Erythropoietic protoporphyria and X-linked protoporphyria

INTRODUCTION — Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria characterized by painful, nonblistering photosensitivity usually first noted in early childhood and occurring acutely after sunlight exposure but leaving little residual skin damage. The cutaneous phenotype can result from altered activity of one of two enzymes in the heme biosynthetic pathway, either a deficiency of ferrochelatase (FECH), which causes EPP; or a gain-of-function mutation of the erythroid-specific form of delta-aminolevulinic acid synthase (ALAS2), which causes X-linked protoporphyria (XLP). An acquired, adult-onset form of EPP has also been described, in which a clone of cells with a pathogenic variant in the FECH gene expands in the setting of a myeloproliferative or myelodysplastic syndrome. The term "protoporphyria" includes both EPP and XLP.

The pathogenesis, clinical features, and treatment of EPP and XLP will be discussed here.

Other cutaneous porphyrias, as well as a general overview, are presented separately:

●Overview – (See "Porphyrias: An overview".)

●PCT and HEP diagnosis – (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)

●PCT and HEP management – (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis".)

●CEP – (See "Congenital erythropoietic porphyria".)

●HCP – (See "Hereditary coproporphyria".)

●VP – (See "Variegate porphyria".)

PATHOGENESIS — EPP and XLP result from accumulations of protoporphyrin, initially in the bone marrow, and then in erythrocytes and plasma, leading to nonblistering cutaneous photosensitivity.

Genetics — The characteristic protoporphyria phenotype can be due either to loss-of-function mutations in the gene for ferrochelatase (FECH), causing EPP, or, less commonly, to gain-of-function mutations in the gene for the erythroid form of delta-aminolevulinic acid synthase (ALAS2), causing XLP (figure 1) [1,2].

FECH catalyzes insertion of iron into protoporphyrin to form heme, and zinc insertion into most of the remaining small amount of protoporphyrin. (See "Porphyrias: An overview", section on 'Enzymes and intermediates'.)

●In most protoporphyria families, the disease is EPP (OMIM #177000) and is due to a pathogenic variant in the FECH gene, which encodes the final enzyme in the heme biosynthetic pathway, ferrochelatase (figure 1). Inheritance is autosomal recessive because biallelic loss-of-function variants are required to cause the disease.

●Less commonly, the clinical phenotype can occur with gain-of-function mutations in ALAS2, which encodes the initial enzyme of the heme biosynthetic pathway in developing red blood cells. This form of protoporphyria is termed X-linked protoporphyria (XLP) or X-linked erythropoietic protoporphyria (XLEPP; OMIM #300752) because ALAS2 is located on the X chromosome. Inheritance is X-linked.

●A case report has described EPP in a family with a pathogenic variant in CLPX, which encodes a mitochondrial chaperone that regulates the abundance of ALAS2 [3]. A dominantly acting mutation in CLPX that interfered with its ATPase activity caused ALAS2 to be stabilized and its activity increased, with overproduction of delta-aminolevulinic acid (ALA) and accumulation of protoporphyrin.

●Rarely, adults can develop new onset EPP in the setting of a myeloproliferative neoplasm or myelodysplastic syndrome, in which a clone of erythroid precursor cells carrying a pathogenic variant in FECH expands and is responsible for a significant portion of hematopoiesis [4,5].

EPP due to FECH variant — EPP results from reduction of FECH activity to less than approximately 30 percent of normal, due to loss-of-function variants affecting both FECH alleles. Most often, an allele with a severe FECH variant is paired with a common low-expression variant allele (also called a hypomorphic variant), which itself has no phenotype. Many severe loss-of-function FECH variants have been described, including missense, nonsense, and splice site mutations and deletions that lead to absent or substantially reduced enzyme activity. FECH deficiency impairs the formation of zinc protoporphyrin as well as heme synthesis in bone marrow red blood cell precursors (erythroblasts and reticulocytes); as a result, protoporphyrin accumulates mostly in its metal-free form in EPP.

●The most common molecular basis for EPP is compound heterozygosity for a severe FECH variant inherited from one parent and a hypomorphic variant, IVS3-48T/C, inherited from the other parent [6]. The IVS3-48T/C variant results in increased use of an aberrant splice site and production of an mRNA that is more prone to degradation, leading to a decreased amount of FECH enzyme. In a French study, this allele occurred in approximately 10 percent of the White individuals [7]; it is more common in Japan and China, and very rare in Africans [6-9]. This IVS3-48T/C allele does not cause clinical disease, even if homozygous.

●Rarely, EPP is due to severe variants affecting both FECH alleles; but at least one allele must be able to produce a small amount of functioning FECH enzyme [10-14].

These findings explain the inheritance of EPP due to FECH variants, which is autosomal recessive. Before the discovery of the IVS3-48T/C hypomorphic FECH variant, inheritance of EPP was generally described as autosomal dominant with incomplete penetrance. This erroneous designation occurred because severe FECH variants had been identified but the common hypomorphic FECH variant had not yet been discovered.

XLP due to ALAS2 gain-of-function mutations — XLP was recognized when some families with an EPP phenotype were noted to lack pathogenic variants in FECH, to have a higher concentration of zinc protoporphyrin in their erythrocytes relative to patients with EPP due to FECH variants, and to have an X-linked inheritance pattern. These observations led to the identification of a pathogenic variant in the only heme biosynthetic gene located on the X chromosome, the erythroid form of delta-aminolevulinic acid synthase (ALAS2) [15]. These families were classified as having XLP, also called X-linked EPP (XLEPP).

ALAS is the initial enzyme in the heme biosynthetic pathway (figure 1), and ALAS2 variants responsible for XLP cause C-terminal deletions that lead to enzymatic gain of function. ALA and downstream heme pathway intermediates are overproduced. The resulting excess protoporphyrin in bone marrow erythroblasts and reticulocytes greatly exceeds the amount needed for heme synthesis, and because FECH is not deficient, more of the excess protoporphyrin is liganded with zinc than in EPP. (See 'Erythrocyte protoporphyrin' below.)

ALAS2 is transcribed only in bone marrow erythroblasts. In contrast to the gain-of-function mutations in XLP, loss-of-function mutations of ALAS2 have been described in cases of sex-linked sideroblastic anemia. A ubiquitous (housekeeping) form of ALAS (ALAS1) is transcribed in all tissues including the liver. Naturally occurring mutations of ALAS1 have not been described. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'X-linked sideroblastic anemia (ALAS2 mutation)'.)

EPP due to CLPX mutation — In a 2017 report, a family was described with autosomal dominant protoporphyria associated with a point mutation in the CLPX gene, identified by whole exome sequencing after no pathogenic variants could be detected in FECH or ALAS2 [3]. ClpX is a mitochondrial AAA+ ATPase, and together with ClpP, forms the AAA+ protease ClpXP. Under normal conditions, ALAS2 is activated by ClpX via its unfoldase activity. A negative feedback loop is constituted by ClpP-mediated degradation of ALAS2 in response to high heme levels. The CLPX mutation inactivated the ATPase activity of the enzyme, and thereby active ALAS2 is not available to ClpP for degradation, in turn leading to an increase of ALAS2 and accumulation of ALA and protoporphyrin [16].

Protoporphyrin accumulation — The FECH enzyme exists as a homodimer in the inner mitochondrial membrane and is essential for the final step of heme formation, which is the insertion of iron into the protoporphyrin IX ring (figure 1) [17-19]. FECH also catalyzes the insertion of zinc into most of the small amount of protoporphyrin IX that normally remains after completion of heme synthesis.

Insufficient FECH activity results in excessive accumulation of protoporphyrin that lacks iron or other metals, particularly zinc (metal-free protoporphyrin). The primary source of the excess plasma and erythrocyte protoporphyrin in EPP is metal-free protoporphyrin produced by bone marrow reticulocytes. Production of protoporphyrin by the bone marrow may increase further in EPP under conditions in which erythropoiesis is stimulated, leading to further increases in plasma and erythrocyte protoporphyrin levels. The liver had been proposed as an additional source of excess protoporphyrin, but this is now considered unlikely [20].

In XLP, there is increased generation of the protoporphyrin substrate for FECH. The functioning FECH enzyme can utilize zinc to form zinc protoporphyrin. Thus, in XLP, zinc protoporphyrin makes up a greater proportion of excess protoporphyrin than seen with EPP. However, metal-free protoporphyrin predominates in most XLP cases, suggesting that the capacity of normal FECH activity to insert zinc into protoporphyrin is exceeded.

Total, metal-free, and zinc protoporphyrin are most conveniently measured in circulating erythrocytes. Plasma protoporphyrin is a separate pool, and its level may reflect both bone marrow production and liver uptake of protoporphyrin. (See 'Diagnostic evaluation' below.)

●Accumulation of metal-free protoporphyrin (>85 percent of total erythrocyte protoporphyrin) is a distinctive feature of EPP and is accounted for by FECH deficiency. In EPP, only approximately ≤15 percent of the total protoporphyrin is in the form of zinc protoporphyrin.

●Accumulation of metal-free protoporphyrin is also characteristic of XLP. However, a greater proportion of zinc protoporphyrin (approximately 15 to 50 percent of total erythrocyte protoporphyrin) is characteristic of XLP due to ALAS2 gain-of-function mutations.

●Protoporphyrin that accumulates in other erythrocyte disorders, such as iron deficiency, lead poisoning, anemia of chronic disease, and hemolytic disorders, is predominantly zinc protoporphyrin, since FECH activity is not appreciably decreased relative to the amount of available substrate (protoporphyrin) in these conditions.

Metal-free protoporphyrin in erythrocytes is bound to hemoglobin, and light irradiation may promote its release from hemoglobin (and from erythrocytes), perhaps thereby increasing plasma porphyrin levels and photosensitivity [21]. Metal-free protoporphyrin diffuses from circulating erythrocytes into plasma more readily than does zinc protoporphyrin, most of which remains within erythrocytes for their full life span [22]. It is also likely that bone marrow reticulocytes contribute protoporphyrin directly to the plasma pool.

As a result of diffusion of metal-free porphyrin from erythrocytes as they age, the total protoporphyrin content of erythrocytes declines with increasing red blood cell age in EPP, and "fluorocytes" seen on peripheral blood smears by fluorescence microscopy are younger erythrocytes that contain large amounts of metal-free protoporphyrin [1,22-24].

The excess protoporphyrin in plasma in EPP and XLP is bound to albumin and is taken up by the liver for secretion into bile, which is the only mechanism for removing this water-insoluble dicarboxyl porphyrin from the body (table 1) [21,23,25]. After entering the small intestine, some protoporphyrin may be absorbed and undergo enterohepatic circulation.

Iron in EPP and XLP — Patients with EPP or XLP often have borderline iron deficiency, and it has been suggested that the excess protoporphyrin in EPP may downregulate iron absorption or lead to a redistribution of iron stores [26-28]. Although iron absorption was considered to be impaired [26,27], elemental iron absorption has been found to be normal and hepcidin levels appropriately low in these patients. For example, a study that assessed iron absorption in eight individuals with EPP compared with nine controls did not find evidence for impaired iron absorption or increased hepcidin levels in the individuals with EPP [29].

Preclinical studies suggest that iron status may modulate porphyrin accumulation in EPP and XLP. As an example, iron is important for formation of the non-catalytic iron-sulfur cluster in FECH and may thereby enhance post-translational stability of the FECH protein [30]. Consequently, iron deficiency might further impair FECH stability. Furthermore, because iron is a substrate for FECH, its deficiency in EPP might, as in other iron deficiency states, might increase protoporphyrin accumulation. Conversely, however, iron can upregulate ALAS2 and might increase protoporphyrin production [31]. Therefore, it is unclear whether iron deficiency is harmful or beneficial in patients with EPP or XLP. (See 'Iron' below.)

Effects on skin — Protoporphyrin is hydrophobic and deposited in lipid layers such as cell membranes; therefore, its tissue and subcellular distribution may differ from the hydrophilic porphyrins that accumulate and cause blistering manifestations in other cutaneous porphyrias [32].

Porphyrins are photoactive and absorb light and enter an excited energy state, also known as a triplet form [33]. They can then transfer energy to dissolved oxygen to form the superoxide ion (O₂^-), which in turn can form hydroxyl ions (OH^-). These highly oxidizing species of oxygen can interact with many biological molecules, such as proteins, lipids, and DNA, and can form adducts with carbon-carbon double bonds [32,34,35]. Porphyrins absorb wavelengths of light especially in the 400 to 420 nm range (ie, the Soret peak for porphyrins), which is in the visible light range and close to the range of long wavelength ultraviolet light (ie, UVA; range 315 to 400 nm). Patients with EPP and other cutaneous porphyrias are sensitive to sunlight and to some extent fluorescent and even incandescent indoor lights. Window glass transmits this light (but not short wave ultraviolet light [ie, UVB]) and therefore is not protective. Porphyrin photoreactivity causes tissue damage through lipid peroxidation, oxidation of nucleic acids and polypeptides, complement activation, and mast cell degranulation [34,36-39].

Liver damage — As noted below, hepatopathy is a rare but potentially severe complication of EPP, affecting fewer than 5 percent of patients. (See 'Liver disease' below.)

It is not clear what predisposes some patients and not others to develop hepatopathy. In some cases, protoporphyric hepatopathy was precipitated by another cause of liver disease, such as excess alcohol consumption or viral hepatitis [40,41]. Iron deficiency might also contribute by impairing the conversion of protoporphyrin to heme in the bone marrow, resulting in increasing amounts of protoporphyrin circulating to the liver. However, this possibility has not been well studied.

When it does occur, hepatopathy results from accumulation of protoporphyrin in the liver in amounts that are damaging to hepatocytes and cholangiocytes [42]. This results in reduced biliary excretion of protoporphyrin and a progressive further buildup of protoporphyrin in the liver, plasma, and erythrocytes. Protoporphyrin has been shown to be cholestatic in an animal model [43]. Hepatopathy develops in association with a severe FECH mutation and also in patients with ALAS2 mutations, but no clear relationship to specific mutations has been found [44,45]. In a mouse model with inherited FECH deficiency, the development of hepatopathy is influenced by genetic background, but important modifier genes have not been identified [46]. Studies in a mouse model of EPP have shown that a deficiency of the protoporphyrin transported ABCG2 protects against development of liver damage and suggests that protoporphyrin is especially damaging to cholangiocytes [47].

As liver damage and impaired biliary excretion progress, protoporphyrin levels in plasma, erythrocytes, and liver increase further, causing more severe photosensitivity and further liver damage [48]. Erythrocyte survival is reduced by splenic enlargement, which may stimulate erythropoiesis and further increases in marrow protoporphyrin overproduction [10,49]. A vicious cycle results from worsening hepatopathy and increased protoporphyrin production and retention.

EPIDEMIOLOGY — EPP was first comprehensively described in 1961 [50]. Since this initial description, EPP has been reported worldwide [51,52]. It is now recognized as the most common porphyria in children and the third most common in adults, after porphyria cutanea tarda (PCT) and acute intermittent porphyria (AIP) [53].

The incidence is similar in males and females.

Prevalence estimates for the general population based on surveys have ranged from 1:75,000 in the Netherlands to 1:200,000 in Wales [54,55]. A UK Biobank study of FECH variants suggests that EPP is more underrecognized than previously thought (prevalence, 1 in 17,000) [56].

EPP is very rare in Africa and is more common in East Asian countries than in European and North American countries, related to differing prevalence of the common hypomorphic FECH allele in individuals living in these regions. (See 'EPP due to FECH variant' above.)

XLP was initially described as a variant form of EPP without pathogenic variants in FECH and was characterized genetically in 2008; XLP comprises up to 10 percent of those with the protoporphyria phenotype [15,57].

CLINICAL FEATURES

Overview of clinical features — EPP and XLP typically present in early childhood with painful photosensitivity, although the cause of the photosensitivity these patients experience is often overlooked until later in life. In a review of over 100 cases in the United States, the average age of presentation was under four years [53]. Presentation is similar in males and females.

Children may be misdiagnosed as having an allergic reaction or primary angioedema. (See 'Differential diagnosis' below.)

In a large series from the United Kingdom (UK), the median ages at onset and diagnosis were 1 and 12 years, respectively [58]. In the review of over 100 cases in the United States, the average delay between presenting symptoms and ultimate diagnosis of EPP was 13 years [53]. Nearly 40 percent had seen at least five clinicians before the diagnosis was made; 22 percent had seen more than 10 clinicians.

The predominant clinical manifestation in EPP and XLP is painful, nonblistering cutaneous photosensitivity that differs distinctly from the chronic, blistering skin manifestations of the other cutaneous porphyrias. (See 'Skin findings' below.)

Hepatobiliary complications include protoporphyrin-containing gallstones and, in less than 5 percent of cases, severe liver failure. (See 'Hepatobiliary manifestations' below.)

Many patients with EPP will have normal results on routine laboratory testing, with the possible exception of mild hypochromic microcytic anemia, accompanied by low serum ferritin and low transferrin saturation. (See 'Anemia' below.)

The defining laboratory manifestation of EPP is a marked elevation of total erythrocyte protoporphyrin that is mostly metal-free (85 to 100 percent metal-free protoporphyrin); the defining finding in XLP is marked elevation of total erythrocyte protoporphyrin that is approximately 50 to 85 percent metal-free protoporphyrin. (See 'Diagnostic evaluation' below.)

Skin findings — In most cases, photosensitivity is first experienced in infancy or early childhood [50,51,58,59]. Patients report that shortly after exposure to sunlight (often within minutes) they develop severe pain, described as burning, stinging, tingling, or a pricking sensation that may be accompanied or followed by redness, swelling, or blanching, lasting from minutes to days (table 2). Papulovesicles may form with prolonged exposure. In one case series, the median time to onset of symptoms and signs (swelling, redness) following sun exposure was 20 minutes, and the median time to resolution of well-developed symptoms was three days [58]. In addition to sunlight, including sunlight passing through window glass or a car windshield, symptoms can also be elicited by non-sun exposures such as fluorescent lights and operating room lights.

When these symptoms resolve, there is little or no residual scarring. Patients with EPP learn to avoid sunlight and only rarely present to clinicians with findings such as edema, petechiae, telangiectasia, and scarring (picture 1 and picture 2). Therefore, physical findings on examination are usually absent, or there may be subtle findings such as cobblestone-like thickening or lichenification of the skin on the backs of the hands, especially over the knuckles, and the face, or a waxy or leathery texture, along with loss of lunulae of fingernails, petechiae, ecchymoses and minor scarring on the face and vertical grooving of the lips [60-62]. These changes develop due to repeated exposure to light and generally are seen in patients who experience more sun exposure (often children). Bullae, vesicles, and crusts, which are frequent in porphyria cutanea tarda (PCT), are uncommon in EPP [42].

Variation in the severity of symptoms among different individuals relates in part to levels of erythrocyte protoporphyrin (see 'Erythrocyte protoporphyrin' below) and also inherent differences in pigmentation (Fitzpatrick skin type). Symptoms change little with age. Unexplained decreases in porphyrin levels and symptoms may occur during pregnancy [58]. Variations in skin manifestations over time are primarily related to the degree of sun exposure (eg, milder symptoms in winter). Priming (more pronounced symptoms after the second of two sunlight exposures) has been reported as common [58].

Hepatobiliary manifestations

Gallstones — The risk of gallstones is increased in patients with EPP and XLP; presentation is similar to patients without protoporphyria [50,63]. Gallstones were recognized in 8 percent of patients in one series [58]. Protoporphyria should be considered as a possible cause of gallstones in children [42]. Development of stones containing protoporphyrin is related to the overproduction of this water-insoluble porphyrin and its excretion exclusively in bile [64].

Liver disease — A cholestatic form of liver disease, referred to as protoporphyric hepatopathy, is the most serious complication of EPP and XLP. This complication is rare, occurring in fewer than 5 percent of patients [54,58]. Higher prevalence in some series may reflect referral bias or possibly closer monitoring and earlier detection. In contrast, most patients with uncomplicated EPP have normal liver function tests, and, although data are limited, little or no elevation in liver protoporphyrin concentration. Hepatopathy may be more likely in individuals with higher protoporphyrin levels; however, prospective data to support this impression are seldom available.

Protoporphyric hepatopathy often presents as an acutely and rapidly progressive form of liver disease with severe right upper quadrant pain, jaundice, nausea, and vomiting [63,65]. Dramatic elevations of liver function tests are seen. The abdominal pain may be mistakenly attributed to gallstones, which may be present but asymptomatic. Such patients may already have underlying chronic liver disease or cirrhosis with splenomegaly and other evidence of portal hypertension [49,66]. Severe hepatopathy may lead to the initial diagnosis of EPP in a patient with a long history of previously unexplained photosensitivity. As noted above, hepatopathy may also lead to worsening skin findings, as greater amounts of porphyrins accumulate. (See 'Liver damage' above.)

Chronic hepatopathy results in persistent elevations of liver function tests, but other causes should be excluded. The significance of mild, transient hepatic aminotransferase (transaminase) elevations is uncertain and should prompt diagnostic evaluation for other causes of liver disease.

Peripheral neuropathy — Peripheral neuropathy resembling that seen in the acute porphyrias may develop in late stages of protoporphyric hepatopathy and may progress to respiratory failure [67,68]. To our knowledge, EPP with peripheral neuropathy has been reported only once in the absence of liver failure, although the diagnosis of EPP in that case was not convincing [69]. (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Peripheral neuropathy'.)

Vitamin D deficiency and osteoporosis — Patients with EPP or XLP are predisposed to vitamin D insufficiency as a result of sun avoidance, which may lead to osteoporosis [70,71]. A Dutch study showed a high prevalence of vitamin D deficiency in individuals with EPP (46 percent); vitamin D deficiency was more common in males and correlated with severity of EPP [70]. Vitamin D supplementation is advised. (See 'Routine monitoring and interventions' below.)

Anemia — Some patients with EPP or XLP have a mild hypochromic microcytic anemia. This is often accompanied by low or borderline low serum ferritin levels and decreased transferrin saturation [72]. These features suggest the presence of iron deficiency without blood loss, and there is often an unexplained poor response to oral iron administration. (See 'Routine monitoring and interventions' below.)

Some individuals with EPP or XLP have ring sideroblasts on the iron-stained bone marrow aspirate smear, indicative of sideroblastic anemia. (See "Sideroblastic anemias: Diagnosis and management", section on 'Autosomal recessive forms'.)

Pregnancy — For unclear reasons, pregnancy may be associated with decreases in protoporphyrin levels and improvement in photosensitivity in patients with EPP or XLP [58,73,74]. This was demonstrated in a series of 32 pregnancies in 19 Swedish women with EPP; photosensitivity during pregnancy was reduced, unchanged, or increased in 53, 44, and 3 percent, respectively [75]. The postpartum period was associated with reduced photosensitivity in one-third and no change in two-thirds. All newborns were healthy, with one later diagnosis of EPP.

DIAGNOSTIC EVALUATION

When to suspect — Delays in diagnosis are especially concerning in EPP and XLP; these delays may be greater than with any other type of porphyria [58]. (See 'Overview of clinical features' above.)

The index of suspicion for EPP and XLP is often low because there are many causes of photosensitivity (table 2). Moreover, in contrast to other cutaneous porphyrias, skin findings are usually minimal and transient. Delay may also result from measuring urine porphyrins (which are not elevated) rather than total erythrocyte protoporphyrin.

Abnormal liver chemistries may also be due to other more common liver diseases such as steatohepatitis rather than protoporphyric hepatopathy.

The diagnosis of protoporphyria (EPP or XLP) should be considered in any patient with photosensitivity that is primarily acute and nonblistering. The diagnosis is readily established or excluded by measurement of total erythrocyte protoporphyrin followed by fractionation, if elevated. Proper diagnosis provides an explanation for years of unexplained pain and decreased quality of life. The ease of diagnosis and favorable impact of appropriate diagnosis and genetic counseling make the importance of considering the diagnosis of EPP and XLP especially compelling.

Erythrocyte protoporphyrin — As with other porphyrias, our approach to diagnosis is to perform a sensitive screening test first, in this case total erythrocyte protoporphyrin, followed by fractionation (into metal-free and zinc protoporphyrin) using the same sample if the initial result is positive (algorithm 1). If biochemical testing confirms the diagnosis of EPP or XLP, we measure plasma porphyrins and perform genetic testing in all patients.

Urinary and fecal porphyrin testing is not required in the evaluation for EPP or XLP. If done, total porphyrins in feces may be normal or modestly increased, and consist mostly of protoporphyrin (table 1). Urinary porphyrins, delta-aminolevulinic acid (ALA), and porphobilinogen (PBG) are normal, with the exception of patients with protoporphyric hepatopathy, in whom urinary porphyrins, especially coproporphyrin, may be increased, as occurs in liver disease from any cause.

Normal range and fractionation — The normal range for total erythrocyte protoporphyrin is up to approximately 80 mcg/dL. The most reliable assays extract and measure all erythrocyte porphyrins fluorometrically and express the total as protoporphyrin. Erythrocyte porphyrins in health and disease are almost entirely protoporphyrin, with the exception of patients with congenital erythropoietic porphyria (see "Congenital erythropoietic porphyria"). The upper limit of normal varies with age and among laboratories, but this is not problematic for diagnosis of EPP or XLP because values in these patients are markedly elevated, to approximately 300 to 8000 mcg/dL (table 3).

If total erythrocyte protoporphyrin is elevated, it is essential to fractionate the total and report the proportions of zinc protoporphyrin and metal-free protoporphyrin. An increase in total erythrocyte protoporphyrin is a nonspecific finding that can occur in many conditions, including iron deficiency, lead poisoning, anemia of chronic disease, and hemolytic disorders [76,77]. However, in conditions other than EPP and XLP, the excess is mostly zinc protoporphyrin, whereas in EPP and most cases of XLP, it is predominantly metal-free protoporphyrin. In some XLP cases, the proportion of zinc protoporphyrin may exceed metal-free protoporphyrin [78]; in such cases, other causes of increased erythrocyte zinc protoporphyrin should be excluded and ALAS2 gene sequencing relied upon for diagnosis of XLP. (See 'Molecular/genetic testing' below.)

●EPP – In EPP due to pathogenic variants in FECH, the excess protoporphyrin in erythrocytes is almost always >85 percent metal-free protoporphyrin and <15 percent zinc protoporphyrin.

●XLP – In XLP due to ALAS2 gain-of-function mutations, a predominance of metal-free protoporphyrin is typically seen as well, but the proportion of zinc protoporphyrin is often as high as 15 to 50 percent or greater. This greater abundance of zinc protoporphyrin can almost always differentiate XLP from EPP, but confirmation by DNA studies is strongly advised.

Selecting a testing laboratory — Confusion among laboratories about terminology and methods for measuring erythrocyte porphyrins can complicate testing for EPP and XLP [79]. This occurs because some major laboratories that do not focus on diagnosis of protoporphyrias use a particular fluorescence instrument (hematofluorometer) for measuring erythrocyte protoporphyrin that was originally developed for screening for lead poisoning and is tuned to measure only zinc protoporphyrin; however, these laboratories may incorrectly report the results as "erythrocyte protoporphyrin" (implying that total erythrocyte protoporphyrin was measured) or "free erythrocyte protoporphyrin" (implying metal-free protoporphyrin but in fact signifying protoporphyrin free of iron but not zinc). Therefore, one must select a laboratory that measures total erythrocyte protoporphyrin and can then fractionate metal-free and zinc protoporphyrin.

Certified laboratories that can perform this fractionation include:

●United States – The University of Texas Medical Branch (UTMB) Health Porphyria Center and Mayo Clinic Laboratories [80-82].

●Europe – Appropriate laboratories at specialist centers in Europe can be accessed through the website of the European Porphyria Network (EPNET).

Plasma porphyrins — The total plasma porphyrin concentration is elevated in most patients with EPP and XLP, but less so than in other cutaneous porphyrias, and it may be normal in milder cases. In addition, plasma porphyrins in EPP and XLP are especially sensitive to light and may degrade rapidly during sample processing [83]. Therefore, plasma porphyrin measurement should not be used alone as an initial screening test for protoporphyria.

Fluorescence scanning of plasma is performed in addition to measurement of plasma porphyrins; it can be performed on the same plasma sample. In EPP or XLP, the fluorescence of plasma (diluted at neutral pH) shows a peak at a wavelength of approximately 634 nm. However, this may be absent in mild cases. This fluorescence peak near 634 nm differs from other porphyrias (eg, peak near 626 nm in variegate porphyria [VP], peak near 620 nm in porphyria cutanea tarda [PCT] and congenital erythropoietic porphyria [CEP]) (table 3) [54].

In individuals with EPP and XLP, plasma porphyrin levels correlate roughly with the levels of total erythrocyte protoporphyrin. The latter is believed to remain fairly constant throughout life. Limited longitudinal data suggest that variations in total erythrocyte protoporphyrin of approximately 25 percent over time may not be of concern; plasma protoporphyrin levels are much more variable [84]. This is likely to be because the plasma pool of protoporphyrin turns over more rapidly. Plasma porphyrin is also likely to be the source of protoporphyrin uptake by the liver. Therefore, a higher plasma level may indicate a greater risk for hepatic complications. (See 'Hepatobiliary manifestations' above.)

Diagnosis — The diagnosis of protoporphyria (EPP and XLP) is made by demonstrating both of the following (table 4 and algorithm 1):

●Increased total erythrocyte protoporphyrin (usually 300 to 8000 mcg/dL; normal <80 mcg/dL)

●Increased percentage of erythrocyte metal-free protoporphyrin rather than zinc protoporphyrin

In EPP, metal-free protoporphyrin generally represents >85 percent of total porphyrins. In XLP, metal-free protoporphyrin generally represents 50 to 85 percent of total porphyrins.

Measurement of erythrocyte total protoporphyrin rather than molecular testing is advised for initial screening of patients with nonblistering photosensitivity, in part because finding the common hypomorphic FECH allele can be expected as an incidental benign finding in approximately 10 percent of individuals of European background.

Distinction between EPP and XLP using molecular (genetic) testing is not required for diagnosis or therapy, but it is important and confirmatory and should be done on all patients to characterize the disease and to inform genetic counseling and testing of family members. (See 'Molecular/genetic testing' below.)

Molecular/genetic testing — We perform genetic testing in all patients to facilitate diagnosis and genetic counseling. (See 'Diagnosis' above.)

Molecular (DNA) studies are more important in EPP and XLP than in most other porphyrias because these diseases are genetically heterogeneous, and identification of the familial disease variant(s) will both confirm the diagnosis and enable genetic counseling (table 4).

Moreover, in most families, EPP develops with a severe pathogenic variant in FECH, but only with the additional presence of a hypomorphic FECH allele that is common in the general population but itself has no phenotype. Thus, the risk for future generations depends on transmission of the severe variant as well as on carriage of the common hypomorphic allele by present and future partners.

Genetic testing for FECH mutations is widely available. Genetic counseling is appropriate especially for individuals of childbearing potential. (See 'Genetic counseling and testing of family members' below.)

Tissue biopsy — Biopsy is rarely required in the evaluation of EPP or XLP, with the exception of liver biopsy to confirm a diagnosis in some cases of protoporphyric hepatopathy and exclude other causes of liver disease. The following findings may be seen if biopsy is performed:

●Skin – In the skin, the findings may differ depending on the stage of the disease. There may be an acute inflammatory reaction may be seen microscopically with extravasation of red cells, deposition of PAS-positive material in the perivascular spaces, and proliferation of the epidermal basal membrane [37,59,85-88]. Immunohistochemistry shows deposition of immunoglobulins and complement [89]. These changes are not specific for EPP and, except for absence of subepidermal blisters, may not be distinguishable from changes seen in the other cutaneous porphyrias.

●Liver – In patients with hepatopathy, histologic damage may be mild at the early stages, but protoporphyrin content is increased in the liver at all stages of this complication [90]. With advanced disease, the liver appears black on gross examination due to marked deposition of protoporphyrin and bilirubin [48]. Histologically, there is usually micronodular cirrhosis with cholestatic features and marked deposition of protoporphyrin seen as dark brown pigment that forms inclusions that are birefringent on polarizing microscopy with a "Maltese cross" appearance [91-93]. By electron microscopy, protoporphyrin appears as crystalline deposits mainly in hepatocytes but also in Kupffer cells and bile canaliculi, accompanied by ultrastructural damage to the endoplasmic reticulum, mitochondria, and cell membrane [90,91,94-96]. There is little information on liver histology and protoporphyrin content in the majority of patients with EPP who have no abnormalities in liver function tests.

●Bone marrow – In the bone marrow, fluorescence may be seen as a result of protoporphyrin accumulation in erythroid precursors. This fluorescence is maximal in reticulocytes [7,8,69].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of EPP and XLP is extensive (table 2). Before diagnosis, which is often delayed, most individuals with EPP or XLP were regarded as having sensitivity to sunlight of unknown cause.

●Polymorphous light eruption – Polymorphous light eruption (PMLE; sometimes called "sun poisoning" or "sun allergy") is a common photodermatosis that typically occurs during the first three decades of life. Like EPP or XLP, the symptoms occur on sun-exposed areas, and family members may have similar symptoms. Unlike EPP or XLP, individuals with PMLE generally have discrete lesions such as pruritic papules, papulovesicles, or plaques, and the lesions develop later than EPP or XLP (hours to days rather than minutes); individuals with PMLE do not have elevations of total erythrocyte protoporphyrin as measured by a reliable laboratory (see 'Diagnostic evaluation' above). (See "Polymorphous light eruption".)

●Solar urticaria – Solar urticaria is a condition in which exposure to sunlight causes urticaria. Like EPP and XLP, symptoms often develop within minutes. Unlike EPP and XLP, the symptoms of solar urticaria are often pruritic rather than painful. Unlike EPP and XLP, individuals with solar urticaria do not have elevations of total erythrocyte protoporphyrin. (See "Physical (inducible) forms of urticaria", section on 'Solar urticaria'.)

●Drug-induced photosensitivity – Drug-induced photosensitivity, also called phototoxicity, results when a sensitizing agent has been ingested or applied to the skin. Like EPP or XLP, patients may have painful erythema soon after sun exposure, often within minutes. Unlike EPP or XLP, phototoxic reactions are associated with use of the photosensitizing agent, and erythrocyte protoporphyrin is not elevated. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity' and "Drug eruptions", section on 'Photosensitivity reactions'.)

●Sunburn – Sunburn 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 dependent on the degree of skin pigmentation. Like EPP or XLP, sunburn is a transient, painful, erythematous reaction that often does not cause blistering or scarring, and members of a family may have similar sensitivities. Unlike EPP or XLP, most individuals, even those who sunburn easily, do not develop symptoms upon normal daily sunlight exposure. Unlike EPP or XLP, individuals with sunburn do not have elevations of erythrocyte protoporphyrin. (See "Sunburn".)

Additional discussions of the general approach to a patient with photosensitivity are presented separately. (See "Overview of cutaneous photosensitivity: Photobiology, patient evaluation, and photoprotection" and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment".)

MANAGEMENT — There is no effective way of lowering circulating porphyrin levels in individuals with EPP or XLP. Patients learn to avoid sunlight or fluorescent light as much as possible. However, these compensatory behaviors greatly impair daily activities and quality of life. Parents and caregivers of children with EPP and XLP also learn how to protect them from sunlight exposure. This requires considerable adjustments in lifestyle and may limit educational and employment opportunities. Other forms of photoprotection and other interventions are discussed below. (See 'Photoprotection' below.)

Photoprotection

Sun and UV light avoidance — Protection from sunlight is a cornerstone of EPP management. The use of protective clothing and hats is beneficial for most patients when outdoors. Patients seek shaded areas when outdoors, and refer to themselves as "shadow jumpers."

Broad spectrum sunscreen preparations with high sun protection factor (SPF) are of some benefit. Those protective against UVB are not. As in other cutaneous porphyrias, window glass is not protective when indoors (or in a vehicle), and house and car windows should be equipped with protective tinted glass. Patients may require clinician letters for state permission to use adequately tinted glass in their automobiles. Many patients also find it necessary to avoid indoor lighting. (See "Selection of sunscreen and sun-protective measures".)

Other sources of long wave ultraviolet (UVA) and visible light such as operating room lights may also cause phototoxic reactions [97]. Protection from light during surgical procedures using light filters has been best studied in the setting of liver transplantation, which is a prolonged operation in patients with hepatopathy and particularly high porphyrin levels [98] (see 'Liver transplantation' below). Complications in patients without hepatopathy undergoing more routine surgical procedures are uncommon.

We do not use topical application of dihydroxyacetone and lawsone (naphthoquinone), because of concerns about potential adverse cosmetic effects and carcinogenic potential with long-term use [99-101].

Although avoiding light is highly beneficial in preventing symptoms of EPP and XLP, it greatly limits options for employment and prevents engagement in many pleasurable outdoor activities with family and friends, thereby substantially reducing some important life opportunities. Therefore, it is important to consider other therapies that may increase light tolerance and allow patients to have more normal lifestyles.

Afamelanotide — Afamelanotide is a synthetic analogue of alpha-melanocyte stimulating hormone (alpha-MSH), a naturally occurring hormone that increases skin pigmentation by increasing melanin production, and reduces free radical formation and cytokine production [102,103]. Afamelanotide increases sunlight tolerance in EPP and XLP, by these and possibly other mechanisms [104].

For adults with EPP or XLP, we suggest afamelanotide, unless their lifestyle and/or employment needs do not require greater sunlight tolerance. Pediatric administration has not been evaluated and pediatric dose implants are not available. Afamelanotide became available in parts of Europe in 2009 and was approved by the US Food and Drug Administration in October of 2019 [105,106].

Afamelanotide is administered as a controlled-release 16 mg implant injected subcutaneously every other month, and can be used especially during the summer months.

Evidence for the efficacy of afamelanotide includes the following:

●Two multicenter, randomized trials in individuals 18 years or older with EPP or XLP found that afamelanotide substantially reduced photosensitivity and improved sunlight tolerance [103]. In the European trial (74 patients followed for nine months), the duration of pain-free time in direct sunlight was longer with afamelanotide versus placebo (median 6.0 versus 0.8 hours) and the number of phototoxic reactions was lower in the afamelanotide group (77 versus 146). In the United States (US) trial (94 patients followed for six months) the duration of pain-free time in direct sunlight was longer in the afamelanotide group (median 69.4 versus 40.8 hours); the greater number of hours in the United States trial reflects a longer portion of the day in which sunlight tolerance was assessed. In both trials, quality of life improved with afamelanotide therapy. Some participants described this treatment as 'life changing' in terms of activities they could engage in during treatment, which previously were not possible.

●In addition, in a retrospective study of 115 individuals with EPP who received afamelanotide at one of two porphyria centers for up to six years, 74 percent found the therapy to be effective [107]. Of the remaining individuals, 23 percent had to discontinue therapy for pregnancy or financial reasons, and 3 percent found the therapy to be ineffective. The mean quality of life scores for the group rose from 32 to 74 percent during the first six months of therapy and remained high (69 to 91 percent) for the duration of the study. Melanin density also increased but was challenging to interpret due to reduced therapy during the winter and increased sun exposure with effective therapy in some patients. The most frequent reasons for drug discontinuation were financial restrictions and pregnancy. This study population represented two-thirds of all individuals with EPP at these centers.

Toxicities of afamelanotide appear to be minimal; the major adverse events are nausea and headache [103,107]. Temporary skin darkening is expected [108]. However, clinical experience is limited. European product information for afamelanotide states it is not to be used during pregnancy or in individuals with hepatic or renal impairment, as there are no long term data regarding safety [108]. Although the tanning effect makes it difficult to blind patients or clinicians completely to the treatment, improved symptoms occurred in some in the placebo groups.

Although afamelanotide improves sun tolerance, it does not affect porphyrin production or alter the underlying disease process. (See 'Protoporphyrin accumulation' above.)

A novel, orally-administered, small molecule that selectively activates melanocortin-1 receptor (MC1R) is being developed to increase skin pigmentation and light tolerance in individuals with protoporphyria, similar to afamelanotide [109].

Beta-carotene — Some patients note increased tolerance to sunlight with beta-carotene use, especially in the summer [110]. The proposed protective mechanism is quenching of oxygen free radicals by beta-carotene.

For most patients with EPP or XLP, we suggest the use of oral beta carotene. However, many patients do not find this therapy to be very beneficial, and many patients who wish to avoid the associated costs or skin discoloration elect to discontinue therapy. Some patients believe that they benefit and save on cost by taking beta-carotene mostly in spring and summer, which permits greater sunlight exposure and acquisition of a suntan that provides further sunlight protection.

Evidence supporting the efficacy of beta-carotene includes several small studies and case series [111-119]. In the largest series with 133 patients, 22 reported no effect and 111 reported moderate to substantial improvement in sunlight tolerance. A single randomized crossover trial enrolled 14 children; this showed that compared with placebo, individuals receiving beta-carotene had a small increase in time spent outdoors (equivalent to approximately 13 minutes daily) but no major difference in symptoms reported in diaries [120].

When we administer beta-carotene, we use pharmaceutical grade medication (brand name, Lumitene) developed specifically for treating EPP. It was originally available by prescription but is now available over the counter. For adults, we use oral doses of 30 to 300 mg (1 to 10 capsules) daily, and titrate to maintain serum carotene levels in the range of 600 to 800 mcg/dL or a tolerable degree of yellowish skin pigmentation, which is most prominent on the palms of the hands. Carotene levels can be assessed three to four weeks after a dose change. Doses in children are in the range of 30 to 150 mg/day (1 to 5 capsules). Capsules may be opened and the contents mixed into orange or tomato juice to aid administration. If the patient is not experiencing reduced symptoms with an adequate carotene level after three months, the therapy may be discontinued. Most individuals notice a protective effect within one to three months. High-dose beta-carotene supplementation may increase the risk of lung cancer among current smokers [121].

Plasma and erythrocyte protoporphyrin levels are not affected by beta carotene administration. (See 'Protoporphyrin accumulation' above.)

Mild, dose-related skin discoloration, especially on the palms of the hands, is expected because an effective dose is associated with carotenemia.

Other agents — A number of other methods of photoprotection have been employed, with variable success.

●Narrow-band UVB phototherapy that provides exposure to UVB in the range of 311 to 313 nm, which stimulates melanin formation but does not activate porphyrins, has been described as beneficial [122]. (See "UVB therapy (broadband and narrowband)".)

●Oral cysteine, which is available as a nutritional supplement, may improve light tolerance in EPP by quenching excited oxygen species at doses of 500 mg twice daily [123,124]. However, experience is limited, and we have not used this approach. N-acetylcysteine, a closely related product was shown to be ineffective in two double blind crossover placebo-controlled trials [125,126].

We do not use vitamin C to treat EPP, as it did not show benefit in a double blind randomized controlled trial [127], and therefore is not recommended.

At present, we also do not recommend oral cimetidine, which has been used in acute hepatic porphyrias, but in the absence of evidence for efficacy and safety. Cimetidine inhibits hepatic cytochrome P450 enzymes, and thereby ameliorates porphyria in an animal model (rodents treated with chemicals that are activated by these enzymes). Cimetidine inhibition of bone marrow ALAS2 has been suggested but not demonstrated. In a 2016 report, decreased photosensitivity in response to oral cimetidine was described in three children with EPP [128]. However, this was not a formal pilot study or trial, and decreases in protoporphyrin levels were not documented. A double-blind placebo-controlled trial is underway in the United States to determine if cimetidine is effective and safe in patients with protoporphyria.

Iron — Iron supplementation in patients with EPP and XLP is controversial. As noted above, the reason for mild iron deficiency commonly seen in these patients is not understood. In a 2015 study, patients were able to absorb iron well from the gastrointestinal tract and did not have inappropriately high levels of hepcidin [29]. (See 'Iron in EPP and XLP' above.)

Some authorities feel that because iron can upregulate ALAS2, iron deficiency may be protective and iron supplementation is contraindicated [31]. Some patients have had unexplained worsening of photosensitivity with iron therapy, although increases in porphyrin levels were not documented [129-132]. In such cases it is possible that correction of iron deficiency may have transiently increased erythropoiesis, with a resulting short term increase in protoporphyrin production. However, in one patient with EPP, intravenous iron sucrose lowered porphyrin levels and improved sunlight tolerance [133]. It is generally agreed that patients with XLP benefit from iron replacement [78]. Larger systematic studies of iron therapy are needed.

Until further data become available, we use iron supplementation (eg, ferrous sulfate 325 mg one to three times daily) in patients with clearly low levels of serum ferritin (ie, less than approximately 15 to 20 ng/mL). The goal is to treat anemia, improve fatigue and subtle cognitive impairment that may be caused by iron deficiency [134], and possibly to reduce porphyrin accumulation [134]. Future systematic studies may alter this practice.

Pain control/anti-inflammatory agents — Initial or prodromal symptoms resolve rapidly if the patient escapes from sun to shade [135]. Acute cutaneous symptoms from more prolonged exposure generally resolve spontaneously within hours or days, but before resolution patients may have severe pain and systemic symptoms and may be bedridden. Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and even opioids may provide little relief. Cold compresses may be helpful. (See "Sunburn".)

Routine monitoring and interventions — Individuals with EPP and XLP should have at least annual monitoring of:

●Liver function tests

●Complete blood count (CBC)

●Ferritin

This may help in the early detection of protoporphyric hepatopathy and anemia, respectively. Additionally, monitoring of hepatic function may help identify other possible causes of liver disease that may precipitate protoporphyric hepatopathy. However, this practice has not been studied prospectively, and it is not yet possible to identify those patients at risk of developing protoporphyria-related liver disease.

Erythrocyte and plasma porphyrin levels should be measured annually for early detection of increases in levels due to liver disease or change in iron status. Of note, on average, porphyrin levels are higher in XLP than in EPP, and individuals with higher total erythrocyte porphyrin levels are likely to be at greater risk for hepatopathy. Patients should be encouraged to enroll in longitudinal studies being conducted by the Porphyrias Consortium in the United States and EPNET in Europe in order to gain knowledge and develop better guidelines for long-term management.

If liver function tests are abnormal, the evaluation should exclude other causes of liver disease including biliary obstruction. Any reversible causes of liver dysfunction that might precipitate hepatopathy, including excess alcohol use, should be identified and treated. There is no association of EPP with hepatitis C virus (HCV) or other viral infection; however, screening for HCV and hepatitis B virus infection is appropriate if an individual with EPP has elevated liver function tests. Liver biopsy is generally required to establish a diagnosis of protoporphyric hepatopathy and to exclude other liver diseases, and to plan further management aimed to prevent progression to liver failure [136].

Additionally, patients should avoid excess exposure to alcohol and hepatotoxic drugs, drugs or hormone preparations that impair hepatic excretory function. Severe calorie restriction, which is harmful in acute hepatic porphyrias, is avoided as a precaution in EPP and XLP.

Patients with EPP are very likely to develop vitamin D deficiency because of sunlight avoidance. Measurements of serum 25-hydroxy vitamin D are performed annually, and we ensure that patients have a daily intake of 800 international units of vitamin D and 1000 mg of calcium; typically this requires vitamin D supplementation because sunlight avoidance is extreme. Individuals with vitamin D deficiency despite this intake may require higher doses of vitamin D.

Vaccination to prevent hepatitis A and B is important in EPP or XLP, as viral hepatitis could have especially deleterious consequences in individuals with underlying liver disease. (See "Immunizations for patients with chronic liver disease".)

Treatment of gallstones and protoporphyric hepatopathy

Gallstones — Management of gallstones is the same as in patients without EPP. Cholecystectomy may be needed during childhood. (See "Approach to the management of gallstones".)

Management of hepatopathy — A combination of treatments is often used for patients with decompensated hepatopathy. None of these has been validated in controlled trials, given the rarity and severity of the disorder. The aim is to reduce the amount of protoporphyrin entering plasma and delivered to the liver and also ameliorate its toxic effects, allowing the liver a chance to recover [137]. More often this approach helps to bridge patients to liver transplantation.

A regimen for patients with severe and rapidly progressing hepatopathy may include all of the following [138]:

●Intravenous hemin has been found to reduce plasma porphyrin levels presumably by reducing protoporphyrin production by the marrow, but the mechanism is not established [139-142]. Hemin is administered at a dose of 4 mg/kg body weight daily for at least four days, as discussed in more detail separately. (See "Acute intermittent porphyria: Management", section on 'Indications and mechanism of action'.)

●Plasmapheresis may reduce the plasma porphyrin concentration up to 40 percent and thereby reduce liver uptake of protoporphyrin from the plasma compartment, which is important because hepatic uptake is from plasma [143,144]. Erythrocyte exchange has also been used because the amount of protoporphyrin in erythrocytes greatly exceeds that in plasma [145]. However, this may be less successful because the aim in the treatment of hepatopathy is to lower the level of plasma protoporphyrin, which turns over rapidly and likely derives primarily from the marrow rather than circulating erythrocytes.

●It is important to correct anemia by erythrocyte transfusions because, even if well tolerated, anemia can stimulate erythropoiesis and might increase overproduction of protoporphyrin by the bone marrow [140,146]. An increased hemoglobin level after erythrocyte transfusions (eg, >10 g/dL) can decrease erythropoietin levels and reduce erythropoiesis. Response may be less in patients with shortened red cell survival due to splenomegaly [147].

●Ursodeoxycholic acid (UDCA) may increase biliary excretion of protoporphyrin. Chenodeoxycholic acid should be avoided because of potential hepatotoxicity [148,149]. UDCA is administered as 10 mg/kg daily, in two divided doses.

●Cholestyramine at a dose of 4 grams one to two times daily can be used to interrupt the enterohepatic circulation of protoporphyrin and thereby reduce plasma protoporphyrin levels [150,151].

●Vitamin E 400 international units by mouth daily can be used to reduce oxidative damage to hepatocytes [152].

These treatments are administered simultaneously based on experience in patients with advanced hepatopathy, which is the most common presentation. Some patients recover from an acute episode or are bridged to liver transplantation. However, studies documenting efficacy of these treatments alone or in combination are lacking, due to the rarity and the acute, life-threatening presentation of this hepatic complication.

Liver transplantation — Any patient with EPP who develops cirrhosis or severe protoporphyric hepatopathy should be referred for evaluation for possible liver transplantation. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

Liver transplantation for protoporphyric hepatopathy was first reported in 1980; subsequent experience has expanded to more than 40 cases [153,154]. Compilation of cases in the United States and European transplant registries has shown that even though liver disease commonly recurs, overall survival is comparable to that of patients transplanted for other liver diseases [139,155-157]. As an example, in the United States, survival of adults who underwent liver transplantation for EPP was 85 percent at one year and 69 percent at five years [156]. Biliary complications occurred in 45 percent of patients, which is higher than in other liver transplant recipients. This is attributed to high levels of protoporphyrin in bile and damaging effects of "toxic bile" on cholangiocytes. Therefore, construction of a Roux loop to more safely transport "toxic bile" has been recommended in preference to duct-to-duct anastomosis [139,155,156].

The perioperative course in these patients is often complicated by severe motor neuropathy, as described in a case report [68]. This may be prevented or lessened in severity with the use of intravenous hemin and plasmapheresis prior to liver transplantation, although controlled studies are lacking. Dosages of hemin have been similar to those used in acute porphyrias (eg, 4 mg/kg body weight daily). (See "Acute intermittent porphyria: Management", section on 'Indications and mechanism of action'.)

Because these patients have very high plasma and erythrocyte porphyrin levels at the time of surgery, there is a risk of severe phototoxicity to the skin and visceral surfaces from the surgical lighting. Protective filters can prevent this phototoxicity. Three types of filters have been studied: CLS-200-X and TA-81 from Madico Inc. and 61011 from Reflective SA. CLS-200-X has the least visual distortion, while TA-81 and 61011 offer more protection. These authors recommended 61011 filters as the best compromise between visual distortion for the surgeon and light protection [98].

Liver transplantation restores normal liver function, including hepatic excretion of protoporphyrin, but it does not correct the metabolic abnormality in the bone marrow, which continues to produce excessive amounts of protoporphyrin. Patients should be monitored closely to avoid anemia, pronounced iron deficiency, and other factors that may cause the bone marrow to produce greater amounts of protoporphyrin. Recurrent liver disease has been reported as early as eight months after transplantation. There is anecdotal evidence that chronic plasmapheresis and intravenous hemin can stabilize and improve recurrent protoporphyric hepatopathy after liver transplantation [158].

Patients with recurrent hepatopathy should be evaluated for hematopoietic cell transplantation to avoid loss of the grafted liver [139,159]. (See 'Hematopoietic stem cell transplantation' below.)

Hematopoietic stem cell transplantation — Indications for hematopoietic stem cell transplantation (HSCT) in EPP are complex, in part because predictors of developing hepatopathy are lacking [157,160]. In patients with protoporphyric hepatopathy, sequential liver transplantation and HSCT may be appropriate in order to prevent future damage to the allograft liver, if a suitable hematopoietic stem cell donor is available [159]. In patients who recover from hepatopathy and have minimal or no fibrosis, HSCT may be performed without liver transplantation, which if successful will essentially cure the EPP or XLP and prevent a recurrence of hepatopathy [70,157].

HSCT was first performed in a patient with acquired EPP in the setting of leukemia and resulted in resolution of the EPP phenotype [161]. Subsequently, additional reports have described individuals with protoporphyria who had developed severe cholestasis, with documented resolution of the disease in many, although some individuals do not experience hematopoietic stem cell engraftment [137,156,159,162].

It is not possible with available data to predict which patients with EPP are at greatest risk to develop cholestatic liver disease, for whom HSCT would be appropriate [160]. Decisions regarding the choice of donor are at the discretion of the transplant center.

Genetic counseling and testing of family members — A confirmed genetic diagnosis of EPP or XLP provides a rational basis for genetic counseling. The details of the counseling and genetic testing differ for these protoporphyrias:

●EPP – Inheritance of EPP due to pathogenic variants in the FECH gene is autosomal recessive. (See 'EPP due to FECH variant' above.)

•For families in which a child has EPP due to a severe FECH variant plus the common hypomorphic FECH allele IVS3-48T/C, the likelihood of having another child who inherits the severe variant is approximately 50 percent, and of having another affected child (who inherits both the severe variant and the hypomorphic allele) is approximately 25 percent.

•For patients with EPP due to a severe FECH mutation plus the hypomorphic FECH allele IVS3-48T/C, the likelihood of having an affected child will depend on whether the other parent carries the hypomorphic IVS3-48T/C allele, which is more common in some populations than others (see 'EPP due to FECH variant' above). Testing the other parent can determine this likelihood. If the other parent's FECH genes are both normal, half the children will inherit the severe FECH mutation (which may be passed on to future generations); however, they will not have EPP because they also inherited one normal FECH allele.

●XLP – Inheritance of XLP (due to an ALAS2 gain-of-function mutation) is sex linked. Males who inherit the mutation are affected. Less commonly, females who inherit the mutation are affected if skewed lyonization (random X chromosome inactivation) results in preferential inactivation of the unaffected X chromosome. (See 'XLP due to ALAS2 gain-of-function mutations' above.)

•For families in which a child has XLP due to an ALAS2 gain-of-function mutation, the mother is an obligate carrier. The likelihood of having another child who inherits the mutation is approximately 50 percent; sons will have XLP and most daughters will be carriers. The father with a normal ALAS2 allele will not transmit the disease.

•For males with XLP, the mutation will be transmitted only to daughters, so no sons will have XLP. All daughters will have one ALAS2 gain-of-function mutation (and may or may not be affected) and will transmit the mutation to half of their children, resulting in disease in male children who inherit the mutation and carrier status in most female children who inherit the mutation. Some females will be affected due to skewed lyonization.

Additional information about these inheritance patterns and genetic counseling issues for children is presented separately. (See "Genetic testing", section on 'Testing children' and "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Mendelian inheritance patterns'.)

PROGNOSIS — EPP and XLP have been described in the past as diseases that cause non-life-threatening photosensitivity that can be managed by avoiding sunlight. Life expectancy generally is normal, unless porphyric hepatopathy develops. However, although these diseases may not shorten life expectancy, they have a greater impact on quality of life than do other cutaneous porphyrias and other diseases that cause photosensitivity because pain in EPP and XLP is more acute and intense and necessitates alterations in lifestyle and employment [58,163]. These adverse consequences are accentuated in children and adults who are undiagnosed and as yet have no explanation for their symptoms.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Porphyria".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Erythropoietic protoporphyria (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Genetics and pathogenesis – Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) result from accumulations of protoporphyrin in bone marrow reticulocytes and in turn in the circulation, leading to nonblistering cutaneous photosensitivity. The characteristic phenotype in EPP is due to loss-of-function mutations in the gene for ferrochelatase (FECH) (figure 1), or, in the less common condition XLP, to gain-of-function mutations in the gene for the erythroid form of delta-aminolevulinic acid synthase (ALAS2). A single family has been described with protoporphyria due to a variant in CLPX, which encodes a protein that inactivates ALAS2. (See 'Pathogenesis' above.)

●Prevalence – EPP is the most common porphyria in children and the third most common in adults, after porphyria cutanea tarda and acute intermittent porphyria. The incidence is similar in males and females. EPP is very rare in Africa and is more common in East Asia than in White European or American populations. (See 'Epidemiology' above.)

●Clinical features – The predominant clinical manifestation in protoporphyria is painful, nonblistering cutaneous photosensitivity, often within minutes of sun exposure. Vesiculation may occur after prolonged exposure, and subtle residual skin changes are seen with repeated exposure over months or years. Most patients avoid sunlight and have no physical findings. Hepatobiliary complications include protoporphyrin-containing gallstones and, in less than 5 percent of cases, severe liver failure. Patients are at risk for vitamin D deficiency due to sun avoidance, and often have mild iron deficiency anemia, which is unexplained. Symptoms may improve during pregnancy. (See 'Clinical features' above.)

●Evaluation – EPP and XLP should be considered in any patient with acute and primarily nonblistering photosensitivity; delays in diagnosis are common. The primary screening test is total erythrocyte (red blood cell) protoporphyrin; if this is elevated, fractionation is used to distinguish between metal-free and zinc protoporphyrin (algorithm 1 and table 4). The diagnosis is made if total erythrocyte protoporphyrin is elevated with an increased percentage of erythrocyte metal-free protoporphyrin (usually >85 percent in EPP and 50 to 85 percent in XLP). Genetic testing is confirmatory and important for genetic counseling and is strongly advised, especially for differentiating EPP and XLP. (See 'Diagnostic evaluation' above.)

●Differential diagnosis – The differential diagnosis of EPP and XLP includes other photosensitivity disorders such as polymorphous light eruption, solar urticaria, drug-induced phototoxicity, and sunburn (table 2). (See 'Differential diagnosis' above.)

●Treatment

•Protection from sunlight – Protection from sunlight is a cornerstone of EPP management. Patients learn to avoid sunlight exposure, but this limits occupational and recreational opportunities and impairs quality of life. The use of protective clothing, hats, and protective tinted automobile window glass is essential for most patients when outdoors or driving. Other strong sources of light including operating room lights should be used with caution.

•Afamelanotide and beta carotene – For adults with EPP or XLP, we suggest afamelanotide to improve sunlight tolerance and quality of life (Grade 2B). This is administered as a subcutaneous implant every other month. Although less effective, we also suggest beta-carotene for patients of all ages with EPP or XLP (Grade 2C). These therapies do not alter porphyrin levels. (See 'Photoprotection' above.)

●Monitoring – Individuals with EPP and XLP should have monitoring of erythrocyte and plasma protoporphyrin levels, liver function tests, complete blood count (CBC), and ferritin at least once per year. Vitamin D supplementation is usually required. Vaccination to prevent hepatitis A and B is important. (See 'Routine monitoring and interventions' above.)

●Liver transplant and HSCT – A combination of treatments is often used for patients with decompensated hepatopathy. Any patient with EPP who develops cirrhosis or severe protoporphyric hepatopathy should be referred for evaluation for possible liver transplantation. In some individuals with severe hepatopathy, sequential liver transplantation and hematopoietic stem cell transplantation (HSCT) may be appropriate. (See 'Treatment of gallstones and protoporphyric hepatopathy' above.)

●Genetic testing and counseling – Genetic testing and counseling are appropriate for individuals with EPP or XLP and their first-degree relatives. (See 'Genetic counseling and testing of family members' above.)