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)

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

Hepatocellular carcinoma (HCC) is the seventh most common cancer in men and the ninth most common cancer in women with 500,000 to 1,000,000 new cases per year. Several risk factors (sex hormones, alcohol, thorotrast, aflatoxin B1, hepatitis B or C, haemochromatosis, alpha 1-antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda, acute intermittent porphyria, Wilson's disease) associated with the development of HCC have been identified from epidemiological studies. The diagnosis is usually based on a combination of clinical and laboratory findings together with radiographic and histopathologic characteristics. HCC remains difficult to treat with a median survival of 3 to 6 months after the onset of symptoms. Surgical resection is the mainstay of treatment for HCC. Transcatheter arterial embolization and percutaneous ethanol injection have been used but neither therapy has been evaluated in a prospective randomized study. Combination treatment (e.g. chemotherapy and resection) may be of value but randomized controlled trials with long-term follow-up are still needed. Liver transplantation should be reserved for carefully selected patients.
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PMID:Management options for primary hepatocellular carcinoma. An overview. 781 21

The histology of 72 livers from 72 children who underwent liver transplantation was reviewed. Nine children (12.5%) had hepatocellular carcinoma (HCC) and/or liver cell dysplasia (LCD) in their native livers. Ages at the time of transplantation ranged from 2 months to 11 years. Primary liver diseases included tyrosinemia (3), biliary atresia (2), chronic active hepatitis B (1), chronic active non-A non-B non-C hepatitis (1), idiopathic neonatal hepatitis (1), and neonatal iron storage disease (1). Explanted livers showed large multifocal HCC in two cases, incidental HCC in three, and dysplastic nodules in four. LCD also was present in three cases in conjunction with HCC. All patients had cirrhosis. Alpha-fetoprotein was measured in six children and was elevated in all six (range, 300 to 1,770,000 ng/mL; normal, 0 to 15 ng/mL). Abdominal computed tomography, ultrasonography, and/or magnetic resonance imaging showed large masses in two cases, but did not detect the tumors of less than 2 cm or the dysplastic nodules in the other seven children. After a follow-up period of 2 months to 3 years (mean, 19.8 +/- 12.1 months), eight children are alive and have no evidence of recurrence. The patient with neonatal iron storage disease died 2 months after transplantation, without evidence of tumor recurrence. The authors conclude that children with end-stage liver disease of diverse causes referred for liver transplantation may have LCD and/or HCC. Serial determination of alpha-fetoprotein and images studies may detect early lesions curable by liver transplantation.
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PMID:Hepatocellular carcinoma and liver cell dysplasia in children with chronic liver disease. 784 22

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

The most early cirrhosis is observed in newborns with neonatal hemachromatosis. Early cirrhosis occurs in hereditary tyrosinemia type I, peroxisomal diseases and glycogen storage disease (type IV). In Wilson's disease, a case complicated with cirrhosis was reported in a 4-year-old patient. Slowly progressive cirrhosis is seen in patients with familial progressive intrahepatic cholestasis. Focal biliary cirrhosis is found in cystic fibrosis of the pancreas. Moreover, many other metabolic disorders, except for urea cycle disorders, are occasionally or rarely complicated with cirrhosis. Early diagnosis and proper management could prevent the development of cirrhosis in patients with galactosemia, hereditary fructose intolerance, etc. The occurrence of hepatoma must be monitored in these patients. Liver transplantation is indicated in a part of the patients with cirrhosis.
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PMID:[Liver cirrhosis in metabolic disorders]. 811 97

Tyrosinemia represents a very small percentage of patients undergoing liver transplantation world-wide. This disease is endemic within our referral area however, one-third of the liver transplantations at our institution are done for this disease. Since 1986, 16 patients with tyrosinemia and 34 patients with various other indications (non-tyrosinemic) have undergone a total of 55 liver transplantation. The survival rate for tyrosinemic patients is 87%, compared to 75% for non-tyrosinemic patients. Liver transplantation for hereditary tyrosinemia and other metabolic disorders without portal hypertension or previous portohepatic operations is notably easier to perform. Intraoperative blood loss was less, length of hospital stay was shorter and incidence of infections was lower in tyrosinemic than in non-tyrosinemic patients. Less than 10% of tyrosinemic patients had foci of hepatocellular carcinoma at the time of transplantation. For this reason, and while most patients with tyrosinemia will eventually require liver transplantation, our results do not support systematic early transplantation.
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PMID:[Surgical and metabolic aspects of liver transplantation for tyrosinemia]. 814 43

Tyrosinemia is the diagnosis of a very small percentage of patients undergoing liver transplantation worldwide. Tyrosinemia is endemic within our referral area however, and fully one-third of the liver transplantations at our institution are done for this disease. Since 1986, 15 patients with tyrosinemia (TYR) and 31 patients with various other indications (non-TYR) have undergone a total of 51 liver transplantations. The 36-month actuarial survival for TYR patients is 87%, compared with 74% for non-TYR patients. Liver transplantation for hereditary tyrosinemia and other metabolic disorders without portal hypertension or previous portohepatic operations is notably easier to perform. Intraoperative blood loss was less, length of hospital stay was shorter, and incidence of infections was lower in TYR than in non-TYR patients. Less than 10% of TYR patients had foci of hepatocellular carcinoma at the time of transplantation. For this reason, and while most patients with tyrosinemia will eventually require liver transplantation, our results do not support systematic early transplantation before the age of two years.
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PMID:Surgical and metabolic aspects of liver transplantation for tyrosinemia. 827 6

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

Tyrosinemia, a genetic disorder of the liver and kidneys, is caused by reduced activity of fumarylacetoacetate hydrolase (FAH), the final enzyme in the degradation of tyrosine. The consequent presence of succinylacetone in urine or blood is pathognomonic of tyrosinemia and is used as a confirmatory test in the Quebec neonaral screening program. Due to a complex founder effect, the province of Quebec has an unusually high prevalence of tyrosinemia, particularly in the Saguenay-Lac Saint-Jean region (where the prevalence is 1 in 1850). Tyrosinemia has several different clinical presentations, ranging from acute liver failure with severe coagulopathy early in life, to slowly progressing cirrhosis with multiple nodules and variable renal dysfunction, to normal liver function with renal failure. Hepatocarcinoma has been found in approximately one third of cases. FAH complementary DNA has been cloned and mapped to chromosome 15q23-q25. The mutation observed in Quebec is a splice mutation at intron 12. This mutation is common and has been observed in other areas of the world as well, although more than 20 mutations causing tyrosinemia have now been described. Liver transplantation remains the definitive treatment. The author's team has carried out 28 liver transplantations (including 2 combined liver-kidney transplantations) in 25 children. The overall survival rate has been 92%; two children died as a result of primary nonfunction. The primary indications for transplantation were hepatic nodules (in 14 cases), neurological crises (6) and hepatic (3) or renal failure (2). An abnormal glomerular filtration rate (GFR) of less than 80 mL/min per 1.73 m2 was documented before transplantation in 54% of the cases. The rate normalized after liver transplantation in most patients, with rapid improvement in tubular function. However, patients with a severely low rate (less than 55 mL/min per 1.73 m2) before transplantation still had borderline renal function and poor growth after the transplantion, despite normal liver function. Therefore, for children with a consistently low GFR, careful consideration should be given to performing a combined liver-kidney transplantation, and a renal biopsy should form part of the pretransplantation evaluation.
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PMID:Tyrosinemia: the Quebec experience. 888 68

Hereditary tyrosinemia 1 (HT1) is characterized by progressive liver damage, from infancy, and by a high risk for hepatocellular carcinoma. HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. Lethal albino deletion c14CoS mice and mice with target-disrupted Fah are models for HT1, but they die in the perinatal period, albeit with a different phenotype from that seen in HT1 in humans. We first asked whether homozygous null mutation of the 4-hydroxyphenylpyruvate dioxygenase gene Hpd could rescue the homozygous c14CoS mice (c14CoS/c14CoS or Fah-/-). The double mutant Fah-/- Hpd-/- mice appeared normal, at least until age 18 months, and there was no evidence of liver disease, findings that facilitated examination of the effect of Fah-/- on mature and unmodified hepatocytes in vivo. The hepatocytes of Fah-/- undergo rapid apoptosis, and acute death follows. Essentially the same phenomena were observed when Fah-/- Hpd-/- mice were administered homogentisate intraperitoneally. These changes in liver pathology in Fah-/- Hpd-/- mice after the administration of homogentisate were associated with massive urinary excretion of succinylacetone. These results suggest that accumulation of fumarylacetoacetate, maleylacetoacetate, or succinylacetone seems to trigger the endogenous process of apoptosis in hepatocytes that lack fumarylacetoacetate hydrolase activity. This apoptosis may be related to the development of hepatocellular carcinomas seen in HT1 patients and pharmaceutically treated fumarylacetoacetate hydrolase-deficient mice.
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PMID:Complete rescue of lethal albino c14CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway. 930 2


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