Protoporphyria 

Updated: Dec 18, 2019
Author: Jose A Plaza, MD; Chief Editor: William D James, MD 

Overview

Background

The term protoporphyria now encompasses two clinically similar disorders that most often result from hereditary mutations in one of three different genes. The most common is erythropoietic protoporphyria (EPP). It is an inherited disorder caused by partial deficiency in mitochondrial ferrochelatase (FECH), the terminal enzyme of heme biosynthesis. The resultant accumulated excess of its substrate, metal-free protoporphyrin, causes two principal manifestations: (1) an acute cutaneous photosensitivity typically first appearing during childhood and (2) hepatobiliary disease.[1, 2, 3, 4, 5]

The predominant genotype associated with phenotypic expression of EPP is one mutant ferrochelatase allele (FECH) encoding a defective enzyme protein with little or no function, paired with a relatively common polymorphic allele (IVS3-48T>C) with low gene expression that only mildly affects heme synthesis.[6, 7] This type of inheritance has been termed pseudodominant[8, 9] or semidominant,[10] but is often referred to as autosomal recessive[11] in that anomalies in both paired FECH alleles are required for disease expression, even though one alteration causes marked reduction or abrogation of residual enzyme activity while the polymorphism causes little clinically noticeable harm when unpaired with a severely dysfunctional allele. Infrequently, two deleterious FECH mutations are paired in a recessive genotype of EPP that may impart a higher risk for hepatic dysfunction.[12, 13] Rarely, acquired somatic mutation or deletion of a ferrochelatase gene secondary to myelodysplastic or myeloproliferative disorders leads to an adult-onset protoporphyric disorder.[14, 15, 16]

A far less frequent type (< 10%) of hereditary protoporphyria, now recognized as a separate disorder, is X-linked dominant protoporphyria (XLDPP, OMIM 300752), or simply XLP. XLP arises from C-terminal deletions or alterations in the gene encoding the erythroid-specific enzyme 5-aminolevulinic acid synthase-2 (ALAS2), increased function of which leads to overproduction of protoporphyrin.[11, 17] Like EPP, XLP is caused by bone marrow heme synthetic dysfunction, but most often results in a greater ratio of accumulated erythrocyte zinc-protoporphyrin to metal-free protoporphyrin than is typical for EPP. XLP manifests as an acute, childhood-onset, cutaneous photosensitivity indistinguishable from that of EPP, but appears to have a higher risk for hepatic dysfunction.[17] An adult-onset case of XLP in an 89-year-old man with evolving myelodysplasia exhibited somatic mosaicism in erythroid hematopoietic cells associated with an ALAS2 mutation that predicted a C-terminal deletion.[18]

Mutation in a third gene, CLPX, which encodes the mitochondrial AAA+ unfoldase ClpX, has been linked to a familial disorder with biochemical and clinical features of protoporphyria in individuals without either FECH or ALAS2 mutations.[19] ClpX acts to control ALAS activation and degradation during heme synthesis. Defective CLPX leads to increased ALAS post-translational stability, which results in excess accumulation of erythrocyte protoporphyrin.[19]

Pathophysiology

Protoporphyrin is a lipophilic molecule capable of transformation to excited states by absorption of light energy. Excited-state protoporphyrin mediates photoxidative damage to biomolecular targets in the skin,[20] resulting in immediate phototoxic symptoms variously described as tingling, stinging, or burning that may be followed by the appearance of erythema, edema, and purpura.[1, 20] Excess protoporphyrin is formed during maturation of erythroid cells in the bone marrow and present at the highest levels in reticulocytes and young erythrocytes.[21] Metal-free protoporphyrin escapes from red blood cells into the plasma, from which it is cleared by the liver and secreted into bile. Protoporphyrin-rich bile facilitates gallstone formation.[22] Toxic effects of protoporphyrin deposition in the liver may lead to life-threatening hepatic dysfunction.[22, 23, 24] 99

Etiology

The cytogenetic location of the ferrochelatase gene is 18q21.3.[25] Loss of activity by as much as 50% as the result of one FECH mutant gene is generally insufficient to cause overt disease when its complementary allele has normal function.[6] FECH genotypes composed of either two mutant alleles (< 1-4% of cases) or one mutation and a variant allele with a specific intronic single nucleotide polymorphism (IVS3-48C) (~82-94% of cases) have been found in most symptomatic individuals.[9, 12, 13, 26, 27] This polymorphism enhances aberrant splicing and rapid degradation of FECH mRNA, with resultant low expression.[7] The allele frequency of this polymorphism varies widely in diverse populations studied, as follows:

  • Japanese - 43.3%[13] ; 45.2%[28]

  • Southeast Asian - 31%[13]

  • White French - 11.3%[13]

  • North African - 2.7%[13]

  • Black West African - < 1%[13]

  • United States - 3.5%[29]

  • South Africans of European descent - 9%

  • United Kingdom - 6.5%[12]

  • Chinese (different regions) - 28-41.4%[30]

  • Swedish - 8%[31]

The pairing of a mutated allele encoding a severely impaired enzyme protein with this low-expressing polymorphic allele typically yields enzyme activity diminished to less than 30% of normal, low enough to cause protoporphyrin accumulation. Individuals with no FECH mutation but who are heterozygous for this polymorphism typically do not have sufficiently diminished FECH activity to cause clinical abnormalities. Individuals with no FECH mutation, but who are homozygous for this polymorphism, may exhibit slightly abnormal erythrocyte protoporphyrin levels and mild photosensitivity.[32]

Adult-onset protoporphyric photosensitivity and increased protoporphyrin levels have been associated with an acquired somatic mutation or deletion of a FECH gene due to myelodysplastic or myeloproliferative disorders.[14, 15, 16]

Eight families were described in 2008[17] with a protoporphyric disorder indistinguishable clinically from the predominant form of the disease, but without FECH mutations, that is now called X-linked dominant protoporphyria or X-linked protoporphyria (XLDPP, XLP or XLEPP [OMIM 300752]). Two different C-terminal deletions in the gene encoding the erythroid-specific isoform of aminolevulinic acid synthase were identified among these families. The locus for this gene was identified on the X-chromosome, and the inheritance pattern in the families was consistent with X-linked dominant transmission. Both mutations caused a marked increase in activity of ALAS2 that eventuated in large accumulations of erythrocyte metal-free protoporphyrin and zinc-protoporphyrin. Seventeen percent of affected individuals in that study exhibited overt liver disease (40% of affected males), a significantly greater number than the 2-5% of individuals with ferrochelatase-deficient protoporphyria who develop this complication.

Additional cases of XLP and novel associated gain-of-function ALAS2 mutations have subsequently been recognized.[9, 11, 18, 33, 34, 35] A higher prevalence (~10%) of XLP was found among 226 North American individuals with the protoporphyria phenotype; this is 2-5 times greater than observed among Western Europeans previously studied.[11]

Epidemiology

Frequency

United States

Until the recently established registry for protoporphyria sponsored by the American Porphyria Foundation collects sufficient data, accurate enumeration in the United States cannot be provided, but it is probably similar to data from European countries. A study of 226 North American individuals exhibiting the protoporphyria phenotype identified 22 with ALAS2 mutations and 187 with FECH anomalies.[33] The ALAS2/FECH ratio of approximately 10% in this study is greater than ratios reported elsewhere.

International

Estimates of one EPP case in populations of 75,000-200,000 have been reported for several Western European populations and in the South African population of European ancestry.[3, 36, 37, 38] XLP remains rare but has been identified in increasing numbers.[9, 11, 17, 33, 34, 35, 39]

Race

EPP has been reported most often in people with white heritage, but it has also been reported in persons with Japanese, Chinese, East Indian, or north or central African ancestry. XLP has been identified chiefly among individuals of Western European ancestry but also in an African American and Pacific Islander[11] and a Japanese boy.[34]

Sex

EPP and XLP occur in both males and females.

Age

Photocutaneous symptoms usually appear during childhood,[1] but they also may be noted for the first time in adult life.[14, 15, 16, 18, 39] Gallstones may become symptomatic in young adulthood or in middle age.[1] Liver failure and its complications, sufficiently severe to result in liver transplantation and/or death, may develop in children and adolescents as well as adults.[22, 24, 40, 41, 42]

Prognosis

In the absence of hepatic failure, individuals with EPP have normal life expectancies.

Painful cutaneous photosensitivity reduces the sunlight tolerance of individuals with protoporphyria and may influence their lifestyles over entire lifetimes.[1]

An increased prevalence of cholelithiasis in both men and women can result in signs and symptoms of gallstone disease at relatively early ages.[1]

Hepatotoxic effects of excess protoporphyrin deposition have led to liver dysfunction that progressed to life-threatening severity in approximately 2-5% of known cases of protoporphyria.[3]

 

Presentation

History

Skin manifestations after sunlight exposure typically begin during infancy or childhood, most often involving dorsal hands, the face and ears, and, occasionally, legs and dorsal feet, after short periods of exposure. If exposure is promptly discontinued, visible skin lesions may not ensue. Longer exposure, or multiple exposures on sequential days, can elicit swelling with or without redness in the exposed skin that evolves into sheets of petechiae. This exquisitely painful reaction resolves over several days to leave skin that may appear normal. The onset after sun exposure varies but may be within 10 minutes. Older children and adults, particularly those with darker skin, may handle being outdoors for an hour or more.

Patients with protoporphyria who report skin pain but have minimal findings may be considered malingerers until an acute reaction is observed. Gallstones may remain silent or evoke reports of indigestion and/or right upper quadrant abdominal pain consistent with symptomatic cholelithiasis. Individuals with protoporphyria associated with hepatotoxicity may report loss of appetite, nausea, vomiting, weakness and fatigue, anorexia, malaise, weight changes, increasing abdominal girth, abdominal pain, jaundice, and increasing photosensitivity.

Physical Examination

The acute phototoxic reaction typically includes edema, erythema, and petechiae. Blisters, crusted erosions, and scarring may occur but are less florid and less frequent than in other porphyrias. Chronic changes include shallow, elongated depressions in facial skin, especially over the nose; perioral furrowing; and prematurely aged skin of the dorsal hands, often most prominent over the knuckles. In more severe cases, sclerodermalike waxy induration or a cobblestone texture of facial and hand skin may develop. Mechanical fragility, when present, is less severe than in other porphyrias; hypertrichosis is infrequent.

Some individuals with autosomal recessive (two deleterious FECH mutations) erythropoietic protoporphyria (EPP) exhibit palmar keratoderma that often worsens in summer and remits in winter.[43, 44] Neuropathy has been observed in some of these individuals, but not severe liver dysfunction, suggesting that protoporphyrin hepatotoxicity may be mitigated in this subset of recessive protoporphyria patients by efficient hepatobiliary protoporphyrin excretion mechanisms yet to be elucidated.[44]

With progressive liver dysfunction, hepatosplenomegaly and jaundice may develop, as may signs of increasing cutaneous photosensitivity. End-stage liver disease is signaled by intense jaundice, ascites, vomiting, fever, encephalopathy, axonal polyneuropathy that may progress to paresis and respiratory failure, hemorrhage from esophageal varices, and extreme photosensitivity.

Complications

Severe neurological dysfunction (eg, encephalopathy, axonal polyneuropathy, respiratory failure) characteristic of acute porphyria attacks has been observed in patients with end-stage hepatic failure associated with erythropoietic protoporphyria (EPP).[45, 46, 47]

Pregnancy does not cause worsening of EPP; photosensitivity may actually improve during gestation.[37]

 

DDx

 

Workup

Laboratory Studies

Protoporphyrin concentration is elevated in red blood cells, plasma, bile, and feces. The diagnosis is usually made by finding the abnormal levels in erythrocytes and plasma. Urinary porphyrin levels are normal in patients without liver dysfunction. Abnormal coproporphyrinuria develops when liver function is deteriorating.[48, 49]

The screening test for either type of protoporphyria is measurement of total blood porphyrin, which includes both metal-free protoporphyrin and zinc protoporphyrin. Levels that are 5-50 times the upper limit of the normal range are diagnostic. Separate determination of zinc protoporphyrin as a fraction of the total is helpful for a preliminary differentiation between erythropoietic protoporphyria (EPP) and X-linked protoporphyria. In EPP, zinc protoporphyrin constitutes approximately 5% of the total protoporphyrin in blood, whereas in X-linked protoporphyria, it constitutes 20-40%. The determination directs attention to the appropriate gene for mutation analysis. Some reference laboratories measure only zinc protoporphyrin but label it, misleadingly, as “free protoporphyrin.” The level of zinc protoporphyrin is elevated in patients with iron deficiency and lead poisoning. The test is not useful in screening for protoporphyria.

Obtain a serum liver function panel at diagnosis. Monitor indices of liver function at 6- to 12-month intervals if baseline values are normal. If liver function is abnormal, complicating factors (eg, gallstones, viral hepatitis, alcohol or drug abuse, other toxic, infectious, immunologic, or metabolic storage disorders) should be excluded by appropriate testing.

Perform a hematological assessment. Microcytic anemia, which may occur in 20-60% of individuals with protoporphyria,[50] often associated with mild iron deficiency, may be found.[1, 51] Iron therapies have resulted in both beneficial[52, 53, 54] and adverse[55, 56] effects in EPP. Iron supplementation has been beneficial in some cases of XLP.[35]

A lifetime of sunlight avoidance predisposes to vitamin D deficiency among individuals with protoporphyria.[57, 58] Determine serum 25-hydroxyvitamin D level at diagnosis and at intervals as needed to monitor response to supplementation, if indicated.

Imaging Studies

If cholelithiasis is suspected, abdominal ultrasonography or other imaging procedures are indicated.

Bone mineral density studies may reveal osteopenic or osteoporotic changes due to vitamin D deficiency as a result of chronic sunlight avoidance.[58]

Other Tests

Impending liver failure may be signaled by progressively rising levels of urinary coproporphyrin.[49] Urinary porphyrin levels are within normal limits in persons with uncomplicated protoporphyria. Protoporphyrin, being lipophilic, is not excreted by renal mechanisms and does not normally appear in urine. Coproporphyrin, which accumulates as a result of liver disease, has intermediate water solubility, and levels become abnormally elevated in the urine of patients developing protoporphyrin-induced hepatotoxicity.[48]

Procedures

In the event of overt liver dysfunction, liver biopsy is indicated. Some experts suggest that individuals with genotypes associated with higher risk of liver disease, such as a "null-allele" FECH mutation that encodes an enzyme with essentially no residual activity, biallelic FECH mutations, one of the ALAS2 increased-function mutations, or a family history of protoporphyric liver disease, should undergo liver biopsy even before liver function tests become abnormal.[24, 36] The presence of other risk factors for liver disease, such as viral hepatitis, hemochromatosis, or alcoholic or nonalcoholic fatty liver, increases the weight of argument for earlier liver biopsy.

Liver transplantation may be life-saving, but does not cure protoporphyria because the source of most of the excess protoporphyrin is bone marrow erythropoiesis. Continued overproduction of protoporphyrin eventually leads to its deposition in the engrafted liver, which may again become dysfunctional.[42] Bone marrow or peripheral stem cell transplantation can be curative, but attendant risks have restricted use of these procedures to a limited number of highly selected cases.[15, 35, 41, 59, 60] Research in animal models has shown promising developments in gene therapy strategies that may eventually be transferrable to humans.

Histologic Findings

Light microscopy examination of the acute skin reaction shows nonspecific perivascular and interstitial neutrophilic dermal infiltrates. Subepidermal blisters similar to those seen in porphyria cutanea tarda can be seen in early lesions of erythropoietic protoporphyria (EPP). These blisters are cell-poor and inflammatory infiltrate is sparse. “Caterpillar bodies” may be seen in the basal layer epidermis overlying blisters. Ultrastructural findings in the acute reaction include damage of endothelial cells with extravasation of intravascular contents and degranulated mast cells.[61]

Biopsy specimens of chronically damaged skin show deposition of hyaline masses in the upper dermis and markedly thickened walls of upper dermal capillaries.[62] The deposition can be extensive and involve the surrounding dermis to mimic a colloid milium. The hyaline material surrounding blood vessels is periodic acid-Schiff–positive and diastase-resistant. Ultrastructural findings in chronically damaged skin include replicated basal laminae around dermal vessels, degranulated mast cells, and amorphous dermal deposits.[62] Direct immunofluorescence studies show deposition of immunoglobulins and complement in and around upper dermal vessel walls and, to a lesser extent, at the dermoepidermal junction.[62]

Liver biopsy typically reveals brown pigment in hepatocytes, Kupffer cells, portal macrophages, and small biliary structures.[22, 42] Many of these protoporphyrin deposits are crystalline when examined under electron microscopy and birefringent when examined under polarization microscopy.[22, 42] Cirrhotic changes are seen in advanced disease, including fibrous expansion of portal areas and regenerative nodules.[22, 42]

 

Treatment

Medical Care

For protoporphyria uncomplicated by hepatobiliary disease, the major problem is lifelong cutaneous photosensitivity. Avoiding sunlight is the mainstay of management.

Opaque topical sunscreens or ultraviolet (UV) B phototherapy may improve the tolerance of light. Symptom prevention was impossible until 2006 when afamelanotide, a melanocyte-stimulating hormone analogue that induces epidermal melanin skin-tanning and has an anti-inflammatory effect on the skin, became available. Afamelanotide is a newer therapy based on the observation that sun-related symptoms are inversely related to skin pigmentation in people with protoporphyria.[63, 64, 65] This congener of α-melanocyte–stimulating hormone increases production of eumelanin. It is supplied as a sustained-release subcutaneous implant. Skin darkening starts within a few days after placement of the implant and persists for 3-4 weeks.[66]

US approval of afamelanotide was based on 2 multicenter, randomized, double-blind, placebo-controlled trials in patients residing in the European Union (n=74) and the United States (n=94). Patients were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of 5 implants in the European Union study and 3 in the US study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. In the US study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 h vs 40.8 h in the placebo group; P = .04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6 h vs 0.8 h; P = .005), and the number of phototoxic reactions was lower in the afamelanotide group (77 vs 146, P = .04).[67]

Note the following treatment measures for photosensitivity:

  • Shield skin from sunlight by using protective clothing and lifestyle adjustments.
  • Because the wavelengths of light causing porphyrin-sensitized phototoxicity are chiefly in the visible spectrum, window glass is not an effective barrier. Plastic films that attenuate transmission of portions of the visible light and long UV spectra are available and can be applied to window or windshield glass. [68]
  • Topical sunscreens are not effective unless transmission of long UV and visible light rays is reduced by their use. Sun-blocking formulations containing zinc oxide or titanium dioxide reflect visible light and may be helpful. [68]
  • Topical sunless tanning gels or creams containing dihydroxyacetone produce superficial pigmentation that blocks some of the offending wavelengths. [68]
  • Induction of endogenous melanin by exposure of skin to broad- or narrow-band UV-B lamps or to UV-A in conjunction with a psoralen UV-A photosensitizer also may increase tolerance to natural sunlight. [69]
  • Afamelanotide can be prescribed. It is a melanocyte-stimulating hormone analogue that induces epidermal melanin skin-tanning and has an anti-inflammatory effect on the skin.
  • Oral beta-carotene has been reported to reduce photosensitivity in some, but not all, patients. Some experts consider it of little or no value. [1, 70, 71]
  • Attenuation of photosensitivity using oral cysteine or pyridoxine has been reported but not widely confirmed. [72]
  • H1-receptor antagonists can mitigate histamine-mediated components of the acute reaction, but they rarely suppress all signs and symptoms. Suppression of heme synthesis by inhibition of cytochrome P-450 formation and of heme oxygenase activity is a mechanism proposed for transient improvement of isolated cases of various porphyrias after H2-receptor antagonist use that remains unproven. Lessened photosensitivity reported in three children with erythropoietic protoporphyria (EPP) after H2-receptor antagonist administration remains to be confirmed in controlled studies. [73, 74]
  • A pilot study of the oral enteric sorbent colestipol found less photosensitivity in three subjects with EPP after its use, but reductions in erythrocyte protoporphyrin levels were not significant. [75]

Anemia, if present in EPP, most often is mild but may have features of iron deficiency. Iron supplementation has both improved[52, 53, 54] and worsened[55, 56] EPP. In one X-linked dominant protoporphyria patient, iron therapy was followed by improvements in protoporphyrin overload, liver damage, and anemia.[35] Cholelithiasis is managed surgically. Liver dysfunction is an ominous development for which medical remedies are not consistently effective. Progressive intractable liver insufficiency is an indication for liver transplantation.[22, 24, 76]

Although adverse reactions to porphyrinogenic drugs known to exacerbate acute hepatic porphyrias are not characteristic of protoporphyria, avoid or administer with caution drugs with cholestatic properties, such as estrogenic hormones. Assess the risk-to-benefit ratio for each individual with protoporphyria when considering use of cholestatic therapies.

Immunization against viral hepatitis agents should be offered.

Supplementation with cholecalciferol (vitamin D3) should be given if serum vitamin D levels are low and/or bone density studies reveal osteopenia or osteoporosis.

Medical approaches to reversing protoporphyric liver dysfunction are not well established, owing to inconsistent or uncertain efficacy and experience in relatively few cases. These include the following:

  • Orally administered cationic exchange resins or activated charcoal aimed at reducing enterohepatic recirculation of porphyrin and/or bile acids to enhance hepatic porphyrin excretion may have some level of efficacy in selected patients. [48, 75, 77, 78]
  • Hypertransfusion to slow erythropoiesis [79] and intravenous infusion of heme analogues to repress endogenous porphyrin production [80, 81] have been beneficial in some cases.
  • Reduction in erythrocyte protoporphyrin levels and improved liver function followed administration of vitamin E to a protoporphyric patient with cirrhosis. [82]
  • Plasmapheresis [81] or exchange transfusion [83] to reduce the circulating protoporphyrin burden appeared helpful in a small number of advanced cases.
  • Medical regimens are often used in combination or rapid sequence in progressively deteriorating patients and are best instituted by experts in a referral center for advanced liver disease.

Surgical Care

Failure of medical reversal of protoporphyrin-induced hepatic decompensation warrants liver transplantation. Operating room illumination has caused acute phototoxic damage to skin and internal organs during liver transplantation for protoporphyric liver failure.[45, 46, 60, 84] This procedure requires several hours' exposure of skin and internal organs to intense visible light at a time when the patient's accumulated protoporphyrin levels are typically extremely high, causing severe photosensitivity. Preoperative exchange transfusions, plasmapheresis, and/or infusion of a heme analogue may lower the circulating burden of protoporphyrin in the blood, reducing intraoperative phototoxic potential.[85] These treatments may also aid postoperatively in retarding the development of protoporphyrin hepatotoxicity in the engrafted liver.[80, 81]

It has been recommended that a specific flexible yellow filter excluding wavelengths below 470 nm be used over operating room lamps to optimally attenuate phototoxic damage to patients with EPP during liver transplantation, yet provide acceptable illumination for the surgeons.[86] They found the risk of phototoxic injury in endoscopic, laparoscopic, and non–liver transplant surgery in such patients to be low and recommended that protective measures, including filters for operating room lamps, should be reserved for liver transplantation or for other prolonged surgical procedures in cholestatic patients. Case-by-case judgment was advised before any procedure involving intense lighting, considering duration of irradiation, light emission spectrum, and patient variables such as evidence of cholestasis or liver impairment, after burning pain, edema, and erythema developed in an arm exposed to unfiltered surgical lighting after a one-hour procedure performed on a man whose erythrocyte protoporphyrin 18 months prior was 98.3 μM/L (~ 5532 μg/dL).[87]

Biliary complications (stones, sludge, strictures) are more frequent after liver transplantation for EPP compared with the general population of transplant patients; therefore, consideration of Roux loop reconstruction is recommended.[42, 60]

Adverse reactions to anesthetic agents problematic in acute hepatic porphyrias are not characteristic of protoporphyria.

Consultations

Consultation with a hematologist should be sought for management of anemia, particularly before instituting iron supplementation, or if hypertransfusion, exchange transfusion, or plasmapheresis is considered. Rarely, bone marrow transplantation may have a role in the management of selected patients with severe manifestations.[41, 59]

Referral to specialists at a comprehensive liver center should be arranged at the earliest signs of liver decompensation for assistance in evaluation and management of progressive liver dysfunction. If liver transplantation becomes necessary, a successful outcome is more likely if the procedure is performed before the patient is gravely debilitated.

Referral to a medical geneticist can aid in counseling patients and families about risks of inheriting or transmitting the mutations and polymorphisms associated with protoporphyrias.[88, 89]

Preoperative consultation with anesthesiologists and biomedical engineers is essential concerning use of appropriate filters over operating room lighting during liver transplantation or for other procedures for protoporphyria patients with high circulating protoporphyrin levels and/or anticipated severe photosensitivity.

Diet

Do not severely curtail carbohydrate intake; a "glucose effect" may beneficially modulate abnormal heme synthesis.[90] Limit use of ethanol; alcohol excess has been implicated in fatal protoporphyria associated with liver failure.[91] Vitamin D and calcium-rich foods or supplements may reduce the incidence of osteopenia or osteoporosis associated with chronic sunlight avoidance.

Activity

Sunlight avoidance is mandatory. Recommend adjustment of outdoor activities to avoid midday sunlight. Stylish and comfortable sun-protective clothing is commercially available that can reduce time constraints on many outdoor sports or activities. Specialized programs for photosensitive children can be found that offer safe and healthy recreational experiences, even a summer camp organized by the Xeroderma Pigmentosum Society.

 

Medication

Medication Summary

Synthetic beta-carotene (Lumitene), an oral photoprotective agent, is available as a nonprescription product. Cysteine showed benefit in clinical trials, but is rarely used. Pyridoxine was reported effective in two cases. H1-receptor blockade may reduce symptoms due to mast cell histamine release during acute phototoxic reactions if established prior to exposure. Whether H2-receptor antagonists reproducibly slow porphyrin production in various porphyrias remains unproven.

Afamelanotide is a synthetic alpha-melanocyte–stimulating hormone analogue that increases the production of eumelanin in skin, thus producing a tan. Afamelanotide binds to the melanocortin-1 receptor (MC1R). MC1R signaling up-regulates the synthesis of eumelanin and pheomelanin, induces antioxidant activity, enhances DNA repair processes, and modulates inflammation. It is administered as a subcutaneous implant containing 16 mg of afamelanotide. It is approved in the European Union and the United States for use in adults with erythropoietic protoporphyria (EPP).

Liver dysfunction warrants individualized design of therapeutic regimens that may include the administration of enteric sorbents to promote protoporphyrin excretion, bile acids to enhance porphyrin clearance from the liver, and hematin to repress porphyrin production. Combinations of these and other adjunctive agents and modalities may moderate the urgency presented by a failing organ, allowing orderly preparation for an optimal transplantation.

Alpha-Melanocyte Stimulating Hormone Analog

Class Summary

Alpha melanocyte stimulating hormone analogs increase production of eumelanin (the most common type of melanin) in the skin independent of exposure to sunlight or artificial light sources. 

Afamelanotide (Scenesse)

Erythropoietic protoporphyria is a rare disorder caused by mutations leading to impaired activity of ferrochelatase, an enzyme involved in heme production; decreased ferrochelatase activity leads to protoporphyrin IX (PPIX) accumulation in the body; light reaching the skin can react with PPIX causing intense skin pain and skin changes (eg, redness, thickening). Afamelanotide, a melanocortin-1 receptor (MC1-R) agonist, increases production of eumelanin (the most common type of melanin) in the skin independent of exposure to sunlight or artificial light sources. It is indicated to increase pain-free light exposure in adults with history of phototoxic reactions from erythropoietic protoporphyria (EPP).

Photoprotectants

Class Summary

Beta-carotene is a scavenger of singlet-exited oxygen and is believed to interfere with the efficiency of porphyrin-sensitized photoxidative damage in the skin. Ingestion of beta-carotene at recommended doses produces carotenodermia after several weeks. Increasing tolerance of sunlight develops during this loading period. Tolerance diminishes over several weeks when treatment is stopped. Only some individuals with EPP reported that beta-carotene provided photoprotection; others reported no noticeable benefit.

Beta carotene (Lumitene)

The exact mechanism of action is not completely elucidated. The patient must become carotenemic before effects are observed. More than one internal light screen may be responsible for effects. This agent may provide a limited level of photoprotection. It causes yellowing of skin (carotenoderma). Any photoprotection afforded increases slowly over a 4- to 6-week period after drug therapy is commenced. When discontinued, skin color and benefit diminish over several weeks.

Antihistamines

Class Summary

H1-receptor antagonists modulate effects of histamine in skin. If taken prior to anticipated strong sunlight exposure that cannot be avoided, acute reactions may be attenuated to some extent; minimal benefit is expected if taken afterward.

Fexofenadine (Allegra)

Fexofenadine is a nonsedating second-generation medication with fewer adverse effects than first-generation medications. It competes with histamine for H1 receptors in the GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. Fexofenadine does not sedate. It is available in daily and twice-daily preparations.

Antihistamines, H2 blocker

Class Summary

These agents produce blockade of H2 receptors.

Cimetidine (Tagamet)

Cimetidine is an H2 antagonist, which, when combined with an H1-type, may be useful in treating itching and flushing in urticaria. Porphyria-specific usage for inhibiting overproduction of porphyrins is experimental.

Enteric adsorbents

Class Summary

Agents that bind protoporphyrin in the intestinal lumen promote its excretion by interrupting enterohepatic recirculation, thereby reducing the porphyrin load presented to the liver for clearance.

Cholestyramine (Questran)

Cholestyramine is a polymeric resin that binds bile acids, porphyrins, and other molecules to form nonabsorbable complexes that are excreted unchanged in feces. It adsorbs many drugs and nutrients; long-term use requires proper timing of oral drugs and may warrant supplementation of vitamins D, E, A, and K.

Activated charcoal (Actidose)

Activated charcoal prevents absorption by adsorbing porphyrin in the intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. It does not dissolve in water. It adsorbs many medications and nutrients; long-term use requires proper timing of oral drugs and may warrant supplementation of vitamins D, E, A, and K.

Gallstone dissolution agents

Class Summary

Increasing bile flow enhances secretion of protoporphyrin by the liver into the enteric tract and clearance from the body.

Ursodiol (Actigall)

Ursodiol has been shown to promote bile flow in cholestatic conditions associated with a patent extrahepatic biliary system. It decreases the cholesterol content of bile and therefore reduces bile stone and sludge formation.

Heme analogues

Class Summary

Intravenous infusion of a heme analogue may repress heme synthesis in liver and bone marrow cells, thereby reducing rate of protoporphyrin overproduction.

Hemin (Panhematin)

Hemin in an enzyme inhibitor derived from processed red blood cells and is an iron-containing metalloporphyrin. It was previously known as hematin, a term used to describe the chemical reaction product of hemin and sodium carbonate solution.

It has an anticoagulant effect and may cause thrombophlebitis at the infusion site. It must be reconstituted from lyophilized powder. Reconstitute it with human serum albumin 25% (132 mL of 25% human serum albumin to 1 vial of hemin [301 mg heme]).