GastroenterologyTier 2Disease (DEADMAN)

Liver disease of less common aetiology - haemochromatosis

Description

Iron overload -> parenchymal deposition -> fibrosis and organ failure
Primary (hereditary) - inappropriately low hepcidin -> unregulated intestinal iron absorption
- HFE-related (type 1) accounts for >90% - C282Y homozygosity
- Non-HFE: type 2 juvenile (HJV, HAMP - severe, cardiac and endocrine failure by 30), type 3 (TFR2), type 4 ferroportin disease (autosomal DOMINANT; macrophage loading, high ferritin with NORMAL transferrin saturation)
Secondary iron overload - transfusion or ineffective erythropoiesis
- Thalassaemia, sideroblastic anaemia, sickle cell disease, myelodysplasia, chronic haemolysis
- Reticuloendothelial rather than parenchymal loading early - hence organ damage is later for a given ferritin

C282Y homozygosity in ~1 in 200 Australians of northern European ancestry - the commonest inherited disease in this population
Carrier frequency ~1 in 8-10
*Low penetrance: only ~25-30% of male and ~1-10% of female* homozygotes develop clinically significant disease
M>>F, and men present ~10 years earlier (menstruation and pregnancy are protective)
Presentation usually 40-60 in men, post-menopausal in women

Hepcidin is the master regulator - binds ferroportin -> internalisation -> blocks iron export from enterocytes and macrophages
HFE mutation -> failure to upregulate hepcidin despite iron loading
- -> ferroportin stays open -> unregulated absorption (3-4 mg/day vs normal 1-2)
- -> transferrin saturates -> non-transferrin-bound iron (NTBI) -> taken up by hepatocytes, cardiac myocytes, pancreatic beta cells, pituitary, joints
NTBI -> Fenton reaction -> hydroxyl radicals -> lipid peroxidation -> stellate cell activation -> fibrosis
Genotypes
- C282Y/C282Y - the disease-causing genotype (~90% of clinical cases)
- C282Y/H63D compound heterozygote - rarely causes overload unless a cofactor is present
- H63D/H63D, simple heterozygotes - *not a cause of iron overload; if ferritin is high, look elsewhere*
Cofactors drive expression: alcohol, MASLD/metabolic syndrome, hepatitis B/C, obesity

Clinical findings

Slate-grey / bronze skin pigmentation (melanin + iron)
Hepatomegaly, later stigmata of chronic liver disease
Diabetes ("bronze diabetes") - beta cell iron + insulin resistance; lipodystrophy
Displaced apex beat - dilated cardiomyopathy; also restrictive physiology, arrhythmia, conduction block
Arthropathy - *2nd and 3rd MCP joints ("iron fist" handshake)*, plus wrists, knees, hips
- Chondrocalcinosis and pseudogout (CPPD)
- Arthropathy is the symptom that does NOT improve with venesection
Hypogonadotrophic hypogonadism - testicular atrophy, loss of libido, impotence, amenorrhoea, osteoporosis
Fatigue, hypothyroidism
Look for decompensated cardiac and liver failure

Biochemistry - the screening pair

Fasting transferrin saturation - >45% (F) / >50% (M) = the most sensitive early marker
Ferritin - marker of total body stores, but an acute phase reactant
- Raised ferritin with a NORMAL transferrin saturation is much more likely alcohol, MASLD, inflammation or malignancy than haemochromatosis
Ferritin >1000 microg/L -> significant risk of cirrhosis

Confirm

HFE genotyping for C282Y and H63D
*MRI (T2/R2) to quantify hepatic iron** - has largely replaced biopsy
Liver biopsy now reserved for: ferritin >1000, raised ALT, hepatomegaly, or age >40 -> to stage fibrosis and give prognosis
- Perls Prussian blue; hepatic iron index

End-organ assessment

Fasting glucose / OGTT and HbA1c
Pituitary function, especially gonadotrophins (LH, FSH, testosterone); TFTs
ECG and echocardiogram if cardiomyopathy suspected; *cardiac T2 MRI** if suspected
DEXA (hypogonadism-related osteoporosis)
Liver ultrasound + AFP 6-monthly once cirrhotic

1. Venesection - the treatment

Induction: 500 mL weekly (or fortnightly) - each unit removes ~200-250 mg iron
- Target ferritin <50 microg/L and transferrin saturation <50%
- Monitor Hb before each bleed; stop if Hb falls below ~110-120 g/L
Maintenance: 2-4 venesections per year, target ferritin 50-100
Australian Red Cross Lifeblood accepts therapeutic venesection donors - free, and the blood is used
Erythrocytapheresis if venous access or frequency is a problem
Iron chelation (deferasirox, desferrioxamine) only if venesection is impossible - anaemia, cardiac failure, or secondary overload where the patient is transfusion-dependent

2. What responds - and what does not

Improves with venesection	Does NOT improve
Fatigue, skin pigmentation	Arthropathy (may worsen)
Cardiomyopathy, liver enzymes, fibrosis	Established cirrhosis
	Diabetes (usually)
	Hypogonadism

*Treat BEFORE cirrhosis and diabetes appear - that is the entire point of screening relatives*

3. Adjuncts

Abstain from alcohol (or minimise) - the strongest modifiable cofactor
Avoid iron and vitamin C supplements (vitamin C mobilises iron and can precipitate arrhythmia)
Avoid raw shellfish - siderophilic organisms (Vibrio vulnificus, Yersinia) thrive in iron-replete hosts; fatal sepsis
Vaccinate against hepatitis A and B
Testosterone replacement, bisphosphonates for osteoporosis

4. Family screening

Test all first-degree relatives (adults) with transferrin saturation, ferritin, and HFE genotype
Children of a homozygote need only be tested if the other parent is a carrier; test the partner instead (cascade testing)
Population screening is not recommended - low penetrance

Diabetes mellitus, hypogonadotrophic hypogonadism, hypothyroidism, hypoparathyroidism
Dilated and restrictive cardiomyopathy, arrhythmia, conduction disease
Arthropathy of 2nd/3rd MCPs; chondrocalcinosis and pseudogout
Porphyria cutanea tarda - HFE mutations markedly over-represented
Hepatocellular carcinoma - the leading cause of death
Osteoporosis
**Vibrio vulnificus, Yersinia enterocolitica, Listeria - siderophilic organisms**
Alcohol, MASLD, hepatitis B/C - cofactors that accelerate everything

Normal life expectancy if venesected before cirrhosis and diabetes develop - the key prognostic statement
Cirrhosis reduces survival markedly and the HCC risk persists even after iron depletion
- HCC risk ~20-30x; *continue 6-monthly ultrasound surveillance for life once cirrhotic, regardless of ferritin*
- Risk of cirrhosis is low if ferritin <1000 microg/L, ALT normal, and no hepatomegaly
Cardiac disease is the other major cause of death, and cardiomyopathy can reverse with aggressive iron removal
Arthropathy progresses independently of iron status and is the commonest cause of ongoing disability

6 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.