Porphyria Cutanea Tarda (PCT) is the most common and also the most readily treated form of Porphyria. Blisters and crusting of sun-exposed areas of skin are the most prominent features. PCT is caused by a deficiency of the enzyme uroporphyrinogen decarboxylase (UROD) in the liver. UROD is the fifth in the series of eight enzymes that are responsible for the synthesis of heme. PCT is somewhat more common in men than it is in women. It usually develops in middle age, hence, the name tarda which is Latin for late.
Causes of PCT
How a deficiency of UROD develops in the liver is not completely understood. Most of the time, this reduced level of activity of UROD is nevertheless sufficient to carry out heme synthesis normally. However, at other times, the activity is insufficient and results in a decreased synthesis of heme and an accumulation of the products of the early part of the heme biosynthetic pathway, which is still working normally. When this happens, porphyrins accumulate in the site of synthesis, which is mainly the liver, and spill out into the blood, from where they may be either excreted into the urine, or deposited in various tissues around the body. When these porphyrins are deposited in the skin, they can absorb light. Other porphyrins (for example, chlorophyll, which is a heme-like molecule containing magnesium) are able to absorb light and store the energy in the form of carbohydrates, but the porphyrins that accumulate in PCT are unable to store the energy of the light. This energy is released into the skin in photochemical reactions that cause damage to the skin. Persistent exposure to light thus leads to skin damage, blistering, and scarring. Most of the known causative factors (listed below) are acquired and, therefore, can be avoided or treated. Not all of these factors are present in every patient with PCT.
Approximately 20% of PCT patients have an inherited (autosomal dominant) deficiency of UROD and are said to have familial (Type II) PCT. More than one case may occur in the same family (Type II). At birth UROD is approximately 50% normal in all tissues in these patients. However one or more of the additional causative factors listed below are important in these patients. Type II PCT becomes manifest when the enzyme activity in liver becomes much less than 50% of normal, due to one or more of these additional factors. Patients with familial PCT respond to the same treatments as those who do not have an inherited enzyme deficiency.
Iron has a central role in causing PCT. Liver iron is often increased in PCT. Removal of iron from the body always leads to a remission. Most PCT patients do not have a great excess of iron, and in most cases, removal of only 5-6 pints of blood is needed for successful treatment. A serum ferritin measurement is often used to assess the degree of excess iron. The ferritin is usually normal to moderately increased. Marked increases in ferritin suggest that the patient has an iron overload condition called hemochromatosis, in addition to PCT. Because iron overload contributes to PCT and hemochromatosis is one of the most common genetic diseases (occurring in about 1 of 200 people in the population), it is not surprising that some patients have both conditions.
Excess alcohol intake is very common in PCT. How iron and alcohol lead to UROD deficiency in the liver is not known, but both can generate reactive and damaging forms of oxygen within liver cells.
Hepatitis C is common in PCT. In some areas where this viral infection is quite prevalent, especially in southern Europe and some parts of the U.S., as many as 80% of PCT patients are infected with this virus. How this particular virus contributes to developing PCT is not known. Other hepatitis viruses are seldom implicated.
Estrogens are contributing factors, especially in women. PCT develops in some women taking estrogen-containing oral contraceptive pills and in older women taking estrogens after menopause. Men have developed PCT after being treated with estrogens (for example, for cancer of the prostate). Other types of hormones do not appear to be important in causing PCT.
Other factors are important in some patients. High iron levels are known to inhibit the activity of UROD. Therefore, unusual diets which are very rich in iron, or iron supplementation of the diet with tablets, are contraindicated in PCT. Barbiturates and other drugs that increase porphyrin synthesis in the liver commonly exacerbate Acute Intermittent Porphyria, but are less important in PCT. Human immunodeficiency virus (HIV), the virus that causes AIDS, can be associated with PCT, but much less often than Hepatitis C. Industrial chemicals such as dioxin and hexachlorobenzene are sometimes implicated. Deficiencies in vitamin C and other nutrients may also contribute.
When UROD does become markedly deficient in the liver, porphyrins accumulate and spill out into the blood. They are then transported to other tissues such as the skin and are excreted in urine and feces. Porphyrins in the skin absorb light and release this absorbed energy in a manner that leads to generation of reactive forms of oxygen that damage the skin. Therefore, exposure to light leads to skin fragility, blistering and scarring.
The most common symptoms of PCT are fragility and blistering of light-exposed areas of the skin—especially the backs of the hands, the lower arms and the face. Patients often report that their skin is unusually fragile, so small bumps or knocks can scrape away the upper layer of the skin or cause a blister. The blisters contain fluid, rupture easily, crust over and then heal slowly. Skin infections, scarring and changes in coloration may result. Small white spots called "milia" are commonly found on the hands and fingers.
Another feature which is often seen is excessive growth of facial hair. The reason for this is not at present understood, but once the disease is under control, the hair can usually be easily and effectively removed by conventional methods. Some patients develop severe scarring and thickening of the skin, which is referred to as "pseudoscleroderma".
PCT is accompanied by some degree of liver damage. This is often mild or moderate. But over time there is a risk of developing cirrhosis and even liver cancer. Liver damage in PCT may be due in part to the excess porphyrins, which accumulate in very large amounts particularly in the liver. But other factors, such as alcohol, Hepatitis C and excess iron, can be important causes of liver damage.
Neurological symptoms, which are common in acute porphyrias, such as pain in the abdomen and extremities, are not features of PCT.
The best screening test when PCT is suspected may be a plasma total porphyrin measurement. A normal result excludes active PCT. This test will also detect any other type of Porphyria that is causing skin problems. Further testing is then needed to establish the type of Porphyria. Urine porphyrins are commonly measured for screening for PCT and other porphyrias. But it must be remembered that increases in urinary porphyrins can occur in medical conditions other than Porphyria, especially in conditions that affect the liver and bone marrow.
The excess porphyrins in plasma and urine in PCT are mostly uroporphyrin (octacarboxylporphyrin) and heptacarboxylporphyrin. These porphyrins have 8 and 7 carboxyl groups respectively on the porphyrin molecule. Coproporphyrin (tetracarboxylporphyrin - with 4 carboxyl groups) is also increased in urine, but this is not a finding that is specific for PCT or even for Porphyria. Fecal total porphyrins are usually only slightly increased, but a predominance of isocoproporphyrins, which are measured only in some specialty laboratories, is very specific for PCT.
UROD can be measured in red blood cells to establish whether or not a patient has inherited a deficiency of the enzyme. This is not essential in all cases, because the treatment of patients with familial PCT is not fundamentally different from that for those who do not have an inherited enzyme deficiency.
Some patients with "pseudoporphyria" have skin lesions that are essentially identical to those in PCT. PCT is most readily ruled out in these patients by finding normal levels of porphyrins in plasma. A photosensitizing drug is found to cause the sensitivity to light in some of these individuals.
It is important to discontinue use of alcohol and, if possible, other contributing factors such as estrogens. Resumption of heavy alcohol intake is likely to lead to recurrence. However, in postmenopausal women who have been treated for PCT, there is seldom a recurrence when estrogens are restarted.
The most widely preferred treatment is repeated phlebotomy (venesection). The objective of the treatment is to decrease the amount of iron in the body to the lower limit of normal. Red blood cells contain large amounts of iron (in hemoglobin). When red blood cells are removed from the body, new cells and hemoglobin are made by the bone marrow. With repeated phlebotomy, the body's iron stores are gradually depleted. This process also removes iron from the liver, and the activity of the UROD is gradually restored. A pint of blood is removed every 1-2 weeks until the ferritin reaches the lower limit of normal.
The course of treatment is best followed by measuring the serum ferritin and plasma or serum porphyrin levels. Blood hematocrit or hemoglobin is also measured to avoid developing significant anemia. The plasma porphyrin levels also then gradually decrease, and the development of new skin lesions stops. Healing of damaged skin occurs more gradually. After the plasma porphyrin levels become normal, the patient is able to tolerate sunlight.
Low-dose chloroquine is a suitable alternative treatment, especially in patients who cannot tolerate phlebotomies. Chloroquine mobilizes excess porphyrins from the liver. Normal doses of chloroquine (as used for treating malaria or rheumatoid arthritis) can markedly worsen PCT and also cause liver damage before inducing a remission of PCT. If very small doses are used for treating PCT, these adverse effects are usually avoided. Only 125mg of chloroquine or 100mg of hydroxychloroquine should be given to patients twice weekly. Because tablets this small are not manufactured, the tablets must be cut by the patient or a pharmacist. Chloroquine and hydroxychloroquine rarely damage the retina of the eye.
PCT may be unusually severe in patients with advanced kidney diseases. Erythropoietin and phlebotomy, but not low-dose chloroquine, can be effective in these cases.
Treatment of Hepatitis C with interferon alpha and ribavirin is available but is often not effective. Patients with PCT and Hepatitis C should usually first undergo treatment of PCT. Treatment of Hepatitis C can be considered later. There is some evidence that iron depletion may improve the results of treatment of Hepatitis C.
The treatment of PCT is almost always successful, and the prognosis is usually excellent. The condition is not progressive and is seldom disabling. After treatment, periodic measurement of plasma porphyrins may be advised, especially if a contributing factor such as estrogen exposure is resumed. If there is a recurrence, it can be detected early and retreated promptly.