Hemochromatosis: Beyond 50 shades of gray

By Warren R. Heymann, MD, FAAD
March 6, 2024
Vol. 6, No. 10

As a medical student, I was enamored by the term “bronze diabetes” as a depiction of hemochromatosis; ever since I have been magnetically attracted to the disease. Hereditary (primary) hemochromatosis is a common autosomal-recessive disorder, with a prevalence up to 1 in 300 white people. Secondary hemochromatosis is seen in patients with erythropoietic disorders requiring periodic blood transfusions, such as thalassemia and sickle cell anemia. Hemochromatosis results in excess iron deposition as hemosiderin causing multiple organ dysfunction (liver, pancreas, heart, thyroid, joints, pituitary, gonads, and skin), by inducing cell death and fibrosis. (1,2) This commentary will focus on the cutaneous manifestations of hemochromatosis.

Although there are 4 hereditary types of hemochromatosis, the most common is Type I. This occurs in homozygotes with a mutation in the HFE gene, present on the short arm of chromosome 6 (6p21.3), with C282Y and H63D being the most common mutations. These mutations cause increased absorption of iron despite normal dietary intake. Men are affected at least twice as often as women, with a later appearance in women because of iron excretion due to menstruation. Phlebotomy remains the cornerstone of therapy. (2) As iron stores decrease, patients improve — including their skin and appendages.

Patel et al state, “Hyperpigmentation is the presenting symptom in one-third of patients with hemochromatosis and is usually generalized, yet prominence can be noted on exposed skin. Skin often appears slate gray (due to dermal iron) or brown (due to increased melanin production). In a minority of patients, the mucous membranes and conjunctiva are also affected. This hyperpigmentation is reflected in the description of hemochromatosis as “bronze diabetes.” (3) Abdel-Naser describes the hyperpigmentation as “a color range of metallic gray or slate gray to brownish-bronze.” Hyperpigmentation is most pronounced on the face; less commonly, discoloration of the genitalia, flexural folds, scars, and nipple areolae is observed. (1) (The depictions of the color are correct — I often wonder if I would have been as intrigued if the condition was called “gray diabetes.”)

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In their study of 100 hemochromatosis cases in which 98% displayed hyperpigmentation, Chevrant-Breton et al made several landmark observations: 1) histologic siderosis in eccrine sweat glands was characteristic; 2) an ichthyosis-like appearance was noted in 46% of patients, ranging from xerosis to generalized ichthyosis vulgaris — including a diminution or absence of the granular layer on biopsied patients; 3) koilonychia was observed in 49%, mainly involving the thumb, index, and middle finger; 4) partial loss of body hair was noted in 62%, frequently in the pubic region; 5) skin atrophy, most often on the anterior aspect of the legs, was noted in 42% (4). The pathophysiology of each of these findings is poorly understood. Heavy metal pigmentation is attributed to the metal itself and stimulation of melanogenesis (5) — the precise how and why of this phenomenon requires further definition. Could iron in the eccrine unit affect sweat function, thereby contributing to xerosis or ichthyosis? Hair loss has been presumed to be due to hypogonadism, but are there other mechanisms? The pathophysiology of koilonychia is likely due to nail matrix pathology, but why?

Leung et al reported 4 cases of alopecia areata (AA) in which hereditary hemochromatosis (HH) was diagnosed from iron studies performed as part of an alopecia work-up. Although the genetic association between HH and AA is unknown, given the prevalence of both disorders in the general population, the authors advocate screening iron studies in AA patients. (6) While intriguing, further studies are warranted before this becomes standard practice.

An established association of hemochromatosis in patients with porphyria cutanea tarda (PCT) is observed in 2-27% of PCT patients. PCT may be observed in primary or secondary hemochromatosis. (7) An example of the latter is the case of a 69-year-old woman who had been taking ferrous sulfate (325 mg 3 times daily for 25 years) for fibroid-related menorrhagia that was treated surgically (see image). Iron promotes the formation of non-porphyrin products that directly inhibit uroporphyrinogen III decarboxylase. (8)

The risk of hepatocellular carcinoma in patients with hemochromatosis is approximately 30% (2); this risk is hypothesized to be due to iron-catalyzed oxidative damage. Pan et al the relationship of HH with nonmelanoma skin cancer (NMSC) in a retrospective review of 321 HH patients and 374 matched controls. The adjusted odds ratio of 2.02 did not reach statistical significance; when looking at tumor subtypes, the authors observed that the association between HH and basal cell carcinoma had an adjusted odds ratio of 2.11, which was significant. Excess iron’s role with reactive oxygen species in the pathogenesis of NMSC warrants further study. (9)

In conclusion, recognizing the multiple cutaneous manifestations of hemochromatosis, especially the shades of hyperpigmentation, should trigger questioning about relatives with the disease, obtaining iron studies (serum ferritin, serum transferrin saturation), and if warranted, genetic studies. Confirming the diagnosis can be life-saving.

Point to Remember: There are multiple cutaneous manifestations of hemochromatosis, of which hyperpigmentation in sun exposed sites is most frequent. A significant association is with porphyria cutanea tarda. There is new data to suggest that hereditary hemochromatosis may be associated with nonmelanoma skin cancer, although this association warrants further investigation.

Our expert’s viewpoint

Vinod E. Nambudiri, MD, MBA, EdM, FAAD
Associate Professor, Harvard Medical School
Dermatology, Internal Medicine

As noted in the commentary above, hemochromatosis is a genetic disease with a fairly high prevalence and a number of long-established cutaneous associations, including with cutaneous dyspigmentation and porphyria cutanea tarda. Prevalence varies across the globe; a fascinating historical feature notes that genetic anthropologists have been able to identify carriers of a common hemochromatosis mutation — the C282Y mutation discussed in the commentary — among skeletons from the Bronze Age 4,000-5,000 years ago discovered in Ireland, making it the first known Mendelian disease variant identified in a prehistoric individual! (10) Iron plays a complex role in the regulation of multiple physiologic processes, and the dangers of iron-overload on particular organs such as the liver and pancreas in hemochromatosis are well-established. We were intrigued by potential associations with skin cancer, which was triggered by a clinical observation I made wherein multiple patients with hemochromatosis presented to me for new skin cancers in a short time period — including one with multiple separate metachronous melanomas arising de novo in the span of a few months. After finding limited data in the literature, we sought to investigate further using a fairly large electronic data warehouse affiliated with our academic medical center and integrated hospital system. Our initial observations using retrospectively gathered data suggest further exploration is needed to understand the link — if any — between hemochromatosis and both melanoma and keratinocyte carcinomas, with a potentially stronger association for the latter. As we gather longer-term epidemiologic data on patients and populations with hemochromatosis — paired with future insights gained from basic science research advances exploring the role of iron in cutaneous neoplasm carcinogenesis — we will hopefully be able to shed greater light on possible associations between this dysregulation of the iron pathway and cutaneous malignancy sequelae in our patients, adding to the breadth of its potential skin-related consequences.

1. Abdel-Naser MB. The color of skin: gray diseases of the skin, nails, and mucosa. Clin Dermatol. 2019 Sep-Oct;37(5):507-515. doi: 10.1016/j.clindermatol.2019.07.011. Epub 2019 Jul 31. PMID: 31896405.

2. Porter JL, Rawla P. Hemochromatosis. 2022 Oct 9. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 28613612.

3. Patel AD, Katz K, Gordon KB. Cutaneous Manifestations of Chronic Liver Disease. Clin Liver Dis. 2020 Aug;24(3):351-360. doi: 10.1016/j.cld.2020.04.003. Epub 2020 May 29. PMID: 32620276.

4. Chevrant-Breton J, Simon M, Bourel M, Ferrand B. Cutaneous manifestations of idiopathic hemochromatosis. Study of 100 cases. Arch Dermatol. 1977 Feb;113(2):161-5. PMID: 836692.

5. Granstein RD, Sober AJ. Drug- and heavy metal--induced hyperpigmentation. J Am Acad Dermatol. 1981 Jul;5(1):1-18. doi: 10.1016/s0190-9622(81)70072-0. PMID: 6268671.

6. Leung B, Lindley L, Cruz PD Jr, Cole S, Ayoade KO. Iron Screening in Alopecia Areata Patients May Catch Hereditary Hemochromatosis Early. Cutis. 2022 Oct;110(4):E30-E32. doi: 10.12788/cutis.0650. PMID: 36446088.

7. Larrondo J, Gosch M. Porphyria Cutanea Tarda Due to Primary Hemochromatosis. Am J Med. 2020 Nov;133(11):e681-e682. doi: 10.1016/j.amjmed.2020.03.053. Epub 2020 May 13. PMID: 32416179.

8. Leasure AC, Turner N, Lim I. Facial hyperpigmentation and crusted papules on the hands. JAAD Case Rep. 2021 Nov 19;20:23-25. doi: 10.1016/j.jdcr.2021.09.043. PMID: 35036499; PMCID: PMC8753054.

9. Pan CX, Yang K, Lau CB, Zhou G, Nambudiri VE. Nonmelanoma skin cancer in patients with hereditary hemochromatosis: A case-control study. J Am Acad Dermatol. 2023 Mar;88(3):692-694. doi: 10.1016/j.jaad.2022.07.029. Epub 2022 Jul 22. PMID: 35872262.

10. Cassidy LM, Martiniano R, Murphy EM, Teasdale MD, Mallory J, Hartwell B, Bradley DG. Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome. Proc Natl Acad Sci U S A. 2016 Jan 12;113(2):368-73. doi: 10.1073/pnas.1518445113. Epub 2015 Dec 28. PMID: 26712024; PMCID: PMC4720318.

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