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Hereditary hemochromatosis (HHC)

Normal iron homeostasis in humans:

The human body normally contains 3 to 4 g of iron, two thirds of which is contained in hemoglobin, myoglobin, and a variety of enzymes, and one third as storage iron in ferritin and hemosiderin within hepatocytes and macrophages of the liver, bone marrow, spleen, and muscle.

Although the typical Western diet contains 10 to 20 mg of iron a day, only 1 to 2 mg is absorbed daily by the duodenal mucosa, which balances the iron loss from exfoliated gastrointestinal epithelial cells and desquamation of the skin.

Hepcidin is normally synthesized by the liver under the control of a variety of proteins and cytokines. When plasma iron is low, hepcidin is also low, allowing efflux of iron into serum through the iron exporter ferroportin (FPN) on duodenal enterocytes and macrophages. When plasma iron is elevated, hepcidin is increased and binds to FPN, causing internalization and degradation and resulting in less iron release into serum.

In HHC there is an abnormality of one of the iron regulatory proteins, which leads to excess gastrointestinal iron absorption that ranges from 3 to 4 mg per day; this results in accumulation of 15 to 35 g of iron in tissues over a 35- to 60-year period.

  • Hereditary hemochromatosis (HHC) occurs in 1 in 500 individuals (Northern European ancestry)

HHC typically presents with:

  • Asymptomatic abnormal liver function tests, with 95% of patients having hepatomegaly. Liver disease usually progresses to hepatic cirrhosis in untreated cases. Comorbid factors that increase hepatic steatosis including obesity, diabetes, and excess alcohol consumption. Hepatocellular carcinoma risk is increased by a factor of 20 to 200.

  • Characteristic arthropathy: occurs in 40% to 80% of patients and may be the initial manifestation.

  • Other manifestations: slate-gray skin caused by iron in eccrine sweat glands and brown skin pigmentation due to melanin deposition (50%), diabetes mellitus, and hypogonadism manifest as decreased libido (20% to 40%), impotence, amenorrhea, or sparse body hair.

  • Constitutional symptoms (80%) such as weakness or lethargy are also common.

  • Cardiac involvement, manifested most commonly as congestive heart failure, is present in approximately 30% of patients and is a principal cause of death in untreated patients.

  • Increased susceptibility to infections.

Clinical features of HHC arthropathy:

Most joints can be affected, but pain and stiffness affecting the second and third MCPs are the most characteristic complaints. Limited flexion in these two joints accounts for the “iron fist” sign. Other joints affected are the proximal interphalangeal joints, radiocarpal joints, knees, hips, ankles, shoulders, and occasionally metatarsophalangeal joints. Joint examination usually reveals firm swelling with mild tenderness, but warmth and effusions are absent, helping to distinguish HHC from rheumatoid arthritis.

A few patients may suffer from inflammatory “flares” due to pseudogout. Arthritis may be the initial manifestation in 33% of patients with HHC. Synovial fluid is noninflammatory. Treatment is for symptom alleviation using analgesics and nonsteroidal antiinflammatory drugs.


Pubmed

UpToDate

Images Hemochromatosis

Images Iron homeostasis


Web:

Genetics Home Reference

Mayoclinic

Medscape

Hemochromatosis.org

Canadian Hemochromatosis Society


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