Porphyria Cutanea Tarda - Pathogenesis

Pathogenesis

As stated previously, porphyria cutanea tarda is primarily caused by uroporphyrinogen decarboxylase deficiency (UROD). Uroporphyrinogen decarboxylase occurs in nature as a homodimer of two subunits. It participates in the fifth step in heme synthesis pathway, and is active in the cytosol. This enzymatic conversion results in coproporphyrinogen III as the primary product. This is accomplished by the clockwise removal of the four carboxyl groups present in the cyclic uroporphyrinogen III molecule. Therefore, a deficiency in this enzyme causes the aforementioned buildup of uroporphyrinogen in the urine, which can be helpful in the diagnosis of this disorder.

The dermatological symptoms of PCT that include blistering and lesions on sun-exposed areas of the skin are caused by a buildup of porphyrin compounds (specifically uroporphyrinogen) close to the surface of the skin. Due to the highly conjugated structure of porphyrins involving alternating single and double carbon bonds, these compounds exhibit a deep purple color, resulting in the discoloration observed in the skin. The excess uroporphyrinogen that lead to these lesions is primarily produced in the liver, but exposure to excess sunlight is thought to lead to the production of reactive oxygen species, disrupting the activity of uroporphyrinogen decarboxylase and contributing to the buildup of uroporphyrinogen. This is thought to be the underlying biochemical pathway behind the photosensitivity observed in patients with PCT. The strong association of PCT with Hepatitis C infection is not entirely understood. Studies have suggested that the cytopathic effect of the virus on hepatocytes can lead to the release of free iron. This iron can disrupt the activity of cytochrome p450, releasing activated oxygen species. These can oxidize the UROD substrate uroporphyrinogen, which can result in the inhibition of UROD and lead to deficient activity of this key enzyme.

Excess alcohol abuse is frequently associated with both inducing PCT and aggravating a preexisting diagnosis of the disorder. It is thought to do so by causing oxidative damage to liver cells, resulting in oxidized species of uroporphyrinogen that inhibit the activity of hepatic UROD. It is also felt to increase the uptake of iron in liver cells, leading to further oxidation of uroporphyrinogen by the release of activated oxygen species. Additionally, exposure to chlorinated cyclic hydrocarbons can lead to a deficiency in the activity of uroporphyrinogen decarboxylase, causing the buildup of excess uroporphyrinogen.