Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tyrosinaemia type I is a recessively inherited disorder caused by a deficiency of fumarylacetoacetase (FAH), the last enzyme in tyrosine degradation. The presumed toxic agents are fumaryl- and maleylacetoacetate which are converted to succinylacetone (SA), a metabolite found in increased amounts in urine and plasma of the patients. The major clinical features are progressive liver damage and renal tubular defects with hypophosphataemic rickets. Renal tubular dysfunctions with secondary rickets may be lacking altogether, even in chronic patients. Hepatocellular carcinoma is a major cause of death in the chronic form. Diagnosis of the disorder is made by assay of SA in urine and serum and by determination of FAH in lymphocytes or fibroblasts. Prenatal diagnosis is performed by SA assay in amniotic fluid supernatant and FAH analysis in cultured amniotic fluid cells or chorionic villus material. Presence of a 'pseudodeficiency' gene for FAH prevents prenatal diagnosis by enzyme analysis in some families, and this gene also precludes identification of heterozygotes outside tyrosinaemia families. Immunoblot analyses show that acute patients and some chronic patients lack immunoreactive FAH protein. cDNA probes for FAH have been developed and several polymorphisms related to the FAH gene have been reported, which may allow prenatal diagnosis in families with complex genotypes. The gene for FAH has been mapped to chromosome 15 q23-q25. Liver transplantation is the ultimate treatment; most patients continue to excrete SA in urine after liver transplantation and therefore there is a possibility of kidney disease after transplantation.
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PMID:Tyrosinaemia type I--an update. 174 21

Hereditary tyrosinemia type I presents with either acute hepatic failure in the neonatal period or later in infancy with progressive liver dysfunction secondary to cirrhosis. The inevitably fatal outcome in those children with the chronic form has been transformed with the advent of liver transplantation. Native livers from five children who received allografts were studied pathologically and compared with earlier hepatic biopsies in two of these patients that had been performed several years before transplantation. Our findings support the conclusion that a sequence of morphologic changes from the initial micronodular cirrhosis through an intermediate mixed cirrhotic pattern to macronodular cirrhosis occurs. The micronodular phase is transitory, over a period of only a few months, since mixed micronodular macronodular cirrhosis was already present in the livers of children who received transplants by 11 months of age. Focal hepatocellular dysplasia was present in one of the livers with mixed cirrhosis but was not identified in the other two cases. Macronodular cirrhosis accompanied two cases of hepatocellular carcinoma in this study. In order to preclude the latter complication, liver replacement is necessary before the age of 2 years.
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PMID:Hereditary tyrosinemia type I (chronic form): pathologic findings in the liver. 253 31

Hereditary tyrosinemia type I is a metabolic disorder of autosomal recessive inheritance. The disorder is characterized by progressive liver disease and renal tubular defects with accompanying hypophosphatemic rickets. It occurs in an acute and a chronic form. Hepatocellular carcinoma is frequently encountered in the chronic form of the disorder. The primary enzyme defect is a deficiency of fumarylacetoacetase (FAH) (EC 3.7.1.2), the last enzyme in the degradation of tyrosine. The enzyme defect results in accumulation of fumaryl- and maleyl-acetoacetate which are thought to cause the cellular damage in tyrosinemia. Fumaryl- and maleyl-acetoacetate are reactive compounds and have not been identified in tyrosinemia patients. Succinylacetone, however, presumably derived from these metabolites by reduction and decarboxylation, is elevated in serum and urine from the patients. The diagnosis of tyrosinemia can be established by determination of succinylacetone in urine or serum and by assay of FAH in lymphocytes and fibroblasts. Heterozygotes for FAH can be identified by fumarylacetoacetase analysis in lymphocytes and fibroblasts. Prenatal diagnosis of tyrosinemia is possible by analysis of succinylacetone in amniotic fluid supernatant and by assay of FAH in cultured amniotic fluid cells or chorionic villus material. Genetic variants of FAH may interfere in the prenatal diagnosis of tyrosinemia by the FAH assay and in the detection of the carrier state. Immunoblotting technique has shown absence of immunoreactive protein in liver tissue from tyrosinemia patients. Liver transplantation is as yet the only definite treatment of the disorder.
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PMID:Hereditary tyrosinemia type I--an overview. 329 30

Tyrosinaemia type I is, untreated, a fatal disease: in the acute form from liver failure, in the chronic form often from hepatocellular carcinoma. Acute neurological crisis is also a cause of death. Traditionally the treatment has been with diet, but for a decade liver transplantation has been the ultimate treatment. The continuous production of the pathological metabolites in the kidneys after transplantation appears to be without significance. Introduction of the enzyme inhibitor NTBC in the treatment of tyrosinaemia has reduced the need for liver transplants. Neonatal screening may be justified as efficient treatment has become available. The complex phenotype of lethal albino mice, with severe alterations in gene expression, has been shown to be caused by fumarylacetoacetase deficiency. Prolonged hypoglycaemia in otherwise adequately treated tyrosinaemia patients may result from depressed expression of genes coding for enzymes in gluconeogenesis, as seen in the mouse model. Self-induced genetic correction in liver tissue that occurs in many tyrosinaemia patients may reduce the risk of liver failure in some patients.
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PMID:Tyrosinaemia--treatment and outcome. 749 96

Hereditary tyrosinemia type I (HTT-I) is an inherited metabolic disorder with severe liver disease and a high risk for hepatic malignancy. Patients with HTT-I are monitored with repeated analyses of serum amino acids, urine succinylacetone, and serum alpha-fetoprotein (AFP). Oncofetal markers CA 125 and CA 19-9 are elevated in serum of patients with various gastrointestinal diseases and malignancy. To study the biology of oncofetal antigens in tyrosinemia and to assess the possible usefulness of these markers in HTT-I, we studied serum concentrations of CA 125 (n = 160) and CA 19-9 (n = 188), together with AFP (n = 337), in serial samples from 10 patients. At early stages of the disease, most children with an acute type of disease had a remarkably elevated serum CA 125 concentration (153-1560 IU/L) that normalized gradually after the institution of therapy. Serum CA 125 levels may thus reflect acute metabolic imbalance in fulminant HTT-I. The patients with a chronic type of disease showed CA 125 levels within the normal range at diagnosis that slowly increased as the liver condition worsened. These concentrations, however, never reached values seen in acute HTT-I. Serum concentration CA 19-9 in HTT-I was mostly normal. Serum AFP levels fluctuated in all patients and positively correlated with tests for metabolic state and biliary function. A distinct increase in the serum AFP level was recorded in association with the detection of massive hepatocellular carcinoma and also preceded metabolic imbalance leading to porphyria crises.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum levels of oncofetal markers CA 125, CA 19-9, and alpha-fetoprotein in children with hereditary tyrosinemia type I. 751 78

Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.
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PMID:Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. 754 95

Hereditary tyrosinemia type I (McKusick 27670) is a heterogeneous disease with poor prognosis, yet there are few reports of the long-term prognosis. It is therefore difficult to decide on the treatment for individual patients. We have conducted an international survey of patients with tyrosinemia type I and examined the probability of survival on dietary treatment and the causes of death in 108 patients with tyrosinemia type I. The survival after the onset of symptoms varied with the age at onset; the earlier the symptoms developed the poorer the outlook. Liver failure and recurrent bleeding (67%), hepatocellular carcinoma (17%) and the porphyria-like syndrome with respiratory failure (10%) were the most common causes of death. The 1- and 2-yr survival probability after the onset of symptoms in patients in whom symptoms developed before 2 mo, between 2 and 6 mo and after 6 mo were 38%/29%, 74%/74% and 96%/96%, respectively. On the basis of these survival rates, a new classification--which is important with respect to choices in treatment--is proposed: very early (onset of symptoms < 2 mo), early (2 to 6 mo) and late presenting form (> 6 mo).
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PMID:Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment. 792 51

Hereditary tyrosinemia type I (HTI) (MIM 276700) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (EC 3.7.1.2), which is the last enzyme in the tyrosine degradation pathway. The enzyme block causes accumulation of toxic metabolites in the liver and kidneys, which are the organs where tyrosine is mainly degraded. The disorder is characterized by severe liver disease, which either causes liver failure in infancy or may take a more protracted course, with death often occurring during childhood or adolescence because of hepatoma development. Treatment with a diet restricted in phenylalanine nd tyrosine does not prevent progression of the liver disease and development of hepatocellular carcinoma. Liver transplantation was previously the only option for these patients. Important achievements from metabolic and molecular biology studies of the disease include a new treatment for patients with HTI using an enzyme inhibitor, detection of self-induced correction of the genetic defect in regenerative liver nodules in HTI patients, identification and development of useful animal models for HTI, and studies of the molecular genetics of HTI. These advances will have great implications for our understanding of pathogenetic mechanisms, which is the basis for improved diagnostic methods and improved treatment of patients with HTI.
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PMID:Diagnosis and management of tyrosinemia type I. 877 26

Hereditary tyrosinemia type I (HT I, McKusick 276,700) is a metabolic disease with a pattern of autosomal recessive inheritance. The disease is caused by a deficiency of the enzyme involved in the last step in the degradation of the amino acid tyrosine, fumarylacetoacetate hydrolase (FAH). The result of this block is the accumulation of catabolites some of which have been proposed to be highly toxic due to their alkylating potential. In humans, hereditary tyrosinemia is often associated with the development of hepatocellular carcinoma in young patients. The reasons for the high incidence of hepatocellular carcinoma are unknown but it has been suggested that it may be caused by accumulated metabolites such as fumarylacetoacetate (FAA) and maleylacetoacetate (MAA). The various mutational defects in the FAH gene are reviewed. The use of two mouse models of this disease to study the molecular basis of the pathologies associated with HT I are discussed. Finally, some preliminary data on the mutagenic potential of FAA and MAA in a gene reversal assay are presented.
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PMID:Tyrosine and its catabolites: from disease to cancer. 879 Jul 25

Hereditary tyrosinemia type I (HTI, McKusick 276700) is an autosomal recessive disease caused by deficient fumarylacetoacetate hydrolase (FAH, EC 3.7.1.2) activity. HTI is characterized by progressive liver dysfunction with nodular cirrhosis often leading to hepatocellular carcinoma. Two extremes of the clinical phenotype have been described: the "acute" (severe, early onset and death) and "chronic" (delayed onset and slow course) phenotype. Allelic heterogeneity and/or mutation reversion in hepatic cells have been proposed earlier to explain the clinical heterogeneity. Two probands (one "acute," one "chronic") from the French-Canadian isolate where HTI is prevalent were studied. Both were homozygous (germ line) for the severe splice mutation IVS12 + 5g --> a; both showed liver mosaicism for FAH immunoreactivity with evidence for mutation reversion to heterozygosity (IVS12 + 5g --> a/+) in FAH-stained nodules as shown by amplification of DNA extracted from microdissected nodules. Western blot analysis of proteins from a reverted FAH-expressing nodule showed 29 +/- 3% FAH immunoreactive material as compared to an average normal liver. This was consistent with the measured FAA hydrolytic activity (25%) in this large regenerating nodule. These findings show that genotypic heterogeneity is not a sufficient explanation for clinical heterogeneity and implicate epigenetic and other factors modifying the phenotype in HTI.
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PMID:Different clinical forms of hereditary tyrosinemia (type I) in patients with identical genotypes. 970 36


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