Dermatologic Manifestations of Hemochromatosis 

Hereditary hemochromatosis (HH) is a fairly common disease in whites and is a result of iron deposition in hepatocytes, myocardial fibers, and other visceral cells. The disease is usually inherited in an autosomal recessive manner and is caused by mutations in the HFE gene.

The classic tetrad of manifestations resulting from hemochromatosis consists of (1) cirrhosis, (2) diabetes mellitus, (3) hyperpigmentation of the skin, and (4) cardiac failure. Clinical consequences also include hepatocellular carcinoma, impotence, and arthritis. The cutaneous hyperpigmentation seen in patients with hereditary hemochromatosis is primarily due to melanin rather than iron.^[1]

[#IntroductionFrequencyUnitedStates] Although clinical expression of hemochromatosis is presumed to be less frequent and less severe in women than in men, because of the iron loss associated with menses and pregnancy, women with the hemochromatosis genotype can have full phenotypic expression of the disease.^[2] Moirand et al found that while men had a higher incidence of serious complications of hereditary hemochromatosis, primarily diabetes mellitus and cirrhosis, women complained more often of fatigue and skin hyperpigmentation.^[2]

Go to Hemochromatosis and Neonatal Hemochromatosis for complete information on these topics.

Iron excess is known to be responsible for hypermelanosis. However, the mechanism is not fully understood.

Tsuji found that hyperpigmentation of the skin occurs after iron injections in hairless mice.^[3] This hyperpigmentation was accompanied by hemosiderin accumulation in the skin. Stronger pigmentation of the fascial skin rather than the dorsal skin corresponded with elevated iron accumulation in the fascial part of the skin. The study suggests that the brownish discoloration of the skin in hemochromatosis may be dependent to some degree on hemosiderin accumulation. Hemosiderin is supposed to increase activation of melanocytes.

On the other hand, Smith et al in 1978 found normal levels of immunoreactive beta-melanocyte-stimulating hormone (beta-MSH) in patients with hereditary hemochromatosis and concluded that elevation of beta-MSH played no role in the pathogenesis of hyperpigmentation.^[4]

The tetrad of cirrhosis, diabetes mellitus, hyperpigmentation of the skin, and cardiac failure may be evident. However, symptomatology of hereditary hemochromatosis has changed in recent years, and its full clinical expression is seen in only a minority of patients.^[5] In addition, any patient admitted to the hospital with an isolated case of asthenia or with arthralgia or hypertransaminasemia should be examined by means of transferrin-saturation testing.

General symptoms comprise chronic fatigue, weakness, lethargy, and apathy. Among organ-related symptoms, hepatomegaly is seen in more than 95% of patients and can be accompanied by signs of chronic liver disease, such as abdominal pain and cutaneous stigmata of liver disease (palmar erythema, spider angioma, or jaundice), and liver failure (ascites or encephalopathy). Liver biopsy and histologic evaluation of tissue iron accumulation was considered the criterion standard for diagnosis of hereditary hemochromatosis until testing of the HFE gene was introduced.^[6]

Skin findings

Cutaneous hyperpigmentation is seen in more than 90% of patients with idiopathic hemochromatosis, although it may be mild.^[1] Hyperpigmentation is one of the earliest signs of the disease, and it tends to be most pronounced on sun-exposed skin, particularly on the face, with a coloration of brownish bronze or, at times, slate gray.

In one series of 100 patients, approximately one half had metallic gray pigmentation, one fifth had a frankly brown pigmentation, and the remainder had an intermediate shade. External genital hyperpigmentation was seen in one third of patients, and one fifth had hyperpigmentation of flexural folds, scars, and nipple areolae.

Structures of skin are injured by iron deposits and increased synthesis of melanin in melanocytes. The rapid tanning with minimal sun exposure reflects the synergistic effects of iron accumulation and sun exposure, but is the result of melanin, rather than the iron itself. Hyperpigmentation often accentuates during exacerbations and regresses with therapy. Treatment with phlebotomy does not immediately resolve the hyperpigmentation.^[7]

Ichthyosiform alterations, skin atrophy, koilonychia, and hair loss may also be evident. In the series of 100 patients, ichthyosis-like changes were evident in 46% of patients.^[1] Ichthyosiform changes may be mild or marked. Skin affected with ichthyosiform changes is very dry.^[7] Cutaneous atrophy was observed in 42% of 100 patients, usually on the anterior surface of the leg.

The cutaneous hyperpigmentation in patients with hereditary hemochromatosis should be differentiated from drug-induced hyperpigmentation and actinic reticuloid.

A skin biopsy specimen may confirm the diagnosis of hereditary hemochromatosis. Any cutaneous site, hyperpigmented or not, may be selected for biopsy, but avoid performing cutaneous skin biopsies on the legs because iron deposition in that area may be due to stasis. In healthy people, iron deposition may be evident only around apocrine glands and not around eccrine glands. Histologic findings

Microscopically, cutaneous hyperpigmentation appears as increased melanin within the epidermal basal layers.^[1] An iron stain, such as Perls Prussian blue stain, should be used to detect azure granules around the blood vessels and within the basement membrane zone of sweat glands and the connective tissue cells surrounding them. Siderosis around eccrine glands may be specific for idiopathic hemochromatosis.

Hemochromatosis may be associated with porphyria; therefore, evaluate patients for this complication. In one study, homozygosity for the C282Y hemochromatosis mutation was linked to an earlier onset of skin lesions in patients with either familial or sporadic porphyria cutanea tarda; the effect is more marked in familial porphyria cutanea tarda, in which anticipation was demonstrated in family studies.^[8] Analysis of the frequencies of hemochromatosis genotypes in each type of porphyria cutanea tarda indicated that C282Y homozygosity is a significant susceptibility factor in both types.