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 Abstract
University Medical Center, Dallas, TX, The porphyrias are a group of disorders characterized by defects in the heme biosynthesis
2
Department of Dermatology, Mayo Clinic,
pathway. Many present with skin findings including photosensitivity, bullae, hypertrichosis,
Rochester, MN, 3Department of
and scarring. Systemic symptoms may include abdominal pain, neuropsychiatric changes,
Dermatology, Tufts Medical Center, Boston,
MA, and 4Department of Laboratory anemia, and liver disease. With advances in DNA analysis, researchers are discovering the
Medicine and Pathology, Mayo Clinic, underlying genetic causes of the porphyrias, enabling family members to be tested for
Rochester, MN, USA genetic mutations. Here we present a comprehensive review of porphyria focusing on
those with cutaneous manifestations. In Part I, we have included the epidemiology,
Correspondence
Ali Alikhan, MD
pathogenesis, presentation, diagnosis, and histopathology. Treatment and management
Department of Dermatology options will be discussed in Part II.
Mayo Clinic
200 First Street SW
Rochester
MN 55905
USA
E-mail: alikhan.mirza@mayo.edu

Conflicts of interest: None.

photosensitivity. While the main defect lies in the erythro-

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 (erythro-
poietic porphyrias). Hepatic porphyrias are subdivided
into acute and chronic subtypes, and tend to have second-
ary triggers (e.g., drugs, alcohol, hormone fluctuation,
infection, and fasting). Acute hepatic porphyrias present
with episodes (acute attacks) of abdominal or neurologi-
cal symptoms caused by a genetic predisposition with a
secondary metabolic trigger. Porphyria cutanea tarda
(PCT), the only chronic hepatic porphyria, has a pro-
longed course of liver damage and photosensitivity.
Erythropoietic porphyrias present in childhood with
1464
cytes, 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 intermit-
tent porphyria, variegate porphyria (VP), hereditary
coproporphyria (HCP), and aminolevulinic acid (ALA)
dehydratase-deficient porphyria. They are indistinguish-

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Horner et al. Cutaneous porphyrias part I Review 1465

100
Table 1 Symptoms and heme precursor changes in each of the cutaneous porphyrias

Symptoms Blood/plasma Urine Stool

PCT Fragility, bullae, hypertrichosis, pigment, Fluorescence emission peak at 620 nm ⇑⇑⇑ Uroporphyrin ⇑⇑ Isocoproporphyrin
and sclerodermoid changes (plasma) ⇑ Heptaporphyrin ⇑ Heptacarboxylporphyrin III
⇑ Other porphyrinsa
VP PCT-like skin findings  neurovisceral Fluorescence emission peak at 626 nm ⇑⇑⇑ ALA and PBG ⇑⇑⇑ Protoporphyrin IX
attacks (plasma) ⇑⇑ Coproporphyrin ⇑ Coproporphyrin III–I ratio
⇑ Uroporphyrin
HCP Neurovisceral acute attacks  PCT-like Fluorescence emission peak at 620 nm ⇑⇑ ALA and PBG ⇑⇑ Ratio coproporphyrin
skin findings (plasma) (⇑ Zinc–protoporphyrin – RBC) ⇑⇑ Coproporphyrin III–I > 2.0 (usually >10)
⇑ Uroporphyrin
CEP Bullae on sun-exposed areas leading to ⇑ Uroporphyrin I ⇑⇑ Uroporphyrin I ⇑ Coproporphyrin I
superinfection, scarring, bone resorption, ⇑ Coproporphyrin I ⇑⇑ Coproporphyrin I
eye changes, hepatosplenomegaly, etc. ⇑ Protoporphyrin (in RBC)
Onset ranges from hydrops fetalis to
mid-adulthood
EPP Burning pain after sun exposure; ⇑ Free protoporphyrin (in RBC) Normal ⇑ Protoporphyrin
5% have hepatic complications
HEP Severe photosensitivity in childhood ⇑ Zinc protoporphyrin (RBC) ⇑⇑ Uroporphyrin ⇑⇑ Coproporphyrin
Fluorescence emission peak at 620 nm ⇑ Coproporphyrin ⇑⇑ Uroporphyrin
(plasma)

⇑, 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 protoporphyrino-
gen oxidase (PPO) enzyme mutation. Twelve cases have
been reported with homozygous PPO mutations with
severe disease in infancy, mental retardation, hand defor-
mities, 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 through-
out the body.4 Deposition predisposes to cutaneous symp-
toms and acute neurologic attacks.3 Factors that induce
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, hyper-
tension, 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 protoporphy-
rins; (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,

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1466 Review Cutaneous porphyrias part I Horner et al.

Succinyl CoA + glycine Mitochondria Cytosol

1  δ-Aminolevulinic acid synthase X-linked hereditary
(ALA synthase) sideroblastic anemia
δ-aminolevulinic acid

δ-aminolevulinic acid
ALA dehydratase
2  δ-Aminolevulinic acid dehydratase deficient porphyria
Porphobilinogen (ALA dehydratase)

Acute intermittent
3  Porphobilinogen demainase
porphyria
Hydroxymethylbilane
4  Uroporphyrinogen III synthase & Congenital erythropoietic
Uroporphyrinogen III cosynthase porphyria
Uroporphyrinogen III + uroporphyrinogen I
5  Porphyria
Uroporphyrinogen III decarboxylase cutanea tarda
Coproporphyrinogen III + coproporphyrinogen I
Cytosol
Mitochondria
Coproporphyrinogen III
Hereditary
6  Coproporphyrinogen III oxidase
coproporphyria
Protoporphyrinogen IX
7  Protoporphyrinogen IX oxidase Variegate porphyria
Protoporphyrin IX
8  Ferrochelatase Erythropoietic
Heme
protoporphyria
+ +
Globin Apoprotein

Hemoglobin 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 coproporph-
yrin.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
PPO plasma levels than controls).14 This analysis, how-
ever, 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 super-
ficial 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

International Journal of Dermatology 2013, 52, 1464–1480 ª 2013 The International Society of Dermatology

Horner et al.
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 abnor-
malities have also triggered HCP, and women tend to
become symptomatic with menarche or initiation of con-
traceptive 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 asymptom-
atic carriers who have never had an attack; (2) acute
attack, in currently symptomatic patients; and (3) subclin-
ical, 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 copro-
porphyrin isomers III/I is the most important diagnostic
marker but cannot rule out subclinical HCP.18 This iso-
mer fractionation test is not performed in all laborato-
ries.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 copro-
porphyrin 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
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Cutaneous porphyrias part I Review 1467
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 uro-
porphyrinogen III decarboxylase (UROD) gene (unlike in
type I), but with multiple affected family members (sug-
gesting a genetic component distinct from UROD expres-
sion). 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 perox-
ides 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 hepato-
cytes (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 20
Sweden28 10
United States21 4
Norway22 1
United Kingdom26 0.2–0.5
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1468 Review Cutaneous porphyrias part I Horner et al.

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 diabe-
tes, 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 symp-
toms.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 uro-
porphyrinogen to uroporphyrin.31 Once uroporphyrino-
mutation may work synergistically with HCV to cause
PCT, while the C282Y mutation independently predis-
poses 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 predis-
posing risk factors or if HCV contributes to PCT develop-
ment. 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 free-
radical 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 geogra-
phy in relation to PCT and HCV. A meta-analysis of
1164 patients from various geographic regions demon-
strated 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 synergisti-
cally to cause hepatic damage and PCT.40
Table 3 Mutations in HFE gene in patients with PCT by
region26,101,102
Region or % PCT with % PCT with
country C282Y mutation H63D mutation

gen is oxidized to uroporphyrin, it cannot re-enter the

UK 44 NS
heme biosynthesis pathway. Additionally, iron may inhi- Australia 44 NS
bit UROD via formation of non-porphyrin products of Denmark 23 NS
porphyrinogen oxidation, which directly inhibit France 17 NS
UROD.26,34 USA 41 NS
Brazil 17 NS
Perhaps through iron excess, hemochromatosis and Germany 39 85
human hemochromatosis protein (HFE) gene mutations Italy NS 29
are associated with increased incidence of PCT.33 There
are two HFE alleles associated with PCT; their prevalence NS, no significant difference compared to control population;
in PCT varies according to region (Table 3).35 The H63D PCT, porphyria cutanea tarda.

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Horner et al.
Cytochrome P450
Cytochrome p450 enzymes metabolize drugs, hormones,
and other compounds, including oxidation of uro-
porphyrinogen, which depletes the UROD substrate.41
They also metabolize alcohol, estrogen, and other chemi-
cals 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 Cyto-
chrome 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, sulf-
onamides, 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 oxi-
dized 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 ane-
mic patients. PCT has been shown to improve with eryth-
ropoietin 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 treat-
ment.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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Cutaneous porphyrias part I Review 1469
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 fra-
gility (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 occasion-
ally 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 sero-
hemorrhagic; milia, which develop secondary to damage
of the basement membrane in subepidermal blistering dis-
orders, may present after resolution of bullae. Skin fragil-
ity 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, cre-
ate 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 sur-
rounded by atrophy and hyperpigmentation.26 Unlike
other skin findings, these lesions can also affect non-
sun-exposed areas.
Deposition of photoactive porphyrins near the eye
causes lid scarring, ectropion, lacrimal scarring, sclero-
malacia, and corneal thinning.56 One case of corneal per-
foration 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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1470 Review Cutaneous porphyrias part I
(a)
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 demon-
strating increased uroporphyrins with an elevated uro-
porphyrin 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 5-
carboxylate porphyrins, coproporphyrin, and iso-
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Horner et al.
(b)
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 chroma-
tography have been used in the past to measure different
types of porphyrins,58 but high-performance liquid chro-
matography 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
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Horner et al.
Histopathology
Caterpillar bodies are the diagnostic histopathological
finding in PCT. Caterpillar bodies are linear eosinophilic
PAS-positive globules in the epidermis overlying subepi-
dermal bullae of PCT. They contain degenerating kerati-
nocytes, colloid bodies, and basement membrane bodies.59
Colloid bodies have whorled clumps of filaments, which
contain degenerating melanosomes, vacuoles, mitochon-
dria, and desmosomes.59 Basement membrane bodies have
convoluted basement membrane with collagen.59 The
occasional fusion of basement membrane bodies with col-
loid 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 diastase-
resistant glycoprotein material in and around the vessels
near the dermal–epidermal junction. Superficially, there is a
compact corneal layer with necrotic epithelium, sparse lym-
phocytic 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.
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)
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Cutaneous porphyrias part I Review 1471
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 accu-
mulate 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 iso-
coproporphyrin, can help distinguish the two entities.31
Other porphyrias. See Table 1.31
Epidermolysis bullosa acquisita. Both epidermolysis bull-
osa acquisita and PCT have similar bullous lesions and
milia, but epidermolysis bullosa acquisita is usually asso-
ciated 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
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1472 Review Cutaneous porphyrias part I
cause hypertrichosis and hyperpigmentation. Addison’s
disease is evaluated by measuring cortisol and adrenocor-
ticotropic hormone, while hypertrichosis lanuginosa ac-
quisita 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 iso-
coproporphyrin accumulate in erythrocytes and liver,
occasionally causing hemolytic anemia and associated
splenomegaly.1
Presentation and diagnosis
Hepatoerythropoietic porphyria is characterized by scar-
ring, photo-mutilation, sclerodermoid changes, and
hypertrichosis.63 Similar to other homozygous forms of
porphyria, it usually begins in infancy or young child-
hood. Unlike PCT, HEP does not require environmental
triggers to manifest.64 Although enzyme activity should
be much lower in HEP compared to PCT, the erythro-
cyte 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 por-
phyrins occurs within bone marrow.
Erythropoietic protoporphyria
Epidemiology
It is the most common porphyria in childhood – preva-
lence ranges from 0.06 to 1.75 per 100,000 (Table 4).65–67
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Horner et al.
Table 4 Prevalence per 100,000 of erythropoietic
protoporphyria per country65,67
Country Prevalence (per 100 000)
Slovenia 1.75
United Kingdom 0.77
North Ireland 1.27
Netherlands 1.33
South Africa (Parker)
General population 0.06
European immigrant population 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 atten-
tion later in life, others are associated with myeloprolifer-
ative 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 hepato-
cytes, 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 pro-
toporphyrin deposits around vessels causing tissue dam-
age 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 dis-
ease 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 pos-
sible that two low-expression alleles may manifest clini-
cally 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
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Horner et al. Cutaneous porphyrias part I Review 1473

mutation is not the only cause of EPP; compound hetero-

zygosity 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 expo-
sure tingling, prickling, and stinging sensations. The burn-
ing sensation occurs before any visible skin changes in
95% of cases77 and can persist for several days or mani-
fest as solar urticaria. While 10% of patients never expe-
rience visible skin changes, those with skin findings report
Figure 7 Linear erosions of the lateral nasal bridge and
swelling (80%), reddening (20%), blistering (17%), crust- lower lip in a patient with erythropoietic protoporphyria
ing/eczema (14%), petechiae/bruising (9%), and fissuring
(5%).77 The severity of skin changes correlates with dura-
tion 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 dor-
sum of hands, shallow pitted or linear scars of face (espe-
cially 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, hemoly-
sis, and accelerated photosensitivity.81
Figure 8 Erosions with crusting on the left helix of a patient
Although there is no consensus, experts recommend
with erythropoietic protoporphyria
measuring liver enzymes and blood protoporphyrin levels
every 6–12 months, and, if needed, ultrasound or com- risk factors for liver disease, elevated liver enzymes, or
puted tomography scanning for further evaluation. Any clinical signs of hepatic decomposition should have a liver
patient with EPP with a family history of liver disease, biopsy every five years.72 Patients with EPP should avoid

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1474 Review Cutaneous porphyrias part I
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 canalic-
uli.82 Optic nerve atrophy has also been reported in
EPP.83
Diagnosis
The most specific way to diagnose EPP is quantitative
porphyrin analysis via high-performance liquid chroma-
tography, demonstrating increased free erythrocyte proto-
porphyrin.84 Unlike other porphyrias, urinary excretion
of porphyrins remains normal in EPP due to the hydro-
phobic nature of protoporphyrin. The one exception is in
EPP with hepatic failure where coproporphyrins may be
detected in urine.82 Diagnosis via blood involves chemi-
cally extracting protoporphyrin for concentration mea-
surement 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 protopor-
phyrin 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 porphy-
rias and are normal in EPP.
Histology
Chronically sun-exposed skin shows progressive thicken-
ing of blood vessels in the papillary dermis, which stains
with PAS. Immunofluorescence shows that this PAS mate-
rial is type IV collagen likely from concentric reduplica-
tion of perivascular basal lamina from chronic sun
exposure. Fine granular material appears at the basement
membrane and in the superficial dermis.86 Direct immu-
nofluorescence shows mostly IgG, as well as IgA, IgM,
and C3 within vessel walls.86 Acute lesions show vacuoli-
zation of epidermal cells with intercellular edema, and
vacuolization and cytolysis of endothelial cells of superfi-
cial blood vessels without other changes to the surround-
ing 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
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Horner et al.
in the ALAS2 gene that encodes 5-aminolaevulinate syn-
thase), lipoid proteinosis, and colloid milium,68 which
can be distinguished by measuring blood and stool por-
phyrins.
Congenital erythropoietic porphyria
Epidemiology
Congenital erythropoietic porphyria is rare with 130
cases published worldwide.87 It has been reported in
patients of various ethnic backgrounds.
Etiology and pathogenesis
Congenital erythropoietic porphyria is caused by autoso-
mal recessive mutations in the gene coding for uro-
porphyrinogen 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 hydrox-
ymethylbilane to uroporphyrinogen III (Fig. 1). Without
UROIIIS, hydroxymethylbilane quickly degrades into uro-
porphyrinogen 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 reti-
culocytes and erythrocytes as slender needle-like inclu-
sions causing hemolysis, and deposit in various tissues.88
The excess porphyrins deposited into skin are activated
by sunlight and cause toxic oxidative damage (subepider-
mal bullae and inflammation).
The pathogenesis of CEP is entirely genetic; 39 differ-
ent 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 relation-
ship 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, hemo-
lytic 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
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Horner et al. Cutaneous porphyrias part I Review 1475

childhood causes second- and third-degree burns, with

Figure 9 Pink fluorescence due to porphyrin deposition in the
teeth of a patient with congenital erythropoietic porphyria
ulceration and scarring.87 Patients present with bullae,
hyper- and hypopigmentation, fibrosis, alopecia, hypertri-
chosis, and deformities from resorption of the distal pha-
langes and nose.87 Lesions often become infected, which
can cause further scarring and inflammation.
Chronic anemia is caused by decreased erythrocyte life-
span, 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, potas-
sium, 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

No Associated with acute neurovisceral attacks? Yes

-Abdominal pain, peripheral neuropathy, psychiatric symptoms
No Yes
Adult onset
Measure urine,
Measure urine, blood, and/or Measure urine, blood, and stool, and/or
stool porphyrins stool porphyrins plasma porphyrins
& Confirm with DNA analysis

⇑ Fecal coproporphyrin ⇑ Fecal

⇑ ⇑ Urine ⇑ Urine uroporphyrin and isomers III>I protoporphyrin >
uroporphyrin I ⇑ Fecal heptaporphyrin coproporphyrin
⇑ Urinary uro-and
⇑ ⇑ Fecal uro- and isocoproporphyrin ⇑ Blood-free Plasma fluorescense
coproporphyrin, ALA and
coproporphyrin I ⇓ Erythrocyte UROD protoporphyrins emission at 626 nm
PBG
&⇑ activity
⇓ Erythrocyte
No Yes
protoporphyrin
UROD activity

CEP HEP EPP Acquired PCT Familial PCT HEP VP

- Evaluate for - Consider - Screen for - Screen for hepatitis C - Consider genetic testing - Consider screening - Consider
other organ genetic testing liver disease virus. of relatives for UROD relatives for CPO genetic
involvement of relatives for with liver - Consider genetic testing mutation and/or gene mutation. testing of
including eyes, UROD function tests for hemochromatosis gene hemochromatosis gene relatives for
bones, and mutation. and imaging. mutation. mutation. PPO gene
anemia. 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

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1476 Review Cutaneous porphyrias part I
quently, patients have short stature and are at risk for
fractures.93 Porphyrins have affinity for calcium phos-
phate 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 fluores-
cence under Wood’s lamp.87 Eye complications include
conjunctivitis, complete loss of eyelashes and eyebrows,
scleral thinning, ulcerations, and even one case of bilat-
eral 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 scar-
ring, which dries out the eye, and incomplete eyelid clo-
sure 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 coproporphy-
rin. 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 lipo-
philic 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 iso-
mers 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. PAS-
positive 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 predomi-
nance for both, increased blood porphyrins, and normal
UROD activity, while HEP has increased fecal
isocoproporphyrin.
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Horner et al.
Differential diagnosis and approach to
cutaneous porphyrias
Owing to variability in presentation and rarity, porphy-
rias 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 photo-
patch testing. In patients with photosensitivity and bul-
lous lesions, bullous lupus erythematosus, bullous
pemphigoid, drug reaction, hydroa vacciniforme, ery-
thema 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 fur-
ther help distinguish the specific enzyme defect. Solar urti-
caria 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 spe-
cific 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 wave-
length?
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
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Horner et al.
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 histopatholog-
ical 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 inflamma-
tory 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 fash-
ion
D It causes burning pain after short amounts of sun
exposure
8 Which disorder should typically be included in the dif-
ferential 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 asso-
ciated with erythropoietic protoporphyria?
A Diabetes insipidus
B Gallstones
C Cardiac valvular dysfunction
D Vasculitis
10 Which of the following systemic associations is incor-
rect?
A Porphyria cutanea tarda: hepatic cirrhosis
B Hereditary coproporphyria: syndrome of inappro-
priate antidiuretic hormone secretion
C Congenital erythropoietic porphyria: conjunctivitis
D Variegate porphyria: emphysema
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Cutaneous porphyrias part I Review 1477
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Answers to questions
1 a
2 c
3 a
4 b
5 d
6 c
7 a
8 d
9 b
10 d
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