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Erythropoietic Protoporphyria

EPP

Erythropoietic protoporphyria is a genetic disease characterized by reduced activity of ferrochelatase, an enzyme responsible for binding of ferrous iron to protoporphyrin. As a result, protoporphyrin accumulates in the liver and mature erythrocytes. Skin photosensitivity is the main clinical presentation, together with liver damage. Clinical criteria, as well as evaluation of protoporphyrin levels in blood and stool are necessary. Avoiding sun exposure and liver transplantation is the mainstay of therapy.

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Presentation

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].

Splenomegaly
  • As hepatic complications worsen the patient will develop splenomegaly, leading to entrapment and hemolysis of erythrocytes. In rare cases, neurological symptoms such as progressive polyneuropathy have been reported.[clinicaladvisor.com]
  • Health problems associated with erythropoietic porphyrias include a low number of red blood cells ( anemia ) and enlargement of the spleen (splenomegaly). The other types of porphyrias are considered hepatic porphyrias.[ghr.nlm.nih.gov]
  • This disease is characterized by splenomegaly; anemia; photosensitivity; cutaneous lesions; accumulation of hydroxymethylbilane; and increased excretion of uroporphyrins and coproporphyrins.[icd10data.com]
  • Patients may display signs and symptoms of anemia usually hemolytic with splenomegaly and porphyrin rich gallstones.[tmg.org.rs]
Pain
  • Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life.[ncbi.nlm.nih.gov]
  • A 33-year-old woman with a history of photosensitivity, persistent abdominal pain, and liver dysfunction was admitted to our department because of abdominal pain and progression of liver dysfunction.[ncbi.nlm.nih.gov]
  • Gallstones cause characteristic abdominal pain. Liver damage may lead to increasing liver failure, with jaundice, abdominal pain, and enlargement of the spleen.[merck.com]
  • On the third hospital day, the intensity of the upper abdominal pain increased, concomitantly with elevated levels of serum amylase. Ultrasonography and computed tomography scanning revealed a slightly enlarged pancreas.[ncbi.nlm.nih.gov]
  • A 21-year-old Japanese man was admitted to our hospital because of severe abdominal pain and jaundice. He had been suffering from abdominal pain attacks and liver dysfunction since 18 years of age.[ncbi.nlm.nih.gov]
Swelling
  • We report the case of a 5-year-old Caucasian female with EPP who presented with a long-standing 3-year history of recurrent facial blisters and erythematous swelling and lesions of other sun-exposed areas of the skin.[ncbi.nlm.nih.gov]
  • A 31-year old man presented with swelling and purpura of the dorsum of the hands following sun exposure.[ncbi.nlm.nih.gov]
  • This is characterized by cutaneous photosensitivity in early childhood such as itching, burning, swelling and redness in sun-exposed areas.[ncbi.nlm.nih.gov]
  • Severe skin pain and swelling develop soon after even brief exposure to sunlight. Crusting may develop around the lips and on the back of the hands after prolonged sun exposure.[merck.com]
  • Antihistamines are beneficial for those patients who have swelling, as a result of this condition.[epainassist.com]
Burning Pain
  • Older children complain of burning pain . Repeated exposure to the sun causes skin thickening on the knuckles and scars on the nose, cheeks, and back of the hands.[epainassist.com]
  • Older children complain of burning pain. Repeated exposure to the sun causes skin thickening on the knuckles and scars on the nose, cheeks, and back of the hands.[epainassist.com]
  • A 66-year-old Caucasian man presented for the evaluation of stinging–burning pain that developed immediately after exposure to sunlight and was restricted to the exposed skin.[doi.org]
  • Patients experience severe, burning pain--typically on the hands and face--with sun exposure, followed by swelling and redness. The pain can be excruciating and is often is not alleviated by pain medications.[news-medical.net]
  • Usually the effect is of a burning, painful discomfort, although occasionally skin thickening and mild scarring can occur on commonly photosensitive areas, such as the face and the backs of the hands.[netdoctor.co.uk]
Weakness
  • During this episode, he also complained of various neurological symptoms, including reduced mental alertness, weakness of extremities, constipation, profound sweating, and urinary retention.[ncbi.nlm.nih.gov]
  • Finally, profound muscle weakness may be a manifestation of critical illness polyneuropathy.[anesthesiology.pubs.asahq.org]
  • Nine out of ten partners will not carry this weak gene and for such couples the risk of having a child with EPP is very low, less than one in a 100. But if your partner does carry the weak gene, the risk becomes much higher at one in 4.[porphyria.eu]
  • This results in acute cutaneous photosensitivity upon light exposure with production of reactive oxygen species (ROS) and ultra-weak photon emission (UPE) as a by-product.[ncbi.nlm.nih.gov]
  • During an episode, a person may also experience muscle weakness, seizures, fever, and mental changes such as anxiety and hallucinations.[ghr.nlm.nih.gov]
Severe Pain
  • Erythropoietic protoporphyria is a photodermatosis presenting in childhood with severe pain on sun exposure. The diagnosis is often delayed because of the lack of awareness among pediatricians.[ncbi.nlm.nih.gov]
  • BACKGROUND: In erythropoietic protoporphyria (EPP), an inherited disease of porphyrin-biosynthesis, the accumulation of protoporphyrin in the skin causes severely painful phototoxic reactions.[ncbi.nlm.nih.gov]
  • EPP is a group of genetic disorders that is characterized by photosensitivity that often manifests as severe pain, swelling and/or burning.[fda.gov]
  • Accumulation of protoporphyrin in the skin results in extreme sensitivity to sunlight and severe pain soon after exposure. The sunlight activates the protoporphyrin molecules, which damage the surrounding tissue.[merck.com]
  • 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.[symptoma.com]
Abdominal Pain
  • A 33-year-old woman with a history of photosensitivity, persistent abdominal pain, and liver dysfunction was admitted to our department because of abdominal pain and progression of liver dysfunction.[ncbi.nlm.nih.gov]
  • On the third hospital day, the intensity of the upper abdominal pain increased, concomitantly with elevated levels of serum amylase. Ultrasonography and computed tomography scanning revealed a slightly enlarged pancreas.[ncbi.nlm.nih.gov]
  • A 21-year-old Japanese man was admitted to our hospital because of severe abdominal pain and jaundice. He had been suffering from abdominal pain attacks and liver dysfunction since 18 years of age.[ncbi.nlm.nih.gov]
  • Six months after the treatment, he was doing well without any abdominal pain or photosensitivity.[ncbi.nlm.nih.gov]
  • In December 1992, she presented with colicky upper abdominal pain, dyspepsia and mild jaundice. Diagnosis of beginning cholestasis in erythrohepatic protoporphyria and coincidental choledocholithiasis was made.[ncbi.nlm.nih.gov]
Nausea
  • The patient, a 33-year-old man, was admitted to our hospital complaining of upper abdominal pain, nausea, and vomiting of 3 days' duration. Laboratory tests on admission demonstrated liver dysfunction, anemia, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • Only minor adverse events attributable to afamelanotide, predominantly nausea, were recorded.[ncbi.nlm.nih.gov]
  • Autonomic disturbance can cause nausea, vomiting and constipation. Sympathetic overactivity causes tachycardia, hypertension and postural hypotension. Muscular weakness can occur.[patient.info]
  • […] face occur on the areas exposed to the highest doses of sunlight and the areas that are more shaded typically are not affected.[13] Non-skin symptoms have also been reported and involved difficulty with sleep, irritability, temperature insensitivity, nausea[jcadonline.com]
  • The symptoms include abdominal pain and cramps, nausea and vomiting, diarrhea or constipation, urinary retention, and the development of peripheral neuropathies with muscle pain and weakness and changes in sensation.[albertaporphyriasociety.weebly.com]
Vomiting
  • The patient, a 33-year-old man, was admitted to our hospital complaining of upper abdominal pain, nausea, and vomiting of 3 days' duration. Laboratory tests on admission demonstrated liver dysfunction, anemia, and thrombocytopenia.[ncbi.nlm.nih.gov]
  • Episodes of acute porphyria can cause abdominal pain, vomiting, constipation, and diarrhea. During an episode, a person may also experience muscle weakness, seizures, fever, and mental changes such as anxiety and hallucinations.[ghr.nlm.nih.gov]
  • Symptoms include pain in the chest or abdomen, vomiting, and diarrhea or constipation. During an attack, symptoms can include muscle numbness, tingling, paralysis, cramping, and personality or mental changes.[icd9data.com]
  • Autonomic disturbance can cause nausea, vomiting and constipation. Sympathetic overactivity causes tachycardia, hypertension and postural hypotension. Muscular weakness can occur.[patient.info]
  • The symptoms include abdominal pain and cramps, nausea and vomiting, diarrhea or constipation, urinary retention, and the development of peripheral neuropathies with muscle pain and weakness and changes in sensation.[albertaporphyriasociety.weebly.com]
Jaundice
  • Afterwards, the jaundice, liver dysfunction and abdominal symptoms improved and UDCA, cimetidine, and lactulose administration was continued.[ncbi.nlm.nih.gov]
  • An 8-year-old boy was referred to the Hepatology Clinic after an abrupt onset of jaundice with a longstanding history of dermatitis.[ncbi.nlm.nih.gov]
  • In December 1992, she presented with colicky upper abdominal pain, dyspepsia and mild jaundice. Diagnosis of beginning cholestasis in erythrohepatic protoporphyria and coincidental choledocholithiasis was made.[ncbi.nlm.nih.gov]
  • Liver damage may lead to increasing liver failure, with jaundice, abdominal pain, and enlargement of the spleen.[merck.com]
  • Progressive hepatocellular disease : Symptoms include upper abdominal pain and jaundice.[flipper.diff.org]
Hepatomegaly
  • Patients can also present with splenomegaly and hepatomegaly. Liver biopsy in such patients may reveal features of appreciable hepatocellular injury[ 5, 13, 22 - 24 ].[doi.org]
  • Patients can also present with splenomegaly and hepatomegaly. Liver biopsy in such patients may reveal features of appreciable hepatocellular injury. Progressive hepatocellular disease : Symptoms include upper abdominal pain and jaundice.[flipper.diff.org]
Photosensitivity
  • The study confirms changes in photosensitivity during menstruation and pregnancy. Amelioration during breast-feeding is a new finding.[ncbi.nlm.nih.gov]
  • It is characterized by cutaneous photosensitivity, usually difficult to keep under control.[ncbi.nlm.nih.gov]
  • This defect results in accumulation of protoporphyrin in erythrocytes, plasma, liver, and skin, which causes severe photosensitivity. Liver disease can occur in 1-4% of the patients with EPP, usually after at least a decade of photosensitivity.[ncbi.nlm.nih.gov]
  • Extra care was needed when collecting photographic and radiographic records for this patient and during some treatment procedures to avoid causing a photosensitive reaction of the skin or oral mucosa.[ncbi.nlm.nih.gov]
  • Conclusions The study confirms changes in photosensitivity during menstruation and pregnancy. Amelioration during breast‐feeding is a new finding.[doi.org]
Blister
  • We report the case of a 42-year-old man with a 5-year history of myelodysplastic syndrome and photosensitivity who had developed painful erythema and blisters on sun-exposed sites.[ncbi.nlm.nih.gov]
  • We report the case of a 5-year-old Caucasian female with EPP who presented with a long-standing 3-year history of recurrent facial blisters and erythematous swelling and lesions of other sun-exposed areas of the skin.[ncbi.nlm.nih.gov]
  • EPP is characterised by cutaneous manifestations of acute painful photosensitivity with erythema and oedema, sometimes with petechiae, together with stinging and burning sensations upon exposure to sunlight, without blisters.[ncbi.nlm.nih.gov]
  • EPP is characterized by cutaneous manifestations of acute painful photosensitivity with erythema and edema, sometimes with petechiae, together with stinging and burning sensations without blistering, upon exposure to sunlight or artificial light (400-[orpha.net]
Erythema
  • Skin PpIX was associated with erythrocyte PpIX (P 0·002, R 2 0·34), skin erythema (P 0·001, R 2 0·47) and symptoms during illumination. Furthermore, skin PpIX increased during the hours after illumination.[ncbi.nlm.nih.gov]
  • We report the case of a 42-year-old man with a 5-year history of myelodysplastic syndrome and photosensitivity who had developed painful erythema and blisters on sun-exposed sites.[ncbi.nlm.nih.gov]
  • BACKGROUND: Erythropoietic protoporphyria (EPP) is the most common porphyria in childhood, presenting with painful and burning skin sensations as well as erythema and edema after sun exposure.[ncbi.nlm.nih.gov]
  • Following sunlight exposure, the resulting photosensitivity is manifested first as pain, later as erythema, edema and dermal lesions.[ncbi.nlm.nih.gov]
  • […] dominant disorder, a form of erythropoietic porphyria, characterized by increased levels of protoporphyrin in the erythrocytes, plasma, liver, and feces and a wide variety of photosensitive skin changes, ranging from a burning or pruritic sensation to erythema[medical-dictionary.thefreedictionary.com]
Urticaria
  • […] disorder of porphyrin metabolism due to a deficiency of ferrochelatase associated with enhanced fecal excretion of protoporphyrin, red-purple urine, and increased protoporphyrin IX in red blood cells, plasma, and feces; characterized by acute solar urticaria[medical-dictionary.thefreedictionary.com]
  • Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angio-oedema and, in some cases, other types of porphyria.[ncbi.nlm.nih.gov]
  • Differential diagnosis Differential diagnosis includes phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, angioedema and, in some cases, other types of porphyria (see these terms).[orpha.net]
Cutaneous Manifestation
  • Erythropoietic protoporphyria (EPP) is an inherited disorder of the haem metabolic pathway characterised by accumulation of protoporphyrin in blood, erythrocytes and tissues, and cutaneous manifestations of photosensitivity.[ncbi.nlm.nih.gov]
  • Erythropoietic protoporphyria (EPP) is the most common inherited porphyria in children and is diagnosed in most individuals after the onset of cutaneous manifestations.[ncbi.nlm.nih.gov]
  • Erythropoietic protoporphyria (EPP) is an inherited disorder of the heme metabolic pathway that is characterized by accumulation of protoporphyrin in the blood, erythrocytes, and tissues, and cutaneous manifestations of photosensitivity, all resulting[ncbi.nlm.nih.gov]
  • Cutaneous manifestations of photosensitivity usually appear in early infancy upon the first sun exposures. This normally requires the co-inheritance of a common hypomorphic FECH allele and a deleterious FECH mutation.[ncbi.nlm.nih.gov]
  • EPP is characterized by cutaneous manifestations of acute painful photosensitivity with erythema and edema, sometimes with petechiae, together with stinging and burning sensations without blistering, upon exposure to sunlight or artificial light (400-[orpha.net]
Facial Swelling
  • However, the patient’s father reported a prior history of “recurrent” episodes of hand and facial swelling that also seemed to occur from prolonged exposure to sunlight and/or heat.[jcadonline.com]
Tingling
  • Burning pain, pruritus and tingling sensation accompanied by edema after as little as few minutes of exposure are most frequent symptoms.[symptoma.com]
  • Once patients learn to recognize early symptoms including tingling, burning, and itching, they avoid further sun exposure, with major implications for their daily activities, careers and quality of life.[news-medical.net]
  • Signs and Symptoms of Erythropoietic Protoporphyria (EPP) Symptoms vary from patient to patient in severity and commonly consist of: Patient experiences tingling, burning, itching sensation of the skin upon sun exposure.[epainassist.com]
  • During an attack, symptoms can include muscle numbness, tingling, paralysis, cramping, and personality or mental changes. Certain triggers can cause an attack, including some medicines, smoking, drinking alcohol, infections, stress and sun exposure.[icd9data.com]
Polyneuropathy
  • His OLT was uneventful, and he developed neither polyneuropathy nor exacerbation of photosensitivity.[ncbi.nlm.nih.gov]
  • One year after transplantation, her general condition has markedly improved, but there is still a disabling polyneuropathy.[ncbi.nlm.nih.gov]
  • In addition to polyneuropathy, our patient also experienced photosensitivity.[anesthesiology.pubs.asahq.org]
  • Liver failure in erythropoietic protoporphyria associated with choledocholithiasis and severe posttransplantation polyneuropathy. Liver. 1996; 16 :211–217. [ PubMed ] 26. Nguyen L, Blust M, Bailin M, Melendez L, Raines DE.[ncbi.nlm.nih.gov]
  • In rare cases, neurological symptoms such as progressive polyneuropathy have been reported. Treatment Options Treatment options are summarized in Table I . Table I.[clinicaladvisor.com]
Encephalopathy
  • […] sinensis, liver flukes, distomatosis hepatis, hepatodistomiasis 肝静脈閉塞 hepatic veno occlusive disease 肝性骨髄性ポルフィリン症 hepatoerythropoietic porphyria 肝腎型チロシン血症 hepatorenal tyrosinemia 肝腎症候群 hepatorenal syndrome 肝性骨ジストロフィー hepatic osteodystrophy 肝性脳症 hepatic encephalopathy[jsge.or.jp]
  • Very occasionally, acute attacks are accompanied by a severe adrenergic crisis with dangerous hypertension, encephalopathy, seizures and ischaemic changes on a CT brain scan. [ 1 ] Liver transplantation has been carried out successfully in severe cases[patient.info]

Workup

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].

Microcytic Anemia
  • Microcytic anemia occurs in 20% to 60% of patients. We investigated 178 patients with dominant EPP confirmed by molecular analysis.[ncbi.nlm.nih.gov]
  • We report a 16-year-old male with EPP characterized by acute episodes of painful photosensitivity since early infancy, permanent changes in the photoexposed skin, microcytic anemia, thrombocytopenia, and mild hepatic dysfunction.[ncbi.nlm.nih.gov]
  • This patient presented cutaneous photosensitivity similar to the heterozygous cases, but a higher protoporphyrin accumulation in erythrocytes, microcytic anemia, and early signs of liver engagement.[ncbi.nlm.nih.gov]
Free Erythrocyte Protoporphyrin
  • Porphyrin analysis revealed elevated free erythrocyte protoporphyrin (FEP) levels confirming the diagnosis of EPP.[ncbi.nlm.nih.gov]
  • Diagnosis The diagnosis of EPP is established by finding an abnormally high free erythrocyte protoporphyrin in the FEP test, which is done on red blood cells.[apfdev.xptise.com]
  • High levels of free plasma protoporphyrin levels, and free erythrocyte protoporphyrin levels (may be greater than1000mcg/dl, whereas normal is less than 60mcg/dl) are indicative of EPP and elevated levels of zinc-protoporphyrin are indicative XLDPP.[clinicaladvisor.com]
  • Diagnosis is by measuring free erythrocyte protoporphyrin. Carotene treatment may be helpful, as it raises tolerance to sunlight. Liver and bone marrow transplantation have been successfully carried out as treatment.[patient.info]
Liver Function Tests Abnormal
  • The present report describes the clinical features of a patient with erythropoietic protoporphyria and liver function test abnormalities associated with treatment with beta-carotene.[ncbi.nlm.nih.gov]
Protoporphyrin Increased
  • RCE decreased RBC protoporphyrin levels from 2,879 to 1,225 μg/dL but plasma protoporphyrin increased from 180.4 to 1,044.1 μg/dL, and liver function failed to improve.[ncbi.nlm.nih.gov]

Treatment

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].

Prognosis

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.

Etiology

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.

Epidemiology

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].

Sex distribution
Age distribution

Pathophysiology

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

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].

Summary

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.

Patient Information

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.

References

Article

  1. Anstey AV, Hift RJ. Liver disease in erythropoietic protoporphyria: insights and implications for management. Gut. 2007;56:1009-1018.
  2. Lecha M, Puy H, Deybach JC. Erythropoietic protoporphyria. Orphanet J Rare Dis. 2009;4:19.
  3. Balwani M, Doheny D, Bishop DF, et al. Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. Mol Med. 2013;19:26-35.
  4. Todd DJ. Erythropoietic protoporphyria. Br J Dermatol. 1994;131:751-766.
  5. Harms J, Lautenschlager S, Minder CE, et al. An alpha-melanocyte-stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med. 2009;360(3):306-307.
  6. Gouya L, Martin-Schmitt C, Robreau AM, et al. Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Am J Hum Genet. 2006;78:2-14.
  7. Balwani M, Bloomer J, Desnick R. Erythropoietic protoporphyria, autosomal recessive. GeneReviews. Seattle,WA:University of Washington; 2014.
  8. Wahlin S, Floderus Y, Stål P, et al. Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics. J Intern Med. 2011;269:278-288.
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Last updated: 2018-06-21 19:38