The hallmark of EPP is the onset of skin photosensitivity at first exposure to the sun or ultraviolet light in the neonatal period or infancy [7]. Burning pain, pruritus and tingling sensation accompanied by edema after as little as few minutes of exposure are most frequent symptoms [1]. In some patients, pain may persist for several hours or even days and may be so excruciating that it affects normal sleeping habits [4]. Although blistering of the skin is rather uncommon, repeated exposure can lead to lichenification, loss of nail lunulae, development of pseudovesicles and other chronic skin changes [7]. Erythema of the skin and petechiae may be observed as well [2]. Additionally, approximately 20-30% have some form of liver impairment, most commonly gallstones and cholestasis due to accumulation of protoporphyrin in bile [7]. As a result, abdominal pain in the right upper quadrant may be observed [7]. 5% of patients progress to advanced liver failure, including cirrhosis and cholestasis [7].

Clinical suspicion toward EPP can be made based on clinical criteria only, implying that a thorough patient history and a detailed physical examination are most important steps in workup. To confirm the diagnosis, microscopic evaluation of erythrocytes on a fresh blood smear and visualization of fluorescent RBCs (fluorocytes) is recommended [2]. Measurement of protoporphyrin in serum and stool is also a useful diagnostic procedure, as it will be invariably elevated in these samples [2]. Liver examination is mandatory for all patients in whom EPP is suspected. Abdominal ultrasonography and liver function tests, including transaminases (ALT and AST), gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) must be performed to exclude cholestasis [2].

Symptomatic measures and liver transplantation are current therapeutic strategies, as there is no cure for this condition. Application of wet and cold compresses to skin areas that are affected is recommended to for pain reduction [2]., whereas the role of β-carotene in improving light tolerance has been disputed. However, some benefit has been reported in many patients, which is why it is often used in doses of 90-120 mg/day in children and 180-300 mg/day in adults [2]. Recent trials have shown that an analog of α-MSH, afamelanotide, can be of great use in patients suffering from EPP [5]. In the case of extensive liver damage, the main therapeutic strategy is liver transplantation, with the idea of removing the accumulated protoporphyrin and good post-transplantation survival rates have been observed [10]. This procedure does not affect the production of protoporphyrin from the bone marrow, however, which is why liver recipients are at a severe risk of disease recurrence [11]. For this reason, concomitant bone marrow transplantation may be performed. As light exposure during the operating room may induce skin damage, placement of filters on lights in the operating room are necessary measures. Additionally, the use of hematin and/or plasmapheresis in the setting of severe neuropathy and pain is advocated by certain authors [10].

Acute hepatic failure as a result of protoporphyrin accumulation in the liver is the most important and most serious complication in these patients, as it may be rapidly fatal without appropriate treatment [4]. From social and individual aspects, EPP has shown to be a severely debilitating disease because of its distinctive clinical features that can significantly impact the quality of life among patients afflicted this illness [9]. For these reasons, prompt recognition in early life is vital.

Many controversies have existed regarding the mode of EPP inheritance, but it was determined that both autosomal dominant and recessive patterns were identified in patients [2]. Mutations of FECH on one allele and a hypomorphic FECH allele in trans position are most frequently observed, but various types of mutations have been identified in EPP, including missense, nonsense, deletions, insertions and splicing [6]. Inciting factors leading to this phenomenon, however, are still not known.

EPP is considered to be one of the most common types of porphyria, occurring in 2-5 per 1,000,000 individuals, and it is the most frequent porphyria identified in children [7]. Studies in the Netherlands and Wales have established prevalence rates of 1 per 75,000 and 1 per 200,000 individuals, respectively [7]. Similar rates were observed in Sweden, where prevalence rates of 1 per 180,000 were observed [8]. EPP is equally distributed across gender and cases of EPP have been diagnosed across all continents. Being of African ancestry has shown to be a negative risk factor for the development of EPP [2] [6].

The pathogenesis of EPP starts with genetic mutations that cause reduced activity (below 35% of normal) of ferrochelatase, the enzyme that mediates the last step of heme biosynthesis - insertion of ferrous iron to protoporphyrin in the mitochondria [6]. Since protoporphyrin is not degraded, it accumulates in bone marrow reticulocytes, after which it is released into the circulation from both the bone marrow and matured erythrocytes [3]. Additionally, a small proportion of protoporphyrin is produced in the liver, the site of secondary erythropoiesis. This molecule is excreted in the bile and feces and deposits in the liver parenchyma because it cannot be eliminate by the kidneys due to water insolubility. Liver disease ensues due to hepatotoxic effects of protoporphyrin, such as reduction of bile formation and obstruction of its flow, together with inhibition of cellular metabolism and induction of cell fragility [1] [3]. When it comes to the main clinical feature of EPP, skin photosensitivity, the reaction of visible blue-violet light near 400 nm to protoporphyrin triggers the release of free radicals that are responsible for the appearance of symptoms [3] [7].

Prevention of EPP is currently not possible, but long-term follow-up and implementation of various strategies may be of significant benefit in this group of patients. Avoidance of sun exposure is equally important both in therapy and in prevention, together with frequent use of vitamin D, since the production of this vital nutrient necessitates exposure of the skin to sunlight [7]. Additionally, regular evaluations of hepatic function is advocated in all patients, to prevent liver failure as a result of protoporhyrin accumulation [7]. Although the chance of transferring the disease from a parent with the classical form of FECH allele mutations is less than 2.5% [2]., genetic counselling and prenatal testing is advised for families in whom EPP is already diagnosed [7].

Erythropoietic protoporphyria (EPP) is one of the types of porphyria, that are diseases of inadequate heme synthesis due to reduced activity of various enzymes necessary for its formation [1]. Specifically, EPP occurs due to reduced activity of ferrochelatase, an enzyme responsible for insertion of ferrous iron into protoporphyrin to form heme, which is the last step of heme synthesis [1]. EPP is a genetic disease and is transferred by both autosomal dominant and recessive patterns of inheritance [2]. Epidemiologic studies show that it is the most common pediatric porphyria and the pathogenesis starts with accumulation of protoporphyrin in the bone marrow (where 80% of heme is formed) and the liver [1]. Extensive production of protoporphyrin in reticulocytes situated in the bone marrow and hepatocytes triggers a progressive release of this molecule from these sites into plasma [3]. The liver is the principal site of its deposition, as it is not excreted through the renal system because of its water insolubility [3]. Apart from liver disease that is seen in 20-30% of patients (ranging from mild cholestasis to severe and life-threatening liver failure), skin sensitivity to light is the most important clinical manifestation of the disease [4]. When light rays (either from the sun or strong ultraviolet light) penetrate the skin, its interaction with protoporphyrin creates a severely painful reaction mediated by release of free radicals. Consequently, the main symptoms are pain, itching and tingling within minutes after exposure of the skin to light for the first time [2]. Erythema and petechiae are readily observed, but blistering lesions are not encountered in these patients [2]. Clinical criteria are sufficient for the initial diagnosis, but serum and fecal determination of EPP levels, as well as microscopic visualization of fluorescent erythrocytes (because of protoporphyrin reaction to light) are used for confirmation [2]. Liver function tests and abdominal ultrasonography must be performed to assess potential liver damage. Symptomatic treatment of photosensitivity by applying cold and wet compresses and β-carotene are useful techniques, but avoiding exposure to sunlight is the main therapeutic and preventive strategy [2]. In patients who develop liver failure, transplantation is recommended, but protoporphyrin production from the bone marrow is not resolved by this procedure, which is why concomitant bone marrow transplantation may be indicated. In recent years, the use of α-melanocytic stimulating hormone (α-MSH) analog, afamelanotide, has show to be of significant benefit for EPP patients [5]. Curative therapy, however, does not exist at this moment. As for many diseases, the principle of an early diagnosis of EPP is detrimental, especially in the setting of liver disease. Patients who are treated in a timely manner have a better prognosis.

Erythropoietic Protoporphyria (EPP) is an inherited disease that belongs to a group of porphyrias, conditions that arise as a result of either reduced activity or deficiency of enzymes responsible for production of heme, the main product of hemoglobin degradation. In the setting of EPP, the enzyme that binds iron and a precursor of heme, protoporphyrin, is minimally present (below 35% of its physiological activity), which leads to accumulation of this substance in the bone marrow (where it is principally produced) and the liver. EPP patients acquired mutated genes from one (or rarely both) of their parents and it's appearance in the population is estimated between 1 in 75,000 to 1 in 200,000 individuals. Once protoporphyrin accumulates in the bone marrow, it is stored in mature red blood cells and travels throughout the body. When it is situated in distal blood vessels close to the skin and exposed to sunlight, a reaction involving release of free radicals causes the most prominent clinical feature of EPP - skin photosensitivity. Namely, patients suffering from EPP develop a severe reaction of the skin during first exposure to sunlight, characterized by severe pain, itching and tingling. These symptoms may persist for hours or even days. Redness of the skin, as well as swelling, is frequently observed, while repeated exposure may cause chronic skin changes. In addition to photosensitivity, the liver is also affected, as protoporphyrin eventually deposits in the liver, where it should be excreted through bile and feces. Through unknown mechanisms, obstruction of bile flow and damage to liver cells, known as hepatocytes, is seen in approximately 20-30% of EPP patients and 5% of individuals develop severe and life-threatening liver failure. Based on findings obtained in patient history and during physical examination, the initial diagnosis should be made easily, whereas a confirmation can be obtained through determining values of protoporphyrin in blood and stool. Additionally, a detailed liver examination consisting of tests that evaluate its synthetic function and abdominal ultrasonography are necessary. Avoiding sun exposure is currently the single most important therapeutic measure, while symptomatic treatment through application of wet compresses on the skin and use of β-carotene have been shown to be beneficial. In patients with severe liver disease, transplantation is indicated in order to remove the stores of protoporphyrin in this organ, but because its production in the bone marrow is unaffected by this procedure, bone marrow transplantation should also be considered to prevent disease recurrence. Although it is considered to be rare in clinical practice, an early diagnosis of EPP carries a much better prognosis, which is why physicians must consider this disease among patients presenting with skin photosensitivity and liver damage.

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