PCT is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for the development of the disorder. These factors are not necessarily the same for each individual. These factors contribute either directly or indirectly to decreased levels or ineffectiveness of an enzyme known as uroporphyrinogen decarboxylase (UROD) within the liver. When UROD levels in the liver decrease to approximately 20% of normal levels, the symptoms of PCT may develop.
The UROD enzyme is essential for breaking down (metabolizing) certain chemicals in the body known as porphyrins. Low levels of functional UROD result in the abnormal accumulation of specific porphyrins in body, especially within the blood, liver and skin. The symptoms of PCT occur because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in the skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin found in individuals with PCT. The liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in the liver, they can cause toxic damage to the liver.
The exact, underlying mechanisms that cause PCT are complex and varied. It is determined that iron accumulation within the liver plays a central role in the development of the disorder in most individuals. Recently, researchers have discovered that a substance called uroporphomethene, which is an oxidized form of a specific porphyrin known as uroporphyrinogen, is an inhibitor that reduces the activity of the UROD enzyme in the liver. The oxidation of uroporphyrinogen into uroporphomethene has been shown to be iron dependent, emphasizing the importance or elevated iron levels in the development of PCT.
The relationship between iron levels and PCT has long been established and PCT is classified as an iron-dependent disease. Clinical symptoms often correlate with abnormally elevated levels of iron in the liver (iron overloading). Iron overloading in the liver may only be mild or moderate. The exact relationship between iron accumulation and PCT is not fully understood, however, as there is no specific level of iron in the liver that correlates to disease in PCT (e.g. some individuals with symptomatic PCT have normal iron levels).
There is an increased prevalence of mutations in the HFE gene in individuals with PCT. Mutations in the HFE gene can cause hemochromatosis, a disorder characterized by the accumulation of iron in the body, especially the liver. Hemochromatosis occurs when a person inherited two mutated HFE genes (one from each parent). Hemochromatosis is associated with low levels of hepcidin, a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract and liver.
Additional risk factors that have been associated with PCT include alcohol, certain infections such as hepatitis C or HIV, and drugs such as estrogens. Some studies have indicated that smoking is a risk factor for PCT in susceptible individuals. Less often, certain chemical exposures (e.g. hexachlorobenzene), kidney dialysis, and lupus appear to be connected to the development of PCT. It is believed that these susceptibility factors reduce hepcidin in the body and consequently lead to iron accumulation in the liver. However, the exact relationship among most susceptibility factors with the development of symptoms in PCT is not fully understood. For example, alcohol clearly contributes to the development of the disorder in some cases, but PCT is not common in alcoholics. Most individuals with PCT have three or more susceptibility factors present.
In some cases, individuals develop PCT without a known susceptibility factor, suggesting that additional, as yet unidentified risk factors exist.
The underlying cause of UROD deficiency in the acquired form of PCT is unknown. Affected individuals have approximately 50% residual UROD activity and do not develop symptoms unless additional factors are present. The most common factors associated with acquired PCT are hemochromatosis or chronic hepatitis C infection. In individuals with acquired PCT, UROD levels are only deficient in the liver.
In the familial form of PCT, individuals have a mutation in the UROD gene. This mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new (de novo) mutation in the affected individual with no family history. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
The UROD gene creates (encodes) the UROD enzyme, which is the fifth enzyme in the heme synthesis pathway. A mutation in one of these genes leads to abnormally low levels of this enzyme in all tissues of the body (not just the liver). However, one mutation alone is insufficient to cause familial PCT as residual UROD enzyme levels remain above 20% of normal. In fact, most individuals with a mutation in the UROD gene do not develop the disorder. Additional factors must be present for the disorder to develop.