<unk>  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 and hepta-carboxylic porphyrinogen, and to a lesser extent hexa-carboxylic porphyrinogen, and penta-carboxylic porphyrinogen in the urine, which can be helpful in the diagnosis of this disorder. The dermatological symptoms of<unk>  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 that have been oxidized by free radicals or sunlight. The oxidized porphyrins initiate degranulation of dermal mast cells, which release proteases that catabolize the surrounding proteins. This begins a cell-mediated positive feedback loop which matches the description of a type 4 delayed hypersensitivity reaction. The resulting blisters, therefore, do not appear immediately but begin to show up 2–3 days after sun exposure. 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. Excess alcohol intake decreases hepcidin production which leads to increased iron absorption from the gut and an increase in oxidative stress. This oxidative stress then leads to inhibition of uroporphyrinogen decarboxylase, creating an excess of uroporphyrinogen III which is oxidized from the relatively harmless porphyrinogens into their oxidized porphyrins form. Concentrated instances of oxidative stress (alcohol, physical trauma, psychological stress, etc.) cause the liver to hemorrhage these porphyrins into the blood stream where they are then susceptible to oxidation. The strong association of<unk>  with Hepatitis C virus 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 use is frequently associated with both inducing<unk>  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. Additionally, alcohol has been shown to increase the activity of the delta-aminolevulinic acid synthetase (ALA synthetase), the rate-limiting enzymatic step in heme synthesis in the mitochondria, in rats. Therefore, alcohol consumption may increase the production of uroporphyrinogen, exacerbating symptoms in individuals with<unk> .
Porphyria cutanea tarda
Prurigo pigmentosa
Phakomatosis pigmentovascularis
Dermatopathia pigmentosa reticularis
Urticaria pigmentosa
Variegate porphyria
Hepatic porphyria
Phakomatosis pigmentokeratotica