Clinical Challenge: A patient with erosions and reddish urine

This patient was diagnosed with porphyria cutanea tarda (PCT). The term porphyria encompasses a group of acquired or familial metabolic diseases that occur due to deficiencies in enzymes involved in the heme biosynthetic pathway and result in the accumulation of...

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This patient was diagnosed with porphyria cutanea tarda (PCT). The term porphyria encompasses a group of acquired or familial metabolic diseases that occur due to deficiencies in enzymes involved in the heme biosynthetic pathway and result in the accumulation of precursor proteins called porphyrins. There are eight porphyrias, which dermatologists categorize as acute or non-acute. 

Acute porphyrias are characterized by potentially life-threatening neurological attacks, which do not occur in the non-acute forms of the disease. Acute porphyrias include acute intermittent porphyria, variegate porphyria, hereditary coproporphyria and enzyme delta-aminolevulinic acid dehydratase (ALAD) deficiency porphyria. 

Non-acute porphyrias consist of PCT, erythropoietic protoporphyria, congenital erythropoietic porphyria and hepatoerythropoietic porphyria. With the exception of acquired PCT, the porphyrias are inherited diseases.^1,2

PCT, the most common porphyria, results from decreased activity of the enzyme uroporphyrinogen decarboxylase (UROD) and has an average age of onset of 45 years. There are both acquired and inherited forms of PCT, but the acquired form is significantly more common (80% vs. 20%).

When UROD activity decreases in patients with PCT, uropophyrin accumulates in the skin and in the urine. Uroporphyrin absorbs light intensely in the Soret-band region (400-410 nanometer, UVA wavelength), which can result in the development of reactive oxygen species that damage tissue. This manifests clinically as increased photosensitivity, skin fragility, erosions, blisters, scarring and milia in sun-exposed skin — particularly 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

Due to the excessive porphyrin accumulation, urine may appear reddish after exposure to natural light and may have a bright pink fluorescence when exposed to UVA light from a Wood’s lamp.  However, these urinary color changes are not sensitive or specific. ^1,2 

Liver disease is common in patients with PCT. Alcoholism, estrogen therapy, hepatitis, HIV and hereditary hemochromatosis are among factors that contribute to hepatic dysfunction and excess accumulation of iron in the liver. The excess iron leads to oxidation products, which inhibit UROD. In order for clinical disease to manifest, patients must experience a 75% reduction in the activity of hepatic UROD.³ 

In the United States, 94% of PCT patients have hepatitis C, and 20% have hereditary hemochromatosis. Approximately 15% to 20% of patients with PCT have diabetes. 

Diagnosis

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

Patients with pseudoporphyria develop blistering and skin fragility similar to those with PCT, but porphyrin levels are normal, and hypertrichosis and sclerodermoid changes are not present. A reaction to the nonsteroidal anti-inflammatory drug naproxen most commonly causes pseudoporphyria, but the disease may occur in response to various other medications, as well as in association with hemodialysis or tanning-bed use. Ibuprofen is a safe alternative to naproxen in patients with pseudoporphyria. ^1,2

Erythropoietic protoporphyria (EPP) is an autosomal dominant or recessive disorder that occurs as a result of a defect in the enzyme ferrocheletase. EPP generally presents in early childhood, and the hallmark symptom is an immediate burning sensation of the skin upon sun exposure. 

Cutaneous EPP manifestations include waxy scars limited to sun-exposed areas. Patients with EPP are also at increased risk for cholestatic liver disease. In contrast to PCT, urinary porphyrin levels are normal in patients with EPP. ^1,2

Variegate porphyria is an autosomal dominant disorder caused by decreased activity of protoporphyrinogen oxidase, and most commonly occurs in South Africa. Patients may have skin lesions similar to PCT, but also experience acute neurologic attacks. Elevated urinary coproporphyrins are a symptom of variegate porphyria, rather than the increased uroporphyrins that occur in PCT. ^1,2               

Treatment

Therapeutic phlebotomy is the treatment of choice for PCT. Removing 500 mL of blood at two-week intervals until hemoglobin levels reach 10-11 g/dl elicits iatrogenic iron deficiency anemia, which lowers hepatic iron stores. This treatment may take several months, during the course of which the patient’s cutaneous manifestations gradually resolve. 

An alternative to phlebotomy is low-dose antimalarial therapy. Remission after either therapy may last many years.  In the event of a relapse, treatment should be repeated. Discontinuing precipitating factors, such medications (estrogens) and alcohol, is also important. Be sure to emphasize the importance of sun protection in the form of physical blockers, such as clothing, hats and inorganic sunscreens (zinc oxide). ^1,2

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

Adam Rees, MD, is a graduate of the University of California Los Angeles School of Medicine and a resident in the Department of Dermatology at Baylor College of Medicine in Houston.

References

1. Bolognia J, Jorizzo JL and Rapini RP. “Chapter 49: Porphyria.” Dermatology. St. Louis, Mo.: Mosby/Elsevier, 2008.
2. James WD, Berger TG, Elston DM and Odom RB. “Chapter 26: Errors in Metabolism.” Andrews’ Diseases of the Skin: Clinical Dermatology. Philadelphia: Saunders Elsevier, 2006.

3. Poh-Fitzpatrick MB. “Porphyria cutanea tarda.” Medscape Reference. Published May 30, 2012. Available online. Accessed 1 Jul 2012.