Background Information

Definition

There are 2 types of haemochromatosis:

• Primary (genetic) haemochromatosis: a genetic condition of defective iron regulation, characterised by inappropriately increased intestinal iron absorption → excess iron accumulation in tissue
• Secondary haemochromatosis (secondary iron overload): iron overload that occurs due to another underlying condition or external source, NOT because of a genetic defect in iron regulation

Aetiology

Primary (genetic) haemochromatosis:

• Most commonly caused by a mutation in the HFE gene on chromosome 6 (type 1) (there are 4 types in total, but the other types are rare)
• Autosomal recessive (with incomplete penetrance)

Secondary haemochromatosis (secondary iron overload):

• Repeated blood transfusion (e.g. beta thalassaemia major, sickle cell disease) – most common
• Chronic liver disease
• Renal failure / dialysis
• Alcohol use
• Iron-loading anaemias (characterised by ineffective erythropoiesis → excess iron absorption)
  • Sideroblastic anaemia
  • Congenital haemolytic anaemia
  • Thalassaemia
  • Sickle cell anaemia

Clinical Manifestation

Clinical manifestation of haemochromatosis is best grouped by organ system:

Systemic / general	Fatigue Weakness Malaise
Joints	Arthralgia (esp. 2nd and 3rd MCP joints) → painful handshake sign Pseudogout (chondrocalcinosis) Premature osteoarthritis
Skin	Bronze or slate-grey hyperpigmentation
Liver	Hepatomegaly RUQ pain / discomfort Cirrhosis HCC (major cause of death)
Pancreas	Late-onset diabetes mellitus
Heart	Dilated / restrictive cardiomyopathy Arrhythmias (e.g. atrial fibrillation) / conduction abnormalities
Brain / pituitary gland	Hypogonadotropic hypogonadism → Loss of libido / impotence Amenorrhoea Infertility

Note that the following manifestations / complications are NOT reversible, even with treatment:

• Cirrhosis and HCC 
• Diabetes mellitus (pancreatic damage is permanent)
• Hypogonadotropic hypogonadism (pituitary damage becomes structural)
• Arthropathy

Diagnosis

Approach:

• Initial screening test: FBC, serum ferritin, and transferrin saturation (+/- LFTs)
• If BOTH serum ferritin and transferrin saturation are above the diagnostic threshold → perform genetic testing (definitive test)

 

Diagnostic criteria (primary / genetic haemochromatosis):

• Biochemical evidence of iron overload (BOTH ferritin and transferrin saturation elevated), PLUS
• Genetic testing (identifying HFE gene mutation), PLUS
• Exclusion of secondary causes of iron overload

Iron Studies

BOTH parameters should be measured and must be elevated to meet the diagnostic criteria (and proceed to genetic testing):

Test	Diagnostic threshold
Serum ferritin	> 300 µg/L in men >200 µg/L in women
Transferrin saturation	>50% in men >40% in women

Overall iron profile trends in haemochromatosis:

• ↑ Ferritin
• ↑ Transferrin saturation
• ↑ Serum iron
• ↓ Total iron-binding capacity

Genetic Testing

Genetic testing is the definitive test to diagnose primary (genetic) haemochromatosis

 

Perform HFE genotyping (C282Y +/- H63D)

• C282Y homozygosity is diagnostic (responsible for ~90% cases)

LFTs

LFT pattern in haemochromatosis is typically hepatocellular

• ↑ AST and ALT (mild elevation, typically <300 IU/L)
• ↑ GGT (common)
• Normal ALP
• Normal bilirubin

Imaging

Imaging of choice: MRI

• MRI is NOT routinely performed, it is used when the patient does not have the common genotype or to quantify liver iron non-invasively

 

Purpose of MRI:

• Quantify liver iron concentration accurately (preferred over biopsy, since it’s non-invasive)
• Assess total body iron load (esp. when serum ferritin doesn’t correlate with tissue iron)
• Support diagnosis if HFE genetics are -ve
• Helps decide on the need for biopsy

Liver Biopsy

Liver biopsy is NOT used to diagnose haemochromatosis itself; its primary role is to assess liver fibrosis and diagnose cirrhosis in atypical cases

• Liver biopsy is NOT routinely performed to assess for fibrosis
• If ferritin >1000 µg/L or abnormal LFTs → perform fibrosis assessment with transient elastography (e.g. FibroScan)
• Only perform liver biopsy if transient elastography is unavailable or inconclusive

 

Histology findings in haemochromatosis:

• Haemosiderin deposition (blue with Prussian blue stain, but golden yellow on microscopy)
• Pronounced haemosiderin accumulation within hepatocytes and bile duct epithelium
• Hepatic fibrosis +/- cirrhosis

Management

Definitive Management

1st line: venesection (weekly)

• Therapeutic goal: maintain ferritin at ~50-100 µg/L (transferrin saturation is NOT used as a treatment target)

 

2nd line (if venesection is not appropriate): iron chelation therapy

• Deferasirox (oral) (preferred)
• Deferiprone
• Deferoxamine (subcutaneous infusion)

General / Conservative Management

Lifestyle Advice

Avoid the following:

• Alcohol (alcohol excess increases serum ferritin level)
• Vitamin C and iron supplements
• Raw shellfish 

 

General advice:

• Maintain a balanced diet (no strict restriction needed)
• Manage metabolic risk factors
• Maintain a healthy weight and regular exercise

Genetic Screening

Parents, siblings, partner and children of the index case should be screened

 

Screening approach:

• Initial test: HFE genotyping
• If genotyping is +ve → iron studies

Complication Screening

If the patient develops cirrhosis, screen for the following complications (also see the Cirrhosis article for more information):

Complication	Test
Hepatocellular carcinoma	Ultrasound +/- AFP every 6 months
Oesophageal varices	Perform upper GI endoscopy after diagnosis (unless planning to take carvedilol or propranolol)

References