endocrine and metabolic disorders
Porphyria Cutanea Tarda
Pathophysiology of Porphyria Cutanea Tarda
Porphyria cutanea tarda (PCT) results from hepatic deficiency of uroporphyrinogen decarboxylase (UROD—see table). Porphyrins accumulate in the liver and are transported to the skin, where they cause photosensitivity. The drugs that commonly trigger acute porphyria (see theDrug Database for Acute Porphyriaor theAmerican Porphyria Foundation drug database) do not trigger PCT. Liver disease is common in PCT and may be due partly to porphyrin accumulation, Hepatitis C, Chronic , concomitant There aretwo main typesof porphyria cutanea tarda: Type 1: Acquired or sporadic (75 to 80% of cases) Type 2: Hereditary or familial (20 to 25% of cases) There is also a rare type 3, which accounts for<1% of cases. Intype 1 porphyria cutanea tarda,decarboxylase deficiency is restricted to the liver and no genetic predisposition is present. It usually manifests in middle age or later. The enzyme deficiency is thought to be acquired due to increased oxidative stress in hepatocytes that leads to increased oxidation of uroporphyrinogen or uroporphyrin, which is not a substrate for the enzyme, and to the formation of the inhibitor uroporphomethene. Estrogen, excess iron, and hepatitis C infection also increase such oxidative stress in hepatocytes. Intype 2 porphyria cutanea tarda,decarboxylase deficiency is inherited in an autosomal dominant fashion with limited penetrance. Deficiency occurs in all cells, including red blood cells. It may develop earlier than type 1, occasionally in childhood. The partial (~50%) deficiency in UROD activity in heterozygous patients itself is not sufficient to cause biochemical or clinical features of PCT; additional factors are required to cause the > 75% decrease in hepatic UROD activity needed for features of PCT to manifest. Such factors can include elevated hepatic iron, alcohol use, halogenated hydrocarbon exposure, hepatitis C virus or HIV infection,estrogens, and smoking. These factors increase the oxidation of uroporphyrinogens and other porphyrinogens to the corresponding porphyrins and also help form inhibitors of UROD. Hepatoerythropoietic porphyria (HEP—see table), which features profound UROD deficiency, is very rare and is often regarded as an autosomal recessive form of type 2 PCT. Type 3 PCT,which is very rare, is hereditary but without any defect in theURODgene; a defect in another, unidentified gene appears to be the cause. Types 1 and 2 are the major forms of porphyria cutanea tarda. They have the same precipitants, symptoms, and treatment. Overall prevalence may be on the order of 1/10,000 but is probably higher in people exposed to halogenated aromatic hydrocarbons or other precipitants of the disease. End-stage renal disease, ultraviolet radiation (UVA), and certain medications can cause PCT-like symptoms without elevated porphyrin levels (pseudoporphyria). Commonly implicated medications arefurosemide, tetracyclines, sulfonamides, andnaproxenand other nonsteroidal anti-inflammatory drugs (NSAIDs). Because porphyrins are poorly dialyzed, some patients receiving long-term hemodialysis develop a skin condition that resembles PCT; this condition is termed pseudoporphyria of end-stage renal disease. 