eMedicine Specialties > Pediatrics: General Medicine > Hematology

Porphyria, Cutaneous

Author: Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP, Associate Professor of Pediatric Hematology and Oncology, Department of Pediatrics, Albany Medical Center; Faculty, Alden March Bioethics Institute
Coauthor(s): Thomas G DeLoughery, MD, Professor of Medicine and Pathology, Divisions of Hematology/Oncology and Laboratory Medicine, Associate Director, Department of Transfusion Medicine, Division of Clinical Pathology, Oregon Health Sciences University; Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston; Darius J Adams, MD, Assistant Professor, Department of Pediatrics, Section of Genetics and Metabolism, Albany Medical Center
Contributor Information and Disclosures

Updated: Aug 7, 2008

Introduction

Background

Porphyria is a predominantly inherited metabolic disorder, resulting from a deficiency of an enzyme in the heme production pathway and overproduction of toxic heme precursors. Eight different enzymes are involved in the pathway, and deficiencies of the second to eighth enzyme result in a family of disorders with various, and often overlapping, clinical presentations.

Porphyrias are divided into 2 types according to the predominant symptoms. The two types are (1) the neurovisceral or acute porphyrias with abdominal pain, neuropathy, autonomic instability, and psychosis and (2) the cutaneous porphyrias with symptoms of photosensitive lesions on the skin.

Aminolevulinic acid dehydrase (ALAD) porphyria and acute intermittent porphyria (AIP) cause predominately neurovisceral symptoms, whereas congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic porphyria (EP) cause mostly cutaneous symptoms. Two porphyrias overlap these categories and can cause both neurovisceral and cutaneous symptoms, namely hereditary coproporphyria (HCP) and variegate porphyria (VP).

Only the cutaneous manifestations of the porphyrias are considered in this article. For explanation of diagnosis and management of the acute porphyrias and the acute manifestations of porphyrias with both neurovisceral and cutaneous components, please refer to the companion article Porphyria, Acute.

Some of the confusion with reference to the porphyrias is derived from the many synonyms for each particular disorder. The synonyms are as follows:

• Congenital erythropoietic porphyria (CEP)
  • Uroporphyrinogen III synthase deficiency
  • Hereditary erythropoietic porphyria
  • Congenital hematoporphyria
  • Erythropoietic uroporphyria
  • Gunther porphyria
• Porphyria cutanea tarda (PCT)
  • Symptomatic porphyria
  • Uroporphyrinogen decarboxylase deficiency
• Hepatoerythropoietic porphyria (HEP) - Homozygous type II PCT
• Hereditary coproporphyria (HCP)
  • Coproporphyria
  • Coproporphyrinogen oxidase deficiency
• Variegate porphyria (VP)
  • Protoporphyrinogen oxidase deficiency
  • South African porphyria
  • Porphyria variegata
  • Protocoproporphyria hereditaria
• Erythropoietic protoporphyria (EPP)
  • Protoporphyria
  • Ferrochelatase deficiency

PCT is the most common porphyria in the United States and Europe.¹ Its manifestations are prototypical of the cutaneous porphyrias. Cutaneous lesions independent of acute attacks are experienced by 50% of patients with VP, whereas cutaneous manifestations of HCP occur with acute attacks. CEP and EPP have onset in infancy. CEP lesions are a more severe form of PCT lesions. EPP lesions are milder than PCT lesions but may approach PCT lesions in severe cases. HEP is a rare homozygous form of PCT that presents in childhood.

Pathophysiology

An outline of the porphyrin pathway reveals the pathophysiological mechanisms that cause porphyria.^2,3

Biosynthesis of one heme molecule requires 8 molecules of glycine and succinyl-coenzyme A (CoA). Heme is essential in many critical biochemical functions. For example, oxygen binding and transport, mixed-function oxidation in the cytochrome P-450 pathway, activation and decomposition of hydrogen peroxide, oxidation of tryptophan and prostaglandins, and the production of cyclic guanosine monophosphate (cGMP) cannot occur without heme. The liver produces approximately 15% of the body's heme, and the remainder is produced in the bone marrow. Heme produced in the liver is primarily used to produce cytochromes and peroxisomes, and heme produced in the bone marrow is primarily used for hemoglobin synthesis and oxygen transport.

As demonstrated in Media file 1, enzymes are located in either the mitochondria or the cytosol.

Delta-aminolevulinic acid (ALA) synthase is the first step in the heme biosynthesis pathway. This enzyme condenses glycine and succinyl-CoA and has 2 isoforms that are encoded by separate genes; the housekeeping isoform is expressed in all tissues, whereas the erythroid isoform is expressed only in hematological tissue.

• ALA synthase is the rate-limiting step for heme production in the liver but not the bone marrow. Indeed, the erythron responds to stimuli for heme synthesis by increasing cell numbers.
• In the liver, ALA dehydratase and porphobilinogen (PBG) deaminase levels are typically low, resulting in ALA and PBG accumulation with increased ALA production under normal conditions.
• High ALA levels induce heme oxygenase, increase bilirubin production, and inhibit ALA synthase.
• Heme inhibits ALA synthase synthesis, mitochondrial transfer, and catalytic activity in the liver. This leads to tight control of ALA production because ALA synthase turnover is rapid.
• Exogenous chemicals can induce ALA synthase by depleting existing heme or inhibiting heme synthesis. The 3 common mechanisms for this include the destruction or enhanced production of cytochrome P-450 heme and rapid inhibition of ferrochelatase.
• In contrast to the liver, heme increases the synthesis of hemoglobin and ALA synthase in the bone marrow. In addition, erythroid ALA synthase is not affected by exogenous chemicals.

ALA dehydratase condenses 2 molecules of ALA to form the monopyrrole PBG ALA dehydratase, which is inhibited by lead, levulinic acid, hemin, succinylacetone, and alcohol.

• Lead displaces zinc from the enzyme. This inhibition can be completely reversed by supplemental zinc or dithiothreitol.
• Succinylacetone, a substrate analogue of ALA that is found in the blood and urine of patients with hereditary tyrosinemia, is the most potent inhibitor of ALA dehydratase.

PBG deaminase catalyzes the polymerization of 4 molecules of PBG in a head-to-tail orientation, yielding a linear tetrapyrrole intermediate, hydroxymethylbilane. The tissue and erythrocyte isozymes are encoded by the same structural gene.

Uroporphyrinogen III cosynthase forms uroporphyrinogen III from hydroxymethylbilane by reversing the orientation of the last pyrrole ring before cyclizing the linear molecule. Uroporphyrinogen I cosynthase forms uroporphyrinogen I from hydroxymethylbilane by cyclizing the linear molecule without modifying any of the pyrrole rings. Normal tissues contain an excess of uroporphyrinogen cosynthases compared to PBG deaminase.

Uroporphyrinogen decarboxylase sequentially removes a carboxylic group from the acetic side chains of each of the pyrrole rings to yield coproporphyrinogen. This enzyme has highest affinity for uroporphyrinogen III. It is inhibited by several metals, including copper, mercury, and platinum, but the evidence indicating that iron has an effect on this enzyme is controversial.

Coproporphyrinogen oxidase removes a carboxyl group from the propionic groups on 2 of the pyrrole rings to yield protoporphyrinogen IX.

Protoporphyrinogen oxidase forms protoporphyrin by removing 6 hydrogen atoms from protoporphyrinogen IX. This enzyme has been identified in human fibroblasts, erythrocytes, and leukocytes. It is noncompetitively and irreversibly inhibited by hemin.

Iron is inserted into protoporphyrin by ferrochelatase as the last step in the heme synthesis pathway. Enzyme activity is stimulated by fatty acids and is inhibited by metals, such as cobalt, zinc, lead, copper, and manganese, as well as by metalloporphyrins.

Porphyria cutanea tarda

Porphyrin overproduction occurs in the liver and the skin. Singlet oxygen, which is the primary toxic agent in the photodermatoses of porphyria, is the high-energy form of oxygen in which all the outer shell electrons are paired. It is generated by visible light (400 nm) in the presence of photosensitizers, such as the various porphyrins⁴ Abnormally high complement, polymorphonucleocytes, and prostaglandins occur in lesions.

Erythropoietic protoporphyria

Mechanisms are similar to PCT, except that locally cutaneous production of porphyrins probably does not occur.

Congenital erythropoietic porphyria

Bone marrow is the primary site of the enzyme defect. Conspicuous porphyrin-laden normoblasts and reticulocytes are found in the marrow. Photolysis of porphyrin-laden erythrocytes occurs in the dermal capillaries, causing subepidermal lesions. Repeated trauma causes secondary skin changes and results in joint contractures. An intrinsic erythrocyte abnormality results in autohemolysis.

Splenomegaly occurs as a consequence of the removal of damaged and hemolyzed erythrocytes. Cholecystitis results from porphyrin-rich gallstones. Bone marrow hyperexpansion results in fragile bones.

Frequency

United States

The absence of a porphyria registry in the United States impedes an accurate calculation of frequencies, but the overall prevalence is estimated as 4 per 100,000. However, as indicated in Table 2, the porphyria incidence varies significantly by type, with PCT being the most common and CEP being very rare. The lack of recognition of these disorders may contribute to inaccurate knowledge of their true incidence.

Despite earlier reports, the frequency of the genetic defect and phenotypic expression have a moderately strong relationship. A highly variable penetrance rate has been noted. Expression of the genetic defect is more common in familial cases, suggesting that such families may have an additional undetected genetic abnormality or environmental exposure. Around one half of individuals with genetic defects are symptomatic.

International

In general, porphyrias do not have a geographic preference. However, certain porphyrias have a high incidence in certain parts of the world.

PCT type I (ie, sporadic) is more common than PCT types II and III (ie, familial) in Europe, South Africa, and South America; however, the reverse is true in North America. Incidence of HCP is widely varies by race. Incidence of VP is particularly high in South Africans of Danish descent.

Table 1. Frequency Varies with the Specific Porphyria

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Mortality/Morbidity

CEP is associated with a significant decrease in life expectancy.

Race

• PCT does not have a racial predilection, except in South Africa, where it is more prevalent among  persons of Bantu origin. This is believed to be caused by a higher incidence of hemosiderosis in these individuals.
• The incidence of HCP greatly depends on race.
• VP has a particularly high incidence in South African persons of Dutch descent.
• See International.

Sex

• Most porphyrias do not demonstrate a sex predilection (see International).
• A change to a nearly equal sex distribution is attributed to the higher rate of alcoholism in males combined with the recent increase in the use of estrogens by women. Both factors exacerbate manifestations of the porphyrias.
• The sex predilection of HCP varies with race (see International).

Age

• CEP and EP usually present in infancy, but manifestations can be delayed until childhood. CEP can cause hydrops fetalis and recurrent fetal loss.
• HCP has a variable age of onset but usually does not present before adolescence. However, cases have been reported at younger ages.
• Symptoms of PCT and VP most often manifest in adulthood. However, inheritance of 2 abnormal genes can cause onset in childhood. Childhood onset is more unusual for VP than PCT, and, in the case of PCT, onset in infancy has been reported. Because PCT has a relatively high prevalence and low penetrance, 2 asymptomatic carriers each can transmit an abnormal gene without knowledge of the existing abnormality. HEP represents the onset of homozygous PCT type II in childhood.

Clinical

History

Porphyria cutanea tarda (PCT), hereditary coproporphyria (HCP), and variegate porphyria (VP) usually manifest after the second decade, and skin symptoms are chronic and appear several days after sun exposure. Increased fragility, blistering, and scarring are noted, especially over the back of the hands. Remission may occur in the winter months, if sunlight exposure is decreased.

Erythropoietic protoporphyria (EEP) typically presents in early childhood, and skin symptoms arise immediately after sun exposure with burning, edema, and erythema.

The presence of neurologic symptoms and abdominal pain, in association with cutaneous symptoms, would favor VP or HCP as the likely underlying porphyria.

PCT is associated with several precipitating factors.

• Alcoholism
• Iron overload (eg, in transfused patients with thalassemia)
• Hemochromatosis or HFE locus mutations
• Dialysis
• Estrogen
• Hepatitis C virus (HCV),⁵ cytomegalovirus (CMV), and human immunodeficiency virus (HIV) infection

Physical

Skin changes are the hallmark of the cutaneous porphyrias. They can be acute (EP), with erythema, edema, and erosions that eventually lead to facial scarring, or more chronic (PCT, VP, HCP), with skin fragility, blistering, and scarring, often over the backs of the hands.

• Congenital erythropoietic porphyria (CEP)
  • Diaper - Pink-stained or dark-stained urine
  • Cutaneous lesions
    • Subepidermal bullous lesions that worsen with exposure to sunlight
    • Hyperpigmented or hypopigmented healing subepidermal lesions
    • Epidermal atrophy
    • Pseudoscleroderma
    • Mutilation of facial skin and cartilage
  • Hair - Hypertrichosis, alopecia
  • Eyes - Keratoconjunctivitis, vision loss
  • Musculoskeletal
    • Resorption of distal phalanges
    • Contractures
    • Decreased range of motion
    • Pathological fractures
    • Vertebral compression and collapse
    • Osteolytic and sclerotic lesion
  • Growth - Shortness of stature
  • Abdomen - Splenomegaly, upper right quadrant tenderness, positive Murphy sign
• PCT
  • Cutaneous lesions (See the Dermatology Online Atlas for images of cutaneous lesions.)
    • Vesicle and bullae formation occurs in areas exposed to light, including the dorsum of hands and face.
    • Legs and feet commonly are involved in women.
  • Secondary skin changes from vesicular and bullous lesions
    • Skin fragility with erosion from mild shearing trauma
    • Hyperpigmentation or hypopigmentation of areas exposed to light
    • Melanosis and violaceous-brown discoloration in areas exposed to light
    • Milia
    • Pseudoscleroderma
    • Atrophy and scaring of healed skin
    • Alopecia
    • Dystrophic calcification
    • Nonhealing ulcerations
  • Light urticaria (rare)
  • Hair: Hypertrichosis slowly develops.
• EPP 
  • Exposure to light, especially in the spring and summer, causes cutaneous stinging and burning followed by erythema and edema.
  • Petechiae, purpura, vesicles, and crusting may develop.
  • Lesions similar to those of PCT may be seen in severe sun exposure but are much less common.

Causes

Table 2. Causes by Type of Porphyria

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*AR = Autosomal recessive, AD = Autosomal dominant

• CEP is associated with uroporphyrinogen III cosynthase activity of about 40% normal activity.
• PCT type II and type III are inherited, whereas type I spontaneously occurs. Type I and type III are localized defects in liver enzyme activity, whereas type II involves a defect in both the liver and erythrocyte enzymes. Overall, 75% of affected individuals have PCT type I. Type II affects approximately 20%, and type III affects 5% of individuals. Familial PCT has about a 10% penetrance rate.
• Expression of the disorder is precipitated by many factors, including the following:
  • Alcoholism
  • Beta-thalassemia major
  • Diabetes mellitus
  • Dialysis
  • Estrogen
  • HCV, CMV, and HIV infection
  • Hematologic malignancy
  • Hemochromatosis
  • Hepatocellular carcinoma
  • Lupus erythematosus
  • Renal failure
• HEP is considered the homozygous form of PCT type II and is associated with a 75% decrease in enzyme activity in all tissues.

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