Iron Overload

Iron overload is an excess of total body iron that exceeds the capacity of transferrin and ferritin to bind it, leading to deposition in the liver, heart, pancreas, endocrine glands, and joints, and causing oxidative organ damage. It may be primary (hereditary haemochromatosis) or secondary (transfusion and ineffective erythropoiesis).

• Hereditary haemochromatosis: HFE-related (C282Y homozygosity in about 1 in 200 to 300 people of Northern European ancestry; C282Y/H63D compound heterozygotes with low penetrance); non-HFE types (hepcidin, hemojuvelin, transferrin receptor 2, ferroportin disease) in other populations.
• Secondary iron overload: repeated red cell transfusions (thalassaemia major, sickle cell disease, myelodysplasia, aplastic anaemia, after more than 20 units), ineffective erythropoiesis (thalassaemia intermedia, sideroblastic anaemia, congenital dyserythropoietic anaemia), excess oral iron or iron injections, chronic liver disease (alcohol, hepatitis C, non-alcoholic fatty liver disease with hyperferritinaemia), African dietary iron overload (traditional beer brewed in iron drums, associated with a variant in ferroportin), and porphyria cutanea tarda.
• Hyperferritinaemia is not always iron overload: inflammation, infection, alcohol, liver disease, metabolic syndrome, malignancy, haemophagocytic lymphohistiocytosis, and Still disease also raise ferritin.
• Iron toxicity in acute overdose is a different condition.

• Early disease is often asymptomatic, detected by raised ferritin and transferrin saturation.
• Symptoms: fatigue, joint pain (second and third metacarpophalangeal joints, hips, knees), abdominal pain, loss of libido, impotence, amenorrhoea.
• Organ damage: liver (hepatomegaly, cirrhosis, hepatocellular carcinoma), skin (bronze or grey pigmentation), pancreas (diabetes mellitus, "bronze diabetes"), heart (cardiomyopathy, heart failure, arrhythmia, conduction disease), pituitary and gonads (hypogonadism, osteoporosis), thyroid, and joints (arthropathy, chondrocalcinosis).
• Secondary overload: signs of the underlying anaemia, transfusion history, delayed puberty, growth failure, heart failure.
• Family history: first degree relatives with haemochromatosis, liver disease, diabetes, or early death.
• Alcohol and hepatitis risk factors; supplement and iron use.

• Fasting transferrin saturation (over 45 percent suggests overload) and serum ferritin (over 300 micrograms/L in men and postmenopausal women, over 200 micrograms/L in premenopausal women); repeat on a second sample.
• If the transferrin saturation is over 45 percent: HFE genotyping (C282Y and H63D).
• Liver assessment: liver function tests, hepatitis B and C serology, alcohol history, liver ultrasound, elastography (FibroScan), and liver biopsy only if ferritin is over 1000 micrograms/L, liver enzymes are abnormal, or there is a risk of cirrhosis with unclear diagnosis.
• Magnetic resonance imaging (T2) of the liver and heart to quantify iron: liver iron concentration (over 7 mg/g dry weight is overload; over 15 severe); cardiac T2 under 20 ms indicates overload and under 10 ms severe risk of heart failure.
• Organ screening: fasting glucose or HbA1c, testosterone, LH and FSH, thyroid function, ECG, echocardiogram, bone density, and joint X-rays.
• Alpha fetoprotein and ultrasound every 6 months for cirrhosis (hepatocellular carcinoma surveillance).
• Exclude inflammatory and metabolic causes of raised ferritin when the transferrin saturation is normal.
• Screen first degree relatives with transferrin saturation, ferritin, and HFE genotype.

Hereditary haemochromatosis

• Therapeutic venesection (phlebotomy) is the treatment: remove 400 to 500 mL of blood (about 200 to 250 mg of iron) once or twice weekly (or every 1 to 2 weeks in older or frail patients) until ferritin is 50 to 100 micrograms/L; check haemoglobin before each session and allow it to fall by no more than 20 percent (stop if haemoglobin under 110 g/L, or reduce frequency).
• Maintenance: venesection every 2 to 4 months to keep ferritin at 50 to 100 micrograms/L and transferrin saturation under 50 percent; monitor ferritin every 3 months in the first year.
• Erythrocytapheresis (red cell apheresis) is an alternative that removes more red cells at each session.
• Proton pump inhibitor (omeprazole 20 mg daily) reduces iron absorption and may reduce venesection needs.
• Diet: avoid iron supplements and high dose vitamin C supplements (over 500 mg daily), avoid raw shellfish (Vibrio vulnificus infection risk), avoid alcohol or limit it strictly, and no need for dietary iron restriction beyond these; tea with meals reduces absorption.
• Complications: treat diabetes (metformin or insulin), hypogonadism (testosterone replacement or oestrogen), osteoporosis (calcium, vitamin D, alendronate 70 mg weekly), heart failure (usual heart failure drugs plus aggressive iron removal), arthritis (analgesics, physiotherapy), and cirrhosis surveillance with ultrasound every 6 months.
• Hepatitis A and B vaccination; liver transplantation for end stage disease.

Secondary iron overload (iron chelation, specialist)

• Start when serum ferritin is over 1000 micrograms/L, after 10 to 20 transfusions, or liver iron concentration over 5 mg/g: deferasirox 14 to 28 mg/kg/day orally once daily (dispersible tablets in water or film coated tablets 14 to 28 mg/kg; monitor creatinine, liver enzymes, proteinuria, ferritin monthly; side effects include gastrointestinal upset, rash, renal and hepatic toxicity, and cytopenias).
• Deferiprone 75 to 100 mg/kg/day orally in three divided doses (monitor neutrophils weekly because of agranulocytosis risk; effective for cardiac iron).
• Deferoxamine 25 to 60 mg/kg/day subcutaneously over 8 to 12 hours, 5 to 7 nights a week, or 40 to 60 mg/kg/day continuous intravenous infusion for severe cardiac overload (monitor hearing and vision, growth, infection; Yersinia risk); give vitamin C 100 to 200 mg daily with deferoxamine, only when on infusion.
• Combination chelation for cardiac iron; target ferritin under 1000 micrograms/L, liver iron concentration under 7 mg/g, and cardiac T2* over 20 ms.
• Treat the underlying condition (for example, reduce transfusion needs; erythropoiesis support) and monitor annually with MRI.
• Venesection is not possible in anaemic patients, except in thalassaemia after stem cell transplant.

Iron overload from dietary or excess intake

• Stop supplements and traditional iron rich beverages; venesection if the patient is not anaemic, or chelation, according to severity.

Follow up

• Ferritin and transferrin saturation every 3 to 6 months initially; liver ultrasound and alpha fetoprotein every 6 months in cirrhosis; annual glucose, endocrine, cardiac assessment; family screening.