Iron overload (hemochromatosis)

Hereditary hemochromatosis (HH)

• Most common: HFE gene mutations (chromosome 6p):
  • C282Y homozygotes: classic phenotype (~80% of European HH cases). Northern European Caucasian (1:200 to 400 prevalence).
  • C282Y/H63D compound heterozygotes: milder phenotype.
  • H63D homozygotes: usually no phenotype unless cofactors (alcohol, viral hepatitis, NAFLD).
• Pathophysiology: HFE mutations → ↓ hepcidin → unrestricted iron absorption from gut → progressive iron accumulation in liver, heart, pancreas, joints, pituitary, skin.
• Penetrance variable: only ~30% of homozygotes develop overt disease (cofactors: male sex, alcohol, viral hepatitis, NAFLD).

Clinical features

• Classic "bronze diabetes": hyperpigmentation + diabetes + cirrhosis (late finding).
• Common manifestations:
  • Fatigue, malaise (often the only symptom).
  • Hepatic: elevated LFTs, hepatomegaly, cirrhosis, HCC (~200 × ↑ risk in cirrhosis).
  • Cardiac: cardiomyopathy (restrictive then dilated), arrhythmias, conduction disease.
  • Endocrine: diabetes (pancreatic deposition), hypogonadism (pituitary), hypothyroidism, secondary hypopituitarism, adrenal insufficiency.
  • Arthropathy: MCP joints (especially 2nd and 3rd), wrists, ankles. CPPD ("pseudogout").
  • Skin: bronze hyperpigmentation (chronic; melanin + hemosiderin).
  • Susceptibility to certain infections: Vibrio vulnificus (raw seafood), Yersinia, Listeria.

Diagnosis

• Screening: not population-based; consider with family history, suggestive labs, or end-organ damage.
• Iron studies: fasting TSAT >45% (women) or >50% (men) + ferritin >200 (women) or >300 (men) → suggestive.
• Genetic testing: HFE C282Y, H63D.
• Liver assessment: MRI R2*/T2* for liver iron concentration (LIC), non-invasive, replaces liver biopsy in most cases. Biopsy if diagnosis unclear or fibrosis assessment needed.
• Cardiac assessment: MRI T2* if cardiac involvement suspected.

Treatment of HH

• Therapeutic phlebotomy: mainstay. 500 mL weekly (~250 mg iron each) until ferritin 50 to 100 ng/mL or borderline anemia. Then maintenance q2 to 4 months to keep ferritin 50 to 100.
• Pre-cirrhotic patients with adequate phlebotomy: normal life expectancy.
• Iron chelation (deferoxamine, deferasirox, deferiprone): for those who cannot tolerate phlebotomy or have transfusion-dependent overload.
• Avoid exogenous iron, vitamin C supplements (can ↑ iron absorption and toxicity), and uncooked seafood/shellfish (Vibrio risk).
• HCC screening if cirrhosis: ultrasound ± AFP q6 months.
• Family screening: first-degree relatives of HH patients should have iron studies + HFE genotyping.

Other iron overload disorders

• Non-HFE hereditary hemochromatosis (rare):
  • HJV (hemojuvelin): juvenile HH type 2A; severe early-onset cardiac/endocrine.
  • HAMP (hepcidin): juvenile HH type 2B.
  • TFR2 (transferrin receptor 2): HH type 3.
  • SLC40A1 (ferroportin disease, autosomal dominant): HH type 4; loss-of-function causes macrophage iron loading; gain-of-function gives the classic phenotype.
• Aceruloplasminemia: CP gene; iron overload + neurologic symptoms (ataxia, dementia, retinal degeneration); low TSAT (low serum iron, mild microcytic anemia) with ↑ ferritin (key distinguishing feature).
• Atransferrinemia: rare; severe microcytic anemia + iron overload (paradoxical).
• African iron overload: dietary (traditional brewing in iron pots) + genetic predisposition (SLC40A1 polymorphisms).
• Secondary iron overload: chronic transfusions (thalassemia major, SCD, MDS, aplastic anemia, chemotherapy); ineffective erythropoiesis (suppressed hepcidin in thalassemia, MDS-RS).
• Liver disease: NAFLD, alcoholic liver disease, chronic hepatitis C, can cause moderate ferritin elevation without true iron overload.

Iron overload from chronic transfusion

• Each unit of pRBC contains ~200 to 250 mg iron. There is no mechanism to excrete iron, so it deposits in organs. Iron accumulation becomes significant after ~15 to 20 units.
• Organ deposition: liver (fibrosis, cirrhosis, HCC); heart (heart failure, arrhythmia); endocrine (hypogonadotropic hypogonadism, decreased bone mineral density, diabetes, hypothyroidism, hypoparathyroidism, growth failure).
• When to start chelation: once ferritin >1000 µg/L, OR after the first ~10 to 20 transfusions, OR after approximately 20 units of blood. Also for LIC >7 mg Fe/g dry weight.
• Monitoring: serum ferritin every 3 months (rough proxy); liver MRI (R2* or T2*) for LIC if ferritin >1000 ng/mL; In transfusion-dependent thalassemia, obtain scheduled cardiac T2* MRI (typically from age 8 to 10), frequency set by cardiac iron burden; cardiac iron can be high despite normal LVEF and near-normal liver iron. Reserving cardiac MRI for high-risk patients applies to sickle cell disease. Liver and cardiac iron by MRI are the most accurate stores measurements.

Chelation targets

Iron chelators

• Deferoxamine (Desferal): older parenteral chelator; SC 8 to 12 hr infusion 5 to 7 nights/week or IV. Toxicities: ototoxicity (high-frequency hearing loss), ophthalmotoxicity (cataracts, retinopathy), growth retardation in children, infusion-site reactions. Annual audiology/ophthalmology screen. Yersinia infection risk.
• Deferasirox (Exjade, Jadenu): oral once daily; standard for chronic transfusional overload. Toxicities: renal (Cr ↑, possible Fanconi syndrome), hepatic (LFT elevation, rarely failure), GI; rash, cytopenias. Deferasirox: monitor renal function/tubular markers weekly during the first month after start or dose change, then at least monthly; check AST, ALT, and bilirubin every 2 weeks during the first month, then at least monthly.
• Deferiprone (Ferriprox): oral 3 times/day; combined with deferoxamine for cardiac iron. Toxicity: agranulocytosis (~1 to 2%); monitor ANC before starting, weekly for the first 6 months, every 2 weeks for months 6 to 12, then every 2 to 4 weeks thereafter (per current Ferriprox label); arthropathy, GI.
• Combination therapy: deferoxamine + deferiprone for severe cardiac iron (better cardiac penetration).
• Monitoring: ferritin q3 months; LIC by MRI R2*/T2* annually; cardiac T2* annually if cardiac involvement; renal/hepatic per drug.

High yield

• HFE C282Y homozygote = most common HH; variable penetrance.
• Therapeutic phlebotomy is the mainstay for HFE-HH; normal life expectancy if pre-cirrhotic.
• Avoid Vibrio vulnificus (raw oysters), can be fatal in iron overload.
• Cirrhosis + HH = ~200 × HCC risk; surveil with ultrasound/AFP q6 months.
• Aceruloplasminemia: iron overload + neurologic findings + low TSAT with high ferritin (distinct).
• Transfusional overload: chelate when ferritin >1000 or LIC >7 mg Fe/g dry weight; keep cardiac T2* >20 ms.
• Chelator toxicities: deferoxamine = oto/ophthalmotoxicity; deferasirox = renal/hepatic; deferiprone = agranulocytosis (weekly CBC).