Erythropoietic protoporphyria = البروتو بورفيريا المكونة للدم |
Erythropoietic protoporphyria
Erythropoietic protoporphyria is a genetic disorder most often 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: (1) a distinctive acute cutaneous photosensitivity typically appearing in childhood and (2) hepatobiliary disease.1,3,4,5
PathophysiologyProtoporphyrin 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,14 resulting in immediate phototoxic symptoms variously described as tingling, stinging, or burning that may be followed by the appearance of erythema, edema, and purpura.3,14 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.15 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.16 Toxic effects of protoporphyrin deposition in the liver may lead to life-threatening hepatic dysfunction.
HistoryUncomfortable 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. PhysicalThe 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. CausesThe ferrochelatase gene is located on band 18q21.3.23 Ferrochelatase mutations listed at the Human Gene Mutation Database numbered 124 as of May 2010. 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 94% of cases) have been found in most symptomatic individuals.8,9,24 This polymorphism enhances aberrant splicing and rapid degradation of ferrochelatase mRNA, with resultant low expression.7 The allele frequency of this polymorphism varies widely in diverse populations studied, as follows:
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
Laboratory StudiesProtoporphyrin 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.28,29 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.3,31 The mean corpuscular volume may be below the normal limit. Imaging StudiesIf cholelithiasis is suspected, abdominal ultrasonography or other imaging procedures are indicated. Other TestsImpending liver failure may be signaled by progressively rising levels of urinary coproporphyrin.29 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.28 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. ProceduresIn 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" ferrochelatase mutation that encodes an enzyme with essentially no residual activity, mutations of both ferrochelatase alleles, one of the aminolevulinic acid 2 increased-function mutations, or with a family history of protoporphyric liver disease, may warrant liver biopsy even before liver function tests become abnormal.18,19 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. Histologic FindingsLight 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.33 Biopsy specimens of chronically damaged skin show deposition of hyaline masses in the upper dermis and markedly thickened walls of upper dermal capillaries.34 Ultrastructural findings in chronically damaged skin include replicated basal laminae around dermal vessels, degranulated mast cells, and amorphous dermal deposits.34 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.34 Liver biopsy typically reveals brown pigment in hepatocytes, Kupffer cells, portal macrophages, and small biliary structures.16,22 Many of these protoporphyrin deposits are crystalline when examined under electron microscopy and birefringent when examined under polarization microscopy.16,22 Cirrhotic changes are seen in advanced disease, including fibrous expansion of portal areas and regenerative nodules
Medical CareFor 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.16,18,35
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. Medical approaches to reversing protoporphyric liver dysfunction are not well established, owing to inconsistent or uncertain efficacy and experience in relatively few cases. Note the following:
Surgical CareSurgical 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.53,54 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.55 These treatments may also aid postoperatively in retarding the development of protoporphyrin hepatotoxicity in the engrafted liver.47,48 ConsultationsConsultation 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.21,32 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.56,57 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.53,54 Filtering operating room lamps appropriately can block the most harmful portions of the visible light spectrum.55 DietDo not severely curtail carbohydrate intake; a beneficial glucose effect may be modulating abnormal heme synthesis.58 Limit use of ethanol; alcohol excess has been implicated in fatal protoporphyria associated with liver failure.59 ActivitySunlight 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. MedicationThe 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. PhotoprotectantsBeta-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. Vitamin A (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. Adult120-300 mg/d PO in divided doses Pediatric30-120 mg PO in divided doses Coadministration with vitamin A may result in additive toxic effects Documented hypersensitivity; use by tobacco smokers may further increase risk of lung cancer PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals PrecautionsCaution 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 AntihistaminesH1-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. Adult180 mg PO 2-3 h prior to sunlight exposure Pediatric<6 years: Not recommended Toxicity increases with coadministration of erythromycin and ketoconazole Documented hypersensitivity PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsNo data available on use while breastfeeding; reduce dose in renal insufficiency Enteric adsorbentsAgents 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. Adult4 g PO tid ac; may increase to 24 g/d PO in divided doses Pediatric<6 years: Not established 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 Documented hypersensitivity PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals PrecautionsCaution 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. Adult25-100 g or 1 g/kg PO susp in 4-8 oz of water Pediatric<1 year: Not recommended Effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases absorptive properties) Documented hypersensitivity PregnancyC - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus PrecautionsAdminister supplemental vitamins D, E, A, and K with long-term use Antihistamines, H2 blockerProduce 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. AdultExperimental doses reported for inhibiting heme synthesis: 400 mg PO bid to 800 mg PO qid; not to exceed 2400 mg/d (recommended) PediatricNot established for experimental use in porphyrias Can increase blood levels of theophylline, warfarin, TCAs, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine Documented hypersensitivity PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals PrecautionsElderly 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 agentsIncreasing 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. Adult10-15 mg/kg/d PO divided bid Pediatric20-30 mg/kg/d PO divided bid Decreased effect with aluminum-containing antacids, cholestyramine, colestipol, clofibrate, and oral contraceptives Documented hypersensitivity PregnancyB - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals PrecautionsCaution in patients with a nonvisualizing gallbladder |