Vesicles and Erosions in a Middle-aged Man With Diabetes

Over the past 8 years, fragile vesicles,painful ruptured bullae, and erosionshave developed on the sun-exposed skinof a 57-year-old man. Some of the vesicleserupt at sites of minor trauma; othersarise spontaneously. A corticosteroidcream prescribed by another practitionerfor presumed atopic dermatitisfailed to clear the lesions. Two of thepatient's sisters have similar lesions.The patient has type 2 diabetesmellitus, hypertension, and coronaryartery disease. His medications aremetformin and enalapril.Several erosions, vesicles, and bullaeare noted on the face, neck, legs,forearms, and the dorsa of the hands.Pink, atrophic scars cover healed lesions(Figure 1). Small bullae withnoninflamed bases are visible on thesecond finger of the left hand (Figure2). Posthealing hyperpigmentation withdystrophic calcification and white miliaare present (Figures 3 and 4). Excessiveperiorbital hair growth is noted.The photosensitivity, irritationand blistering, increased skin fragility,hypertrichosis, scarring, and pigmentdeposition raise the possibility of anaberration in porphyrin metabolism.In addition to an elevated bloodglucose level (which is attributed to thepatient's diabetes), laboratory studiesreveal high levels of uroporphyrins inthe urine and plasma and isocoproporphyrinand 7-carboxylporphyrin in thestool. Hepatic and plasma iron levelsare also elevated. A characteristicorange-red fluorescence is seen on aWood lamp examination of the urine.These findings confirm the diagnosisof porphyria cutanea tarda (PCT). Phlebotomy was initiated to treatthe hereditary PCT. The patient was lostto follow-up 6 months after diagnosis.PORPHYRIAS
The porphyrias comprise a numberof clinical disorders that resultfrom a genetic defect in enzymes ofthe heme biosynthetic pathway. Aspecific enzymatic defect in porphyriametabolism has been identified foreach of the disordersPCT is a hepatic porphyriacaused by decreased uroporphyrinogendecarboxylase activity, which is amid enzyme step in the heme biosyn-thetic pathway. This enzyme is presentprimarily in the liver and is foundin the red blood cells as well. Whenthe concentration is decreased or activityinhibited, carboxylated porphyrinis concentrated in the skin.Porphyrins are activated by UV-Brays and generate oxygen radicalsthat damage the skin.EPIDEMIOLOGY
PCT is the most frequently occurringporphyria in the UnitedStates.¹ About 20% of patients withPCT have inherited the disease as anautosomal dominant trait. Onset isusually delayed until adulthood; typically,patients present between ages30 and 50 years. No gender predilectionhas been noted; however, womenbetween ages 18 and 30 yearswho take oral contraceptives andmen older than 60 years who receiveestrogen therapy for prostate cancermay be at increased risk. Approximately25% of patients with the skindisease have a history of diabetesmellitus.The 80% of nonfamilial cases aresporadic, toxic, or acquired. Amongthe known precipitating factors ofthe acquired disorder are viral diseases-particularly HIV and hepatitisB and C virus infections-and longtermrenal hemodialysis. Excessivealcohol intake is a precipitant thatmay be related to the developmentof chronic liver disease. Certainhalogenated hydrocarbons containedin fungicides and herbicides, otherchemicals, and iron-overload statesmay precipitate or exacerbate thedisease.¹PRESENTATION
Photosensitivity with consequentabnormalities on exposed skin is thepredominant symptom. In additionto the vesicles, bullae, erosions, andatrophic scarring described in this patient,a pronounced purple-red color("heliotrope") can develop on the centralface, especially on the periorbitalareas. Dystrophic calcifications ofsclerotic cutaneous plaques can ulcerateand exude white calcific material;these lesions may be visible onx-ray films.Scleroderma-like skin changescan manifest as diffuse or circumscribed,waxy, yellowish white plaqueson sun-exposed areas of the face,neck, and trunk. Hypertrichosis mayproduce dark brown or black hair onthe temples and cheeks and, in severedisease, on the trunk and extremities.Hyperpigmentation caused by excessivemelanin production can alsooccur on the face. Occasionally, thehyperpigmentation may generalize.PCT has been associated with acutelymphoblastic and nonlymphoblasticleukemia.²DIFFERENTIAL DIAGNOSES
Chief among the conditions thatresemble PCT are other forms ofporphyrin anomalies. The differentialincludes the following:

• Variegate porphyria, or porphyriavariegata. The skin lesions associatedwith variegate porphyria and PCTare identical; however, variegate porphyriais characterized by an earlierage of onset, typically between ages15 and 30 years. This inherited conditionis associated with wide-rangingsystemic symptoms. GI manifestationsinclude acute attacks of abdominalpain, constipation, nausea, andvomiting. Depression and other psychiatricdisorders, coma, seizures,bulbar paralysis, sensory loss, paresthesias,and muscle weakness alsocan occur. Markedly elevated fecalprotoporphyrin levels are found inpatients with variegate porphyria;this enzyme is absent in the stool ofthose with PCT.
• Pseudoporphyria cutanea tarda. Thisis a distinctive cutaneous syndrome ofblisters and erosions that are indistinguishablefrom PCT lesions. Systemicporphyrin abnormalities are absent.Drugs that can provoke this conditioninclude naproxen, ibuprofen, tetracycline,nalidixic acid, dapsone, amiodarone,bumetanide, cyclosporine,etretinate, furosemide, chlorthalidone,diazine, and pyridoxine.^3,4
• Chronic renal failure. Porphyrin levelsincrease in some patients withchronic renal failure who are undergoinghemodialysis. In these patients,a dermatosis that is identical to PCTcan develop.
• Epidermolysis bullosa acquisita. Laboratorystudies may be needed torule out porphyria in the diagnosisof epidermolysis bullosa acquisita,which presents with skin fragility,light-induced lesions, and other clinicaland histologic features of PCT.
• Dyshidrotic eczema. This eruption issimilar in appearance to PCT; however,in contrast to the dorsal distributionof the porphyria, eczema involvesthe palms and soles.

MANAGEMENT

Discontinue medications thatmay precipitate the disease, and consideralternative agents. Counsel thepatient to avoid exposure to the sunand to chemicals that may provokethe disease, such as chlorinated phenols,hexachlorobenzene and otherfungicides, and herbicides. Recommendabstinence from alcohol consumption;some patients who completelyavoid alcohol have achievedclinical and biochemical remissionand normalized levels of iron storesin the liver.

^1,5

Phlebotomy is the treatment ofchoice to reduce hepatic iron storesand induce remission. About 500 mLof blood is removed weekly or biweeklyuntil the hemoglobin level decreasesto 10 g/dL or the serum iron levelfalls to between 50 and 60 μg/dL.6Remission usually is achieved within5 to 12 months of regular treatmentand may last from 6 months to 10years. As many as 20% of patients relapsewithin a year of treatment.

⁶

Chloroquine is an alternative forpatients in whom phlebotomy is contraindicated.When given in highdoses, the antimalarial agent can inducesevere hepatotoxicity; therefore,twice-weekly administration of lowdosechloroquine is given to achievedisease remission.Combination therapy has alsoproved to be effective. In this regimen,a short series of phlebotomy sessionsis completed before low-dose chloroquineis initiated.

References:

REFERENCES:

1. Cohen DJ, McKay M. Porphyria cutanea tarda: a clinical review. Compr Ther. 1996;22:175-178.

2. McKenna DB, Browne M, O’Donnell R, Murphy GM. Porphyria cutanea tarda and hematologicmalignancy: a report of 4 cases. Photodermatol Photoimmunol Photomed. 1997;13:143-146.

3. Rich MW. Porphyria cutanea tarda. Don’t forget to look at the urine. Postgrad Med. 1999;105:208-214.

4. Checketts SR, Morrison KA, Baughman RD.Nonsteroidal anti-inflammatory–induced pseudoporphyria:is there an alternative drug? Cutis. 1999;63:223-225.

5. Elder GH. Porphyria cutanea tarda. Semin Liver Dis. 1998;18:67-75.6. Freedberg IM, Eisen AZ, Wolff K, et al, eds.Fitzpatrick’s Dermatology in General Medicine. 5th ed.New York: McGraw-Hill; 1999:1790-1791.

FOR MORE INFORMATION:

• Lim HW. Role of viral infection in porphyria cutanea tarda. Photodermatol Photoimmunol Photomed.1997;13:75-77.
• McAlister F, McClean K, Hamilton PG, Houston S.Human immunodeficiency virus infection andporphyria cutanea tarda: coexistence of risk factorsor causative association? Clin Infect Dis. 1995;20:348-351.

• Murphy GM. The cutaneous porphyrias: a review.Br J Dermatol. 1999;140:573-581.

• O’Connor WJ, Badley AD, Dicken CH, MurphyGM. Porphyria cutanea tarda and human immunodeficiencyvirus: two cases associated with hepatitisC. Mayo Clin Proc. 1998;73:895-897.

• Smith KE, Fenske NA. Cutaneous manifestationsof alcohol abuse. J Am Acad Dermatol. 2000;43:1-16.

• Thadani H, Deacon A, Peters T. Diagnosis andmanagement of porphyria. BMJ. 2000;320:1647-1651.