Historical Background and Epidemiology
The characteristic symptom complex was first described by Trousseau in 1871. He identified the combination of diabetes mellitus, skin pigmentation, and liver cirrhosis, associating them with iron accumulation. In 1890, von Recklinghausen introduced the term "hemochromatosis," which reflects the brown coloration of the skin and internal organs due to the deposition of melanin and hemoglobinogenic pigments.
Idiopathic hemochromatosis has numerous synonyms: primary hemochromatosis, siderophilia, and hereditary iron storage disease. In the past, it was also referred to as "bronze diabetes" and pigmented cirrhosis.
The prevalence of the disease varies: it is extremely rare in the UK and Scandinavia, has a frequency of 0.01–0.07% in Central Europe, and ranges from 0.001 to 0.1% in the USA. Men suffer 10 times more often than women, with the disease typically manifesting between the ages of 40 and 60. In women, the pathology more commonly appears after the onset of menopause.
Pathogenesis and Clinical Presentation
Idiopathic hemochromatosis is based on a hereditarily determined metabolic disorder (autosomal recessive inheritance). The primary pathogenetic link is a defect in the enzyme systems that regulate intestinal iron absorption. The metal enters in excess and primarily deposits in hepatocytes.
The disease develops gradually, with characteristic symptoms forming over 1 to 3 years. In the fully developed stage, the classical triad manifests:
- Pronounced pigmentation of the skin and mucous membranes.
- Liver cirrhosis.
- Diabetes mellitus.
The skin and internal organs acquire a specific rusty-brown or chocolate color. In the skin, the pigment accumulates in dermal macrophages and fibroblasts, accompanied by an increase in melanin within melanocytes.
Pathological Anatomy of the Liver
The liver is the primary target organ of the disease. Macroscopically, it is heavily pigmented. Biopsy reveals massive deposition of hemosiderin (yielding a positive Perls' Prussian blue reaction).
Dynamics of microscopic changes:
- Accumulation: Hepatocytes (especially periportal) become overloaded with hemosiderin. Hepatic macrophages (Kupffer cells) contain significantly less pigment.
- Damage: Increasing pigment volume leads to reduced activity of oxidation-reduction enzymes. Necrobiosis and hepatocyte necrosis ensue.
- Late stages: Hemosiderin is detected in the epithelium of bile ducts and connective tissue.
- Fibrosis: Fibrous tissue proliferates in place of destroyed cells. Septa form, dividing the parenchyma into small monolobular pseudolobules.
The ultimate outcome is micronodular liver cirrhosis, which can transform into macronodular cirrhosis. A characteristic morphological feature is the presence of broad bands of mature connective tissue surrounding the pseudolobules.
Extrahepatic Manifestations and Diagnosis
In addition to the liver, iron is deposited in other organs, causing sclerosis and dystrophy:
- Pancreas: Pigment accumulation causes interstitial inflammation, fibrosis, and atrophy of the islets of Langerhans (the cause of diabetes).
- Spleen: Changes are secondary and associated with portal hypertension driven by cirrhosis.
- Systemic involvement: Pigment is detected in the myocardium, synovial membranes of joints, and endocrine glands (pituitary, adrenal glands, thyroid, parathyroid glands, and ovaries).
Diagnosis is based on laboratory findings: hyperferremia, elevated ferritin levels, and transferrin saturation exceeding 50% (normal is 16–45%).
Prognosis and Causes of Death
The course of hemochromatosis is prolonged, especially in older patients. Timely therapy can extend life by several decades.
Main causes of death:
- Liver failure.
- Hemorrhage from esophageal and gastric varices.
- Primary liver cancer (develops in 6–42% of cases, requiring regular ultrasound and monitoring of α-fetoprotein levels).
- Heart failure, diabetic coma, and intercurrent diseases.