Porphyria Cutanea Tarda
(See also Overview of Porphyrias and Overview of Cutaneous Porphyrias.)
Pathophysiology
Porphyria cutanea tarda (PCT) results from hepatic deficiency of uroporphyrinogen decarboxylase (UROD—see table Substrates and Enzymes of the Heme Biosynthetic Pathway). Porphyrins accumulate in the liver and are transported to the skin, where they cause photosensitivity.
The drugs that commonly trigger acute porphyria (see table Drugs and Porphyria) do not trigger PCT.
Liver disease is common in PCT and may be due partly to porphyrin accumulation,chronic hepatitis C infection, concomitant hemosiderosis, or excess alcohol ingestion. Cirrhosis occurs in ≤ 35% of patients, and hepatocellular carcinoma occurs in 7 to 24% (more common among middle-aged men).
There are two main types of porphyria cutanea tarda:
Type 1 accounts for 75 to 80% of cases, and type 2 for 20 to 25%.
In type 1 porphyria cutanea tarda, decarboxylase deficiency is restricted to the liver and no genetic predisposition is present. It usually manifests in middle age or later.
In type 2 porphyria cutanea tarda, decarboxylase deficiency is inherited in an autosomal dominant fashion with limited penetrance. Deficiency occurs in all cells, including red blood cells. It may develop earlier than type 1, occasionally in childhood. The partial (~50%) deficiency in UROD activity in heterozygous patients itself is not sufficient to cause biochemical or clinical features of PCT; additional factors are required to cause the > 75% decrease in hepatic UROD activity needed for features of PCT to manifest. Such factors can include elevated hepatic iron, alcohol use, halogenated hydrocarbon exposure, hepatitis C virus or HIV infection, estrogens, and smoking. These factors increase the oxidation of uroporphyrinogens and other porphyrinogens to the corresponding porphyrins and also help form inhibitors of UROD.
Hepatoerythropoietic porphyria (HEP—see table Some Less Common Porphyrias), which features profound UROD deficiency, is very rare and is often regarded as an autosomal recessive form of type 2 PCT.
Type 3 PCT, which is very rare, is hereditary but without any defect in the UROD gene; a defect in another, unidentified gene appears to be the cause. Type 3 accounts for < 1% of PCT cases.
Types 1 and 2 are the major forms of porphyria cutanea tarda. They have the same precipitants, symptoms, and treatment. Overall prevalence may be on the order of 1/10,000 but is probably higher in people exposed to halogenated aromatic hydrocarbons or other precipitants of the disease.
Pseudoporphyria
End-stage renal disease, ultraviolet radiation (UVA), and certain drugs can cause PCT-like symptoms without elevated porphyrin levels (pseudoporphyria). Commonly implicated drugs are furosemide, tetracyclines, sulfonamides, and naproxen and other nonsteroidal anti-inflammatory drugs (NSAIDs).
Because porphyrins are poorly dialyzed, some patients receiving long-term hemodialysis develop a skin condition that resembles PCT; this condition is termed pseudoporphyria of end-stage renal disease.
Symptoms and Signs
Patients with porphyria cutanea tarda present with fragile skin, mainly on sun-exposed areas. Phototoxicity is delayed: patients do not always connect sun exposure with symptoms.
Porphyria cutanea tarda affects predominantly sun exposed areas including the earlobes in this patient.
Erythema, bullae, and milia over the dorsum of the hand of a man with porphyria cutanea tarda.
Atrophic scars have developed after rupture of bullae. Some bullae are hemorrhagic.
Spontaneously or after minor trauma, tense bullae develop. Some bullae are hemorrhagic. Accompanying erosions and ulcers may develop secondary infection; they heal slowly, leaving atrophic scars. Sun exposure occasionally leads to erythema, edema, or itching.
Hyperemic conjunctivitis may develop, but other mucosal sites are not affected.
Areas of hypopigmentation or hyperpigmentation may develop, as may facial hypertrichosis and pseudosclerodermoid changes.
Diagnosis
In otherwise healthy patients, fragile skin and blister formation suggest porphyria cutanea tarda. Differentiation from acute porphyrias with cutaneous symptoms (variegate porphyria [VP] and hereditary coproporphyria [HCP]) is important because in patients with VP and HCP, the erroneous prescription of porphyrogenic drugs may trigger the severe neurovisceral symptoms of the acute porphyrias. Previous unexplained neurologic symptoms or abdominal pain may suggest an acute porphyria. A history of exposure to chemicals that can cause pseudoporphyria should be sought.
Although all porphyrias that cause skin lesions are accompanied by elevated plasma porphyrins, elevated urinary uroporphyrin and heptacarboxyl porphyrin and fecal isocoproporphyrin indicate PCT. Urine levels of porphyrin precursor porphobilinogen (PBG) is normal in PCT. Urinary delta-aminolevulinic acid may be slightly increased (< 3 times the upper limit of normal). Red blood cell activity of UROD is normal in type 1 and type 3 PCT but decreased (by ~50%) in type 2.
All patients with PCT should be tested for hepatitis C and HIV infections. They should also be tested for iron overload with serum iron and ferritin levels, and total iron-binding capacity; if results suggest iron overload, genetic testing for hereditary hemochromatosis is done.
Treatment
Two different therapeutic strategies are available:
These strategies can be combined for more rapid remission. The treatment is monitored by determinations of serum ferritin (if iron reduction therapy is used) and urinary porphyrin excretion every other or every 3rd month until full remission.
Iron removal by therapeutic phlebotomy is usually effective. A unit of blood is removed every week or two. When serum ferritin falls slightly below normal, phlebotomy is stopped. Usually, 6 to10 sessions are needed. Urine and plasma porphyrins fall gradually with treatment, lagging behind but paralleling the fall in ferritin. The skin eventually becomes normal. After remission, further phlebotomy is needed only if there is a recurrence.
Low-dose chloroquine or hydroxychloroquine 100 to 125 mg orally twice a week removes excess porphyrins from the liver and perhaps other tissues by increasing the excretion rate. Higher doses can cause transient liver damage and worsening of porphyria. When remission is achieved, the regimen is stopped.
Chloroquine and hydroxychloroquine are not effective in advanced renal disease, and phlebotomy is usually contraindicated because of underlying anemia. However, recombinant erythropoietin mobilizes excess iron and resolves the anemia enough to permit phlebotomy. In end-stage renal disease, deferoxamine is an adjunct to phlebotomy for reduction of hepatic iron, the complexed iron being removed during dialysis. Dialyzers with ultrapermeable membranes and extra high blood flow rates are needed.
Patients with overt PCT and hepatitis C infection should be evaluated for treatment with direct-acting antiviral drugs. Previous iron depletion augments the response to antiviral therapy.
Children with symptomatic PCT are treated with small-volume phlebotomies or oral chloroquine; dosage is determined by body weight.
Skin symptoms occurring during pregnancy are treated with phlebotomy. In refractory cases, low-dose chloroquine can be added; no teratogenic effects have been recognized. Depending on degree of hemodilution and iron depletion, the skin symptoms usually abate as pregnancy advances.
Postmenopausal estrogen supplementation is interrupted during treatment for PCT. Stopping estrogens often induces remission. Substituting systemic with transdermal estrogens is sometimes done if postmenopausal symptoms are troublesome, but there may still be some risk due to systemic absorption.
Prevention
Patients should avoid sun exposure; hats and clothing protect best, as do zinc or titanium oxide sunscreens. Typical sunscreens that block UV light are ineffective, but UVA-absorbing sunscreens, such as those containing dibenzylmethanes, may help somewhat. Alcohol ingestion should be avoided permanently, but estrogen supplementation can usually be resumed safely after a disease remission.
Key Points
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Porphyria cutanea tarda (PCT) is usually acquired but may be hereditary.
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Triggers include elevated hepatic iron, alcohol use, halogenated hydrocarbon exposure, and hepatitis C virus or HIV infection.
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Drugs that commonly trigger acute porphyria do not trigger PCT.
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Measure urinary uroporphyrin and heptacarboxyl porphyrin, and fecal isocoproporphyrin.
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Test for iron overload with serum iron and ferritin levels and total iron-binding capacity.
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Reduce elevated iron stores by phlebotomy.
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Remove excess porphyrins by giving low-dose chloroquine or hydroxychloroquine.
More Information
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
hydroxychloroquine |
PLAQUENIL |
deferoxamine |
DESFERAL |
chloroquine |
ARALEN |
furosemide |
LASIX |
estrogens |
Estrogens |
naproxen |
ALEVE, NAPROSYN |
