Porphyria cutanea tarda | |
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Other names | PCT |
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Blister on the hand of a person with porphyria cutanea tarda | |
Specialty | Endocrinology ![]() |
Porphyria cutanea tarda is the most common subtype of porphyria. [1] The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.
Hepatoerythropoietic porphyria has been described as a homozygous form of porphyria cutanea tarda, [2] although it can also be caused if two different mutations occur at the same locus.
Porphyria cutanea tarda (PCT) is recognized as the most prevalent subtype of porphyritic diseases. [3]
PCT is characterized by onycholysis and blistering of the skin in areas that receive higher levels of exposure to sunlight. The primary cause is a deficiency of uroporphyrinogen decarboxylase (UROD), a cytosolic enzyme that is a step in the enzymatic pathway that leads to the synthesis of heme. Behind the direct cause there are a number of genetic and environmental risk factors. [4]
Patients who are diagnosed with PCT typically seek treatment following the development of photosensitivities causing blisters and erosions on exposed areas of the skin. This is usually observed in the face, hands, forearms, and lower legs. Healing is slow and leaves scarring. Though blisters are the most common skin manifestations of PCT, other skin manifestations include hyperpigmentation (similar to a tan) and hypertrichosis (mainly on the cheeks) also occur. PCT is a chronic condition, with external symptoms often subsiding and recurring as a result of multiple factors. In addition to the skin lesions, chronic liver disease is very common in patients with sporadic PCT. This involves hepatic fibrosis (scarring of the liver), and inflammation. However, liver problems are less common in patients with the inherited form of the disease. [5] Additionally, patients will often void a wine-red color urine with an increased concentration of uroporphyrin I due to their enzymatic deficiency. [6]
Certain vitamin and minerals deficiencies are common in people with porphyria cutanea tarda. The most common deficiencies are beta-Carotene, [7] retinol, [8] vitamin A [9] and vitamin C. Beta-Carotene is required to synthesize vitamin A and vitamin A is needed to synthesize retinol. A lack of retinol-binding protein is due to a lack of retinol which is required to trigger its production. [9]
Porphyrins interact with iron, absorbing photons to create reactive oxygen species is the mechanism of action causing the itchy, painful blisters of PCT. [7] The reactive oxygen species consume the skin antioxidants beta-carotene, vitamin E, and vitamin C. Supplementation of these three vitamins reduces the oxidation and potentially diminishes the severity of blister formation. [10] No single one of the three vitamins can inhibit the damaging effects of oxidized porphyrins, specifically uroporphyrins and coproporphyrins, but all three working together synergistically are capable of neutralizing their damaging effects.[ citation needed ]
Inherited mutations in the UROD gene cause about 20% of cases (the other 80% of cases do not have mutations in UROD, and are classified as sporadic). UROD makes an enzyme called uroporphyrinogen III decarboxylase, which is critical to the chemical process that leads to heme production. The activity of this enzyme is usually reduced by 50% in all tissues in people with the inherited form of the condition.[ citation needed ]
Nongenetic factors such as excess iron or partially genetic factors such as alcohol use disorder and others listed above can increase the demand for heme and the enzymes required to make heme. The combination of this increased demand and reduced activity of uroporphyrinogen decarboxylase disrupts heme production and allows byproducts of the process to accumulate in the body, triggering the signs and symptoms of porphyria cutanea tarda.[ citation needed ]
The HFE gene makes a protein that helps cells regulate the absorption of iron from the digestive tract and into the cells of the body. Certain mutations in the HFE gene cause hemochromatosis (an iron overload disorder). People who have these mutations are also at an increased risk of developing porphyria cutanea tarda.[ citation needed ]
In the 20% of cases where porphyria cutanea tarda is inherited, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to decrease enzyme activity and cause the signs and symptoms of the disorder.[ citation needed ]
While inherited deficiencies in uroporphyrinogen decarboxylase often lead to the development of PCT, there are a number of risk factors that can both cause and exacerbate the symptoms of this disease. One of the most common risk factors observed is infection with the Hepatitis C virus. [11] One review of a collection of PCT studies noted Hepatitis C infection in 50% of documented cases of PCT. Additional risk factors include alcohol use disorder, excess iron (from iron supplements as well as cooking on cast iron skillets), and exposure to chlorinated cyclic hydrocarbons and Agent Orange.[ citation needed ]
It can be a paraneoplastic phenomenon. [12]
Porphyria cutanea tarda is primarily caused by uroporphyrinogen decarboxylase deficiency (UROD). Uroporphyrinogen decarboxylase occurs in nature as a homodimer of two subunits. It participates in the fifth step in heme synthesis pathway, and is active in the cytosol. This enzymatic conversion results in coproporphyrinogen III as the primary product. This is accomplished by the clockwise removal of the four carboxyl groups present in the cyclic uroporphyrinogen III molecule. Therefore, a deficiency in this enzyme causes the aforementioned buildup of uroporphyrinogen and hepta-carboxylic porphyrinogen, and to a lesser extent hexa-carboxylic porphyrinogen, and penta-carboxylic porphyrinogen in the urine, which can be helpful in the diagnosis of this disorder. [16] [17]
The dermatological symptoms of PCT that include blistering and lesions on sun-exposed areas of the skin are caused by a buildup of porphyrin compounds (specifically uroporphyrinogen) close to the surface of the skin that have been oxidized by free radicals or sunlight. [18] The oxidized porphyrins initiate degranulation of dermal mast cells, [19] which release proteases that catabolize the surrounding proteins. [20] This begins a cell-mediated positive feedback loop which matches the description of a type 4 delayed hypersensitivity reaction.[ citation needed ] The resulting blisters, therefore, do not appear immediately but begin to show up 2–3 days after sun exposure. Due to the highly conjugated structure of porphyrins involving alternating single and double carbon bonds, these compounds exhibit a deep purple color, resulting in the discoloration observed in the skin. Excess alcohol intake decreases hepcidin production which leads to increased iron absorption from the gut and an increase in oxidative stress. This oxidative stress then leads to inhibition of uroporphyrinogen decarboxylase, creating an excess of uroporphyrinogen III which is oxidized from the relatively harmless porphyrinogens into their oxidized porphyrins form. [21] Concentrated instances of oxidative stress (alcohol, physical trauma, psychological stress, etc.) cause the liver to hemorrhage these porphyrins into the blood stream where they are then susceptible to oxidation.[ citation needed ]
The strong association of PCT with Hepatitis C virus infection is not entirely understood. Studies have suggested that the cytopathic effect of the virus on hepatocytes can lead to the release of free iron. This iron can disrupt the activity of cytochrome p450, releasing activated oxygen species. These can oxidize the UROD substrate uroporphyrinogen, which can result in the inhibition of UROD and lead to deficient activity of this key enzyme. [22]
Excess alcohol use is frequently associated with both inducing PCT [23] and aggravating a preexisting diagnosis of the disorder. It is thought to do so by causing oxidative damage to liver cells, resulting in oxidized species of uroporphyrinogen that inhibit the activity of hepatic UROD. It is also felt to increase the uptake of iron in liver cells, leading to further oxidation of uroporphyrinogen by the release of activated oxygen species. Additionally, exposure to chlorinated cyclic hydrocarbons can lead to a deficiency in the activity of uroporphyrinogen decarboxylase, causing the buildup of excess uroporphyrinogen. Additionally, alcohol has been shown to increase the activity of the delta-aminolevulinic acid synthetase (ALA synthetase), the rate-limiting enzymatic step in heme synthesis in the mitochondria, in rats. [24] Therefore, alcohol consumption may increase the production of uroporphyrinogen, exacerbating symptoms in individuals with porphyria cutanea tarda.[ citation needed ]
While the most common symptom of PCT is the appearance of skin lesions and blistering, their appearance is not conclusive. Laboratory testing commonly reveals high levels of uroporphyrinogen in the urine, clinically referred to as uroporphyrinogenuria. Additionally, testing for common risk factors such as hepatitis C and hemochromatosis is strongly suggested, as their high prevalence in patients with PCT may require additional treatment. If clinical appearance of PCT is present, but laboratories are negative, the diagnosis of pseudoporphyria should be seriously considered.[ citation needed ]
Some sources divide PCT into two types: sporadic and familial. [2] Other sources include a third type, [25] but this is less common.
Type | OMIM | Description |
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Type I ("sporadic") | 176090 | Type I porphyria cutanea tarda, the sporadic form, is indicated by UROD deficiency that is observed only in hepatic cells and nowhere else in the body. Genetically, these individuals will not exhibit deficiency in the UROD gene, although other genetic factors such as HFE deficiency (resulting in hemochromatosis and the buildup of iron in the liver) are thought to play a key role. Typically in these individuals, a variety of risk factors such as alcohol use disorder and Hepatitis C virus infection co-occur to result in the clinical manifestation of PCT. |
Type II ("familial") | 176100 | Patients exhibiting Type II PCT have a specific deficiency in the UROD gene, passed down in an autosomal dominant pattern. Those possessing this deficiency are heterozygous for the UROD gene. They do not show a complete lack of functional uroporphyrinogen decarboxylase, only a deficient form of the enzyme that is marked by reduced conversion of uroporphyrinogen to coproporphyrinogen. Therefore, the expression of uroporphyrinogen decarboxylase will be reduced throughout the body of these individuals, while it is isolated to the liver in Type I patients. While this genetic deficiency is the main distinction between Type I and Type II PCT, the risk factors mentioned before are often seen in patients presenting with Type II PCT. In fact, many people who possess the deficient UROD gene often go their entire lives without having a clinical manifestation of PCT symptoms. |
Type III | - | The least common is Type III, which is no different from Type I insofar as the patients possess normal UROD genes. Despite this, Type III PCT is observed in more than one family member, indicating a genetic component unrelated to the expression of uroporphyrinogen decarboxylase. |
One study used 74% as the cutoff for UROD activity, with those patients under that number being classified as type II, and those above classified as type III if there was a family history, and type I if there was not. [26]
Genetic variants associated with hemochromatosis have been observed in PCT patients, [13] which may help explain inherited PCT not associated with UROD.
Since PCT is a chronic condition, a comprehensive management of the disease is the most effective means of treatment. Primarily, it is key that patients diagnosed with PCT avoid alcohol consumption, iron supplements, excess exposure to sunlight (especially in the summer), as well as estrogen and chlorinated cyclic hydrocarbons, all of which can potentially exacerbate the disorder. Additionally, the management of excess iron (due to the commonality of hemochromatosis in PCT patients) can be achieved through phlebotomy, whereby blood is systematically drained from the patient. A borderline iron deficiency has been found to have a protective effect by limiting heme synthesis. In the absence of iron, which is to be incorporated in the porphyrin formed in the last step of the synthesis, the mRNA of erythroid 5-aminolevulinate synthase (ALAS-2) is blocked by attachment of an iron-responsive element (IRE) binding cytosolic protein, and transcription of this key enzyme is inhibited. [27]
Low doses of antimalarials can be used. [28] Orally ingested chloroquine is completely absorbed in the gut and is preferentially concentrated in the liver, spleen, and kidneys. [29] They work by removing excess porphyrins from the liver via increasing the excretion rate by forming a coordination complex with the iron center of the porphyrin as well as an intramolecular hydrogen bond between a propionate side chain of the porphyrin and the protonated quinuclidine nitrogen atom of either alkaloid. [30] Due to the presence of the chlorine atom, the entire complex is more water-soluble allowing the kidneys to preferentially remove it from the blood stream and expel it through urination. [29] [31] [32] Chloroquine treatment can induce porphyria attacks within the first couple of months of treatment due to the mass mobilization of porphyrins from the liver into the blood stream. [29] Complete remission can be seen within 6–12 months as each dose of antimalarial can only remove a finite amount of porphyrins and there are generally decades of accumulation to be cleared. Originally, higher doses were used to treat the condition but are no longer recommended because of liver toxicity. [33] [34] Finally, due to the strong association between PCT and Hepatitis C, the treatment of Hepatitis C (if present) is vital to the effective treatment of PCT. Chloroquine, hydroxychloroquine, and venesection are typically employed in the management strategy. [35]
PCT prevalence is estimated at 1 in 10,000. [36] An estimated 80% of porphyria cutanea tarda cases are sporadic. The exact frequency is not clear because many people with the condition never experience symptoms and those that do are often misdiagnosed with anything ranging from idiopathic photodermatitis and seasonal allergies to hives.[ citation needed ]
Porphyria cutanea tarda is implicated in the origin of vampire myths.[ original research? ] This is because people with the disease tend to avoid the sun due to photosensitivity and may develop disfigurement that eats away their noses, eyelids, lips, and gums giving their teeth a fang-like appearance. It has also been suggested[ citation needed ] they may have developed a craving for healthy blood to replace their own in a self medicated treatment in prior centuries.
Some folklore scholars[ who? ] claim that this is a mistake, first suggested in the 1990s,[ citation needed ] because vampires of myth did not have photosensitivity, nor were they described as looking like the modern incarnation of vampires. They were described as unintelligent roaming beings who fed on their victims to the point that they became reddened and heavily bloated, fattened on blood. Fangs were very rarely mentioned. Photosensitivity was not added to the vampire mythology until the 1922 film Nosferatu. Count Dracula of Bram Stroker's novel could walk about freely in daylight unharmed but not as powerful in the book.[ citation needed ]
Porphyria cutanea tarda is the name of a song by the rock band AFI on their fourth album Black Sails in the Sunset , released on May 18, 1999. [37]
Porphyria cutanea tarda is the disease that both Dabney Pratt and Brother Rush suffer from in Virginia Hamilton's children's novel Sweet Whispers, Brother Rush.[ citation needed ]
Hereditary haemochromatosis type 1 is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no mechanism to regulate excess iron, simply losing a limited amount through various means like sweating or menstruating.
Porphyria is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration. Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. Complications may include paralysis, low blood sodium levels, and seizures. Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. If the skin is affected, blisters or itching may occur with sunlight exposure.
Heme, or haem, is a ring-shaped iron-containing molecular component of hemoglobin, which is necessary to bind oxygen in the bloodstream. It is composed of four pyrrole rings with 2 vinyl and 2 propionic acid side chains. Heme is biosynthesized in both the bone marrow and the liver.
Hereditary coproporphyria (HCP) is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the CPOX gene, and is inherited in an autosomal dominant fashion, although homozygous individuals have been identified. Unlike acute intermittent porphyria, individuals with HCP can present with cutaneous findings similar to those found in porphyria cutanea tarda in addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of acute porphyrias. Like other porphyrias, attacks of HCP can be induced by certain drugs, environmental stressors or diet changes. Biochemical and molecular testing can be used to narrow down the diagnosis of a porphyria and identify the specific genetic defect. Overall, porphyrias are rare diseases. The combined incidence for all forms of the disease has been estimated at 1:20,000. The exact incidence of HCP is difficult to determine, due to its reduced penetrance.
Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.
Erythropoietic protoporphyria is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. The severity varies significantly from individual to individual.
Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the Fenton reaction. Iron overload is often primary but may also be secondary to repeated blood transfusions. Iron deposition most commonly occurs in the liver, pancreas, skin, heart, and joints. People with iron overload classically present with the triad of liver cirrhosis, secondary diabetes mellitus, and bronze skin. However, due to earlier detection nowadays, symptoms are often limited to general chronic malaise, arthralgia, and hepatomegaly.
Aminolevulinic acid synthase (ALA synthase, ALAS, or delta-aminolevulinic acid synthase) is an enzyme (EC 2.3.1.37) that catalyzes the synthesis of δ-aminolevulinic acid (ALA) the first common precursor in the biosynthesis of all tetrapyrroles such as hemes, cobalamins and chlorophylls. The reaction is as follows:
Gunther disease is a congenital form of erythropoietic porphyria. The word porphyria originated from the Greek word porphura. Porphura actually means "purple pigment", which, in suggestion, the color that the body fluid changes when a person has Gunther's disease. It is a rare, autosomal recessive metabolic disorder affecting heme, caused by deficiency of the enzyme uroporphyrinogen cosynthetase. It is extremely rare, with a prevalence estimated at 1 in 1,000,000 or less. There have been times that prior to birth of a fetus, Gunther's disease has been shown to lead to anemia. In milder cases patients have not presented any symptoms until they have reached adulthood. In Gunther's disease, porphyrins are accumulated in the teeth and bones and an increased amount are seen in the plasma, bone marrow, feces, red blood cells, and urine.
Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the PPOX gene.
Uroporphyrinogen III decarboxylase is an enzyme that in humans is encoded by the UROD gene.
Uroporphyrinogen III synthase is an enzyme involved in the metabolism of the cyclic tetrapyrrole compound porphyrin. It is involved in the conversion of hydroxymethyl bilane into uroporphyrinogen III. This enzyme catalyses the inversion of the final pyrrole unit of the linear tetrapyrrole molecule, linking it to the first pyrrole unit, thereby generating a large macrocyclic structure, uroporphyrinogen III. The enzyme folds into two alpha/beta domains connected by a beta-ladder, the active site being located between the two domains.
Coproporphyrinogen III is a metabolic intermediate in the biosynthesis of many compounds that are critical for living organisms, such as hemoglobin and chlorophyll. It is a colorless solid.
Uroporphyrinogen III is a tetrapyrrole, the first macrocyclic intermediate in the biosynthesis of heme, chlorophyll, vitamin B12, and siroheme. It is a colorless compound, like other porphyrinogens.
Hepatoerythropoietic porphyria is a very rare form of hepatic porphyria caused by a disorder in both genes which code Uroporphyrinogen III decarboxylase (UROD).
Uroporphyrinogen I is an isomer of uroporphyrinogen III, a metabolic intermediate in the biosynthesis of heme. A type of porphyria is caused by production of uroporphyrinogen I instead of III.
Coproporphyrinogen I is an isomer of coproporphyrinogen III, a metabolic intermediate in the normal biosynthesis of heme. The compound is not normally produced by the human body; its production and accumulation causes a type of porphyria.
Juvenile hemochromatosis, also known as hemochromatosis type 2, is a rare form of hereditary hemochromatosis, which emerges in young individuals, typically between 15 and 30 years of age, but occasionally later. It is characterized by an inability to control how much iron is absorbed by the body, in turn leading to iron overload, where excess iron accumulates in many areas of the body and causes damage to the places it accumulates.
Pseudoporphyria is a bullous photosensitivity that clinically and histologically mimics porphyria cutanea tarda. The difference is that no abnormalities in urine or serum porphyrin is noted on laboratories. Pseudoporphyria has been reported in patients with chronic kidney failure treated with hemodialysis and in those with excessive exposure to ultraviolet A (UV-A) by tanning beds.
Aminolevulinic acid dehydratase deficiency porphyria is an extremely rare autosomal recessive metabolic disorder that results from inappropriately low levels of the enzyme delta-aminolevulinic acid dehydratase (ALAD), which is required for normal heme synthesis. This deficiency results in the accumulation of a toxic metabolic precursor in the heme synthesis pathway called aminolevulinic acid (ALA). Lead poisoning can also disrupt ALAD and result in elevated ALA causing the same symptoms. Heme is a component of hemoglobin which carries oxygen in red blood cells.