Monday, September 26, 2016
PCT- Clinical Presentations
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. 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. 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. Familial porphyria cutanea tarda without detectable UROD mutations has been reported.
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 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.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. Excess iron facilitates formation of toxic oxygen species, thus amplifying porphyrinogenesis by catalyzing formation of oxidative inhibitors of UROD enzyme activity.Accumulating porphyrins in hepatocytes may then further down-regulate hepcidin gene expression. 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. 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.
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