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Hemochromatosis: Iron Overload Genetics, Organ Damage, and Phlebotomy Treatment

What Is Hemochromatosis?

Hemochromatosis is a disorder of excessive iron absorption leading to toxic iron deposition in organs. The most common form is hereditary hemochromatosis (HH), autosomal recessive, usually due to HFE C282Y homozygosity (85–90% of cases in Northern Europeans).

Pathophysiology

  • Mutant HFE protein disrupts hepcidin regulation → inappropriate ferroportin activity → unchecked dietary iron absorption (2–4 mg/day vs. normal 1–2 mg/day).
  • Iron accumulates in liver, pancreas, heart, pituitary, joints, skin.
  • Free iron catalyzes Fenton reaction → ROS → tissue damage.

Clinical Manifestations

OrganFeatures
LiverHepatomegaly, elevated ferritin/transferrin saturation, fibrosis → cirrhosis, HCC risk (200x if cirrhotic)
PancreasDiabetes mellitus ("bronze diabetes") — β‑cell destruction + insulin resistance
HeartCardiomyopathy (restrictive → dilated), arrhythmias, heart failure
JointsArthropathy (2nd/3rd MCP joints, wrists, knees) — chondrocalcinosis (pseudogout)
SkinBronze/gray hyperpigmentation (melanin + iron)
EndocrineHypogonadotropic hypogonadism (pituitary iron), hypothyroidism

Diagnosis

  1. Transferrin saturation (TSAT) ≥45% + Serum ferritin >300 ng/mL (men) / >200 ng/mL (women) → suspect HH.
  2. HFE genotyping: C282Y/C282Y confirms; C282Y/H63D compound heterozygote = milder risk.
  3. Liver biopsy / MRI (FerriScan): Quantify hepatic iron concentration (HIC) if ferritin >1000 or liver enzymes elevated.

Treatment: Iron Depletion

Therapeutic Phlebotomy (Gold Standard)

  • Remove 500 mL blood (≈250 mg iron) weekly/biweekly until ferritin 50–100 ng/mL.
  • Maintenance: 3–4 times/year lifelong.
  • Each unit drops ferritin ~30–50 ng/mL.

Chelation Therapy (If Phlebotomy Contraindicated)

  • Deferoxamine (IV/SC), Deferasirox (oral), Deferiprone (oral).
  • Used in anemia, cardiac failure, venous access issues.

Dietary Adjuncts

  • Limit heme iron (red meat, liver).
  • Avoid vitamin C supplements with meals (enhances absorption).
  • No iron‑fortified foods/multivitamins with iron.
  • Alcohol moderation (synergistic hepatotoxicity).
  • Tea/coffee with meals (tannins inhibit absorption).

Prognosis

Early diagnosis and phlebotomy → normal life expectancy. Cirrhosis, diabetes, cardiomyopathy at diagnosis reduce survival. HCC surveillance (US ± AFP q6mo) if cirrhotic.

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