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Liver and intrahepatic bile ducts-nontumor

Metabolic diseases

Hereditary tyrosinemia


Reviewers: Komal Arora, M.D. (see Reviewers page)
Revised: 2 May 2012, last major update May 2012
Copyright: (c) 2004-2012, PathologyOutlines.com, Inc.

General
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Type I: Autosomal recessive disease caused by deficiency of fumarylacetoacetate hydrolase, the last enzyme in the catabolic pathway of tyrosine; high prevalence (1 per 1846 births) in eastern (Saguenay-Lac Saint-Jean) Quebec (GeneReviews, Tyrosinemia Type 1, last update August 25, 2011)
● Also called FAH Deficiency, Hepatorenal Tyrosinemia, Hereditary Tyrosinemia Type I, Fumarylacetoacetase Deficiency, Fumarylacetoacetate Hydrolase Deficiency
● May be severe, affecting liver, kidneys, nervous system, but also clinically heterogeneous, with no correlation between genotype and phenotype
● Acute form causes hepatic failure in newborns and death by age 1 without treatment (Am J Hum Genet 1990;47:317)
● Chronic form is milder, with chronic liver disease, renal tubular dysfunction, hypophosphatemia with rickets and increased risk for hepatocellular carcinoma
● 80% of patients have reversion of mutant alleles in hepatocytes, associated with better prognosis; i.e. no dysplasia, no carcinoma (Hum Pathol 2003;34:1313)

Diagrams
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Tyrosine metabolic pathway

Treatment
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● 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC) reduces accumulation of toxic metabolites
● Possibly liver transplantation (Pediatr Transplant 2011;15:400)

Micro description
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● Hepatocellular degeneration with focal fatty change, particularly in regenerative nodules
● Pseudorosettes, cholestasis, fibrosis, cirrhosis

Micro images
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Chronic tyrosinemia


Mosaic FAH expression in livers from patients with acute, subacute, and chronic disease:
(A) Acute patient: liver explant from 6 month old patient reveals micronodular cirrhosis with an occasional small focus of reversion when immunostained with anti-FAH antibody
(B) Subacute patient: liver explant from 27 month old patient reveals mixed macronodular-micronodular cirrhosis; reversion occurs primarily in macronodules
(C) Chronic patient: mixed macronodular and micronodular cirrhosis with single well-delimited carcinomatous nodule in explanted liver
(D) Same patient as (C): immunostaining of adjacent section with anti-FAH reveals extensively reverted nodules; note that carcinomatous nodule remains unstained
(E) Chronic patient: liver explant from patient at 10 years, 9 months reveals relatively well-preserved architecture with little fibrosis
(F) Same patient as (E): immunostaining of adjacent section reveals extensive reversion


Electron microscopy description
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● Cholestasis, lipid droplets, increased endoplasmic reticulum, abnormal mitochondria

End of Liver and intrahepatic bile ducts-nontumor > Metabolic diseases > Hereditary tyrosinemia


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