Haemochromatosis

Definition

Excessive accumulation of iron within the body (particularly liver, pancreas, heart and joints) leading to organ toxicity.
Increased iron absorption from upper GI resulting in:
increased serum iron, increased serum ferritin
decreased transferrin, increased fasting transferrin saturation
increased toxic non-transferrin bound iron (NTBI).


The likelihood of severe clinical complications increases with ferritin levels >1000 ng/mL

When interpreting elevated ferritin, consider whether it may be elevated in its role as an acute-phase reactant (compare with CRP)

Primary haemochromatosis

Genetic haemochromatosis (GH)

The mutations associated with GH are highly prevalent in white populations but the disorder has variable penetrance.

Genetic studies: screening for HFE (‘High Iron’ gene, chromosome 6q22.2) mutations and non-HFE haemochromatosis mutations (hepcidin, ferroportin-1, transferrin receptor 2, or haemojuvelin)

Main HFE genetic mutations: homozygous C282Y/C282Y, compound heterozygote C282Y/H63D

Although homozygous C282Y/C282Y haemochromatosis is an autosomal-recessive condition, with approximately equal numbers of male and female homozygotes, clinical disease is more common in men. Iron loss through menses and pregnancy is thought to attenuate disease manifestations in female homozygotes.

Secondary haemochromatosis

  • NAFLD (obesity, hypertension, pre-diabetes, hyperlipidaemia and hyperuricaemia) or Metabolic associated fatty liver disease (MAFLD)

  • Alcoholic liver disease

  • Liver Cirrhosis

  • Hepatitis B, C

  • Myeloproliferative disorders

  • Thyrotoxicosis

  • Renal failure

  • Iron overload from multiple transfusions

History

Risk factors (male gender, middle age, positive family history, high dietary iron intake) and symptoms of iron accumulation (listed below)

Symptoms

General

Fatigue

Weakness

Lethargy

 
 

Organ-specific

Anorexia, abdominal pain, hepatomegaly, jaundice, ascites (Liver cirrhosis, hepatocellular cancer)

Polyuria, polydipsia, weight gain/loss (Pancreas —> diabetes)

Arthralgia (especially 2nd and 3rd MCP hands; X-ray chonedrocalcinosis, osteoporosis)

Dyspnoea, arrhythmias (Cardiomyopathy, Atrial fibrillation or sick sinus syndrome)

Skin pigmentation ‘Bronze’ or porphyria cutanea tarda (fragile skin, blisters, bullae and mild liver dysfunction)

Erectile dysfunction, loss of libido or amenorrhoea (Hypogonadotrophic hypogonadism from pituitary dysfunction)

Cognitive and mood dysfunction (CNS)

 

Physical exam

  • BP, BMI, heart rate/rhythm

  • Changes in skin color

  • Enlargement of the liver or spleen

  • Tenderness in the abdomen over the liver

  • Tenderness and swelling in the joints

Investigations

  1. FBC, UEs, LFTs (add AST), iron studies (serum iron, ferritin, transferrin, transferrin saturation), TFTs, lipids, HBA1c, FPG

  2. Liver screen: GGT, Auto-antibodies (ANF, AMA, ASMA, LKM), Hepatitis B/C/HIV, Imunoglobulins (IgG, IgA, IgG, IgM)

  3. Determine FIB4-score and risk of hepatic fibrosis

  4. Liver ultrasound (determine if any evidence of fatty or cirrhotic change)

  5. Refer for Fibroscan if FIB-4 score > 1.3

  6. Undertake genetic screening if elevated
    sex-specific ferritin:     Men and post-menopausal women ferritin>300 ng/mL, Pre-menopausal women ferritin>200 ng/mL
    fasting transferrin saturation: Male >50%, Female>40%

  7. Undertaken ECG and echocardiogram (to screen out cardiomyopathy)

  8. Screen for hypogonadism (FSH, LH, PRL, testosterone)

  9. Consider screening for osteoporosis (DEXA scan)

Treatment and Monitoring

  • Avoid iron supplements (and vitamin C supplements). Natural sources of iron and vitamin C are considered safe.

  • Lifestyle modifications: patients should be advised to avoid excess alcohol (or avoid altogether if hepatic disease is present)

  • If C282Y homozygous (or C282Y/H63D heterozygous) and ferritin >300 ng/mL for men/postmenopausal women and >200 ng/ML for pre-menopausal women, refer to hepatology for investigation and venesection.

  • Patients without evidence of GH but fasting Transferrin saturation >50% should be referred to hepatology.

  • If C282Y homozygous and ferritin normal, screen with Ferritin and Transferrin saturation annually

Secondary haemochromatosis

Consider referral to hepatology

Alcohol abstinence (refer to alcohol withdrawal service)

Dietary glycaemic and cholesterol/TG control

Weight loss

GH

Refer to heptaology

Initially weekly venesection; interval frequency depends if monitored ferritin<50 ng/mL

Iron chelation if venesection contraindicated, not tolerated or ineffective
Deferasirox, an oral iron chelator

Offer family genetic screening

 

Patients with GH who have been diagnosed pre-cirrhotic, pre-diabetes stage and treated by venesection are likely to have normal life expectancy

 

Monitor

Ferritin, transferrin, serum iron at least yearly

If confirmed liver cirrhosis: 6-monthly serum AFP and 6-monthly liver ultrasound

Dr Rajesh Varma