eMedicine Specialties > Dermatology > Metabolic Diseases

Erythropoietic Protoporphyria

Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee

Updated: Feb 23, 2009

Introduction

Background

Erythropoietic protoporphyria is a genetic disorder arising from impaired activity of ferrochelatase, the ultimate enzyme of heme biosynthesis.^1,2 The resultant accumulated excess of its substrate, protoporphyrin, causes 2 principal manifestations: a distinctive cutaneous photosensitivity and hepatobiliary disease.^1,3,4,5 The predominant genotype associated with phenotypic expression is one mutant ferrochelatase allele encoding a defective protein, with little or no function coupled with a normal variant allele with low gene expression.^6,7 Uncommonly, 2 deleterious mutations have been found in symptomatic individuals.^8,9 Rarely, acquired somatic mutation or deletion of a ferrochelatase gene secondary to myelodysplastic or myeloproliferative disorders leads to adult-onset protoporphyric disease.^10,11,12

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,¹³ resulting in immediate phototoxic symptoms variously described as tingling, stinging, or burning that may be followed by the appearance of erythema, edema, and purpura.^3,13 Excess protoporphyrin is formed during maturation of erythroid cells in the bone marrow and is present at the highest levels in reticulocytes and young erythrocytes.¹⁴ Protoporphyrin escapes from red blood cells into the plasma, from which it is cleared by the liver and secreted into bile. Protoporphyrin-rich bile predisposes the person to gallstone formation.¹⁵ Toxic effects of protoporphyrin deposition in the liver may lead to life-threatening hepatic dysfunction.^15,16,17

Frequency

United States

No registry for erythropoietic protoporphyria is kept for the United States; therefore, accurate data are lacking.

International

Estimates of 1 case in 75,000-200,000 population have been reported for some western European populations and in the South African population of European ancestry.^2,5

Mortality/Morbidity

• Painful cutaneous photosensitivity reduces the sunlight tolerance of individuals with erythropoietic protoporphyria and may influence their lifestyles over entire lifetimes.³
• An increased prevalence of cholelithiasis in both men and women can result in signs and symptoms of gallstone disease at relatively early ages.³
• Hepatotoxic effects of excess protoporphyrin deposition have led to liver dysfunction that progressed to life-threatening severity in approximately 2-5% of known cases.⁵

Race

Erythropoietic protoporphyria has been reported most often in people with European ancestry, but also in Japanese, Chinese, East Indian, and African American people.

Sex

Protoporphyria occurs equally in males and females.

Age

Photocutaneous symptoms usually appear during childhood,³ but they also may be noted for the first time in adult life.^10,11,12 Gallstones may become symptomatic in young adulthood or in middle age.³ 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.^{15,17,18,19,20}

Clinical

History

Uncomfortable sensations in skin exposed to sunlight 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. Eventually, chronic changes may develop that are highly suggestive, but, when subtle, can be overlooked.

Individuals with protoporphyria who report skin pain but have minimal objective 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, pain in the epigastrium or right upper quadrant and back, jaundice, and increasing photosensitivity.

Physical

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, thickened, or coarsely textured skin of the dorsal hands, often most prominent over the knuckles. In more severe cases, sclerodermalike waxy induration or a cobblestone texture of the face and hands develops. Mechanical fragility, when present, is less severe than in other porphyrias; hypertrichosis is infrequent.

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.

Causes

The ferrochelatase gene is located on band 18q21.3.²¹ Ferrochelatase mutations listed at the Human Gene Mutation Database numbered 112 as of November 2008.

Loss of ferrochelatase activity by as much as 50% as the result of 1 mutant gene is generally insufficient to cause overt disease when its complementary allele has normal function.⁶ Ferrochelatase genotypes composed of either 2 mutant alleles (approximately 4% of cases) or 1 mutation and a nonmutant allele with a specific intronic single nucleotide polymorphism (IVS3-48C) (approximately 95% of cases) have been found in most symptomatic individuals.^8,9  This polymorphism enhances aberrant splicing and rapid degradation of ferrochelatase mRNA, with resultant low expression.⁷

The prevalence of this polymorphism in populations studied varies widely, as follows:

• Japanese - 43%
• Southeast Asian - 31%
• White French - 11%
• North African - 2.7%
• Black West African - <1%⁹
• American - 7%²²
• South Africans of European descent - 9%²

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 heteroallelic or homoallelic for this polymorphism do not have sufficiently diminished ferrochelatase activity to cause clinical abnormalities, although their erythrocyte protoporphyrin levels may be mildly abnormal.²

Adult-onset protoporphyric photosensitivity and increased protoporphyrin levels have been associated with an acquired somatic mutation or deletion of a ferrochelatase gene due to myelodysplastic or myeloproliferative disorders.^10,11,12

Differential Diagnoses

Other Problems to Be Considered

Other porphyrias (see also Erythropoietic Porphyria, Porphyria Cutanea Tarda, Pseudoporphyria, and Variegate Porphyria)
Prurigo aestivalis

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.^23,24
  • Erythrocyte and plasma protoporphyrin levels are increased several-fold over the reference range. Fecal protoporphyrin excretion may be increased, but, in many patients, it remains within the reference range.
  • In impending liver failure, the dynamic equilibrium between rates of protoporphyrin production and excretion is altered, producing progressively rising erythrocyte and plasma porphyrin levels and progressively diminishing fecal porphyrin excretion.^23,25
• Obtain a complete blood cell count and serum liver function panel at diagnosis. Monitor serum 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 of anemia. Individuals with protoporphyria often have mildly lowered hemoglobin and hematocrit levels, which do not cause symptoms and do not require treatment.^3,26 The mean corpuscular volume may be below the normal limit.

Imaging Studies

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

Other Tests

• Impending liver failure may be signaled by progressively rising levels of urinary coproporphyrin.²⁴  Urinary porphyrin levels are within normal limits in persons with uncomplicated erythropoietic 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.²³
• Measurement of ferrochelatase enzyme activity remains a research procedure. Mutation analysis of the ferrochelatase gene (ie, DNA testing) is performed at several porphyria research units in various countries and is now commercially available in the United States. See the American Porphyria Foundation for further information.

Procedures

• In the event of liver dysfunction, liver biopsy may be indicated.¹⁷
• Liver transplantation may be life saving, but it does not cure protoporphyria because the source of most of the excess protoporphyrin is the bone marrow. Continued overproduction of protoporphyrin eventually leads to protoporphyrin deposition in the engrafted liver, which may again become dysfunctional.²⁰ While bone marrow transplantation is potentially curative, its risks have warranted its application in only a few cases to date.^11,19,27 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 perivascular and interstitial neutrophilic dermal infiltrates. Ultrastructural findings in the acute reaction include damage of endothelial cells with extravasation of intravascular contents and degranulated mast cells.²⁸

Biopsy specimens of chronically damaged skin show deposition of hyaline masses in the upper dermis and markedly thickened walls of upper dermal capillaries.²⁹ Ultrastructural findings in chronically damaged skin include replicated basal laminae around dermal vessels, degranulated mast cells, and amorphous dermal deposits.²⁹ 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.²⁹

Liver biopsy typically reveals brown pigment in hepatocytes, Kupffer cells, portal macrophages, and small biliary structures.^15,20 Many of these protoporphyrin deposits are crystalline when examined under electron microscopy and birefringent when examined under polarization microscopy.^15,20 Cirrhotic changes are seen in advanced disease, including fibrous expansion of portal areas and regenerative nodules.^15,20

Treatment

Medical Care

For protoporphyria uncomplicated by hepatobiliary disease, the major problem is lifelong cutaneous photosensitivity. Anemia, if present, typically is mild and rarely requires specific therapy. 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.^15,17,30

• 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.³¹
• 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.³¹
• Topical sunless tanning gels or creams containing dihydroxyacetone produce superficial pigmentation that blocks some of the offending wavelengths.³¹
• 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.³²
• Afamelanotide, an alpha-melanocyte–stimulating hormone analogue that increases melanin production in the skin, is a novel injectable photoprotective agent currently in clinical trials in Australia and several European countries.
• Oral beta-carotene reduces photosensitivity in some, but not all, patients.^3,33,34
• Attenuation of photosensitivity using oral cysteine³⁵ or pyridoxine³⁶ has been reported but not widely confirmed.
• H1-receptor antagonists can mitigate histamine-mediated components of the acute reaction, but they rarely suppress all signs and symptoms.³⁷ 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, but it remains unproven.³⁸
• 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.
• Medical approaches to reversing protoporphyric liver dysfunction are not well established, owing to inconsistent or uncertain efficacy and experience in relatively few cases.
  • 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.^23,39,40
  • Hypertransfusion to slow erythropoiesis⁴¹ and intravenous infusion of heme analogues to repress endogenous porphyrin production^42,43  have been beneficial in some cases.
  • Administration of iron with the rationale of enhancing protoporphyrin conversion to heme appeared beneficial in one case,⁴⁴ but it aggravated the disease in others.⁴⁵
  • Reduction in erythrocyte protoporphyrin levels and improved liver function followed administration of vitamin E to a protoporphyric patient with cirrhosis.⁴⁶
  • Plasmapheresis⁴³ or exchange transfusion⁴⁷ 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 rapidly deteriorating patients and are best instituted by experts in a referral center for advanced liver disease.

Surgical Care

Surgical removal of gallstones usually poses no more risk for individuals with protoporphyria than for the general population, although phototoxic sequelae from high-intensity operating room lighting is a theoretical possibility. Adverse reactions to anesthetic agents problematic in acute hepatic porphyrias are not characteristic of protoporphyria. Failure of medical reversal of protoporphyrin-induced hepatic decompensation warrants liver transplantation. Operating room lamps have caused acute phototoxic damage to skin and internal organs during transplantation.^48,49 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.⁵⁰ These treatments may also aid postoperatively in retarding the development of protoporphyrin hepatotoxicity in the engrafted liver.^42,43

Consultations

• Consultation with a hematologist should be sought for management of anemia 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.^19,27
• 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 the disease.^51,52
• Preoperative consultation with anesthesiologists and biomedical engineers concerning operating room lighting is essential. The intense visible light emitted by surgical lamps can cause intraoperative burns of the skin and internal organs due to the massive protoporphyrin tissue accumulations that result from failure of hepatic excretory mechanisms.^48,49 Filtering operating room lamps appropriately can block the most harmful portions of the visible light spectrum.⁵⁰

Diet

Do not severely curtail carbohydrate intake; a beneficial glucose effect may be modulating abnormal heme synthesis.⁵³ Limit use of ethanol; alcohol excess has been implicated in fatal protoporphyria associated with liver failure.⁵⁴

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. See Camp Sundown.

Medication

The only oral photoprotective agent approved by the US Food and Drug Administration and widely used for the treatment of protoporphyria is a synthetic beta-carotene formulation now available over the counter as Lumitene. Cysteine has shown benefit in clinical trials. Pyridoxine was reported effective in 2 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.

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.

Photoprotectants

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.

Beta-carotene (Lumitene)

Exact mechanism of action not completely elucidated. Patient must become carotenemic before effects are observed. More than one internal light screen may be responsible for effects. May provide a limited level of photoprotection. Causes yellowing of skin (carotenoderma). Any photoprotection afforded increases slowly over 4- to 6-wk period after drug is commenced. When discontinued, skin color and benefit fade over several weeks.

Dosing

Adult

120-300 mg/d PO in divided doses

Pediatric

30-120 mg PO in divided doses

Interactions

Coadministration with vitamin A may result in additive toxic effects

Contraindications

Documented hypersensitivity; use by tobacco smokers may further increase risk of lung cancer

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in patients with renal or hepatic impairment; may increase risk for lung cancer in heavy smokers; may cause orange stools and diarrhea or loose stools at onset of therapy that tend to resolve with continued use

Antihistamines

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)

Nonsedating second-generation medication with fewer adverse effects than first-generation medications. Competes with histamine for H1 receptors on GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. Does not sedate. Available in qd and bid preparations.

Dosing

Adult

180 mg PO 2-3 h prior to sunlight exposure

Pediatric

<6 years: Not recommended
6-11 years: 30-60 mg PO 2-3 h prior to sunlight exposure
>12 years: Administer as in adults

Interactions

Toxicity increases with coadministration of erythromycin and ketoconazole

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

No data available on use while breastfeeding; reduce dose in renal insufficiency

Enteric adsorbents

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)

Polymeric resin that binds bile acids, porphyrins, and other molecules to form nonabsorbable complexes that are excreted unchanged in feces. 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.

Dosing

Adult

4 g PO tid ac; may increase to 24 g/d PO in divided doses

Pediatric

<6 years: Not established
>6 years: 2 g PO bid initially; may increase up to 8 g/d PO divided tid/qid

Interactions

Inhibits absorption of numerous drugs, including warfarin, thyroid hormone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, and penicillin G

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in constipation and phenylketonuria

Activated charcoal (Actidose)

Prevents absorption by adsorbing porphyrin in intestine. Multidose charcoal may interrupt enterohepatic recirculation and enhance elimination by enterocapillary exsorption. Does not dissolve in water. 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.

Dosing

Adult

25-100 g or 1 g/kg PO susp in 4-8 oz of water

Pediatric

<1 year: Not recommended
>1 year: Administer as in adults

Interactions

Effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer supplemental vitamins D, E, A, and K with long-term use

Antihistamines, H2 blocker

Produce blockade of H2 receptors.

Cimetidine (Tagamet)

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.

Dosing

Adult

Experimental doses reported for inhibiting heme synthesis: 400 mg PO bid to 800 mg PO qid; not to exceed 2400 mg/d (recommended)

Pediatric

Not established for experimental use in porphyrias

Interactions

Can increase blood levels of theophylline, warfarin, TCAs, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Elderly patients may experience confusional states; may cause impotence and gynecomastia in young males; may increase levels of many drugs; adjust dose or discontinue treatment if changes in renal function occur

Gallstone dissolution agents

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

Ursodiol (Actigall)

Shown to promote bile flow in cholestatic conditions associated with a patent extrahepatic biliary system. Decreases cholesterol content of bile, therefore reduces bile stone and sludge formation.

Dosing

Adult

10-15 mg/kg/d PO divided bid

Pediatric

20-30 mg/kg/d PO divided bid

Interactions

Decreased effect with aluminum-containing antacids, cholestyramine, colestipol, clofibrate, and oral contraceptives

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in patients with a nonvisualizing gallbladder

Heme analogues

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

Hemin (Panhematin)

Enzyme inhibitor derived from processed red blood cells and is an iron-containing metalloporphyrin. Previously known as hematin, a term used to describe the chemical reaction product of hemin and sodium carbonate solution.
Has anticoagulant effect and may cause thrombophlebitis at infusion site. Must be reconstituted from lyophilized powder. Reconstitute with human serum albumin 25% (132 mL of 25% human serum albumin to 1 vial of hemin [301 mg heme]).

Dosing

Adult

Dosing levels and intervals must be individualized based on clinical criteria
1-4 mg/kg/d IV over 10-15 min qd or qwk (or longer intervals); in severe cases, may repeat no earlier than q12h, not to exceed 6 mg/kg/24h; if given in conjunction with plasmapheresis, infuse after plasma exchange is complete

Pediatric

Not established

Interactions

May further increase effect of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Asymptomatic and reversible renal shutdown, oliguria, and increased nitrogen retention have occurred; no worsening of renal function observed with recommended dosages; infusion into a large vein or central venous catheter recommended to reduce risk of phlebitis; because reconstituted hematin is not transparent and particulate matter may not be visible, a 0.45-µm or smaller terminal filter should be placed in infusion line

Heme arginate

A heme analogue not available in the United States that would have similar uses to hemin as described above.

Dosing

Adult

3-4 mg/kg/d IV; dosing schedule individualized by clinical criteria over 3-4 d or longer or at longer intervals

Pediatric

Not established

Interactions

May further increase effect of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

Precautions

Not effective in repairing neuronal damage

Follow-up

Complications

• Severe neurological dysfunction (eg, encephalopathy, axonal polyneuropathy, respiratory failure) characteristic of attacks of acute porphyrias has been observed in persons with end-stage hepatic failure associated with protoporphyria.^48,49,55
• Pregnancy is not complicated by protoporphyria. Pregnancy does not cause worsening of protoporphyria. Photosensitivity may actually improve during gestation.⁵⁶

Prognosis

• In the absence of hepatic failure, individuals with erythropoietic protoporphyria have normal life expectancies.

References

1. Cox TM. Erythropoietic protoporphyria. J Inherit Metab Dis. Jun 1997;20(2):258-69. [Medline].

2. Parker M, Corrigall AV, Hift RJ, Meissner PN. Molecular characterization of erythropoietic protoporphyria in South Africa. Br J Dermatol. Jul 2008;159(1):182-91. [Medline].

3. DeLeo VA, Poh-Fitzpatrick M, Mathews-Roth M, Harber LC. Erythropoietic protoporphyria. 10 years experience. Am J Med. Jan 1976;60(1):8-22. [Medline].

4. Baart de la Faille H, Bijlmer-Iest JC, van Hattum J, Koningsberger J, Rademakers LH, van Weelden H. Erythropoietic protoporphyria: clinical aspects with emphasis on the skin. Curr Probl Dermatol. 1991;20:123-34. [Medline].

5. Todd DJ. Erythropoietic protoporphyria. Br J Dermatol. Dec 1994;131(6):751-66. [Medline].

6. Gouya L, Puy H, Lamoril J, et al. Inheritance in erythropoietic protoporphyria: a common wild-type ferrochelatase allelic variant with low expression accounts for clinical manifestation. Blood. Mar 15 1999;93(6):2105-10. [Medline].

7. Gouya L, Puy H, Robreau AM, et al. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet. Jan 2002;30(1):27-8. [Medline].

8. Whatley SD, Mason NG, Khan M, et al. Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease. J Med Genet. Aug 2004;41(8):e105. [Medline].

9. Gouya L, Martin-Schmitt C, Robreau AM, et al. Contribution of a common single-nucleotide polymorphism to the genetic predisposition for erythropoietic protoporphyria. Am J Hum Genet. Jan 2006;78(1):2-14. [Medline].

10. Goodwin RG, Kell WJ, Laidler P, et al. Photosensitivity and acute liver injury in myeloproliferative disorder secondary to late-onset protoporphyria caused by deletion of a ferrochelatase gene in hematopoietic cells. Blood. Jan 1 2006;107(1):60-2. [Medline].

11. Poh-Fitzpatrick MB, Wang X, Anderson KE, Bloomer JR, Bolwell B, Lichtin AE. Erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations. J Am Acad Dermatol. Jun 2002;46(6):861-6. [Medline].

12. Aplin C, Whatley SD, Thompson P, et al. Late-onset erythropoietic porphyria caused by a chromosome 18q deletion in erythroid cells. J Invest Dermatol. Dec 2001;117(6):1647-9. [Medline].

13. Poh-Fitzpatrick MB. Porphyrin-sensitized cutaneous photosensitivity: pathogenesis and treatment. Clin Dermatol. Apr-Jun 1985;3(2):41-82. [Medline].

14. Piomelli S, Lamola AA, Poh-Fitzpatrick MF, Seaman C, Harber LC. Erythropoietic protoporphyria and lead intoxication: the molecular basis for difference in cutaneous photosensitivity. I. Different rates of disappearance of protoporphyrin from the erythrocytes, both in vivo and in vitro. J Clin Invest. Dec 1975;56(6):1519-27. [Medline].

15. Bloomer JR. The liver in protoporphyria. Hepatology. Mar-Apr 1988;8(2):402-7. [Medline].

16. Gross U, Frank M, Doss MO. Hepatic complications of erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. Apr 1998;14(2):52-7. [Medline].

17. Anstey AV, Hift RJ. Liver disease in erythropoietic protoporphyria: insights and implications for management. Gut. Jul 2007;56(7):1009-18. [Medline].

18. Cripps DJ, Gilbert LA, Goldfarb SS. Erythropoietic protoporphyria: juvenile protoporphyrin hepatopathy cirrhosis and death. J Pediatr. Nov 1977;91(5):744-8. [Medline].

19. Rand EB, Bunin N, Cochran W, Ruchelli E, Olthoff KM, Bloomer JR. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria. Pediatrics. Dec 2006;118(6):e1896-9. [Medline].

20. McGuire BM, Bonkovsky HL, Carithers RL Jr, et al. Liver transplantation for erythropoietic protoporphyria liver disease. Liver Transpl. Dec 2005;11(12):1590-6. [Medline].

21. Brenner DA, Didier JM, Frasier F, Christensen SR, Evans GA, Dailey HA. A molecular defect in human protoporphyria. Am J Hum Genet. Jun 1992;50(6):1203-10. [Medline].

22. Risheg H, Chen FP, Bloomer JR. Genotypic determinants of phenotype in North American patients with erythropoietic protoporphyria. Mol Genet Metab. Sep-Oct 2003;80(1-2):196-206. [Medline].

23. Gross U, Frank M, Doss MO. Hepatic complications of erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. Apr 1998;14(2):52-7. [Medline].

24. Doss MO, Frank M. Hepatobiliary implications and complications in protoporphyria, a 20-year study. Clin Biochem. Jun 1989;22(3):223-9. [Medline].

25. Poh-Fitzpatrick MB, Whitlock RT, Leftkowitch JH. Changes in protoporphyrin distribution dynamics during liver failure and recovery in a patient with protoporphyria and Epstein-Barr viral hepatitis. Am J Med. May 1986;80(5):943-50. [Medline].

26. Mathews-Roth MM. Letter: Anemia in erythropoietic protoporphyria. JAMA. Nov 11 1974;230(6):824. [Medline].

27. Wahlin S, Aschan J, Bjornstedt M, Broomé U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol. Jan 2007;46(1):174-9. [Medline].

28. Wolff K, Honigsmann H, Rauschmeier W, Schuler G, Pechlaner R. Microscopic and fine structural aspects of porphyrias. Acta Derm Venereol Suppl (Stockh). 1982;100:17-28. [Medline].

29. Epstein JH, Tuffanelli DL, Epstein WL. Cutaneous changes in the porphyrias. A microscopic study. Arch Dermatol. May 1973;107(5):689-98. [Medline].

30. Bloomer JR, Rank JM, Payne WD, et al. Follow-up after liver transplantation for protoporphyric liver disease. Liver Transpl Surg. Jul 1996;2(4):269-75. [Medline].

31. Johnson JA, Fusaro RM. Broad-spectrum photoprotection: the roles of tinted auto windows, sunscreens and browning agents in the diagnosis and treatment of photosensitivity. Dermatology. 1992;185(4):237-41. [Medline].

32. Roelandts R. Photo(chemo)therapy and general management of erythropoietic protoporphyria. Dermatology. 1995;190(4):330-1. [Medline].

33. Mathews-Roth MM, Pathak UA, Fitzpatrick TB, Harber LC, Kass EH. Beta-carotene as an oral photoprotective agent in erythropoietic protoporphyria. JAMA. May 20 1974;228(8):1004-8. [Medline].

34. Mathews-Roth MM. Carotenoid functions in photoprotection and cancer prevention. J Environ Pathol Toxicol Oncol. Jul-Oct 1990;10(4-5):181-92. [Medline].

35. Mathews-Roth MM, Rosner B. Long-term treatment of erythropoietic protoporphyria with cysteine. Photodermatol Photoimmunol Photomed. Dec 2002;18(6):307-9. [Medline].

36. Ross JB, Moss MA. Relief of the photosensitivity of erythropoietic protoporphyria by pyridoxine. J Am Acad Dermatol. Feb 1990;22(2 Pt 2):340-2. [Medline].

37. Farr PM, Diffey BL, Matthews JN. Inhibition of photosensitivity in erythropoietic protoporphyria with terfenadine. Br J Dermatol. Jun 1990;122(6):809-15. [Medline].

38. Yamamoto S, Hirano Y, Horie Y. Cimetidine reduces erythrocyte protoporphyrin in erythropoietic protoporphyria. Am J Gastroenterol. Sep 1993;88(9):1465-6. [Medline].

39. McCullough AJ, Barron D, Mullen KD, et al. Fecal protoporphyrin excretion in erythropoietic protoporphyria: effect of cholestyramine and bile acid feeding. Gastroenterology. Jan 1988;94(1):177-81. [Medline].

40. Gorchein A, Foster GR. Liver failure in protoporphyria: long-term treatment with oral charcoal. Hepatology. Mar 1999;29(3):995-6. [Medline].

41. van Wijk HJ, van Hattum J, Baart de la Faille H, van den Berg JW, Edixhoven-Bosdijk A, Wilson JH. Blood exchange and transfusion therapy for acute cholestasis in protoporphyria. Dig Dis Sci. Dec 1988;33(12):1621-5. [Medline].

42. Dellon ES, Szczepiorkowski ZM, Dzik WH, et al. Treatment of recurrent allograft dysfunction with intravenous hematin after liver transplantation for erythropoietic protoporphyria. Transplantation. Mar 27 2002;73(6):911-5. [Medline].

43. Do KD, Banner BF, Katz E, Szymanski IO, Bonkovsky HL. Benefits of chronic plasmapheresis and intravenous heme-albumin in erythropoietic protoporphyria after orthotopic liver transplantation. Transplantation. Feb 15 2002;73(3):469-72. [Medline].

44. Gordeuk VR, Brittenham GM, Hawkins CW, Mukhtar H, Bickers DR. Iron therapy for hepatic dysfunction in erythropoietic protoporphyria. Ann Intern Med. Jul 1986;105(1):27-31. [Medline].

45. McClements BM, Bingham A, Callender ME, Trimble ER. Erythropoietic protoporphyria and iron therapy. Br J Dermatol. Mar 1990;122(3):423-4. [Medline].

46. Komatsu H, Ishii K, Imamura K, et al. A case of erythropoietic protoporphyria with liver cirrhosis suggesting a therapeutic value of supplementation with alpha-tocopherol. Hepatol Res. Nov 2000;18(3):298-309. [Medline].

47. Eichbaum QG, Dzik WH, Chung RT, Szczepiorkowski ZM. Red blood cell exchange transfusion in two patients with advanced erythropoietic protoporphyria. Transfusion. Feb 2005;45(2):208-13. [Medline].

48. Shehade SA, Chalmers RJ, Prescott RJ. Predictable and unpredictable hazards of erythropoietic protoporphyria. Clin Exp Dermatol. May 1991;16(3):185-7. [Medline].

49. Herbert A, Corbin D, Williams A, Thompson D, Buckels J, Elias E. Erythropoietic protoporphyria: unusual skin and neurological problems after liver transplantation. Gastroenterology. Jun 1991;100(6):1753-7. [Medline].

50. Meerman L, Verwer R, Slooff MJ, et al. Perioperative measures during liver transplantation for erythropoietic protoporphyria. Transplantation. Jan 1994;57(1):155-8. [Medline].

51. Morris SD, Mason NG, Elder GH, Hawk JL, Sarkany RP. Ferrochelatase gene polymorphism analysis for accurate genetic counselling in erythropoietic protoporphyria. Br J Dermatol. Sep 2002;147(3):572-4. [Medline].

52. Schneider-Yin X, Gouya L, Meier-Weinand A, Deybach JC, Minder EI. New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care. Eur J Pediatr. Oct 2000;159(10):719-25. [Medline].

53. Redeker AG, Sterling RE. The "glucose effect" in erythropoietic protoporphyria. Arch Intern Med. May 1968;121(5):446-8. [Medline].

54. Bonkovsky HL, Schned AR. Fatal liver failure in protoporphyria. Synergism between ethanol excess and the genetic defect. Gastroenterology. Jan 1986;90(1):191-201. [Medline].

55. Rank JM, Carithers R, Bloomer J. Evidence for neurological dysfunction in end-stage protoporphyric liver disease. Hepatology. Dec 1993;18(6):1404-9. [Medline].

56. Poh-Fitzpatrick MB. Human protoporphyria: reduced cutaneous photosensitivity and lower erythrocyte porphyrin levels during pregnancy. J Am Acad Dermatol. Jan 1997;36(1):40-3. [Medline].

Keywords

erythropoietic protoporphyria, erythrohepatic protoporphyria, congenital erythropoietic protoporphyria, protoporphyria, porphyria, light sensitivity, photoprotection, end-stage liver disease, endstage liver disease, ESLD, ferrochelatase, FECH

Contributor Information and Disclosures

Author

Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University; Professor of Medicine (Dermatology), University of Tennessee
Maureen B Poh-Fitzpatrick, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and New York Academy of Medicine
Disclosure: Nothing to disclose.

Medical Editor

Günter Burg, MD, Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland
Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Edward F Chan, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

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