Elevated iron levels and erosions on the hands

The porphyrias are metabolic diseases caused by deficiencies in enzymes involved in the heme biosynthetic pathway. The enzymatic deficiencies lead to accumulation of precursor proteins called porphyrins. There are eight porphyrias, which are categorized as acute or nonacute. The acute...

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The porphyrias are metabolic diseases caused by deficiencies in enzymes involved in the heme biosynthetic pathway. The enzymatic deficiencies lead to accumulation of precursor proteins called porphyrins. There are eight porphyrias, which are categorized as acute or nonacute. The acute porphyrias are characterized by potentially life-threatening neurologic attacks that do not occur in the nonacute porphyrias.

The acute porphyrias include acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and ALA-D-deficiency porphyria. The nonacute porphyrias include porphyria cutanea tarda (PCT), erythropoietic protoporphyria, congenital erythropoietic porphyria, and hepatoerythropoietic porphyria. With the exception of acquired PCT, the porphyrias are inherited diseases.^1,2

The man in this case was diagnosed with PCT, the most common porphyria, associated with an average age of onset of 45 years. PCT results from decreased activity of the enzyme uroporphyrinogen decarboxylase (UROD). PCT can be inherited or acquired, with the acquired form being significantly more common.

The decreased activity of UROD leads to the accumulation of uroporphyrins in the skin and in the urine. Uroporphyrin absorbs light intensely in the Soret band (400-410 nm, UVA wavelength). When this energy is absorbed, the porphyrins enter into an excited state, leading to reactive oxygen species that cause tissue damage. This action is manifested clinically as increased photosensitivity, skin fragility, erosions, blisters, scarring, and milia in sun-exposed skin (particularly on the dorsal hands, face, and posterior neck). Other cutaneous manifestations include hypertrichosis (most frequently seen on the temples and cheeks) and scleroderma-like skin changes.^1,2

Because of the excessive accumulation of porphyrins, the urine may appear reddish after exposure to natural light and may have a bright-pink fluorescence when exposed to UVA light (e.g., a Wood’s lamp). However, these urinary color changes are not sensitive or specific.^1,2

Liver disease is common in individuals with PCT. Alcoholism, estrogen therapy, hepatitis, HIV, and hereditary hemochromatosis are among the factors contributing to hepatic dysfunction, which results in excess accumulation of iron stores in the liver. The excess iron leads to oxidation products that inhibit UROD. A 75% reduction in the activity of hepatic UROD as compared with normal is required for clinical disease expression.³

In the United States, 94% of PCT patients are infected with hepatitis C. Additionally, 20% of patients have hereditary hemochromatosis. Diabetes mellitus is associated with PCT in 15% to 20% of patients.^1,2

PCT can be suspected on the clinical presentation, but the definitive test is the demonstration of elevated urinary porphyrin levels in a 24-hour urine collection, with a greater than 3:1 ratio of uroporphyrin to coproporphyrin. Skin biopsy of a blister demonstrates a subepidermal split with hyalinized blood vessel walls in the mid and upper dermis.^1,2

The differential for PCT includes pseudoporphyria, epidermolysis bullosa acquisita, polymorphous light eruption, and hydroa vacciniforme. It is important to recognize that porphyrin studies of urine, stool, and other body fluids will be normal in these diseases.

Also included in the differential are the other porphyrias that present with blistering (congenital erythropoietic porphyria, hepatoerythropoietic porphyria, variegate porphyria, and hereditary coproporphyria).^1,2

In pseudoporphyria, individuals develop blistering and skin fragility similar to that of PCT. However, porphyrin levels are normal. Hypertrichosis and sclerodermoid changes are not present. Pseudoporphyria is most commonly caused by the nonsteroidal anti-inflammatory drug naproxen. Ibuprofen is a safe alternative. Pseudoporphyria may occur with use of various other medications, in association with hemodialysis, and with tanning-bed use.^1,2

Epidermolysis bullosa acquisita is an acquired blistering disease in which individuals develop autoantibodies to type VII collagen, which is found at the dermal-epidermal junction. Patients may develop blistering at areas of pressure or friction. Porphyrin studies are normal in cases of epidermolysis bullosa acquisita.⁴

Polymorphous light eruption is the most common photosensitive skin disease. Lesions present on sun-exposed areas and may be papulovesicular, eczematous, or plaquelike. Patients frequently complain of itching following sun exposure, with subsequent development of skin lesions 24 to 96 hours later. Porphyrin studies are normal.⁵

Hydroa vacciniforme is a rare photosensitive skin disease of childhood. Within six hours of sun exposure, a stinging sensation develops, which progresses to vesicles over the next 24 hours. Lesions heal with pockmark-like scars. The ears, cheeks, and backs of the arms and hands are the most commonly affected areas. Porphyrin studies are normal.⁵

Congenital erythropoietic protoporphyria is a rare, severe, mutilating autosomal recessive porphyria caused by deficiency of the enzyme uroporphyrinogen III synthase. This condition presents at birth with severe painful photosensitivity. Patients subsequently develop blistering that leads to mutilating scarring on sun-exposed areas. Porphyrin deposition causes the teeth appear red in individuals with erythropoietic protoporphyria. Increased levels of uroporphyrin and coproporphyrin are found in the patient’s urine, stool, and red blood cells, which have a red fluorescence.^1,2

Hepatoerythropoietic porphyria is a rare autosomal- recessive porphyria attributable to a defect in UROD, which is the same enzyme impaired in PCT. The biochemical studies are similar to PCT, but the clinical presentation resembles congenital erythropoietic protoporphyria.^1,2

Variegate porphyria, most common in South Africa, is an autosomal dominant disorder caused by decreased activity of protoporphyrinogen oxidase. Patients may have skin lesions similar to those seen in PCT and will suffer from acute neurologic and GI attacks. In contrast to PCT, urinary coproporphyrins are increased over uroporphyrins.^1,2

Hereditary coproporphyria is a rare autosomal dominant porphyria that results from a deficiency of coproporphyrinogen oxidase. Patients present with photosensitivity and acute neurologic and GI attacks. The level of fecal coproporphyrin is increased.^1,2

The treatment of choice for PCT is therapeutic phlebotomy, which creates iatrogenic iron-deficiency anemia to lower hepatic iron stores. This procedure consists of removing 500 mL of blood at two-week intervals until the hemoglobin level is between 10 g/dL and 11 g/dL. This process may take several months, and the patient’s cutaneous manifestations will gradually resolve.

An alternative to phlebotomy is low-dose antimalarial therapy. After either treatment, remission may last many years. If the patient relapses, treatment is repeated. Removal of such precipitating factors as medications (particularly estrogens) and alcohol is also important. Finally, sun protection in the form of physical blockers (e.g., clothing, hats, and such inorganic sunscreens as zinc oxide) is emphasized.^1,2

In this case, the patient’s urinary uroporphyrin level was significantly elevated over the coproporphyrin level, thus confirming the suspected diagnosis of PCT. He underwent five months of therapeutic phlebotomy and ultimately achieved a sustained remission.

Adam Rees, MD, is a first-year dermatology resident at Baylor College of Medicine in Houston.

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