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Hemochromatosis
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Hemochromatosis

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Contributors: Tracy Fuhrmann MD, Brian Poligone MD, Lowell A. Goldsmith MD, MPH
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Synopsis

Hemochromatosis : Abdominal pain, Fatigue, Hepatomegaly, Ferritin increased, Serum iron elevated, Arthralgia
Hereditary hemochromatosis (HH) is a genetic disorder of iron overload. In the classic form, a C282Y mutation in the HFE gene inappropriately increases iron absorption from the duodenum. Other forms of HH involve mutations in various molecules that regulate iron homeostasis. While usually autosomal recessive, an autosomal dominant form is caused by a mutation in ferroportin.

In all forms, excess iron deposits in the joints and in organs such as the liver, pancreas, heart, and skin, causing damage. Historically, the disease is known by the classic triad of hyperpigmentation, cirrhosis, and diabetes mellitus ("bronze diabetes"). Iron deposits also lead to arthropathy (arthritis), edema, hypopituitarism, hypogonadism, hair loss, and cardiac arrhythmias, and advanced liver fibrosis or liver cancer. Individuals are also at increased risk of Vibrio vulnificus and other infections. Patients initially present between the ages of 40 and 60 with nonspecific symptoms such as fatigue, abdominal pain, joint pain, and loss of libido. Hyperpigmentation is eventually seen in about 70% of cases.

There are a few theories regarding the possible mechanism for hyperpigmentation. Deposition of iron in the skin may cause an increase in melanin contained in giant melanosomes. Iron excess may stimulate adrenocorticotropic hormone (ACTH) or melanocyte-stimulating hormone (MSH). Hyperpigmentation may also be a direct manifestation of hemosiderin deposition in the skin.

HFE-associated hemochromatosis most commonly affects White populations, with prevalence in Europe of 1:400. In North America, the prevalence among White people is approximately 1:227. In contrast, non-HFE HH is found worldwide. In southern Europe and Asia, a larger proportion of HH involves non-HFE mutations. It is associated with HLA-A3. Men and women are equally affected, but there are variable clinical manifestations between men and women. Symptoms are more common and often more severe in men, and there is increased mortality in men.

Pediatric patient considerations: Juvenile hemochromatosis (hemochromatosis type 2) is caused by a mutation in the TFR2 gene on chromosome 7. This form is rapidly progressive. Hypogonadism is the typical presenting feature. Cardiac involvement is frequent, and most fatalities are due to heart failure.

Neonatal forms cause liver failure within the first 30 days of life. The condition is likely caused by genetic factors as well as various in utero insults. It presents with jaundice.

Codes

ICD10CM:
E83.110 – Hereditary hemochromatosis

SNOMEDCT:
399187006 – Hemochromatosis

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Diagnostic Pearls

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Differential Diagnosis & Pitfalls

The differential of iron overload includes but is not limited to the following:
Cutaneous findings:
  • Addison disease – Hyperpigmentation preferentially on sun-exposed areas in association with low secretion of adrenal hormones.
  • Cushing syndrome – Generalized hyperpigmentation but most pronounced in sun- and trauma-exposed areas.
  • Radiation dermatitis – In ionizing forms, look for small hypopigmented spots intermingled with zones of hyperpigmentation.
  • Drug-induced pigmentation – Examples include amiodarone, minocycline, chloroquine, and phenothiazines, which can cause blue-gray pigmentation in sun-exposed areas.
  • Argyria – Generalized blue-gray pigmentation with nail and sclerae involvement.
  • Advanced metastatic melanoma – Associated with diffuse, generalized melanosis of the skin that is slate blue-gray to brown in color.
  • Ochronosis– Hyperpigmentation of face, side and back of neck, back, and extensor surfaces of extremities.
  • Excessive ingestion of iron, ascorbic acid, and alcohol may also cause an increase in body iron loads.

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References

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Last Updated:01/11/2023
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Hemochromatosis
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A medical illustration showing key findings of Hemochromatosis : Abdominal pain, Fatigue, Hepatomegaly, Ferritin increased, Serum iron elevated, Arthralgia
Clinical image of Hemochromatosis - imageId=5420735. Click to open in gallery. caption: 'Diffuse bronze discoloration of the skin.'
Diffuse bronze discoloration of the skin.

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