Random Dermatology MCQ - Hemochromatosis

A 55-year-old man with a history of type 2 diabetes mellitus and mild chronic liver enzyme elevation presents with a new, persistent, slate-gray to metallic hyperpigmentation on his face, neck, and sun-exposed forearms. The pigmentation has a bronzed quality and is most pronounced in skin folds. He also complains of fatigue and arthralgias. Laboratory studies reveal an elevated fasting transferrin saturation and serum ferritin. Which of the following is the most likely diagnosis and the definitive diagnostic test?

A. Addison's disease; confirmed by a low morning serum cortisol and high ACTH.
B. Drug-induced hyperpigmentation (e.g., from minocycline); confirmed by history and skin biopsy showing pigment in dermal macrophages.
C. Hereditary hemochromatosis; confirmed by genetic testing for the HFE gene mutation (C282Y homozygosity).
D. Porphyria cutanea tarda (PCT); confirmed by elevated uroporphyrins in a 24-hour urine collection.
E. Lichen planus pigmentosus; confirmed by a lichenoid infiltrate on skin biopsy.

Correct Answer: C. Hereditary hemochromatosis; confirmed by genetic testing for the HFE gene mutation (C282Y homozygosity).

Answer and Explanation

The correct answer is C. This question describes the classic presentation of hereditary hemochromatosis. The dermatologic hallmark is a slate-gray or bronzed hyperpigmentation due to both increased melanin and iron deposition in the skin, accentuated in sun-exposed areas and flexures. The systemic triad of "bronze diabetes" (skin pigmentation, diabetes mellitus, and liver disease) is classic. The presence of fatigue and arthralgias (from iron deposition in joints) further supports the diagnosis. While elevated transferrin saturation and ferritin are suggestive, the definitive diagnosis in a patient of Northern European descent is genetic testing for the HFE C282Y homozygous mutation.

Why the Other Options are Incorrect:

• A. Addison's disease: This causes diffuse hyperpigmentation, often with darkening of scars and mucous membranes, due to elevated ACTH. However, it would not explain the liver enzyme abnormalities, diabetes, or arthralgias. The specific "bronzed" quality and association with liver disease are more characteristic of hemochromatosis.

• B. Drug-induced hyperpigmentation: Minocycline can cause blue-gray pigmentation, often localized to scars or lower legs, but does not cause the systemic triad of liver disease, diabetes, and arthritis.

• D. Porphyria cutanea tarda (PCT): PCT presents with photosensitivity, skin fragility, vesicles/milia on the hands, and hyperpigmentation. It is associated with liver disease (often from alcohol or hepatitis C) and can have elevated iron studies, but the absence of blistering and the presence of diabetes and arthralgias point more toward hemochromatosis. PCT is diagnosed by elevated urinary uroporphyrins.

• E. Lichen planus pigmentosus: This presents as gray-brown macules in sun-exposed areas and flexures, which can look similar. However, it is an inflammatory dermatosis without systemic manifestations like diabetes, liver disease, or abnormal iron studies. Biopsy would show a lichenoid infiltrate with pigment incontinence, not iron deposition.

Additional High-Yield Information for Exams:

• Pathogenesis: Autosomal recessive disorder of iron metabolism, most commonly due to homozygosity for the C282Y mutation in the HFE gene on chromosome 6. This leads to unregulated intestinal iron absorption and progressive deposition in parenchymal organs (liver, pancreas, heart, pituitary, skin).

• Dermatologic Features:

  • Hyperpigmentation: The classic "bronzing" is due to increased melanin and perivascular hemosiderin deposition in the dermis.

  • Skin dryness, pruritus, and koilonychia (spoon nails) can occur.

  • Loss of body hair (axillary, pubic) is common.

• Systemic Manifestations:

  • Liver: Hepatomegaly, cirrhosis, hepatocellular carcinoma (primary cause of death).

  • Endocrine: Diabetes mellitus ("bronze diabetes"), hypogonadism (loss of libido, impotence).

  • Cardiac: Dilated cardiomyopathy, arrhythmias.

  • Joints: Arthropathy (especially of the 2nd and 3rd metacarpophalangeal joints).

• Differential Diagnosis: Other causes of generalized hyperpigmentation with systemic disease (Addison's, POEMS syndrome, pellagra) and other iron overload disorders (secondary hemochromatosis from transfusions, thalassemia).

• Prognosis: If untreated, leads to death from cirrhosis, heart failure, or hepatocellular carcinoma. With early diagnosis and treatment (phlebotomy), life expectancy is normal, and organ damage can be prevented or halted.

• Management & Rationale:

  • Rationale: The goal is to remove excess iron stores and prevent end-organ damage.

  • First-line/Definitive Treatment: Therapeutic phlebotomy. Removal of one unit of blood (~500 mL, containing 250 mg of iron) weekly or biweekly until ferritin is <50 ng/mL and transferrin saturation is <50%. Maintenance phlebotomy is then continued for life (typically 3-4 times per year).

  • Monitoring: Serial measurement of hemoglobin, ferritin, and transferrin saturation to guide phlebotomy frequency.

  • Screening: Screening of first-degree relatives with genetic testing and iron studies is mandatory.

  • Dermatologic: Sun protection may help minimize pigmentation. The hyperpigmentation often improves with phlebotomy.