Erythropoietic protoporphyria

Erythropoietic protoporphyria also called EPP is a rare inherited disorder of the heme biosynthetic pathway resulting in the accumulation of protoporphyrins in red blood cells that causes painful, non-blistering photosensitivity to sunlight and artificial light (phototoxicity) and potential liver disease ¹, ², ³, ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³. On sun exposure, patients with erythropoietic protoporphyria (EPP) may first experience tingling, itching, burning of their skin. After continued exposure to light, the skin may become red and swollen. The hands, arms, and face are the most commonly affected areas.

Erythropoietic protoporphyria (EPP) is caused by mutations in the FECH gene. The FECH gene provides instructions for making an enzyme known as ferrochelatase ¹⁴. The ferrochelatase (FECH) enzyme is involved in the production of a molecule called heme. The production of heme is a multi-step process that requires eight different enzymes. Ferrochelatase is responsible for the eighth and final step in this process, in which an iron (Fe²⁺) atom is inserted into the center of protoporphyrin IX (the product of the seventh step) to form heme. Heme is vital for all of your body’s organs, although it is most abundant in your blood, bone marrow, and liver. Heme is an essential component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Due to abnormally low levels of ferrochelatase (FECH) enzyme, excessive amounts of protoporphyrin IX (PPIX) build up in the bone marrow, blood plasma, and red blood cells ¹⁵. Protoporphyrin IX (PPIX) compounds are formed during the normal process of heme production, but reduced activity of ferrochelatase allows them to accumulate to toxic levels. The excess porphyrins can leak out of developing red blood cells and be transported through the bloodstream to your skin and other tissues. High levels of porphyrins compounds in the skin cause the oversensitivity to sunlight that is characteristic of erythropoietic protoporphyria (EPP). Large amounts of porphyrins in the gallbladder can also cause gallstones. Less commonly, a buildup of porphyrins in the liver can result in liver damage that leads to cirrhosis and liver failure.

Some patients with symptoms of protoporphyria have a genetic change (gain-of-function variants in exon 11 of ALAS2) in a different gene called ALAS2 gene and follows an X-linked inheritance pattern ¹⁶, ¹⁷. When a patient has a genetic change in the ALAS2 gene located on the X chromosome, the condition is referred to as X-linked protoporphyria (XLP) ¹⁸. XLP accounts for 2–10% of protoporphyria cases ¹. The ALAS2 gene provides instructions for making an enzyme called 5′-aminolevulinate synthase 2 or erythroid ALA-synthase ¹⁷. This version of the enzyme is found only in developing red blood cells called erythroblasts. ALA-synthase enzyme also plays an important role in the production of heme. The production of heme is a multi-step process that requires eight different enzymes. ALA-synthase is responsible for the first step in this process, the formation of a compound called delta-aminolevulinic acid (δ-ALA). The excess delta-aminolevulinic acid (δ-ALA) is converted by other enzymes to compounds called porphyrins. If porphyrins compounds build up in erythroblasts, they can leak out and be transported through the bloodstream to your skin and other tissues. High levels of porphyrins in the skin cause the oversensitivity to sunlight that is characteristic of X-linked protoporphyria (XLP).

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by a buildup of protoporphyrin in the skin, blood, and liver. It typically presents in early childhood with immediate pain and crying upon exposure to bright sunlight (e.g., babies may cry in the sun or in the car). Erythropoietic protoporphyria signs and symptoms is seasonal in nature with symptoms principally occurring in the spring and summer season.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) signs and symptoms include:

• Painful, non-blistering skin reactions to sunlight or artificial light, most often on the tops of the hands and feet, face and ears. Most individuals with EPP develop acute cutaneous photosensitivity within 30 minutes after exposure to sun or ultraviolet light. Pain can be severe and and can last up to a week after sun exposure ⁶.
• Itching, burning, or redness of the skin.
• Swelling or edema in the affected areas.
• Persistent redness or inflammation of the skin.
• Pregnancy has been associated with decreased protoporphyrin levels and increased tolerance to sun exposure, but these are inconsistent ¹⁹, ²⁰, ²¹, ²², ²³, ²⁴, ²⁵, ²⁶.
• Over the years, the skin on the backs of the hands and cheeks can have some thickening with subtle pitted scarring.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) causes skin pain on exposure to sunlight. There may not be anything to see at the time. Prolonged exposure can result in some redness and swelling, and uncommonly in blistering and crusting.

EPP is a very rare inherited disorder that affects males and females in equal numbers. It is estimated that erythropoietic protoporphyria (EPP) occurs in about 1 in about 75,000 to 1 in 200,000 individuals in Europe, with prevalence figures ranging between 1 in 75,000 (The Netherlands) and 1 in 200,000 (Wales) ²⁷, ²⁸, ⁹. However, recent genetic evidence has revealed erythropoietic protoporphyria true prevalence is ∼1 in 17,000 ²⁹, ³⁰, ³¹. The number of patients affected by these disorders in the US is unknown. Erythropoietic protoporphyria (EPP) seems that males and females are equally affected ³².

X-linked protoporphyria (XLP) accounts for about 10% of erythropoietic protoporphyria cases in the United States. X-linked protoporphyria (XLP) is more likely to present in males. Females with XLP may or may not have symptoms ⁹.

The onset of symptoms affecting the skin usually occurs in infancy, with an average of diagnosis at age 4; however, in some cases, onset may not occur until adolescence or rarely even adulthood. A clinical diagnosis of EPP is often made during childhood. The blood needs to be sent for porphyrin analysis in a tube protected from light with aluminium foil.

• The patient’s red blood cells may be noted to fluoresce by ultraviolet microscopy.
• The characteristic change is the elevation of the red cell protoporphyrin.
• Genetic testing for mutations in the ferrochelatase (FECH) gene can be performed.
• A skin biopsy is rarely performed as the skin often appears normal; however, EPP has some characteristic features on histopathology.

Once the diagnosis has been made, regular checks of liver function are required with intermittent liver imaging. Genetic counseling is recommended for affected individuals and their families.

Erythropoietic protoporphyria is a lifelong disease, and repeated phototoxic reactions eventually lead to thickening of the skin and wax-like scarring on the face. In a small number of patients with erythropoietic protoporphyria, the accumulation of protoporphyrins in the liver leads to cirrhosis and liver failure. Onset in adulthood is rare, but an acquired form has been identified, in which clones of cells with mutated ferrochelatase expand in the setting of the myelodysplastic or myeloproliferative syndrome ³³.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) diagnosis is made by finding increased levels of the protoporphyrin in the plasma or red blood cells. High performance liquid chromatography or extraction methods that measure total, metal-free, and zinc protoporphyrin are recommended for the diagnosis of protoporphyria ³⁴. Current lists of laboratories that perform such testing can be found on websites for the United Porphyrias Association, the European Porphyria Network, and the American Porphyria Foundation. These laboratories can also give advice regarding the optimal laboratory testing or differential diagnosis of biochemical abnormalities. As sample materials and pre‐analytical specifications depend on the specific diagnostic methods, it is advisable to contact the respective laboratory prior to sample collection. Genetic testing is useful to confirm the diagnosis.

For the initial screening for porphyrias with skin symptoms, a plasma fluorescence scan detecting increased plasma porphyrin concentrations is recommended. This approach offers the added benefit of recognizing other forms of porphyrias associated with cutaneous symptoms, that is, porphyria cutanea tarda (PCT), porphyria variegata (VP), hereditary coproporphyria (HC) and congenital erythropoietic porphyria (CEP). Moreover, a negative test result excludes any form of porphyria as the underlying cause of concurrent skin symptoms. In the case of the protoporphyrias, protoporphyrin IX (PPIX) present in the plasma typically causes a positive plasma‐fluorescence scan with a peak at around 633–635 nm ³⁵. The diagnosis of the protoporphyrias is confirmed by the quantification of protoporphyrin IX (PPIX) in red blood cells (erythrocytes), whereby metal‐free PPIX and zinc protoporphyrin IX (ZnPP) are determined separately. A metal‐free PPIX ≥3 times the upper limit of normal (ULN) establishes the diagnosis of protoporphyrias.

To reliably perform a plasma fluorescence scan and the protoporphyrin IX (PPIX) measurement in red blood cells (erythrocytes), the vial of blood (5 mL) needs to be protected from light with an aluminium foil. Exposure of the blood tube to light can lead to photobleaching of PPIX, resulting in a decrease in measured PPIX levels in the sample as compared to the actual levels in the subject. This effect is related to the ability of conjugated double bonds in the porphyrin rings to absorb the energy from visible light ³⁶. To avoid diagnostic delay, plasma porphyrins should be measured at the same time with erythrocyte protoporphyrin ³⁷.

Other test materials used for the diagnosis of other forms of porphyrias are urine and faeces. Urinary porphyrins are not diagnostic in protoporphyrias as, due to its hydrophobicity, excess PPIX is excreted by the biliary route and faeces. Therefore, in the faeces, an increase in PPIX can be present, but the diagnosis requires confirmation by a significant increase of PPIX and zinc protoporphyrin IX (ZnPP)P in the erythrocytes.

Erythropoietic protoporphyria treatment includes the following:

• Avoid sunlight and wear protective clothing
• Use topical anesthetic creams
• Take vitamin D supplements
• Avoid alcohol to prevent additional cause of liver damage
• Narrowband UVB phototherapy. Narrowband UVB phototherapy does not cause the EPP pain. It is given 3 days a week over 6 weeks in Spring. It increases melanin content causing a tan and induces skin thickening so to provide some level of protection from the sun.
• Scenesse (afamelanotide). Scenesse (afamelanotide) is an alpha-melanocyte stimulating hormone that is given by subcutaneous implantation and works by increasing skin pigmentation which provides protection and improves sun tolerance ¹⁰. There is no data on the safety of Scenesse (afamelanotide) during pregnancy so this cannot be recommended for pregnant women.
• Due to insufficient data related to efficacy, the following therapies are not recommended for the prevention of phototoxic symptoms: beta-carotene, cysteine, cimetidine, isoniazid, warfarin, quinacrine, oral zinc, N-acetylcysteine, vitamin C, omega-3 fatty acids, oral adenosine monophosphate, canthaxanthine, terfenadine, inosine, dithiothreitol (DTT) and glycerol, pyridoxine, and hydroxyethylrutosides ³⁸, ³⁹, ⁴⁰, ¹. Although several previous studies have investigated beta carotene in EPP, the evidence shows unclear or no benefit ¹. Dersimelagon is a synthetic, orally administered, small molecule agonist of melanocortin-1 receptor (MC1R) being tested for the prevention of protoporphyria phototoxicity. A positive Phase 2 clinical trial has been completed showing promising results, and a Phase 3 study is ongoing ⁴¹. There are no approved therapies for children patients.

Figure 1. Erythropoietic protoporphyria

Footnote: Acute photosensitivity reaction in erythropoietic protoporphyria (EPP).

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Figure 2. Erythropoietic protoporphyria

Footnotes: a) Child with extensive edema of the face with erythema and petechiae; b) Adult patient with skin redness (erythema) and skin swelling (edema) during phototoxic episode, with hypopigmented scars and skin thickening present

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Figure 3. Chronic erythropoietic protoporphyria skin lesions

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Figure 4.  Heme chemical structure

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Figure 5. Heme synthesis pathway

Footnotes: The heme biosynthetic pathway requires 8 enzymatic steps. Heme synthesis pathway showing the enzymes involved in the heme synthesis pathway and the associated porphyrias with the disruption of each specific enzyme. Gain-of-function variants in ALAS2 result in X-linked protoporphyria (XLP), and loss-of-functions variants in FECH result in erythropoietic protoporphyria (EPP). In both X-linked protoporphyria (XLP) and erythropoietic protoporphyria (EPP), metal-free protoporphyrin IX (PPIX) accumulates in erythroblasts, erythrocytes, the plasma, and the biliary system. Metal-free protoporphyrin IX (PPIX) is photosensitive, particularly to visible light in the blue range, and the light-mediated activation of metal-free protoporphyrin IX (PPIX) produces free radicals that damage the surrounding tissues.

Enzymes, encoded by genes, catalyze each of the steps. Gene mutations cause deficient enzyme production. Disruptions are indicated by red lines connecting enzymes with the resultant porphyrias. ALAS (ALAS2) = aminolevulinate synthase (aminolevulinate synthase 2); ALAD = delta-aminolevulinic acid dehydratase; PBGD = porphobilinogen dehydratase; HMBS = hydroxymethylbilane synthase; UROS = uroporphyrinogen-III synthase; UROD = uroporphyrinogen III decarboxylase; CPOX = coproporphyrinogen-III oxidase; PPOX = protoporphyrinogen oxidase; FECH = ferrochelatase.

Porphyrias resulting from disruption of enzyme production. XLP (X-linked protoporphyria); ADP (aminolevulinic acid dehydratase porphyria); AIP (acute intermittent porphyria); CEP (congenital erythropoietic porphyria); PCT (porphyria cutanea tarda); HCP (hereditary coproporphyria); VP (variegate porphyria); EPP (erythropoietic protoporphyria).

Abbreviations: ALA = aminolevulinic acid; PBG = porphobilinogen; HMB = hydroxymethylbilane; URO III = uroporphyrinogen III; COPRO III = coproporphyrinogen III; PROTO’gen IX protoporphyrinogen IX; PPIX = protoporphyrin IX; Fe2+ = iron.

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Erythropoietic protoporphyria causes

Erythropoietic protoporphyria (EPP) is caused by mutations in the FECH gene. The vast majority of patients with EPP are compound heterozygotes for both a rare pathogenic FECH variant and a common low expression FECH allele that is present in ~10% of the Caucasian population (c.315-48T>C), a combination that results in ~30% of normal enzyme activity ⁴³, ⁴⁴. Homozygosity for FECH c.315-48T>C does not cause EPP ⁴⁵. The FECH gene provides instructions for making an enzyme known as ferrochelatase ¹⁴. The ferrochelatase (FECH) enzyme is involved in the production of a molecule called heme. The production of heme is a multi-step process that requires eight different enzymes. Ferrochelatase is responsible for the eighth and final step in this process, in which an iron (Fe²⁺) atom is inserted into the center of protoporphyrin IX (the product of the seventh step) to form heme. Heme is vital for all of your body’s organs, although it is most abundant in your blood, bone marrow, and liver. Heme is an essential component of iron-containing proteins called hemoproteins, including hemoglobin (the protein that carries oxygen in the blood). Due to abnormally low levels of ferrochelatase (FECH) enzyme, excessive amounts of protoporphyrin build up in the bone marrow, blood plasma, and red blood cells. Porphyrins compounds are formed during the normal process of heme production, but reduced activity of ferrochelatase allows them to accumulate to toxic levels. The excess porphyrins can leak out of developing red blood cells and be transported through the bloodstream to your skin and other tissues such as your liver. High levels of porphyrins compounds in the skin cause the oversensitivity to sunlight that causes severe pain and inflammation resulting in symptoms of EPP. Large amounts of porphyrins in the gallbladder can also cause gallstones. Less commonly, a buildup of porphyrins in the liver can result in liver damage that leads to cirrhosis and liver failure.

Some patients with symptoms of protoporphyria have a genetic change (gain-of-function variants in exon 11 of ALAS2) in a different gene called ALAS2, a gene located on the X chromosome and follows an X-linked inheritance pattern ¹⁶. When a patient has a genetic change in the ALAS2 gene, the condition is referred to as X-linked protoporphyria (XLP). XLP accounts for 2–10% of protoporphyria cases ¹. The ALAS2 gene provides instructions for making an enzyme called 5′-aminolevulinate synthase 2 or erythroid ALA-synthase ¹⁷. This version of the enzyme is found only in developing red blood cells called erythroblasts. ALA-synthase enzyme also plays an important role in the production of heme. The production of heme is a multi-step process that requires eight different enzymes. ALA-synthase is responsible for the first step in this process, the formation of a compound called delta-aminolevulinic acid (δ-ALA). The excess delta-aminolevulinic acid (δ-ALA) is converted by other enzymes to compounds called porphyrins. If porphyrins compounds build up in erythroblasts, they can leak out and be transported through the bloodstream to your skin and other tissues. High levels of porphyrins in the skin cause the oversensitivity to sunlight that is characteristic of X-linked protoporphyria (XLP).

Erythropoietic protoporphyria inheritance pattern

Erythropoietic protoporphyria (EPP) is inherited in an autosomal recessive manner ⁴⁶, ⁹. Everyone has two copies of the FECH gene, one inherited from the mother and one from the father. Most individuals with EPP have a different gene mutation on each copy of the FECH genes. On one copy, the change, called a mutation, has stopped this copy of the FECH gene from working properly. On the other copy, there is a small change called a “low-expression allele” or a polymorphism. This alteration still affects the way the FECH gene works; it produces less ferrochelatase enzyme than normal. This small change is common in the general population, with up to 10% of Caucasians with one copy of this change. This alteration will not cause EPP by itself, and people who have the alteration on each copy of the FECH gene will NOT develop EPP. But when someone inherits the small alteration from one parent and a mutation from the other, they will develop EPP, because there will not be enough ferrochelatase (FECH) enzyme made. Most patients with EPP have the low-expression alteration on one copy of the FECH gene and a mutation on the other copy. The risk for patients with EPP to have a child who also has the condition depends on the genetic changes in their partner.

X-linked protoporphyria (XLP) is passed down through families in an X-linked manner ⁹. Males have one X chromosome and one Y chromosome, while females have two X chromosomes.This means that males have only one copy of the ALAS2 gene and females have two copies of the ALAS2 gene. When a male has a mutation is his single copy of ALAS2 gene, he is expected to have symptoms of X-linked protoporphyria (XLP). In a woman with a mutation in one of her ALAS2 genes, the second functioning copy of the ALAS2 gene can help compensate and may lead to less severe symptoms or no symptoms at all. It is not possible to predict or control the severity of X-linked protoporphyria (XLP) in females. Men with XLP pass on their X chromosome to their daughters and their Y chromosome to their sons. Therefore, a man with X-linked protoporphyria (XLP) with pass on his genetic change to all his daughters, and none of his sons. For a female with XLP, she will pass on the X chromosome with the genetic change 50% of the time. Thus, in each pregnancy, there is a 50% chance of having a child with a mutation in ALAS2 gene.

Genetic counseling is recommended for affected individuals and their families.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://findageneticcounselor.nsgc.org) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://abgc.learningbuilder.com/Search/Public/MemberRole/Verification) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (https://www.acmg.net/ACMG/Directories.aspx) has a searchable database of medical genetics clinic services in the United States.

Figure 6. Erythropoietic protoporphyria (EPP) autosomal recessive inheritance pattern

Figure 7. X-linked protoporphyria (XLP) inheritance pattern

Erythropoietic protoporphyria signs and symptoms

The most common symptom of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) is severe pain on sun exposure also called phototoxicity. Some patients may also be sensitive to some types of artificial light such as fluorescent lights. When the skin is exposed to sun, people with erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) first develop tingling, itching, and/or burning of the skin ⁹. These symptoms serve as warning signs as longer exposure can result in severe pain. Affected individuals may also have an abnormal accumulation of body fluid under affected areas (edema) and/or persistent redness or inflammation of the skin (erythema) ⁹. In rare cases, affected areas of the skin may develop sac-like lesions (blisters) and scar if exposure to sunlight is prolonged ⁹. However, scarring and/or discoloring of the skin is uncommon and rarely severe ⁹. The affected areas of skin may become abnormally thick.

The severity and degree of symptoms is different from case to case. Some patients may only be able to tolerate a few minutes of sun exposure while others may be able to tolerate longer sun exposure without symptoms. The amount of sun tolerated may also be different based on weather conditions. Symptoms are often seen during infancy; however, in some cases, it may not occur until adolescence or rarely in adulthood.

Symptoms usually start in childhood but diagnosis is often delayed since skin blistering is not common and because the porphyrins are insoluble, they cannot be detected on urine analysis.

In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, gallstones can cause obstruction and/or inflammation of the gallbladder (cholecystitis).

Patients with EPP and XLP may also have mild anemia (low blood counts). In many cases, this may be due to low iron stores. They may also have high levels of liver enzymes on blood tests.

Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring liver transplantation. As liver transplantation does not cure erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP), a bone marrow transplant following liver transplant may be necessary in some cases ⁹.

Liver involvement

Patients with erythropoietic protoporphyria (EPP) may also have liver disease that require specialist medical treatment and possibly liver transplantation. Liver disease develops in association with erythropoietic protoporphyria (EPP) in 1 to 4% of cases ²⁸, ³², with usual features of visceral enlargement and portal hypertension. Liver disease in protoporphyria is related to the excess protoporphyrin cleared by the entero-hepatic circulation leading to paracrystalin protoporphyrin deposition in liver cells (hepatocytes) and precipitation in the biliary canaliculiy. The percentage of patients who will develop liver disease is not established, nor specific factors that may influence its development. In EPP, the degree of severity of the liver disease is variable. Liver disease in EPP may include: gallstones (cholelithiasis) with possible obstructive episodes and chronic liver disease evolving to rapid acute liver failure ⁴⁷, ⁴⁸.

The incidence of gallstones (cholelithiasis) is frequent in about 20% of EPP patients EPP ⁶. Gallstones with high protoporphyrin content are generated due to the accumulation of insoluble protoporphyrin and increased biliary protoporphyrin concentration ⁴⁹.

It is not possible to predict whether or not acute liver failure will occur. Studies have revealed that an increase in coproporphyrin urinary excretion, together with a change in isomer predominance from isomer III to isomer I, and increasing levels of protoporphyrinaemia may precede this complication ⁵⁰.

Progression of protoporphyric liver deterioration leads to splenomegaly, splenic sequestration of erythrocytes with haemolysis (which increases erythropoiesis) and protoporphyrin generation ending in fulminant liver failure ⁴⁷, ⁵⁰, ⁵¹.

Erythropoietic protoporphyria complications

The main serious complication associated with EPP is protoporphyrin-related liver disease, which may be fatal ⁸. In the later stages of liver disease, the patient may develop peripheral nerve damage (neuropathy), which mimics the peripheral neuropathy of acute porphyria and may lead to breathing failure ⁸. On repeated exposure to sunlight, the skin over the face, dorsum of hands (knuckles), can become thickened or lichenified along with loss of lunulae of fingernails. Due to regular sunlight avoidance, patients with EPP are more prone to develop a vitamin-D deficiency, which can lead to osteoporosis ¹⁸.

Erythropoietic protoporphyria diagnosis

The diagnosis of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) may be made by a thorough clinical evaluation, and specialized laboratory tests. EPP and XLP are usually diagnosed during infancy or early childhood, due to characteristic symptoms, and by testing the red blood cells (erythrocytes) for increased levels of protoporphyrin. The blood needs to be sent for porphyrin analysis in a tube protected from light with aluminium foil. Exposure of the blood tube to light can lead to photobleaching of PPIX, resulting in a decrease in measured PPIX levels in the sample as compared to the actual levels in the subject. This effect is related to the ability of conjugated double bonds in the porphyrin rings to absorb the energy from visible light ³⁶. To avoid diagnostic delay, plasma porphyrins should be measured at the same time with erythrocyte protoporphyrin ³⁷.

The normal total protoporphyrin level in red blood cells (erythrocytes) is 80 mcg/dL, but in a patient with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), protoporphyrin level in red blood cells (erythrocytes) is elevated up to 300 to 8000 mcg/dL ⁸. There is an increased percentage of red blood cell (erythrocyte) metal-free protoporphyrin rather than zinc protoporphyrin ⁸. In patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP), the urinary porphyrin levels are normal.

Genetic testing of the FECH and ALAS2 genes is useful to confirm the diagnosis and identify if it is EPP or XLP ⁴³. This information is useful for genetic counseling and testing family members as both are inherited in a different manner. Genetic counseling is recommended for couples with a personal or family history of protoporphyria who are planning to have children.

Figure 8. Erythropoietic protoporphyria diagnostic algorithm

Abbreviations: ADP = aminolevulinic acid dehydratase porphyria; AIP = acute intermittent porphyria; ALA = aminolevulinic acid; HCP = hereditary coproporphyria; HMBS = hydroxymethylbilane synthase; PBG = porphobilinogen; VP = variegate porphyria.

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Pitfalls of testing

The biochemical diagnosis of protoporphyrias is based on the measurement of red blood cell (erythrocyte) total and metal-free protoporphyrin ³. The latter comprises 85% to 100% of total red blood cell (erythrocyte) protoporphyrin in EPP, and 50% to 85% in XLP ⁵², ³⁴. Zinc protoporphyrin predominates in other conditions that increase red blood cell (erythrocyte) protoporphyrin. Plasma and fecal porphyrin levels can be variably increased, and urine porphyrin levels are normal. Genetic testing is recommended to distinguish between EPP and XLP and to confirm the diagnosis ⁵².

Measurement of red blood cell (erythrocyte) protoporphyrin levels is fraught with a lack of standardized nomenclature and methodology ⁵³. Some large commercial laboratories measure protoporphyrin by hematofluorometry, a method that only measures zinc protoporphyrin and that was developed to screen for lead poisoning and iron deficiency. Hematofluorometers report the molar ratio of zinc protoporphyrin to heme by fluorescence but do not measure total or metal-free protoporphyrin ³⁴. Nevertheless, these major laboratories report “free erythrocyte protoporphyrin” (FEP) levels that, in actuality, reflect only zinc protoporphyrin, which may not be increased in EPP. This inappropriate method and inaccurate terminology propagates confusion that can lead to missed diagnoses of protoporphyria ⁵³. Accurate testing reports should only refer to erythrocyte total protoporphyrin, zinc protoporphyrin, and metal-free protoporphyrin, and comment whether the results are consistent with protoporphyria. The term FEP became unclear after the discovery of zinc protoporphyrin in erythrocytes in the 1970s and should no longer be used ³.

High performance liquid chromatography or extraction methods that measure total, metal-free, and zinc protoporphyrin are recommended for the diagnosis of protoporphyria ³⁴. Current lists of laboratories that perform such testing can be found on websites for the United Porphyrias Association, the European Porphyria Network, and the American Porphyria Foundation. These laboratories can also give advice regarding the optimal laboratory testing or differential diagnosis of biochemical abnormalities. As sample materials and pre‐analytical specifications depend on the specific diagnostic methods, it is advisable to contact the respective laboratory prior to sample collection.

Erythropoietic protoporphyria differential diagnosis

Erythropoietic protoporphyria differential diagnosis include ⁸:

• Phototoxic drug reaction: Phototoxic drug reaction is a non-immunologic skin reaction that appears acutely within minutes to hours on sun-exposed skin after taking photosensitising medications. There must be a history of the introduction of any new drug. Phototoxic skin damage begins when the drug or its metabolite within the skin absorbs ultraviolet radiation (UVR) or visible light. Patients experience painful reddish skin immediately after sun exposure ⁵⁴, ⁵⁵.
• Hydroa vacciniforme: Hydroa vacciniforme is one of the rarest forms of photosensitivity dermatoses. Hydroa vacciniforme affects sun-exposed skin and is characterized by recurrent fluid-filled blisters (‘hydroa’) over sun-exposed sites that heal with pox-like (‘vacciniform’) scars ⁵⁶.
• Solar urticaria: Solar urticaria is a condition in which exposure to sunlight or an artificial light source emitting ultraviolet radiation causes urticaria ⁵⁷. Like EPP, symptoms often develop within minutes. Symptoms of solar urticaria are often itchy rather than painful. The reaction may subside within a few minutes or it may persist for up to an hour or more where it can become very disabling. The cause of solar urticaria is not clearly defined but may be due to an antigen-antibody reaction ⁵⁷. It seems that a chemical created in the body (a photoallergen) reacts with UV radiation to cause an allergic reaction that manifests as urticaria.
• Polymorphic light eruption (PMLE): Polymorphic light eruption also called a sun allergy or sun poisoning. Polymorphic light eruption is a common seasonal, acquired, idiopathic photodermatosis occurring in spring and early summer that typically occurs during the first three decades of life ⁵⁸. Symptoms occur in sun-exposed areas. Patients present with discrete lesions such as pruritic papules, vesicles, or plaques on sun-exposed areas.
• Discoid lupus erythematosus: It presents as scaly erythematous plaques on sun-exposed areas.
• Sunburn: It is a transient inflammatory skin response to ultraviolet radiation from sunlight or artificial sources. Sunburn can occur in individuals without an underlying dermatologic condition, with sensitivity depending on the degree of skin pigmentation and hair and eye color ⁵⁹.

Erythropoietic protoporphyria treatment

There is no cure for erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Lifelong photosensitivity is the main problem. To reduce pain, avoid unnecessary exposure to sunlight will be of benefit to individuals with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). The use of sun protective clothing such as long sleeves, wide-brimmed hats, and sunglasses will also benefit individuals with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Tanning creams which increase skin pigmentation or sunscreens which contain physical reflecting agents such as zinc oxide or titanium dioxide that reflect visible light may be beneficial to some patients. Individuals with EPP and XLP may also benefit from window tinting or using films to cover the windows in their car or house. Other sources of light may also cause symptoms, including fluorescent and halogen lights. Protect the skin from exposure to operating visible light and ultraviolet A (UVA) light during a surgical procedure. Light filters that limit transmission of the wavelengths 340–470 nm (i.e., acrylate yellow filter) are recommended and should be used in operating rooms to protect the patient, especially in case of long surgical procedures like liver transplantation in a patient with erythropoietic protoporphyria (EPP) or X-linked protoporphyria (XLP) ⁶⁰, ⁶¹, ⁶². No specific anesthetic agents or other medications are contraindicated in protoporphyria.

Vitamin D supplementation to prevent vitamin D deficiency is appropriate in erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) patients that strictly avoid exposure to sunlight.

Avoidance of alcohol is important to reduce the risk of liver damage and liver failure. A drug called Prevalite (cholestyramine) or activated charcoal maybe prescribed to interrupt the circulation of protoporphyrin through the liver and intestines in patients with liver disease.

Once the pain has started, pain relief can be difficult to achieve. Most patients immerse the affected areas in cold water or use ice packs. Topical anesthetic creams can be helpful.

In 2019, the Food and Drug Administration (FDA) approved Scenesse (afamelanotide) for the treatment of adult patients with EPP. Scenesse (afamelanotide) is an alpha-melanocyte stimulating hormone that is given by subcutaneous implantation and works by increasing skin pigmentation which provides protection and improves sun tolerance ¹⁰. Afamelanotide binds to the melanocortin-1 receptor (MC1R) and increases eumelanin production from dermal cells and melanocytes, thus increasing pigmentation and providing photoprotection. Melanin is additionally a strong antioxidant thought to inactivate the reactive oxygen species (ROS) produced during phototoxic reactions ⁶³. In the setting of erythropoietic protoporphyria (EPP), melanin production may provide defense against oxidative stress by neutralizing free radicals and the reactive oxygen species produced, thus helping decrease symptom severity ⁶⁴ Scenesse (afamelanotide) was available in Europe for a period of time before its approval in the United States. There is no data on the safety of Scenesse (afamelanotide) during pregnancy so this cannot be recommended for pregnant women.

Iron supplementation should be avoided unless severe iron deficiency is present — as iron can increase photosensitivity in EPP. Both clinical improvement and increased photosensitivity have been reported during iron replacement therapy ⁶⁵, ⁶⁶, ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹, ⁷², ⁷³, ⁷⁴.

• Iron deficiency in ferrochelatase-deficient EPP:  If symptomatic from iron deficiency and/or have hemoglobin levels <10g/dL and ferritin <10ug/L. Iron supplementation to a goal ferritin of 50–100ug/L
• Iron deficiency in XLP: If any iron deficiency: Oral iron to a goal ferritin of 50–100 ug/L

Trials of treatment for erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) have been difficult to assess. Effective treatment should reduce pain and increase time outdoors without pain.

• Narrowband UVB phototherapy does not cause the EPP pain. It is given 3 days a week over 6 weeks in Spring. It increases melanin content (causing a tan) and induces skin thickening so to provide some level of protection from the sun.
• Oral antioxidants such as beta-carotene, Polypodium leucotomas extract, warfarin and N-acetyl cysteine have been used but studies showing effectiveness are lacking. In EPP, a high potency form of oral Lumitene (oral beta-carotene) 120-180 mg/dL has been used to improve an affected individual’s tolerance of sunlight. The dose of Lumitene depends on age, ranging from two to ten 30-mg capsules per day and usually started six to eight weeks before summer. While some patients report improvement, recent studies show that there is no data to support the benefit of this treatment ⁷⁵.

In addition, individuals with high levels of protoporphyrin in the plasma and red blood cells should be observed closely by a physician for possible liver malfunction that could eventually lead to liver failure.

Liver transplantation has been performed as a life-saving measure in patients with EPP and XLP related liver failure. Bone marrow transplant can also be performed after liver transplant to prevent further damage to the liver.

EPP and XLP patients should also receive vaccination against hepatitis A and B to prevent other causes of liver damage.

Patients should be seen at least yearly to monitor protoporphyrin levels, anemia, liver enzymes, iron and vitamin D levels.

Other treatment is symptomatic and supportive.

Liver disease treatment

Some affected individuals develop severe liver complications that are difficult to treat, often requiring liver transplantation ²⁵. Liver complications may be accompanied by motor neuropathy.

Rapidly progressive and severe liver disease can be treated with a regimen that includes intravenous hemin (to reduce plasma porphyrin level), plasmapheresis, ursodeoxycholic acid, cholestyramine, vitamin-E (400IU), and correction of anemia ⁸, ⁷⁶. Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement ⁷⁷.

Liver transplantation is the treatment choice for severe protoporphyric liver damage or for patients who develop liver cirrhosis as a life-saving measure in individuals with severe protoporphyric liver disease ⁷⁸, ⁷⁹, ⁸⁰. However, liver transplant recipients may experience a recurrence of protoporphyric liver disease in the transplanted liver. Combined bone marrow and liver transplantation is indicated in patients with liver failure to prevent future damage to the allografts ⁸¹.

Bone marrow transplant is a newer treatment that may be done in conjunction with liver transplantation to prevent the recurrence of EPP, and reports show that it may be able to reverse or treat both photosensitivity and protoporphyric hepatopathy ⁸², ⁸³. The presumed mechanism is related to a majority of heme synthesis in the bone marrow, thus allowing for a possibility of curative treatment in some case reports, particularly as some case reports show recurrence of erythropoietic protoporphyria activity leading to fatal outcomes rapidly ⁸⁴, ⁸³, ⁸⁵.

Erythropoietic protoporphyria prognosis

Erythropoietic protoporphyria (EPP) is a lifelong disease. Liver damage is the major risk, so regular liver follow-up is important. Up to 5% of affected individuals may develop more advanced liver disease, most notably cholestatic liver failure ⁸⁶, ⁴⁶. In most of these individuals, underlying liver cirrhosis is already present; however, some may present with rapidly progressive cholestatic liver failure ⁴⁶.

Life expectancy is usually normal in patients with EPP unless liver damage develops due to hepatotoxic effects of protoporphyrins that lead to liver dysfunction. EPP generally does not decrease life expectancy but does have a great influence on the quality of life. Since the pain after photosensitivity is intense and acute, it is necessary for the patient to modify lifestyle and employment ⁸⁷.

Annual assessment of red blood cell (erythrocyte) protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile including iron, total iron binding capacity (TIBC), and ferritin is appropriate.

Liver function test including aspartate aminotransferase (AST), alanine aminotransferase (AST), total bilirubin, alkaline phosphatase (ALP) should be monitored every 6 to 12 months. Liver imaging studies including abdominal ultrasound are indicated if gallstones (cholelithiasis) is suspected.

Vitamin D 25-OH levels should be monitored in all patients whether or not they are receiving supplements.

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