Approach
Start treatment after establishing the diagnosis of PCT and excluding other types of porphyria. The goal of treatment is to reduce porphyrin levels to normal and achieve a remission of cutaneous signs and symptoms. Choice of treatment depends on contraindications and comorbidities. Options include phlebotomy and low-dose hydroxychloroquine or chloroquine. Management of all patients should be guided by identification of susceptible risk factors for PCT (i.e., excessive alcohol intake, smoking, estrogen therapy, hepatitis C, HIV, hereditary hemochromatosis gene mutations and other causes of iron overload, and inherited partial deficiency of uroporphyrinogen decarboxylase [UROD] due to mutations of the gene for this enzyme). When possible, these susceptibility factors should be removed. Stopping drinking alcohol, smoking, and estrogen treatment may hasten remission but these are generally not sufficient on their own. Estrogen therapy can be resumed if clinically indicated after PCT is in remission. Hepatitis C should be treated with effective direct-acting antiviral agents.
Patients with no phlebotomy contraindications
Repeated phlebotomy
PCT results from reduced (<20% of normal) activity of UROD in the liver. This occurs when uroporphyrinogen is partially oxidized to form uroporphomethene, which is a competitive inhibitor of hepatic UROD. This in turn results in accumulation of uroporphyrin and other highly carboxylated porphyrins, the oxidized substrates of UROD, in the liver. These circulate in plasma and are excreted renally.[3] Because PCT is an iron-related disease, reduction of iron stores by repeat phlebotomy is effective, and is standard treatment in most centers.
Phlebotomy is also preferred by some patients because it does not involve potential adverse effects of drug administration. However, phlebotomy is costly, inconvenient, and sometimes poorly tolerated. It is contraindicated in patients with anemia due to concurrent medical conditions, those with a cardiopulmonary disease that might be compromised by a modest drop in hemoglobin, those with poor venous access, or patients with frequent presyncope after phlebotomies.
The degree of iron overload is assessed by serum ferritin, and liver biopsy is often performed when clinically indicated as part of evaluation of iron overload and/or chronic liver disease. Serum ferritin may be increased in patients with liver disease (acute phase response), but ferritin is still a useful target for therapeutic phlebotomy.
Phlebotomy of approximately 450 mL every 2 weeks is usually performed until the desired serum ferritin target of 15 to 20 nanograms/mL is achieved, then phlebotomy is stopped. Plasma (and urine) porphyrins fall less rapidly. Therefore, treatment is usually completed before porphyrins are normal and skin lesions completely resolved.
Monitor ferritin, plasma total porphyrins, and hematocrit or hemoglobin while the patient is having repeated phlebotomy.[16] If the hematocrit or hemoglobin levels are too low and target ferritin is not yet achieved, stop phlebotomies for about 2 weeks to allow hematocrit or hemoglobin to increase as erythropoiesis continues.
In patients with chronic renal failure/end-stage renal failure on hemodialysis, iron reduction is accomplished by administration of erythropoietin (to correct erythropoietin deficiency and restore red cell production by the bone marrow). This supports small volume (approximately 100 mL) phlebotomies, administered if possible at each hemodialysis session. This treatment is guided by following the serum ferritin concentration.
Supportive care includes removal of susceptible risk factors.
Patients in whom phlebotomy is contraindicated or poorly tolerated
Low-dose hydroxychloroquine or chloroquine
These drugs are recommended for patients in whom phlebotomy is contraindicated, difficult, or poorly tolerated.[23][24][25][26][27] Hydroxychloroquine has a better safety profile than chloroquine.
With this treatment, porphyrins are mobilized from the liver by a poorly understood mechanism and excreted in urine.
Usual doses of these drugs are not used because they can cause transient but sometimes severe liver damage and worsening of photosensitivity in PCT patients.
This treatment is contraindicated in patients with substantial serum ferritin elevations (>500 nanograms/mL), advanced liver disease, continuing heavy alcohol intake, end-stage renal disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, or intolerance to these medications. Ophthalmological evaluation is recommended before and at 12-month intervals during treatment.
The low-dose regimen is continued until plasma porphyrins have been normal for about 3 months, after which they can be discontinued.
Low-dose hydroxychloroquine is generally as effective as phlebotomy for treatment of PCT, but longer studies are needed to compare relapse rates.[23][28]
Supportive care includes removal of susceptible risk factors.
Patients with comorbid hepatitis C
Direct-acting antivirals are highly effective for treatment of hepatitis C, and limited evidence suggests that this treatment should be initiated in PCT patients with hepatitis C without first treating with phlebotomies or low-dose hydroxychloroquine.[29] Studies are under way to compare times to remission and durability of this treatment when compared with phlebotomy or low-dose hydroxychloroquine.[30]
Patients with comorbid HIV
HIV infection is potentially life-threatening, especially if treatment is interrupted. Therefore it is important to continue treatment for HIV concurrently with treatment of PCT. However, if patients are newly diagnosed with both PCT and HIV, specialist guidance should be sought from infectious diseases specialists regarding decision and timing to start antiretroviral therapy.
Patients who have relapsed after remission
Management includes identification and, when possible, removal of susceptibility risk factors for PCT (excessive alcohol intake, smoking, and estrogen therapy). According to the patient's previous sensitivities to treatment, recurrences of PCT should be treated with either phlebotomies or low-dose hydroxychloroquine.
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