Porphyria Cutanea Tarda, PCT

including Hepatoerythropoietic porphyria, HEP


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Introduction to Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT) is an autosomal dominant disorder that is a member of a family of disorders referred to as the porphyrias. Each disease in this family results from deficiencies in a specific enzyme involved in the biosynthesis of heme (also called the porphyrin pathway). The term porphyria is derived from the Greek term porphura which means "purple pigment" in reference to the coloration of body fluids in patients suffereing from a porphyria. The porphyrias are classified on the basis of the tissue that is the predominant site of accumulation of metabolic intermediates. These classifications are "hepatic" or "erythroid". Each disease is also further characterized as being acute or cutaneous dependent upon the major clinical features of the disease. PCT results from deficiencies in uroporphyrinogen decarboxylase (UROD) in the liver and other tissues of the body. PCT is the most commonly occurring porphyria of any type and it is classified as an hepatic porphyria. PCT has also been called symptomatic porphyria or idiosyncratic porphyria.

PCT is divided into three subtypes: type I is the sporadic type, type II is the familial autosomal dominant type, and type III is the familial rare type. Type I PCT accounts for approximately 80% of all PCT patients worldwide. All three types of PCT have similar clinical features. However, only type II PCT has been directly associated with mutations in the UROD gene and the disorder is an autosomal dominant inherited trait with the characteristic of incomplete penetrance. No mutations in UROD have been found in type I or type III PCT patients. Type I PCT is believed to be the result of multifactorial effects on the level of activity of the UROD encoded enzyme within hepatocytes. Type III disease is a rare familial form of the disease resulting from an as yet unknown inherited defect that secondarily affects hepatic UROD activity. Hepatoerythropoietic porphyria (HEP) is the homozygous dominant form of type II PCT. HEP receives its name because the deficiency in UROD leads to the accumulation of porphyrins in both the liver and bone marrow. The symptoms of HEP are similar to those of congenital erythropoietic porphyria (CEP).

The uroporphyrinogen decarboxylase gene (UROD) is located on chromosome 1p34 covering just 3 kb and encompassing 10 exons that generate two alternatively spliced mRNAs. Only one of the resultant mRNAs code for functional enzyme and this protein is 367 amino acids. Several mutations have been identified in the UROD gene resulting in type II autosomal dominant PCT. These mutations include missense, nonsense, and splicing mutations. Most of the identified mutations are unique to a given PCT patient.

Reaction catalyzed by uroporphyrinogen decarboxylase (UROD)

Reaction Catalyzed by UROD

Clinical Features of PCT

PCT is characterized by blistering skin lesions on sun-exposed areas of the skin and the urinary excretion of large amounts of uroporphyrin. Because of this characteristic feature, PCT is strongly indicated in persons who develop skin lesions, particularly on the back of the hands, upon exposure to sunlight. Symptom of PCT can be precipitated by excess hepatic iron, alcohol consumption, hepatitis C infection, estrogen administration, HIV infection and by induction of cytochrome P450 (CYP) enzymes such as is typically seen in smokers. Persons harboring mutations in the HFE gene which results in hemochromatosis are also highly predisposed to PCT.

The blistering lesions of PCT rupture easily and heal slowly. The poor healing of the wounds can lead to secondary infections. Due to repeated blistering and rupture, the skin becomes thickened, scarred and calcified resembling features of scleroderma (referred to as pseudoscleroderma). In addition to the cutaneous clinical features of PCT, there are also hepatic abnormalities that can be evidenced by abnormal liver function tests. Histologically the liver of PCT patients shows necrosis, inflammation, increased iron deposition and increased fatty deposits. In spite of these hepatic findings cirrhosis is only reported in one third of PCT patients.

HEP usually presents in infancy or childhood with red urine, blistering skin lesions and scarring. Hemolytic anemia, associated with splenomegaly, is commonly present in these patients due in part to the deposition of porphyrins in the bone marrow. As indicated above, these symptoms are similar to those seen in congenital erythropoietic porphyria, CEP.

The specific treatment regimen for PCT patients depends upon several factors. All patients need protection from sunlight while they are in the symptomatic phase. It is important to ensure that eliminate of known susceptibility factors is adhered to. These factors include alcohol consumption, smoking, oral estrogen use, and hepatotoxins. Reductions in total body iron stores and liver iron content may be necessary and is effected by phlebotomy and administration of low dose anti-malarial agents (chloroquine or hydroxychloroquine). Iron chelation therapy with the use of deferasirox, deferiprone, or desferrioxamine, may be necessary if phlebotomy is contraindicated. Other porphyrias that cause blistering skin lesions, such as HEP, are not responsive to the same treatment regimen and, therefore, it is important to make a correct diagnosis of PCT before treatment is initiated.

 

 

 

 

 

 

 

 

 

 

 


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Last modified: October 27, 2016