Cutaneous porphyrias primarily affect the skin. Areas of skin exposed to the sun become fragile and blistered, which can lead to infection, scarring, changes in skin coloring (pigmentation), and increased hair growth. Cutaneous porphyrias include congenital erythropoietic porphyria, erythropoietic protoporphyria and X-linked protoporphyria, porphyria cutanea tarda, and hepatoerythropoietic porphyria.
Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)
Erythropoietic protoporphyria (EPP) is the third most common porphyria, with an incidence of possibly 2 to 5 per 1,000,000, and the most common in children. Most cases are due to the markedly reduced activity of the enzyme, ferrochelatase (20-30% of normal). The inheritance of EPP follows an autosomal recessive pattern. In about 95% of EPP cases, the individual has a severe mutation of the ferrochelatase (FECH) gene inherited from one parent, and a common genetic variation of the same gene, inherited from the other parent. This common genetic variation causes reduced production of the enzyme, but does not cause disease in the absence of a severe mutation. The frequency of this common genetic variation in the FECH gene varies by population, such that it is present in about 10% of Caucasians, 43% of Japanese, 31% of Southeast Asians, and 1 to 3% in Blacks. Alternatively, in about 5% of EPP cases, two severe FECH gene mutations, one inherited from each parent, are found in the same patient,
In some cases, EPP is an X-linked porphyria caused by a mutation in the last exon of the δ-aminolevulinate synthase-2 (ALAS2) gene. The ALAS2 gene mutation results in a “gain of function” and results in increased stability and/or activity of this enzyme. Therefore, more protoporphyrin than is needed for hemoglobin synthesis is produced by the bone marrow. In all cases of EPP, protoporphyrin accumulates in the marrow and is transported to the skin in the plasma and red blood cells, causing photosensitivity. Protoporphyrin is not excreted by the kidneys, but is taken up by the liver and excreted in bile. It can reduce bile flow and damage the liver.
Photosensitivity begins in early childhood, and can be difficult to diagnose, since there is usually no blistering and little scarring. Photosensitivity is typically acute – appearing soon after exposure to sunlight – rather than chronic. It is also painful, and may be accompanied by swelling of the skin. These symptoms greatly impair quality of life and limit employment opportunities and life style. Patients are sensitive to sunlight that passes through window glass (long wave ultraviolet light). Large amounts of protoporphyrin in bile can form stones rich in this porphyrin. Severe liver complications are difficult to treat and sometimes require liver transplantation.
The diagnosis is established biochemically by finding increased protoporphyrin in red blood cells, with a predominance of free protoporphyrin rather than zinc protoporphyrin. Plasma porphyrins are also increased in almost all cases, and fecal porphyrins, consisting mostly of protoporphyrin, may be normal or increased. Urine porphyrins are not increased.
Treatment and Prognosis
Treatment with pharmaceutical grade β-carotene (Lumitene, Tishcon) or cysteine may improve sunlight tolerance but does not lower porphyrin levels. Most patients must learn to avoid sunlight as much as possible. Deficiencies of iron and vitamin D should be prevented. To protect the liver from injury that might precipitate protoporphyric liver failure, Hepatitis A and B vaccinations are recommended, as is the avoidance of alcohol and other hepatotoxins.
Protoporphyric liver failure can appear suddenly and progress rapidly, and is generally treated with a combination of plasmapheresis, blood transfusion, hemin, cholestyramine, vitamin E, and ursodeoxycholic acid, which may reverse or delay liver damage. Levels of porphyrins in plasma and red blood cells should be followed closely during treatment. Liver transplantation is sometimes necessary. It is not yet possible to predict which patients will develop liver failure. Bone marrow transplantation is potentially curative in EPP and can prevent recurrent damage to the transplanted liver.