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home - Liver - Metabolic Conditions - Haemochromatosis Pathology Written by Dr Sebastian Zeki
Knowledge


Recognises and appropriately investigates patients with auto-immune
liver diseases

Aware of management and complications of autoimmune liver
disease including extra-hepatic manifestations and associations
including malignant complications in PSC

Skills
Appreciates and understands that this range of liver disease is
frequently under-diagnosed and may have been inappropriately
managed

Selects appropriate immunomodulatory therapy has awareness of
side effects and may well require specialist care

Behaviours
Responds urgently to the management challenge of these severe and
often acute diseases and involves more specialist services where
required
Skills
Maintains diagnostic vigilance as uncommon metabolic liver diseases
may go unrecognised and so retains awareness of them as
diagnostic possibilities

Behaviours
Recognises the potential need to screen relatives and keeps up to
date with contemporary developments of screening protocols



Liaises with clinical genetic unit where appropriate

Manages patients with steatohepatitis clearly and always
sympathetically

Haemochromatosis Pathology

Transfusional iron overloadIf transfusional iron overload in patient who no longer needs transfusion, can do phlebotomyif still need transfusion, iron chelation.Neonatal or perinatal iron overload—=Neonatal hepatic siderosis of unknown causeInsulin resistance —Insulin may have a role in hepatic iron overload by stimulating cellular iron uptake through increased transferrin receptor externalization.Anaemia due to ineffective erythropoiesis—Hyperplastic erythroid marrows absorbs increased amounts of Fe leading to Fe overload.Iron absorption much higher with ineffective erythropoiesis-probably due to decreased hepcidin production- the reasons for this are unclearDiagnosis —Transferrin sats not useful as the rapid cycling of iron may lead to sats> 60% even if normal iron levelsFerritin much more usefulTherapy —If organ involvement, and Hb 10-12 g/dL phlebotomy + recombinant erythropoietin to force iron mobilizationMay need iron chelation if refractory Iron status in HH heterozygotesMuch less risk of iron overload.Liver disease due to HH alone is rare in heterozygotes Mutations83% of patients are HH homozygous for cysteine-to-tyrosine substitution at amino acid 282- (C282Y). Linked HLA-3 Porphyria cutanea tardaLiver siderosis causes decrease in activity of uroporphyrinogen decarboxylase (UROD) in the liver-Cause unknown- may be HCV decompartmentalizing iron from within the hepatocyte, leading to the release of "free" ironSporadic PCT is associated with HCV in 70%There is also an association with HFE mutationsLiver iron overload with normal transferrin sats—This has been described in patients with insulin resistance.Also in alcoholismAnd in hereditary iron overload due to a ferroportin mutation and hereditary hyperferritinemia/cataract syndrome, although this condition is not associ-ated with iron overload.African iron overload—Possibly related to a polymorphism involving the ferroportin 1 gene and not beer being produced in big steel drums HFE Protein HH genotype and clinical disease72-99 % of C282Y homozygotes are phenotypically normal at time of diagnosis.Penetrance <1 %. H63D C282Y/H63D compound heterozygotes Penetrance <1.5 %.60 % have intermediate Fe loading; 35 % normal Fe. Liver disease due to HH alone unlikely Defects in HFE other than homozygosity for C282Y —37 % either H63D/H63D , or C282Y/H63D mutation, or compound heterozygotes.5 % compound heteozygotes (C282Y/wt and H63D/wt)1 % H63D/H63D.7 % heterozygotes for C282Y or H63D6 % with HH phenotype have no identif-able mutations The HFE Gene:PrevalenceWhite 0.44 %;Native American 0.11 %; Hispanic 0.027 %; Black 0.014 %; Pacific Islander 0.012 %; Asian 0.00004 % C282Y HFE Gene Chromosome 6 Iron overload syndromes other than hereditary hemochromatosis Written by Dr Sebastian Zeki

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