Эритропоиетическая протопорфирия: симптомы, причины и течение заболевания.

Erythropoietic protoporphyria (or commonly called EPP) is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. The severity varies significantly from individual to individual. A clinically similar form of porphyria, known as X Linked dominant protoporphyria, was identified in 2008.

EPP usually presents in childhood with the most common mode of presentation as acute photosensitivity of the skin. It affects areas exposed to the sun and tends to be intractable. A few minutes of exposure to the sun induces pruritus, erythema, swelling and pain. Longer periods of exposure may induce second degree burns. After repetitive exposure, patients may present with lichenification, hypopigmentation, hyperpigmentation and scarring of the skin. EPP usually first presents in childhood, and most often affects the face and the upper surfaces of the arms, hands, and feet and the exposed surfaces of the legs. Most patients, if the EPP is not as severe, manifest symptoms with onset of puberty when the male and female hormone levels elevate during sexual development and maintenance. More severe EPP can manifest in infancy. EPP can be triggered through exposure to sun even though the patient is behind glass. Even the UV emissions from arc welding with the use of full protective mask have been known to trigger EPP. EPP can also manifest between the ages of 3 and 6. Prolonged exposure to the sun can lead to edema of the hands, face, and feet, rarely with blistering and petechiae. Skin thickening can sometimes occur over time. People with EPP are also at increased risk to develop gallstones. One study has noted that EPP patients suffer from vitamin D deficiency.

Protoporphyrin accumulates to toxic levels in the liver in 5–20% of EPP patients, leading to liver failure. The spectrum of hepatobiliary disease associated with EPP is wide. It includes cholelithiasis, mild parenchymal liver disease, progressive hepatocellular disease and end stage liver disease.

EPP photosensitivity symptoms are reported to lessen in some female patients during pregnancy and menstruation, although this phenomenon is not consistent, and the mechanism is not understood.

Most cases of EPP are results of inborn errors of metabolism Mutation of the gene that encodes for ferrochelatase in the long arm of chromosome 18 is found in majority of the cases. Ferrochelatase (FECH) catalyzes the insertion of ferrous iron into the protoporphyrin IX ring to form heme. EPP exhibits both recessive and dominant patterns of inheritance and a high degree of allelic heterogeneity with incomplete penetrance. Most heterozygotes are asymptomatic. Symptoms do not occur unless FECH activity is less than 30% of normal, but such low levels are not present in a majority of patients.

Cells which synthesize heme are predominantly erythroblasts/reticulocytes in the bone marrow (80%) and hepatocytes (20%). Deficiency of FECH results in increased release of protoporphyrin, which binds to albumin in plasma and subsequently undergoes hepatic extraction. Normally, most protoporphyrin in hepatocytes is secreted into bile; the remainder undergoes transformation into heme. Some protoporphyrin in bile is returned to the liver as a consequence of the enterohepatic circulation; the remaining protoporphyrin in the intestine undergoes fecal excretion. Protoporphyrin is insoluble and hence unavailable for renal excretion. In EPP, subnormal biotransformation of protoporphyrin into heme results in accumulation of protoporphyrin in hepatocytes. Since FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes, plasma, skin and liver, retention of protoporphyrin in skin predisposes to acute photosensitivity. As a result of absorption of ultraviolet and visible light (peak sensitivity at 400 nm, with lesser peaks between 500–625 nm) by protoporphyrin in plasma and erythrocytes when blood circulates through the dermal vessels, free radicals are formed, erythrocytes become unstable and injury to the skin is induced.

EPP is generally suspected by the presence of acute photosensitivity of the skin and can be confirmed by detection of a plasmatic fluorescence peak at 634 nm. It is also useful to find increased levels of protoporphyrin in feces and the demonstration of an excess of free protoporphyrin in erythrocytes. Screening for FECH mutation on one allele or aminolevulinic acid synthase 2 gain of function mutation in selected family members may be useful, especially in genetic counseling. Liver biopsy confirms hepatic disease in EPP by the presence of protoporphyrin deposits in the hepatocytes that can be observed as a brown pigment within the biliary canaliculi and the portal macrophages. Macroscopically, the cirrhotic liver can have a black color due to protoporphyrin deposits. Using polarized light the characteristic Maltese cross shape of birefringent crystalline pigment deposits is found. The examination of liver tissue under a Wood’s lamp reveals a red fluorescence due to protoporphyrin. Liver biopsy is not helpful for estimation of prognosis of liver disease.). Sun protective clothing can also be very helpful, although clothing with UPF values are only rated based on their UV protection (up to 400 nm) and not on their protection from the visible spectrum. Some sun protective clothing manufacturers use zinc oxide in their fabrics, such as Coolibar's ZnO Suntect line, which will offer protection from visible light. Window films which block UV and visible light up to 450 nm can provide relief from symptoms if applied to the patient's automobile and home windows. An example of such would be Madico Amber 81 which can protect through the 500 nm range. Blue blocking screen protectors can help provide relief from symptoms caused by televisions, phones, tablets and computer screens. EPP is considered one of the least severe of the porphyrias. Unless there is liver failure, it is not a life threatening disease.

Afamelanotide, developed by Australian based Clinuvel Pharmaceuticals, was approved in Europe in December 2014 and in the United States in October 2019 for treatment or prevention of phototoxicity in adults with EPP.

Case reports suggest that EPP is prevalent globally. The prevalence has been estimated somewhere between 1 in 75,000 and 1 in 200,000 however it has been noted that the prevalence of EPP may be increasing due to a better understanding of the disease and improved diagnosis. An estimated 5,000–10,000 individuals worldwide have EPP. EPP is considered the most common form of porphyria in children. The prevalence in Sweden has been published as 1:180,000.

Erythropoietic protoporphyria was first described in 1953 by Kosenow and Treibs and completed in 1960 by Magnus et al. at the St John's Institute of Dermatology in London.