INTRODUCTION — The porphyrias are metabolic disorders caused by altered activity of enzymes in the heme biosynthetic pathway. Porphyria cutanea tarda (PCT; previously called symptomatic porphyria, chemical porphyria, toxic porphyria) is the most common and the most readily treated of the porphyrias.
This topic review discusses the management and prognosis of PCT, a cutaneous porphyria caused by deficient activity of uroporphyrinogen decarboxylase (UROD) in the liver, and hepatoerythropoietic porphyria (HEP), an extremely rare condition caused by biallelic UROD mutation. The pathogenesis, clinical manifestations, and diagnostic evaluation for PCT and HEP are presented in detail separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)
Additional topic reviews discuss management of other cutaneous porphyrias:
●Congenital erythropoietic porphyria (CEP) – (See "Congenital erythropoietic porphyria", section on 'Management'.)
●Erythropoietic protoporphyria (EPP) – (See "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Management'.)
●Variegate porphyria (VP) – (See "Variegate porphyria", section on 'Management'.)
●Hereditary coproporphyria (HCP) – (See "Hereditary coproporphyria", section on 'Management'.)
An overview of porphyrias is also presented separately. (See "Porphyrias: An overview".)
OVERVIEW OF MANAGEMENT — PCT is a readily treated and nonfatal condition.
Phlebotomy and low-dose hydroxychloroquine are both highly effective and safe treatment options for PCT. These therapies are also specific for PCT and are not effective for any other type of porphyria. Therefore, other less common porphyrias that cause the same skin manifestations must be excluded before treatment for PCT is initiated. All patients with PCT and active skin lesions who can tolerate phlebotomy or low-dose hydroxychloroquine should have one of these therapies in addition to reducing modifiable susceptibility factors. Limited experience suggests that patients with PCT and hepatitis C virus (HCV) infection should be treated with direct-acting antiviral agents rather than these standard treatments. (See 'Primary therapies for PCT' below.)
Additional management considerations include the following:
●It is important to identify and address the effects of susceptibility factors, which are multiple, vary from patient to patient, and may have additional health effects. These include use of alcohol and estrogen, smoking, nonalcoholic fatty liver disease, chronic HCV infection, HIV infection, and UROD and HFE (hereditary hemochromatosis gene) mutations. Early involvement of a hepatologist is advisable because PCT is a liver disease and many of the associated susceptibility factors affect the liver. (See 'Treatment of HCV and HIV infection' below and 'Avoidance of susceptibility factors' below.)
●Skin protection from sunlight is important until porphyrin levels have normalized with treatment. Patients may not appreciate that the skin manifestations are due to sun exposure. Wearing cloth gloves, broad-brimmed hats, long trousers, and shoes is advised. Some skin fragility and blistering may continue for some time after porphyrin levels are normal, probably due to slow healing of previously damaged skin. (See 'Skin protection' below.)
●Genetic counseling may also be appropriate in families with UROD or HFE mutations or suspected familial inheritance. Individuals with a heterozygous UROD mutation but with no porphyrin elevations have latent type 2 (familial) PCT and do not require intervention or monitoring, but they are advised to avoid additional susceptibility factors. (See 'Genetic counseling and management of individuals with asymptomatic UROD mutations' below.)
It is not known whether heterozygotes with porphyrin elevations but no symptoms should be treated, as longitudinal observations of such individuals are lacking.
●For the exceedingly rare patient with HEP, the only intervention known to be reliably effective is avoidance of sun exposure. However, PCT-related susceptibility factors may play a role in some patients and should be evaluated. (See 'HEP management' below.)
PCT is a chronic disease, and relapses can occur over time (see 'Prognosis' below). Control of modifiable susceptibility factors, such as alcohol avoidance and treatment of hepatitis C, can reduce the chances of recurrence. After remission is achieved, porphyrin levels in plasma or urine can be monitored, and re-treatment may be based on porphyrin elevations as an early sign of recurrence rather than waiting for skin lesions to develop.
Iron chelation is much less efficient for removing iron than is phlebotomy, and studies have not documented success comparable to phlebotomy or low-dose hydroxychloroquine in treating PCT. Thus, chelation is only used for individuals with PCT and substantial iron overload who cannot tolerate phlebotomies or who have poor venous access (see 'Iron chelation' below). Evidence is also lacking for efficacy of other treatments such as thalidomide, plasmapheresis, vitamin E, N-acetylcysteine, anastrozole, urinary alkalization, or cimetidine [1-6]. These should not be considered alternatives to phlebotomy or low-dose hydroxychloroquine. As already noted, limited experience suggests that PCT associated with HCV infection can be treated initially with direct-acting antiviral agents. Liver transplantation would likely be curative but is not indicated because highly effective therapy is available (eg, phlebotomy, low-dose hydroxychloroquine, antiviral agents for HCV).
ADDITIONAL TESTING ONCE DIAGNOSIS IS ESTABLISHED — Patients diagnosed with PCT or HEP should have the following additional laboratory testing if not done during the course of the initial evaluation:
●Complete blood count (CBC) including platelet count.
●Serum ferritin level.
●Serum chemistries and creatinine.
●Hepatic function tests including serum bilirubin, alkaline phosphatase, transaminases (ALT, AST), albumin, and prothrombin time.
●Hepatitis C virus (HCV) testing. (See "Screening and diagnosis of chronic hepatitis C virus infection".)
●HIV testing. (See "Screening and diagnostic testing for HIV infection".)
●UROD mutation testing or erythrocyte UROD activity measurement [7]. In type 2 familial PCT, erythrocyte UROD activity will be approximately half-normal and a familial UROD mutation can be identified. In HEP, erythrocyte UROD activity will be more markedly decreased (typically, <20 percent of normal) and mutation of both UROD alleles will be seen.
●HFE mutation testing, which has implications for choice of therapy and for screening of relatives for unrecognized hemochromatosis before onset of symptoms. (See 'Genetic counseling and management of individuals with asymptomatic UROD mutations' below.)
●Liver imaging to assess for advanced liver disease. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Radiographic examinations' and "Clinical manifestations and diagnosis of alcohol-associated fatty liver disease and cirrhosis", section on 'Imaging studies'.)
●Hepatocellular carcinoma screening after age 50 years or in any patient with advanced hepatic fibrosis or cirrhosis. (See "Surveillance for hepatocellular carcinoma in adults".)
The full diagnostic evaluation for PCT and HEP is presented separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation'.)
PRIMARY THERAPIES FOR PCT — All patients with PCT who have active skin lesions should receive primary therapy for PCT in addition to reducing susceptibility factors [8]. Repeated phlebotomy and low-dose hydroxychloroquine are both considered effective primary therapy for PCT and are almost always able to produce a complete remission. Although controlled trials are lacking, either of these treatments appears to result in faster improvements than removal of susceptibility factors (eg, discontinuation of alcohol) alone. (See 'Avoidance of susceptibility factors' below.)
Experience suggests that direct-acting antiviral treatment of associated chronic hepatitis C virus (HCV) infection can be effective primary therapy for PCT as an alternative to phlebotomy or low-dose hydroxychloroquine.
The choice between phlebotomy and low-dose hydroxychloroquine is based on clinical features including susceptibility factors and the degree of iron overload, along with patient preference. Phlebotomy is preferred at most centers based on greater experience. Phlebotomy is clearly preferred for individuals with evidence of iron overload (eg, substantially elevated serum ferritin or finding of HFE-related [hereditary] hemochromatosis). Hydroxychloroquine may be contraindicated with advanced liver disease, regular use of alcohol or hepatotoxic drugs, glucose-6-phosphate dehydrogenase (G6PD) deficiency, psoriasis, retinal disease (unless cleared by an ophthalmologist), and end-stage kidney disease. There are also major differences in the cost, convenience, and side effects of these treatments. (See 'Phlebotomy' below and 'Hydroxychloroquine (or chloroquine)' below.)
For individuals with a UROD mutation and isolated porphyrin elevation without active skin lesions, we reduce susceptibility factors but do not use other interventions. Longitudinal observations to determine how many of these individuals will develop overt PCT without treatment are lacking. (See 'Genetic counseling and management of individuals with asymptomatic UROD mutations' below.)
Phlebotomy and low-dose hydroxychloroquine were compared in a prospective pilot study involving 48 consecutive patients with PCT, which found that time needed to normalize plasma porphyrin levels, which predicts clinical improvement, was similar for both treatments [9]. In this study, patients underwent phlebotomy (one unit of blood every two weeks) or treatment with low-dose hydroxychloroquine (100 mg twice a week). Most patients were either ineligible for one of these treatments or preferred to choose the type of treatment and therefore were not randomly assigned to treatment. Nevertheless, clinical features were comparable in both treatment groups.
●Time to achieving a normal plasma porphyrin concentration in 30 evaluable patients was similar at 6.9 months for phlebotomy and 6.1 months for hydroxychloroquine. Normalization of plasma porphyrin levels rather than skin findings was used to define remission because resolution of skin lesions was highly variable and difficult to assess.
●Costs were lower and compliance was better with hydroxychloroquine.
With both therapies, a longer time is needed to reverse the predominance of highly carboxylated porphyrins in urine and for skin lesions to heal and skin friability to resolve. Studies comparing recurrence rates after each of these treatments and as related to various susceptibility factors are needed.
Phlebotomy — Phlebotomy is appealing because PCT is an iron-related disorder, and iron depletion presumably prevents formation of the uroporphomethene UROD inhibitor. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'UROD inhibitor'.)
Repeated phlebotomy is highly effective for treating PCT associated with iron overload as well as in patients with normal iron stores [10-18].
●Phlebotomy is clearly preferred in patients with substantial iron overload, as indicated by a serum ferritin that exceeds approximately 600 ng/mL, or with homozygosity or compound heterozygosity for HFE mutations, since iron overload can cause other health issues. Importantly, iron reduction is not effective for treating other porphyrias; thus, it is important before starting treatment to be sure that the diagnosis of PCT is confirmed and other much less common cutaneous porphyrias are excluded. For example, patients with variegate porphyria (VP), hereditary coproporphyria (HCP), mild congenital erythropoietic porphyria (CEP), or hepatoerythropoietic porphyria (HEP) are frequently misdiagnosed initially as having PCT and then not appropriately treated. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnostic evaluation' and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)
●Either phlebotomy or low-dose hydroxychloroquine is appropriate for patients with normal serum ferritin, serum ferritin below approximately 600 ng/mL, heterozygosity for an HFE mutation, or no HFE mutation. (See 'Hydroxychloroquine (or chloroquine)' below.)
We initiate phlebotomy, with removal of one unit of whole blood (approximately 450 mL) at intervals of approximately every two weeks, with monitoring of serum ferritin and hemoglobin (Hgb) levels (see 'Monitoring' below). Phlebotomy is performed until the serum ferritin is reduced to approximately ≤20 ng/mL (the lower limit of normal). Phlebotomy can also be stopped if the ferritin was less than approximately 25 ng/mL when drawn two weeks previously. Phlebotomy is deferred and rescheduled for an Hgb below a level that is preset for each patient. The preset Hgb level depends on the starting Hgb level and an assessment of other health conditions that might be adversely affected by lowering the Hgb level. This approach leads to remission of PCT while avoiding development of symptomatic anemia.
Lack of response to phlebotomy despite an adequate reduction in serum ferritin is rare. Most patients will require only six to eight phlebotomies to reach the target ferritin level because severe iron overload is not common in PCT. Once the target ferritin level is reached, phlebotomy is discontinued, even if skin lesions are still evident and plasma/urinary porphyrin elevations persist [12]. The large amounts of porphyrins in the liver are gradually mobilized and excreted, and porphyrin levels will continue to decrease [13]. Hypertrichosis and hyperpigmentation also improve gradually. Pseudo-sclerodermatous skin changes improve in some patients [13]. Improvement in liver function and histology are reported but are inconsistent, reflecting the role of commonly associated susceptibility factors that also cause liver damage [17].
Following remission, continued phlebotomies are usually not needed unless the patient's HFE genotype is C282Y/C282Y or C282Y/H63D, in which case phlebotomies should be repeated often enough to keep the ferritin below 100 ng/mL. In a case series of 147 patients with PCT, C282Y/C282Y and C282Y/H63D genotypes were found in 6 and 8 percent, respectively [19].
Plasma or urine porphyrins can be monitored at 6- to 12-month intervals, and phlebotomy can be reinitiated if porphyrin levels again become elevated. For a patient who has repeated recurrences of PCT, limited experience suggests that keeping the ferritin level below 100 ng/mL may prevent further recurrences.
Advantages of phlebotomy include proven efficacy based on uncontrolled observations over many decades and a strong rationale for treating an iron-related disease. However, phlebotomy may be expensive, inconvenient, and uncomfortable, and may cause syncope or anemia in some patients. As a result, compliance with phlebotomy can be challenging [9].
Iron reduction is also effective but often difficult in patients with PCT in the setting of end-stage kidney disease. Stopping iron supplementation, initiating erythropoietin (or increasing the erythropoietin dose if the patient is already taking erythropoietin) and small-volume phlebotomies can be effective [20,21]. Specific recommendations on the use of erythropoietin as well as relative contraindications in patients with end-stage kidney disease are presented separately. (See "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)
Hydroxychloroquine (or chloroquine) — Hydroxychloroquine (or chloroquine) is an effective treatment for PCT, either for initial therapy or as a suitable alternative when phlebotomies are difficult to perform or poorly tolerated. As primary therapy, hydroxychloroquine is an appropriate choice for patients with serum ferritin below approximately 600 ng/mL, heterozygosity for an HFE mutation, or no HFE mutation, as is phlebotomy.
Hydroxychloroquine and chloroquine are 4-aminoquinoline antimalarial drugs that are considered interchangeable, although hydroxychloroquine is thought to be safer in terms of retinal toxicity [22]. The preferred regimen is hydroxychloroquine, 100 mg (half of a 200 mg tablet), or chloroquine, 125 mg (half of a 250 mg tablet), orally twice per week (half-pills are used because pills containing the preferred dose for PCT are not available) [9]. This regimen of hydroxychloroquine has been shown to achieve a normal plasma porphyrin level as quickly as phlebotomy [9]. Higher doses have been used but have not been shown to lead to more rapid remission and are likely to cause more frequent side effects [23-29].
The optimal duration of treatment is not established, but we and others continue until plasma or urine porphyrin levels have been normal for at least several months [24]. PCT recurrences after treatment with low-dose hydroxychloroquine can be re-treated in the same manner. However, the safety and efficacy of continuing hydroxychloroquine during remission to prevent recurrence of PCT has not been studied and is not advisable.
Even with a regimen of hydroxychloroquine, 100 mg twice per week, mild transaminase and porphyrin elevations may occur initially, but these increases are not usually accompanied by symptoms and they typically resolve with continued treatment. However, this treatment causes a noticeable initial increase in photosensitivity in some patients. Further, even minor hepatotoxicity is a concern if the patient has advanced liver disease, is consuming large amounts of alcohol, or is being treated with a hepatotoxic drug.
There is at least some risk of retinopathy with hydroxychloroquine or chloroquine treatment [30]. Although this is unlikely to occur with the low doses described herein, ophthalmological examination should be performed according to standard guidelines (eg, before treatment, at the end of treatment, or after one year if continued treatment is needed to achieve remission, which is unusual).
Advantages of hydroxychloroquine include ease of use, low cost, and low incidence of toxicities of the recommended low-dose regimen. Disadvantages include the need for ophthalmologic examinations and the need for assistance in cutting pills. Hydroxychloroquine may have less potential for adverse effects than chloroquine [22]. Adverse effects of these agents are discussed in more detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects'.)
Contraindications to treatment with hydroxychloroquine (or chloroquine) include pregnancy; lactation; advanced liver disease; regular use of alcohol or hepatotoxic drugs such as acetaminophen, isoniazid, or valproic acid; glucose-6-phosphate dehydrogenase (G6PD) deficiency; psoriasis; and retinal disease (unless cleared by an ophthalmologist). Patients with marked iron overload or HFE-related hemochromatosis should be treated by phlebotomy rather than hydroxychloroquine or chloroquine. In addition, hydroxychloroquine or chloroquine should not be used to treat PCT in patients with end-stage kidney disease because mobilized porphyrins are poorly dialyzed.
A retrospective review suggested that chloroquine was not effective for treating PCT in individuals with homozygosity for the C282Y HFE mutation [31]. This conclusion was based on the observation that of three patients with PCT and C282Y/C282Y genotype treated with low-dose chloroquine, skin lesions failed to improve in one, and improved but recurred in two. All others with PCT responded with sustained resolution of skin lesions, including nine C282Y heterozygotes, 18 H63D homozygotes, eight C282Y/H63D compound heterozygotes, and 24 patients without an HFE mutation.
The use of hydroxychloroquine and chloroquine in PCT has an interesting history. It was noted initially that the larger doses of these drugs used for other diseases such as rheumatoid arthritis may, when administered in patients who also have PCT, induce fever, malaise, nausea, and marked increases in urinary uroporphyrin and heptacarboxyl porphyrin, plasma porphyrins, serum transaminases, other liver function tests, and ferritin levels. A usual dose of chloroquine for malaria prophylaxis can even unmask previously unrecognized PCT [32,33]. This initial adverse response was followed by complete remission of PCT [34]. The dose-related acute increases in porphyrin levels and cutaneous manifestations of PCT are manifestations of acute hepatic damage and the release of large amounts of porphyrins stored in hepatocytes. These drugs are weak bases and are mostly taken up in hepatocytes and especially in lysosomes, where excess porphyrins are stored in PCT. They may lower hepatocyte iron uptake but do not lower ferritin levels significantly, so they do not appear to act by causing iron depletion [9]. Subsequently, it was found that a low-dose regimen was preferred compared with standard doses because porphyrins are mobilized from the liver more gradually with little increase in plasma porphyrins or hepatocellular damage.
Monitoring — Treatment is monitored by measuring serum ferritin (during phlebotomies) and plasma porphyrins (during either treatments). For phlebotomies, the interval is individualized to coordinate with treatment visits.
●Phlebotomy – Individuals undergoing phlebotomy may have measurement of serum ferritin and plasma porphyrins at the time of each phlebotomy. At each visit, the ferritin result from the previous visit is reviewed and phlebotomies are continued until the ferritin level from two weeks earlier is less than approximately 25 ng/mL, at which point phlebotomies are stopped and a ferritin level is drawn to document a level of less than approximately 20 ng/mL.
Of note, ferritin is an acute phase reactant and can become elevated in the setting of inflammation associated with liver disease or other concurrent conditions (see "Acute phase reactants"). However, a predictable downward trend to a target value of less than 20 ng/mL is observed in almost all patients with PCT treated by phlebotomy at approximately two-week intervals.
Plasma and urine porphyrins are almost always decreased from baseline but remain elevated when the target ferritin is reached and phlebotomies are stopped. Porphyrins can then be measured monthly to document normalization.
●Low-dose hydroxychloroquine – Individuals treated with low-dose hydroxychloroquine have measurement of plasma and urine porphyrins monthly, and the drug is stopped after the levels have been normal for at least several months. Monitoring of ferritin is not helpful during treatment with hydroxychloroquine; even low-dose hydroxychloroquine may cause transient hepatocellular damage accompanied by an acute phase response and a transient increase in ferritin. Ophthalmologic monitoring is described above. (See 'Hydroxychloroquine (or chloroquine)' above.)
For patients treated with phlebotomy or hydroxychloroquine who are in remission, longer term monitoring consists of visits at 6- to 12-month intervals. If porphyrin levels start to increase, treatment can be started again before skin lesions recur.
SKIN PROTECTION — Sunlight exposure should be avoided at least until plasma porphyrin levels are normal but is generally not needed once plasma porphyrin levels normalize. Skin protection measures include the use of gloves, hats, and other protective clothing, inorganic sunscreens (eg, zinc oxide, titanium dioxide), and sunglasses.
The skin lesions associated with PCT 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. Skin fragility, which can persist for some time after biochemical remission, is not itself an indication that treatment was not successful.
AVOIDANCE OF SUSCEPTIBILITY FACTORS — As noted above, the majority of patients with PCT have multiple susceptibility factors, which may include alcohol use, smoking, estrogen use, HCV infection, HIV infection, UROD mutations, and/or HFE mutations (see "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Susceptibility factors'). Patients are advised to favorably alter the factors they can control by stopping alcohol, estrogen use, and smoking. Limited experience suggests that these behavioral changes alone are not sufficient for remission but may hasten response to phlebotomy or hydroxychloroquine and prevent recurrences. It is not clear why recurrences occur in some patients and not others; in many individual cases, resumption of excess alcohol intake is often implicated.
●Alcohol – Patients are advised to abstain from use of alcohol, and many do so at least for a period of time. Additional strategies for alcohol cessation for individuals with an alcohol use disorder are presented separately. (See "Alcohol use disorder: Psychosocial treatment" and "Brief intervention for unhealthy alcohol and other drug use: Efficacy, adverse effects, and administration".)
●Smoking – Patients are also advised to discontinue smoking, including marijuana. For many patients, this is more difficult than stopping alcohol use. Strategies are discussed separately. (See "Overview of smoking cessation management in adults" and "Pharmacotherapy for smoking cessation in adults".)
●Estrogen – Patients receiving estrogen therapy are advised to discontinue use at least until remission is achieved, after which an estrogen patch may be used safely, if necessary [35].
●Iron – Patients should be counseled to avoid potential sources of excessive iron intake such as dietary and nutritional supplements or multivitamins containing iron; however, avoidance of normal dietary sources of iron such as red meat is not required.
●Medications – Estrogens are the only drugs that are commonly implicated in causing PCT, and drugs known to exacerbate acute porphyrias are seldom reported to precipitate PCT (table 1). Little induction of ALAS1 is needed to account for the large amounts of porphyrins excreted in urine in PCT (in contrast to the much larger amounts of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) that are excreted in the acute hepatic porphyrias) [36]. However, the medications that induce hepatic ALAS1 may sometimes contribute in PCT and should be avoided [37]. Additional information on drugs that are considered harmful in acute hepatic porphyrias based on existing (but often limited) evidence can be accessed at websites of the American Porphyria Foundation (https://porphyriafoundation.org/) and the European Porphyria Network (EPNET; www.porphyria-europe.com).
TREATMENT OF HCV AND HIV INFECTION
Hepatitis C virus (HCV) — Hepatitis C virus (HCV) infection is an important susceptibility factor for PCT. In the past, PCT patients with chronic hepatitis C were first treated by phlebotomy or low-dose hydroxychloroquine, followed by treatment for HCV infection [38]. Because direct-acting antiviral (DAA) agents are highly effective for treating chronic HCV infection and have excellent safety profiles, all individuals with chronic HCV infection should be offered DAA treatment; delays in treating HCV should be avoided [38-40]. Subclinical PCT, although uncommon in chronic hepatitis C, has been observed to resolve with DAA treatment [41]. In another report, 5 of 86 patients who had porphyrin abnormalities consistent with PCT who were treated for HCV had normalization of their porphyrin levels and resolution of symptoms with curative DAA therapy [41]. Anecdotal experience suggests that treatment with a DAA alone will lead to remission of symptomatic PCT [42]. Whether this occurs as quickly and dependably as with phlebotomy or low-dose hydroxychloroquine is under study by the Porphyrias Consortium (NCT03118674). In the interim, available evidence supports treatment of patients with PCT and chronic hepatitis C with a DAA alone.
Specific HCV treatment recommendations are discussed in detail separately:
●Overview and selection of therapy – (See "Overview of the management of chronic hepatitis C virus infection".)
●Genotype 1 – (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults".)
●Genotype 2 or 3 – (See "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults".)
●Genotype 4, 5, or 6 – (See "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults".)
●HCV and HIV coinfection – (See "Treatment of chronic hepatitis C virus infection in the patient with HIV".)
HIV — Optimal therapy for HIV is important in patients with PCT. Unless there is another indication to stop or defer therapy for HIV, PCT and HIV should be treated concurrently. HIV-infected patients are almost always able to tolerate phlebotomy or low-dose hydroxychloroquine. To our knowledge, PCT has not been found to be an indication for altering treatment for HIV. It is also not clear if optimal HIV therapy alone will lead to improvement of PCT. Recommendations for HIV therapy are presented in detail separately. (See "Primary care of adults with HIV" and "Acute and early HIV infection: Treatment" and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
IRON CHELATION — Iron chelating agents are less efficient in removing iron than phlebotomy but may be used in patients with PCT and substantial iron overload who cannot tolerate phlebotomies or who have poor venous access. A number of studies indicate that iron chelation is less useful than standard of care treatment by phlebotomy or low-dose hydroxychloroquine. Examples include the following:
●Phlebotomy versus deferoxamine – A non-randomized study compared phlebotomy in 15 patients with deferoxamine (DFO, Desferal) in 10 patients with PCT who had various contraindications to phlebotomy [11]. Efficacy was found for both, with remission occurring in 6 to 14 months with chelation. However, the number of phlebotomies needed for the comparison was unusually large (15 to 32 phlebotomies per patient, 300 mL each), and times to remission were unusually long (9 to 19 months). Times to achieving target ferritin levels were not compared. Deferoxamine was given as 1.5 g by subcutaneous pump five days a week, which was more expensive and required a greater time commitment than phlebotomy.
●Hydroxychloroquine versus deferoxamine – A well-designed trial randomly assigned 40 patients with PCT and heavy alcohol use to hydroxychloroquine (200 mg twice a week) versus deferoxamine (30 mg/kg daily subcutaneous dose, administered for one week every three months) and found improvement in both groups [43]. However, decreases in serum ferritin with chelation (eg, to 55 ng/mL at six months) were not comparable to what is generally achieved with phlebotomy (to approximately 20 ng/mL) (see 'Phlebotomy' above). Urine total porphyrins were normal at one year with hydroxychloroquine and had decreased but remained elevated with chelation. The authors concluded that hydroxychloroquine rather than chelation should be the preferred alternative to phlebotomy.
●Deferasirox – In a pilot study of deferasirox (Exjade), decreased blistering occurred in all eight evaluable patients, but serum ferritin decreased by only 41 percent to 226 ng/mL, which is not comparable to the target ferritin levels generally achieved by phlebotomy [44]. Two patients did not initially have uroporphyrin elevations as expected in PCT. Therapy was given for six months, at an initial dose of 250 mg daily (equivalent to approximately 5 mg/kg daily), and was increased to 500 mg daily at two months due to continued new blister formation in all patients. This dose of 500 mg daily (equivalent to approximately 10 mg/kg daily) is lower than doses used for patients with transfusional iron overload. (See "Iron chelators: Choice of agent, dosing, and adverse effects".)
Thus, chelation is not considered for treatment of PCT unless there are strong contraindications to both phlebotomy and low-dose hydroxychloroquine. Chelation therapy also requires additional monitoring (eg, audiology examination, ophthalmology evaluation, liver function testing), which is different for each chelating agent. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Monitoring for adverse events'.)
HEP MANAGEMENT — Protection from sunlight is the cornerstone of management of HEP and the only intervention known to improve symptoms reliably. In contrast to PCT, reduction of hepatic iron does not appear to be effective in managing HEP, likely because in the absence of a normally functioning gene, hepatic uroporphyrin decarboxylase (UROD) activity remains low from birth [45,46]. However, it is reasonable to evaluate these patients for the susceptibility factors that are important in PCT because it is possible that generation of a UROD inhibitor could sometimes contribute to further lowering of hepatic UROD activity. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'UROD inhibitor'.)
Low-dose chloroquine was apparently useful in one case [46]. Oral charcoal, which can bind porphyrins in the gastrointestinal tract, was helpful in a case of severe disease that resembled congenital erythropoietic porphyria (CEP) but had UROD deficiency and dyserythropoiesis [47].
Additional aspects of dermatologic and eye care, dental care, and the importance of vitamin D supplementation in patients practicing strict sun avoidance, are similar to those for patients with CEP; these are presented separately. (See "Congenital erythropoietic porphyria", section on 'Skin and eye care' and "Congenital erythropoietic porphyria", section on 'Vitamin D' and "Congenital erythropoietic porphyria", section on 'Dental care'.)
Anemia is unusual in HEP, but in one case, severe anemia was successfully treated with erythropoietin [48]. Other potential causes of anemia should also be investigated and addressed if present (eg, iron deficiency, hemolytic anemia).
There is no evidence that hematopoietic stem cell transplantation is an effective therapy for HEP. It is presumed that most of the excess porphyrins in this disease are produced by the liver, and it is unlikely that restoration of UROD activity in hematopoietic cells alone would overcome the hepatic UROD deficiency and excessive hepatic porphyrin production [49]. Strategies utilizing gene therapy may be effective in the future [50]. Use of liver transplant has not been reported.
GENETIC COUNSELING AND MANAGEMENT OF INDIVIDUALS WITH ASYMPTOMATIC UROD MUTATIONS
●PCT – For individuals or families with PCT and a suspected genetic component, appropriate testing of the index patient should be reviewed. This should include testing for a mutation in the gene encoding uroporphyrinogen decarboxylase (UROD) and mutation in the hereditary hemochromatosis gene HFE. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'Significance of UROD mutations' and "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis", section on 'HFE mutations'.)
•Sporadic (type 1) disease – Family members of patients with PCT who do not have a UROD mutation (ie, sporadic [type 1] PCT) can be counseled that they do not require genetic testing for the PCT mutation.
Individuals with PCT who have an HFE mutation can be counseled regarding the inheritance and consequences of HFE mutations. (See "Management and prognosis of hereditary hemochromatosis".)
•Familial (type 2) disease (UROD mutation) – For individuals or families with PCT who have a known UROD mutation (ie, familial type 2 disease), a genetic counselor or other expert can explain the inheritance of PCT to the family (autosomal dominant with limited penetrance). During counseling, appropriate testing of family members can be facilitated; this is only done after identification of a UROD mutation in an index case. The likelihood of a carrier passing the mutation to her or his children is approximately 50 percent.
Family members who have inherited a UROD mutation but do not have overt disease (ie, asymptomatic heterozygotes) can be counseled, along with appropriate laboratory testing and interventions to modify disease risk, including avoidance of heavy alcohol use and smoking. The optimal management of asymptomatic carriers of a UROD mutation is unknown, and we do not use interventions or monitoring other than reduction of behavioral susceptibility factors.
Of interest, a study that measured porphyrin levels in 16 unaffected relatives of patients with PCT who carried the familial UROD mutation found increased urinary porphyrins in six (38 percent) [51]. However, the likelihood of progression to symptomatic PCT, and the benefit of treating such individuals to prevent symptoms of PCT, have not been evaluated. For individuals without active skin lesions, a primary therapy is unlikely to be necessary.
Testing of children usually can be deferred until they reach an age of consent since disease manifestations generally occur in mid- to late adulthood. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)
•Familial (type 3) disease (no UROD mutation) – If more than one PCT case occurs in a family in the absence of a UROD mutation, an effort should be made to identify shared inherited (eg, HFE mutations) or environmental susceptibility factors. Counseling of family members can be tailored to these identified factors.
●HEP – For individuals or families with HEP, genetic and reproductive counseling may be more complex. In addition to discussion of the inheritance pattern, counseling may include information regarding the possible use of pre-implantation genetic testing, prenatal testing, or donor gametes [52]. However, relatives with heterozygous UROD mutations are at low risk to develop PCT, because penetrance is low. (See "Preimplantation genetic testing" and "Donor insemination" and "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Diagnostic amniocentesis" and "Chorionic villus sampling".)
PROGNOSIS
●PCT
•Quality of life – Evidence from a Norwegian registry suggests that PCT negatively affects health-related quality of life, especially among untreated patients [53].
•Disease course – PCT may relapse following successful treatment, especially in patients who resume excess alcohol intake, but the frequency of relapses and relationship to other susceptibility factors are unclear.
In a meta-analysis of 12 studies involving 525 patients with PCT, relapse rates after treatment with phlebotomy or antimalarial drugs were approximately 20 to 35 percent over a median follow-up of 1 to 11 years [29]. The pooled relapse rate per person-year of follow-up was 5.1 percent after initial remission with phlebotomy, 8.6 percent with high-dose hydroxychloroquine, and 17.1 percent after low-dose hydroxychloroquine. However, most of the series were single-arm and did not directly compare relapse rates with different therapies.
Such estimates may be affected by adequacy of follow-up, which may be better in those who relapse, and by inclusion of cases where initial treatment was incomplete. Many other considerations factor into the choice of therapy, as discussed above. (See 'Primary therapies for PCT' above.)
•Survival – PCT is a readily treated, nonfatal condition, so a normal life expectancy might be expected. However, underlying liver disease and other concurrent conditions are often present, and some patients have developed hepatocellular carcinoma. In a case-control study in Denmark patient survival at 20 years was lower in PCT vs. matched control individuals (43 vs. 61%), with the higher mortality mainly due to gastrointestinal diseases and cancers of the gut, liver, gallbladder and lungs [54].
●HEP – HEP can be disfiguring, but life-threatening complications are rare and life expectancy appears to be normal [55].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Porphyria".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Porphyria cutanea tarda (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Disease mechanisms and diagnosis – Porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP) are cutaneous porphyrias caused by reduced activity of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD) in liver (figure 1). Approximately 80 percent of PCT cases are sporadic, and the remaining 20 percent are familial. Acquired susceptibility factors (alcohol use, smoking, hepatitis C virus [HCV] infection, HIV infection, estrogen, fatty liver disease, use and certain genetic traits [UROD or HFE variants]) and account for disease development. Pathophysiology, clinical manifestations, and the diagnostic evaluation for PCT and HEP are presented in detail separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Pathogenesis, clinical manifestations, and diagnosis".)
●General management considerations – PCT is the most readily treatable porphyria. Phlebotomy and low-dose hydroxychloroquine are effective treatments of PCT. These treatments are also specific for PCT and are not effective for any other type of porphyria. (See 'Overview of management' above.)
●Testing after the diagnosis is made – Individuals diagnosed with PCT should have baseline complete blood count (CBC) with platelet count; serum ferritin, kidney and liver biochemical panels; testing for HCV and HIV infections; and testing for UROD and HFE (the hereditary hemochromatosis [HH] gene) mutations. Screening for hepatocellular carcinoma is recommended in a patient with advanced fibrosis or cirrhosis. (See 'Additional testing once diagnosis is established' above.)
●Treatment of active skin lesions – Patients with PCT who have active skin lesions should be treated with phlebotomy or low-dose hydroxychloroquine in addition to controlling susceptibility factors (see 'Primary therapies for PCT' above). If chronic hepatitis C is present, this infection and PCT can be treated with direct-acting antiviral (DAA) agents alone. The choice between phlebotomy and hydroxychloroquine depends on the degree of iron overload and other factors:
•Phlebotomy – Phlebotomy is preferred for individuals with substantial iron overload, as indicated by a serum ferritin that exceeds approximately 600 ng/mL, or with homozygosity or compound heterozygosity for HFE variants (C282Y/C282Y or C282Y/H63D). Phlebotomy is performed every two weeks, guided by the serum ferritin and porphyrin levels. After remission, continued phlebotomies usually are not required, but patients with HH should be managed according to guidelines. Maintenance phlebotomy may be used to prevent recurrence in the minority of patients prone to frequent relapse of PCT. (See 'Phlebotomy' above.)
•Hydroxychloroquine – Individuals who do not have substantial iron overload may be treated with phlebotomy or low-dose hydroxychloroquine. The choice between these is based on other susceptibility factors, contraindications to either treatment, and other factors that may affect preference (eg, cost, convenience, side effect profile). Contraindications to the use of hydroxychloroquine including pregnancy, advanced liver disease, regular alcohol use, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and retinal disease. Hydroxychloroquine is administered 100 mg twice weekly, with measurement of porphyrin levels. Higher doses are likely to cause transient liver damage and increased photosensitivity. Recurrences can be re-treated with hydroxychloroquine; however, long-term administration during remission is not advisable. (See 'Phlebotomy' above and 'Hydroxychloroquine (or chloroquine)' above.)
Most patients do not have relapse of PCT after treatment, especially when susceptibility factors are addressed. However, re-treatment for early recurrence of PCT based on porphyrin elevations may be appropriate for some individuals rather than waiting for skin lesions to develop. (See 'Overview of management' above.)
●Treatment of asymptomatic individuals – For an asymptomatic UROD mutation carrier identified by family testing, susceptibility factors should be evaluated and managed appropriately. If porphyrins are elevated, treatment may be considered, especially if overt PCT occurred in the past. (See 'Genetic counseling and management of individuals with asymptomatic UROD mutations' above.)
●Avoidance of exacerbating factors – Sun avoidance is used until plasma porphyrin levels have normalized. Alcohol, smoking, excess iron intake, and exogenous estrogens should be avoided. Drugs known to exacerbate acute porphyrias are seldom reported to precipitate PCT (table 1); however, they should be avoided when possible. (See 'Skin protection' above and 'Avoidance of susceptibility factors' above.)
●Hepatitis C and HIV treatment – Therapy for HCV infection with DAA agents can be initiated instead of specific treatment of PCT, although experience is limited. Studies are underway to determine whether these drugs achieve remission as quickly as treatment with phlebotomy or low-dose hydroxychloroquine. If present, HIV infection should be treated concurrently with PCT. (See 'Treatment of HCV and HIV infection' above.)
●Additional considerations for HEP (biallelic UROD mutations) – For hepatoerythropoietic porphyria (HEP), management consists of protection from sunlight. In contrast to PCT, reduction of hepatic iron does not appear to be effective in managing HEP. (See 'HEP management' above.)
●First-degree relatives – Genetic counseling is important in families with a known pathogenic variant in UROD, emphasizing that disease penetrance of familial (type 2) PCT is low and that HEP results from inheritance of UROD variants from both parents. Acquired susceptibility factors should also be discussed. (See 'Genetic counseling and management of individuals with asymptomatic UROD mutations' above.)
●Life expectancy – Life expectancy for patients with PCT may be limited by concurrent conditions such as liver disease or cancer resulting from alcohol use, HCV infection, and smoking. (See 'Prognosis' above.)
ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
