biopsy specimens from 4 groups: (1) patients with cirrhotic-stage NASH (n = 6), (2) patients with cirrhosis caused by hepatitis C virus (HCV) (n = 6), (3) patients with cirrhosis secondary to primary biliary cirrhosis (PBC) (n = 6), and (4) healthy controls (n = 6). Genes were considered to be expressed differentially in NASH only if there was a greater than 2-fold difference in abundance of mRNA when compared with each of the control groups. Sixteen genes were uniquely differentially expressed (4 overexpressed and 12 underexpressed) in patients with cirrhotic-stage NASH. Genes that were significantly underexpressed included genes important for maintaining mitochondrial function (copper/zinc superoxide dismutase, aldehyde oxidase, and catalase). Glucose 6-phospatase, alcohol dehydrogenase, elongation factor-TU, methylglutaryl coenzyme A (CoA), acyl CoA synthetase, oxoacyl CoA thiolase, and ubiquitin also were underexpressed in NASH. Genes that were overexpressed in NASH included complement component C3 and hepatocyte-derived fibrinogen-related protein, potentially contributing to impaired insulin sensitivity. In conclusion, these studies provide evidence for a transcriptional or pretranscriptional basis for impaired mitochondrial function (attenuated capacity for the dismutation of reactive oxygen species) and diminished insulin sensitivity (increased acute phase reactants) in patients with histologically progressive NASH. Further studies are required to determine the mechanism and the physiologic significance of these findings.
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PMID:Hepatic gene expression in histologically progressive nonalcoholic steatohepatitis. 1283 8

Ethanol toxicity on liver is a function of duration of alcoholism, amount of daily intake of alcohol and patient's nutrition. The threshold of alcohol toxicity on the liver is about 40 g of ethanol daily in men and 20-30 g in women, however liver cirrhosis develops in no more than 8-20% of patients exceeding this values. Ethanol is oxidized in the liver to acetaldehyde--a compound considerably more toxic than ethanol itself. Despite small amount of alcohol dehydrogenase (ADH) found in gastric mucosa, the metabolism of ethanol in this site may have an important hepatoprotective effect. The oxidation of ethanol is associated with a change of hepatocyte redox homeostasis, which leads to a number of metabolic disorders such as lactic acidosis, hyperlipidaemia and hyperuricaemia. Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, in particular cytochrome CYP2E1. This fact is responsible for development in alcoholic liver associated with rise of oxygen consumption, excessive production of free radicals and increased metabolism of ethanol, vitamin A and testosterone. Ethanol and acetaldehyde have a deleterious effect, both the direct and indirect, on hepatocytes e.g., generating radical oxygen species and damaging intestinal mucosal barrier. Cellular oxidative stress that is caused by both an excess of free radicals and the antioxidatives' deficiency (glutathion, vitamin E, phosphatidylcholine), may be the principal factor responsible for progression of alcoholic liver disease. Among other factors accelerating alcohol-related liver lesion there are certain drugs, high fat diet, infection with HCV and genetic factors (female sex, enzymatic polymorphic forms of ADH and ALDH, hemochromatosis). Great importance in pathogenesis of necrotic and inflammatory hepatic events is being attributed to portal endotoxaemia and cytokines induced within the liver, in particular TNF-alpha and interleukin 8. These cytokines play a key role in development of alcoholic hepatitis, which clinical severity ranges from subclinical to fatal forms. Apart from abstinence, the treatment of alcohol liver disease is based on hyperalimentation, since alcoholism is generally associated with protein malnutrition. In severe forms of alcohol hepatitis corticosteroids are recommended.
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PMID:[Alcoholic liver disease]. 1290 Dec 71

Early esophageal squamous cell carcinoma detected by esophageal iodine staining can be easily treated by endoscopic mucosectomy, and identifying its predictors is important in better selecting candidates to screen for this high-mortality cancer. The common etiologies of elevated mean corpuscular volume (MCV) and esophageal cancer, including folate deficiency, smoking, drinking and high acetaldehyde exposure, suggest testing MCV as such a predictor. Japanese alcoholic men with (n = 65) and without (n = 206) esophageal squamous cell carcinomas, excluding those with liver cirrhosis, were assessed for MCV within 7 days of their last drink, alone or in combination with findings from either the alcohol flushing questionnaire or genotyping to identify inactive aldehyde dehydrogenase-2 (ALDH2*1/2*2) and the less-active form of alcohol dehydrogenase-2 (ADH2*1/2*1), which pose risks for esophageal squamous cell carcinoma. MCV was higher in cancer patients than in the control group. MCV was higher in both groups in those who were heavier smokers, had lower body mass index (BMI), experienced alcohol flushing, and had ALDH2*1/2*2. After adjusting for age, drinking and smoking habits, BMI and ALDH2/ADH2 genotypes, macrocytosis of MCV > or =106 fl was associated with increased risk for esophageal cancer (OR = 2.75). Men with both MCV > or =106 fl and alcohol flushing had an even higher cancer risk (OR = 5.51). The combinations of MCV > or =106 fl with ALDH2*1/2*2 or ADH2*1/2*1 alone, and both ALDH2*1/2*2 and ADH2*1/2*1 (ORs = 11.44, 21.22 and 319.7, respectively) showed consistently higher risk than the corresponding group with MCV <106 fl (ORs = 7.24, 4.71 and 27.01, respectively). In conclusion, MCV measurement, alone or in combination with the markers of alcohol sensitivity, provides a new means of predicting risk for esophageal squamous cell carcinoma in Japanese alcoholic men.
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PMID:Macrocytosis, a new predictor for esophageal squamous cell carcinoma in Japanese alcoholic men. 1294 54


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