Dermatologic Manifestations of Hemochromatosis
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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. Early diagnosis and treatment may prevent complications, facilitated by population screening. [1] It may be viewed as a metal-related toxicosis. [2]
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 2 missense mutations (C282Y and H63D) of the HFE gene are responsible for most cases of HH in patients of European descent. Analysis of HFE gene polymorphisms may help detect early disease. [3] The cutaneous hyperpigmentation seen in patients with hereditary hemochromatosis is primarily due to melanin rather than iron. [4]
Hereditary hemochromatosis affects 1 in 200-300 individuals of northern European descent. The prevalence of HH in the United States is 1 case in 200-500 individuals. The frequency of the C282Y and H63D mutations is 5.4% and 13.5%, respectively. Symptoms of HH occur more frequently in males than in females, with a male-to-female ratio of 3:1. In relatives of patients with hemochromatosis who are homozygous for the C282Y mutation, expression of iron overload phenotype was noted in 85% males and 69% females. 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. [5] 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. [5]
The Greek population may differ genetically from the northern European population, owing to influences from neighboring Asian and African populations. These findings also suggest that there is no sex-associated inheritance of these polymorphisms, and sex-specific symptoms appear as a result of independent biological processes. Thus, early detection of the tendency towards iron accumulation may be achieved by the genotypic analysis of the polymorphisms that may contribute to the development of the hemochromatosis.
Go to Hemochromatosis, Neonatal Hemochromatosis, and Hemochromatosis Imaging 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. [6] 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. [7]
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. [8] 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. [9]
Some patients feel stigmatized by family members and report social isolation and fear of workplace discrimination. [10]
Cutaneous hyperpigmentation is seen in more than 90% of patients with idiopathic hemochromatosis, although it may be mild. [4] 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. Another survey of 22 hemochromatosis patients found the most common presentation was cutaneous pigmentation, which was evident in 17 (77%) of them. [11]
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. [12]
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. [4] Ichthyosiform changes may be mild or marked. Skin affected with ichthyosiform changes is very dry. [12] Cutaneous atrophy was observed in 42% of 100 patients, usually on the anterior surface of the leg.
Hyperpigmentation of the oral mucosa was found in 15-20% of patients. Dental pigmentation with enamel loss may be noted. [13] Sanchez-Pablo and coworkers found hyposialia in hemochromatosis-affected patients. [14]
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.
Microscopically, cutaneous hyperpigmentation appears as increased melanin within the epidermal basal layers. [4] 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. [15] 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. [16] 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. Early initiation of treatment, usually phlebotomy, is pivotal for preventing irreversible organ damage. [17]
de Graaff B, Neil A, Sanderson K, Si L, Yee KC, Palmer AJ. A Systematic Review and Narrative Synthesis of Health Economic Studies Conducted for Hereditary Haemochromatosis. Appl Health Econ Health Policy. 2015 Oct. 13 (5):469-83. [Medline].
Brissot P, Cavey T, Ropert M, Gaboriau F, Loréal O. Hemochromatosis: a model of metal-related human toxicosis. Environ Sci Pollut Res Int. 2018 Jan. 25 (3):2007-2013. [Medline].
Katsarou MS, Latsi R, Papasavva M, Demertzis N, Kalogridis T, Tsatsakis AM, et al. Population-based analysis of the frequency of HFE gene polymorphisms: Correlation with the susceptibility to develop hereditary hemochromatosis. Mol Med Rep. 2016 May 20. [Medline].
Chevrant-Breton J, Simon M, Bourel M, Ferrand B. Cutaneous manifestations of idiopathic hermochromatosis. Study of 100 cases. Arch Dermatol. 1977 Feb. 113(2):161-5. [Medline].
Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y. Clinical features of genetic hemochromatosis in women compared with men. Ann Intern Med. 1997 Jul 15. 127(2):105-10. [Medline].
Tsuji T. Experimental hemosiderosis: relationship between skin pigmentation and hemosiderin. Acta Derm Venereol. 1980. 60(2):109-14. [Medline].
Smith AG, Shuster S, Bomford A, Williams R. Plasma immunoreactive beta-melanocyte-stimulating hormone in chronic liver disease and fulminant hepatic failure. J Invest Dermatol. 1978 Jun. 70(6):326-7. [Medline].
Durupt S, Durieu I, Nove-Josserand R, Bencharif L, Rousset H, Vital Durand D. [Hereditary hemochromatosis]. Rev Med Interne. 2000 Nov. 21(11):961-71. [Medline].
Gochee PA, Powell LW. What’s new in hemochromatosis. Curr Opin Hematol. 2001 Mar. 8(2):98-104. [Medline].
Manz U. Genetic explanations, discrimination and chronic illness: A qualitative study on hereditary haemochromatosis in Germany. Chronic Illn. 2016 May 12. [Medline].
Parkash O, Akram M. Hereditary Hemochromatosis. J Coll Physicians Surg Pak. 2015 Sep. 25 (9):644-7. [Medline].
Hazin R, Abu-Rajab Tamimi TI, Abuzetun JY, Zein NN. Recognizing and treating cutaneous signs of liver disease. Cleve Clin J Med. 2009 Oct. 76(10):599-606. [Medline].
Schemel-Suárez M, López-López J, Chimenos-Küstner E. Dental pigmentation and hemochromatosis: A case report. Quintessence Int. 2017. 48 (2):155-159. [Medline].
Sánchez-Pablo MA, González-García V, del Castillo-Rueda A. Study of total stimulated saliva flow and hyperpigmentation in the oral mucosa of patients diagnosed with hereditary hemochromatosis. Series of 25 cases. Med Oral Patol Oral Cir Bucal. 2012 Jan 1. 17(1):e45-9. [Medline]. [Full Text].
Handler NS, Handler MZ, Stephany MP, Handler GA, Schwartz RA. Porphyria cutanea tarda: an intriguing genetic disease and marker. Int J Dermatol. 2017 Mar 21. [Medline].
Brady JJ, Jackson HA, Roberts AG, et al. Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda. J Invest Dermatol. 2000 Nov. 115(5):868-74. [Medline].
Kawabata H. The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis. Int J Hematol. 2018 Jan. 107 (1):31-43. [Medline].
Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi
Disclosure: Nothing to disclose.
Jacek Drobnik, MD, PhD Assistant Professor of Physiology and Medicine, Department of General and Experimental Pathology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.
David F Butler, MD Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society for MOHS Surgery, Association of Military Dermatologists, Phi Beta Kappa
Disclosure: Nothing to disclose.
Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, American College of Rheumatology
Disclosure: Received income in an amount equal to or greater than $250 from: Lilly; Amgen <br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.
Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
Dermatologic Manifestations of Hemochromatosis
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