INTRODUCTION — Porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP) are porphyric conditions due to deficient activity of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme biosynthetic pathway (figure 1) [1]. (See "Porphyrias: An overview".) Both are associated with chronic blistering photosensitivity, but are otherwise different clinically.
- PCT, the most common human porphyria, is an iron-related disease that usually presents in mid or late life. About 20 percent of patients with PCT are heterozygous for inherited UROD mutations, and are said to have familial (or type 2) disease, an autosomal dominant condition with low penetrance. Those without UROD mutations are said to have sporadic (type 1) PCT. In both type 1 and type 2 cases, the disease becomes manifest when hepatic UROD is inhibited, and its activity reduced to less than about 20 percent of normal, likely due to the presence of a uroporphomethene inhibitor [2].
- HEP is the autosomal recessive form of familial PCT. This rare disease is associated with a more severe deficiency of UROD [3], and usually presents in childhood with features that resemble congenital erythropoietic porphyria (CEP).
PCT and HEP will be reviewed here. The other porphyric conditions are discussed separately.
PORPHYRIA CUTANEA TARDA
Definition and history — Porphyria cutanea tarda (PCT) is due to an acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD) and is defined both by clinical features and biochemical findings. An inherited deficiency of UROD contributes in some cases. The chronic blistering skin manifestations are characteristic, but not specific. Highly carboxylated porphyrins (mostly uroporphyrin and heptacarboxyl porphyrins) accumulate in large amounts in the liver and then appear in plasma and urine [1,4].
In 1911, Gunther classified adults with painful skin lesions on sun-exposed areas of skin and increased porphyrin levels as chronic hematoporphyria [5]. This condition was renamed “porphyria cutanea tarda” by Waldenstrom in 1937 to emphasize the predominant cutaneous manifestations and relatively late onset of disease [6]. The disease was subsequently clearly differentiated from other porphyrias that cause blistering skin lesions.
In the 1950s, exposure to hexachlorobenzene caused an outbreak of PCT in thousands of adults and children in eastern Turkey. This occurred after seed wheat, which had been treated with hexachlorobenzene as a fungicide, was consumed during a famine. Subsequently, it was shown that hexachlorobenzene and other chlorinated polyaromatic hydrocarbons can cause a deficiency of hepatic UROD activity in laboratory animals, with porphyrin elevations resembling those seen in PCT.
The human disease has been associated with excess alcohol consumption, estrogen use, hepatic siderosis, hepatitis C, HIV, and smoking. The hepatic UROD inhibitor in PCT is a uroporphomethene, derived by oxidation of a bridge carbon in the uroporphyrinogen molecule [2]. (See 'Decreased hepatic UROD activity' below.)
Prevalence and epidemiology — PCT is reported worldwide. The prevalence of symptomatic disease has been estimated at approximately 1 in 25,000 in the United States [7]. Onset is usually after age of 30, and is rare in children. Earlier onset is noted in some patients with UROD mutations or in patients with hepatic iron overload due to HFE mutations [8].
Clinical features — PCT is primarily characterized by manifestations due to skin and liver involvement.
Skin findings — Cutaneous manifestations of PCT include blisters, bullae, increased fragility, scarring and hyper- and hypopigmentation affecting sun-exposed areas of the body, such as the backs of the hands, forearms, face, ears, neck and feet (picture 1 and picture 2 and picture 3) [1,4,9,10]. Bullae contain porphyrin-rich serous or serosanguinous fluid, and may be painful and become infected [9]. Hirsutism is also common, especially on the cheeks and forearms. Scarring may progress to “pseudoscleroderma” and resemble the cutaneous findings in systemic scleroderma [9]. Scarring and calcification may resemble that seen in systemic scleroderma [11].
Porphyrins that accumulate in plasma and presumably also in the skin in PCT are photosensitizing. On exposure to light with a wavelength near 400 nm, porphyrins enter an excited state and release photons that activate oxygen in the tissues to the higher energy and more reactive singlet oxygen [12,13], which damage proteins, lipids, and basement membranes, and cause complement activation, mast cell degranulation, and release of transforming growth factor (TGF)-beta [13,14]. Characteristic histological features include subepidermal blister formation and deposition of periodic-acid-Schiff (PAS) positive amorphous hyaline material containing immunoglobulin around the vessel walls, with little inflammation unless there is secondary infection [15,16].
Hepatic findings — PCT is almost always associated with mild elevations in serum liver enzymes, especially serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Advanced liver disease is uncommon at initial presentation, but may be seen in older patients with recurrent disease [9,17].
Hepatic injury in PCT can result from both porphyrin accumulation and some of the important susceptibility factors (eg, alcohol, hepatitis C virus). Massive porphyrin accumulation in the liver can be demonstrated by biochemical measurement or by reddish fluorescence on illumination of fresh liver tissue using a Wood's lamp (a UVA light source) or fluorescence microscopy. Accumulated porphyrins are mostly uroporphyrin and heptacarboxyl porphyrin, and characteristic birefringent needle-shaped inclusions are evident histologically [18]. Nonspecific histopathologic findings may include varying degrees of siderosis, steatosis, portal triaditis, focal lobular necrosis, and periportal fibrosis [9,19,20].
Patients with PCT have an increased long-term risk for cirrhosis and hepatocellular carcinoma [9,19,21,22].
Susceptibility factors — Human PCT is a highly heterogeneous disease, in that a multiplicity of factors in various combinations contribute to susceptibility in individual patients [23]. Most of these factors contribute to iron accumulation or oxidative stress in hepatocytes. In one series, three or more simultaneous susceptibility factors were identified in 70 percent of the 143 patients with documented PCT [23]. Although many of these factors are highly prevalent in PCT, none is found in all patients.
Genetic susceptibility — Heterozygous carriers of mutations in hepatic uroporphyrinogen decarboxylase (UROD) have approximately half-normal UROD activity in all tissues from birth. If clinical manifestations develop, these patients are classified as having familial (type 2) PCT. Although susceptibility to PCT is increased in these individuals, the disease does not develop unless other factors are present and hepatic UROD activity becomes reduced to less than about 20 percent of normal. Urinary porphyrins are increased in more than 30 percent of asymptomatic carriers of UROD mutations [24]. (See 'UROD mutations' below.) Other genetic susceptibility factors discussed below include HFE mutations and CYP1A2 variants.
Iron — PCT is an iron-dependent disease. Support for this association comes from two observations: iron deficiency protects against its development in humans and animal models [1,25,26], and repeated phlebotomy to reduce hepatic iron content is effective and the most widely accepted treatment. (See 'Repeated phlebotomy' below.)
Hepatic siderosis is found in the great majority of patients with PCT who undergo liver biopsy; marked iron overload is sometimes seen. Serum ferritin levels are usually either normal or modestly increased [27-33]. In one study, for example, high hepatic iron levels, as measured by MRI, were found in only 11 of 20 patients with PCT [33]. A high prevalence of PCT in Sub-Saharan Africa has been attributed to high dietary iron intake with a presumed genetic component [1]. (See "Iron overload syndromes other than hereditary hemochromatosis", section on 'African iron overload'.)
Dysregulation of hepcidin production by the liver has been demonstrated in PCT patients even in the absence of HFE mutations [34], which helps explain increased absorption of iron in this disease, along with the development of iron overload [27].
There is an increased prevalence of HFE mutations in PCT, although clinically overt hemochromatosis is rare [17,35,36]. For example, in one study, C282Y homozygosity was detected in 19 percent of 108 patients with PCT; 7 percent were compound heterozygotes (C282Y/H63D) [35]. In a large meta-analysis of disease associations with HFE genotypes, PCT was most strongly associated with the C282Y/C282Y and C282Y/H63D genotypes (odds ratios 48 and 8.1, respectively) [37]. These HFE mutations result in impaired secretion of hepcidin by the liver, resulting in unregulated intestinal iron absorption.
Alcohol — PCT was initially described as a disease of males with alcohol abuse, and alcohol has been reported as an important and common susceptibility factor in many series [9,17,23,38]. For example, in one large series, 87 percent of PCT patients reported excess alcohol intake [23]. However, the disease is not common among alcoholics. In one report of 360 patients with alcoholic cirrhosis followed for 10 years, only 2 percent had PCT [39]. Alcohol may contribute by down-regulation of hepcidin [40,41], increasing oxidative stress, and by induction of cytochrome P450 enzymes (CYPs), perhaps including CYP2E1 [42].
Smoking and cytochrome P450 enzymes — As discussed below, CYP1A2 may be involved in generation of the hepatic UROD inhibitor in PCT, and exposure to polycyclic aromatic hydrocarbons in cigarette smoke may contribute by inducing this enzyme [2]. In a large series, 81 percent of patients with PCT were smokers [23]. In a group of PCT patients without UROD mutations, disease onset was earlier among smokers [43].
A genetic polymorphism that favors greater inducibility of CYP1A2 has been found to be more common in PCT patients than in controls [44].
Hepatitis C — A strong association between hepatitis C virus infection and PCT was first reported in 1992 [45]. Prevalences have ranged from 8 to 85 percent in reports from various countries, and are higher in the United States and southern Europe than in northern Europe and eastern Asia [9,17,35,36,38]. For example, prevalence of this viral infection is low in Norway, where none of 50 consecutive PCT patients tested positive for this infection [46]. These variations presumably reflect differences in hepatitis C prevalence in at risk populations in various countries. Hepatitis C may be more common in PCT patients with advanced fibrosis or cirrhosis than in patients with less advanced hepatic damage [46,47]. Anti-HCV antibodies in the absence of circulating HCV RNA are rare in PCT [23,48,49].
This viral infection may contribute to the development of PCT by increasing oxidative stress in hepatocytes [50], and increasing iron absorption by dysregulation of hepcidin production by the liver [51]. Other potential mechanisms are discussed separately. (See "Porphyria cutanea tarda and hepatitis C virus infection", section on 'Pathogenesis'.)
HIV infection — PCT was first reported in patients with HIV infection in 1987, and many additional cases have been described since then [52,53]. PCT may occur early or late in the course of HIV disease [54,55]. A mechanism whereby HIV infection might contribute to development of this porphyria has not been established. Co-infection with hepatitis C was found in only half of the cases in one series [23].
Estrogens — Use of estrogens in oral contraceptives or for estrogen replacement after menopause is commonly identified in women as a susceptibility factor [9,17,38,56-58]. Estrogen was a factor in 66 percent of women with PCT in a one series [23]. In the past, this association was also described in men, when estrogens were commonly used for treatment of advanced prostate cancer [59]. PCT has been reported uncommonly during pregnancy; this association may be due to chance. The mechanism of precipitation of PCT by estrogens is unclear. Estrogens undergo redox cycling and cause oxidative damage in the kidney of rodents [60], but this has not been demonstrated in the liver.
Chemical exposures — A large outbreak of PCT resulting from ingestion of hexachlorobenzene was described in Turkey in the 1950s (referred to in the past as “toxic porphyria”) [61,62]. Smaller outbreaks have been associated with industrial exposure to tetrachlorodibenzo-p-dioxin (TCDD) [63]. Sporadic cases attributed to exposure to other chemicals such as lindane and diazinon [64,65] are of uncertain significance.
Other associations — PCT has also been associated with systemic lupus erythematosus [66], but other co-existing factors were not evaluated. Diabetes mellitus and hepatic steatosis, which can cause oxidative damage in the liver, have been prevalent in some series [9,67]. The disease is sometimes seen in patients with myeloproliferative neoplasms and other bone marrow disorders, usually in association with substantial iron overload [68].
End-stage renal disease — PCT may occur in patients on hemodialysis or peritoneal dialysis for advanced chronic renal disease [69,70], often with associated iron overload. The disease is often especially severe in such cases, reflecting plasma porphyrin levels that may be much higher than in patients with normal renal function.
Etiology and pathogenesis
Decreased hepatic UROD activity — PCT results from a decrease in activity hepatic uroporphyrinogen decarboxylase (UROD) to approximately 20 percent of normal. UROD is the fifth enzyme in the heme biosynthetic pathway (figure 1), is found in the cytosol, and catalyzes the four-step decarboxylation of uroporphyrinogen to coproporphyrinogen, which have 8 and 4 carboxyl groups, respectively [71,72]. The four carboxyl groups are removed sequentially in a clockwise fashion starting from ring D. The enzyme has greater affinity for uroporphyrinogen III than uroporphyrinogen I.
A UROD inhibitor has been identified from liver extracts of murine models of PCT as a uroporphomethene, which is derived by oxidation of one of the four bridge carbons in the uroporphyrinogen macromolecule [2]. This inhibitor appears to be stable within the enzyme active site but is unstable when free in solution. Its formation from uroporphyrinogen I or III may be catalyzed by CYP1A2 in the presence of iron [2] (figure 2). Iron does not directly inhibit UROD.
The rate-limiting enzyme for heme synthesis in liver is the house-keeping form of delta-aminolevulinic acid synthase (ALAS1). Only a 15 to 20 percent increase in ALAS1 activity is required to account for the degree of excess porphyrin production in PCT [1]. This is in contrast to active stages of the acute hepatic porphyrias in which ALAS1 is markedly induced. (See "Porphyrias: An overview", section on 'Regulation of heme synthesis'.)
Porphyrin accumulation — Markedly decreased activity of hepatic UROD leads to accumulation of large amounts of uroporphyrinogen and hepta-, hexa-, and penta-carboxyl porphyrinogen in the liver, mostly as the corresponding oxidized porphyrins. Substantial amounts of these porphyrins accumulate in the liver, and then appear in plasma and urine. The resulting pattern of excess porphyrins, consisting of both I and III isomers, is complex, but characteristic (table 1). These highly carboxylated porphyrins are water soluble, and therefore mostly excreted in urine, but some also appear in feces.
Other porphyrin metabolic changes result from UROD deficiency, in that pentacarboxyl porphyrinogen accumulates and is further metabolized by coproporphyrinogen oxidase, the sixth enzyme in the pathway, to dehydro-isocoproporphyrinogen, an atypical tetracarboxyl porphyrinogen. After oxidation, this appears in feces and urine as isocoproporphyrins, with additional modifications by intestinal bacteria (table 1).
UROD mutations — Approximately 20 percent of patients with PCT have inherited a UROD mutation from one parent, which results in half-normal UROD in all tissues from birth (table 2). This inherited deficiency contributes, along with one or more of the other inciting factors discussed above, to reducing hepatic UROD activity to less than 20 percent of normal, which is required to cause overt, symptomatic PCT. (See 'Susceptibility factors' above.)
The UROD gene is located on chromosome 1p34.1. There are no tissue-specific forms of the enzyme. Multiple mutations have been described in different families with type 2 PCT and hepatoerythropoietic porphyria (HEP), including missense and nonsense mutations, deletions and insertions [73-78].
Laboratory findings — Highly carboxylated porphyrins (heptacarboxyl porphyrins usually exceed hexa- and penta-carboxyl porphyrins) are increased in patients with PCT, especially in liver, plasma, and urine, and usually with a predominance of uroporphyrin and heptacarboxyl porphyrin (table 1). Total fecal porphyrins may be normal or moderately increased with a complex pattern including the presence of isocoproporphyrins; heptacarboxyl porphyrins may exceed hexacarboxyl and pentacarboxyl porphyrins [1]. Urinary delta-aminolevulinic acid may be modestly increased, but porphobilinogen excretion is normal.
Liver findings — Serum transaminases are elevated in almost all cases. Liver tissue on biopsy shows marked reddish fluorescence when viewed under long wave UV light, reflecting large amounts of porphyrins. The red fluorescence does not intensify on oxidation, suggesting that the accumulated porphyrins are in their oxidized form and are not porphyrinogens. Microscopy shows these as needle shaped crystals within hepatocytes. (See 'Hepatic findings' above.)
Diagnosis — Blistering skin lesions on the backs of the hands and other sun exposed areas of skin should suggest the diagnosis of PCT. It is essential to confirm the diagnosis of PCT biochemically, because identical skin lesions can be seen in a number of other porphyrias, especially variegate porphyria (VP) and less commonly hereditary coproporphyria (HCP) (table 3).
PCT is supported by demonstrating a marked increase in porphyrins in plasma and/or urine, with a predominance of uroporphyrin and heptacarboxyl porphyrins, with lesser amounts of hexa- and penta-carboxyl porphyrins. Erythrocyte porphyrins are normal or only modestly increased. A total plasma porphyrin measurement may be most useful for initial screening. Fluorescence scanning of diluted plasma at a pH of 7.4 to determine the peak wavelength is useful for rapidly distinguishing PCT from VP (table 1) [79,80]. Elevation in isocoproporphyrins, which is more readily demonstrated in feces than urine, also helps confirm the diagnosis, but is usually not essential [80]. Erythrocyte porphyrins are markedly increased in PCT, in contrast to congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP), and erythropoietic protoporphyria (EPP).
Measurement of erythrocyte UROD activity is useful in patients with a confirmed diagnosis of PCT to identify those with UROD mutations, who are then classified as familial (type 2) disease. Molecular studies are more accurate in detecting these mutations [81].
After the diagnosis of PCT is confirmed, patients should be evaluated for the presence of susceptibility factors discussed above, as this can affect management [23,82,83]. (See 'Susceptibility factors' above.)
Differential diagnosis — A number of different porphyric conditions and some medical conditions may be associated with cutaneous lesions similar to those seen in PCT. Blistering and scarring are usually more severe in CEP and HEP than in PCT. EPP is distinguishable from PCT by nonblistering and immediate photosensitivity, usual onset early in life, and by laboratory testing. The table indicates the major biochemical findings associated with the cutaneous porphyrias (table 3).
Other differential diagnostic points include the following:
- Elevations in urine porphyrins occur in many medical conditions, especially liver and bone marrow diseases. In contrast to PCT, coproporphyrin usually predominates when urine porphyrins are nonspecifically elevated in conditions other than porphyria.
- Measurement of fecal porphyrins is needed to document hereditary coproporphyria (HCP) as a cause of coproporphyrinuria.
- Variegate porphyria (VP) is diagnosed by characteristic elevations in plasma and fecal porphyrins.
- Total plasma porphyrins can be elevated in cholestasis and renal failure [80,84], but usually less than in PCT and other porphyrias causing blistering skin lesions. Plasma porphyrin measurements are essential for evaluating patients with advanced renal disease and skin lesions suggesting PCT [80].
- Rare cases of primary hepatic tumors with cutaneous lesions suggesting PCT have been described, suggesting that porphyrins may be overproduced by the tumors [85,86]. However, these cases are not well documented biochemically or at the molecular level.
- Pseudoporphyria is a condition with skin lesions resembling PCT but without significant porphyrin elevations [87].
Treatment — PCT is the most readily treated type of porphyria. The preferred treatment at most centers is repeated phlebotomy, whether or not there is evidence of iron overload. A low-dose regimen of hydroxychloroquine is a suitable alternative if phlebotomies cannot be tolerated [4,82]. Remission can be achieved within about six months in most cases. Until then, patients should avoid exposure to sunlight by wearing protective clothing. The skin lesions may be painful and require oral analgesics. Affected areas should be kept clean and skin infections treated with antibiotics. Topical steroids are of little or no benefit.
Patients are advised to cease use of alcohol and to stop smoking. Estrogens should be discontinued at least until remission is achieved, after which an estrogen patch may be used safely, if necessary [88]. Drugs known to exacerbate acute porphyrias are seldom reported to precipitate PCT [89]. However, they may contribute and should be avoided when possible. (See "Etiology and pathogenesis of acute intermittent porphyria", section on 'Drugs and chemicals'.)
Repeated phlebotomy — The efficacy of phlebotomy has been recognized and widely reported for many years [90-98]. The rationale for this approach is supported by evidence that PCT is an iron-related disorder, including animal studies showing that iron depletion protects against development of uroporphyria and UROD inhibition (figure 2). The recommended approach is to remove one unit of whole blood (450 mL) at intervals of approximately two weeks until the serum ferritin is reduced to below approximately 20 ng/mL, which is near the lower limit of normal [91,97,99]. The hemoglobin or hematocrit is followed to prevent significant anemia.
Severe iron overload is uncommon in PCT, such that most patients require only six to eight phlebotomies in order to reach the target ferritin level. At that point, phlebotomy should be stopped, even if skin lesions are still present and porphyrins are not yet normal. The large amounts of porphyrins in the liver are mobilized and excreted gradually, and porphyrin levels will continue to decrease. Additional phlebotomies are of no benefit and may cause symptomatic iron deficiency anemia. It is most convenient to monitor improvement by measuring total plasma porphyrins rather than urine porphyrins.
Phlebotomy achieves remission in nearly all patients with PCT [90-95,100-102]. Lack of response suggests that the target ferritin has not yet been reached, or that the patient has a type of porphyria other than PCT.
Hypertrichosis and hyperpigmentation also improve gradually. Pseudosclerodermatous skin changes improve in some patients [95]. Improvement in liver function and histology are reported, but are inconsistent [94], reflecting that some associated susceptibility factors can cause liver damage. A predominance of highly carboxylated porphyrins may persist after total plasma and urine porphyrin levels become normal, but eventually a normal pattern with a predominance of coproporphyrin returns [95].
It is generally not necessary to continue phlebotomies after achieving remission. Relapses may occur, especially in patients who resume excess alcohol intake, but the frequency and relationship to other susceptibility factors are unclear. Relapse rates of 10 to 50 percent within two to four years of treatment have been reported [94]. It is prudent to measure plasma or urine porphyrins, perhaps annually, so that a relapse can be detected and treated early. Serum ferritin should be monitored in patients with HFE genotypes C282Y/C282Y or C282Y/H63D, and these patients should probably undergo periodic phlebotomies to maintain a serum ferritin below 50 ng/mL, as currently recommended for hereditary hemochromatosis [103]. (See "Treatment of hereditary hemochromatosis", section on 'Maintenance'.)
Phlebotomy may be difficult in patients with poor venous access, anemia, cardiac disease, and other medical conditions. Removal of iron by the use of iron chelating agents is a potential option, but is a less efficient method for iron reduction than phlebotomy [100,104]. (See "Chelation therapy for iron overload states".)
Administration of erythropoietin can correct anemia and support the ability of patients with PCT and end-stage renal disease to tolerate repeated phlebotomies [70,105].
Hydroxychloroquine or chloroquine — A low-dose regimen of the 4-aminoquinoline antimalarials hydroxychloroquine or chloroquine is effective treatment of PCT and is a suitable alternative when phlebotomies are difficult or poorly tolerated. These drugs are concentrated in the liver, particularly in lysosomes, and mobilize porphyrins from the liver by a poorly defined mechanism. Hydroxychloroquine may have less potential for adverse effects than chloroquine. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects'.)
These drugs cause substantial adverse effects when given to patients with PCT in doses approaching those used for other conditions, including an acute hepatotoxic reaction with an increase in plasma transaminases and an increase in plasma porphyrins and worsening of photosensitivity. Over time, the excess porphyrins are excreted in the urine, followed by remission of the disease [106]. In an attempt to avoid these complications, low-dose regimens of these agents were devised and found to be effective. A variety of regimens have been reported as effective for this disease (eg, hydroxychloroquine 100 mg three times weekly [107] or chloroquine 250 to 1000 mg daily for 7 to 10 days [106,108-111], 500 mg twice weekly [112], 300 mg twice weekly [113], 250 mg twice weekly [114]). The recommended regimen is 100 mg of hydroxychloroquine or 125 mg of chloroquine taken orally twice weekly [20,115-118]. Patients are instructed to cut the smallest available tablets (200 mg of hydroxychloroquine and 250 mg of hydroxychloroquine) in half. Mild transaminase and porphyrin elevations may occur initially, but are usually not accompanied by symptoms. Since this low-dose regimen seems as effective as phlebotomy, there is little justification for higher doses.
Retinopathy is a potential dose-related risk with hydroxychloroquine or chloroquine. Although this is unlikely to occur with a low-dose regimen, ophthalmological examination before and during treatment has been recommended. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)
The optimal duration of treatment is not established, but most experts continue hydroxychloroquine or chloroquine until plasma or urine porphyrin levels have been normal for at least several months [115]. In a preliminary report of an ongoing comparative study, response rates in patients treated with low-dose hydroxychloroquine were comparable to those treated by phlebotomy [119].
Relapse rates after these treatments have not been directly compared. After treatment with chloroquine (250 mg twice per week), relapse rates of 12 percent at one year and 49 percent at three years [114], and 35 percent at four years [120] have been reported, which were comparable to reported relapse rates after phlebotomy. A longer time to achieve remission (6 versus 11 months) appeared to predict relapse in one study [114].
Contraindications to treatment with hydroxychloroquine or chloroquine include pregnancy; lactation; advanced liver disease; recent and continued use of alcohol or hepatotoxic drugs such as acetaminophen, isoniazid or valproic acid; glucose-6-phosphate dehydrogenase deficiency; psoriasis and retinal disease. Chloroquine has been reported to be ineffective in PCT patients with C282Y homozygous hereditary hemochromatosis [121]; this observation presumably applies to hydroxychloroquine as well. Because iron itself can cause organ damage and these antimalarial agents do not reduce iron overload, patients with substantial iron overload should be treated with phlebotomy. (See "Treatment of hereditary hemochromatosis", section on 'Phlebotomy'.)
These drugs should not be used to treat PCT in patients with end-stage renal disease, because mobilized porphyrins are poorly dialyzed. Phlebotomy supported by administration of recombinant human erythropoietin is clearly preferred in this setting.
Other treatment options — There is little evidence for efficacy of other treatments, such as thalidomide [122], plasmapheresis [123], vitamin E [124], N-acetylcysteine [125], anastrazole [126], or urinary alkalization [127]. These should not be considered as alternatives to phlebotomy or low-dose hydroxychloroquine or chloroquine.
Treatment of hepatitis C and HIV — PCT should be considered an indication for treatment of HCV. However, patients with both PCT and hepatitis C should first be treated for PCT, which is usually more symptomatic and more likely to respond to therapy, usually within a few months. Treatment for hepatitis C is more prolonged and can be considered at a later time. Repeated phlebotomy may not be feasible during treatment with interferon and ribavirin, which often causes anemia. Treatment of HCV after PCT is in remission is likely to prevent recurrence of PCT. However, since multiple susceptibility factors are found in individual patients, these may contribute to recurrence even in the absence of HCV.
When PCT first appears or relapses during treatment of hepatitis C, low-dose hydroxychloroquine is an option, although experience with this drug is limited in this setting. Response to treatment of hepatitis C with interferon is reportedly impaired in patients with a history of PCT [128], but our limited unpublished experience suggests that such individuals respond as often to combined interferon-ribavirin as those who have never had porphyria. (See "Porphyria cutanea tarda and hepatitis C virus infection", section on 'Treatment'.)
PCT is not a reason to delay treatment for HIV infection.
Genetic counseling — Patients with familial (type 2) PCT usually have no family history of the disease because penetrance is low. Heterozygous carriers of UROD mutations who are asymptomatic may have increased urinary porphyrins, which can be monitored [129], and they can be advised to avoid additional susceptibility factors that might lead to development of overt disease, such as heavy alcohol use, smoking and perhaps oral estrogens. (See 'Susceptibility factors' above.)
Patients without UROD mutations are classified as type 1, or as type 3 if another family member is affected. Type 3 disease is rare and may be due in part to HFE mutations or other genetic factors that may increase susceptibility for developing PCT in relatives, or perhaps to shared environmental influences. (See 'Genetic susceptibility' above.)
HEPATOERYTHROPOIETIC PORPHYRIA
Definition and prevalence — Hepatoerythropoietic porphyria (HEP) is a rare disorder (approximately 40 cases have been documented) that is the homozygous or compound heterozygous form of familial porphyria cutanea tarda (PCT) [130,131]. Cutaneous photosensitivity usually begins in childhood and is usually more severe than in PCT. Disease onset is usually prior to two years of age, although onset in adulthood has been reported [76,132]. The disease occurs worldwide and in both males and females.
Clinical features — Skin photosensitivity is manifested early in life as blistering, scarring, hypertrichosis and pigment changes, resembling congenital erythropoietic porphyria. (See "Congenital erythropoietic porphyria", section on 'Clinical findings'.)
Clinical features in milder and later onset cases may be indistinguishable from PCT. Bacterial infections and scarring may be disfiguring. Mild anemia due at least in part to hemolysis is common, and may be accompanied by hepatosplenomegaly [1].
Etiology and pathogenesis — HEP is due to markedly reduced activity of hepatic uroporphyrinogen decarboxylase (UROD) to usually less than 20 percent of normal as measured in erythrocytes. Patients are either homozygous for one UROD mutation or compound heterozygous for a different UROD mutation inherited from each parent. At least one of the inherited mutations must express some UROD enzymatic activity, since a null mutation would be lethal in the homozygous state [2]. Thus, null mutations are much less common in HEP than in heterozygotes with familial (type 2) PCT.
HEP is primarily hepatic, although a marked increase in erythrocyte zinc protoporphyrin indicates that the heme biosynthetic pathway in the bone marrow is also affected. The excess zinc protoporphyrin in erythrocytes is probably formed from pathway intermediates that accumulate during hemoglobin synthesis and are later metabolized to protoporphyrin, and then complexed with zinc.
UROD activity is markedly reduced in HEP, which is sufficient to lead to accumulation of highly carboxylated porphyrinogens and porphyrins in liver and possibly other tissues. The hepatic UROD inhibitor and susceptibility factors that are important in PCT generally do not have a significant role in HEP. (See 'Decreased hepatic UROD activity' above.)
Laboratory findings — As in PCT, highly carboxylated porphyrins and isocoproporphyrins are increased in HEP especially in liver, plasma, urine, and feces. Erythrocyte zinc protoporphyrin is markedly increased. Porphyrin precursors (ie, delta aminolevulinic acid and porphobilinogen) are normal.
Hematological abnormalities may include mild, normocytic and normochromic anemia due in part to hemolysis. Mild and nonspecific abnormalities in liver function and histology are common, usually without siderosis.
Diagnosis — The possible presence of HEP should be considered in children with chronic, blistering photosensitivity. HEP is differentiated from congenital erythropoietic porphyria by the patterns of individual porphyrins in plasma, urine, and erythrocytes, and by a marked reduction in erythrocyte UROD activity (table 3). (See 'Diagnosis' above.)
Porphyrin patterns in HEP closely resemble those seen in PCT, but a marked elevation in erythrocyte protoporphyrin (mostly zinc protoporphyrin) is characteristic of HEP, and erythrocyte UROD activity is more reduced (usually to less than 20 percent of normal) than in type 2 (familial) PCT [133-136]. The diagnosis of HEP should be confirmed by molecular studies that demonstrate mutations affecting both UROD alleles [130,131,133].
Treatment and prognosis — Protection from sunlight is especially important in patients with HEP and is the only recognized treatment for this disorder. With such management, the overall prognosis is good, but fingers and facial features may be disfigured in severe cases. Identification of UROD mutations in a previous case in a family can enable genetic counseling and prenatal diagnosis [137].
Since excess iron and hepatic siderosis are not features of HEP, treatments for PCT, such as phlebotomy, are usually not helpful [76,130]. Other treatments that have been considered include:
- Low dose chloroquine was apparently useful in one case [130].
- Recombinant erythropoietin may be useful for treatment of anemia if not due to increased red cell destruction [132].
- Because the enzyme deficiency in liver is the most important cause of HEP, bone marrow transplantation is not useful [3].
- Oral charcoal, which can bind porphyrins in the gastrointestinal tract [138], was helpful in a case of severe disease associated with dyserythropoiesis [139].
- Retrovirus-mediated gene transfer can correct porphyria in cell lines from HEP patients, suggesting that gene replacement therapy may be effective in the future [140].
SUMMARY AND RECOMMENDATIONS — Porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP) are porphyric conditions due to deficient activity of hepatic uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme biosynthetic pathway. Both are associated with chronic blistering photosensitivity. (See 'Clinical features' above.)
- PCT, the most common human porphyria, is an iron-related disease that usually presents in mid or late life.
- HEP is the autosomal recessive form of familial PCT. This very rare disease is associated with a more severe deficiency of UROD, and usually presents in childhood with features that resemble congenital erythropoietic porphyria (CEP).
Suspecting the diagnosis — Blistering skin lesions on the backs of the hands and other sun exposed areas of skin should suggest this disease. Most patients with PCT will have multiple inherited and acquired “susceptibility factors” for this disorder, including smoking, excess use of alcohol, hepatitis C virus or HIV infection, estrogen use, and HFE mutations. Some are heterozygous for UROD mutations. (See 'Susceptibility factors' above.)
Confirming the diagnosis — The diagnosis of PCT is made by demonstrating the increased presence of highly carboxylated porphyrins in plasma or urine, usually with a predominance of uroporphyrin and heptacarboxyl porphyrin (table 1). The familial form of PCT will demonstrate approximately half-normal UROD activity in all tissues from the time of birth, with a more severe deficiency developing in the liver when the disease becomes active. Patients with HEP will have similar laboratory findings and will also demonstrate markedly increased levels of erythrocyte zinc protoporphyrin along with erythrocyte UROD activity usually to less than 20 percent of normal. (See 'Diagnosis' above.)
Treatment of PCT — We recommend that patients with symptomatic PCT be treated with either repeated phlebotomies to reduce the serum ferritin to a target level of about 20 ng/mL or with a low-dose regimen of hydroxychloroquine (100 mg twice weekly), which achieves remission by mobilizing the accumulated porphyrins from the liver (Grade 1B). Phlebotomy is preferred at most centers. (See 'Treatment' above.)
Treatment of HEP — Other than protecting against exposure to sunlight, there is no effective treatment for this disorder. Identification of UROD mutations in a previous case in a family can enable genetic counseling and prenatal diagnosis.
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