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Porphyria cutanea tarda

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Porphyria cutanea tarda

Maureen B. Poh-Fitzpatrick

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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The term porphyria cutanea tarda (PCT) encompasses several related inherited or acquired disorders in which insufficient hepatic uroporphyrinogen decarboxylase enzyme activity causes overproduction of polycarboxylated porphyrins. These porphyrins mediate cutaneous photosensitivity manifested as fragility, bullae, hypertrichosis, dyspigmentation, sclerodermoid features, and scarring. Multiple factors may contribute to disease expression: mutant uroporphyrinogen decarboxylase genes, hemochromatosis genes or other predisposing genetic determinants, ethanol abuse, tobacco smoking, medicinal estrogen, iron, hepatitis and/or human immunodeficiency viral infections, chronic dialysis treatment, toxic aromatic hydrocarbon exposure and, rarely, hepatic tumors. Increased tissue iron, commonly seen with alcoholism, hepatitis C infection, hemochromatosis, and end-stage renal disease, plays a central role in the pathogenesis of PCT. Iron-dependent partial oxidation of uroporphyrinogen to uroporphomethene, a competitive inhibitor of uroprophyrinogen decarboxylase, may be the mechanism by which its enzymatic activity is reduced in PCT (Phillips et al. Proc Natl Acad Sci USA 2007; 104: 5079–84). Iron-enhanced complete oxidation of uroporphyrinogen accumulated due to inhibited enzyme activity yields photoactive uroporphyrin. Hepatic siderosis or porphyrin crystallization in hepatocytes may lead to hepatocellular carcinoma, a known complication of chronic active PCT. Ferrodepletion by serial phlebotomy is preferred first-line therapy for PCT patients with demonstrable iron overload.

Management strategy

A precise diagnosis is essential because optimal management consists of induction of remission using strategies inappropriate for other porphyrias or pseudoporphyrias. Associated disorders that may influence management, such as viral infections, hemochromatosis or other causes of excess iron storage, lupus erythematosus, diabetes mellitus, and anemias, should be identified.

Eliminating exacerbating factors and pursuing ferrodepletion by serial phlebotomy, iron chelation, or erythropoietin bone marrow stimulation can induce biochemical and clinical remissions. Porphyrin excretion can be increased using chloroquine or hydroxychloroquine, enteric sorbents, or metabolic alkalinization. Interferon-α or antiretroviral drugs may benefit PCT associated with hepatitis C or AIDS, respectively. Children can be treated by phlebotomy protocols adjusted for pediatric parameters. Rare reports of chloroquine or hydroxychloroquine treatment of children suggest that cautious low-dose schedules may be safe and effective. Vitamins E and C, plasmapheresis or plasma exchange, high-flux hemodialysis, and cimetidine have been reported as beneficial alternative or adjunctive therapies. Skin should be protected from sunlight exposure and mechanical trauma until full clinical remission is achieved. Hepatoerythropoietic porphyria, caused by co-inheritance of two uroporphyrinogen decarboxylase gene mutations, resists induction of remission, and so requires lifelong vigilant skin photoprotection. Photothermolysis using light with selected wavelengths may reduce persistent hypertrichosis.

Specific investigations

First-line therapies

image Serial phlebotomies B
image Chloroquine, hydroxychloroquine B

Treatment of porphyria cutanea tarda with chloroquine.

Kordać V, Semrádová M. Br J Dermatol 1974; 90: 95–100.

Twenty-one adults received oral chloroquine 125 mg twice a week until cutaneous blistering and fragility ceased and urinary uroporphyrins fell below three times the normal limit. Mean duration of treatment was 8.5 months (range 4–11 months) in 19 patients. Serum transaminases and urinary uroporphyrins rose during initial weeks of therapy, and then progressively diminished.

Chloroquine risks include irreversible retinopathy after large cumulative doses (>100–300 g), but this is infrequent at dose rates <4 mg/kg daily (<6.5 mg/kg daily for hydroxychloroquine). Ophthalmologic examinations at baseline and 6-monthly intervals are recommended. The risk of hemolysis can be minimized by pretreatment testing for glucose-6-phosphate dehydrogenase deficiency and interval monitoring of hematological profiles during therapy.

Choice of therapy in porphyria cutanea tarda.

Adjarov D, Naydenova E, Ivanov E, Ivanova A. Clin Exp Dermatol 1996; 21: 461–2.

The effectiveness of phlebotomy (500 mL weekly for 4 weeks, then monthly) versus oral chloroquine 250 mg twice weekly alone versus combined phlebotomy/chloroquine therapies was retrospectively analyzed in unequal groups totaling 115 patients. Remissions occurred more quickly and reliably with phlebotomy than with chloroquine. Combined therapy shortened the mean total treatment course by approximately 1.5 months only when initial urinary uroporphyrin levels exceeded 3000 nmol/24 hours.

Others found remissions more rapid with chloroquine than with venesection (10.2 months in 24 patients, 12.5 months in 15 patients, respectively). Combination therapy was quickest (3.5 months in 20 patients) (Seubert S, Seubert A, Stella AM, Guzman H, Battle A. Z Hautkr 1990; 65: 223–225). In another study, urinary porphyrin excretion significantly improved in 22 of 30 hydroxychloroquine-treated subjects (200 mg twice weekly), but in only eight of 31 phlebotomy-treated subjects (400 mL whole blood twice monthly) after 1 year, while clinical improvement was similarin both groups. (Cainelli T, Di Padova C, Marchesi L, Gori G, Rovagnati P, Podenzani SA, et al. Br J Dermatol 1983; 108: 593–600).

Second-line therapies

image Deferoxamine (desferrioxamine) B
image Erythropoietin D

Liver iron overload and desferrioxamine treatment of porphyria cutanea tarda.

Rocchi E, Cassanelli M, Borghi A, Paolillo F, Pradelli M, Pellizzardi S, et al. Dermatologica 1991; 182: 27–31.

Ferrodepletion by desferrioxamine 1.5 g subcutaneous pump infusions 5 days/week (18 patients) or 200 mg/kg infused intravenously once weekly (five patients), or by serial phlebotomies (22 patients) led to clinical remission after nearly 6 months with all treatments. Normalization of serum ferritin and uroporphyrins occurred at approximately 11 months with chelation, and approximately 13 months with venesection; liver function improved with both modalities.

Subcutaneous chelation is expensive and cumbersome, and thus best reserved for cases in which first-line therapies are inadequate or inappropriate. Oral iron chelators (i.e., deferasirox, deferiprone) are now available, but also expensive, and efficacy and safety in PCT not yet proven in completed clinical trials or shown anecdotally in case reports.

Third-line therapies

image Antiretroviral therapy E
image Interferon-α E
image Vitamins E and C D
image Plasmapheresis, plasma exchange D
image High-flux hemodialysis D
image Enteric sorbents (cholestyramine, activated charcoal) D
image Metabolic alkalinization by oral sodium bicarbonate D
image Cimetidine E
image Photothermolysis E

Dramatic resolution of skin lesions associated with porphyria cutanea tarda – interferon-alpha therapy in a case of chronic hepatitis C.

Shiekh MY, Wright RA, Burruss JB. Dig Dis Sci 1998; 43: 529–33.

Anecdotal reports of PCT improvement during interferon treatment of concurrent hepatitis C infection must be balanced against those of PCT appearing 1 to 4 months after initiation of hepatitis C treatment with interferon/ribavirin protocols (Thevenot T, Bachmeyer C, Hammi R, Dumouchel P, Ducamp-Posak I, Cadranel J-Fl. J Hepatol 2005; 42: 607–608). Ribavirin-induced hemolysis may increase liver iron, thereby triggering PCT. Measures to reduce liver iron (i.e., phlebotomy) prior to initiation of interferon, especially when combined with ribavirin, are recommended in patients with viral hepatitis and coincident symptomatic PCT or indices of excess tissue iron stores.

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