GeneticsTier 1Medical Sciences concept

HFE gene mutations and hereditary haemochromatosis genotype-phenotype (C282Y, H63D)

Core concept

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HFE mutation

dec HFE-transferrin receptor signalling in hepatocyte/crypt cell
-> dec hepcidin
-> ferroportin NOT internalised on enterocytes and macrophages
-> unrestrained iron absorption and release
-> transferrin saturates -> non-transferrin-bound iron -> parenchymal deposition

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Hepcidin is the master negative regulator; HFE haemochromatosis is a hepcidin-deficiency state

Genotype	Frequency (Northern European)	Penetrance
C282Y/C282Y	~1 in 200 (carrier ~1 in 10)	The clinically relevant genotype, but only ~10-30% of men and <10% of women develop organ disease
C282Y/H63D (compound het)	~1 in 50	Mild iron loading only; disease needs a cofactor
H63D/H63D	common	Not a cause of clinical haemochromatosis
Simple heterozygote	~1 in 10	Not a cause

C282Y = cysteine to tyrosine at 282 - disrupts a disulphide bond -> HFE fails to reach the cell surface. H63D is a milder missense.
Biochemistry - transferrin saturation is the screening test
- Fasting transferrin saturation >45% -> proceed to HFE genotype
- Ferritin is an acute-phase reactant - raised in alcohol, metabolic syndrome, inflammation, malignancy; raised ferritin with a NORMAL transferrin saturation is almost never haemochromatosis
Non-HFE (rarer, often more severe)
- HJV (hemojuvelin) and HAMP (hepcidin) - AR juvenile haemochromatosis, type 2: cardiomyopathy + hypogonadism in the 2nd-3rd decade
- TFR2 - type 3, AR
- Ferroportin disease (SLC40A1) - autosomal DOMINANT, high ferritin with normal or low transferrin saturation, macrophage loading, poorly tolerant of venesection

Phenotype needs the genotype PLUS time and cofactors - male sex, alcohol, hepatic steatosis, viral hepatitis; menstruation and pregnancy protect women (presentation ~10 yr later)
Organ involvement: liver (fibrosis -> cirrhosis -> HCC, which can occur without cirrhosis), 2nd/3rd MCP joint arthropathy with hook osteophytes and chondrocalcinosis, diabetes, cardiomyopathy (dilated/restrictive, arrhythmia), hypogonadotrophic hypogonadism, skin bronzing, fatigue
*MRI T2 / R2 quantifies liver iron non-invasively - biopsy is now reserved for staging fibrosis*
- Ferritin >1000 microg/L, raised ALT or hepatomegaly -> significant fibrosis risk -> assess liver
Venesection: weekly 450-500 mL until ferritin 50-100 microg/L, then maintenance 2-4 times/year
- Arthropathy and hypogonadism do not reverse; fatigue, transaminitis and cardiac function do
Cascade family screening (transferrin saturation, ferritin, HFE genotype) of first-degree relatives - not population screening, because penetrance is low
HCC surveillance if cirrhotic - 6-monthly ultrasound

Iron studies pattern - iron deficiency vs anaemia of chronic disease vs haemochromatosis
Hepcidin and iron homeostasis; anaemia of chronic disease
Crystal arthropathy (chondrocalcinosis); secondary diabetes
Cirrhosis and hepatocellular carcinoma surveillance
Pedigree analysis; incomplete penetrance

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