Tyrosinemia I Hepatotoxicity

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Tyrosinemia I Hepatotoxicity

• Choonchu Kim (choonchu.kim_at_utoronto.ca)
• Earl Kim (earl.kim_at_utoronto.ca)
• Wilson Kwong (wilson.kwong_at_utoronto.ca)
• Tommy Pan (thomas_paine8_at_hotmail.com)
• March 12, 2008

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Tyrosinemia

• Error of metabolism
• Inability to break down tyrosine
• Tyrosine build up in body, plasma, urine
• 3 types (I, II, III)

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Tyrosine
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Type I Tyrosinemia

• aka hereditary infantile tyrosinemia
• most severe form
• death within 1 year if untreated
• affects 1 in 100,000
• most prevalent in Quebec, France,
  Scandinavia

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Type I Tyrosinemia

• deficient in enzyme fumarylacetoacetate
  hydrolase
• found in liver and renal proximal tubules
• genetic mutation on chromosome 15
• autosomal recessive inheritance

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Diagnosis

• diagnosed by the observation that plasma
  tyrosine and methionine levels were
  significantly elevated
• nodular cirrhosis ? post-mortem hallmark of the
  disease
• lab diagnosis tissue deficiency of
  fumarylacetoacetate hydrolase or
  presence of urinary succinylacetone

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Tyrosine catabolism
http//www.rxlist.com/images/rxlist/orfadin_cp_fig
2.gif
Source http//www.rxlist.com/images/rxlist/orfadi
n_cp_fig2.gif
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Symptoms

• Symptoms appear within the first few months of
  life
• reduced weight gain and growth rate
• diarrhea and vomiting
• jaundice
• smells like cabbage
• increased nosebleeds
• liver and kidney failure
• liver cancer
• nervous system effects
• death

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Genetics Overview

• The defect lies in the fumarylacetoacetate
  hydrolase (FAH) gene
• It is inherited in an autosomal recessive manner
• 25 chance of Tyrosinemia in the offspring of two
  carrier parents

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Genetics Overview
Source http//www.newbornscreening.info/Parents/
aminoaciddisorders/Tyrosinemia.html7
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Possible Defects

• The FAH gene is located on chromosome 15 on the
  long (q) arm between positions 23 and 25
• Approximately 35 kbs in length
• Many variants of mutation in the FAH gene have
  been found to date

Source Genetics Home Reference
http//ghr.nlm.nih.gov/genefah
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Examples of Possible Defects

• .0001 TYROSINEMIA, TYPE I FAH, ASN16ILE
• .0002 TYROSINEMIA, TYPE I FAH, ALA134ASP
• .0003 TYROSINEMIA, TYPE I FAH, IVS12, G-A, 5
• .0004 TYROSINEMIA, TYPE I FAH, GLU357TER
• .0005 TYROSINEMIA, TYPE I FAH, GLU364TER
• .0006 FUMARYLACETOACETASE PSEUDODEFICIENCY FAH,
  ARG341TRP
• .0007 TYROSINEMIA, TYPE I FAH, GLU337SER
• .0008 TYROSINEMIA, TYPE I FAH, ARG381GLY
• .0009 TYROSINEMIA, TYPE I FAH, TRP262TER
• .0010 TYROSINEMIA, TYPE I FAH, IVS6, G-T, -1
• .0011 TYROSINEMIA, TYPE I FAH, GLN279ARG
• The mutations are primarily amino acid
  substitutions or transcription terminations
• Also, intron-exon splice errors are present

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Epidemiology

• Throughout the world, no greater than 1 in
  100,000 with few exceptions
• In the Saguenay-Lac Saint Jean region of Quebec,
  1 in 1846 live births
• Newborn screening has indicated that 1 in 25
  people is a carrier for a mutation
• Introduced by early French settlers
• In Norway, 1 in 60,000 live births
• Exceptions also exist in Finland, Southern
  Europe, among Ashkenazi Jews and in the U.S.
• Genetic defect appears to have originated in
  Europe

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Biochemistry Overview
Source Orejuela, D. et al. 2008. Hepatic stress
in hereditary tyrosinemia type 1 (HT1) activates
the AKT survival pathway in the fah -/- knockout
mice model. Journal of Hepatology 48(2)308-317
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Biochemistry Overview

• FAH protein forms a homodimer within the
  cytoplasm
• Requires no cofactors
• Primarily expressed in liver and kidney but
  widely expressed in most tissues at very low
  levels

Fumarylacetoacetate hydrolase (FAH) Protein
Source Fumarylacetoacetate hydrolase - Wikipedia
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Biochemical Implications of FAH Mutation

• Lack of FAH produces an accumulation of toxic
  upstream metabolites
• Fumarylacetoacetate (FAA)
• Succinylacetone (SA)

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Biochemical Implications of FAH Mutation

• Fumarylacetoacetate (FAA)
• Believed to be responsible for the progressive
  injury to hepatocytes as it causes chromosomal
  instability
• Induces spindle disturbances and segregational
  defects
• Distorted spindles, lagging chromosomes,
  multinucleation
• Golgi complex is rapidly disturbed
• Succinylacetone (SA)
• Potent inhibitor of two enzymes -
  4-hydroxyphenylpyruvate dioxygenase (4-HPPD) and
  d-ALA dehydratase
• 4-HPPD is responsible for conversion of
  4-hydroxyphenylpyruvate into homogentisic acid
• Inhibition of 4-HPPD causes a buildup of tyrosine
• Inhibition of D-ALA dehydratase causes
  porphyria-like crises and neurologic symptoms

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Biochemical Implications of FAH Mutation

• AKT Survival Pathway
• Accumulation of toxic metabolites activates the
  AKT survival pathway
• AKT survival pathway inhibits intrinsic apoptosis
  to confer cell death resistance
• Favors hepatocarcinogenesis

Source Orejuela, D. et al. 2008. Hepatic stress
in hereditary tyrosinemia type 1 (HT1) activates
the AKT survival pathway in the fah -/- knockout
mice model. Journal of Hepatology 48(2)308-317
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Current Treatments

• Nitisinone (Orfadin)
• FDA approved in 2002
• Should be prescribed as soon as diagnosis is
  confirmed
• Prevents the enzymatic breakdown of tyrosine and
  accumulation of metabolites
• Early detection should reduce the risk of
  hepatocellular carcinoma
• Requires management of diet to control intake of
  phenylalanine and
• tyrosine
• Liver Transplant
• Indicated only if Nitisinone has failed
• Long term survival for 85 of transplant patient
• Challenges include shortage in donor organs and
  life long
• immunosuppression treatment

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Current Treatments
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Current Research

• Stem Cell Therapy
• In adult liver, mature hepatocytes can
  proliferate due to injury
• Source and nature of action is stillunknown
• Studies found bone marrow
• transplants in mouse with
• Tyrosinemia I gave rise to
• hepatocytes
• Hematopoietic stem cells in bone marrow gave rise
  to hepatocytes
• Advantage easy source of stem
• cells for liver therapy since donors already
  listed in registries,
• moderately invasive procedure,
• implication for use in other severe liver
  conditions

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Summary

• Tyrosinemia is a disease caused by an error in
  metabolism
• results in an inability to completely break down
  tyrosine
• type I is the most severe form and is usually
  fatal within 1 year if untreated
• diagnosed by tissue deficiency of
  fumarylacetoacetate hydrolase or presence of
  urinary succinylacetone
• symptoms appear within the first few months of
  life
• generally, 1 in 100,000 of live births inherit
  the disease
• autosomal recessive disorder
• the defect lies in the fumarylacetoacetate
  hydrolase (FAH) gene
• mutation in the FAH gene is primarily an amino
  acid substitution, a transcription termination,
  or a splice-site error
• FAH protein forms a homodimer within the
  cytoplasm, requiring no cofactors
• FAH protein metabolizes 4-fumarylacetoacetate to
  fumarate and acetoacetate
• without FAH, toxic metabolites fumarylacetoacetate
  (FAA) succinylacetone (SA) accumulate
• FAA causes chromosomal instability and disruption
  of golgi complex
• SA is a potent inhibitor of 4-hydroxyphenylpyruvat
  e (4-HPPD) d-ALA dehydratase
• recent research suggests activation of AKT
  survival pathway, inhibiting apoptosis to confer
  cell death resistance
• and promoting hepatocarcinogenesis
• Current treatments include the use of Nitisinone
  and liver transplant
• While both are effective, Nitisinone requires
  ongoing monitoring of diet liver transplant
  patients face challenges
• of donor shortages and life long use of
  immunosuppresant medications

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References

• Deepali, K. 2004. Tyrosinemia type I A
  clinico-laboratory case report. The Indian
  Journal of Pediatrics. 71(10)929-932.
• Lagasse, E. et al. Purified hematopoietic stem
  cells can differentiate into hepatocytes in vivo.
  Nature Medicine. 6 (11), 1229-1234 (2000).
• Lee, L.A. 2001. Advances in hepatocyte
  transplantation a myth becomes reality. The
  Journal of Clinical Investigation. 108(3)367-369
  
• McKiernan, P.J. 2006. Nitisinone in the Treatment
  of Hereditary Tyrosinaemia Type 1. Drugs.
  66(6)743-750
• Mitaka, T. 2001. Hepatic Stem Cells From Bone
  Marrow Cells to Hepatocytes. Biochemical and
  Biophysical Research Communications. 2811-5.
• Orejuela, D., Jorquera, R., Bergeron A., Finegold
  M.J., Tanquay R.M. 2008. Hepatic stress in
  hereditary tyrosinemia type 1 (HT1) activates the
  AKT survival pathway in the fah -/- knockout mice
  model. Journal of Hepatology 48(2)308-317
• Scott, C.R. 2006. The Genetic Tyrosinemias. Am J
  Med Genet C Semin Med Genet. 142(2)121-126
• Roth, Karl S. Tyrosinemia. eMedicine. 2007.
  WebMD. 8 March 2008.
  
  http//www.emedicine.com/ped/topic2339.htm
• http//ghr.nlm.nih.gov/genefah
• http//www.newbornscreening.info/Parents/aminoacid
  disorders/Tyrosinemia.html7
• http//www.rxlist.com/images/rxlist/orfadin_cp_fig
  2.gif