Review

Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology Mary E. Horner1, MD, Ali Alikhan2, MD, Suzanne Tintle3, MD, Silvia Tortorelli4, MD, PhD, Dawn Marie R. Davis2, MD, and Jennifer L. Hand2, MD

1 Department of Dermatology, Baylor University Medical Center, Dallas, TX, 2 Department of Dermatology, Mayo Clinic, Rochester, MN, 3Department of Dermatology, Tufts Medical Center, Boston, MA, and 4Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

Correspondence Ali Alikhan, MD Department of Dermatology Mayo Clinic 200 First Street SW Rochester MN 55905 USA E-mail: [email protected]

Abstract The porphyrias are a group of disorders characterized by defects in the heme biosynthesis pathway. Many present with skin findings including photosensitivity, bullae, hypertrichosis, and scarring. Systemic symptoms may include abdominal pain, neuropsychiatric changes, anemia, and liver disease. With advances in DNA analysis, researchers are discovering the underlying genetic causes of the porphyrias, enabling family members to be tested for genetic mutations. Here we present a comprehensive review of porphyria focusing on those with cutaneous manifestations. In Part I, we have included the epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Treatment and management options will be discussed in Part II.

Conflicts of interest: None.

Introduction The porphyrias are a group of disorders characterized by defects in heme production, resulting in buildup of toxic heme precursors (Table 1). Cutaneous findings are common and include photosensitivity, painful burning, bullae, and scarring. Diagnosis requires laboratory measurement of heme precursors in plasma, urine, stool, and erythrocytes. Heme is made from glycine and succinyl-coenzyme A in eight steps (Fig. 1). Heme synthesis is ubiquitous throughout the body, but 85% occurs in bone marrow, becoming hemoglobin.1 Porphyrias are classified into two categories based on whether heme precursors build up in the liver (hepatic porphyrias) or bone marrow (erythropoietic porphyrias). Hepatic porphyrias are subdivided into acute and chronic subtypes, and tend to have secondary triggers (e.g., drugs, alcohol, hormone fluctuation, infection, and fasting). Acute hepatic porphyrias present with episodes (acute attacks) of abdominal or neurological symptoms caused by a genetic predisposition with a secondary metabolic trigger. Porphyria cutanea tarda (PCT), the only chronic hepatic porphyria, has a prolonged course of liver damage and photosensitivity. Erythropoietic porphyrias present in childhood with

photosensitivity. While the main defect lies in the erythrocytes, the liver may also be involved. Materials and methods A comprehensive literature search was initially performed using PubMed. Broad searches were performed using the terms “porphyria,” “coproporphyria,” and “protoporphyria” in the title, and “skin diseases, genetic” in the medical subject heading, but excluding for medical subject heading “acute intermittent.” Articles from January 1, 1960, through November 8, 2009, were included. Our search yielded 689 articles, but only nine addressed hereditary coproporphyria; another search was conducted using “hereditary” and “coproporphyria” from January 1, 1994 through February 27, 2010 (of note, coproporphyrinogen oxidase [CPO] was localized to chromosome 3q12 in 1994), which yielded 103 articles. Searches were also performed on GoogleTM Scholar and Embase.

Acute hepatic porphyrias The four acute hepatic porphyrias include acute intermittent porphyria, variegate porphyria (VP), hereditary coproporphyria (HCP), and aminolevulinic acid (ALA) dehydratase-deficient porphyria. They are indistinguish-

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Table 1 Symptoms and heme precursor changes in each of the cutaneous porphyrias

Review

100

Symptoms

Blood/plasma

Urine

Stool

PCT

Fragility, bullae, hypertrichosis, pigment, and sclerodermoid changes

Fluorescence emission peak at 620 nm (plasma)

⇑⇑ Isocoproporphyrin ⇑ Heptacarboxylporphyrin III

VP

PCT-like skin findings  neurovisceral attacks

Fluorescence emission peak at 626 nm (plasma)

HCP

Neurovisceral acute attacks  PCT-like skin findings

Fluorescence emission peak at 620 nm (plasma) (⇑ Zinc–protoporphyrin – RBC)

CEP

Bullae on sun-exposed areas leading to superinfection, scarring, bone resorption, eye changes, hepatosplenomegaly, etc. Onset ranges from hydrops fetalis to mid-adulthood Burning pain after sun exposure; 5% have hepatic complications Severe photosensitivity in childhood

⇑ Uroporphyrin I ⇑ Coproporphyrin I ⇑ Protoporphyrin (in RBC)

⇑⇑⇑ Uroporphyrin ⇑ Heptaporphyrin ⇑ Other porphyrinsa ⇑⇑⇑ ALA and PBG ⇑⇑ Coproporphyrin ⇑ Uroporphyrin ⇑⇑ ALA and PBG ⇑⇑ Coproporphyrin ⇑ Uroporphyrin ⇑⇑ Uroporphyrin I ⇑⇑ Coproporphyrin I

⇑ Free protoporphyrin (in RBC)

Normal

⇑ Protoporphyrin

⇑ Zinc protoporphyrin (RBC) Fluorescence emission peak at 620 nm (plasma)

⇑⇑ Uroporphyrin ⇑ Coproporphyrin

⇑⇑ Coproporphyrin ⇑⇑ Uroporphyrin

EPP HEP

⇑⇑⇑ Protoporphyrin IX ⇑ Coproporphyrin III–I ratio ⇑⇑ Ratio coproporphyrin III–I > 2.0 (usually >10) ⇑ Coproporphyrin I

⇑, increased; CEP, congenital erythropoietic porphyria; EPP, erythropoietic protoporphyria; HCP, hereditary coproporphyria; HEP, hepatic erythropoietic porphyria; PCT, porphyria cutanea tarda; VP, variegate porphyria. a Pentacarboxyporphyrin, hexacarboxyporphyrin, heptacarboxyporphyrin.

able during an acute episode, but 60–80% of patients with VP and 5–20% of patients with HCP have cutaneous symptoms.2 Variegate porphyria

Epidemiology Variegate porphyria is rare, with a reported prevalence of 0.5–2 per 100,0003 but more common in South Africa, affecting 1 in 300 people due to a founder effect.4 VP usually presents between 20 and 40 years of age. Most patients are heterozygous carriers of a protoporphyrinogen oxidase (PPO) enzyme mutation. Twelve cases have been reported with homozygous PPO mutations with severe disease in infancy, mental retardation, hand deformities, and nystagmus.4–6 While VP affects men and women equally, women are more likely to suffer acute neurovisceral attacks, and men are more likely to have cutaneous manifestations.7 Pathogenesis Protoporphyrinogen oxidase, the enzyme deficient in VP, is located on the mitochondrial membrane and catalyzes the seventh step in heme biosynthesis. Because PPO deficiency decreases levels of heme, hepatic ALA synthase is upregulated, such that porphyrins and other heme precursors accumulate in the liver and disperse throughout the body.4 Deposition predisposes to cutaneous symptoms and acute neurologic attacks.3 Factors that induce ª 2013 The International Society of Dermatology

the cytochrome p450 system increase the demand for heme, and can trigger an attack.4 Variegate porphyria is an autosomal dominant (AD) disorder with incomplete penetrance affecting only about 40% of carriers.8 Most individuals worldwide have a unique mutation,3,9 with the exception of South African patients (share a common founder mutation R59W)4 and Chilean patients (share a common founder mutation1239delTACAC).10 Presentation Variegate porphyria can present with skin lesions alone (similar to those in PCT), acute systemic attacks alone, or both.9 Acute attacks may involve abdominal pain, hypertension, fever, neurologic changes, and/or respiratory paralysis.9 Diagnosis is frequently delayed, resulting in a 10% mortality rate.11 Diagnosis Variegate porphyria diagnosis is made in three ways: (1) clinical symptoms with elevated fecal protoporphyrins; (2) plasma fluorescence emission spectrum of 626 nm; and/or (3) low lymphocyte PPO activity. Although PPO enzymatic testing is not available in the USA, direct DNA testing of the PPO gene is performed at the Mayo Clinic (Minnesota) and at the Mount Sinai Genetic Testing Laboratory (New York). Patients with VP have elevated fecal protoporphyrin and coproporphyrin both during attacks and remissions, International Journal of Dermatology 2013, 52, 1464–1480

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Mitochondria

Succinyl CoA + glycine

1

 δ-Aminolevulinic acid synthase

δ-aminolevulinic acid

(ALA synthase)

δ-aminolevulinic acid

Cytosol

X-linked hereditary sideroblastic anemia

2 

ALA dehydratase deficient porphyria

3  Porphobilinogen demainase

Acute intermittent porphyria

δ-Aminolevulinic acid dehydratase (ALA dehydratase) Porphobilinogen

Hydroxymethylbilane

4 

Congenital erythropoietic porphyria

Uroporphyrinogen III synthase & Uroporphyrinogen III cosynthase

Uroporphyrinogen III + uroporphyrinogen I

5 

Uroporphyrinogen III decarboxylase

Coproporphyrinogen III + coproporphyrinogen I

Porphyria cutanea tarda Cytosol Mitochondria

Coproporphyrinogen III

6 

Coproporphyrinogen III oxidase

Hereditary coproporphyria

Protoporphyrinogen IX

7 

Protoporphyrinogen IX oxidase

Variegate porphyria

Protoporphyrin IX

8 

Ferrochelatase

Heme

+ Globin Hemoglobin

+

Erythropoietic protoporphyria

Apoprotein Cytochromes

Figure 1 Hemoglobin biosynthesis pathway and associated porphyrias. The porphyrias with cutaneous manifestations are in bold.100,103–106 Numbers on the left side of the figure refer to enzymatic steps. AIP, acute intermittent porphyria; ALA, aminolevulinic acid; CEP, congenital erythropoietic porphyria; EPP, erythropoietic protoporphyria; HCP, hereditary coproporphyria; PCT, porphyria cutanea tarda; VP, variegate porphyria

with protoporphyrin more concentrated than coproporphyrin.4 Fecal porphyrin analysis is highly specific for VP, but is only 80% sensitive, making it a poor screening test for asymptomatic patients.4,12 Although urinary ALA and porphobilinogen (PBG) are increased during severe acute attacks, they can be normal during mild attacks and are nonspecific for VP.4 Plasma analysis of symptomatic patients with VP reveals a characteristic fluorescence emission spectrum at 626 nm.7 Fluorometric emission analysis is specific and inexpensive, but is only 50% sensitive and not regularly employed for screening.13 As the PPO protein is located on the mitochondrial membrane, it can only be measured in lymphocytes, liver tissue, or fibroblast culture (patients that have 80% lower

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PPO plasma levels than controls).14 This analysis, however, is difficult to perform and not widely available.15 Histopathology Affected skin shows periodic acid-Schiff (PAS)-positive depositions in the basement membrane and thickened superficial dermal vessels, with blistering occurring below the lamina densa. Immunofluorescence demonstrates IgG and fibrinogen deposition in vessel walls of sun-exposed skin. Hereditary coproporphyria

Epidemiology Hereditary coproporphyria is very rare, with a reported prevalence of about 1 in 100,000.16 Acute attacks affect

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women more often than men (2.5 : 1 to 19 : 1, by region).16 Pathogenesis Hereditary coproporphyria is caused by deficiency of the mitochondrial enzyme CPO, which catalyzes the sixth step of heme synthesis (Fig. 1). It is an AD disorder with incomplete penetrance, affecting about 30% of carriers.16 In addition to usual porphyria triggers, hormonal abnormalities have also triggered HCP, and women tend to become symptomatic with menarche or initiation of contraceptive therapy.17 CPO activity is decreased by 50% in heterozygotes and by 98% in homozygotes.18 Rare homozygous cases have been reported in childhood with severe hemolytic anemia, jaundice, and hepatosplenomegaly.18 A rare homozygous erythropoietic variant of HCP is harderoporphyria, which presents with fetal hemolytic anemia and sometimes photosensitivity. Harderoporphyrin is excreted in large amounts and can be measured in stool. Presentation Symptoms usually begin after puberty. About one-quarter of patients with HCP have skin phototoxicity along with neurovisceral attacks, but isolated skin symptoms are uncommon. Kuhnel et al.18 classified symptoms as abdominal (89%), neurologic (33%), psychiatric (28%), cardiovascular (25%), and cutaneous (14%). Without skin findings, HCP resembles acute intermittent porphyria, but with skin lesions, it is similar to VP. Diagnosis There are three stages of HCP: (1) latent, in asymptomatic carriers who have never had an attack; (2) acute attack, in currently symptomatic patients; and (3) subclinical, in carriers with previous attacks but no current symptoms.18 During an acute attack, urine and fecal coproporphyrin III levels are substantially increased, and stool fluoresces bright red.18 The increased ratio of coproporphyrin isomers III/I is the most important diagnostic marker but cannot rule out subclinical HCP.18 This isomer fractionation test is not performed in all laboratories.19 Furthermore, only a few laboratories test for HCP mutations; thus, diagnosis is usually based on increased urinary ALA and PBG excretion, along with stool coproporphyrin elevation. Additionally, some symptomatic patients have a plasma emission peak between 615 and 620 nm.20 The most specific and sensitive technique for screening at-risk relatives for HCP is DNA analysis.18 Nevertheless, fecal coproporphyrin isomer III/I ratio appears to be a highly sensitive alternative for screening relatives over the age of 10.20 CPO activity analysis is another screening ª 2013 The International Society of Dermatology

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tool, but requires cultured fibroblasts, lymphocytes, or hepatocytes and is technically difficult to perform.18 Chronic hepatic porphyrias Porphyria cutanea tarda

Epidemiology Porphyria cutanea tarda is the most common porphyria in the USA, accounting for 80–90% of all porphyrias, with an estimated prevalence of 1 in 25,000.21 Table 2 displays reported prevalence in other countries. Porphyria cutanea tarda can be familial (type I) or acquired (also referred to as sporadic or type II). A rare type III PCT occurs in patients with a normal uroporphyrinogen III decarboxylase (UROD) gene (unlike in type I), but with multiple affected family members (suggesting a genetic component distinct from UROD expression). The ratio of familial to sporadic PCT is 1 : 4 worldwide but varies geographically.22–24 Familial PCT involves either an inherited defect in hepatocyte UROD production alone or defects in hepatocyte and erythrocyte UROD production.21 Only one gene encodes UROD, which is present in all tissues, making the pathogenesis of the hepatocyte-only defect a mystery.21 Overall, PCT affects males and females equally,22 with some studies suggesting male predominance in the acquired form.25 Sporadic PCT typically presents in the fourth decade, whereas familial PCT can present at any age. Pathogenesis A defect in UROD, which catalyzes the fifth step in heme synthesis, causes PCT. Decreased UROD activity increases production of symptom-causing carboxylic porphyrins.26 Porphyrins in skin absorb ultraviolet A, generating peroxides that cause oxidative damage and inflammation. Over 70 UROD gene mutations cause AD PCT23 but penetrance remains low (10%).26 As UROD is not a rate-limiting enzyme, many people with UROD mutations never develop PCT.23 Sporadic and familial PCT symptoms are due to increased demand for heme synthesis or injury to hepatocytes (e.g., iron overload, estrogen, hepatic injury, or Table 2 Prevalence of porphyria cutanea tarda by country Country

Prevalence per 100 000

Czech Republic and Slovakia21 Sweden28 United States21 Norway22 United Kingdom26

20 10 4 1 0.2–0.5

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drugs).22 Erythrocyte UROD measurement distinguishes familial from sporadic PCT: familial cases have low UROD levels, while sporadic cases have normal UROD levels but low hepatic UROD function.22 Porphyria cutanea tarda is a multifactorial disease; alcohol, exogenous hormones, iron overload, hepatitis C (HCV), and human immunodeficiency virus (HIV) are commonly associated. In a study of 39 patients with PCT, 92% had three or more of the above factors.27 In another study of 84 patients with PCT, 17% had diabetes, 57% had hemochromatosis gene mutations, 38% of men abused alcohol, 55% of women used estrogen, and 29% of men had HCV.28 Alcohol Alcohol abuse is reported in 30–90% of patients with PCT.29 Although alcohol is hepatotoxic, sporadic PCT is not a common complication of alcoholism; only 2% of alcoholics with cirrhosis have PCT according to one study.30 Alcohol increases iron absorption, dissociates iron from its binding proteins, stimulates ALA synthase, and inhibits UROD.29,30 Additionally, alcohol stimulates free-radical production and induces forms of cytochrome p450 known to generate reactive oxygen species.31 Free radicals cause oxidative changes to uroporphyrinogen, which inhibits UROD, thus contributing to PCT.31 Hormones Porphyria cutanea tarda can present in pregnancy and childbirth, with worsening during the first trimester and improvement after delivery.32 Estrogen is associated with increased iron stores in studies of female rats,31 and some studies suggest that progesterone induces ALA synthase.32 Estrogen-containing oral contraceptives can trigger PCT and should be avoided. Iron and hemochromatosis Iron undoubtedly contributes to PCT; phlebotomy, chelation, and decreased iron intake improves symptoms.31 Between 60 and 70% of patients with PCT have mild-to-moderate iron overload.33 Iron catalyzes reactive oxygen species formation, increasing oxidation of uroporphyrinogen to uroporphyrin.31 Once uroporphyrinogen is oxidized to uroporphyrin, it cannot re-enter the heme biosynthesis pathway. Additionally, iron may inhibit UROD via formation of non-porphyrin products of porphyrinogen oxidation, which directly inhibit UROD.26,34 Perhaps through iron excess, hemochromatosis and human hemochromatosis protein (HFE) gene mutations are associated with increased incidence of PCT.33 There are two HFE alleles associated with PCT; their prevalence in PCT varies according to region (Table 3).35 The H63D International Journal of Dermatology 2013, 52, 1464–1480

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mutation may work synergistically with HCV to cause PCT, while the C282Y mutation independently predisposes to PCT.33 Hepatitis C While a small proportion of patients with HCV have PCT, a significant percentage of patients with PCT have HCV. It is unclear if both disorders have similar predisposing risk factors or if HCV contributes to PCT development. Patients with HCV are five times more likely to have sporadic PCT than familial PCT.23 One mechanism of how HCV may cause PCT involves increased free hepatocellular iron. About 30–40% of patients with HCV have elevated serum iron, and patients with HFE mutations generally have more severe HCV liver disease than those without the mutation.36 Iron overload may worsen HCV, with a synergistic influence on PCT. A second mechanism is that HCV causes freeradical oxidation of uroporphyrinogens. Others propose that HCV reduces UROD indirectly via hepatocyte injury, alteration of cytochrome P450 mRNA, and increasing UROD inhibitor production.26,37 Large epidemiological studies have examined geography in relation to PCT and HCV. A meta-analysis of 1164 patients from various geographic regions demonstrated a 50% prevalence of HCV in PCT.38 Chuang et al.'s37 case–control study and meta-analysis found that patients with PCT in the USA or southern Europe are 64 times more likely to have HCV than patients with no PCT. Human immunodeficiency virus HIV is associated with altered porphyrins, direct hepatic damage, impaired cytochrome oxidase, and increased estrogen levels – all of which predispose to PCT.26,39 As HIV produces increased HCV viral load, it acts synergistically to cause hepatic damage and PCT.40 Table 3 Mutations in HFE gene in patients with PCT by region26,101,102 Region or country

% PCT with C282Y mutation

% PCT with H63D mutation

UK Australia Denmark France USA Brazil Germany Italy

44 44 23 17 41 17 39 NS

NS NS NS NS NS NS 85 29

NS, no significant difference compared to control population; PCT, porphyria cutanea tarda. ª 2013 The International Society of Dermatology

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Cytochrome P450 Cytochrome p450 enzymes metabolize drugs, hormones, and other compounds, including oxidation of uroporphyrinogen, which depletes the UROD substrate.41 They also metabolize alcohol, estrogen, and other chemicals associated with PCT (that may break down to form a UROD inhibitor).42 Additionally, CYP1A2 p450 may directly inhibit UROD in hepatocytes43; polymorphisms are linked to PCT.42 Drugs and chemicals Porphyria cutanea tarda-like symptoms have been reported after hexachlorobenzene exposure.44 Cytochrome p450 may activate hexachlorobenzene, which then inhibits UROD, but there are no human studies associating hexachlorobenzene and true PCT.45 Drugs associated with PCT include griseofulvin, sulfonamides, barbiturates, statins, and hydantoins.46 Oxidative stress and ascorbic acid deficiency Oxidized, or reactive, uroporphyrins have been found in the urine of patients with PCT, supporting that PCT is associated with oxidative stress, but it is not clear if oxidized uroporphyrins are produced mainly in liver, blood, or sun-exposed skin.31 Ascorbic acid is an antioxidant found to be low in 84% of untreated patients with PCT in one study.41 Ascorbic acid may play a role in PCT pathogenesis or may simply be associated with PCT. Furthermore, as ascorbic acid can inhibit CYP1A2, its deficiency may allow overactivity of CYP1A2, which inhibits UROD.41 Other etiological factors • Diabetes. PCT is associated with diabetes, which affects up to 25% of patients with PCT.47 • Dialysis-dependent renal failure. Decreased production of erythropoietin and downregulation of erythropoiesis may contribute to PCT by increasing unused iron throughout tissues.48 Unfortunately, the primary therapy for PCT is phlebotomy, which is contraindicated in anemic patients. PCT has been shown to improve with erythropoietin therapy in dialysis-dependent patients.31 Dialysis-dependent renal failure may also result in pseudoporphyria.49 • Hepatocellular carcinoma (HCC). Several reports describe HCC presenting with acquired porphyria, with normalization of porphyrin levels upon HCC treatment.50 Having PCT for over 10 years may increase HCC risk, with some surveys finding a small increase in all cancers (mainly liver 20 9 and lung 3 9).51 However, a study of 39 patients (average 9.7-year follow-up) found only one patient developed HCC.52 Of those patients,

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76% had hepatitis B or C, 87% abused alcohol, and 68% had hepatic fibrosis. Both PCT and HCC are caused by long-term liver injury so the association may not be causal. Presentation Cutaneous findings include erosions, vesicles, bullae, crusts, milia, hypo- and hyperpigmentation, and skin fragility (Figs. 2–4). Lesions often present on the dorsal hands and forearms, with more generalized sclerodermoid changes on the face. The lesions are symmetric, associated with delayed healing and chronic blistering, and occasionally fluoresce red with Wood’s lamp. Less commonly, PCT presents with scarring alopecia and darkening hair color.46 Two cases of hair pigment changes from gray to brown have been reported, although the mechanism is unclear.53 There are also reports of associated melanosis, cutis rhomboidalis, and morphea.46 Bullae and vesicles, triggered by minor trauma or sun exposure, are usually 0.5–1.0 cm in diameter. Bullae are tense with clear fluid, which then becomes cloudy or serohemorrhagic; milia, which develop secondary to damage of the basement membrane in subepidermal blistering disorders, may present after resolution of bullae. Skin fragility is seen with shearing of skin from minor trauma, forming erosions that are susceptible to infection, slow healing, and scarring. Chronic scarring may cause shortening of the distal phalanges. Patients, particularly females, may have lanugo-like hypertrichosis on the periorbital, temporal, malar, and eyebrow regions. Severe elastosis, seen in chronically sun-exposed facial skin, and sclerodermoid changes, create a mask-like expression.54 This sclerodermoid process, due to uroporphyrinogen-1-dependent collagen synthesis in the dermis, is seen in up to 18% of patients with PCT.55 Some patients have hypopigmented, yellow, scleroderma-like plaques on sun-exposed areas surrounded by atrophy and hyperpigmentation.26 Unlike other skin findings, these lesions can also affect nonsun-exposed areas. Deposition of photoactive porphyrins near the eye causes lid scarring, ectropion, lacrimal scarring, scleromalacia, and corneal thinning.56 One case of corneal perforation has been reported.56 Owing to photoactivity of uroporphyrin deposited in the conjunctiva, pinguecula incidence is eight times higher and pterygium two times higher, compared to controls.57 Actinic damage of the periorbital skin was seen in 96% of patients with PCT in one study, compared to 25% in controls.57 Hepatomegaly is common in PCT, and cirrhosis is found in 30–40% of patients.21 Urine is often discolored with a red-brown tinge.

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(b)

Figure 2 (a) Right hand of a patient with porphyria cutanea tarda, revealing numerous erosions and erythematous patches; (b) close-up photograph of right hand

Figure 3 Left foot of a patient with porphyria cutanea tarda with blistering and erosions

Diagnosis Diagnosis is best made with a random urine test demonstrating increased uroporphyrins with an elevated uroporphyrin I/uroporphyrin III ratio. The urine must be protected from light to ensure accurate results. The urine must be protected from light to ensure accurate results.25 The urine fluoresces bright pink under Wood’s lamp. An increased urine uroporphyrin/coproporphyrin ratio also suggests PCT; there are also other porphyrin patterns (e.g., hexacarboxyporphyrin, pentacarboxyporphyrin, heptacarboxyporphyrin) that may suggest PCT.31 Although not commonly used for diagnosis, 7-, 6-, and 5carboxylate porphyrins, coproporphyrin, and isoInternational Journal of Dermatology 2013, 52, 1464–1480

Figure 4 Hands of a patient with porphyria cutanea tarda demonstrating erythematous plaques, erosions, and a large bullae of the left hand

coproporphyrin can be found in the stool of patients with PCT.31 Solvent extraction techniques and thin-layer chromatography have been used in the past to measure different types of porphyrins,58 but high-performance liquid chromatography has largely replaced these modalities. Measuring erythrocyte UROD activity helps distinguish familial from sporadic PCT, as sporadic PCT does not affect erythrocyte heme production, but only hepatic heme production. Testing for PCT in family members of patients with known mutations of the UROD gene is available.24 ª 2013 The International Society of Dermatology

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Histopathology Caterpillar bodies are the diagnostic histopathological finding in PCT. Caterpillar bodies are linear eosinophilic PAS-positive globules in the epidermis overlying subepidermal bullae of PCT. They contain degenerating keratinocytes, colloid bodies, and basement membrane bodies.59 Colloid bodies have whorled clumps of filaments, which contain degenerating melanosomes, vacuoles, mitochondria, and desmosomes.59 Basement membrane bodies have convoluted basement membrane with collagen.59 The occasional fusion of basement membrane bodies with colloid bodies suggest they were formed at the same time, likely by repeated blistering and re-epithelialization.59 Biopsy of a blister shows subepidermal bullae with little or no inflammatory infiltrate and an upward projection of papilla into the bullae (festooning) (Fig. 5). Chronic lesions show thickened dermal vessels with PAS-positive diastaseresistant glycoprotein material in and around the vessels near the dermal–epidermal junction. Superficially, there is a compact corneal layer with necrotic epithelium, sparse lymphocytic infiltrate, and marked actinic elastosis in the upper stratum corneum.54 Sclerodermoid lesions of PCT are very similar to those of true scleroderma with increased collagen deposition, acellularity, and lack of adnexae.60 Some report looser deposition of collagen relative to true scleroderma.60 Direct immunofluorescence shows IgG, IgM, fibrinogen, and complement in the basement membrane and around vessels of the upper dermis (Fig. 6).60 No anti-basement membrane antibodies are found in serum, and indirect immunofluorescence is negative.

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Figure 6 Direct immunofluorescence demonstrates IgM and C3 in vessels due to hyaline material deposits. (Courtesy of Dr. Michael Camilleri, Mayo Clinic, Department of Dermatology)

Differential diagnosis of porphyria cutanea tarda Pseudoporphyria. Cutaneous lesions are similar clinically and histologically to PCT, but patients have normal UROD activity. Pseudoporphyria is seen in dialysis-dependent renal failure patients treated with phototoxic drugs.61 It may also occur with tanning bed use, nonsteroidal anti-inflammatory drugs, antibiotics (i.e., nalidixic acid and tetracycline), diuretics (primarily sulfur-bearing), systemic retinoids, dapsone, and cyclosporine.31,54,60 Although the exact mechanism of pseudoporphyria in dialysis-dependent renal failure is unknown, it is most likely from a high molecular weight hemopexin–porphyrin complex formed with subclinical UROD deficiency if the complex is too large for removal with hemodialysis.62 After months to years of hemodialysis, porphyrins accumulate and present similarly to PCT. Pseudoporphyria is especially difficult to distinguish from UROD-deficient PCT because hemodialysis-dependent patients make little urine for analysis, and the plasma porphyrins can be similarly elevated. Measuring plasma uroporphyrin and heptacarboxylated porphyrins, as well as fecal isocoproporphyrin, can help distinguish the two entities.31 Other porphyrias. See Table 1.31

Figure 5 Histology of porphyria cutanea tarda demonstrates subepidermal vesiculation, minimal inflammatory infiltrate, and protuberance of rigid dermal papillae into blister cavity (festooning) in acral skin (hematoxylin and eosin staining; 910 magnification) ª 2013 The International Society of Dermatology

Epidermolysis bullosa acquisita. Both epidermolysis bullosa acquisita and PCT have similar bullous lesions and milia, but epidermolysis bullosa acquisita is usually associated with traumatized skin such as palms and soles; uninvolved skin appears normal. In PCT, blisters are often confined to sun-exposed areas such as the dorsum of hands with a reddish-brown hue to the face and neck. Endocrine and neoplastic diseases. Addison’s disease and paraneoplastic hypertrichosis lanuginosa acquisita can International Journal of Dermatology 2013, 52, 1464–1480

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cause hypertrichosis and hyperpigmentation. Addison’s disease is evaluated by measuring cortisol and adrenocorticotropic hormone, while hypertrichosis lanuginosa acquisita requires systemic evaluation for neoplasms. Chronic hand eczema. Although physical findings may be similar, disease course, risk factors, and laboratory findings will distinguish the two. Hepatoerythropoietic porphyria

Epidemiology Hepatoerythropoietic porphyria (HEP) is extremely rare with only 30 cases in 24 families reported by 2004.63 Etiology Homozygous mutations of the UROD gene cause HEP. Uroporphyrin, hepatocarboxyl porphryin, and isocoproporphyrin accumulate in erythrocytes and liver, occasionally causing hemolytic anemia and associated splenomegaly.1 Presentation and diagnosis Hepatoerythropoietic porphyria is characterized by scarring, photo-mutilation, sclerodermoid changes, and hypertrichosis.63 Similar to other homozygous forms of porphyria, it usually begins in infancy or young childhood. Unlike PCT, HEP does not require environmental triggers to manifest.64 Although enzyme activity should be much lower in HEP compared to PCT, the erythrocyte UROD activity alone will not distinguish PCT from HEP, so the two are distinguished clinically and by DNA analysis.64 Differential diagnosis of hepatoerythropoietic porphyria Hepatoerythropoietic porphyria presents clinically like congenital erythropoietic porphyria (CEP), as it begins in early childhood with red urine, blisters, hypertrichosis, and scarring (see the CEP differential diagnosis section for further details). Erythropoietic porphyrias This category includes erythropoietic protoporphyria (EPP), CEP, and X-linked dominant protoporphyria. In erythropoietic porphyrias, primary accumulation of porphyrins occurs within bone marrow. Erythropoietic protoporphyria

Epidemiology It is the most common porphyria in childhood – prevalence ranges from 0.06 to 1.75 per 100,000 (Table 4).65–67 International Journal of Dermatology 2013, 52, 1464–1480

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Table 4 Prevalence per 100,000 protoporphyria per country65,67

of

erythropoietic

Country

Prevalence (per 100 000)

Slovenia United Kingdom North Ireland Netherlands South Africa (Parker) General population European immigrant population

1.75 0.77 1.27 1.33 0.06 0.70

It usually presents in childhood, affects all races, and may have a slight male predominance.68,69 A few adult-onset cases of EPP are described – while some are mild hereditary EPP coming to medical attention later in life, others are associated with myeloproliferative disorders (i.e., acquired mutation of the ferrochelatase [FECH] allele within bone marrow).70,71 Etiology and pathogenesis Ferrochelatase catalyzes chelation of ferrous iron with protoporphyrin IX to form heme (Fig. 1). FECH is in all heme-producing cells, including erythrocytes and hepatocytes, but the majority (80%) of protoporphyrin IX is made in the bone marrow.72 Protoporphyrin IX is created in erythrocytes during erythropoiesis then diffuses across the erythrocyte membrane on to plasma carrier proteins and is filtered out in the liver where most is excreted in bile. The remaining protoporphyrin IX is converted to heme by liver FECH.72 Protoporphyrin is hydrophobic, enabling its transfer from the erythrocyte membrane to endothelial cells once a concentration gradient is established. Excess protoporphyrin deposits around vessels causing tissue damage if oxidized by the Soret band of light (wavelengths 400–408 nm). The endothelial cell injury activates the complement cascade and causes degranulation of mast cells. The widespread inflammation can present as solar urticaria. The distinction between AD and autosomal recessive EPP is blurred by a low-functioning wild-type allele. Most cases are AD with incomplete penetrance involving a disease allele combined with a low-functioning wild-type IVS3-48C allele.72 Only 13 homozygous (recessive) EPP cases have been reported – these have been extremely severe with four having severe liver disease (exceeding the 5% observed in the AD EPP population).73 It is also possible that two low-expression alleles may manifest clinically as EPP.74 The IVS3-48C low-expression allele polymorphism affects a splice site involved in producing FECH and causes fewer functional enzymes.72,75 The IVS3-48C ª 2013 The International Society of Dermatology

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mutation is not the only cause of EPP; compound heterozygosity for mutations within the promoter region and introns of the FECH gene are also described.76 The FECH protein concentration must fall below 25– 35% of normal to manifest EPP symptoms.75 Therefore, although genetic mutations might be identified in an asymptomatic carrier, incomplete penetrance makes recommendations unclear. Furthermore, not enough is known about correlating genotype and phenotype as expressivity is so variable. About half of patients have no family history of photosensitivity,77 and there is marked variability in the presentation of EPP even among siblings.78 Presentation Patients with EPP usually describe burning pain and edema about 20 minutes after sun exposure, lasting about six days. Additionally, patients describe post-sun exposure tingling, prickling, and stinging sensations. The burning sensation occurs before any visible skin changes in 95% of cases77 and can persist for several days or manifest as solar urticaria. While 10% of patients never experience visible skin changes, those with skin findings report swelling (80%), reddening (20%), blistering (17%), crusting/eczema (14%), petechiae/bruising (9%), and fissuring (5%).77 The severity of skin changes correlates with duration of sun exposure, and over half of patients describe exacerbation of symptoms with wind.77 The chronic skin changes of EPP are relatively mild, but affect 79% of patients; they include dyspigmentation, papular thickening, pseudo-lichenification (particularly of knuckles and bridge of nose), hyperkeratosis of the dorsum of hands, shallow pitted or linear scars of face (especially the nose), and linear furrows around the lips (Figs. 7 and 8).77 Between one-third and one-half of patients with EPP have mild microcytic, hypochromic anemia.79 This is more prominent with very low FECH activity.80 Unlike many disorders of erythropoiesis, patients with EPP have no iron overload, but some have iron deficiency. A unique correlation is theorized between protoporphyrin build-up and decreased absorption of iron creating a steady state of decreased erythropoiesis.79 Protoporphyrin deposition in the liver causes disease ranging from cholelithiasis, caused by protoporphyrin crystalizing out of bile, to progressive liver failure and death.81 Liver failure presents with severe upper abdominal pain, splenomegaly, hemolysis, and accelerated photosensitivity.81 Although there is no consensus, experts recommend measuring liver enzymes and blood protoporphyrin levels every 6–12 months, and, if needed, ultrasound or computed tomography scanning for further evaluation. Any patient with EPP with a family history of liver disease, ª 2013 The International Society of Dermatology

Figure 7 Linear erosions of the lateral nasal bridge and lower lip in a patient with erythropoietic protoporphyria

Figure 8 Erosions with crusting on the left helix of a patient with erythropoietic protoporphyria

risk factors for liver disease, elevated liver enzymes, or clinical signs of hepatic decomposition should have a liver biopsy every five years.72 Patients with EPP should avoid International Journal of Dermatology 2013, 52, 1464–1480

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hepatic insults by abstaining from alcohol, and receiving hepatitis A and B vaccinations.72 Those with severe liver disease may require a transplant, but the disease affects the new liver as protoporphyrin deposits in bile canaliculi.82 Optic nerve atrophy has also been reported in EPP.83

in the ALAS2 gene that encodes 5-aminolaevulinate synthase), lipoid proteinosis, and colloid milium,68 which can be distinguished by measuring blood and stool porphyrins.

Diagnosis The most specific way to diagnose EPP is quantitative porphyrin analysis via high-performance liquid chromatography, demonstrating increased free erythrocyte protoporphyrin.84 Unlike other porphyrias, urinary excretion of porphyrins remains normal in EPP due to the hydrophobic nature of protoporphyrin. The one exception is in EPP with hepatic failure where coproporphyrins may be detected in urine.82 Diagnosis via blood involves chemically extracting protoporphyrin for concentration measurement in peripheral erythrocytes or by directly visualizing fluorocytes. There is a characteristic peak of plasma protoporphyrin fluorescence at 634 nm.69 Attempts to automate a diagnosis of EPP have used plasma fluorescence scanning, which measures protoporphyrin through its characteristic fluorescence, and has up to 83% sensitivity.67 FECH activity can be measured through its zinc chelatase activity but is less common due to the technical difficulty of the test.82 Diagnosis of EPP is typically delayed, with a mean lag time of 10–20 years after symptoms begin.85 Based on a study of 233 British patients, the average age of onset was one year, but the average age of diagnosis was 12 years.77 EPP is particularly difficult to diagnose as urine porphyrins are often measured to screen for porphyrias and are normal in EPP.

Epidemiology Congenital erythropoietic porphyria is rare with 130 cases published worldwide.87 It has been reported in patients of various ethnic backgrounds.

Histology Chronically sun-exposed skin shows progressive thickening of blood vessels in the papillary dermis, which stains with PAS. Immunofluorescence shows that this PAS material is type IV collagen likely from concentric reduplication of perivascular basal lamina from chronic sun exposure. Fine granular material appears at the basement membrane and in the superficial dermis.86 Direct immunofluorescence shows mostly IgG, as well as IgA, IgM, and C3 within vessel walls.86 Acute lesions show vacuolization of epidermal cells with intercellular edema, and vacuolization and cytolysis of endothelial cells of superficial blood vessels without other changes to the surrounding dermis.68 Differential diagnosis of erythropoietic protoporphyria The differential diagnosis for EPP includes X-linked dominant protoporphyria (which can present similarly to EPP, is rare, and is due to a gain-in-function mutation International Journal of Dermatology 2013, 52, 1464–1480

Congenital erythropoietic porphyria

Etiology and pathogenesis Congenital erythropoietic porphyria is caused by autosomal recessive mutations in the gene coding for uroporphyrinogen III synthase (UROIIIS; also known as uroporphyrinogen III isomerase and hydroxymethylbilane hydrolase), causing uroporphyrin I to accumulate in all cells and tissues. UROIIIS is the fourth enzyme in heme production and catalyzes the cyclization of hydroxymethylbilane to uroporphyrinogen III (Fig. 1). Without UROIIIS, hydroxymethylbilane quickly degrades into uroporphyrinogen I, which cannot act as a substrate for heme synthesis. Uroporphyrinogen I is metabolized to coproporphyrinogen I. Both are oxidized to uroporphyrin I and coproporphyrin I, respectively. Both deposit in reticulocytes and erythrocytes as slender needle-like inclusions causing hemolysis, and deposit in various tissues.88 The excess porphyrins deposited into skin are activated by sunlight and cause toxic oxidative damage (subepidermal bullae and inflammation). The pathogenesis of CEP is entirely genetic; 39 different mutations have been associated with CEP, accounting for variability of the disease.89 The C73R mutation causes about 30% of CEP cases and is associated with a severe presentation.90 Expression of at least one gene with residual function results in a milder case of CEP even when in combination with the C73R mutation.91 Even with the same mutations, patients present differently due to variations in stimulation of erythropoiesis, sunlight exposure, and other lifestyle choices. While the relationship between genotype and phenotype is unclear, it appears that residual UROIIIS activity below 5% causes severe disease and 5–10% UROIIIS activity causes mild and moderate disease.89 Presentation Features of CEP include extreme photosensitivity, hemolytic anemia, erythrodontia (red discoloration of teeth), hypertrichosis, ocular complications, and bone fragility. The severity ranges from non-immune hydrops fetalis or dependence on blood transfusions to milder adult-onset cutaneous lesions.92 Extreme photosensitivity in early ª 2013 The International Society of Dermatology

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Figure 9 Pink fluorescence due to porphyrin deposition in the teeth of a patient with congenital erythropoietic porphyria

Review

childhood causes second- and third-degree burns, with ulceration and scarring.87 Patients present with bullae, hyper- and hypopigmentation, fibrosis, alopecia, hypertrichosis, and deformities from resorption of the distal phalanges and nose.87 Lesions often become infected, which can cause further scarring and inflammation. Chronic anemia is caused by decreased erythrocyte lifespan, poor erythropoiesis, and erythrocyte fragility from high porphyrin concentrations. CEP is associated with splenomegaly and occasionally hepatomegaly, and can present with pancytopenia, purpura, or epistaxis.87 Patients have increased plasma indirect bilirubin, potassium, lactate dehydrogenase, and fecal urobilinogen. Severely affected patients are transfusion-dependent for their entire lives.91 To compensate for chronic anemia, the bone marrow expands heme production; conse-

Bullae and photosensitivity Suspect cutaneous porphyria Associated with acute neurovisceral attacks?

No

Yes

-Abdominal pain, peripheral neuropathy, psychiatric symptoms No

Yes

Adult onset

Measure urine, blood, and/or stool porphyrins & Confirm with DNA analysis ⇑ ⇑ Urine uroporphyrin I ⇑ ⇑ Fecal uro- and coproporphyrin I &⇑ protoporphyrin

⇑ Fecal isocoproporphyrin ⇓ Erythrocyte UROD activity

Measure urine, stool, and/or plasma porphyrins

Measure urine, blood, and stool porphyrins

⇑ Fecal coproporphyrin isomers III>I ⇑ Urinary uro-and coproporphyrin, ALA and PBG

⇑ Urine uroporphyrin and heptaporphyrin ⇑ Blood-free protoporphyrins

CEP

HEP

EPP

- Evaluate for other organ involvement including eyes, bones, and anemia.

- Consider genetic testing of relatives for UROD mutation.

- Screen for liver disease with liver function tests and imaging.

No

⇓ Erythrocyte UROD activity

Acquired PCT - Screen for hepatitis C virus. - Consider genetic testing for hemochromatosis gene mutation.

⇑ Fecal protoporphyrin > coproporphyrin Plasma fluorescense emission at 626 nm

Yes

Familial PCT - Consider genetic testing of relatives for UROD mutation and/or hemochromatosis gene mutation.

HEP - Consider screening relatives for CPO gene mutation.

VP - Consider genetic testing of relatives for PPO gene mutation.

Figure 10 Diagnostic algorithm for cutaneous porphryias. Note that all diagnoses are confirmed by porphyrin analysis of urine, blood, and stool. Included below each diagnosis are recommendations for further work-up given disease associations and risk factors.103–105,107,108 AIP, acute intermittent porphyria; ALA, aminolevulinic acid; CEP, congenital erythropoietic porphyria; CPO, coproporphyrinogen oxidase; EPP, erythropoietic protoporphyria; HCP, hereditary coproporphyria; PBG, porphobilinogen; PCT, porphyria cutanea tarda; PPO, protoporphyrinogen IX oxidase; UROD, uroporphyrinogen III decarboxylase; VP, variegate porphyria ª 2013 The International Society of Dermatology

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quently, patients have short stature and are at risk for fractures.93 Porphyrins have affinity for calcium phosphate and therefore deposit in bone and tooth dentine, creating a reddish hue that fluoresces red (erythrodontia; Fig. 9).94 The resultant thinning of tooth enamel predisposes to dental caries. Urine may be pink-colored with an intense red fluorescence under Wood’s lamp.87 Eye complications include conjunctivitis, complete loss of eyelashes and eyebrows, scleral thinning, ulcerations, and even one case of bilateral necrotizing scleritis.95 Ophthalmologic alterations are due to phototoxicity from accumulation of porphyrins, which have been demonstrated to be elevated in the tears of patients with CEP.96 The combination of corneal scarring, which dries out the eye, and incomplete eyelid closure due to skin scarring (lagophthalmos) exposes the eye to further phototoxicity.96 Diagnosis Diagnosis is made by the porphyrin concentration profile in erythrocytes, urine, and stool – differentiating among isomers I and III for both uroporphyrin and coproporphyrin. Urinary porphyrin concentrations are 100–1000 times higher than normal with mostly uroporphyrin I, but also hepta-, hexa-, penta-, and copro-porphyrin isomers.87 Stool porphyrins consist mainly of the bile-soluble lipophilic coproporphyrin and protoporphyrin.87 Erythrocyte UROIIIS activity can be measured directly using certain sensitive assays of cultured red blood cells; however, these assays are less accurate in transfused patients.92 In an affected pregnancy, amniotic fluid is dark brown in color, and the diagnosis is confirmed by increased type I uroporphyrin and coproporphyrin isomers in the amniotic fluid.97 Six cases of prenatal CEP have been reported; prenatal ultrasounds showed hydrops fetalis and nuchal translucency (due to anemia), as well as hyperechoic kidneys and bones (suggestive or uroporphyrin I deposition).97 Histopathology Congenital erythropoietic porphyria skin samples may demonstrate subepidermal bullae (similar to PCT), with scarring and hyalinization of the connective tissue. PASpositive material is deposited in the perivascular space of both skin and liver.87 Differential diagnosis Congenital erythropoietic porphyria can be mistaken for a severe form of HEP.87 CEP has increased urine uroporphyrin and coproporphyrin with isomer I predominance for both, increased blood porphyrins, and normal UROD activity, while HEP has increased fecal isocoproporphyrin. International Journal of Dermatology 2013, 52, 1464–1480

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Differential diagnosis and approach to cutaneous porphyrias Owing to variability in presentation and rarity, porphyrias are often misdiagnosed. A broad differential and high level of suspicion is crucial for early, accurate diagnosis. Photosensitive dermatoses should be evaluated with detailed history, physical exam, phototesting, and photopatch testing. In patients with photosensitivity and bullous lesions, bullous lupus erythematosus, bullous pemphigoid, drug reaction, hydroa vacciniforme, erythema multiforme, and phytophotodermatitis should be considered.60,98 There are also reports of patients with multiple heme enzyme deficiencies (dual porphyrias). Deficiency of porphyrobilinogen deaminase and PPO is termed Chester Porphyria.99 When contemplating the diagnosis of a porphyria based on physical exam and history, the primary question is whether the patient is experiencing acute neurovisceral attacks, helping to differentiate acute hepatic porphyrias (Fig. 10). Neurovisceral symptoms consistent with an acute attack should be evaluated for PBG with the rapid Hoesch test or Watson–Schwartz test.100 In those without such attacks, age of onset further assists in diagnosis, as PCT typically occurs in adulthood. Porphyrin assays further help distinguish the specific enzyme defect. Solar urticaria or acute photosensitivity suggest protoporphyria; screening for erythrocytic porphyrins is warranted.100 For bullous lesions, screening for urinary porphyrins should be performed to rule in/out PCT, HCP, and VP.100 DNA analysis may isolate the genetic defect, confirming a specific diagnosis. Questions (see answers on page 1480) 1 Which enzyme is mutated in variegate porphyria? A Protoporphyrinogen oxidase B Uroporphyrinogen decarboxylase C Ferrochelatase D Uroporphyrinogen III synthase 2 Plasma of patients with variegate porphyria classically demonstrates fluorescence emission at which wavelength? A 311 nm B 365 nm C 626 nm D 595 nm 3 Hereditary coproporphyria is characterized by which of the following porphyrin anomalies? A Elevated coproporphyrin III–I ratio B Elevated coproporphyrin I–III ratio C Elevated uroporphyrin–coproporphyrin ratio D Elevated porphobilinogen at baseline ª 2013 The International Society of Dermatology

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4 Porphyria cutanea tarda is primarily inherited in which manner? A Autosomal recessive B Autosomal dominant C X-linked dominant D X-linked recessive 5 Which of the following are associated with porphyria cutanea tarda? A Alcohol use B Hepatitis C C Hemochromatosis D All of the above 6 Which answer choice best characterizes histopathological features in a blister from a patient with porphyria cutanea tarda? A Subepidermal bullae with prominent mixed inflammatory infiltrate and an upward projection of papilla into the bullae B Intraepidermal bullae with neutrophilic infiltrate and an upward projection of papilla into the bullae C Subepidermal bullae with little or no inflammatory infiltrate and an upward projection of papilla into the bullae D Intraepidermal bullae with little or no inflammatory infiltrate and an upward projection of papilla into the bullae 7 Which answer choice is false regarding erythropoietic protoporphyria? A It is primarily a disease of adulthood B It is due to mutations in ferrochelatase C It can be inherited in an autosomal dominant fashion D It causes burning pain after short amounts of sun exposure 8 Which disorder should typically be included in the differential for congenital erythropoietic porphyria? A Porphyria cutanea tarda B Erythropoietic protoporphyria C Acute intermittent porphyria D Hepatoerythropoietic porphyria 9 Which of the following systemic findings may be associated with erythropoietic protoporphyria? A Diabetes insipidus B Gallstones C Cardiac valvular dysfunction D Vasculitis 10 Which of the following systemic associations is incorrect? A Porphyria cutanea tarda: hepatic cirrhosis B Hereditary coproporphyria: syndrome of inappropriate antidiuretic hormone secretion C Congenital erythropoietic porphyria: conjunctivitis D Variegate porphyria: emphysema ª 2013 The International Society of Dermatology

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References 1 Richard E, Robert-Richard E, Ged C, et al. Erythropoietic porphyrias: animal models and update in gene-based therapies. Curr Gene Ther 2008; 8: 176–186. 2 Murphy GM. The cutaneous porphyrias: a review. The British Photodermatology Group. Br J Dermatol 1999; 140: 573–581. 3 DAmato M, Bonuglia M, Barile S, et al. Genetic analysis of variegate porphyria (VP) in Italy: identification of six novel mutations in the protoporphyrinogen oxidase (PPOX) gene. Hum Mutat 2003; 21: 448. 4 Frank J, Christiano AM. Variegate porphyria: past, present and future. Skin Pharmacol Appl Skin Physiol 1998; 11: 310–320. 5 Grabczynska SA, McGregor JM, Hawk JL. Late onset variegate porphyria. Clin Exp Dermatol 1996; 21: 353– 356. 6 Poblete-Gutierrez P, Wolff C, Farias R, et al. A Chilean boy with severe photosensitivity and finger shortening: the first case of homozygous variegate porphyria in South America. Br J Dermatol 2006; 154: 368–371. 7 Stone MS. Central-facial papular lymphangiectases: an uncommon manifestation of porphyria. J Am Acad Dermatol 1997; 36: 493–495. 8 Hift RJ, Meissner D, Meissner PN. A systematic study of the clinical and biochemical expression of variegate porphyria in a large South African family. Br J Dermatol 2004; 151: 465–471. 9 Frank J, Jugert FK, Breitkopf C, et al. Recurrent missense mutation in the protoporphyrinogen oxidase gene underlies variegate porphyria. Am J Med Genet 1998; 79: 22–26. 10 Frank J, Aita VM, Ahmad W, et al. Identification of a founder mutation in the protoporphyrinogen oxidase gene in variegate porphyria patients from chile. Hum Hered 2001; 51: 160–168. 11 Lip GY, McColl KE, Moore MR. The acute porphyrias. Br J Clin Pract 1993; 47: 38–43. 12 von und zu Fraunberg M, Tenhunen R, Kauppinen R. Expression and characterization of six mutations in the protoporphyrinogen oxidase gene among Finnish variegate porphyria patients. Mol Med 2001; 7: 320– 328. 13 Da Silva V, Simonin S, Deybach JC, et al. Variegate porphyria: diagnostic value of fluorometric scanning of plasma porphyrins. Clin Chim Acta 1995; 238: 163– 168. 14 Ferrer MD, Tauler P, Sureda A, et al. Enzyme antioxidant defences and oxidative damage in red blood cells of variegate porphyria patients. Redox Rep 2009; 14: 69–74. 15 Lecha M, Badenas C, Puig S, et al. Genetic studies in variegate porphyria in Spain. Identification of gene mutations and family study for carrier detection. J Eur Acad Dermatol Venereol 2006; 20: 974–979. International Journal of Dermatology 2013, 52, 1464–1480

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32 Loret de Mola JR, Muise KL, Duchon MA. Porphyria cutanea tarda and pregnancy. Obstet Gynecol Surv 1996; 51: 493–497. 33 Elder GH, Worwood M. Mutations in the hemochromatosis gene, porphyria cutanea tarda, and iron overload. Hepatology 1998; 27: 289–291. 34 Lambrecht RW, Bonkovsky HL. Hemochromatosis and porphyria. Semin Gastrointest Dis 2002; 13: 109–119. 35 Nordmann Y, Puy H. Human hereditary hepatic porphyrias. Clin Chim Acta 2002; 325: 17–37. 36 Fargion S, Fracanzani AL. Prevalence of hepatitis C virus infection in porphyria cutanea tarda. J Hepatol 2003; 39: 635–638. 37 Chuang TY, Brashear R, Lewis C. Porphyria cutanea tarda and hepatitis C virus: a case–control study and meta-analysis of the literature. J Am Acad Dermatol 1999; 41: 31–36. 38 Gisbert JP, Garcia-Buey L, Pajares JM, et al. Prevalence of hepatitis C virus infection in porphyria cutanea tarda: systematic review and meta-analysis. J Hepatol 2003; 39: 620–627. 39 Lim HW. Role of viral infection in porphyria cutanea tarda. Photodermatol Photoimmunol Photomed 1997; 13: 75–77. 40 Gomi H, Hatanaka K, Miura T, et al. Type of impaired porphyrin metabolism caused by hepatitis C virus is not porphyria cutanea tarda but chronic hepatic porphyria. Arch Dermatol 1997; 133: 1170–1171. 41 Sinclair PR, Gorman N, Shedlofsky SI, et al. Ascorbic acid deficiency in porphyria cutanea tarda. J Lab Clin Med 1997; 130: 197–201. 42 Gardlo K, Selimovic D, Bolsen K, et al. Cytochrome p450A1 polymorphisms in a Caucasian population with porphyria cutanea tarda. Exp Dermatol 2003; 12: 843–848. 43 Christiansen L, Bygum A, Jensen A, et al. Association between CYP1A2 polymorphism and susceptibility to porphyria cutanea tarda. Hum Genet 2000; 107: 612–614. 44 American Porphyria Foundation History of Porphyria. The American Porphyria Foundation, Houston, 2010. http://www.porphyriafoundation.com/about-porphyria/ history-of-porphyria. (Accessed June 21, 2013). 45 Kim JJ, Lim HW. Hexachlorobenzene and porphyria cutanea tarda. Arch Dermatol 1999; 135: 459–460. 46 Brazzelli V, Chiesa MG, Vassallo C, et al. Clinical spectrum of porphyria cutanea tarda. Haematologica 1999; 84: 276–277. 47 Schindl A, Trautinger F, Pernerstorfer-Schon H, et al. Porphyria cutanea tarda induced by the use of pravastatin. Arch Dermatol 1998; 134: 1305–1306. 48 Shieh S, Cohen JL, Lim HW. Management of porphyria cutanea tarda in the setting of chronic renal failure: a case report and review. J Am Acad Dermatol 2000; 42: 645–652. 49 Green JJ, Manders SM. Pseudoporphyria. J Am Acad Dermatol 2001; 44: 100–108. 50 Huang WS, Liao LY, Wang CS, et al. Hepatocellular carcinoma presenting with acquired porphyria: a case

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report and review of the literature. Changgeng Yi Xue Za Zhi 1999; 22: 111–116. Linet MS, Gridley G, Nyren O, et al. Primary liver cancer, other malignancies, and mortality risks following porphyria: a cohort study in Denmark and Sweden. Am J Epidemiol 1999; 149: 1010–1015. Gisbert JP, Garcia-Buey L, Alonso A, et al. Hepatocellular carcinoma risk in patients with porphyria cutanea tarda. Eur J Gastroenterol Hepatol 2004; 16: 689–692. Shaffrali FC, McDonagh AJ, Messenger AG. Hair darkening in porphyria cutanea tarda. Br J Dermatol 2002; 146: 325–329. Fritsch C, Lang K, von Schmiedeberg S, et al. Porphyria cutanea tarda. Skin Pharmacol Appl Skin Physiol 1998; 11: 321–335. Giunta A, Demin F, Campione E, et al. Dermatitis artefacta in sporadic sclerodermoid hepatitis C virusassociated porphyria cutanea tarda. J Eur Acad Dermatol Venereol 2009; 23: 849–850. Zaborowski AG, Paulson GH, Peters AL. Sight threatening complications in porphyria cutanea tarda. Eye (Lond) 2004; 18: 949–950. Hammer H, Korom I. Photodamage of the conjunctiva in patients with porphyria cutanea tarda. Br J Ophthalmol 1992; 76: 592–593. Lai CK, Lam CW, Chan YW. High-performance thinlayer chromatography of free porphyrins for diagnosis of porphyria. Clin Chem 1994; 40: 2026–2029. Raso DS, Greene WB, Maize JC, et al. Caterpillar bodies of porphyria cutanea tarda ultrastructurally represent a unique arrangement of colloid and basement membrane bodies. Am J Dermatopathol 1996; 18: 24–29. Poh-Fitzpatrick MB. Is porphyria cutanea tarda a paraneoplastic disorder? Clin Dermatol 1993; 11: 119– 124. Fevang SA, Kroon S, Skadberg O. Pseudoporphyria or porphyria cutanea tarda? Diagnostic and treatment difficulties. Acta Derm Venereol 2008; 88: 426–427. Moran MJ, Fontanellas A, Santos JL. Enriquez de Salamanca R. Correlation between levels of free and protein-bound plasma porphyrin and urinary porphyrins in porphyria cutanea tarda. Int J Biochem Cell Biol 1995; 27: 585–588. Armstrong DK, Sharpe PC, Chambers CR, et al. Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol 2004; 151: 920–923. Camagna A, Del Duca P, Petrinelli P, et al. Erythrocyte uroporphyrinogen decarboxylase activity: diagnostic value and relationship with clinical features in hereditary porphyria cutanea tarda. Am J Med Sci 1998; 315: 59–62. Marko PB, Miljkovic J, Gorenjak M, et al. Erythropoietic protoporphyria patients in Slovenia.

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