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Porphyria Cutanea Tarda
Porphyria cutanea tarda (PCT) is a comparatively common hepatic porphyria affecting mainly the skin. Liver disease is also common. PCT is due to an acquired or inherited deficiency in the activity of hepatic uroporphyrinogen decarboxylase, an enzyme in the heme biosynthetic pathway (see Table: Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency). Porphyrins accumulate, particularly when there is increased oxidative stress in the hepatocytes, which is usually due to increased hepatic iron, but which may also be due to alcohol, smoking, estrogens, or hepatitis C or HIV infection. Symptoms include fragile, easily blistered skin, mainly on sun-exposed areas. Diagnosis is by porphyrin analysis of urine and stool. Differentiation from the acute, cutaneous porphyrias hereditary coproporphyria and variegate porphyria is important. Treatment includes iron depletion by phlebotomy and enhancing porphyrin excretion by treatment with low dose chloroquine or hydroxychloroquine. Prevention is by avoidance of sunlight, alcohol, smoking, estrogens, and iron-containing drugs and successful treatment of any concomitant hepatitis C and HIV infections.
For porphyria etiology and pathophysiology, see Overview of Porphyrias.
PCT results from hepatic deficiency of uroporphyrinogen decarboxylase (UROD—see Table: Substrates and Enzymes of the Heme Biosynthetic Pathway and the Diseases Associated With Their Deficiency). Porphyrins accumulate in the liver and are transported to the skin, where they cause photosensitivity. The partial (~50%) deficiency in UROD activity in heterozygous patients itself is not sufficient to cause biochemical or clinical features of PCT; additional factors (eg, elevated hepatic iron, alcohol use, halogenated hydrocarbon exposure, hepatitis C virus or HIV infection) are required to cause the > 75% decrease in hepatic UROD activity needed for features of PCT to manifest. These factors increase the oxidation of uroporphyrinogens and other porphyrinogens to the corresponding porphyrins and also help form inhibitors of UROD. 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 PCT: type 1 (acquired or sporadic) and type 2 (hereditary or familial). Type 1 accounts for 75-80% of cases and type 2 for 20-25%. Type 3 accounts for < 1% of cases.
In type 1 PCT, decarboxylase deficiency is restricted to the liver and no genetic predisposition is present. It usually manifests in middle age or later.
In type 2 PCT, decarboxylase deficiency is inherited in an autosomal dominant fashion with limited penetrance. Deficiency occurs in all cells, including RBCs. 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 (eg, elevated hepatic iron, alcohol use, halogenated hydrocarbon exposure, hepatitis C virus or HIV infection) are required to cause the > 75% decrease in hepatic UROD activity needed for features of PCT to manifest. 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.
Types 1 and 2 are the major forms of the disease. 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.
Renal failure, 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 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.
Patients with PCT present with fragile skin, mainly on sun-exposed areas. Phototoxicity is delayed: patients do not always connect sun exposure with symptoms.
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.
In otherwise healthy patients, fragile skin and blister formation suggest PCT. 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 δ-aminolevulinic acid may be slightly increased (< 3 times the upper limit of normal). RBC 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.
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 po twice/wk 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 pegylated interferon alfa-2a, ribavirin, and an antiviral drug (telaprevir, boceprevir). 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.
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.
PCT is usually acquired but may be hereditary.
Triggers include elevated hepatic iron, alcohol use, halogenated hydrocarbon exposure, and hepatitis C virus or HIV infection.
Drugs that commonly trigger acute porphyria do not trigger PCT.
Measure urinary uroporphyrin and heptacarboxyl porphyrin, and fecal isocoproporphyrin.
Test for iron overload with serum iron and ferritin levels and total iron-binding capacity.
Reduce elevated iron stores by phlebotomy.
Remove excess porphyrins by giving low-dose chloroquine or hydroxychloroquine.
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