Introduction
Disorder associated with deposits of excess iron that causes multiple organ dysfunction.
Aetiology
The excess iron is deposited in the cells as hemosiderin. This eventually leads to cell death and replacement of these cells by a fibrous deposition that causes destruction and/or impairment of organ function.
Primary hemochromatosis: HH (Hereditary hemochromatosis)
Iron primarily deposited in the reticuloendothelial cells
- Type 1 | Classical HFE (M/C): Classic form of HH, inherited AR with worldwide prevalence
- Chromosome 6 → Unregulated iron absorption from gut (enterocytes)
- Type 2 | Nonclassical (juvenile hemochromatosis)
- Type 2a: Hemojuvelin (HJV gene)
- Type 2b: Hepcidin gene
- Type 3 | Nonclassical: Transferrin receptor protein 2 (TFR2 gene)
- Type 4 | Nonclassical: Ferroportin (SLC40A1 gene)
Type 4 is the only type that is inherited as an autosomal dominant condition; types 1 through 3 are inherited as autosomal recessive conditions.
Secondary Hemochromatosis:
Iron primarily deposited in the parenchymal cells
- Transfusional iron overload
- Severe chronic hemolysis
- Excess parenteral supplements (Acute: Iron poisoning)
- Excess dietary iron
- Secondary disorders:
- Alcoholic cirrhosis
- Steatohepatitis
- Porphyria cutanea tarda
- Prolonged hemodialysis
- Post-portacaval shunting
Pathophysiology

- Increased absorption of dietary iron in the upper intestine
- Decreased expression of the iron-regulatory hormone hepcidin
- Altered function of HFE protein
- Tissue injury and fibrogenesis induced by iron

Clinical features
Cutaneous manifestations:
Result of both iron and melanin deposition. It does not usually occur before the iron stores exceed five times the normal levels.
- Diffuse hyperpigmentation (> 90% cases)
- Ichthyosiform changes
- Skin atrophy (anterior aspects of legs)

Musculoskeletal involvement:
Can present with arthritis, chondrocalcinosis, and joint swelling commonly involving metacarpophalangeal and proximal interphalangeal joints.
- Arthropathy: Joint pain without joint destruction
- Pseudogout: Calcium pyrophosphate crystal deposition in joints
Liver involvement (70%):
- Liver function abnormalities (75% cases)
- Jaundice (late sign)
- Abdominal pain, hepatomegaly, cirrhosis, portal hypertension, ascites, and splenomegaly
- ↑ 30% risk of hepatocellular carcinoma (HCC) (in coexisting hemochromatosis and cirrhosis)
- Hepatic bruit (indicate hepatocellular carcinoma)
- Hepatic hum (indicate portal hypertension)
Cardiac involvement:
Iron deposition in the cardiac muscle fibers and cells of the conduction system)
- Restrictive/dilated cardiomyopathy
- Arrhythmias
- Cardiac failure
Endocrine dysfunction:
- Diabetes mellitus (pancreatic iron deposition)
- Pituitary hypogonadism (iron-induced hypothalamic and/or pituitary failure)
- Decreased libido & impotence (men)/amenorrhea (women)
- Gynecomastia & decreased body hair (secondary to both chronic liver disease and hypogonadism)
- Hypopituitarism
- Thyroid dysfunction
- Adrenal dysfunction
- Parathyroid defects
- Osteoporosis
Cancers:
Risk of liver cancer is increased by 20 fold in patients with hemochromatosis.
Infections:
Increased risk of infection from select organisms
- Yersinia enterocolitica
- Listeria monocytogenes
- Vibrio vulnificus
Diagnosis
The clinical diagnosis of hemochromatosis is based on documentation of increased iron stores, demonstrated by elevated serum ferritin levels, which reflects an increase in hepatic iron content.

Lab investigations:
- Elevated liver enzymes in a diagnosed case of hemochromatosis
- Serum ferritin levels more than 1000 mcg/L

Differential diagnosis:
- Iron overload from chronic transfusion
- Hepatitis B and C
- Nonalcoholic fatty liver disease (NAFLD)
- Excessive iron supplementation
- Dysmetabolic hyperferritinemia
- Hereditary aceruloplasminemia
- Alcoholic liver disease
- Porphyria cutanea tarda
- Marrow hyperplasia
- Hemolytic anemia
- Biliary cirrhosis
Management
Phlebotomy (bloodletting or erythrocytapheresis)
By drawing off red blood cells, the major mobilizer of iron in the body, iron toxicity, can be minimized. Phlebotomy is usually performed once or twice a week. Once iron levels have normalized, lifelong, but less frequent, phlebotomy (typically 3-4 times a year) is required. Iron removal through phlebotomy improves insulin sensitivity, skin pigmentation, and fatigue; however, cirrhosis, hypogonadism, and arthropathy remain unchanged.
Deferoxamine (Chelating agent)
Although chelation is not as effective in hereditary hemochromatosis, it is of more benefit in erythropoietic hemochromatosis, where phlebotomy is not typically an option.