Metabolic and genetic liver diseases

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  • Created by: z
  • Created on: 20-02-16 18:03

3 consequences of genetic defect in metabolic path

Genrally due to deficiency of an enzyme

  • Accumulation of a toxin
    • if the defect is downstream of metabolism of a toxin
    • e.g. ammonia in urea cycle disease
  • Non producation of a needed molecule
    • e.g. glucose deficiency
  • Accumulation of a non-toxic metabolite proximal to block
    • e.g. in tyrosinemia
    • may become toxic itself after unusual metabolism
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Factors suggestive of metabolic liver disease

  • consanguinity
  • family history
  • dietary history ("trigger foods")
  • provocative symtpoms (e.g. jaundice) 
  • clinical phenotype 
  • hypoglycaemia and/or acidosis
  • biopsy findings
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Treatment of metabolic liver disease (general)

  • dietary (main)
    • manitain growth and anabolism
    • decrease metabolite accumluation
    • replace substrate
  • protein replacement
  • drug treatment
  • liver transplantation
  • somatic gene therapy
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Glycogen storage disease (GSD) Type 1

  • deficiency of glucose-6-phosphatase
    • converts glucose-6-phosphate to glucose
  • essentially means glycogen cannot converted back to glucose to use for cells to use
    • can still store glucose- just can't 'access' it
  • causes hypoglycaemia ~2 hrs after eating once initila glucose is used

Presentation

  • signs and symptoms from hypoglyaemia and lactic acidosis
  • irritability, pallor, cyanosis, hypotonia, tremors, convulsions, loss of consciousness, apnea, diarrhoea 

Management:

  • overnight tube feeding
  • frequent daytime feeds
  • uncooked corn starch
    • absorbed evry slowly- releases glucose over 4-6hrs so may be used overnight by older pts
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Tyrosinaemia Type 1

  • defect in tyrosine (an aa) metabolism
  • deficiency of fumarylacetoacetase (FAH)
  • causes build up of metabolites which are converted to succinylacetone
    • succinylacetone is not normally present on body- causes liver failure and kidney failure
    • disrupts porphyrin synthesis- part of haem synthesis so may present similar to AIP
  • if present v young- die of liver failure
  • if present >6 months- less severe- die of HCC as teens

Management:

  • Nitisinone + dietary tyronsine restriciiton
    • Nitisinone disrupts teh meatbolism proximally to FAH so the toxic meatbolites never accumulate
    • can reverse acute liver failure
    • but doesn't prevent risk of HCC if already have liver disease
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Liver transplant

  • Either because liver failure due to disease (e.g. Tyrosinaemia, Wilson's disease) or because metabolic disease arising form liver is very severe (even if there is no liver damage, e.g. Crigler-Najjar, haemophilia) 
  • in second instance may not need whole liver transplant (as very risky)
    • do auxiliary transplant- don't remove own, just add normal liver from donor

Hepastem

  • stem cell transplant
  • mesenchyme liver progenitor cells isolated form healthy adult tissue engrafted into liver to differentiate into mature hepatocyte-like cells
  • not currently shown to have a long term effect
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