Porphyria Cutanea Tarda

Updated: Mar 24, 2016
  • Author: Maureen B Poh-Fitzpatrick, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Porphyria cutanea tarda (PCT) is a term encompassing a group of acquired and familial disorders in which activity of the heme synthetic enzyme uroporphyrinogen decarboxylase (UROD) is deficient. [1] Approximately 80% of all cases of porphyria cutanea tarda are acquired; 20% are familial, although the ratio may vary among different geographic regions and ethnic groups.

Familial porphyria cutanea tarda most often arises from autosomal dominant inheritance of a single mutation of the UROD gene. Human UROD has been mapped to band 1p34. [2] To date, 121 UROD mutations are listed by the Human Genome Mutation Database. A rare recessive familial type of porphyria cutanea tarda in which both UROD alleles are mutated is termed hepatoerythropoietic porphyria. [3] Familial porphyria cutanea tarda without detectable UROD mutations has been reported. [4, 5]

The common acquired form, sporadic porphyria cutanea tarda, occurs in individuals whose UROD DNA sequences are normal, but who may have other genetically determined susceptibilities to inhibition of UROD activity. Acquired porphyria in large populations exposed to polyhalogenated aromatic hydrocarbon hepatotoxins [6] has been referred to as "epidemic” porphyria cutanea tarda. Hepatic tumors producing excess porphyrins are rare causes of porphyria cutanea tarda–like disorders.

Clinical expression of both sporadic and familial porphyria cutanea tarda most often requires exposure to environmental or infectious agents or the presence of coexisting conditions that adversely affect hepatocytes and result in hepatic siderosis. Ethanol intake, estrogen therapies, hemochromatosis genes, and hepatitis and human immunodeficiency viral infections are among these contributory factors. [1] The increased oxidative stress associated with all of these factors has been shown to reduce hepatic expression of the gene encoding hepcidin, a regulator of iron absorption and metabolism, thus increasing iron absorption and iron overload. [7] Excess iron facilitates formation of toxic oxygen species, thus amplifying porphyrinogenesis by catalyzing formation of oxidative inhibitors of UROD enzyme activity. [8] Accumulating porphyrins in hepatocytes may then further down-regulate hepcidin gene expression. [7]   Most patients with porphyria cutanea tarda have increased iron burden; iron-reduction therapies can lead to clinical and biochemical remissions; subsequent reaccumulation of iron stores may lead to symptomatic recurrence.

Reduced UROD activity causes polycarboxylated porphyrinogen intermediaries of heme synthesis to accumulate in hepatocytes; these excess substrates then undergo iron-facilitated spontaneous oxidization to photoactive porphyrins. Porphyrin by-products of the pathway exit the hepatocytes, are distributed throughout the body in blood plasma, mediate photooxidative chemical reactions causing skin lesions, and yield the abnormal excretory porphyrin profiles that characterize porphyria cutanea tarda. Partial oxidation of uroporphyrinogen to the UROD inhibitor uroporphomethene occurs in murine porphyria cutanea tarda models and has been suggested as a pathogenic mechanism in the human disease. [9] Reduction of hepatic UROD activity to approximately 25% of normal, most often reflecting effects of multiple genetic and/or exogenous inhibitory factors, is required for clinical disease expression. [10, 11]

Other porphyria-related Medscape articles include Erythropoietic Porphyria, Protoporphyria, Pseudoporphyria, and Variegate Porphyria.

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Pathophysiology

When hepatic UROD activity falls below the critical threshold, porphyrin by-products of the heme biosynthetic pathway with 4-8 carboxyl group substituents are overproduced. These porphyrins are reddish pigments that accumulate in the liver and are disseminated in plasma to other organs. Porphyrins with high carboxyl group numbers are water soluble and excreted primarily by renal mechanisms. The porphyrin with 8 carboxyl groups is termed uroporphyrin; 4-carboxyl porphyrins include coproporphyrin and isocoproporphyrin, which are chiefly excreted in feces. Porphyrins are photoactive molecules that efficiently absorb energy in the visible violet spectrum. Photoexcited porphyrins in the skin mediate oxidative damage to biomolecular targets, causing cutaneous lesions.

The most common photocutaneous manifestations of porphyria cutanea tarda are due to increased mechanical fragility after sunlight exposure; erosions and blisters form painful indolent sores that heal with milia, dyspigmentation, and scarring (see images below).

Thickened skin with blisters, scars, and milia. Co Thickened skin with blisters, scars, and milia. Courtesy of Dirk Elston, MD.
Close-up image of blisters, scarring, and milia. C Close-up image of blisters, scarring, and milia. Courtesy of Dirk Elston, MD.

Other common features of porphyria cutanea tarda include hypertrichosis, sclerodermalike plaques that may develop dystrophic calcification, and excretion of discolored urine that resembles port wine or tea, which is due to the presence of porphyrin pigments. [12]

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Epidemiology

Frequency

United States

A registry has been established by the NIH-funded Porphyrias Consortium (http://rarediseasesnetwork.epi.usf.edu/registry/direct.htm) to more accurately enumerate cases of various types of porphyrias occurring in the US population. Until sufficient data have been collected by this registry to allow calculation, approximately 1 case of porphyria cutanea tarda in populations of 10,000-25,000 can be estimated based on data from other countries. Porphyria cutanea tarda is the most common porphyria seen in clinical practice.

International

Higher prevalences of porphyria cutanea tarda have been reported among various European populations. A high prevalence of porphyria cutanea tarda among South African Bantu people has been linked with a propensity for hepatic siderosis. Fractions of studied porphyria cutanea tarda cases reported as familial vary widely: 14.6% in Spain, [13] 24% in Denmark, [14] and 50% in Chile. [15]

Race

Porphyria cutanea tarda occurs in persons of all ethnic groups.

Sex

Porphyria cutanea tarda occurs in both sexes. Older reports indicated a great preponderance of porphyria cutanea tarda in men; more recent surveys include many women.

Age

Sporadic porphyria cutanea tarda typically manifests in adulthood. Symptoms of familial porphyria cutanea tarda typically first appear in adults heterozygous for a UROD gene mutation, but they have also been reported in heterozygote children. [16] When biallelic mutations are present (homozygotes or compound heterozygotes), symptoms may be severe, with onset in early childhood. [17] Milder phenotypes with somewhat later onset have also been observed. [18, 19]

Porphyria cutanea tarda–like disorders resulting from exposure of large numbers of people to hepatotoxic chemicals have afflicted people of all ages. [6]

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Prognosis

The major morbidity of porphyria cutanea tarda is due to skin fragility and blistering, which preclude manual labor and hamper daily activities. The subsequent erosions represent full-thickness epidermal loss; they are painful and often become thickly crusted and secondarily infected. Healing is slow and leaves pigmentary changes, milia, and atrophic scars.

Porphyria cutanea tarda has been associated with the development of hepatocellular carcinoma, chiefly in populations of older men with long-standing active disease, heavy ethanol intake, and cirrhosis. Most studies predate recognition of hepatitis C prevalence in populations with porphyria cutanea tarda or hepatocellular carcinoma; many reported cancers may have been, at least in part, sequelae of chronic hepatitis viral infection. [20]

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Patient Education

Patients should be educated about the role of sunlight in eliciting the skin lesions and in methods of sunlight avoidance. Because porphyrins absorb radiant energy most efficiently at very long ultraviolet and visible light wavelengths, topical sunscreens must contain ingredients that either scatter or block long ultraviolet and visible light rays to offer any practical protection. Use of light-exclusive clothing and lifestyle alterations are usually necessary to alleviate photocutaneous reactions until remissions can be achieved.

The need to avoid iron-containing dietary supplements, alcohol, and smoking should be stressed. Dietary iron is not usually a major problem and can be managed with moderation in consumption of red meats, but some patients may benefit from guidance about the iron content of foods from a nutritionist. Adequate dietary vitamin C should be consumed.

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