Acta Dermatovenerol Croat 2007;15(4):254-263 REVIEW

Porphyria Cutanea Tarda as the Most Common

Vedrana Bulat, Liborija Lugović, Mirna Šitum, Marija Buljan, Lada Bradić 1

University Department of Dermatology and Venereology, Sestre milosrdnice University Hospital; 1Department of Pathophysiology, Zagreb University Hospital Center, Zagreb, Croatia

Corresponding author: SUMMARY are an uncommon, heterogeneous group Vedrana Bulat, MD of metabolic diseases caused by inherited or acquired deficiency of specific enzymes in the biosynthetic pathway resulting in University Department of Dermatology an excess of (red-brown pigments) and their precursors. and Venereology Accumulation of heme precursors, such as that are Sestre milosrdnice University Hospital spontaneously oxidized to porphyrins, is responsible for various clinical features. Porphyrias are classified into three groups: Vinogradska cesta 29 erythropoietic, hepatic and hepatoerythropoietic, depending on the HR-10000 Zagreb primary organ affected. Porphyria cutanea tarda (PCT) is the most Croatia common porphyria, characterized by defective III [email protected] decarboxylase enzyme. There are three types of PCT with typical skin manifestations. Patients with PCT present with skin fragility, erosions, vesicles, bullae, and milia in sun-exposed areas of the skin, Received: June 3, 2007 sometimes periorbital mottled hyperpigmentation and hypertrichosis, Accepted: September 20, 2007 sclerodermoid changes and ulceration. We present the most common pathogenetic, clinical, diagnostic, and therapeutic features of PCT and other types of porphyria.

KEY WORDS: porphyria, porphyria cutanea tarda,

INTRODUCTION Porphyrias are a heterogeneous group of met- taneously oxidized to their respective porphyrins, abolic diseases caused by inherited or acquired is responsible for various clinical features (1). deficiency of specific enzymes in the heme bio- Two main types of clinical manifestation include synthetic pathway resulting in an excess of por- life-threatening attacks of acute porphyria and phyrins and their precursors (porphyrin is a red- chronic skin photosensitization (3). Acute porphyr- brown pigment) (1). Porphyrias are classified into ias include acute intermittent porphyria, variegate three groups: erythropoietic, hepatic and hepato- porphyria, hereditary coproporphyria, and δ-ami- erythropoietic, depending on the primary organ af- nolevulinic acid (ALA) dehydratase deficiency, fected (Table 1) (1,2). while chronic porphyrias include porphyria cu- The accumulation of heme precursors in por- tanea tarda (PCT), erythropoietic porphyria and phyrias, including porphyrinogens that are spon- erythropoietic protoporphyria (3).

254 Bulat et al. Acta Dermatovenerol Croat Porphyria cutanea tarda 2007;15(4):254-263 Table 1. Hepatic erythropoietic Hepatic and Erythropoietic Type of porphyria Clinical features of porphyrias (modified according to Habif (3)) (HCP) coproporphyria Hereditary tarda (PCT) Porphyria cutanea (VP) Variegate porphyria porphyria (AIP) Acute intermittent porphyria Hepatoerythropoietic protoporphyria (EPP) Erythropoietic porphyria (CEP) erythropoietic Congenital AD (20%) AD (80%) Sporadic AD AD AR AD AR Heredity oxidase Coproporphyrinogen decarboxylase Uroporphyrinogen III oxidase Protoporphyrinogen synthase Hydroxymethylbilane decarboxylase Uroporphyrinogen Ferrochelatase III synthase Uroporphyrinogen Enzyme deficiency adulthood Young Middle age adulthood Young Adolescence Infancy Childhood Infancy Age at onset Same as PCT Acute features scleroderma-like scarring thickening Bullous lesions, Chronic Same as PCT Acute None Acute thickening severe scarring Bullous lesions, Chronic blisters thickening rarely Burning edema Chronic severe scarring Bullous lesions, Chronic manifestations Cutaneous Same as AIP siderosis liver function, Decreased Same as AIP psychosis neuropathy, Abdominal pain, function Decreased liver stones disease, gall Rarely fatal liver hemolytic anemia Red teeth, manifestations Extracutaneous during attacks and PBG Copro, ALA fluorescence continuous continuously Uro I >uro III copro>uro during attacks ALA and PBG continuously ALA and PBG Uro I III negative Uro I copro Urine continuously Copro III >copro coproporphyrin ISO porphyrin some copro X continuously Protoporphyrin Negative coproporphyrin Copro III ISO Copro I continuously Protoporphyrin Copro I Feces Negative Negative Negative Negative Protoporphyrin fluorescence transient Protoporphyrin fluorescence Uro I stable Erythrocytes

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Biosynthetic pathway of heme by mutation in the genes other than those directly Heme is synthesized in all nucleated cells, but involved in heme synthesis, e.g., mutation in the the majority is formed in hepatocytes and erythro- hemochromatosis gene. Clinical manifestation is blasts in bone marrow. Heme is necessary for the triggered by medications, hormones (particularly transport and metabolism of oxygen (4). The bio- progesterone), fasting and medical illness. synthetic pathway of heme starts in mitochondria Induction of ALA synthetase increases hepatic when the amino acid glycine (which is found in all heme synthesis and enzyme deficiencies become cells) and succinyl coenzyme A (derived from Krebs apparent as heme precursors accumulate. If heme cycle) are condensed to form ALA (Fig. 1) (5). This breakdown is increasing, the negative feedback reaction is catalyzed by 5-ALA synthase and is the loop causes direct induction of ALA synthetase rate limiting step in the biosynthetic pathway of and clinical manifestations of porphyrias become heme. The activity of the 5-ALA synthase enzyme apparent (5). Heme is the prosthetic group of pro- can be inhibited by heme, glucose and hematin. teins such as hemoglobin, myoglobin, catalase, The next stage of the pathway occurs in the cy- peroxidase and cytochrome P 450. Cytochrome tosol when two molecules of ALA are condensed P 450 is heme oxygenase (about 40% of the he- to form porphobilinogen, a molecule containing a patic heme is incorporated into enzyme), which monopyrrole ring. The reaction is catalyzed by 5- metabolizes a significant number of commonly ALA dehydratase. Then four porphobilinogen mol- used drugs. Medications cause direct induction of ecules are combined to form a linear , this enzyme, increasing its production, then lead hydroxymethylbilane by hydroxymethybilane syn- to heme reduction (heme is incorporated into cy- thase, and then the pathway splits (5). The uro- tochrome P 450) and the negative feedback loop -III cosynthetase enzyme cyclizes causes induction of ALA synthetase. The enzymes linear hydroxymethylbilane to uroporphyrinogen involving heme synthesis are defective and heme III, while in the absence of the enzyme uroporphy- precursors accumulate. Toxins including alco- rinogen I is formed. Uroporphyrinogen III is then hol, metals (iron), hexachlorobenzene and many converted by uroporphyrinogen III decarboxylase other chemical substances are metabolized in the (UROD) to its respective coproporphyrinogen III, liver by cytochrome P 450 and can cause clini- while is spontaneously con- cal manifestation of the most common cutaneous verted to coproporphyrinogen I. Only coproporphy- porphyria, PCT. Also, hepatitis C virus (especially rinogen III participates further in heme synthesis, in HIV-positive patients) can cause a mutation in being oxidized by coproporphyrinogen oxidase to the genes that affects directly transcription and/ protoporphyrinogen IX, which is returned to the or translation of the enzymes of heme synthesis mitochondria. It is then oxidized by protoporphy- (5,6). rinogen oxidase to protoporphyrin IX. At the end Porphobilinogens are oxidized to uroporphy- of heme synthesis iron is added by ferrochelatase rinogens, coproporphyrins and protoporphyrins, to protoporphyrin IX to make heme (5). Different and their solubility changes as they are metabo- forms of porphyrias are caused by enzyme defi- lized (5). Therefore, ALA, porphobilinogen and ciencies, starting from 5-ALA synthase and ending uroporphyrinogen are hydrophilic and excreted in with ferrochelatase, which are almost all inherited the urine, while coproporphyrin and protoporphy- in an autosomal dominant pattern (2,5). Low clini- rin are lipophilic and are found in the stool. cal penetrance of all the autosomal dominant por- Porphyrins (except for ALA and porphobilino- phyrias is an important feature (4). The enzyme gen) absorb the lower range of visible light in the deficiencies are permanent, but clinical symptoms Soret band (400-410 nm), and after exposure to of porphyrias are intermittent and usually do not visible light they show red fluorescence. This ab- present until after puberty, especially in PCT (the sorbed light energy is then transferred to cellular most common porphyria), acute intermittent por- structures of hepatocytes and erythroblasts, and . phyria and variegate porphyria (5) molecular oxygen is transformed into singlet oxy- For the disorder to become clinically manifest, gen. Free radicals and singlet oxygen peroxide an additional decrease in enzyme activity is re- phospholipids of the lysosomal biomembranes. quired, which may result from direct, organ spe- Potent degrading lysosomal enzymes, includ- cific inhibition of the enzyme, e.g., hepatocellular ing proteases, lipases and glycosidases lead to carcinoma, or from a mutation in the genes that tissue damage. After heme precursors in eryth- affects transcription and/or translation of enzymes rocytes have absorbed enough energy, photohe- of heme synthesis. These effects may be caused molysis occurs. Peripheral erythrocytes are no

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Figure 1. Biosynthesis of heme, with sites of enzyme deficiencies in porphyria; adapted from: Braun-Falco O, Plewig G, Wolff HH, Burgdorf WHC, eds. The porphyrias. In: Braun-Falco O, Plewig G, Wolff HH, Burg- dorf WHC, eds. Dermatology. 2nd completely revised edition. Berlin: Springer-Verlag; 2000. pp.1309-26. longer responsive to blood loss and hypoxia. An Classification and types of elevated reticulocyte count indicates an increased porphyria erythrocyte production compensating for the on- Traditionally, porphyrias have been divided going loss of erythrocytes (photohemolysis). into erythropoietic and hepatic, while accord- The most phototoxic porphyrin is protoporphy- ing to some authors porphyrias are classified as rin, which produces free radicals and singlet oxy- erythropoietic, hepatic, and hepatoerythropoietic gen that damage a variety of cellular structures. (Table 1) (1,5). Only one porphyria is purely eryth- Photoprotection from both UVA and the lower ropoietic, i.e. congenital erythropoietic porphyria, range of visible light is necessary in porphyria pa- which is an autosomal recessive variant, suggest- tients due to the peak activation of heme precur- ing that all reticulocytes have to miss the neces- sors in the Soret band (5). sary enzyme in order to manifest the disease. In

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erythropoietic protoporphyria, both red blood cells as skin sensitivity to light (photosensitivity), with and hepatocytes have enzyme deficiencies, while possible disfiguration and scarring (2). in other porphyrias the main problem is in hepato- The skin lesions in PCT, variegate porphyria, cytes (7-10). hereditary coproporphyria, and congenital erythro- Porphyrias have been classified by clinicians poietic porphyria manifest with mechanical fragil- as acute and chronic. Acute porphyrias include ity, subepidermal bullae, hypertrichosis, and pig- acute intermittent porphyria, variegate porphyria, mentation (3). Protoporphyrin is the predominant hereditary coproporphyria, and ALA dehydratase porphyrin in patients with erythropoietic protopor- deficiency, while chronic porphyrias include PCT, phyria. Protoporphyrin and Soret band radiation erythropoietic porphyria and erythropoietic proto- cause the release of mast cell mediators causing porphyria (3,11-13). Acute porphyrias are caused erythema and edema without skin lesions seen in by deficiency of the hepatic heme synthesis en- other types of porphyria. zymes, with the possible emergency admission for Laboratory diagnosis of porphyrias includes sudden attacks of abdominal pain, or may cause measurements of both relevant enzymes and neuropsychiatric symptoms (2,5). metabolites in plasma, urine, feces and erythro- There is also secondary porphyria caused cytes. The most important test for the diagnosis by acute lead poisoning. Lead blocks the action of acute porphyrias is the measurement of PBG of the ALA dehydratase enzyme and massive in urine and plasma (2). Then ALA accumulates amounts of ALA accumulate in the urine, where in the urine, where it serves as a marker of lead they serve as markers of lead intoxication, leading intoxication. to symptoms of acute intermittent porphyria. Lead It is also important to analyze urine (ALA, por- also causes increased fragility and decreased red phobilinogen and total urine porphyrins, mea- blood cell survival due to direct effect on the red sured by ion-exchange resins, chromatographic cell membrane. Patients with chronic renal failure photometric techniques, high-pressure liquid chro- on dialysis sometimes develop clinical manifes- matography) and erythrocytes (erythrocyte fluo- tations that are indistinguishable from the cuta- rescence determine erythropoietic protoporphyria neous lesions seen in PCT, and are associated and congenital erythropoietic porphyria), or to with increased carboxylated porphyrins, mainly measure porphobilinogen deaminase (high-pres- uroporphyrins, that accumulate in serum. Identify- sure liquid chromatography is needed to separate ing these uncommon porphyrins requires a highly various porphyrin products in the urine) and feces specialized laboratory (5). (high-pressure liquid chromatography)(5). All types of porphyria show excess of porphy- rin metabolites in the blood, urine or feces, and Porphyria cutanea tarda in various tissues such as skin and liver. Certain Porphyria cutanea tarda (PCT) (Günther 1922; porphyrin metabolites (porphyrinogens) accumu- Waldenström 1937; Ippen 1959) is the most com- late in the skin and are auto-oxidized to become mon porphyria, characterized by defective uro- porphyrins. Porphyrins absorb UVA light in Soret porphyrinogen III decarboxylase (UROD) enzyme band range, and these excited porphyrins gener- and includes three types of PCT with typical skin ate peroxides that cause blisters seen in PCT and manifestations (1,5). Patients present with skin variegate porphyria (3). fragility, erosions, vesicles, bullae, and milia in Acute intermittent porphyria (AIP) is caused by sun-exposed areas of the skin, sometimes perior- deficiency of the hydroxymethylbilane synthase bital mottled hyperpigmentation and hypertricho- enzyme that combines four porphobilinogen mol- sis, sclerodermoid changes and ulceration (Fig. ecules to form linear tetrapyrrole (Table 1). This 2). It is characterized by increased uroporphyrins type of porphyria is characterized by increased such as 8-,7-, 6-, 5-, and 4-carboxyl porphyrins in concentrations of 5-ALA and PBG in plasma urine and isocoproporphyrin in stool (1,14-16). and urine (2). Hereditary coproporphyria is acute There are three types of PCT: two types of he- porphyria due to the defect in the conversion of reditary PCT (types II and III) and acquired PCT coproporphyrinogen III to protoporphyrinogen III (type I). Acquired PCT (PCT type I) is the most (2). Variegate porphyria is acute porphyria char- common type of PCT (80% of patients with PCT) acterized by clinical manifestations that are indis- with negative family history. The disease is caused tinguishable from the cutaneous lesions seen in by mutation in the genes for the hepatic enzyme AIP. PCT and other porphyrias present clinically UROD, where the hepatic enzyme activity is

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It should also be noted that PCT patients have an increased risk of clinical relapse and hepato- cellular carcinoma, particularly those with long- standing untreated disease, and should be kept under surveillance. Although precise data on the epidemiology of PCT are lacking (more than a single enzyme defect is involved), it was observed that in aver- age dermatological practice, PCT accounts for 80%-90% of porphyria patients with an incidence of 1:25 000 (5). The male/female ratio has been reported to be 1:1 in both inherited types of PCT, but in the acquired form men are by far more fre- quently affected. Etiopathogenesis of PCT Figure 2. Classic clinical presentation of a patient Defective UROD activity results in the charac- with porphyria cutanea tarda. teristic porphyrin profile of PCT. In familial PCT, reduced by 50%, although the structural protein there are several genomic DNA mutations result- is present. In extrahepatic locations, the enzyme ing in defective UROD (indicating that it is a ge- structure and function are normal (17-19). netically heterogeneous entity) (1). Family history is positive in hereditary PCT The porphyrins absorb Soret band radiation, types II and III, and they are inherited in an au- generating reactive oxygen species. Free radicals tosomal dominant pattern. Hereditary PCT type II and singlet oxygen peroxide the phospholipids of is caused by a mutation in the genes that affects the lysosomal biomembranes. Potent degrading directly transcription and/or translation of the he- lysosomal enzymes, including proteases, lipases patic and erythrocyte enzyme UROD, while hered- and glycosidases, lead to tissue damage and re- itary PCT type III is caused by mutation only in the lease of inflammatory mediators, neutrophils, and genes of the hepatic enzyme UROD; the enzyme the activation of the complement system. The lack level is reduced to about 50% of normal in all tis- of direct effect of uroporphyrins (the predominant sues (1,5). porphyrin in patients with PCT) on mast cells ex- In the majority of patients, a mutation in the plain the manifestations of PCT, without erythema UROD gene is not enough to cause clinical mani- and edema. It has also been shown that uropor- festations of PCT (4). However, in contrast to the phyrins stimulate collagen synthesis by fibroblasts autosomal dominant acute porphyrias (with the in vitro, which may explain the sclerodermoid skin same enzyme activities, and symptoms present or lesions occurring both in sun-exposed and sun- not); in familial PCT the hepatic enzyme activity protected areas of the skin in porphyria patients is decreased to below half-normal in symptomatic (1,11). individuals. The hereditary types of PCT tend to have a The additional decrease in hepatic UROD ac- somewhat earlier onset in the first decades of life, tivity results from reversible inactivation by an while acquired cases of PCT typically appear after iron-dependent process, probably initiated by a the age of 30. number of possible triggers such as alcohol, hep- In hereditary and acquired forms of PCT, about atotropic viruses, iron intake, oral estrogens and 20% of patients, the family history of PCT is posi- genetic factors that may influence susceptibility to tive. It has been confirmed that both forms were these causes (4). trigerred by alcohol abuse (60%), estrogens There is a strong genetic association of co-inher- (25%) and liver disease (20%) (1). Association of itance of UROD and hemochromatosis (HFE) gene PCT with human immunodeficiency virus (HIV) mutations, resulting in the earlier onset of symp- infection and hepatitis C infection was confirmed toms. Other candidate predisposing genes include (1,14). ALAS 1 and cytochrome P 450 (4,10,11). However, Medications and hepatomas are responsible there is similar hepatic iron content in PCT patients for chronic reaction in 5% of patients with PCT, with and without HFE mutations, and clearly involv- while in about 10% of patients, the cause is un- ing other factors related to iron metabolism. known (5). Medications cause direct induction of

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the cytochrome P 450 enzyme in hepatocytes. Bullous lesions in PCT appear as noninflammed Cytochrome P 450 is heme oxygenase (about subepidermal blisters in sun-exposed skin, com- 40% of the hepatic heme is incorporated into the monly on the back of the hand, cheeks or temples, enzyme), which metabolizes a significant number ranging in size from a few millimeters to several of commonly used drugs. Thus, the medications centimeters, and are quite stable and painless in the hepatic porphyria lists can be employed for (5,15). The blisters rupture and may produce atro- routine use in PCT patients, but it is wise to avoid phic scars, hypo- and hyperpigmentation and mil- any potentially hepatotoxic medications in PCT pa- ia, producing a polymorphous clinical picture, but tients. High-dose chloroquine and hydroxychloro- patients almost never associate blisters with acute quine therapy causes acute reactions, but severe sunlight exposure and often deny photosensitivity reactions are rare. Besides medications, there are (Fig. 2). other triggering agents in PCT: alcohol (the ma- Other reversible lesions include hypertrichosis jor risk factor, acts at many levels of heme syn- as a common feature, often involving the tem- thesis); estrogens (oral contraceptives, replace- ples, connecting the eyebrows to the hairline and ment estrogens and estrogens given to males cheeks. Facial hyperpigmentation resembling me- with prostate cancer); iron (elevated hepatic iron lasma, and heliotrope discoloration are also mani- stores, often to twice normal), hexachlorobenzene festations of PCT (5,15). (e.g., PCT-like illness with chronic PCT changes, PCT patients often show chronic actinic dam- arthritis, neurologic problems and elevated fecal age, with possible Favre-Racouchot disease, and urine porphyrins in a region of southeastern diffuse actinic elastosis, deep furrows and wrin- Turkey where wheat seeds treated with hexachlo- kles. The presence of marked actinic damage in robenzene were used for food), and dioxin (5,8). a young patient should suggest the possibility of PCT (Birda sign) (5,15). Clinical features of PCT Sclerodermoid lesions (pseudoscleroderma) Genetic predisposition and exposure to se- are also seen in porphyria patients, mostly on the lected exogenous agents contribute to the cutane- skin of the lateral aspects of the face and neck, as ous manifestations of PCT (1). The disorder can firm and indurated skin, with small erosions, hem- start at any age in the autosomally dominant in- orrhagic areas, crusts or varioliform scars (5). herited form (types II and III), while the acquired form (type I) usually begins in adulthood. Several A number of patients have been reported with exogenous agents such as alcohol, estrogen, iron both PCT and lupus erythematosus, which is clini- overload and polychlorinated aromatic hydrocar- cally important, as high-dose chloroquine therapy bons precipitate the onset of PCT by contributing used in lupus erythematosus can cause acute re- to excessive hepatic porphyrinogenesis. The most actions in PCT patients (5). common clinical presentation of PCT is skin fragil- ity, manifested as erosions, vesicles or bullae in Laboratory findings in PCT sun-exposed areas, usually on the dorsa of hands Plasma porphyrin determination is a good and forearms (Fig. 2). Another typical aspect is in- screening test for all types of porphyria with cu- creased skin fragility, and thus the slightest trauma taneous manifestations. Diagnosis should only will damage the sun-exposed skin and the wound be made after evaluation of the complete por- healing is delayed. Bullae and erosions heal with phyrin profile in plasma, erythrocytes, urine, and hyper- and hypopigmented atrophic scars and mil- feces (1). ia. Other cutaneous changes include facial hyper- Porphyrin profiles are essential in differenti- trichosis along the temples and cheeks, periorbital ating PCT from two other less common types of mottled hyperpigmentation, sclerodermoid lesions porphyria, namely variegate porphyria and heredi- on both sun-exposed and sun-protected areas of tary coproporphyria (which can be clinically indis- the neck, face and chest, scarring alopecia; dys- tinguishable from PCT) (Table 1) (1). In variegate trophic calcification with ulceration, and rarely porphyria, the predominant porphyrin is copro- onycholysis (1,5). porphyrin, while ALA and porphobilinogen are in- There often are no sensations of discomfort fol- creased in urine during attacks (1). lowing sun exposure (such as burning and sting- Porphyrins can be identified by serum analy- ing), and no gastrointestinal and neuropsychiatric sis, which is of particular importance in renal di- symptoms. alysis patients, but urine analysis is crucial. The most appropriate test is 24-h urine evaluation;

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screening tests on spot urines are unreliable (5). It is important to think about possible histological There is a massive increase in all urine porphy- features of associated lupus erythematosus. The rins but coproporphyrins usually predominate. The clinical picture of sclerodermoid lesions may ap- urine may be discolored. Feces analysis is not pear as scleroderma, while histological features mandatory but also shows elevated levels of por- such as separation at the epidermal-dermal junc- phyrins and the presence of isocoproporphyrins is tion and amorphous perivascular material suggest taken as diagnostic. PCT. In addition, there is usually actinic elastosis There are several quantitative and qualitative or other elastic fiber changes, while in scleroder- measurement tests of porphyrins, including fluo- ma the elastic fibers are normal. rescence under Wood’s light (invisible long-wave The differential diagnosis of PCT includes drug- ultraviolet radiation at 360 nm), which is a non- induced pseudoporphyria, caused by medications specific finding but serves as a screening test in such as furosemide, nonsteroid anti-inflammatory PCT. If the level of porphyrins is too low, false- drugs; nalidixic acid and tetracycline, clinically in- negative result can be obtained. The 24-hour distinguishable from PCT, but porphyrin studies urine test is a quantitative measurement of por- are negative. Bullous lesions in patients with renal phyrins. If porphyrins are present, the urine may dialysis may be caused by the increased serum be amber-red or burgundy. In most forms of por- porphyrin. Epidermolysis bullosa acquisita may phyria, increased levels of porphyrins are found in look like PCT and can be diagnosed by the pres- the urine. The urine in PCT shows elevated level ence of antibodies to type VII collagen. Excessive of uroporphyrins (isomers I>III) and 7-carboxyl use of tanning beds cause blisters and increased porphyrin (isomers III>I), and lesser elevations of skin fragility independent of burning (5). 6-, 5-, and 4-carboxyl porphyrins. Urine tests are Direct immunofluorescence shows deposition not as accurate as fluorescent spectrophotometric of immunoglobulins and C3 at the basement mem- analysis of plasma. A sharp emission peak at 619 brane zone and in the walls of blood vessels in the nm confirms PCT. The test can also be done on superficial dermis (1). Indirect immunofluorescent a fresh stool specimen. In PCT the predominant examination is negative. stool porphyrin precursor is isomer III of isocop- The prognosis of PCT is good if the patient does roporphyrin, with lesser amounts of uroporphyrin, not have permanent liver damage and avoids fu- coproporphyrin, and 7-carboxyl porphyrin (1,15). ture hepatic insults. A small percentage of patients The analysis of erythrocytes for determination of either have a hepatoma or may develop one. UROD levels is used to separate the acquired Some clinicians consider PCT a paraneoplastic form (normal levels) from the familial form (50% marker and close monitoring is required (5). reduction). Other laboratory tests that should be performed Therapy of PCT include complete blood count (to assess hemoglo- It is important that complete elimination of al- bin and hematocrit levels prior to therapy), serum cohol, estrogen, iron, and environmental toxins iron, ferritin and total iron binding capacity (to as- results in clinical clearing of reversible skin lesions sess iron stores, which are increased in more than of PCT in 2 months to 2 years (1). Protection from 30% of patients), liver enzymes and hepatitis virus both ultraviolet and visible light is required, and (including hepatitis C) screen and ANA screening use of physical sun-blockers such as micronized (1,14). In patients who have risk factors for HIV titanium dioxide is recommended, while chemical infection, HIV serology should be considered. sunscreens do not effectively absorb the Soret Biopsy of a vesicle shows a characteristic sub- band. epidermal blister, with intact dermal papillae ris- Phlebotomy is the treatment of choice; 250-500 ing irregularly from the floor of the bullae into the mL of blood should be removed weekly or biweek- cavity and only sparse inflammatory cells in the ly until hemoglobin drops to 10 to 11 g/dL or until dermis. Thickened capillary walls in the superfi- serum iron drops to 50 to 60 µg/dL), but clinical cial dermis are best observed in sections stained improvement is not noticeable until 3 to 6 months with periodic acid Schiff (PAS) stain and represent and the time necessary for remission ranges from multiple layering of basal lamina, as detected by months to years (7,20,21). electron microscopy (1). Biopsy of a vesicle, which Oral antimalarial agents are quite effective and should include the edge of the lesion, is indicated some physicians use them as first-line therapy. For to differentiate PCT from other blistering diseases. example, chloroquine phosphate base, 125 mg

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twice weekly for 8-18 months in very low dosages Elsevier Limited; 2004. p. 347. may be given. Thereat, chloroquine forms a water- 3. Habif TP. Porphyria cutanea tarda. In: Habif soluble complex with porphyrins and uroporphyrins TP, editor. Skin disease diagnosis and treat- are rapidly eliminated by the urine. It also causes ment. 2nd edition. Philadelphia: Elsevier Mos- a minor hepatotoxic reaction with the release of by; 2005. pp. 368-71. porphyrins, which are excreted in the urine. They 4. Badminton MN, Elder GH. Molecular mecha- can also be useful in patients who are anemic, in nisms of dominant expression in porphyria. J HIV positive patients or in those that cannot tol- Inherit Metab Dis 2005;28:277-86. erate phlebotomy for other reasons. Chloroquine is usually used in very low dosages, as at higher 5. Braun-Falco O, Plewig G, Wolff HH, Burgdorf dosages severe hepatotoxic response may oc- WHC, editors. The porphyrias. In: Braun-Falco cur (5). During this therapy, liver function must be O, Plewig G, Wolff HH, Burgdorf WHC, editors. nd monitored carefully, especially at the beginning of Dermatology. 2 completely revised edition. therapy. Ocular toxicity is possible but unlikely at Berlin: Springer-Verlag; 2000. pp. 1309-26. such low dosages. Some clinicians prefer to com- 6. Herrero C, Vicente A, Bruguera M, Ercilla MG, bine chloroquine 125 mg twice weekly with more Barrera JM, Vidal J et al. Is hepatitis C infec- modest phlebotomies, usually 250 mL every other tion a trigger of porphyria cutanea tarda? Lan- week. It is important to measure plasma uropor- cet 1993;341:788-9. phyrin in order to monitor the progression of PCT. 7. Bickers DR, Poh-Fitzpatrick MB. Günther’s di- Therapy should be continued until plasma uropor- sease and the changing complexion of human phyrin drops below 10 mmol/L. porphyria. Photodermatology 1986;3:315-6. Other less commonly used treatments include 8. Bloomer JR. The liver in protoporphyria. He- cholestyramine, iron chelators, high-dose hydroxy- patology 1988;8:402-7. chloroquine, and erythropoietin (1,20,22). 9. Eales L, Day RS, Blekkenhorst GH. The clini- The iron load is nowhere near as high as in he- cal and biochemical features of variegate mochromatosis, so usually there is no use for the porphyria: an analysis of 300 case studies at aggressive regimens described for this disease (5). Groote Schuur Hospital, Cape Town. Int J Bio- The hemoglobin or hematocrit levels should not be chem 1980;12:837-53. driven below 12 g/dL or 36%, respectively. Serum 10. Lim HW. Pathophysiology of cutaneous lesions iron and urine porphyrin levels drop slowly as the in porphyrias. Semin Hematol 1989;26:114-9. clinical findings improve. Blistering and skin fra- gility improve first, often after several months, hy- 11. Lim HW, Gigli I, Wasserman SI. Differential pertrichosis and sclerodermoid changes may get effects of protoporphyrin and uroporphyrin better over years, while atrophic scars and white on murine mast cells. J Invest Dermatol milia are permanent skin lesions. 1987;88:282-7. Other approaches include the use of iron-bind- 12. Toback AC, Sassa S, Poh-Fitzpatrick MB, ing chelating agents, both orally and intravenous- Schechter J, Zaider E. Hepatoerythropoietic ly, and combining erythropoietin with phlebotomy porphyria: clinical, biochemical, and enzymatic in anemic patients. Local therapy in porphyria studies in a three-generation family lineage. N patients is usually not needed, except for routine Engl J Med 1987;316:645-50. wound care for eroded blisters. Sunscreens may 13. Nakahashi Y, Fujita H, Taketani S, Ishida N, reduce the chronic actinic changes but seem to Kappas A, Sassa S. The molecular defect of help little against blistering (5). ferrochelatase in a patient with erythropoie- tic protoporphyria. Proc Natl Acad Sci USA 1992;89:281-5. References 14. Cohen P. Porphyria cutanea tarda in human 1. Lim HW. The porphyrias. In: Sams WM, Lynch immunodeficiency virus-seropositive men: PJ, editors. Principles and practice of derma- case report and literature review. J AIDS tology. 2nd edition. New York: Churchill Livings- 1991;4:1112-7. tone; 1996. pp. 731-8. 15. Grossman ME, Bickers DR, Poh-Fitzpatrick 2. Baynes J, Dominiczak MH. Special liver fun- MB, Deleo VA, Harber LC. Porphyria cutanea ction. In: Baynes J, Dominiczak MH, editors. tarda: clinical features and laboratory findings Medical . 4th edition. Edinburgh: in 40 patients. Am J Med 1979;67:277-86.

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16. Held JL, Sassa S, Kappas A, Harber LC. Er- region of uroporphyrinogen decarboxylase as- ythrocyte uroporphyrinogen decarboxylase sociated with familial porphyria cutanea tarda. activity in porphyria cutanea tarda: a study Blood 1989;73:892-5. of 40 consecutive patients. J Invest Dermatol 20. Cainelli T, Di Padova C, Marchesi L, Gori G, 1989;93:332-4. Rovagnati P, Podenzani SA et al. Hydroxy- 17. Garey JR, Hansen JL, Harrison LM, Kennedy chloroquine versus phlebotomy in the treat- JB, Kushner JP. A point mutation in the coding ment of porphyria cutanea tarda. Br J Der- region of uroporphyrinogen decarboxylase as- matol 1983;108:593-600. sociated with familial porphyria cutanea tarda. 21. Ippen H. Treatment of porphyria cutanea tarda Blood 1989;73:892-5. by phlebotomy. Semin Hematol 1977;14:253- 18. Garey JR, Harrison LM, Franklin KF, Metcalf 62. KM, Radisky ES, Kushner JP. Uroporphyri- 22. Anderson KE, Goeber DE, Carson RW, Lee nogen decarboxylase: a splice site mutation SM, Stead RB. Erythropoietin for the treat- causes the deletion of exon 6 in multiple fami- ment of porphyria cutanea tarda in a patient lies with porphyria cutanea tarda. J Clin Invest on a long-term hemodialysis. N Engl J Med 1990;86:1416-22. 1990;322:315-7. 19. Garey JR, Hansen JL, Harrison LM, Kennedy JB, Kushner JP. A point mutation in the coding

By winter sport - Nivea cream; year 1936. (from the collection of Mr. Zlatko Puntijar)

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