About urod deficiency

What is urod deficiency?

Porphyria cutanea tarda (PCT) is a type of porphyria in which affected individuals are sensitive to sunlight. Exposed skin shows abnormalities that range from slight fragility of the skin to persistent scarring and disfiguration. Due to fragility of the skin, minor trauma may induce blister formation. Areas of increased and decreased pigment content may be noted on the skin. Blistering of light exposed skin and increased hair growth are also characteristic.

PCT is caused by a deficiency of the uroporphyrinogen decarboxylase (URO-D) enzyme in the liver. The disorder can be acquired or can be caused by an inherited gene mutation in the UROD gene. The inherited form of PCT is also called familial PCT and follows autosomal dominant inheritance. Many individuals with a UROD gene mutation never experience symptoms of the disease.

PCT becomes active and causes symptoms when triggered by an environmental factor that affects liver cells (hepatocytes). These environmental factors include alcohol, estrogens, hepatitis C, and human immunodeficiency viruses (HIV). Individuals who have disorders that lead to excess iron in tissues such as hemochromatosis also have an increased risk of developing PCT. It is usually necessary for an environmental trigger to be present to cause symptoms of either the acquired or inherited type of PCT.

What are the symptoms for urod deficiency?

Blistering symptom was found in the urod deficiency condition

The symptoms of PCT can vary greatly from one individual to another. Skin abnormalities characterize this disorder. Affected individuals are abnormally susceptible to damage of the skin from sunlight (photosensitivity). Extremely Fragile skin that can peel or blister on minimal impact is common. Affected individuals may develop Blistering skin Lesions on areas of the skin that are frequently exposed to the sun such as the hands and face. These Lesions may crust over.

Eventually, scarring may develop and affected skin may darken (hyperpigmentation) or fade (hypopigmentation) in color. Abnormal, excessive hair growth (hypertrichosis), especially on the face may also occur. The hair may be very fine or coarse and can differ in color. In some patients, their hair may grow, thicken and darken. Small Bumps with a distinct white head (milia) may also develop, especially on the backs of the hands.

In some cases, the skin in affected areas may thickened and harden, resembling a condition known as sclerosis, this is sometimes known as pseudosclerosis. Pseudosclerosis in individuals with PCT appears as scattered, waxy, harden patches or Plaques of skin.

Liver abnormalities may develop in some affected individuals including the accumulation of iron in the liver (hepatic siderosis), the accumulation of fat in the liver (steatosis), Inflammation of certain parts of the liver (portal triaditis), and thickening and scarring around the portal vein (periportal fibrosis). Affected individuals may be at a greater risk than the general population of developing scarring of the liver (cirrhosis) or liver cancer known as hepatocellular carcinoma. Advanced liver disease is uncommon, except in older individuals with recurrent disease. In some cases, liver disease is due to an associated condition such as hepatitis C infection.

What are the causes for urod deficiency?

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.

What are the treatments for urod deficiency?

The treatment of PCT is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.

PCT is the most treatable form of porphyria and treatment appears equally effective for both the sporadic and familial forms. The standard treatment of individuals with PCT is regularly scheduled phlebotomies to reduce iron and porphyrin levels in the liver. This is the preferred treatment of affected individuals at many porphyria centers regardless of whether there is confirmed iron overload. A phlebotomy is a simple and safe procedure that involves removing blood via a vein (bloodletting). Since much of the iron in the body is present in red blood cells, regular phlebotomies can reduce excess iron levels in the body. Regularly scheduled phlebotomies usually results in complete remission in most individuals. A phlebotomy schedule is recommended to achieve a target ferritin level of less than 20 nanograms per milliliter.

What are the risk factors for urod deficiency?

PCT is a rare disorder that affects males and females. The disorder usually develops after the age of 30 and its onset in childhood is rare. PCT is found worldwide and in individuals of all races. The prevalence is estimated to be approximately 1 in 10,000 to 25,000 individuals in the general population. PCT is the most common form of porphyria.

Is there a cure/medications for urod deficiency?

UROD deficiency means a Lack of the enzyme uroporphyrinogen decarboxylase (UROD), which is a basic cause of porphyria cutanea tarda (PCT).

  • This is a type of porphyria in which affected individuals are sensitive to sunlight. PCT is caused by a deficiency of UROD enzymes in the liver.
  • There are three types of PCT that can be classified as type-1, type-2, and type-3.
  • To cure these conditions, sunlight avoidance should be necessary for porphyrin levels to normalize.
  • For this, titanium dioxide or zinc oxide containing sunscreen is effective. Effective clothing should also be necessary and affected skin areas should be kept clean to avoid skin infections, and associated pain can be managed with oral analgesics.
  • Also, avoidance of alcohol, smoking, and estrogen therapy, along with limiting any excess intake of iron, should do.
  • The main therapies are Phlebotomy, Hydroxychloroquine or chloroquine, and Chelation for treatments.

Extremely fragile skin that can peel or blister on minimal impact,Blistering skin lesions on areas of the skin that are frequently exposed to the sun,Scarring may develop and affected skin may darken,Abnormal, excessive hair growth, especially on the face may also occur,Small bumps with a distinct white head may also develop, especially on the backs of the hands,Liver abnormalities may develop in some affected individuals including the accumulation of iron in the liver
Hyperpigmentation,Hypopigmentation,Hypertrichosistions,Photosensitivity,Milia,Slerosis,Hepatic siderosis
Phlebotomy,Low doses of chloroquine and hydroxychloroquine, to reduce iron levels in the liver

Video related to urod deficiency