Cutaneous Porphyria 

Updated: Nov 12, 2019
Author: Richard E Frye, MD, PhD; Chief Editor: Hassan M Yaish, MD 

Overview

Practice Essentials

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 two 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.[1, 2, 3, 4]

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).[5]

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.[6] The synonyms are as follows:

Congenital erythropoietic porphyria (CEP)

See the list below:

  • Uroporphyrinogen III synthase deficiency

  • Hereditary erythropoietic porphyria

  • Congenital hematoporphyria

  • Erythropoietic uroporphyria

  • Gunther porphyria

Porphyria cutanea tarda (PCT)

See the list below:

  • Symptomatic porphyria

  • Uroporphyrinogen decarboxylase deficiency

Hepatoerythropoietic porphyria (HEP)

See the list below:

  • Homozygous type II PCT

Hereditary coproporphyria (HCP)

See the list below:

  • Coproporphyria

  • Coproporphyrinogen oxidase deficiency

Variegate porphyria (VP)

See the list below:

  • Protoporphyrinogen oxidase deficiency

  • South African porphyria

  • Porphyria variegata

  • Protocoproporphyria hereditaria

Erythropoietic protoporphyria (EPP)

See the list below:

  • Protoporphyria

  • Ferrochelatase deficiency

Workup in cutaneous porphyria

Demonstration of elevated porphyrins in plasma (particularly for congenital erythropoietic porphyria [CEP]), urine, and stool is very useful for diagnosis of the porphyrias.[7, 8]

Qualitative urine examination can identify urine porphyrins. However, normal urine contains porphyrins, making comparison with a control sample essential. Quantitative urine porphyrin levels can be useful, but prior qualitative testing is desirable.

Stool porphyrin levels that are combined with other laboratory values and clinic correlation help guide the diagnosis. However, levels of porphyrins widely vary, and, in most cases, exact values for each disorder have not been established.

Protoporphyria can be diagnosed by identifying numerous fluorescent erythrocytes in blood examined microscopically with a 100-watt iodine-tungsten lamp.

Management of cutaneous porphyria

Iron depletion can treat several of the cutaneous porphyrias. Phlebotomy and apheresis can remove excessive iron in patients with porphyria cutanea tarda (PCT).[9]

Porphyrin levels can be reduced by direct methods or with medications that bind porphyrins. These methods are useful adjuncts to iron load reduction therapy or when such therapy is ineffective or limited because of comorbid conditions, such as severe renal disease.

Oral photoprotection can be achieved with free radical scavengers, thereby reducing free radicals, singlet oxygen formation, and the photosensitizing effect of porphyrins.

Beta-carotene is a pigment found in various green and yellow fruits and vegetables and can decrease the severity of photosensitivity reactions in patients with porphyria. Sunscreen protection agents should be used if sun exposure is expected.

Cholecystectomy may be required for severe cholelithiasis in CEP. Splenectomy may be required if severe hemolytic anemia develops in CEP.

CEP has been cured with allogenic bone marrow transplant. Risks of this procedure must be carefully considered. Liver transplant alone is not curative for erythropoietic protoporphyria (EPP) but instead needs to be combined with bone marrow transplant.[10]

Pathophysiology

An outline of the porphyrin pathway reveals the pathophysiological mechanisms that cause porphyria.[11, 12, 13, 14]

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, but the majority 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 the following image, enzymes are located in either the mitochondria or the cytosol.

The heme production pathway. Heme production begin The heme production pathway. Heme production begins in the mitochondria, proceeds into the cytoplasm, and is then resumed in the mitochondria for the final steps. This figure outlines the enzymes and intermediates involved in the porphyrias. Enzymes names are presented in the boxes. Names of the intermediates are outside the boxes, between arrows. Multiple arrows leading to a box demonstrate that multiple intermediates are required as substrates for the enzyme to produce one product.

Delta-aminolevulinic acid (ALA) synthase is the first enzyme 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.[15] It is generated by visible light (400 nm) in the presence of photosensitizers, such as the various porphyrins.[16] Abnormally high complement and prostaglandins occur in lesions.

Erythropoietic protoporphyria

Mechanisms are similar to PCT, except that locally cutaneous production of porphyrins probably does not occur.[17]

Congenital erythropoietic porphyria

Bone marrow is the primary site of the enzyme defect.[18, 19] 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 and vitamin D deficiency due to avoiding sun exposure result in fragile bones.

Epidemiology

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.[20] 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.[21]

PCT type I (ie, sporadic) is more common than PCT types II and III (ie, familial) in Europe, South Africa, and South America. Incidence of HCP is widely varies by race.[22] Incidence of VP is particularly high in South Africans of Danish descent.[23]

Table 1. Frequency Varies with the Specific Porphyria (Open Table in a new window)

Type of Porphyria

Age of Onset

Incidence per 100,000 Population

Male-to-Female Ratio

CEP

Infancy to early childhood; rare in adults

300 cases total

1:1

PCT

Type I: Adulthood

Type II (heterozygous mutations): Adulthood

Type III (homozygous mutations): Childhood

United States: 4

United Kingdom: 0.05

1:1

HCP

Predominantly adulthood

Youngest report was child aged 4 y

Japan: 1.5

Czech: 1.5

Israel: 0.7

Denmark: 0.05

1:20

1:4

2:1

1:1

VP

Heterozygous mutation: After puberty

Homozygous mutation: Childhood (rare)

South Africa: 34

1:1

EPP

Infancy to childhood

0.02

1:1

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.

 

Presentation

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 a very different picture in comparison with other photosensitizing porphyrias. Patients experience burning, pain, edema, and erythema without bullous lesions, scarring, or pigmentation changes.

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

Because many patients with cutaneous porphyria avoid sunlight, they may suffer from vitamin D deficiency.[24]

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),[25]  cytomegalovirus (CMV), and human immunodeficiency virus (HIV) infection - A study by Aguilera et al suggested that in most cases, PCT is associated with HIV only if the patient is co-infected with HCV[26]

Physical

Skin changes are the hallmark of the cutaneous porphyrias. They can be acute (CEP), 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.[14]

Congenital erythropoietic porphyria (CEP)

See the list below:

  • Diaper - Pink-stained or dark-stained urine

  • Hair - Hypertrichosis, alopecia

  • Teeth - Red or brown discoloration

  • Eyes - Keratoconjunctivitis, vision loss

  • Growth - Shortness of stature

  • Abdomen - Splenomegaly, upper right quadrant tenderness, positive Murphy sign

Cutaneous lesions include the following:

  • Subepidermal bullous lesions that worsen with exposure to sunlight

  • Hyperpigmented or hypopigmented healing subepidermal lesions

  • Epidermal atrophy

  • Pseudoscleroderma

  • Mutilation of facial skin and cartilage

Musculoskeletal findings include the following:

  • Resorption of distal phalanges

  • Contractures

  • Decreased range of motion

  • Pathological fractures

  • Vertebral compression and collapse

  • Osteolytic and sclerotic lesion

PCT

Cutaneous lesions include the following (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.[27]

  • Legs and feet commonly are involved in women.

Secondary skin changes from vesicular and bullous lesions include the following:

  • Skin fragility with erosion from mild shearing trauma

  • Hyperpigmentation or hypopigmentation (vitiligo) of areas exposed to light[28]

  • Melanosis and violaceous-brown discoloration in areas exposed to light

  • Milia[27]

  • Pseudoscleroderma[28]

  • Atrophy and scaring of healed skin

  • Nonscarring alopecia[28]

  • Dystrophic calcification

  • Nonhealing ulcerations

  • Acquired ichthyosis[28]

Light urticaria (rare) and hypertrichosis (periorbital) that slowly develops are noted.

EPP

See the list below:

  • 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

  • Osteoporosis and osteopenia can occur[24]

Causes

Table 2. Causes by Type of Porphyria (Open Table in a new window)

Porphyria

Deficient Enzyme

Location

Inheritance

Chromosome Band

CEP

Uroporphyrinogen III synthase

Cytosol

Autosomal recessive (AR)

10q25.3-26.3

PCT

Uroporphyrinogen decarboxylase

Cytosol

Autosomal dominant (AD)

1p34

HEP

Uroporphyrinogen decarboxylase

Cytosol

AR

1p34

HCP

Coproporphyrinogen oxidase

Mitochondrial

AD

3q12

VP

Protoporphyrinogen oxidase

Mitochondrial

AD

1q22-23

EPP

Ferrochelatase

Mitochondrial

AD, AR

18q22

CEP is associated with uroporphyrinogen III cosynthase activity of about 40% normal activity.

PCT type I occurs spontaneously, whereas type II and type III are inherited. Since type III is rare, severe, has childhood onset, and is caused by an underlying homozygous gene defect, it is often considered separately (HEP). Type I, or sporadic PCT, affects 75% of all patients, with localized defects in liver enzyme activity. Type II, or familial PCT, accounts for approximately 20% of patients, probably due to the low penetrance rate of the UROD gene defect, and involves a defect in both the liver and erythrocyte enzymes. Sporadic and familial PCT are often clinically indistinguishable.

Expression of the disorder is precipitated by many factors, including the following:

  • Alcoholism

  • Beta-thalassemia major[29]

  • Diabetes mellitus

  • Dialysis

  • Estrogen

  • HCV, CMV, and HIV infection[30]

  • Hematologic malignancy

  • Hemochromatosis

  • Hepatocellular carcinoma

  • Lupus erythematosus

  • Renal failure

HEP is considered the homozygous form of inherited PCT (type III), and is associated with a 75% decrease in enzyme activity in all tissues.

 

DDx

 

Workup

Laboratory Studies

Demonstration of elevated porphyrins in plasma (particularly for congenital erythropoietic porphyria [CEP]), urine, and stool is very useful for diagnosis of the porphyrias.[7, 8]

Qualitative urine examination can identify urine porphyrins. However, normal urine contains porphyrins, making comparison with a control sample essential. In both the amyl alcohol and talc tests, the urine must be adjusted to a pH of 4 by mixing 3 mL of urine with 1 mL of 1 mol/L acetate buffer.

For the amyl alcohol test, 4 mL of amyl alcohol is added to the 4-mL buffered urine solution. After vigorous shaking or low-speed centrifuge, the mixture is examined under a Wood lamp.[31] A pink-to-red fluorescence in the upper organic layer indicates a positive result.

For the talc test, 100 mg of talc is added to 10 mL of the buffered urine solution and shaken vigorously. Low-speed centrifuge for about 10 minutes produces a talc pellet, which can be examined under a Wood lamp. A pink or red color indicates a positive result.

Protoporphyria can be diagnosed by identifying numerous fluorescent erythrocytes in blood examined microscopically with a 100-watt iodine-tungsten lamp.

Qualitative stool studies can help guide the diagnosis. Mix 1-2 g of stool in 2 mL of an amyl alcohol, glacial acetic acid, and ether mixture. Red fluorescence under a Wood lamp indicates that porphyrins are present.

Stool porphyrin levels that are combined with other laboratory values and clinic correlation help guide the diagnosis. However, levels of porphyrins widely vary, and, in most cases, exact values for each disorder have not been established.

Table 3. Quantitative Fecal Porphyrins by Type of Porphyria (Open Table in a new window)

Porphyrin Type

CEP

PCT

HCP

VP

EPP

Uroporphyrin

Significantly increased

Increased

Within reference range

Within reference range

Within reference range

Coproporphyrin

Significantly increased

Increased

Significantly increased

Increased

Within reference range

Protoporphyrin

Within reference range

Within reference range

Increased

Significantly increased

Significantly increased

Quantitative urine porphyrin levels can be useful, but prior qualitative urine testing is desirable. Although hereditary coproporphyria (HCP) and variegate porphyria (VP) have identical urine porphyrin profiles, stool porphyrin testing can differentiate them. CEP and porphyria cutanea tarda (PCT) also have identical porphyrin patterns; however, erythrocyte examination results are positive only for CEP.

Table 4. Quantitative Urine Porphyrins (Open Table in a new window)

Porphyrin type

CEP and PCT

HCP and VP

5-Aminolevulinate

Within reference range

Significantly increased

PBG

Within reference range

Significantly increased

Uroporphyrin

Significantly increased

Increased

Coproporphyrin

Increased

Significantly increased

Iron overload is almost always present in PCT and is reflected by abnormally high serum iron levels, low total iron-binding capacity, and high serum ferritin levels. Hemolytic anemia with polychromasia, poikilocytosis, anisocytosis, and basophilic stippling is observed in CEP. Thrombocytopenia and leukopenia are observed if hypersplenism develops in CEP.

Functional enzyme assays are not widely available and, therefore, are not commonly used in cutaneous porphyria diagnosis. ALAD and AIP assays are useful, and, at specialized centers, assays for other cutaneous porphyria types (eg, coproporphyrinogen oxidase) may be available. Although these other enzyme assays may be available, differential tissue expression of the enzymes makes these assays less useful in some individuals and they are not reliable for diagnostic purposes.

Many genetic defects responsible for porphyria have been identified. However, in general, a large number of defects account for each porphyria type, limiting the practical use of these tests. For example 121 mutations in the PPOX gene result in VP. In the future, advances in microarray technology may make routine DNA testing for multiple mutations possible. Currently, genetic testing is useful in 2 situations, as follows:

  • If a genetic defect is known to be present in an individual, family members can be tested for the defect.

  • Certain ethnic groups have a high incidence of a particular mutation (founder effect). For example, many South African families demonstrate a specific mutation for VP, and in the Swiss most VP patients show a single PPOX gene mutation.[32] Similarly, a limited number of mutations account for CEP in the United Kingdom.[33]

Imaging Studies

In CEP, single-photon emission computed tomography (SPECT) scanning may identify perfusion defects of the brain that were missed by magnetic resonance imaging (MRI).[34]

Procedures

Skin biopsy is not routinely indicated for the diagnosis of cutaneous porphyria and may lead to further scarring and poor healing.

Histologic Findings

Porphyria cutanea tarda

Skin lesions examined under light microscopy reveal subepidermal bullae with dermal papillae at the bases, elastosis and periodic acid-Schiff (PAS)-positive vessels in the dermis, and acid mucopolysaccharides at the dermal-epidermal junction. Immunofluorescence reveals accumulation of immunoglobulin G (IgG) and immunoglobulin M (IgM) and complement around dermal vessels and at the dermal-epidermal junction.[35]

Liver tissue reveals siderosis, fatty changes, necrosis, chronic inflammatory changes, and granuloma formation. Red autofluorescence and needlelike inclusion bodies are also observed. Cirrhosis and neoplastic changes are not uncommon.

Other Tests

Because many patients with cutaneous porphyria avoid sunlight, vitamin D levels should be monitored.[24]  In cases of PCT, consider testing for HCV,[25]  CMV, and HIV infection.[26]

 

Treatment

Medical Care

Iron depletion can treat several of the cutaneous porphyrias. High plasma iron levels inactivate uroporphyrinogen decarboxylase, the enzyme deficient in porphyria cutanea tarda (PCT), and induce 5-aminolevulinate, a major regulatory enzyme in the heme biosynthetic pathway. Thus, the activity of the deficient enzyme is reduced further, and porphyrins that cannot be metabolized are produced in increased quantities. Iron depletion also induces the synthesis of porphyrin pathway enzymes. In addition, iron overload resulting from chronic renal failure, a condition not uncommonly seen in association with PCT, is improved by this therapy.

Phlebotomy and apheresis can remove excessive iron in patients with PCT.[9] Standard phlebotomy for adults consists of removal of 250-500 mL of blood once or twice per week. The patient's tolerance and clinical response regulate the exact amount. In patients with chronic renal failure, more frequent small-volume phlebotomies and high-dose erythropoietin combined with phlebotomy are effective.

Monthly neocyte RBC exchange transfusions are reportedly useful in PCT, variegate porphyria (VP), and erythropoietic protoporphyria (EPP).

Erythropoietin is reportedly effective in PCT. By stimulating erythrogenesis, excess iron stored is mobilized and a drop in serum iron, ferritin, and plasma porphyrins is observed. Combining higher doses of erythropoietin with phlebotomy is effective in patients with renal failure.[36]

Deferoxamine forms a stable complex with iron, thereby preventing it from entering into further chemical reactions in PCT and congenital erythropoietic porphyria (CEP).[37] Long-term therapy slows hepatic iron accumulation and retards progression of hepatic fibrosis. Iron is chelated from ferritin and hemosiderin but not from transferrin, cytochromes, or hemoglobin. The chelate readily passes through the kidney, giving the urine a characteristic reddish color. Egan et al reported improvement in CEP in a woman treated with the iron chelator deferasirox to maintain iron deficiency.[38]

Iron oxidizes vitamin C, causing patients with iron overload to become deficient in vitamin C. Vitamin C supplements also increase the availability of iron.

A placebo-controlled study by Ferrer et al suggested that in women with VP, supplementation with both vitamin C and E restores protoporphyrinogen oxidase activity in lymphocytes.[39]

Toxic metabolites have deleterious effects. Porphyrin levels can be reduced by direct methods or with medications that bind porphyrins. These methods are useful adjuncts to iron load reduction therapy or when such therapy is ineffective or limited because of comorbid conditions, such as severe renal disease.

Therapeutic erythrocytapheresis has been combined with plasma exchange to reduce uroporphyrin blood levels. The procedure is continued until urine uroporphyrins are less than 600 mcg/d.[40]

Chloroquine and hydroxychloroquine, two antimalarial medications that belong to the 4-aminoquinolines, chelate and remove hepatic-bound porphyrins by forming water-soluble complexes that are eliminated in the urine. A study by Singal et al demonstrated that for PCT, the safety and efficacy of low-dose hydroxychloroquine (100 mg twice weekly) matches those of phlebotomy.[41]  However, a report by Salameh indicated that relapses are more common after 4-aminoquinoline treatment as compared with phlebotomy for PCT.[42]  

Cholestyramine is a polymeric resin that binds bile acids to form a nonabsorbable complex, which is excreted unchanged in the feces. This compound also binds carboxylated porphyrins excreted in the bile. By preventing enterohepatic circulation, porphyrins do not reenter the systemic circulation. It has been proposed that sorbent colestipol, operating via the same mechanism, reduces photosensitivity in EPP.[43]

Oral photoprotection can be achieved with free radical scavengers, thereby reducing free radicals, singlet oxygen formation, and the photosensitizing effect of porphyrins.

Beta-carotene is a pigment found in various green and yellow fruits and vegetables and can decrease the severity of photosensitivity reactions in patients with porphyria. Beta-carotene does not alter stool concentrations of protoporphyrins, and plasma or erythrocyte concentrations are not affected. Laboratory evidence suggests that beta-carotene quenches free radicals and singlet oxygen, which are produced when porphyrins are exposed to light and air. Carotenodermia (yellowing of the skin) usually develops after 4-6 weeks and coincides with the start of photoprotection. Protection decreases within 1-2 weeks after discontinuation of therapy. Plasma concentrations of 4-6 mcg/mL are therapeutic for most patients.

Cysteine was found to reduce photosensitivity in patients with protoporphyria.[44] Cysteine is believed to inactivate free radicals. Cysteine is a precursor to glutathione, a free radical scavenger.

N -acetylcysteine has been used, but the efficacy is questionable. Studies have used N -acetylcysteine in PCT elicited by HIV, HCV, and hemodialysis with some benefit.[45]

A small open-label trial by Petersen et al found zinc sulfate to decrease EPP-related photosensitivity.[46]  In two multicenter, randomized, double-blind, placebo-controlled trials, afamelanotide, an α-melanocyte–stimulating hormone analog, was shown to decrease pain and improve quality of life in patients with EPP.[47]

Sunscreen protection agents should be used if sun exposure is expected. Sun E45 lotion sun protection factor (SPF) 15 and Sun E45 cream SPF 25 have superior ultraviolet (UV)-A and blue light protection than Report on Carcinogens (RoC) 15+A+B, although all have good UV-B protection for photosensitive patients with EPP. In general, sun-blocking creams containing titanium dioxide or zinc oxide are useful. Sunless tanning agents that impart a pigment to the stratum corneum, especially those containing dihydroxyacetone, can also help.

Acute scleritis in PCT is treated with indomethacin or systemic steroids when standard treatment does not improve the condition.[48]

There have been case reports that radiation therapy can result in significant cutaneous and soft tissue morbidity in PCT, and this should be considered while discussing risks of this therapy.[49]

Newborns with jaundice, hemolysis, and hepatosplenomegaly precipitated by a rare type of undiagnosed porphyria (Harder porphyria) will develop a severe skin reaction if treated with phototherapy for their jaundice.[50, 51]

Surgical Care

Many anesthetics can exacerbate porphyria, requiring an experienced anesthesiologist for proper treatment during surgery.

Cholecystectomy may be required for severe cholelithiasis in CEP. Splenectomy may be required if severe hemolytic anemia develops in CEP.

CEP has been cured with allogenic bone marrow transplant. Risks of this procedure must be carefully considered.

Liver transplant alone is not curative for EPP but instead needs to be combined with bone marrow transplant.[10]

Consultations

Contact a porphyria expert to assist in diagnosis and management of short-term and long-term treatments. Because porphyria spans many disciplines, experts may be certified in the area of metabolic disease, gastroenterology, or hematology.[52]

A hematologist may be particularly helpful if phlebotomy, apheresis, or exchange transfusion procedures are being used. In addition, management of deferoxamine and erythropoietin therapy may also require such an expert. A hematologist should be consulted if bone marrow transplant or splenectomy is considered for CEP.

Seek dermatologist consultation for management of cutaneous lesions.

Seek ophthalmologist consultation if ocular manifestations arise.

Gynecologist consultation may be necessary for menses control because estrogens should be avoided.

Anesthesiology consultation is necessary before sedation in minor procedures or surgery.

Diet

A high-carbohydrate diet can reduce disease severity. A low-carbohydrate diet is strictly forbidden.

Activity

Contact with direct sunlight should be minimized. Sunscreen protection should be used when skin is exposed to the sun.

Shading of glass windows in cars can minimize light exposure during driving.

Activities that could damage skin lesions should be avoided.

 

Medication

Medication Summary

Iron depletion, porphyrin reduction, and sclera inflammation control are indicated.

Iron-depleting agents

Class Summary

Iron depletion therapy improves uroporphyrinogen decarboxylase activity, reduces the induction of 5-aminolevulinate synthase, and induces synthesis of porphyrin pathway enzymes in patients who have PCT with normal renal function. Patients with chronic renal failure should be treated further for iron overload resulting from chronic transfusion therapy.

Epoetin alfa (Epogen, Procrit)

Glycoprotein normally produced by the kidneys. Increases RBC production by stimulating division and differentiation of committed erythroid progenitors in bone marrow. Has the identical amino acid sequence to the natural isolate. Manufactured by recombinant DNA technology with same biological effects as endogenous erythropoietin.

Deferoxamine (Desferal)

Freely soluble in water. Approximately 8 mg of iron is bound by 100 mg of deferoxamine. Excreted in urine and bile and gives urine a red discoloration. Readily chelates iron from ferritin and hemosiderin, but not transferrin. Most effective when provided to circulation continuously by infusion. May be administered by SC infusion or bolus, IM injection, or slow IV infusion. Does not effectively chelate other trace metals of nutritional importance.

Provided in vials containing 500 mg of lyophilized sterile drug. 2 mL of sterile water for injection should be added to each vial, bringing the concentration to 250 mg/mL. For IV use, this may be diluted in 0.9% sterile saline, 5% dextrose solution, or Ringer solution. Slow, subcutaneous infusions via a battery-operated pump are the preferred route of administration and can be used at home. Treatment needs to be individualized to patient's symptoms and laboratory values. Long-term therapy slows hepatic iron accumulation and retards progression of hepatic fibrosis.

Ascorbic acid (Vitamin C)

Increases bioavailability of iron by reducing ferric iron to ferrous iron. Blocks degradation of ferritin to hemosiderin.

Porphyrin-reducing agents

Class Summary

Several compounds can chelate or bind porphyrins.

Chloroquine (Aralen)

Binds porphyrins and enhances excretion. Anti-inflammatory activity by suppressing lymphocyte transformation. May have photoprotective effect. Use in porphyria requires very small doses once a week. Larger doses may cause severe hepatic necrosis and death. Reported dosing widely varies and must be titrated to clinical effects.

Cholestyramine (Questran, Prevalite)

Polymeric resin that binds bile acids to form nonabsorbable complex that is excreted unchanged in feces.

Hydroxychloroquine (Plaquenil)

Binds porphyrins and enhances excretion. Inhibits chemotaxis of eosinophils, locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions.

Cysteine

Amino acid shown to reduce photosensitivity in erythropoietic protoporphyria. May improve elimination of protoporphyrin, but is still under investigation.

Vitamin A

Exact mechanism of action not completely elucidated. Patient must become carotenemic before effects are observed. More than one internal light screen may be responsible for effects. May provide a limited level of photoprotection. Causes yellowing of skin (carotenoderma). Any photoprotection afforded increases slowly after drug is commenced over 4-wk to 6-wk period. When discontinued, skin color and benefit fade over several weeks.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Class Summary

Inflammation of the sclera can be reduced by strong anti-inflammatory medications.

Indomethacin (Indocin)

Rapidly absorbed; metabolism occurs in liver by demethylation, deacetylation, and glucuronide conjugation; inhibits prostaglandin synthesis.

 

Follow-up

Further Outpatient Care

Patients on antimalarial medications are at risk for ophthalmological and central visual dysfunction, peripheral neuropathy, deafness, and blood dyscrasias. Periodic ophthalmologic examinations, including visual acuity and slitlamp, funduscopic, and visual field tests, should be performed. Periodically evaluate reflexes and muscular strength. Hearing should be periodically objectively tested. Periodically check CBC count.

Cholestyramine can cause vitamin K deficiency. All patients on long-term therapy should be examined for bleeding or bruising and should receive supplemental vitamin K.

Deterrence/Prevention

Many medications can induce or worsen porphyria, whereas others have not been associated with worsening porphyria. Furthermore, many medications have not been tested in patients with known porphyria. The list below is not exhaustive, and any medication used in a patient with porphyria should be researched.

An extensive list of safe drugs is available at the University of Queensland Porphyria Research Unit Web site. Medications likely to be safe for patients with porphyria include the following:

  • Acetaminophen

  • Adrenaline

  • Amitriptyline

  • Aspirin

  • Atropine

  • Bromides

  • Chloral hydrate

  • Chlordiazepoxide

  • Colchicine

  • Diazepam

  • Digoxin

  • Diphenhydramine

  • Ethylenediaminetetraacetic acid (EDTA)

  • Ether

  • Glucocorticoids

  • Guanethidine

  • Ibuprofen

  • Imipramine

  • Indomethacin

  • Insulin

  • Labetalol

  • Lithium

  • Methylphenidate

  • Naproxen

  • Narcotics

  • Neostigmine

  • Nitrous oxide

  • Penicillamine

  • Penicillin

  • Phenothiazines

  • Procaine

  • Propranolol

  • Succinylcholine

  • Tetracycline

  • Thyroxine

  • Tubocurarine

Many medications induce or worsen acute and cutaneous porphyria. Many of these medications are metabolized, at least to some extent, by the liver. Liver metabolism may induce the cytochrome P-450 enzymes that require heme, thus inducing heme production. Other medications sensitize the skin to solar damage. Only common medications are listed below, and any medication used in a patient known to have porphyria should be investigated. In addition, many medications have not been used for patients with porphyria, thus the potential for worsening porphyria is not known. The list below is a guide for determining if a medication could have triggered a porphyria reaction.

Patients should refrain from alcohol ingestion, estrogen use, and iron supplementation.

Medications that are potentially unsafe for use in patients with porphyria include the following:

  • Alfaxalone

  • Alkylating agents

  • Antipyrine

  • Arthrotec

  • Barbiturates

  • Busulfan

  • Butalbital

  • Carbamazepine

  • Carisoprodol

  • Chlordiazepoxide

  • Chloroquine

  • Clonidine

  • Danazol

  • Danocrine

  • Dapsone

  • Diclofenac

  • Ergot

  • Erythromycin

  • Erythropoietin

  • Estrogens

  • Ethchlorvynol

  • Fluroxene

  • Griseofulvin

  • Heavy metals

  • Hydralazine

  • Ketamine

  • Mafenide

  • Meprobamate

  • Methoxsalen

  • Methyldopa

  • Metoclopramide

  • Nitrazepam

  • Nortriptyline

  • Pargyline

  • Pentazocine

  • Phenazopyridine

  • Phenobarbital

  • Phenoxybenzamine

  • Phenylbutazone

  • Phenytoin

  • Plaquenil

  • Porfimer

  • Primidone

  • Progestins

  • Pyrazinamide

  • Ranitidine

  • Rifampin

  • Spironolactone

  • Succinimides

  • Sulfonamides

  • Sulfonylureas

  • Theophylline

  • Tolazamide

  • Tranylcypromine

  • Valproate

  • Voriconazole

Complications

Congenital erythropoietic porphyria (CEP) is associated with splenomegaly, hypersplenism, hemolytic anemia, and cholelithiasis.

Porphyria cutanea tarda (PCT) is associated with an increased incidence of hepatocellular carcinoma and cirrhosis.

Erythropoietic protoporphyria (EPP) is associated with cholelithiasis in a significant number of cases. Severe liver disease may develop as a result of periportal fibrosis and cirrhosis, leading to death in 20% of cases. Rapidly progressive liver failure associated with accelerating photosensitivity and cholestasis can occur and is accompanied by abdominal pain, splenomegaly, and hemolysis.

Prognosis

CEP is associated with a significantly decreased lifespan, whereas the other cutaneous porphyrias are associated with morbidity from the complications of skin lesions.

A literature review by Salameh et al indicated that in patients with PCT, relapse rates by 1-year follow-up are lower for those treated with phlebotomy (20%) than for patients who undergo high-dose or low-dose 4-aminoquinoline therapy (35-36%).  The pooled relapse rate for phlebotomy was 5.1 per 100 person-years, compared with 8.6 and 17.1 per 100 person-years for high-dose and low-dose 4-aminoquinoline treatment, respectively.[53]

Patient Education

The following web resources are useful for patient reference and education.

  • American Porphyria Foundation

  • Canadian Porphyria Foundation

  • European Porphyria Initiative

  • National Institute of Diabetes & Digestive & Kidney Diseases

  • National Organization for Rare Disorders

  • Online Mendelian Inheritance in Man

  • University of Queensland Porphyria Research Unit