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:
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Shield skin from sunlight by using protective clothing and lifestyle adjustments.
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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]
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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]
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Topical sunless tanning gels or creams containing dihydroxyacetone produce superficial pigmentation that blocks some of the offending wavelengths. [68]
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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]
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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.
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Attenuation of photosensitivity using oral cysteine or pyridoxine has been reported but not widely confirmed. [72]
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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]
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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:
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Reduction in erythrocyte protoporphyrin levels and improved liver function followed administration of vitamin E to a protoporphyric patient with cirrhosis. [82]
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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.
