Published on 19/03/2015 by admin
Filed under Dermatology
Last modified 22/04/2025
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Maureen B. Poh-Fitzpatrick
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
In this metabolic disorder, a genetically determined deficiency of ferrochelatase enzyme activity in bone marrow erythroid cells causes abnormally high protoporphyrin levels in erythrocytes, plasma, liver, bile, and feces. Protoporphyrin is a photoactive intermediary of heme synthesis. In the skin, its exposure to long wave ultraviolet (UV) or visible light radiation can elicit oxygen-dependent acute cutaneous phototoxicity. Protoporphyrin undergoes hepatobiliary excretion, facilitating cholelithiasis. Protoporphyrin hepatotoxicity may develop and progress to irreversible liver failure. Hypochromic microcytic anemia, when present, is typically mild and rarely requires treatment.
Protoporphyric photosensitivity is rarely managed adequately by sun avoidance alone (i.e., lifestyle changes, protective clothing, physical barriers). Topical sunscreens containing titanium dioxide, zinc oxide, iron oxide, or dihydroxyacetone block or filter long wave UV and visible light spectra, and may offer limited relief. Epidermal melanization and hyperplasia achieved with UVB or psoralen plus UVA (PUVA) phototherapy, or an α-melanocyte stimulating hormone analogue (afamelanotide), increase sunlight tolerance. Oral agents believed to photoprotect by quenching excited oxygen species include β–carotene, cysteine, vitamin E, vitamin C, flavonoids, and possibly pyridoxine. Antihistamines may attenuate phototoxic flaring. Gallstones are managed surgically. Exacerbators of protoporphyrin-induced hepatotoxicity (alcohol, cholestatic drugs, dietary carbohydrate restriction) are best avoided. Vaccination against hepatitis A and B is recommended. Deteriorating liver function is only sporadically reversible by enteric sorbents (cholestyramine, activated charcoal) that interrupt enterohepatic porphyrin circulation, bile acids (to stimulate biliary protoporphyrin secretion), blood transfusion or exchange, hematin infusion, or glucose loading (to retard endogenous porphyrinogenesis), iron (to increase protoporphyrin conversion to heme), or various combinations thereof. Cimetidine is postulated to inhibit porphyrinogenesis. End-stage liver disease warrants liver transplantation, aided by measures to reduce pre-, intra- and postoperative porphyrin levels (exchange transfusion, hematin infusion, plasmapheresis, vitamin E). Operating room lamps should be filtered to exclude wavelengths that can severely damage porphyrin-photosensitized skin and internal organs. Bone marrow transplantation has been curative in highly selected cases, and would be optimal prophylaxis against protoporphyric hepatopathy in original or transplanted livers.
Porphyrin analyses in erythrocytes, serum or plasma, urine, feces
Hematological profile, iron studies if anemic
Liver function profile, liver imaging and biopsy or non-invasive fibrosis assessment as clinically indicated
Liver failure occurs in <5% of all cases. Because urine is typically free of excess porphyrins in uncomplicated protoporphyria, surveillance for coproporphyrinuria may identify patients with asymptomatic hepatic dysfunction.
Lecha M, Puy H, Deybach JC. Orphanet J Rare Dis 2009; 4: 19.
A recent review of clinical, laboratory, genetic, and therapeutic aspects of the disease.
Doss MO, Frank M. Clin Biochem 1989; 22: 223–9.
Among 55 patients with protoporphyria, impaired liver function occurred in 19, cirrhosis in seven, and fatal liver failure in two. Coproporphyrinuria appeared early in the course of progressive protoporphyric hepatotoxicity.
Kaye ET, Levin JA, Blank IH, Arndt KA, Anderson RR. Arch Dermatol 1991; 127: 351–5.
Iron oxide increases the light-blocking efficacy and cosmetic acceptability of ‘white paste’ sunscreens containing zinc oxide or titanium dioxide.
Fusaro RM, Runge WJ. Br Med J 1970; 1: 730–1.
Seven patients had prolonged sunlight tolerance after applying a 3% dihydroxyacetone and 0.13% lawsone skin cream causing brown coloration of the stratum corneum.
Many ‘sunless tanning’ formulations contain dihydroxyacetone.
Mathews-Roth MM, Pathak MA, Fitzpatrick TB, Harber LH, Kass EH. Arch Dermatol 1977; 113: 1229–32.
Of 133 patients with protoporphyria, 84% had a threefold increase in sunlight tolerance after ingesting pharmaceutical-grade β-carotene.
The same efficiently absorbed β-carotene is available without prescription (Lumitene, Tischcon). Doses producing serum levels of approximately 800 µg/dL (30–120 mg/day in children, 120–300 mg/day in adults, in two to three doses with meals), should be started four to 6 weeks before seasonal symptoms are anticipated. Efficacy varies, and is often nil. Increased incidence of lung cancer among heavy smokers treated with β-carotene in cancer prevention clinical trials raises concern about its use in smokers.
Collins P, Ferguson J. Br J Dermatol 1995; 132: 956–63.
Six patients with protoporphyria had increased sunlight tolerance after serial narrowband UVB treatments.
Roelandts R. Dermatology 1995; 190: 330–1.
PUVA can increase sun tolerance in protoporphyria; other treatments are reviewed.
Harms J, Lautenschlager S, Minder CE, Minder EI. N Engl J Med 2009; 360: 306–7.
Afamelanotide increases skin melanization and may have other beneficial effects. Clinical trials of a subcutaneously implantable form have involved >200 protoporphyria patients worldwide. European Medicines Agency marketing approval is pending.
Mathews-Roth MM, Rosner B. Photodermatol Photoimmunol Photomed 2002; 18: 307–9.
Forty-seven patients received placebo for 1 month followed by cysteine 500 mg twice daily in this phase III 3-year trial. Patient history forms and light exposure diaries were kept; some patients were phototested. Cysteine significantly increased light tolerance subjectively and objectively.
This study expanded a double-blinded smaller trial suggesting the same benefit (Mathews-Roth MM, Rosner B, Benfell K, Roberts JE. Photodermatol Photoimmunol Photomed 1994; 10: 244–8).
Farr PM, Diffey BL, Matthews JNS. Br J Dermatol 1990; 122: 809–15.
Ingestion of this H1 receptor antagonist 60–120 mg twice daily for 48 days significantly reduced the flare surrounding, but not the erythema within, blue light phototest sites on seven subjects, compared to pretreatment reactions.
Antihistamines have not provided much relief in clinical practice.
Yamamoto S, Hirano Y, Horie Y. Am J Gastroenterol 1993; 88: 1465–6.
This H2 receptor antagonist (800 mg four times daily orally) was given to a patient with protoporphyric liver disease. Erythrocyte protoporphyrin fell from 16 000 µg/dL to 11 000 µg/dL during treatment. Inhibition of heme synthesis by cimetidine was postulated.
Only three porphyrin measurements were obtained: before and immediately after 2 weeks of cimetidine, and 2 weeks after discontinuation. More data are required to establish reproducibility and mechanism.
Komatsu H, Ishii K, Imamura K, Maruyama K, Yonei Y, Masuda H, et al. Hepatol Res 2000; 18: 298–309.
A patient with severe protoporphyric hepatopathy received intravenous vitamin E 500 IU/day. Erythrocyte protoporphyrin decreased significantly and liver function improved. Sixteen weeks later, full clinical and biochemical recovery was noted.
Vitamin E has been used sporadically in protoporphyria, usually as adjunctive therapy, but robust data supporting efficacy are lacking.
Boffa MJ, Ead RD, Reed P, Weinkove C. Photodermatol Photoimmunol Photomed 1996; 12: 27–30.
Vitamin C 1 g/day orally for 4 weeks was subjectively assessed by nine of 12 patients to be associated with less photosensitivity than placebo.
Antioxidants such as vitamins C and E are postulated to quench porphyrin-generated oxyradicals in vivo.
Ross JB, Moss MA. J Am Acad Dermatol 1990; 22: 340–2.
Two patients given oral pyridoxine dosages varying from 100 mg/day to 100 mg three times daily to 1 g each morning reported increased sunlight tolerance.
Schoemaker JH, Bousema MT, Zijlstra H, van der Horst FA. Dermatology 1995; 191: 36–8.
A flavonoid mixture was ingested by a patient for 3 months, during which time phototesting and subjective assessment indicated reduced photosensitivity.
Gordeuk VR, Brittenham GM, Hawkins CW, Mukhtar H, Bickers DR. Ann Intern Med 1986; 105: 27–31.
Carbonyl iron 400–4000 mg by mouth was given daily for 15 weeks to a patient with protoporphyria, iron deficiency anemia, and early liver dysfunction. Erythrocyte porphyrin fell, photosensitivity improved, and liver function normalized.
In a subsequent report on the same case, ferrous sulfate 300 mg daily by mouth was started when liver function and porphyrin levels worsened again. Liver function again normalized and remained stable for several years (Mercurio MG, Prince G, Weber Jr FL, Jacobs G, Zaim MT, Bickers DR. J Am Acad Dermatol 1993; 29: 829–33).
Holme SA, Thomas CL, Whatley SD, Bentley AV, Badminton MN. J Am Acad Dermatol 2007; 56: 1070–2.
A patient reported greater sunlight tolerance while taking oral ferrous sulfate 200 mg twice daily.
McClements BM, Bingham A, Callendar ME, Trimble ER. Br J Dermatol 1990; 122: 423–4.
Oral ferrous fumarate 580 mg/day was followed by florid photosensitivity in a patient previously tolerant of iron supplements. Abnormal liver enzymes improved and erythrocyte protoporphyrin diminished after iron discontinuation.
Iron supplementation in protoporphyria is contentious. Patients have been both better and worse after iron.
McCullough AJ, Barron D, Mullen KD, Petrelli M, Mukhtar H, Bickers DR. Gastroenterology 1988; 94: 177–81.
Ingesting cholestyramine 12 g, but not bile acids 300–900 mg, daily increased fecal protoporphyrin excretion threefold in one patient with hepatic dysfunction. Liver function and photosensitivity improved after 1 year of cholestyramine.
Bile acid ingestion was associated with improved liver function and erythrocyte porphyrin levels in another patient who eventually succumbed to liver failure (Doss MO, Frank M. Clin Biochem 1989; 22: 223–9). Efficacy remains uncertain, but bile acids in conjunction with an enteric sorbent in selected cases are rational therapy.
Gorchein A, Foster GR. Hepatology 1999; 29: 995–6.
A patient with deteriorating hepatic function given activated charcoal 10–12.5 g orally four times a day for 2 years exhibited improved liver function, and blood porphyrin and photosensitivity diminished.
Other treatments included blood transfusions, vitamin supplements, amiloride, ranitidine, and lactulose, so it is difficult to assess their relative merits.
Anstey AV, Hift RJ. Gut 2007; 56: 1009–18.
A detailed review of the pathogenesis of protoporphryic hepatopathy and recommendations for its monitoring and treatment.
Mcguire BM, Bonkovsky HL, Carithers RL, Chung RT, Goldstein LI, Lake JR, et al. Liver Transpl 2005; 11: 1590–6.
Experience with 20 protoporphyria patients receiving liver transplants in the US from 1999 to 2004 is reviewed, including preoperative use of hematin with or without plasmapheresis.
Wahlin S, Stal P, Adam R, Karam V, Porte R, Seehofer D, et al. Liver Transpl 2011; 17: 1021–6.
A comparable European review of 35 liver transplants performed from 1983 to 2008. Hematopoietic stem cell transplantation was performed for three patients to prevent graft loss due to disease recurrence. Offering curative stem cell transplantation to patients at high risk for liver failure to forestall liver transplantation is suggested.
Meerman L, Verwer R, Sloof MJH, van Hattum J, Beukeveld GJ, Kleibeuker JH, et al. Transplantation 1994; 57: 155–8.
Protocols for exchange transfusion and shielding of operating room lamps during liver transplantation are detailed.
Reichheld JH, Katz E, Banner BF, Szymanski IO, Saltzman JR, Bonkovsky HL. Transplantation 1999; 67: 922–8.
Three months of heme infusions (4 g daily to weekly), a high carbohydrate diet (300 mg/day), intravenous glucose, ursodeoxycholic acid (900 mg/day orally), and cholestyramine (10 g three times a day orally) initially improved severe liver dysfunction in a patient who then deteriorated and required urgent transplantation. Intensive heme infusions (daily for 18 days), plasmapheresis (exchanges of 1–1.5 × total plasma volume performed 12 times over 19 days) and blood transfusions (14 units packed cells over 19 days) reduced blood porphyrins prior to successful transplantation performed in an illumination filtered environment to exclude 300–480 nm wavelengths.
A barrage of medical therapy is typical in protoporphyric crises, when it is rational to consider any treatments that might reverse deterioration or contribute to successful transplantation. Subsequently, recurrent liver dysfunction was again successfully managed with heme-albumin and plasmapheresis (Do KD, Banner BF, Katz E, Szymanski IO, Bonkovsky HL. Transplantation 2002; 73: 469–7).
Dellon ES, Szczepiorkowski ZM, Dzik WH, Graeme-Cook F, Ades A, Bloomer JR, et al. Transplantation 2002; 73: 911–15.
Hematin given intermittently for 2 years after protoporphyric hepatopathy recurred 700 days after transplantation was well tolerated and aided the achievement and maintenance of disease remission in the allograft.
Poh-Fitzpatrick MB, Wang X, Anderson K, Bloomer JR, Bolwell B, Lichten AE. J Am Acad Dermatol 2002; 46: 861–6.
A symptomatic woman harboring two ferrochelatase gene mutations developed leukemia. Bone marrow transplantation from a mildly affected sibling with only one mutation and minimally elevated blood porphyrin resulted in marked reduction of the recipient’s protoporphyrin levels and cutaneous photosensitivity, as well as leukemia remission.
Rand ER, Bunin ER, Cochran W, Ruchelli E, Olthoff KM, Bloomer JR. Pediatrics 2006; 118: e1896–9.
Bone marrow transplanted 6 months after a liver transplant corrected the severe phenotype of a 14-year-old boy and halted further protoporphyrin-induced liver graft damage.
Wahlin S, Aschan J, Björnstedt M, Broomé U, Harper P. J Hepatol 2007; 46: 174–9.
Eighty days of medical management normalized liver biochemistry and improved histology in a man who then received a bone marrow transplant. Ten months following the transplant, liver and porphyrin tests were normal and no photosensitivity was reported.
Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e
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Topical sunscreens, physical barriers
β-Carotene
Phototherapy (UVB, PUVA)
Afamelanotide
Cysteine
Antihistamines
Vitamin E
Vitamin C
Pyridoxine
Flavonoids
Iron
Cholestyramine, activated charcoal
Blood transfusion or exchange
Hematin infusion
Plasmapheresis
Bile acids
Liver transplantation
Bone marrow transplantation
