Porphyria Cutanea Tarda

Background

Porphyria cutanea tarda (PCT), the most common type of porphyria, is a metabolic disorder in which activity of the heme synthetic enzyme uroporphyrinogen decarboxylase (UROD) is deficient.^[1]  Two types of PCT are recognized: sporadic (acquired) type I PCT and autodomal dominant (hereditary) type II PCT. Approximately 80% of all cases of PCT are acquired and 20% familial, though the ratio may vary in different geographic regions and ethnic groups.

Familial PCT most often arises from autosomal dominant inheritance of a single mutation of the gene UROD. Human UROD has been mapped to band 1p34. To date, more than 140 UROD mutations have been listed in the Human Genome Mutation Database. A rare recessive familial type of PCT in which both UROD alleles are mutated is termed hepatoerythropoietic porphyria.^[2] Familial PCT without detectable UROD mutations has been reported.^[3]

The common acquired form, sporadic PCT, occurs in individuals whose UROD DNA sequences are normal but who may have other genetically determined susceptibilities to inhibition of UROD activity. Ethanol intake, estrogen therapy, hemochromatosis, hepatitis C, and HIV infection are the major predisposing factors. 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, thereby increasing iron absorption and iron overload.^[4]

Acquired porphyria in large populations exposed to polyhalogenated aromatic hydrocarbon hepatotoxins has been referred to as epidemic PCT. Hepatic tumors producing excess porphyrins are rare causes of PCT-like disorders.

Clinical expression of both sporadic and familial PCT most often requires exposure to environmental or infectious agents or the presence of coexisting conditions that adversely affect hepatocytes and result in hepatic siderosis. Excess iron facilitates formation of toxic oxygen species, thus amplifying porphyrinogenesis by catalyzing formation of oxidative inhibitors of UROD enzyme activity.^[5] Accumulating porphyrins in hepatocytes may then further downregulate hepcidin gene expression.^[4]  Most patients with PCT have an increased iron burden; iron-reduction therapies can lead to clinical and biochemical remissions, and subsequent reaccumulation of iron may lead to symptomatic recurrence.^{[6, 7, 8, 9, 10, 11]}

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 photo-oxidative chemical reactions causing skin lesions, and yield the abnormal excretory porphyrin profiles that characterize PCT. Partial oxidation of uroporphyrinogen to the UROD inhibitor uroporphomethene occurs in murine PCT models and has been suggested as a pathogenic mechanism in the human disease.^[12]  

Management includes elimination or modification of contributory factors, photoprotection, and specific treatments (eg, low-dose antimalarials and phlebotomy).^{[13, 14]}

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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 8-carboxyl porphyrin is termed uroporphyrin; 4-carboxyl porphyrins include coproporphyrin and isocoproporphyrin, which are chiefly excreted in feces.

Reduction of hepatic UROD activity to approximately 25% of normal, most often reflecting the effects of multiple genetic or exogenous inhibitory factors, is required for clinical disease expression. Symptomatic disease occurs more often in patients with a genetic predisposition to PCT, in that fewer external or exogenous factors are needed to decrease UROD activity.^[15]

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 PCT are due to increased mechanical fragility after sunlight exposure; erosions and blisters form painful indolent sores that heal with milia, dyspigmentation, and scarring (see the image below).

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Thickened skin with blisters, scars, and milia. Image from Dirk Elston, MD.

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Etiology

The unifying underlying cause of all forms of PCT is reduction of UROD activity to a critical point during hepatic heme synthesis. Genetic, environmental, or infectious contributory or susceptibility factors, acting singly or (more often) in concert,^{[16, 17, 18]} inhibit UROD activity to that critical point of insufficiency, resulting in the onset of clinical symptoms.

Alcohol effects on hepatocytes may precipitate PCT by making stored hepatic iron more available for catalyzing oxidation reactions, by generating reactive oxygen species (ROS), or by inducing hepatic cytochromes, all of which may facilitate oxidation of uroporphyrinogen to UROD inhibitors.^[19]

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

A strong association between PCT and hereditary hemochromatosis genes causing hepatic siderosis has been established.^{[16, 20, 21, 22]}

Hepatitis virus infections are frequently associated with PCT.^{[20, 23, 24]}  Hepatitis C virus (HCV) infection occurs at a rate of greater than 50% in populations studied in several European countries and in the United States, whereas in other regions, the concordance is less frequent.^[25] Increased hepatic iron often is found in patients with hepatitis C.^{[26, 27]}

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 with HCV.^[28]

Tobacco smoking is a behavioral characteristic frequently observed among patients with PCT.^{[16, 18]} Smoking has been associated with earlier onset of symptoms in sporadic PCT, with a putative mechanism involving induction of an hepatic cytochrome that may contribute to oxidation of uroporphyrinogen,^[29] 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.

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Epidemiology

US and international statistics

PCT is the most common porphyria, accounting for 80-90% of all porphyrias seen in clinical practice.^[30] A registry was established by the National Institutes of Health (NIH)-funded Porphyrias Consortium (https://pc.rarediseasesnetwork.org/) to enable more accurate enumeration of cases of various types of porphyria occurring in the US population. Estimates of the frequency of PCT have varied. A 2017 study cited an estimate of one case per 25,000 in the United States.^[28] The Genetic and Rare Diseases Information Center (GARD) stated that fewer than 50,000 people in the United States have PCT.^[31]

PCT has a prevalence of about 40 new diagnoses per 1 million people per year.^[32]  Higher prevalence figures have been reported among various European populations. A high prevalence of PCT among South African Bantu people has been linked with a propensity for hepatic siderosis. Fractions of studied PCT cases reported as familial have varied widely—for example, 14.6% in Spain,^[33] 24% in Denmark,^[34] and 50% in Chile.^[35]

Age-, sex-, and race-related demographics

Sporadic PCT typically manifests in adulthood. Symptoms of familial PCT typically first appear in adults heterozygous for a UROD mutation, but they have also been reported in heterozygous children.^[36] When biallelic mutations are present (homozygotes or compound heterozygotes), symptoms may be severe, with onset in early childhood.^[37] Milder phenotypes with somewhat later onset have also been observed.^[38] PCT-like disorders resulting from exposure of large numbers of people to hepatotoxic chemicals have afflicted people of all ages.

PCT occurs in both sexes. Older reports indicated a great preponderance of PCT in men; subsequent surveys indicated an equal ratio among men and women.^[28]

PCT occurs in persons of all ethnic groups.^[39]

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Prognosis

The major morbidity of PCT 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.

PCT has been associated with the development of hepatocellular carcinoma (HCC), chiefly in populations of older men with long-standing active disease, heavy ethanol intake, and cirrhosis. Most of the studies predate recognition of hepatitis C prevalence in populations with PCT or HCC; many reported cancers may have been, at least in part, sequelae of chronic HCV infection.^[40]

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Patient Education

Patients should be educated about the role of sunlight in eliciting the skin lesions and about methods of sunlight avoidance. Because porphyrins absorb radiant energy most efficiently at very long ultraviolet (UV) and visible light wavelengths, topical sunscreens must contain ingredients that either scatter or block long UV 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.^[28] Use of light-exclusive clothing and lifestyle alterations are usually necessary to alleviate photocutaneous reactions until remissions can be achieved.

Addressing any underlying contributory factors (eg, hepatitis C or alcohol overuse) is essential to effective treatment.

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 a nutritionist's guidance regarding the iron content of foods. Adequate dietary vitamin C should be consumed.

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History

The most common initial symptoms of porphyria cutanea tarda (PCT) are photosensitivity, cutaneous fragility, and blistering of sun-exposed sites (most often the dorsal hands or the forearms; occasionally the face or the scalp). Hypertrichosis (often on the lateral face) and hyperpigmentation may also be reported. A history of dark urine occasionally can be elicited. Patients with PCT often do not realize the role of sunlight exposure in the subsequent appearance of lesions.

In familial PCT, 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 PCT, a history of exposure to one or more environmental or medicinal inducers (eg, ethanol, estrogens, or hepatitis virus) 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 PCT, it is occasionally the case that none of the common inducing agents is discoverable. Childhood onset of PCT should suggest either heterozygous or homozygous familial forms of the disease, unless observed in the context of environmental exposure to a chemical hepatotoxin.

PCT-like disease in multiple members of populations exposed to polyhalogenated aromatic hydrocarbons should suggest epidemic toxic porphyria.^[41]

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Physical Examination

The most common presenting sign of PCT is photosensitivity and fragility of sun-exposed skin after mechanical trauma, leading to erosions and bullae, typically on the hands and forearms and occasionally on the face or feet. These bullae are occasionally hemorrhagic and often tense. Healing of crusted erosions and blisters leaves milia, hyperpigmented patches, and hypopigmented atrophic scars. (See the images below.)

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Thickened skin with blisters, scars, and milia. Image from Dirk Elston, MD.

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

Hypertrichosis is often observed over temporal and malar facial areas and may also involve the 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.^[42]

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. In rare cases, the only physical sign of PCT 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.

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Laboratory Studies

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

Urinary porphyrin levels are abnormally high in PCT 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 the image below).

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Fluorescence of urine with Wood light examination. Image from Brooke Army Medical Center Teaching File.

For patients who have features compatible with PCT and no neurolgic attacks, evaluation includes screening total and fractionated urinary porphyrins (24-hour). The fractionation pattern, notably an elevated uroporphyrin, can narrow down the diagnosis further and can often confirm the diagnosis of PCT. Should uncertanty remain, assessment of fecal and plasma porphyrins may also be performed.

Chromatographic separation according to the carboxyl number of the 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.^[13] 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, where zinc protoporphyrin is elevated.

Mutation analysis of genes encoding UROD is considered the criterion standard for diagnosis of familial PCT. It is most often available at specialized porphyria research centers and is commercially available in the United States. 

A thorough evaluation requires determination of hematologic and iron profiles, including serum ferritin, liver function testing, and screening for hepatitis C virus (HCV) and HIV. Molecular analysis for hemochromatosis gene (HFE) mutations may be positive.

Abnormal glucose tolerance and serum antinuclear antibodies (ANAs) are found more frequently among PCT populations. Serum levels of ascorbic acid (vitamin C, a potent antioxidant) are deficient in some patients with PCT.^[43]  The presence of alpha-fetoprotein (AFP) in serum is useful in screening for hepatocellular carcinoma (HCC).

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Imaging Studies

In selected cases, diagnostic imaging of the liver to evaluate for size, iron content, or tumors (most often found in individuals with long-standing active PCT) is indicated.

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Other Tests

Once a diagnosis is established, it is recommended to test for HCV antibodies, HIV antibodies, and the presence of HFE.^[30] Noninvasive methods (eg, serum fibrotic markers or transient or real-time elastography) may be useful for assessing hepatic fibrosis or cirrhosis.^[44]

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Procedures

Skin biopsy findings on light microscopy and direct immunofluorescence (DIF) techniques may be consistent with a diagnosis of PCT 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. DIF examination can help differentiate PCT from immunobullous diseases with dermoepidermal junction cleavage (eg, epidermolysis bullosa acquisita or lupus erythematosus) in which the perivascular immunoglobulin deposition found in PCT is not observed.

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

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Histologic Findings

Skin biopsy specimens of fresh blisters show pauci-inflammatory subepidermal bullae and dermal papillae protruding upward into the blister cavity (festooning). Thickened upper dermal capillary walls and basement membrane are seen best on periodic acid–Schiff (PAS) stain. Sclerosis of dermal collagen may also be seen. Linear eosinophilic PAS-positive globules composed of basement membrane material and degenerating keratinocytes ("caterpillar bodies"^[45] ) may be observed in the blister roof. Diastase-resistant PAS-positive material may be identified throughout the involved dermis.(See the image below.)

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Subepidermal bulla, festooning of rete ridges, hyalinization of blood-vessel walls, solar elastosis, and caterpillar bodies. Image from Dirk Elston, M....

DIF examination shows deposition of immunoglobulin (Ig; usually IgG and IgM, sometimes IgA) and C3 in and around the dermal capillaries and at the basement membrane zone. 

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

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.

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Medical Care

Sunlight avoidance is the main defense for photosensitivity until clinical remission can be induced. Sunscreen use should be encouraged. Alcohol use must be markedly curtailed. Treatment of an underlying hepatitis C virus (HCV) infection is critical for control of PCT.

Estrogen use should be discontinued unless its necessity 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, repeat treatment can restore remissions. Alternatively, it has been argued that estrogen therapy need not always be stopped entirely; instead, it can be switched from an oral to a patch formulation.^[13]

Therapeutic phlebotomy^[46] 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. Venesections may be scheduled at intervals ranging from twice weekly to once every 2-3 weeks as tolerated by the patient. Care should be taken so as not to induce anemia (hemoglobin < 10-11 g/dL). Phlebotomy is the preferred therapy for individuals with a heavy iron burden. The efficacy of anti–hepatitis C therapy appears to be enhanced if hepatic siderosis is first reduced by phlebotomy.^[47]

For patients in whom phlebotomy is inconvenient or contraindicated or who have relatively mild iron overload, oral chloroquine phosphate at 125-250 mg twice weekly or oral hydroxychloroquine sulfate at 100-200 mg two or three times weekly—dosages much lower than those for antimalarial or photoprotective indications—can be effective.^{[48, 49, 50]} 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 as treatment continues.

Low-dose chloroquine and phlebotomy therapies may be used concomitantly to reach clinical and biochemical remission more rapidly.^[51]

When venesections are not practical, chelation with deferoxamine (desferrioxamine) may be employed as an alternative means of iron mobilization.^[52]  Studies of iron chelation with deferoxamine as an alternative treatment for PCT patients who cannot tolerate therapeutic phlebotomy have suggested subcutaneous infusions of 40-50 mg/kg for 8-10 hours daily for the first 5 days, after which the frequency is 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.^[15]

A pilot study of the oral iron-chelating agent deferasirox in 10 patients with PCT found that seven patients who completed the 6-month trial noted resolution of blistering, six had lesser urinary porphyrin content, and seven had reduced serum ferritin levels.^{[53, 54]} Larger controlled studies would be needed to confirm the utility of this agent as an alternative treatment.

For patients with PCT who are anemic as a consequence of to other chronic diseases (eg, renal failure or HIV infection), human recombinant erythropoietin can be used to stimulate erythropoiesis. 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 offered additional details.^[15]

In patients whose PCT is associated with HCV infection, effective treatment of the infection has resulted in a cure of the PCT as well. Earlier regimens using interferon or ribavirin had been associated with severe flares of the cutaneous disease. Pretreatment with phlebotomy realized this issue. However, newer regimens using direct-acting antivirals have not seemed to cause similar exacerbations of cutaneous fragility and blistering and therefore are preferable.^{[14, 55, 56]} Singal et al suggested that antimalarial therapy might also be beneficial as an adjunctive therapy for PCT in HCV-infected patients.^[50]

Special concerns

Pregnancy in women with PCT has been followed by safe delivery of healthy infants.^[57] Mobilization of maternal excess tissue iron stores to support the growing fetus may actually be beneficial to pregnant women with PCT. 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.

In some cases, reinstitution of estrogenic hormone therapies in women with PCT who have achieved remissions may be completed without inducing the return of overt disease, but the risk of doing so must be weighed against the potential benefits. If a patient accepts the risk (presently unquantifiable) of possibly reactivating PCT 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 PCT in women who receive this agent as treatment for breast carcinoma.^[58] The risks posed by plant-derived estrogenlike compounds to individuals with PCT have not been well defined.

PCT may appear for the first time in patients with end-stage renal disease (ESRD) after several months of long-term dialysis. 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 seen in patients with normal renal function, who excrete large amounts of these water-soluble porphyrins in urine. These patients may be highly photosensitive.

Chronic anemia is often present in ESRD 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, because the 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.^[59]

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Surgical Care

Renal transplantation has been effective at reducing porphyrin levels and improving cutaneous photosensitivity in cases of PCT occurring in patients with ESRD.^{[60, 61]}

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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.

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Activity

Patients should avoid sunlight exposure until biochemical and clinical remission has been induced. Manual labor should be curtailed so as 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.

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Consultations

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

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

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

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Long-Term Monitoring

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

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 discontinuance 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 mo) and tracking serum ferritin levels similarly may detect any trend toward recurrence before cutaneous photosensitivity reappears. A progressive rise in porphyrin and ferritin levels would herald a potential reemergence of symptoms. Reinstitution of therapy to reduce the iron load (as reflected by serum ferritin levels diminishing to a low-normal range) again would be expected to prevent reappearance of symptoms. Thereafter, surveillance of serum or plasma porphyrin levels and serum ferritin levels should again be carried out periodically.

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Chloroquine (Aralen, Chloroquine phosphate)

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Clinical Context: 

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Hydroxychloroquine sulfate (Plaquenil)

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Clinical Context: 

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Deferoxamine (Desferal)

• Dosing, Interactions, etc.

Clinical Context: 

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Epoetin alfa (Epoetin alfa-epbx, Epogen, Eprex)

• Dosing, Interactions, etc.

Clinical Context: 

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