Porphyria Cutanea Tarda

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Background

Porphyria cutanea tarda (PCT) is a term encompassing a group of acquired and familial disorders in which activity of the heme synthetic enzyme uroporphyrinogen decarboxylase (UROD) is deficient.[1] PCT is known by many other names, including symptomatic porphyria, idiosyncratic porphyria, chemical porphyria, or acquired hepatic porphyria.[2] Approximately 80% of all cases of porphyria cutanea tarda are acquired; 20% are familial, although the ratio may vary among different geographic regions and ethnic groups.

Familial porphyria cutanea tarda most often arises from autosomal dominant inheritance of a single mutation of the UROD gene. Human UROD has been mapped to band 1p34.[3] To date, 121 UROD mutations are listed by the Human Genome Mutation Database. A rare recessive familial type of porphyria cutanea tarda in which both UROD alleles are mutated is termed hepatoerythropoietic porphyria.[4] Familial porphyria cutanea tarda without detectable UROD mutations has been reported.[5, 6]

The common acquired form, sporadic porphyria cutanea tarda, occurs in individuals whose UROD DNA sequences are normal, but who may have other genetically determined susceptibilities to inhibition of UROD activity. Acquired porphyria in large populations exposed to polyhalogenated aromatic hydrocarbon hepatotoxins[7] has been referred to as "epidemic” porphyria cutanea tarda. Hepatic tumors producing excess porphyrins are rare causes of porphyria cutanea tarda–like disorders.

Clinical expression of both sporadic and familial porphyria cutanea tarda most often requires exposure to environmental or infectious agents or the presence of coexisting conditions that adversely affect hepatocytes and result in hepatic siderosis. Ethanol intake, estrogen therapies, hemochromatosis genes, and hepatitis and human immunodeficiency viral infections are among these contributory factors.[1] The increased oxidative stress associated with all of these factors has been shown to reduce hepatic expression of the gene encoding hepcidin, a regulator of iron absorption and metabolism, thus increasing iron absorption and iron overload.[8] Excess iron facilitates formation of toxic oxygen species, thus amplifying porphyrinogenesis by catalyzing formation of oxidative inhibitors of UROD enzyme activity.[9] Accumulating porphyrins in hepatocytes may then further down-regulate hepcidin gene expression.[8]   Most patients with porphyria cutanea tarda have increased iron burden; iron-reduction therapies can lead to clinical and biochemical remissions; subsequent reaccumulation of iron stores may lead to symptomatic recurrence.

Reduced UROD activity causes polycarboxylated porphyrinogen intermediaries of heme synthesis to accumulate in hepatocytes; these excess substrates then undergo iron-facilitated spontaneous oxidization to photoactive porphyrins. Porphyrin by-products of the pathway exit the hepatocytes, are distributed throughout the body in blood plasma, mediate photooxidative chemical reactions causing skin lesions, and yield the abnormal excretory porphyrin profiles that characterize porphyria cutanea tarda. Partial oxidation of uroporphyrinogen to the UROD inhibitor uroporphomethene occurs in murine porphyria cutanea tarda models and has been suggested as a pathogenic mechanism in the human disease.[10] Reduction of hepatic UROD activity to approximately 25% of normal, most often reflecting effects of multiple genetic and/or exogenous inhibitory factors, is required for clinical disease expression.[11, 12]  Symptomatic disease occurs more often in patients with a genetic predisposition to PCT as fewer external/exogenous factors are needed to decrease UROD activity.[2]

Other porphyria-related Medscape articles include Erythropoietic Porphyria, Protoporphyria, Pseudoporphyria, and Variegate Porphyria.

Pathophysiology

When hepatic UROD activity falls below the critical threshold, porphyrin by-products of the heme biosynthetic pathway with 4-8 carboxyl group substituents are overproduced. These porphyrins are reddish pigments that accumulate in the liver and are disseminated in plasma to other organs. Porphyrins with high carboxyl group numbers are water soluble and excreted primarily by renal mechanisms. The porphyrin with 8 carboxyl groups is termed uroporphyrin; 4-carboxyl porphyrins include coproporphyrin and isocoproporphyrin, which are chiefly excreted in feces. Porphyrins are photoactive molecules that efficiently absorb energy in the visible violet spectrum. Photoexcited porphyrins in the skin mediate oxidative damage to biomolecular targets, causing cutaneous lesions.

The most common photocutaneous manifestations of porphyria cutanea tarda are due to increased mechanical fragility after sunlight exposure; erosions and blisters form painful indolent sores that heal with milia, dyspigmentation, and scarring (see images below).



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Thickened skin with blisters, scars, and milia. Courtesy of Dirk Elston, MD.



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Close-up image of blisters, scarring, and milia. Courtesy of Dirk Elston, MD.

Other common features of porphyria cutanea tarda include hypertrichosis, sclerodermalike plaques that may develop dystrophic calcification, and excretion of discolored urine that resembles port wine or tea, which is due to the presence of porphyrin pigments.[13]

Etiology

The unifying underlying cause of all forms of porphyria cutanea tarda is reduction of UROD activity to a critical point during hepatic heme synthesis.[11, 12, 14] Genetic, environmental or infectious contributory or susceptibility factors, acting singly or more often in concert,[15, 16, 17] inhibit UROD activity to that point of insufficiency, resulting in the onset of clinical symptoms.

Alcohol effects on hepatocytes may precipitate porphyria cutanea tarda by making stored hepatic iron more available for catalyzing oxidation reactions, by generation of reactive oxygen species, or by induction of hepatic cytochromes, all of which may facilitate oxidation of uroporphyrinogen to UROD inhibitors.[18]

The role of estrogen in inhibition of UROD activity is not firmly established, it but may be similar to that of alcohol in generating toxic oxygen or inducing cytochromes, thus potentiating uroporphyrinogen oxidation.

A strong association between porphyria cutanea tarda and hereditary hemochromatosis genes causing hepatic siderosis has been established.[7, 15, 19, 20, 21, 22]

Hepatitis virus infections are frequently associated with porphyria cutanea tarda.[19, 23, 24, 25] Hepatitis C occurs with a rate of greater than 50% in populations studied in several European countries and in the United States, while in other regions, the concordance is less frequent.[26] Increased hepatic iron often is found in patients with hepatitis C infection.

It was previously believed that coexistent HIV could exacerbate PCT. However, it is now believed that the exacerbation of PCT with contraction of HIV results from coinfection from the hepatitis C virus.[27]

Tobacco smoking is a behavioral characteristic frequently observed among patients with porphyria cutanea tarda.[15, 17] Smoking has been associated with earlier onset of symptoms in sporadic porphyria cutanea tarda, with a putative mechanism involving induction of an hepatic cytochrome that may contribute to oxidation of uroporphyringen,[28] but evidence for smoking as an independent pathogenic factor is not yet robust.

Environmental exposure to aromatic polyhalogenated hepatotoxins also induces hepatic cytochromes, thus potentiating production of oxidation products capable of inhibiting UROD activity.

Epidemiology

Frequency

United States

A registry has been established by the NIH-funded Porphyrias Consortium (http://rarediseasesnetwork.epi.usf.edu/registry/direct.htm) to more accurately enumerate cases of various types of porphyrias occurring in the US population. Until sufficient data have been collected by this registry to allow calculation, approximately 1 case of porphyria cutanea tarda (PCT) in populations of 5,000-100,000 can be estimated based on data from other countries. There is an estimated 1 case per 25,0000 in the United States.[27] PCT has a prevalence of about 40 new diagnoses per 1 million people per year.[29] PCT is the most common porphyria, accounting for 80-90% of all porphyrias seen in clinical practice.[30]

International

Higher prevalences of porphyria cutanea tarda have been reported among various European populations. A high prevalence of porphyria cutanea tarda among South African Bantu people has been linked with a propensity for hepatic siderosis. Fractions of studied porphyria cutanea tarda cases reported as familial vary widely: 14.6% in Spain,[31] 24% in Denmark,[32] and 50% in Chile.[33]

Race

Porphyria cutanea tarda occurs in persons of all ethnic groups.[34]

Sex

PCT occurs in both sexes. Older reports indicated a great preponderance of PCT in men; more recent surveys indicate an equal ratio among men and women.[27]

Age

Sporadic porphyria cutanea tarda typically manifests in adulthood. Symptoms of familial porphyria cutanea tarda typically first appear in adults heterozygous for a UROD gene mutation, but they have also been reported in heterozygote children.[35] When biallelic mutations are present (homozygotes or compound heterozygotes), symptoms may be severe, with onset in early childhood.[36] Milder phenotypes with somewhat later onset have also been observed.[37, 38]

Porphyria cutanea tarda–like disorders resulting from exposure of large numbers of people to hepatotoxic chemicals have afflicted people of all ages.[7]

Prognosis

The major morbidity of porphyria cutanea tarda is due to skin fragility and blistering, which preclude manual labor and hamper daily activities. The subsequent erosions represent full-thickness epidermal loss; they are painful and often become thickly crusted and secondarily infected. Healing is slow and leaves pigmentary changes, milia, and atrophic scars.

Porphyria cutanea tarda has been associated with the development of hepatocellular carcinoma, chiefly in populations of older men with long-standing active disease, heavy ethanol intake, and cirrhosis. Most studies predate recognition of hepatitis C prevalence in populations with porphyria cutanea tarda or hepatocellular carcinoma; many reported cancers may have been, at least in part, sequelae of chronic hepatitis viral infection.[39]

Patient Education

Patients should be educated about the role of sunlight in eliciting the skin lesions and in methods of sunlight avoidance. Because porphyrins absorb radiant energy most efficiently at very long ultraviolet and visible light wavelengths, topical sunscreens must contain ingredients that either scatter or block long ultraviolet and visible light rays to offer any practical protection.

Sunscreens with titanium dioxide or zinc oxide are recommended because the porphyrin-inducing UV wavelength is 400-410 nm, and these barrier sunscreens have better protection for this wavelength than sunscreens with chemical blockers.[27] Use of light-exclusive clothing and lifestyle alterations are usually necessary to alleviate photocutaneous reactions until remissions can be achieved.

The need to avoid iron-containing dietary supplements, alcohol, and smoking should be stressed. Dietary iron is not usually a major problem and can be managed with moderation in consumption of red meats, but some patients may benefit from guidance about the iron content of foods from a nutritionist. Adequate dietary vitamin C should be consumed.

History

The most common initial symptoms of porphyria cutanea tarda are cutaneous fragility and blistering of the hands, forearms, and, sometimes, the face. Discolored urine may also be reported, but this information may need to be elicited. Changes in hair growth and pigmentation may be noted spontaneously or only after inquiry. Patients with porphyria cutanea tarda often do not realize the role of sunlight exposure in the subsequent appearance of lesions.

In familial porphyria cutanea tarda, other affected relatives may be known. However, most related carriers of the mutant gene remain silent, and patients may be unaware of the familial nature of their disease.

In both familial and sporadic porphyria cutanea tarda, a history of exposure to one or more environmental or medicinal inducers (eg, ethanol, estrogens, hepatitis) can often be elicited. Paradoxically, proven carriers of the same mutation as that of a symptomatic relative with exposure to a known inducer may remain clinically and biochemically silent despite similar exposure. In symptomatic familial porphyria cutanea tarda, occasionally none of the common inducing agents is discoverable. Childhood onset of porphyria cutanea tarda should suggest either heterozygous or homozygous familial forms of the disease, unless observed in the context of environmental exposure to a chemical hepatotoxin.

Porphyria cutanea tarda–like disease in multiple members of populations exposed to polyhalogenated aromatic hydrocarbons should suggest epidemic toxic porphyria.[40]

Physical Examination

The most common presenting sign of porphyria cutanea tarda is fragility of sun-exposed skin after mechanical trauma, leading to erosions and bullae, typically on hands and forearms and occasionally on face or feet. Healing of crusted erosions and blisters leaves milia, hyperpigmented patches, and hypopigmented atrophic scars.

Hypertrichosis is often observed over temporal and malar facial areas and may also involve arms and legs. Pigmentary changes include melasmalike hyperpigmentation of the face. An erythematous suffusion or plethora of the central face, neck, upper chest, and shoulders may be present. Scarring alopecia and separation of nail plates from their beds (photo-onycholysis) can be seen in more severely affected patients.[41]

Indurated, waxy, yellowish plaques that resemble lesions of scleroderma can develop over the chest and the back but are most prominent in the preauricular and nuchal areas. These plaques may develop dystrophic calcification. Rarely, the only physical sign of porphyria cutanea tarda is a hyperpigmented sclerodermoid appearance.

In severely affected individuals, particularly familial hepatoerythropoietic or toxic epidemic cases in children, digital shortening, atrophy, and contractures resembling those of dystrophic epidermolysis bullosa have occurred.

A urine sample is often, but not always, grossly discolored with a tea- or wine-colored tint.

Laboratory Studies

Clinical suspicion alone is not enough to make the diagnosis of porphyria cutanea tarda (PCT), and it is confirmed by excess levels of porphyrins in the blood or urine.[30]

Urinary porphyrin levels are abnormally high in porphyria cutanea tarda patients, with several hundred to several thousand micrograms excreted in a 24-hour period. The excess porphyrin pigment is often grossly evident in visible light and yields a pink fluorescence under Wood lamp (black light) radiation (see image below).



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Fluorescence of urine with a Wood light examination. Courtesy of Brooke Army Medical Center Teaching File.

Chromatographic separation by carboxyl number of increased porphyrins present reveals a predominance of 8- and 7-carboxyl porphyrin fractions, with lesser amounts of 6-, 5-, and 4-carboxyl porphyrins, reflecting a uroporphyrinogen decarboxylase (UROD) defect. A similar array of polycarboxylated porphyrins can be found in serum or plasma specimens. The fecal coproporphyrin fraction is often abnormally high and largely consists of isocoproporphyrin. Erythrocyte porphyrin levels are in the reference range, except in hepatoerythropoietic porphyria, in which zinc protoporphyrin is elevated.

UROD enzyme activity assay in red blood cells is available in multiple laboratories in several countries, including the United States. Enzyme activity data may help determine patterns of inheritance in familial porphyria cutanea tarda and confirm the diagnosis in cases with confusing biochemical data.

Mutation analysis of genes encoding UROD is considered the criterion standard for diagnosis of familial porphyria cutanea tarda. It is most often available at specialized porphyria research centers and is commercially available in the United States. Molecular analysis for hemochromatosis gene (HFE) mutations may be positive.

A thorough evaluation requires determination of hematologic and iron profiles, including serum ferritin, liver function profile, and screening for hepatitis viruses and the human immunodeficiency virus.

Abnormal glucose tolerance and serum antinuclear antibodies are found more frequently among porphyria cutanea tarda populations.[13] Serum levels of ascorbic acid (vitamin C, a potent antioxidant) are deficient in some patients with porphyria cutanea tarda.[42] Alpha-fetoprotein presence in serum is useful to screen for hepatocellular carcinoma.

Imaging Studies

Evaluation of the liver for size, iron content, or tumors (most often found in individuals with long-standing active porphyria cutanea tarda) is indicated in selected cases.

Other Tests

Once a diagnosis is established, it is recommended to test for hepatitis C antibodies, HIV antibodies, and the presence of the HFE gene.[30] Novel noninvasive methods may be useful to assess hepatic fibrosis or cirrhosis.[43]

Procedures

Skin biopsy findings by light microscopy and direct immunofluorescence techniques may be consistent with a diagnosis of porphyria cutanea tarda but are not unequivocally diagnostic. Similar findings can be observed in other porphyrias and in pseudoporphyrias associated with certain drugs, intensive use of tanning beds or cabinets, or long-term dialysis therapy for renal failure. Direct immunofluorescence examination can help differentiate porphyria cutanea tarda from immunobullous diseases with dermoepidermal junction cleavage (epidermolysis bullosa acquisita, lupus erythematosus) in which the perivascular immunoglobulin deposition found in porphyria cutanea tarda is not observed.

Liver biopsy may be appropriate in selected patients to evaluate iron burden or damage due to ethanol abuse, viral infections, hemochromatosis, or suspected tumors.

Histologic Findings

Skin biopsy specimens of fresh blisters show subepidermal bullae with minimal dermal inflammatory infiltrate and dermal papillae protruding upward into the blister cavity (festooning); thickened upper dermal capillary walls and dermoepidermal basement membrane zones are evident in routinely stained sections and accentuated with the periodic acid-Schiff stain; elastosis, sclerosis of dermal collagen, and hyaline deposits may be seen in the dermis.[44] Linear, eosinophilic, periodic acid-Schiff–positive globules composed of basement membrane material and degenerating keratinocytes ("caterpillar bodies") may be observed in the blister roof.[45] Note the image below.



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Subepidermal bulla, festooning of rete ridges, hyalinization of blood vessel walls, solar elastosis, and caterpillar bodies. Courtesy of Dirk Elston, ....

Ultrastructural examination of dermal vascular walls and the basement membrane zone reveals replication of basal laminae, reflecting multiple episodes of damage and repair.[44, 46]

Direct immunofluorescence examination shows deposition of immunoglobulins and complement in and around the dermal capillaries and at the basement membrane zone.[44] These deposits do not indicate that porphyria cutanea tarda is an autoimmune disorder; they are believed to be immunoproteins leaked from the damaged vasculature.

Liver biopsy abnormalities range from minimal to severe. Increased iron deposition is frequently present. Other abnormalities may include steatosis, chronic inflammatory infiltrates, fibrosis, cirrhosis, and necrosis. Needlelike intracytoplasmic inclusions believed to be uroporphyrin crystals occur near ferritin iron deposits in hepatocytes.[47]

Medical Care

Sunlight avoidance is the main defense for photosensitivity until clinical remission can be induced. Alcohol must be proscribed. Cessation of tobacco smoking should be recommended, not only for potential beneficial effect on porphyria, but for overall good health. Estrogen use should be discontinued unless its need outweighs its adverse effects on porphyrin metabolism. After achievement of remission, estrogen therapies may be cautiously reinstituted; however, the duration of remissions may be shortened. Remissions may last from several months to many years. If symptoms recur, re-treatment can restore remissions.

Therapeutic phlebotomy[48, 49, 50] reduces iron stores, which improves heme synthesis disturbed by ferro-mediated inhibition of uroporphyrinogen decarboxylase (UROD). The goal of therapy is to reduce serum ferritin levels to the lower limit of the reference range.[51] Venesections may be scheduled at intervals ranging from a unit of whole blood removed twice weekly to every 2-3 weeks as tolerated by the patient. Care should be taken to not induce anemia (hemoglobin < 10-11 g/dL). Phlebotomy is the preferred therapy for individuals with a heavy iron burden. Efficacy of antihepatitis C therapy appears to be enhanced if hepatic siderosis is first reduced by phlebotomy.[52]

For patients in whom phlebotomy is not convenient or is contraindicated or for patients with relatively mild iron overload, oral chloroquine phosphate (125-250 mg PO twice weekly) or hydroxychloroquine sulfate (100-200 mg PO 2-3 times/wk), doses much lower than those used for antimalarial or photoprotective indications, can be effective.[53, 54, 55, 56, 57, 58] Larger doses can cause severe hepatotoxicity. Even low-dose regimens can occasionally produce hepatic toxicity, and careful monitoring is indicated. Some clinicians begin with a single, small test dose. Hepatic transaminases and urinary porphyrin output may rise transiently after institution of therapy, returning to normal levels as treatment continues. Low-dose chloroquine and phlebotomy therapies may be used concomitantly to more rapidly reach clinical and biochemical remissions.[59]

Chelation with desferrioxamine is an alternative means of iron mobilization when venesections are not practical.[60] A pilot study of the oral iron-chelating agent desferasirox in 10 patients with porphyria cutanea tarda found that 7 who completed the 6-month trial noted resolution of blistering, 6 had lesser urinary porphyrin content, and 7 had reduced serum ferritin levels.[61] A larger controlled study may confirm this agent as a useful alternative treatment. In patients who are not tolerant of therapeutic phlebotomy, iron chelation with deferoxamine has been discussed as an alternative treatment for PCT. Studies suggest subcutaneous infusions of 40-50 mg/kg for 8-10 hours daily for the first 5 days and then subsequently reduced to 5-10 days per month. In addition to being an iron chelator, deferoxamine may reduce the compensatory increase of intestinal iron absorption often seen in remission induced by the greater degree of iron reduction achieved by phlebotomies.[2]

For patients with porphyria cutanea tarda who are anemic due to other chronic diseases (eg, renal failure, human immunodeficiency viral infection), human recombinant erythropoietin can be used to stimulate erythropoiesis.[62] This mobilizes tissue iron and may increase the circulating erythrocyte mass to a degree that permits therapeutic phlebotomies to be performed at judicious volumes and intervals.

A tabular outline of management recommendations published in 2012 offers additional details.[63]

In patients with PCT-associated with hepatitis C viral infection, effective treatment of the hepatitis C viral infection has resulted in a cure of the PCT as well. Earlier regimens that involved the use of interferon or ribavirin had been associated with severe flares of the cutaneous disease. Pretreatment with phlebotomy realized this issue. However, newer regimens that use direct-acting antivirals do not seem to result in a similar exacerbation of cutaneous fragility and blistering and are thus preferable. Singal et al also suggest that antimalarial therapy might be beneficial as an adjunctive therapy for PCT in the hepatitis C–infected patient.[58]

Special concerns

Pregnancy in women with porphyria cutanea tarda has been followed by safe delivery of healthy infants.[64] Mobilization of maternal excess tissue iron stores to support the growing fetus may actually be beneficial to pregnant women with porphyria cutanea tarda. Supplemental iron should be withheld during gestation unless iron deficiency is evident. Increased cutaneous photosensitivity in the first trimester, preeclampsia, and gestational diabetes have been noted in a few cases.

Reinstitution of estrogenic hormone therapies in women with porphyria cutanea tarda who have achieved remissions may be completed in some cases without inducing the return of overt disease, but the risk of doing so must be balanced against the benefits of such therapies. If a patient accepts the risk (presently unquantifiable) of possibly reactivating her porphyria cutanea tarda in the hope of regaining the benefits of estrogen therapies, the use of transdermal delivery systems is recommended to mitigate the first-pass effects of oral estrogens reaching the liver from the enteric tract. The estrogen-receptor antagonist tamoxifen has been associated with the development of porphyria cutanea tarda in women treated with this agent for breast carcinoma.[65] The risks posed by plant-derived, estrogenlike compounds to individuals with porphyria cutanea tarda are not well established.

Porphyria cutanea tarda may appear for the first time in patients with end-stage renal disease after several months of long-term dialysis.[66] Anuric individuals can be readily diagnosed by assaying a plasma or serum specimen for the characteristic elevated levels of polycarboxylated porphyrins. Quantitative plasma porphyrin levels are often much higher than those of patients with normal renal function, who excrete large amounts of these water-soluble porphyrins in urine. These patients may be very photosensitive.

Chronic anemia is often present in end-stage renal disease despite increased iron stores, limiting treatment by phlebotomy. Erythropoietin may be used to reduce excess iron stores by stimulating erythropoiesis, which may result in sufficient erythrocyte mass to permit judicious low-volume serial phlebotomy. Chloroquine or hydroxychloroquine should not be used, as porphyrins liberated from hepatocytes by these agents enter the plasma, but cannot be cleared through the kidney, resulting in even higher circulating levels and increased cutaneous photosensitivity. Deferoxamine and ferric carboxymaltose have been used in the setting of renal failure.[67]

Surgical Care

Renal transplantation has been effective in reducing porphyrin levels and in improving cutaneous photosensitivity in porphyria cutanea tarda occurring in patients with end-stage kidney disease.[68, 69]

Consultations

Consultation with a dermatologist for a skin examination as well biopsies sent for hematoxylin and eosin (H&E) staining and direct immunofluorescence is indicated.

Consultation with a gastroenterologist or a hepatologist for evaluation and treatment of viral hepatitis, liver damage due to alcohol abuse or hemochromatosis, and hepatic tumors may be warranted.

Consultation with a hematologist may be helpful in cases of suspected hemochromatosis or for management of phlebotomy or iron chelation therapies.

Consultation with a gynecologist for alternative forms of treatment for female patients in whom therapeutic use of estrogenic hormones is a probable inducing factor is often helpful.

For male patients treated with estrogen for prostatic carcinoma, consultation with the treating oncologist regarding the need for continued therapy is indicated.

Diet

Iron-rich foods such as red meats should be consumed sparingly. Adequate levels of vitamin C may retard oxidation reactions in the liver; consumption of vitamin C‒rich fresh fruits and vegetables, their juices, or an iron-free multivitamin containing vitamin C are recommended.

Activity

Patients should avoid sunlight exposure until biochemical and clinical remission has been induced. Manual labor should be curtailed to minimize the mechanical trauma that causes erosions and blistering. Use of light-exclusive clothing and lifestyle alterations are usually necessary to alleviate photocutaneous reactions until remissions can be achieved.

Long-Term Monitoring

Levels of hemoglobin, serum ferritin, and plasma/serum or urinary porphyrins should be monitored during the course of treatment to guide the frequency of venesections and to determine the point of discontinuation of therapies.

Phlebotomy should be continued until the serum ferritin level has reached the lower border of reference range values. Clinical remission may not be complete until several weeks to months after biochemical remission has been reached.

Urinary and plasma/serum porphyrin levels may continue to decrease for several weeks to months after the ferritin level has reached the target range for discontinuation of phlebotomy.

For patients who have achieved posttherapy clinical and biochemical remissions, checking levels of serum or plasma porphyrins at progressively longer intervals (3, 6, 12 months) and tracking serum ferritin levels similarly may detect any trend toward recurrence prior to reappearance of cutaneous photosensitivity. A progressive rise in levels of porphyrins and of ferritin would herald a potential reemergence of symptoms. Reinstitution of therapy to again reduce iron load (as reflected by serum ferritin levels diminishing to a low-normal range) would be expected to prevent reappearance of symptoms. Thereafter, surveillance of serum or plasma porphyrin levels and of serum ferritin should again be carried out periodically.

Medication Summary

Medical therapy for porphyria cutanea tarda may be used alone or in combination with phlebotomy.

Chloroquine (Aralen)

Clinical Context:  Chloroquine has anti-inflammatory activity by suppressing lymphocyte transformation and may have photoprotective effects. Chloroquine binds porphyrins and enhances excretion. It is available as a 250-mg tablet and 500-mg scored tablet and is not available as a syrup. Crush the tablet and mask the bitter taste in jam, applesauce, or other soft food.

Doses for chloroquine phosphate (125-250 mg PO twice weekly) are much lower than those used for antimalarial or photoprotective indications. Larger doses can cause severe hepatotoxicity and death. Even low-dose regimens can occasionally produce hepatic toxicity, and careful monitoring is indicated. Some clinicians begin with a single, small test dose. Hepatic transaminases and urinary porphyrin output may rise transiently after institution of therapy, returning to normal levels as treatment continues. Dosing information listed in the full drug monograph for standard antimalarial or other nonporphyria indications is inappropriate for treatment of porphyria cutanea tarda.

Hydroxychloroquine (Plaquenil)

Clinical Context:  Hydroxychloroquine inhibits chemotaxis of eosinophils, inhibits locomotion of neutrophils, and impairs complement-dependent antigen-antibody reactions. Doses for hydroxychloroquine sulfate (100-200 mg [77.5-155 mg base] PO 2-3 times/wk) are much lower than those used for antimalarial or photoprotective indications. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. Larger doses can cause severe hepatotoxicity. Even low-dose regimens can occasionally produce hepatic toxicity, and careful monitoring is indicated. Some clinicians begin with a single, small test dose. Hepatic transaminases and urinary porphyrin output may rise transiently after institution of therapy, returning to normal levels as treatment continues. Dosing information listed in the full drug monograph for standard antimalarial or other nonporphyria indications is inappropriate for treatment of porphyria cutanea tarda.

It is available as a 200-mg tablet and is not available as a syrup. Crush tablet and mask the bitter taste in jam, applesauce, or other soft food.

Class Summary

These agents are believed to form complexes with porphyrin molecules within hepatocytes that are then discharged into the circulation and excreted by renal mechanisms. Increased urinary iron excretion has also followed their use. Reported experience in treating children with PCT with antimalarials is limited.

Epoetin alfa (Epogen, Procrit)

Clinical Context:  Epoetin alfa stimulates the division and differentiation of committed erythroid progenitor cells. It induces the release of reticulocytes from bone marrow into the blood stream.

Class Summary

In patients with anemia of chronic disease in whom venesections are relatively contraindicated, stimulation of erythropoiesis can mobilize tissue iron and may even enable low-volume phlebotomies to be performed at judicious intervals.

Deferoxamine (Desferal)

Clinical Context:  In addition to being an iron chelator, deferoxamine may reduce the compensatory increase of intestinal iron absorption often seen in remission induced by the greater degree of iron reduction achieved by phlebotomies.

Class Summary

Iron chelators form complexes with tissue iron to excrete it from the body and remove the tissue iron from use.

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Author

Anthony W Linfante, Jr, MD, Resident Physician, Department of Dermatology, University of Texas Medical Branch School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Brandon Patrick Goodwin, MD, Assistant Professor of Dermatology/Dermatopathology, Assistant Lab Director, Dermatopathology Laboratory, University of Texas Medical Branch School of Medicine; Ambulatory Medical Director, UTMB Health Dermatology Clinic

Disclosure: Nothing to disclose.

Meredith M Gavin, MD Candidate, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Julia R Nunley, MD, Professor, Program Director, Dermatology Residency, Department of Dermatology, Virginia Commonwealth University Medical Center

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: American Board of Dermatology<br/>Co-Editor for the text Dermatological Manifestations of Kidney Disease .

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Craig A Elmets, MD, Professor and Chair, Department of Dermatology, Director, Chemoprevention Program Director, Comprehensive Cancer Center, UAB Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: University of Alabama at Birmingham; University of Alabama Health Services Foundation<br/>Serve(d) as a speaker or a member of a speakers bureau for: Ferndale Laboratories<br/>Received research grant from: NIH, Veterans Administration, California Grape Assn<br/>Received consulting fee from Astellas for review panel membership; Received salary from Massachusetts Medical Society for employment; Received salary from UpToDate for employment. for: Astellas.

Maureen B Poh-Fitzpatrick, MD, Professor Emerita of Dermatology and Special Lecturer, Columbia University College of Physicians and Surgeons

Disclosure: Nothing to disclose.

References

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Thickened skin with blisters, scars, and milia. Courtesy of Dirk Elston, MD.

Close-up image of blisters, scarring, and milia. Courtesy of Dirk Elston, MD.

Fluorescence of urine with a Wood light examination. Courtesy of Brooke Army Medical Center Teaching File.

Subepidermal bulla, festooning of rete ridges, hyalinization of blood vessel walls, solar elastosis, and caterpillar bodies. Courtesy of Dirk Elston, MD.

Thickened skin with blisters, scars, and milia. Courtesy of Dirk Elston, MD.

Close-up image of blisters, scarring, and milia. Courtesy of Dirk Elston, MD.

Subepidermal bulla, festooning of rete ridges, hyalinization of blood vessel walls, solar elastosis, and caterpillar bodies. Courtesy of Dirk Elston, MD.

Fluorescence of urine with a Wood light examination. Courtesy of Brooke Army Medical Center Teaching File.