Updated: Apr 11, 2016
  • Author: Maureen B Poh-Fitzpatrick, MD; Chief Editor: William D James, MD  more...
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The term protoporphyria now encompasses 2 clinically similar but distinct disorders that most often result from hereditary mutations in 2 different genes. The more common of these is erythropoietic protoporphyria, (EPP, OMIM 177000), which is caused by impaired activity of ferrochelatase (FECH), the ultimate enzyme of heme biosynthesis. [1, 2] . The resultant accumulated excess of its substrate, metal-free protoporphyrin, causes 2 principal manifestations: (1) an acute cutaneous photosensitivity typically first appearing during childhood and (2) hepatobiliary disease. [1, 3, 4, 5]

The predominant genotype associated with phenotypic expression of EPP is one mutant ferrochelatase allele (FECH) encoding a defective enzyme protein with little or no function, coupled with a relatively common polymorphic allele with low gene expression that reduces, but does not abrogate, the activity of its encoded enzyme. [6, 7] This complex form of inheritance has been termed pseudodominant [8, 9] or semidominant. [10] Others refer to this genotype as autosomal recessive, [11] because anomalies in both paired alleles are required for disease expression; however, one alteration is far more deleterious than the other. Infrequently, 2 deleterious FECH mutations are present; this recessively inherited form of EPP appears to impart a higher risk for hepatic dysfunction in some cases. [12, 13]

Rarely, acquired somatic mutation or deletion of a ferrochelatase gene secondary to myelodysplastic or myeloproliferative disorders leads to an adult-onset protoporphyric disorder. [14, 15, 16]

A far less frequent type of hereditary protoporphyria, now recognized as a separate disorder, is called X-linked dominant protoporphyria (XLDPP, OMIM 300752), or simply XLP. XLP arises from C-terminal deletions or alterations in the gene encoding the erythroid-specific enzyme 5-aminolevulinic acid synthase-2 (ALAS2), increased function of which leads to overproduction of protoporphyrin. [17, 11] Like EPP, XLP is caused by bone marrow heme synthetic dysfunction, but eventuates in a greater ratio of accumulated erythrocyte zinc-protoporphyrin to metal-free protoporphyrin than is typical for EPP. XLP causes an acute, childhood-onset, cutaneous photosensitivity indistinguishable from that of EPP, but appears to have a higher risk for hepatic dysfunction than does EPP. [17] An adult-onset case of XLP in an 89-year-old man with evolving myelodysplasia exhibited somatic mosaicism in erythroid hematopoietic cells associated with an ALAS2 mutation that predicted a C-terminal deletion. [18]

See the chart below.

The heme production pathway. Heme production begin The heme production pathway. Heme production begins in the mitochondria, proceeds into the cytoplasm, and is then resumed in the mitochondria for the final steps. This figure outlines the enzymes and intermediates involved in the porphyrias. Enzymes names are presented in the boxes. Names of the intermediates are outside the boxes, between arrows. Multiple arrows leading to a box demonstrate that multiple intermediates are required as substrates for the enzyme to produce one product.


Protoporphyrin is a lipophilic molecule capable of transformation to excited states by absorption of light energy. Excited-state protoporphyrin mediates photoxidative damage to biomolecular targets in the skin, [19] resulting in immediate phototoxic symptoms variously described as tingling, stinging, or burning that may be followed by the appearance of erythema, edema, and purpura. [3, 19] Excess protoporphyrin is formed during maturation of erythroid cells in the bone marrow and is present at the highest levels in reticulocytes and young erythrocytes. [20] Metal-free protoporphyrin escapes from red blood cells into the plasma, from which it is cleared by the liver and secreted into bile. Protoporphyrin-rich bile facilitates gallstone formation. [21] Toxic effects of protoporphyrin deposition in the liver may lead to life-threatening hepatic dysfunction. [21, 22, 23]




United States

Until a recently established registry for protoporphyria sponsored by the American Porphyria Foundation collects sufficient data, accurate enumeration in the United States cannot be provided, but is probably similar to data from European countries. A study of 155 North American individuals exhibiting the protoporphyria phenotype identified 15 with ALAS2 mutations and 140 with FECH anomalies. [24] The ALAS2/FECH ratio of approximately 10% in this study is greater than ratios reported in European populations.


Estimates of one erythropoietic protoporphyria case in populations of 75,000-200,000 have been reported for several Western European populations and in the South African population of European ancestry. [2, 5, 25, 26, 27] X-linked dominant protoporphyria remains rare but has been identified in increasing numbers. [9, 11, 17, 24, 28, 29, 30]


Erythropoietic protoporphyria has been reported most often in people with white heritage, but it has also been reported in persons with Japanese, Chinese, East Indian, or north or central African ancestry. X-linked dominant protoporphyria has been identified chiefly among individuals of Western European ancestry but also in an African American and Pacific Islander [11] and a Japanese boy. [28]


Erythropoietic protoporphyria and X-linked dominant protoporphyria occur in both males and females.


Photocutaneous symptoms usually appear during childhood, [3] but they also may be noted for the first time in adult life. [14, 15, 16, 18, 30] Gallstones may become symptomatic in young adulthood or in middle age. [3] Liver failure and its complications, sufficiently severe to result in liver transplantation and/or death, may develop in children and adolescents as well as adults. [21, 23, 31, 32, 33]



In the absence of hepatic failure, individuals with erythropoietic protoporphyria (EPP) have normal life expectancies.

Painful cutaneous photosensitivity reduces the sunlight tolerance of individuals with protoporphyria and may influence their lifestyles over entire lifetimes. [3]

An increased prevalence of cholelithiasis in both men and women can result in signs and symptoms of gallstone disease at relatively early ages. [3]

Hepatotoxic effects of excess protoporphyrin deposition have led to liver dysfunction that progressed to life-threatening severity in approximately 2-5% of known cases of protoporphyria. [5]