PCT

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 which 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, because removal of only 5-6 pints of blood is needed for successful treatment in most cases. 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 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.