Erythropoietic Protoporphyria

Rare genetically transmitted disorder of the porphyrin-heme in which reduced activity of the enzyme ferrochelatase leads to accumulation of protoporphyrins in erythrocytes with cutaneous and systemic manifestations.

Congenital Erythropoietic Protoporphyria; Erythrohepatic Protoporphyria; Heme Synthetase Deficiency; Protoporphyria.

Mode of inheritance in erythropoietic protoporphyria (EPP) is complex and can be either autosomal dominant with low clinical penetrance, as is in most cases, or autosomal recessive. The gene for human ferrochelatase (FECH) has been mapped to 18q21.3.

The basic defect affects the mitochondrial enzyme ferrochelatase. The nature of the defect on the molecular level is uncertain. Protoporphyrin diffuses from the erythrocytes into the plasma to be bound to albumin and the heme-binding protein hemopexin. Protoporphyrin deposits in the skin are responsible for the extreme photosensitivity. The excess porphyrin comes from both erythropoietic and hepatic tissues. Ultraviolet light photoactivates protoporphyrins that then cause tissue damage by release of free oxygen radicals, which manifests as photosensitivity.

Fluorescence of a significant proportion of red blood cells is detectable by ultraviolet microscopy because of the presence of free erythrocyte protoporphyrin. A reduction in the activity of the enzyme ferrochelatase (also called heme synthase, a mitochondrial enzyme responsible for the final step in the heme synthesis pathway, which is the incorporation of ferrous iron into protoporphyrin) to 10 to 25% of normal levels has been demonstrated. This is unlike the other dominantly inherited forms of porphyria, in which only a 50% reduction of activity of the specific enzyme is observed.

Stinging or burning of the skin may result within 1 hour of sun exposure. This is followed by edema and erythema. Solar urticaria, petechiae, vesicles, purpura, and crustification may develop and last for several days. Late skin changes include thickening of the skin with a waxy appearance, shallow pits, and linear creases on the face (particularly cheeks and nose). Artificial lights, particularly operating room lamps, may cause photosensitivity. Cholelithiasis is fairly common (in approximately 30% of patients) and may present at an unusually early age. Hepatic cholestasis is rare (1-4% of patients) but often has a severe course. Rarely, hemolytic or mild hypochromic anemia is present, and mild (nonhemolytic) anemia has been described in up to 25% of cases. Polyneuropathy and quadriparesis may occur. Excessive protoporphyrin is excreted in bile, and hence in feces, but not in urine because protoporphyrin is only poorly water-soluble. It may be deposited in the liver, resulting in progressive and even fatal liver damage. Management includes avoidance of exposure to sunlight (ensure that the chosen sunscreen also protects in the 400-nm range, as common commercial sunscreens often only effectively block light with a wavelength of approximately 300 nm) and/or skin protection by parenteral administration of beta-carotene. Liver disease may be ameliorated by treatment with cholestyramine (to prevent enterohepatic recirculation of protoporphyrin), activated charcoal, and bile salts.

In general, EPP is considered a benign disorder with clinical symptoms mainly affecting the skin. Although it should not be confused with hepatic porphyrias, abnormalities of the liver and biliary tract are not uncommon. Even rapidly progressive liver disease and cirrhosis have been described, so the presence and severity of hepatic involvement must be evaluated. Laboratory investigations should include a complete blood count, serum concentrations of electrolytes, urea, and creatinine, and liver function tests (including coagulation test in jaundiced patients). Hepatobiliary ultrasound may be indicated if symptoms of cholelithiasis are present. Avoid intramuscular premedication in patients with coagulopathy.

Anemia may require treatment prior to surgery. Perioperative maintenance of appropriate hemoglobin levels is desirable because it may reduce hemoglobin synthesis and therefore minimize protoporphyrin levels. In patients without significant hepatic involvement, the anesthetic technique is dictated by the planned procedure and the surgical requirements. Patients with significant hepatic impairment should be managed according to the severity of the dysfunction. Operating room lamp filters should be used (yellow acrylate) to prevent exposure of the patient to light with wavelengths near 400 nm. Recovery should be conducted in a dimly lit room or in a room with light filters if possible.

Morphine may induce or exacerbate spasms of the sphincter of Oddi. The action of succinylcholine may be prolonged in patients with severe hepatic impairment. Pancuronium and vecuronium actions may be prolonged in such patients, and atracurium or cisatracurium may be preferred. Succinylcholine should be avoided in the quadriplegic patient. Attacks in EPP are not triggered by drugs.