Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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 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

Tyrosinaemia I (fumarylacetoacetate hydrolase deficiency) is an autosomal recessive inborn error of tyrosine metabolism that produces liver failure in infancy or a more chronic course of liver disease with cirrhosis, often complicated by hepatocellular carcinoma, in childhood or early adolescence. We studied a 37-year-old woman with tyrosinaemia I whose severe liver disease in infancy and rickets during childhood resolved with dietary therapy. From 14 years of age she resumed an unrestricted diet with the continued presence of the biochemical features of tyrosinaemia, yet maintained normal liver function. In adult years she accumulated only small amounts of succinylacetone. Despite this evolution to a mild biochemical and clinical phenotype, she eventually developed hepatocellular carcinoma. Her fumarylacetoacetate hydrolase genotype consists of a splice mutation, IVS6-1g>t, and a novel missense mutation, Q279R. Studies of resected liver demonstrated the absence of hydrolytic activity and of immunological expression of fumarylacetoacetate hydrolase in liver tumour. In nontumoral areas, however, 53% of normal hydrolytic activity and immunologically present fumarylacetoacetate hydrolase was found. This case demonstrates the high risk of liver cancer in tyrosinaemia I even in a seemingly favourable biological environment.
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PMID:Hepatocellular carcinoma despite long-term survival in chronic tyrosinaemia I. 1119 5

Whereas ch/ch wild-type mice and ch/14CoS heterozygotes are viable, 14CoS/14CoS mice homozygous for a 3800 kb deletion on chromosome 7 die during the first day postpartum. Death is caused by disruption of the fumarylacetoacetate hydrolase (Fah) gene; absence of FAH, final enzyme in the tyrosine catabolism pathway, leads to accumulation of reactive electrophilic intermediates. In this study, we kept 14CoS/14CoS mice alive for 60 d with oral 2-(2-nitro-4-trifluoromethyl-benzyol)-1,3-cyclohexanedione (NTBC), an inhibitor of p-hydroxyphenylpyruvate dioxygenase, second enzyme in the tyrosine catabolic pathway. The 70% of NTBC-treated 14CoS/14CoS mice that survived 60 d showed poor growth and developed corneal opacities, compared with ch/14CoS littermates; NTBC-rescued Fah(-/-) knockout mice did not show growth retardation or ocular toxicity. NTBC-rescued 14CoS/14CoS mice also exhibited a striking oxidative stress response in liver and kidney, as measured by lower GSH levels and mRNA induction of four genes: glutamate cysteine ligase catalytic (Gclc) and modifier (Gclm) subunits, NAD(P)H:quinone oxidoreductase (Nqo1), and heme oxygenase-1 (Hmox1). Withdrawal of NTBC for 24-48 h from rescued adult 14CoS/14CoS mice resulted in severe apoptosis of the liver, detected histologically and by cytochrome c release from the mitochondria, increased caspase 3-like activity, and further decreases in GSH content. In kidney, proximal tubular epithelial cells were abnormal. Human hereditary tyrosinemia type I (HT1), caused by mutations in the FAH gene, is an autosomal recessive disorder in which the patient usually dies of liver fibrosis and cirrhosis during early childhood; NTBC treatment is known to prolong HT1 children's lives-although liver fibrosis, cirrhosis, hepatocarcinoma, and corneal opacities sometimes occur. The mouse data in the present study are consistent with the possibility that endogenous oxidative stress-induced apoptosis may be the underlying cause of liver pathology seen in NTBC-treated HT1 patients.
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PMID:Pharmacological rescue of the 14CoS/14CoS mouse: hepatocyte apoptosis is likely caused by endogenous oxidative stress. 1289 38

Hereditary tyrosinemia I (HT I) is a genetic disorder of tyrosine metabolism caused by abnormalities of fumarylacetoacetate hydrolase. Disturbances in tyrosine metabolism lead to increased levels of succinylacetone and succinylacetoacetate. However, the mechanisms causing liver failure, cirrhosis, renal tubular dysfunction, and hepatocarcinoma are still unknown. Alterations in gene expression found in the livers of patients with HT I are responsible for the pathogenesis of this disease, for example acute liver failure. Therefore, gene expression analysis allows us to better understand its pathogenesis. We analyzed gene expressions in tyrosinemia type I model mice with liver failure using microarrays. The results were confirmed by quantitative PCR to evaluate the pathogenesis of tyrosinemia type I. We found that numerous genes, including amino acid metabolism and apoptosis related genes, were up- or down-regulated at the onset of liver failure. These findings are useful in understanding the pathogenesis of hereditary tyrosinemia.
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PMID:Gene expression profiles of homogentisate-treated Fah-/- Hpd-/-mice using DNA microarrays. 1689 83

Hereditary tyrosinemia I (HT I) is a genetic disorder of tyrosine metabolism characterized by progressive liver damage from infancy and by a high risk for hepatocellular carcinoma. HT I is due to mutations in the fumarylacetoacetate hydrolase (Fah) gene, which encodes the last enzyme in the tyrosine catabolic pathway. Disturbances in tyrosine metabolism lead to increased levels of succinylacetone and succinylacetoacetate. However, the mechanisms causing liver failure, cirrhosis, renal tubular dysfunction, and hepatocarcinoma are still unknown. Lethal albino deletion c14CoS mice and mice with target-disrupted Fah are models for HT I. They die in the perinatal period, although with a different phenotype from that seen in HT I in humans. In addition, 2 mouse strains that carry N-ethyl-N-nitrosourea-induced mutations in the Fah gene have been described. Mice with a splice mutation exhibit the milder features of the clinical phenotype. In mice that carry both Fah and 4-hydroxyphenylpyruvate dioxygenase gene mutations, administration of homogentisate results in rapid apoptosis of hepatocytes. Simultaneously, renal tubular epithelial cells are injured, resulting in Fanconi syndrome. These are central features of visceral injury in patients with HT I. Apoptosis of hepatocyte and renal tubular cells is prevented by the caspase inhibitors acetyl-Tyr-Val-Ala-Asp-CHO or acetyl-Asp-Glu-Val-Asp-CHO. Apoptosis of hepatocytes and renal tubular epithelial cells are central features of this disease. Alterations in gene expression found in the liver of patients with HT I are responsible for the pathogenesis of this disease, for example, acute liver failure. Therefore, gene expression analysis allows a better understanding of the specific pathogenesis. Cell fusion of hematopoietic stem cells with hepatocytes leads to liver regeneration after liver injury. This finding was possible after using the liver injury model of HT I in Fah null mice. Thus, animal models of tyrosinemia are unique and useful tools to reveal mechanisms of interest to both clinical and basic science.
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PMID:Animal models of tyrosinemia. 1751 24

In 1957 Sakai and Kitagawa in Japan reported the clinical and biochemical findings in a patient with tyrosinemia, tyrosyluria, liver cirrhosis, and renal rickets. Subsequently, reports were published from various countries of other patients with hepatorenal tyrosinemia (HRT). 4-Hydroxyphenylpyruvate dioxygenase deficiency was originally proposed as the cause of HRT. However, in 1977 Lindblad et al. found that succinylacetone, which accumulates in the serum and urine from patients with HRT, inhibits delta-aminolevulinic acid (ALA) dehydratase in vitro. They suggested that the primary enzyme deficiency in patients with HRT was fumarylacetoacetate hydrolase, and this was soon confirmed. Thus, the elucidation of the pathogenesis of this disease has led to the possibility that, if a reliable newborn screening method could be developed, the prognosis of these patients would be improved. Early treatment would require a diet low in phenylalanine and tyrosine, administration of 2-(2-nitoro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), and liver transplantation.
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PMID:Hepatorenal tyrosinemia. 2268 40

Tyrosinemia type I is an autosomal recessively inherited metabolic disease of tyrosine metabolism due to the deficiency of fumarylacetoacetate hydrolase. Clinical manifestations include hepatic failure, cirrhosis, hepatocellular carcinoma, renal fanconi syndrome, and neurologic crisis. With the introduction of 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione treatment the prognosis improved with reduced rate of complications. "Neurologic crisis" of tyrosinemia type I is a rare complication seen after discontinuation of treatment characterized with anorexia, vomiting, and hyponatremia in the initial phase continuing with paresthesia and paralysis of the extremities and the diaphragm. Here, we report a tyrosinemia type I patient who admitted to the hospital with nonspecific symptoms such as vomiting, anorexia, weakness, and restlessness only after one month discontinuation of nitisone and diagnosed as neurological crisis.
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PMID:Tyrosinemia type 1 and irreversible neurologic crisis after one month discontinuation of nitisone. 2718 89

Tyrosinemia type I (TYRSN1, TYR I) is caused by fumarylacetoacetate hydrolase (FAH) deficiency and affects approximately one in 100,000 individuals worldwide. Pathogenic variants in FAH cause TYRSN1, which induces cirrhosis and can progress to hepatocellular carcinoma (HCC). TYRSN1 is characterized by the production of a pathognomonic metabolite, succinylacetone (SUAC) and is included in the Recommended Uniform Screening Panel for newborns. Treatment intervention is effective if initiated within the first month of life. Here, we describe a family with three affected children who developed HCC secondary to idiopathic hepatosplenomegaly and cirrhosis during infancy. Whole exome sequencing revealed a novel homozygous missense variant in FAH (Chr15(GRCh38):g.80162305A>G; NM_000137.2:c.424A > G; NP_000128.1:p.R142G). This novel variant involves the catalytic pocket of the enzyme, but does not result in increased SUAC or tyrosine, making the diagnosis of TYRSN1 problematic. Testing this novel variant using a rapid, in vivo somatic mouse model showed that this variant could not rescue FAH deficiency. In this case of atypical TYRSN1, we show how reliance on SUAC as a primary diagnostic test can be misleading in some patients with this disease. Augmentation of current screening for TYRSN1 with targeted sequencing of FAH is warranted in cases suggestive of the disorder.
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PMID:Silent Tyrosinemia Type I Without Elevated Tyrosine or Succinylacetone Associated with Liver Cirrhosis and Hepatocellular Carcinoma. 2739 3

Hereditary tyrosinemia type I (HT1) is caused by a deficiency in the enzyme fumarylacetoacetate hydrolase (Fah). Fah-deficient mice and pigs are phenotypically analogous to human HT1, but do not recapitulate all the chronic features of the human disorder, especially liver fibrosis and cirrhosis. Rats as an important model organism for biomedical research have many advantages over other animal models. Genome engineering in rats is limited till the availability of new gene editing technologies. Using the recently developed CRISPR/Cas9 technique, we generated Fah(-/-) rats. The Fah(-/-) rats faithfully represented major phenotypic and biochemical manifestations of human HT1, including hypertyrosinemia, liver failure, and renal tubular damage. More importantly, the Fah(-/-) rats developed remarkable liver fibrosis and cirrhosis, which have not been observed in Fah mutant mice or pigs. Transplantation of wild-type hepatocytes rescued the Fah(-/-) rats from impending death. Moreover, the highly efficient repopulation of hepatocytes in Fah(-/-) livers prevented the progression of liver fibrosis to cirrhosis and in turn restored liver architecture. These results indicate that Fah(-/-) rats may be used as an animal model of HT1 with liver cirrhosis. Furthermore, Fah(-/-) rats may be used as a tool in studying hepatocyte transplantation and a bioreactor for the expansion of hepatocytes.
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PMID:Efficient liver repopulation of transplanted hepatocyte prevents cirrhosis in a rat model of hereditary tyrosinemia type I. 2751 Feb 66


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