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Update on PhotodermatosesFrank A. Santoro, MD, and Henry W. Lim, MD

Interactions with ultraviolet radiation (UVR) and chromophores in the skin happen on adaily basis. Photodermatoses, which are abnormal responses to UV exposure, can beclassified into subgroups based on pathogenesis. This review will discuss the clinicalfeatures, pathogenesis, photobiologic evaluation, prognosis and therapies of the mostcommon photodermatoses.Semin Cutan Med Surg 30:229-238 © 2011 Elsevier Inc. All rights reserved.

KEYWORDS photodermatoses, polymorphous light eruption, chronic actinic dermatitis,solar urticaria, erythropoietic protoporphyria, porphyria cutanea tarda, phototoxicity,

photoallergy

ah

Photodermatoses is a broad term referring to skin diseasesprovoked by exposure to ultraviolet (UV) radiation. It

can be classified into 4 groups: immunologically mediatedphotodermatoses, chemical- and drug-induced photosensi-tivity, photoaggravated dermatoses, and inherited disorderswith defective DNA repair or with chromosomal instability(Table 1).1 In this review we will discuss the clinical features,

athogenesis, photobiologic evaluation, prognosis, and ther-pies of the more commonly encountered photodermatoses:olymorphous light eruption, chronic actinic dermatitis, so-

ar urticarial, phototoxicity, photoallergy, porphyria cutaneaarda, and erythropoietic protoporphyria. (Table 2)2-5 lists

the characteristics of less commonly seen immunologicallymediated photodermatoses.

Approach to Patient withSuspected PhotodermatosesA detailed history, including the relationship between erup-tion and sun exposure, duration of lesions, effect of windowglass-filtered sunlight, exposure to photosensitizing agents,

Department of Dermatology, Henry Ford Hospital, Detroit, MI.Conflicts of Interest Disclosures: Dr Lim is the President Elect of the American

Board of Dermatology; has provided consultancy services to LaRocehPosay, Proctor & Gamble, and Clinuvel; and has received royalties forSunscreens & Photoprotection and Photodermatology. Dr Santoro has apending grant application for an educational project in dermatologythrough Wayne State University and has received Resident funding fromNeutrogena to attend the annual American Academy of Dermatologymeeting.

Address reprint requests to Henry W. Lim, MD, Department of Dermatol-ogy, Henry Ford Med Center – New Center One, 3031 West GrandBoulevard, Suite 800, Detroit, MI 48202. E-mail addresses:

fsantor1@hfhs.org (Dr Santoro); and hlim1@hfhs.org (Dr Lim)

1085-5629/11/$-see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.sder.2011.07.007

family history, age of onset, seasonal variation, and systemicsymptoms are important elements to consider. A skin exam-ination in which one focuses on the morphology and distri-bution, specifically involvement of the head, face, neck,arms, legs, and torso, and absence underneath the chin, un-derneath the lips, nasolabial folds, and postauricular area canprovide further diagnostic clues. Further investigations, suchas antinuclear antibody titers, skin biopsies, phototesting,photopatch testing, and porphyrin levels, might support di-agnoses.

Phototesting andPhotopatch TestingPhototesting and occasionally photopatch testing are impor-tant parts of evaluation. Phototesting involves exposing apatient’s skin to increasing doses of UVA, UVB, and visiblelight. An immediate assessment to evaluate for solar urticariaand a delayed assessment at 24 hours are performed. Theminimal erythema dose (MED) for UVA (MED-A) and UVB(MED-B), defined as the lowest dose of radiation that pro-duces perceptible erythema covering the entire irradiatedarea, is determined. Phototest responses in common photo-dermatoses are shown in Table 3.

Up to 10% of patients with photosensitivity will have apositive photopatch test.6 Photopatch testing involves thepplication of 2 sets of identical photoallergens. After 24ours, one set will be irradiated with UVA (10 J/cm2, or 50%

of MED-A if the MED-A is decreased), whereas the other setserves as a control and remains unexposed. A reading is per-formed at 24 hours and 7 days after irradiation. A photocon-tact allergic reaction is characterized by a reaction only on the

irradiated site. Positive reactions on both irradiated and unir-

229

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230 F.A. Santoro and H.W. Lim

radiated sites with equal intensity indicate a contact allergy tohe test substance. Positive reactions on both sites withreater intensity at the irradiated site indicate both contact andhotocontact allergy.

ImmunologicallyMediated PhotodermatosesPolymorphous Light EruptionClinical FeaturesPolymorphous light eruption (PMLE) is an immunologically

Table 1 Classification of Photodermatoses*

Immunologically mediatedActinic prurigoChronic actinic dermatitisHydroa vacciniformePolymorphous light eruptionSolar urticaria

Chemical- and drug-induced photosensitivityCaused by exogenous agents

Photoallergy (topical and systemic)Phototoxicity (topical and systemic)

Caused by endogenous agentsCutaneous porphyriasPellagra

Photoaggravated dermatosesAcne vulgarisAtopic dermatitisBullous pemphigoidCarcinoid syndromeCutaneous T-cell lymphomaDarier’s diseaseDermatomyostitisDisseminated superficial actinic porokeratosisErythema multiformeGrover’s diseaseLichen planusLupus erythematosusPemphigusPityriasis rubra pilarisPsoriasisReticular erythematous mucinosisRosaceaSeborrheic dermatitisViral infections

Inherited disorders with defective DNA repair or withchromosomal instability

Ataxia-telangiectasiaBloom syndromeCockayne syndromeHailey–Hailey diseaseHartnup diseaseKindler syndromeRothmund–Thomson syndromeTrichothiodystrophyXeroderma pigmentosum

*Modified from Lim et al.1

mediated photodermatosis that manifests as nonscarring er- d

ythematous, pruritic papules, vesicles, pinpoint papules,papulovesicles, plaques, and nodules that erupt usuallywithin a few hours of sun exposure (Fig. 1). Commonly in-volved sites include the dorsum of the hands, V-area of theneck, and sometimes, malar area of the face. Patients maycomplain of mild pruritus, whereas some also present withtenderness of the skin. Systemic symptoms, including chills,headache, fever, and nausea, can be observed in some pa-tients. For an individual patient, the same morphology usu-ally is present with each eruption. Pinpoint papules are morecommonly seen in patients with darker skin.7 In temperateclimates, the eruption worsens in early spring and improvesas the sunny season progresses; this is known as “hardening.”

Prevalence ranges from 10% to 20%, varying by geo-graphic location.8 PMLE is mostly seen in temperate latitudeswith initial eruptions observed in the spring. In a cohort of138 patients,9 females represented 61.6% of the patients.Sixty-six percent of patients developed PMLE before 30 yearsold, and 11% after 50 years of age.

PathogenesisThere is increasing evidence to indicate that delayed-typehypersensitivity immune reactions to ultraviolet radiation(UVR)-induced neoantigens of the skin plays a role in thepathogenesis of PMLE.10 It is recognized that UVR inducesneoantigens in the skin, although their nature is poorly char-acterized. UVR also has an immunosuppressive effect in theskin. In patients with PMLE, it has been demonstrated thatthey do not have the same degree of immunosuppressionafter exposure to UV, and hence are more likely to react tothese neoantigens, resulting in the development of skin le-sions.11 Proinflammatory markers, such as E-selectin, vascu-ar cell adhesion molecule-1, and intercellular adhesion mol-cule-1 and cytokines (interluekin-1, interleukin-18, andumor necrosis factor-alpha) have also been shown to bencreased in the skin of patients with PMLE.12

PhototestingAlthough many patients with PMLE have normal MEDs (Ta-ble 2), repeated exposure to UVA or UVB (ie, provocationphototesting) can elicit lesions of PMLE in more than 60% ofpatients.13 Testing with UVA (320-400 nm) has been moreffective than UVB (280-320 nm) and combined UVA/UVB atrovoking disease; the ease of PMLE provocation does notorrelate with clinical morphology or disease severity.

rognosisn a patient self-reported survey of 113 individuals on theatural course of PMLE,9 39% declared sun sensitivity re-

mained the same; 40%, increased, and 14%, decreased sunsensitivity. A minority of patients had intervals without erup-tions, however, the vast majority of them developed PMLElesions during the follow-up period.

When PMLE involves the malar area, cutaneous lupus er-ythematosus (LE) needs to be ruled out by appropriate sero-logic testing (antinuclear antibody, anti SSA/Ro antibodies).However, studies following patients with positive antinuclearantibodies (titer � 1:80) and PMLE have shown that PMLE

oes not progress into LE.14

Update on photodermatoses 231

TreatmentFirst-line treatment includes hardening of the skin with nar-rowband UVB (NB–UVB) in the early spring. The mechanismof UV hardening is most likely attributable to the induction ofimmunosuppression in these patients, who are less likely tobe immunosuppressed by exposure to sunlight during dailyactivity.15 In a cohort of 281 patients treated with NB–UVB,16

Table 2 Less Commonly Encountered Immunologically Media

Photodermatosis Clinical Findin

Actinic prurigo ● Age of presentation: childhood● Symptoms/timing: pruritic sensat

after sun exposure. Might have cdisease improves in the winter inand shows no variation in tropica

● Mucosal involvement is commonthe lip in 30%-60% of patients. Aexudative, yellow-crusted lesionsscaling lips are characteristic ofConjunctivitis and photophobia apatients.3

● Morphology: excoriated, papulesresolve with scarring. Chronic prlichenified plaques.

● Distribution: face, ears, forearmsfeet. Involvement of photo-protecreported, especially in patients reUnited Kingdom.

Hydroa vacciniforme ● Age of presentation: childhood● Symptoms/timing: pruritic and st

followed by the appearance of aneruption within a few hours afterWorsens in spring/summer.

● Morphology: the initial lesions arerythematous macules progressinundergo vesiculation and crustinhypopigmented varioliform scars

● Distribution: malar area, bridge odorsal hands and forearms

NB-UVB, narrowband UVB; PUVA, psoralen UV.

Table 3 Commonly Seen Results of Phototesting in Selected

Photodermatosis MED-A MED

Polymorphous light eruption nl(2 in 30%)

nl(2 in 30

Chronic actinic dermatitis 2 or nl 2 or nlSolar urticaria nl nl

Hydroa vacciniforme 2 2 or nlActinic prurigo 2 or nl 2 or nlPhotoallergy, topical nl nlPhotoallergy, systemic 2 nlPhototoxicity, topical nl nlPhototoxicity, systemic 2 nl

MED, minimal erythema dose; nl, normal.

*Modified from Lim et al.1

63% had no PMLE lesions after treatment, 26% had mildPMLE, and 11% did not respond. Treatment protocol con-sists of exposure to NB–UVB 3 times a week for 15 sessions,starting at 70% MED and increased as tolerated by 10%-20%each session. In patients who are exquisitely sensitive, alower starting dose and less aggressive dose increase shouldbe used. In some, oral prednisone (0.6-0.8 mg/kg/d) for the

hotodermatoses

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● Photoprotection● Symptomatic relief: topical and

systemic corticosteroids,antihistamines

● Beta-carotene, antimalarials-low doses of PUVA and NB–UVBwith patient-reported similarefficacy4

● Thalidomide (50-100 mg/d): mostconsistently effective treatment

● With the exception of thalidomide, itis often resistant to treatment.5

sensationematousxposure.

metricpapules that

ing deep,

, lips, ears, and

● Photoprotection● Beta carotene, omega 3

polyunsaturated fatty acids● NB–UVB phototherapy or PUVA● Antimalarials● Immunosuppressive medications:

cyclosporine, thalidomide, andazathioprine

dermatoses*

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first 7-10 days of hardening therapy may need to be admin-istered. Patients are advised to continue the hardening pro-cess at home with intermittent sun exposure (20-30 min ofmid-day summer sun exposure, without sunscreen); other-wise, the effect will be lost in 4-6 weeks.16 NB–UVB is com-parable with psoralen UV; it has gained favor over psoralenUV because it has fewer side effects.16

Other treatment modalities, such as antimalarials, betacarotene, nicotinamide, omega-3 polyunsaturated fatty ac-ids, Escherichia coli filtrate (colibiogen), and Polypodiumleucotomos extract have been reported to be helpful, butarge trials have not been performed to determine theirfficacy.13 Oral and topical corticosteroids treat an acute

flare, but they do not prevent future flares; the former canbe used (0.6-0.8 mg/kg/d) for 5-10 days in otherwise-healthy patients who wish to have a brief visit to sunnylocales during the winter.

Chronic Actinic Dermatitis (CAD)ClinicalThis is an immunologically mediated photodermatosis with acontact dermatitis-like reaction against sunlight-induced en-dogenous cutaneous antigens. Patients present with pruritic,lichenified eruptions involving photo-exposed skin, particu-larly on the face, back of the neck, and forearms and dorsalhands, often with a sharp demarcation from non-photoex-posed areas (Fig. 2). It spares the upper eyelids, fingerwebs,and postauricular area. Clinical variants range from acuteeruption of erythematous patches, papules and plaques tothe more characteristic chronic lesions, which are lichenified,excoriated plaques.

CAD has been reported in Europe, the United States, andAsia. It mostly affects older men. In a study of 178 patients,17

the age distribution was 6% in patients younger than 40 yearsof age, 43% between 40 and 59 years; and 51% older than 60years of age.

Hawk and Magnus18 coined the term CAD, unifying ob-

Figure 1 Polymorphous light eruption. Erythematous patches andplaque on sun-exposed sites.

served presentations of the same condition: persistent light

reactivity, actinic reticuloid, photosensitive eczema, photo-sensitivity dermatitis and actinic reticuloid syndrome. Threediagnostic criteria for CAD are (i) persistent, mostly photo-distributed, eczematous eruption, which might be associatedwith infiltrated papules and plaques; (ii) histologic findingsconsistent with chronic eczema with or without cutaneouslymphoma-like changes; (iii) abnormal results on phototest-ing to UVA and/or to UVB and/or to visible light.19 In a reportfrom the United Kingdom, patients often had allergic contactdermatitis to common or airborne allergens, especially plantantigens (such as Compositae plants), fragrances, and topicalmedications. In addition, CAD has been described in associ-ation with human immunodeficiency virus (HIV)20 andatopic dermatitis.21

PathogenesisThe pathogenesis of CAD is not completely understood. Thepresence of CD8� T-cell infiltrates in affected skin suggests a

elayed-type hypersensitivity immune reaction, likely tohoto-induced cutaneous autoantigen(s).22 The autoantigen

might be an altered carrier protein, nuclear material (RNA orDNA), or a native skin antigen (such as histidine) altered byUV radiation. Immunologic response to contact allergens,such as sesquiterpene lactone, colophony and fragrances isanother potential mechanism.22 In a British study researchersompared patch and photopatch testing in their patientsrom 1987 to 1992 and 2000 to 2005; they found a decreasen sesquiterpene lactone reactions and an increase in nonfra-rance consumer allergens, such as para-phenylenediaminend preservatives.23

Figure 2 Chronic actinic dermatitis. Erythema and lichenification on

sun-exposed site; note the relative sparing of postauricular area.

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Update on photodermatoses 233

PhototestingIn a study of 51 patients, the most common abnormal pho-totesting results were decreased MEDs to both UVA and UVB(65% of patients), followed by decreased MED to UVA alone(14%).24 In patients who have history of exposure to knownphotoallergens, photopatch testing is helpful. In contrast topatients in the United Kingdom, studies of patients seen inthe United States and Japan did not suggest an increase inincidence of positive photopatch tests.25

PrognosisIn a study of 178 patients, 10% of patients had resolution in5 years, 20% in 10 years, and 50% in 15 years.26 If photosen-sitivity resolves, any accompanied contact allergy usuallypersists. Two predictors of poor prognosis are severe UVBphotosensitivity and the presence of 2 or greater contact al-lergens.

TreatmentGiven the marked photosensitivity and wide action spec-trum, CAD proves difficult to treat. Photoprotection withbroad-spectrum UVA and UVB sunscreens is imperative, al-though it rarely provides complete clearance. In addition,clear museum film can be fitted to car windows to minimizeUV penetration.17 Some patients might respond to hardening

ith NB–UVB phototherapy, however; because many areighly sensitive to UVB, oral and topical corticosteroidshould be given to the patient before hardening.17

Systemic treatments include azathioprine (50-200 mg/d),hydroxychloroquine (200 mg daily or BID), mycophenolatemofetil, 25-40 mg/kg17 and for resistant cases, cyclosporine4-5 mg/kg).24 Of all the options, azathioprine is the only one

that has been studied in a double-blind, placebo-controlledmanner, while the others have been anecdotal cases or a smallcase series.

Solar UrticariaClinical FeaturesSolar urticaria (SU) is an uncommon photodermatosis char-acterized by the appearance of erythema and wheals after sunexposure. The wheals usually appear within 30 minutes ofsun exposure with spontaneous resolution within 24 hours.Common locations of eruptions include the V of the neck andarms. Pruritus, and in some, burning, are the primary symp-toms.

SU only accounts for 0.4% cases of urticaria.27 Because itccurs rarely, only case series have been reported. In onecottish study, investigators estimated prevalence in theiropulation of 3.1 per 100,000.27 Although most patients

have strictly symptoms of SU, there have been reports of SUin conjunction with PMLE and CAD. Associations with med-ications, porphyria, lupus erythematosus, or topical tar ap-plication have been reported.27

PathogenesisSU is thought to be mediated through a type I hypersensitiv-ity mechanism. A skin chromophore likely absorbs UV pho-tons and produces a photoallergen, which subsequently be-

comes recognized by specific IgE. The IgE in turn binds to

mast cells, causing the release of histamine and other inflam-matory mediators.27

PhototestingGiven the transient nature of the disease, phototesting fordisease provocation is an important diagnostic tool; evalua-tion should be done within 30 minutes of UV or visible lightexposure (Fig. 3). Reports of sensitivity to UV and visiblelight have been variable. In a group of 40 patients in Japan,Uetsu et al28 reported 60% of their patients were sensitive tonly visible light. In contrast, in a cohort of 84 patients stud-ed in Scotland, 6% were sensitive to UVA alone; 1.2% toVB alone; 31% to visible light alone; 42% to UVA andisible light; and 20% to UVA, UVB and visible light.27

PrognosisReports of natural history vary. One study reported clinicalresolution in 57.5% of patients after 5 years, and 82.5% after6 years.29 Another study showed less dramatic resolutionwith only 15% resolution in 5 years increasing to 24% and46% at 10 and 15 years, respectively.27

TreatmentOral antihistamines, topical corticosteroids, and cool com-presses can provide symptomatic relief of acute eruption. Forlong-term management, oral antihistamines and broad spec-trum sunscreens can be used; however, the latter would notbe very effective for patients with action spectrum extendingto the visible light range. For patients with visible light pho-tosensitivity, photoprotection needs to be achieved with sunavoidance, clothing, and opaque sunscreens. Systemicagents, such as antimalarials and beta carotene are of littlevalue. Although oral corticosteroids could suppress the erup-tion, their known side effects preclude their chronic use.

Figure 3 Solar urticaria. Urticaria 10 min after completion of expo-sure to increasing doses of UVB.

Mycophenolate mofetil and cyclosporine can be effective for

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*Adapted from Lim et al.33

234 F.A. Santoro and H.W. Lim

recalcitrant disease. Because the pathogenesis likely involvesa circulating antibody, both intravenous immunoglobulinand plasmapheresis have been used with some success.30

“Hardening” through phototherapy to UVA, UVB, or visi-ble light can be initiated,31,32 with UVA hardening being themost commonly used therapy. This consists of graduatedexposure to increasing doses of UVA. Because the effects ofhardening dissipate over a couple of days, patients are en-couraged to expose themselves to sunlight, or to continuewith maintenance phototherapy throughout the sunny sea-son.

Chemical- andDrug-Induced PhotosensitivityExposure to UV or visible light can alter topical and systemicagents into potent photosensitizers. Through mechanismsdetailed in the sections to follow, photosensitizing agentscause an irritant (phototoxic) or allergic (photoallergic) reac-tion. Table 433 lists common agents that cause these reac-tions.

PhototoxicityA phototoxic reaction begins when an agent absorbs photonsof energy, usually in the UVA spectrum, and causes excitationof the molecule. When these excited state molecules return totheir ground state, they transfer energy to surrounding oxy-gen, thereby inducing the generation of reactive oxygen spe-cies (ROS). The ROS cause cellular damage through the ox-idation of lipids, nucleic acids and proteins.34

Clinically, a phototoxic reaction resembles a sunburn.Painful erythema and occasional bilstering develop minutesto hours in sun-exposed skin. Less common manifestations,such as pseudoporphyria, photo-onycholysis, slate-gray hy-perpigmentation, and lichenoid eruptions have been re-ported. Removal of the offending agent results in resolution.

Voriconazole, a systemic, broad-spectrum antifungal, hasbeen associated with photosensitivity, photoaging, pseudo-porphyria, chelitis, and xerosis. Voriconazole does not ab-sorb UVA or UVB. However, its main metabolite, voricona-zole N-oxide absorbs UVA and UVB and may be thechromophore for phototoxicity.35 In patients with voricona-ole-induced photosensitivity who were treated for over aear, an association between aggressive squamous cell carci-oma35 and melanoma36 has been observed in photo-ex-

posed sites. The association with skin cancer warrants closeevaluation and follow-up of patients on voriconazole treat-ment of �1 year.

PhotoallergyPhotoallergic reaction requires sensitization of the immunesystem through a delayed-type hypersensitivity mechanism.UV radiation induces the chemical or drug to conjugate witha carrier product. This conjugation forms an antigen thatelicits an immune response.34 Upon reexposure to both theagent and the action spectrum, a delayed hypersensitivity

response occurs. Photoallergy can be induced by small

Table 4 Common Phototoxic and Photoallergic Medications*

PhototoxicMedications (Systemic)

PhotoallergicMedications

ntianxiety drugs AntimalarialAlprazolam QuinidineChlordiazepoxide Antimicrobials

ntiarrhythmics TopicalAmiodarone BithionolQuinidine Chlorhexidine

ntidepressants DibromosalicylanilideDesipramine, imipramine Tetrachlorosalicylanilide

ntifungals TribromosalicylanilideGriseofulvin FentichlorVoriconazole Hexachlorophene

ntimalarials TriclosanChloroquine SystemicQuinine Quinolones

ntimicrobials SulfonamidesQuinolones:

ciprofloxacin,enoxacin,oflaxacin

Fragrances6-methylcoumarinMusk ambretteSandalwood oil

Nonsteroidal anti-inflammatory drugs

KetoprofenPiroxicam

PhenothiazinesChlorpromazine,

promethazineSunscreen ingredients

SulfonamidesTetracyclines:

tetracycline,demeclocycline,doxycycline,minocycline

TrimethoprimntineoplasticsFluorouracilDacarbazine Benzophenoine-3, 4

Padimate-O, AHomosalate

MethotrexateVinblastineiuretics Menthyl anthranilate

para-aminobenzoic acid(PABA)

Avobenzone

FurosemideThiazides

ood additivesSulfites

urocoumarinsPsoralens

ypoglycemicsSulfonylureasTolbutamide, tolazamideGlyburideAcetohexamide

ypolipidemicsFibrates: bezafibrate,

clofibrate,Fenofibrateonsteroidal inflammatory

drugsCelecoxibIbuprofen, ketoprofenNaproxenPiroxicam

A

Update on photodermatoses 235

Table 5 Characteristics of the Porphyrias*

Clinical Features Enzyme DeficiencyElevated Porphyrins orPorphyrin Precursors

cute porphyriasAIP ● Acute neurological attacks

● Absence of photosensitivityand cutaneous signs andsymptoms

Porphobilinogen deaminase Urine: ALA, PBG

VP ● Cutaneous findings clinicallysimilar to PCT

● Acute attacks similar to AIP

Protoporphyrinogenoxidase

Urine: ALA, PBGFeces: protoporphyrin >coproporphyrin

Hereditarycoproporphyria

● Rare● Acute attacks clinically

similar to AIP● Erythema and blistering

Coproporphyrinogenoxidase

Urine: ALA, PBGFeces: coproporphyrin III >protoporphyrin

Delta-aminolevulinicacid dehydratase(ALA-D) deficiencyporphyria

● Extremely rare● Acute attacks clinically

similar to AIP● No photosensitivity or

cutaneous signs andsymptoms

Delta-aminolevulinic aciddehydratase

Urine: ALA

Nonacute porphyriasPCT ● Most common porphyria

● Clinically similar to VP● Moderate to severe

photosensitivity● Skin fragility, vesicles,

bullae, skin fragility,erosions, milia, scarring,hypertrichosis

Uroporphyrinogendecarboxylase

● Urine: isomer III of uroporphyrin,heptacarboxylporphyrins,coproporphyrin

● Feces: isocoproporphyrin

Erythropoieticprotoporphyria (EPP)

● Age of onset: childhood● Erythema, edema, purpura,

skin thickening, waxy scars● Can have liver disease

Ferrochelatase ● Urine: normal● RBC: protoporphyrin● Feces: protoporphyrin

CEP (Günther disease) ● Rare● Age: infancy● Severe clinical course with

vesicles, bullae, erosions,ulcers, scarring,hyperpigmentation,hypertrichosis, mutilation

● Hemolytic anemia,hepatosplenomegaly

● Porphyrins deposit in teethand bones

Uroporphyrinogen IIIsynthase

● Urine: uroporphyrin I,coproporphyrin I

● Feces: coproporphyrin I

Hepatoerythropoieticporphyria

● Rare; consideredhomozygote form of PCT

● Age: infancy● Most patients have severe

photosensitivity● Vesicles, bullae, skin

fragility, erosions, crusts,milia, scarring,hypertrichosis

Uroporphyrinogendecarboxylase

Identical to PCT, except forelevated RBC protoporphyrin

AIP, acute intermittent porphyria; ALA, delta-aminolevulinic acid; CEP, congenital erythropoietic porphyria; PBG, porphobilinogen; PCT,porphyria cutanea tarda porphyria; RBC, red blood cells; VP, variegate porphyria.

*Adapted from Sassa.37

wd

PEt

236 F.A. Santoro and H.W. Lim

amounts of the photoallergen. Currently, because of thewide-spread use, sunscreen actives are the most commonphotoallergen worldwide.

Clinically, a photoallergic reaction resembles contact der-matitis. Pruritic, eczematous eruptions confined to photo-exposed areas erupt in 1-2 days after repeat exposure. Histo-logic examination reveals spongiotic dermatitis. Removal ofthe offending agent causes resolution of the dermatitis. Top-ical and occasionally oral corticosteroids can hasten the res-olution.

PorphyriasThe porphyrias are uncommon metabolic conditions caused bydeficiencies in the activities of enzymes in the heme biosyntheticpathway. Although most of porphyrias are inherited, some areacquired. In addition to a genetic predisposition, environmentalfactors influence their clinical development. Table 537 lists theclinical features of the acute and nonacute porphyrias, their en-zyme deficiencies and notable biochemical findings. The 2 mostcommon types of cutaneous porphyrias will be reviewed: por-phyria cutanea tarda (PCT) and erythropoietic protoporphyria(EPP).

PCTClinicalPCT commonly presents in the fourth to fifth decade of lifewith skin fragility and tense, blisters on photo-exposed skin(Table 5). The vesicles and bullae break easily and leavebehind denuded areas which crust and heal slowly (Fig. 4).Periorbital hypertrichosis and hyperpigmentation are com-mon, whereas sclerodermoid skin changes (which can occurin nonsun exposed sites) are rare. Risk factors include infec-tion with hepatitis C virus and HIV, alcohol abuse, HFE genemutation (causes hereditary hemochromatosis), and estro-gen intake. The accumulation of porphyrins in the liver, inaddition to disease risk factors, leads to low-grade hepatocel-

Figure 4 Porphyria cutanea tarda. Skin fragility, manifested as ero-sions and crusting on traumatized areas.

lular damage. In some patients, without treatment, PCT can s

progress to liver failure and potentially hepatocellular carci-noma.38

Patients with PCT tend to develop glucose metabolismalterations years into their disease course. Associated riskfactors with PCT, combined with intrinsic features of PCT(porphyrin accumulation, chronic liver damage and ironoverload) likely contribute to the development of diabetesmellitus in patients with PCT.39

PathogenesisPCT has 3 subtypes, all associated with decreased hepaticuroporphyrinogen decarboxylase (UROD) activity: type I oc-curs sporadically with normal erythrocyte UROD activity;type II is familial with decreased erythrocyte UROD activity;and type III is also familial but has normal red blood cellUROD activity. The accumulated porphyrins in the skin arephotoactivated by electromagnetic radiation in the Soretband region (400-410). This interaction produces ROS thatcause cellular damage and lead to characteristic cutaneousfindings.37,38 The enzyme deficiency alone is insufficient toproduce the clinical symptoms of PCT, therefore, highlight-ing the importance of the aforementioned environmental andother risk factors in the production of clinically evident dis-ease.40

TreatmentAvoidance of precipitating factors (alcohol, estrogens) andphotoprotection are the first-line treatments. It should benoted that because the action spectrum is in the visible lightrange, only opaque sunscreens are effective. Notably, treat-ment of hepatitis C virus does not always improve PCT. Pe-riodic phlebotomy decreases outbreaks because iron is aknown porphyrinogenic agent. If phlebotomy is ineffectiveor if the patient has contraindications to phlebotomy, lowdose hydroxychloroquine (200 mg twice weekly) can be ef-fective. Antimalarials most likely chelates porphyrins andmakes them more soluble, thereby promoting renal excre-tion.37 Deferoxamine, a chelating agent, has also providedbenefit.41

Erythropoietic ProtoporphyriaClinicalImmediately after sun exposure, patients with erythropoieticprotoporphyria (EPP) usually have symptoms of burning andstinging. Because most children develop symptoms beforethey reach 2 years of age, they cry upon minimal sun expo-sure. Clinical findings include erythema, edema, and pete-chiae in photo-exposed areas. Typically there is an absence ofskin fragility, and blisters are rare. Chronic lesions manifestas lichenification and scarring on chronically exposed areas,such as knuckles of fingers and dorsum of the nose (Fig. 5).Ten percent of patients will develop hepatic injury,42 and 5%

ill develop liver failure. Currently, no markers exist to pre-ict individuals at risk of hepatic involvement.

athogenesisPP has a partial deficiency of ferrochelatase activity leading

o accumulation of protoporphyrin. The mechanism of EPP is

imilar to PCT with activation of the accumulated porphyrins

Update on photodermatoses 237

causing cellular damage. Because protoporphyrin is a lipo-philic 2-carboxyl porphyrin, a prominent target for photo-toxic injury is the endothelial cell. Thickening and hyaliniza-tion of the capillary basement membrane are observed onhistologic examination. In addition, accumulation of proto-porphyrin in the liver can cause direct hepatocyte toxicityand cholestasis.43

TreatmentIn addition to photoprotection and sunlight avoidance, beta-carotene has been reported with varying success as a treat-ment of EPP. Afamelanotide, an alpha melanocyte-stimulat-ing hormone analogue that induces melanin formation, hasbeen shown to improve tolerance to sunlight and less painfulepisodes in a small cohort of patients with EPP.44

Two medical treatments for hepatic disease includecholestyramine (encourages fecal excretion of protophyrin)and inducing iron overload (enhances the conversion of pro-toporphyrin to heme). In severe cases, bone marrow trans-plant might have a role in preventing end-stage liver dis-ease.45 If the patient progresses to end-stage liver disease,liver transplant might be indicated, but because it is notcurative of the underlying enzyme deficiency, EPP can causefibrosis of the transplant.45

ConclusionsThe diagnosis of photodermatoses requires a detailed historyand physical examination. Phototesting, bloodwork, andskin biopsies often confirm clinical suspicion. Improvementsin treatment modalities require understanding the mecha-nisms of diseases and conducting double-blind randomized,multicenter controlled trials. With more objective data, phy-sicians will better serve their patients in controlling the activ-

Figure 5 Erythropoietic protoporphyria. Waxing thickening of theknuckles secondary to repeated phototoxic injury.

ity of their disease.

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