Haemochromatosis
§ Chronic iron overload syndromes of genetic origin § Mean age at diagnosis = 46yrs
Pathophysiology § Continued absorption of iron from the small intestine, despite normal/ increased total body iron § Due to hepcidin deficiency § Low iron – reduced hepcidin – increased absorption § Acute phase reactant § High hepcidin – reduced absorption – anaemia of chronic disease
Classification § HFE § >90% § Type 1 § Caucasians § Chromosome 6 § Autosomal recessive § Juvenile § Type 2 § Hemojuvelin gene – 2a § Hepcidin gene – 2b § Severe phenotype § AR § Transferrin receptor 2 § Type 3 § TFR2 gene § Mimics HFE § Ferroprotin disease § Type 4 § Ferroportin gene § Due to deficiency or malfunction of the main target of hepcidin = cellular iron exporter, ferroprotein § AD § Subtype A § Low transferrin saturation (TS) § Macrophage iron deposition § Subtype B § Mimics HFE haemochromatosis § Type 5 § DMT-1 mutation
Other causes of iron overload § Neonatal haemochromatosis § Congenital atransferrinaemia § Aceruloplasminanemia § Sub-saharan dietary iron overload
Diagnosis § Candidates for testing § European ancestry with § Weakness, abnormal LFTs, arthralgia, impotence, DM, cirrhosis, pigmentation § Transferrin saturation § Earliest biochemical parameter § Check with the CRP to exclude inflammation § Formula = 100 x serum iron/ TIBC § Ideally fasting sample § >55% in men, >50% in pre-menopausal women § Not specific for HFE haemochromatosis § HFE testing § Homozygous C282Y confirms diagnosis § Penetrance is variable, therefore not suitable for population screening § Heterozygotes C282Y/ H63D – mild variant § If negative § Other causes § Other genetic variants § Alcohol § Dysmetabolic syndrome § Quantify iron overload § Ferritin § Close correlation (<300 in men, <200 in women) § >1000, severe clinical complications more likely § Falsely elevated in alcohol, dysmetabolic syndrome and inflammation § Stage phenotypic manifestations § USS, AST +/- liver biopsy § If evidence of liver damage § MRI – iron concentration but no information on cirrhosis § ? role for fibroscanning to detect cirrhosis § ECG and ECHO § Dexa scan § Endocrine tests § Glu, TFTs, bone profile, LH,FSH,testosterone etc.
Differential Diagnosis § <30yrs § Juvenile HC § Massive iron overload with endocrine and cardiac complications § Genetic testing for hemojuvelin and hepcidin mutations § TFR2 HC § >30yrs § TFR2 HC § Ferroportin disease – type B § AD, therofre diagnosis facilitated by documenting hyperferritinaemia in 1st degree relatives
Elevated ferritin with low trasnferrin saturation § Dysmetabolic syndrome § Multiple metabolic abnormalities § High ferritin § Normal TS § Mild hepatic iron excess § Mixed iron deposition § Hepatocyte and macrophage § Ferroportin disease – type A § Macrophage iron excess § Hereditary aceruloplasminaemia § Chromosome 3 § High ferritin § Low TS § Neurological syndrome § Undetectable levels of serum ceruloplasmin
Staging § Stage 0 § C282Y homozygosity § Normal TS and ferritin § No symptoms § Stage 1 § C282Y homozygosity § Increased TS but normal ferritin § No symptoms § Stage 2 § C282Y homozygosity § Increased TS and ferritin § No symptoms § Stage 3 § C282Y homozygosity § Increased TS and ferritin § Symptoms § Stage 4 § C282Y homozygosity § Increased TS and ferritin § Symptoms § Organ damage predisposing to early death § DM, cirrhosis, cardiomyopathy
Treatment § Avoid ingesting large quantities of vitamin C containing food § Venesection § Induction at stage 2 § Weekly – 450-500mls § Aim § Ferritin <20 § TS <16% § Withold if Hb <11 § Maintenance § 1-4 monthly § Aim § Ferritin <50 § TS <50 § Serum ferritin should be checked at least every 2 venesections, and Hb checked within the week prior to venesection. § Liver cirrhosis § AFP and USS 6 monthly § Family screening
Ideas for the future § Oral iron chelators § Poor venous access § Anaemia § Poor tolerance of phlebotomy § Patient choice § Study ongoing with deferasirox § Inhibition of cellular iron transport § Correction of the systemic iron regulating defect § Agents to counteract systemic hepcidin deficiency |
General Haematology >