Hemochromatosis

Epidemiology

• Age of onset: individuals > 40 years
  • Symptoms start to show when body iron levels reach > 20 g.
  • Before menopause, women lose iron via menstruation and pregnancy, which slows down iron accumulation within the body. As a result, symptom onset occurs later in women (typically postmenopausal) than in men.

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Etiology

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Pathophysiology

HFE gene defect (homozygous) → defective binding of transferrin to its receptor → ↓ hepcidin synthesis by the liver → unregulated ferroportin activity in enterocytes → ↑ intestinal iron absorption → iron accumulation throughout the body → damage to the affected organs

Tip

Don’t mess up with Wilson disease

• Wilson disease is accumulation of copper, and has neurologic symptoms.

Clinical features

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Tip

Classic triad of cirrhosis, diabetes mellitus, skin pigmentation (“bronze diabetes”).

• Early/Constitutional: Severe fatigue, generalized lethargy, arthralgias.
• Musculoskeletal: c
  • Pseudogout (CPPD) and degenerative arthropathy.
  • Classically involves the 2nd and 3rd metacarpophalangeal (MCP) joints with “hook-like” osteophytes.
• Dermatologic: “Bronze” skin (hyperpigmentation due to iron deposition and stimulated melanin production).
• Gastrointestinal/Hepatic: Hepatomegaly (early), progresses to cirrhosis, jaundice, and portal HTN.
• Endocrine:
  • “Bronze Diabetes”: Pancreatic islet $\beta$-cell damage $\to$ secondary DM.
  • Secondary Hypogonadism: Iron deposition in anterior pituitary $\to$ $\downarrow$ LH/FSH $\to$ ED, testicular atrophy, loss of libido, amenorrhea. c
  • Hypothyroidism, hypoparathyroidism (less common).
• Cardiac:
  • Dilated cardiomyopathy (more common) or restrictive cardiomyopathy.
  • Conduction abnormalities, sick sinus syndrome, arrhythmias (atrial fibrillation/flutter).
• Infectious Susceptibility:
  • Increased risk of fulminant sepsis from siderophilic organisms:
    • Vibrio vulnificus (exposure to raw oysters/warm seawater $\to$ necrotizing fasciitis/bullae).
    • Yersinia enterocolitica (pseudoappendicitis, bacteremia).
    • Listeria monocytogenes.

Feature	Hemochromatosis (Iron Overload)	Wilson Disease (Copper Overload)
Gene Defect	HFE gene (Autosomal Recessive) → ↑ Iron absorption.	ATP7B gene (Autosomal Recessive) → ↓ Copper excretion.
”Classic” Triad / Signs	1. Cirrhosis (↑ HCC risk) 2. Diabetes Mellitus 3. Skin Pigmentation (“Bronze Diabetes”)	1. Liver Disease (Hepatitis, Cirrhosis) 2. Neurologic Dysfunction (Parkinsonism, tremor) 3. Kayser-Fleischer Rings (Ocular)
Key Labs	↑ Ferritin ↑ Iron ↑ Transferrin Saturation	↓ Ceruloplasmin ↑ Urinary Copper
Treatment	Phlebotomy Iron Chelators (Deferasirox)	Copper Chelators (Penicillamine, Trientine) Oral Zinc

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Diagnostics

• Initial/Screening:
  • Iron panel: ↑ Transferrin saturation (often >45%; most sensitive initial test) and ↑ Ferritin (reflects total body iron stores).
• Confirmatory/Gold Standard:
  • HFE genetic testing (C282Y/H63D mutation analysis).
• Key Labs:
  • Mildly elevated AST/ALT.
• Liver biopsy
  • Hemosiderin (normally golden yellow on microscopy) appears blue with the Prussian blue stain.
  • Pattern of hereditary hemochromatosis: pronounced parenchymal siderosis (accumulation of hemosiderin within the tissue) in hepatocytes and bile duct epithelium
  • Pattern of secondary iron overload: Kupffer cells (specialized macrophages) containing hemosiderin

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Treatment

1. First-line: Therapeutic phlebotomy.
   • Effective and simple. Only required 2 to 4 times a year. HH patients can often perform this via standard blood donations
   • Indication: Ferritin >500 ng/mL or symptomatic iron overload.
   • Target: Maintain ferritin between 50–100 ng/mL and transferrin saturation <50%.
2. Second-line / Alternative: Iron chelation therapy (e.g., Deferoxamine, Deferasirox).
   • Indication: Patients with severe anemia, severe cardiac disease, or poor venous access preventing phlebotomy.
3. Dietary Modifications:
   • Avoid iron supplements, vitamin C (enhances iron absorption), and alcohol.
   • Avoid raw shellfish due to high susceptibility to fatal septicemia.
4. Definitive/End-stage: Liver transplantation for decompensated cirrhosis or localized HCC.

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