Hemochromatosis

Overview

Hemochromatosis is a disorder of iron overload characterized by progressive accumulation of iron in parenchymal organs — primarily the liver, heart, pancreas, pituitary, and joints — leading to tissue damage and organ failure. The most common form is hereditary hemochromatosis (HH), an autosomal recessive condition caused by mutations in the HFE gene.

Classification

Type	Gene Affected	Inheritance	Notes
Type 1 (HFE-related)	HFE (C282Y, H63D)	AR	Most common in Northern Europeans
Type 2A (Juvenile HH)	HJV (hemojuvelin)	AR	Severe; presents in 2nd–3rd decade
Type 2B (Juvenile HH)	HAMP (hepcidin)	AR	Similar to 2A
Type 3	TfR2 (transferrin receptor 2)	AR	Moderate severity
Type 4 (Ferroportin disease)	SLC40A1 (ferroportin)	AD	Unique pattern
Secondary hemochromatosis	N/A	—	Transfusion-dependent anemias, chronic liver disease, dietary iron overload

Pathophysiology

Normally, the body maintains 3–4 g of iron by matching intestinal absorption (~1 mg/day in men, ~1.5 mg/day in menstruating women) to daily losses. The key regulatory hormone is hepcidin — a liver-derived peptide that suppresses basolateral iron export from intestinal enterocytes and iron release from macrophages by binding and internalizing ferroportin.

In hemochromatosis, hepcidin is inappropriately low (or ferroportin is hepcidin-resistant in Type 4), resulting in unregulated intestinal absorption of ≥4 mg/day. Iron progressively saturates transferrin and accumulates in parenchymal cells, generating reactive oxygen species via the Fenton reaction, causing lipid peroxidation, DNA damage, and ultimately fibrosis and organ failure. (Harrison's, p. 11768)

Clinical Features

Symptoms typically appear in the 4th–5th decade in men (later in women due to menstrual iron losses). Classic triad: cirrhosis + diabetes + skin bronzing ("bronze diabetes") — though this represents end-stage disease.

Organ-specific manifestations:

Liver: Hepatomegaly → cirrhosis → hepatocellular carcinoma (HCC; 200× increased risk)
Pancreas: Diabetes mellitus (iron-induced β-cell dysfunction)
Heart: Dilated cardiomyopathy, arrhythmias, heart block
Pituitary/Gonads: Hypogonadotropic hypogonadism, loss of libido, impotence, amenorrhea
Skin: Hyperpigmentation (bronze/slate-gray)
Joints: Arthropathy (especially 2nd and 3rd MCP joints) — often the earliest symptom
Thyroid/Adrenals: Hypothyroidism, adrenal insufficiency

Diagnosis

Lab Workup

Test	Finding in HH	Threshold
Transferrin saturation (fasting)	Elevated	>45% (screening cutoff)
Serum ferritin	Elevated	>300 μg/L (men), >200 μg/L (women)
Liver enzymes (ALT/AST)	Mildly elevated	—
Blood glucose	Elevated (if diabetic)	—

Genetic Testing

HFE C282Y homozygosity confirms Type 1 HH in the right clinical context
Compound heterozygosity (C282Y/H63D) causes milder iron loading

Liver Biopsy

Indicated when: ferritin >1000 μg/L, elevated transaminases, or hepatomegaly — to assess fibrosis stage and hepatic iron index (HII ≥1.9 mol/g/year supports HH).

Prussian Blue stain reveals coarse blue iron granules concentrated in periportal hepatocytes (unlike secondary iron overload, which preferentially loads Kupffer cells):

Prussian Blue stain showing iron deposits in periportal hepatocytes in hereditary hemochromatosis

Prussian Blue (Perls) stain: blue iron granules clustered in periportal hepatocytes — characteristic of HFE-related hereditary hemochromatosis. (webpathology.com)

MRI

T2*-weighted MRI of the liver quantifies iron without biopsy and is increasingly used for noninvasive staging.

Management

1. Phlebotomy (First-Line)

The cornerstone of treatment. (Harrison's, p. 11778)

Induction phase: 500 mL whole blood (200–250 mg iron) removed weekly (or twice-weekly for gross overload)
- Packed red cell volume may dip to ~35 mL/dL initially, then stabilizes
- Transferrin saturation remains elevated until iron stores are depleted
- Target: serum ferritin ≤100 μg/L
- Duration: typically 1–2 years for advanced disease (≥25 g iron may need to be removed)
Maintenance phase: Phlebotomy every 2–4 months to keep ferritin ≤100 μg/L

2. Chelation Therapy

Reserved for patients unable to tolerate phlebotomy (e.g., anemia, cardiovascular instability):

Deferoxamine (IV/SC)
Deferasirox (oral)

3. Management of End-Organ Damage

Complication	Management
Cirrhosis	Surveillance for HCC (ultrasound + AFP every 6 months)
Diabetes	Standard insulin/oral hypoglycemics
Cardiomyopathy	Standard heart failure therapy
Hypogonadism	Testosterone/estrogen replacement
Arthropathy	NSAIDs; joint replacement if severe

4. Dietary Advice

Avoid vitamin C supplements (enhances iron absorption)
Avoid alcohol (synergistic hepatotoxicity)
Avoid raw shellfish (risk of Vibrio vulnificus infection — iron overload increases susceptibility)

5. Liver Transplantation

For end-stage liver disease; outcomes are inferior compared to other indications (due to cardiac and endocrine comorbidities).

Prognosis

If treated before cirrhosis develops: normal life expectancy
If cirrhosis is present at diagnosis: increased mortality, especially from HCC (does not fully regress with iron depletion) and hepatic failure
Phlebotomy reverses or halts: fatigue, hepatomegaly, skin pigmentation, cardiac dysfunction, and some endocrine dysfunction
Arthropathy and hypogonadism may not improve after treatment

Family Screening

First-degree relatives of a C282Y homozygote should be screened with:

Transferrin saturation + ferritin
HFE genotyping

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