Metabolic and genetic liver diseases

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

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

• dietary (main)
  • manitain growth and anabolism
  • decrease metabolite accumluation
  • replace substrate
• protein replacement
• drug treatment
• liver transplantation
• somatic gene therapy

• 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

• 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

• 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