6.2.3 Erythropoietic Protoporphyria (EPP)

AIB2.0; AIB2.1

EPP, acute phototoxic porphyria.

Second most common porphyria (after porphyria cutanea tarda), affecting 1-2 per 100,000 population but still an orphan disease. Symptoms (light sensitivity) start early in life (<10 years) and the condition is often misdiagnosed for up to 10 years because of the absence of clinically visible symptoms (sometimes patients are accused of malingering). There is low clinical penetrance, with less than 10% of mutation carriers developing overt clinical symptoms.

Autosomal-(co-dominant) recessive inherited mutation, usually in the ferrochelatase (FECH)-gene, in which more than 175 mutations have been reported. The single intronic nucleotide polymorphism (SNP) (rs: 2272783) of C at IVS3-48 in trans to a mutated FECH (Gouya et al.). The promoter activity on the transcriptional activity of the FECH is decreased.

A large number of red fluorocytes are observed in the peripheral blood under the fluorescence microscope (green or blue excitation wavelength). The reduced mounting of iron-iones in the hemoglobine of the erythrocytes leads to accumulation of its precursor protoporphyrin, which is released into the circulation, triggering singlet oxygen free radical reactions by visible light and the long wave UVA (400nm, Soret-band), that lead to severe neuropathic pain, which lasts hours to days. Protoporphyrin is excreted through the biliary system.

Rarely EPP-like symptoms can occur in conjunction with sideroblastic anemia related to myelodysplastic conditions.

Variant: X-linked protoporphyria: In contrast to EPP, there is increased activity of the ALA synthase 2 enzyme in the red blood cell line leading to total increased protoporphyrin production with increase in zinc chelated protoporphyrin whereas the activity of the ferrochelatase enzyme is normal.

The clinical features are very different from those of the porphyria cutanea tarda, which presents mainly with blistering, fragility, scarring and formation of milia.

Acute: Burning (not itching) of the skin upon sun exposure, also through window glass or windscreen of the car, which filters only UVB but not the pathogenetically important visible light and UVA. Acute erythema and edema in the light exposed areas (face, hands, lower arms). Never blistering. Edema due to damage of the vessel endothelia. Petechia may occur.

Permanent chronic changes: cerebriform lichenification and thickening of the skin, especially on the back of the nose, margins of the conch of the ear, back of hands and fingers.

Urine: normal color, since protoporphyrin is not water soluble and therefore is excreted through the stool.

• Hepatic porphyrias: porphyria cutanea tarda (Prototype): sporadic, genetic/familiar, toxic

• Erythropoietic porphyrias

  • Erythropoetic protoporphyria

    • Mild phenotype

    • Severe phenotype

    • X-linked protoporphyria

  • Congenital erythropoetic porphyria (Günther).

Diagnostic rapid test: red fluorescence of some (30%) erythrocytes in a blood smear under the fluorescence microscope (blue light excitation). Cave: quick fading. The blood smear should be handled in a dark room.

Urine: negative, since protoporphyrin is not water soluble

Stool: qualitative and quantitative determination of protoporphyrin (special laboratory).

Blood: full blood count and liver function tests; protoporphyrin level (special laboratory).

Determination of the defective enzymes.

Genotyping of FECH and ALA synthase 2.

Acute with chronic sequelae. Risk of liver failure, gallstones and anemia.

Limitation of the open-air mobility; accusation of hypochondric behavior.

Protoporphyrin is cleared by the hepatobiliary system and may exhibit a hepatotoxic effect and potentially lead to liver failure. Mild hypochromic microcytic anemia and cholelithiasis may develop.

Typical clinical features; confirmation by laboratory tests and genotyping.

• Other photodermatoses without blisters.

• Drug-induced phototoxicity and atypical polymorphic light eruption,

• idiopathic solar urticaria.

Blisters never occur in erythropoietic protoporphyria.

Prevention: advice on environmental and behavioural sun exposure, protective clothing and topical sunscreen photoprotection (SPF/LSF > 30). Cave: Vitamin D-deficency due to lack of vitamin-D production in the skin by UVB. Photoprotection against long wave UVA and visible sun light. Afamelanotid, a pigment-inducing analogue of alpha-melancyte-stimulating hormone has an orphan drug approval for patients with EPP and is available in selected centers. Oral β-carotene (60-180 mg/day).