Haemochromatosis

Description

AR iron-overload disorder - inappropriately low hepcidin -> unregulated intestinal iron absorption -> parenchymal iron deposition
Classic triad (late disease): skin pigmentation ("bronze diabetes") + cirrhosis + diabetes
- The triad is now uncommon - most present with fatigue, arthralgia or abnormal LFTs

Organ involvement

Liver - hepatomegaly, fibrosis, cirrhosis, HCC
Joints - arthropathy, 2nd and 3rd MCPJs and wrists, chondrocalcinosis
Heart - dilated cardiomyopathy, arrhythmia, restrictive physiology
Endocrine - diabetes; hypogonadotrophic hypogonadism (pituitary iron), hypothyroidism
Skin - slate-grey/bronze pigmentation (melanin + iron)
Fatigue, weakness - the commonest and least specific presentation

C282Y homozygosity ~1:200 in northern European ancestry - commonest inherited disorder in that population
Penetrance is low: only ~10-30% of male and ~1-10% of female homozygotes develop clinical iron overload
M >> F (~2-3:1) and men present ~10 yr earlier - menstruation and pregnancy are protective
Symptomatic presentation typically 40-60 yr (later in women, after menopause)

Genotype

Genotype	Significance
C282Y/C282Y	~85-90% of clinical cases - the diagnosis
C282Y/H63D	Compound heterozygote - mild; usually needs a cofactor (alcohol, steatosis) to overload
H63D/H63D	Not clinically significant alone
C282Y heterozygote	Carrier - no overload

HFE gene, chromosome 6p21, adjacent to HLA-A
Non-HFE (juvenile and rare): HJV (haemojuvelin) and HAMP (hepcidin) -> juvenile HH (cardiac + hypogonadism in the 2nd-3rd decade); TFR2; SLC40A1 (ferroportin disease - AD, macrophage iron, ferritin high with normal/low transferrin saturation)

Mechanism

HFE senses body iron -> normally upregulates hepcidin
Mutant HFE -> inappropriately low hepcidin
- -> ferroportin not degraded -> unrestrained iron export from enterocytes and macrophages
- -> inc transferrin saturation -> non-transferrin-bound iron taken up by hepatocytes, myocytes, beta cells, pituitary
- -> free radical generation -> fibrosis
Reticuloendothelial iron is spared - the opposite of transfusional overload

Cofactors that decide who becomes symptomatic

Alcohol (the strongest - risk of cirrhosis inc ~9x if >60 g/day), metabolic dysfunction-associated steatotic liver disease, viral hepatitis, male sex

A. Biochemistry - screening

Fasting transferrin saturation is the most sensitive early test
- >45% (some use >50% M / >45% F) -> proceed to HFE genotyping
Ferritin - an acute phase reactant; raised in alcohol, steatosis, inflammation, malignancy, haemophagocytosis
- Raised ferritin with normal transferrin saturation is usually NOT haemochromatosis

B. Genotype

HFE C282Y/H63D testing - confirms the diagnosis in the right biochemical context
Genotype alone does not diagnose iron overload - the phenotype must be demonstrated

C. Assess iron burden and liver damage

*MRI (T2/R2) quantifies hepatic and cardiac iron - has replaced biopsy**
Liver biopsy now reserved for: ferritin >1000 microg/L, raised ALT/AST, hepatomegaly, or age >40 - to stage fibrosis and predict HCC risk
- Perls' Prussian blue; hepatic iron index
Fibroscan as a non-invasive alternative

D. Arthropathy - the exam image

2nd and 3rd MCPJ involvement with hook-like osteophytes on the radial metacarpal heads
Chondrocalcinosis - triangular fibrocartilage of the wrist, knee menisci
Squaring and MCP involvement in a man with fatigue = check iron studies, not just RF

E. Screen for complications at diagnosis

Family screening

A. Venesection - the treatment

Induction: 500 mL weekly (or fortnightly) until ferritin ~50 microg/L and transferrin saturation <50%
- ~250 mg iron removed per unit
- Monitor Hb before each venesection (defer if Hb <110-120 g/L); ferritin every 10-12 units
Maintenance: 2-4 venesections per year, target ferritin 50-100 microg/L
Australian Red Cross Lifeblood accepts therapeutic venesection donors - the blood can be used

What venesection does and does not reverse

Reverses	Does not reverse
Fatigue, malaise	Cirrhosis
Skin pigmentation	Arthropathy (may even worsen)
Cardiomyopathy (often)	Hypogonadism
Transaminitis, fibrosis if pre-cirrhotic	Established diabetes
HCC risk if treated before cirrhosis	HCC risk once cirrhotic

*Treat before cirrhosis and life expectancy is normal* - this is the entire argument for early detection

B. Iron chelation

Deferasirox or desferrioxamine only if venesection is contraindicated (anaemia, poor venous access, cardiac decompensation)

C. Lifestyle

Abstain from alcohol (especially if cirrhotic)
Avoid iron and vitamin C supplements (vitamin C mobilises iron and can precipitate arrhythmia)
Avoid raw shellfish - **Vibrio vulnificus, Yersinia, Listeria thrive in iron excess**
Normal dietary iron is acceptable; no need for a restrictive diet

D. Complications

Cirrhosis -> 6-monthly ultrasound +/- AFP for HCC; variceal screening
Arthropathy: analgesia, NSAIDs, intra-articular steroid; joint replacement as needed
Diabetes, hypogonadism (testosterone replacement), hypothyroidism managed conventionally
Vaccinate against hepatitis A and B
Transplantation for decompensated cirrhosis (deplete iron pre-transplant - better outcomes)

Porphyria cutanea tarda - HFE mutations are a major cofactor
Chondrocalcinosis / CPPD arthropathy
Osteoporosis (hypogonadism + direct iron effect)
Diabetes mellitus, hypogonadotrophic hypogonadism, hypothyroidism
Hepatocellular carcinoma - may arise without cirrhosis, though usually with
Increased susceptibility to siderophilic organisms: Vibrio vulnificus, Yersinia enterocolitica, Listeria
Cardiomyopathy and conduction disease

Long preclinical phase - iron accumulates ~1-2 g/yr; disease manifests once total body iron >10-20 g
Normal life expectancy if venesected before cirrhosis or diabetes develops
Cirrhosis is the key prognostic determinant
- Risk inc markedly if ferritin >1000 microg/L, raised AST, platelets <200, alcohol excess
- HCC accounts for ~30% of deaths in cirrhotic haemochromatosis; relative risk ~20x
Cardiac death from arrhythmia or cardiomyopathy - the dominant cause in juvenile haemochromatosis
Arthropathy progresses independently of iron removal and is the main quality-of-life issue in treated patients

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