(See also Overview of Porphyrias Overview of Porphyrias Porphyrias are rare disorders in which hemoglobin is abnormally metabolized due to genetic or acquired deficiencies of enzymes of the heme biosynthetic pathway. These deficiencies allow heme... read more and Overview of Cutaneous Porphyrias Overview of Cutaneous Porphyrias Cutaneous porphyrias result from deficiency (and in one case, excess) of certain enzymes in the heme biosynthetic pathway (see table Substrates and Enzymes of the Heme Biosynthetic Pathway)... read more .)
Pathophysiology of Porphyria Cutanea Tarda
Porphyria cutanea tarda (PCT) results from hepatic deficiency of uroporphyrinogen decarboxylase (UROD—see table Substrates and Enzymes of the Heme Biosynthetic Pathway 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.
Liver disease is common in PCT and may be due partly to porphyrin accumulation, chronic hepatitis C infection Hepatitis C, Chronic Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more , concomitant hemosiderosis Hemosiderosis Hemosiderosis is focal deposition of iron that does not typically cause tissue damage. (See also Overview of Iron Overload.) Focal hemosiderosis can result from hemorrhage within an organ. Iron... read more , or excess alcohol ingestion. Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more occurs in ≤ 35% of patients, and hepatocellular carcinoma Hepatocellular Carcinoma Hepatocellular carcinoma usually occurs in patients with cirrhosis and is common in areas where infection with hepatitis B and C viruses is prevalent. Symptoms and signs are usually nonspecific... read more occurs in 7 to 24% (more common among middle-aged men).
There are two main types of porphyria cutanea tarda:
Type 1: Acquired or sporadic (75 to 80% of cases)
Type 2: Hereditary or familial (20 to 25% of cases)
There is also a rare type 3, which accounts for < 1% of cases.
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 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 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.
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 of Porphyria Cutanea Tarda
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.
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 of Porphyria Cutanea Tarda
Elevated levels of plasma porphyrins, urinary uroporphyrin and heptacarboxyl porphyrin, and fecal isocoproporphyrin
In otherwise healthy patients, fragile skin and blister formation suggest porphyria cutanea tarda. Differentiation from acute porphyrias with cutaneous symptoms Acute Porphyrias Acute porphyrias result from deficiency of certain enzymes in the heme biosynthetic pathway, resulting in accumulation of heme precursors that cause intermittent attacks of abdominal pain and... read more (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 Hepatitis C, Chronic Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more and HIV Human Immunodeficiency Virus (HIV) Infection Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more 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, HFE gene mutation testing for hereditary hemochromatosis Hereditary Hemochromatosis Hereditary hemochromatosis is a genetic disorder characterized by excessive iron (Fe) accumulation that results in tissue damage. Manifestations can include systemic symptoms, liver disorders... read more should be done.
Treatment of Porphyria Cutanea Tarda
Three different therapeutic strategies are available:
Reduction of body iron stores
Increase in porphyrin excretion
Treatment of chronic hepatitis C, when present
These strategies can be combined for more rapid remission, although combining them is not usually necessary. 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 Treatment Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more . Previous iron depletion augments the response to interferon-based antiviral therapy, but such depletion seems unimportant in the current era of highly effective direct-acting antiviral drugs. Preliminary data have reported remission of PCT skin lesions following antiviral treatment, but documentation of complete reversal of the metabolic defects and long-term improvement is lacking. Nevertheless, it now seems worth first treating and curing hepatitis C virus infection before deciding on iron reduction or hydroxychloroquine therapy in such patients (1 Treatment reference 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... read more ).
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 of Porphyria Cutanea Tarda
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, and smoking should be stopped. Estrogen supplementation, especially administered transdermally in low doses, can usually be resumed safely after a disease remission.
Porphyria cutanea tarda (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.
Test patients who have elevated serum ferritin or transferrin saturation for HFE gene mutations.
Reduce elevated iron stores by phlebotomy.
Remove excess porphyrins by giving low-dose chloroquine or hydroxychloroquine.
Treat patients with hepatitis C with direct-acting antiviral drugs.
The following are some English-language resources that may be useful. Please note that The Manual is not responsible for the content of these resources.
American Porphyria Foundation: Aims to educate and support patients and families affected by porphyrias and to support research into treatment and prevention of porphyrias
American Porphyria Foundation: Safe/Unsafe Drug Database: Provides an up-to-date list of drugs available in the United States to assist physicians in prescribing for patients with porphyrias
European Porphyria Network: Promotes clinical research about porphyrias
The Drug Database for Acute Porphyrias: Provides an up-to-date list of drugs available in Europe to assist physicians in prescribing for patients with porphyrias
Drugs Mentioned In This Article
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