Erythropoietic protoporphyria
Encyclopedia
Erythropoietic protoporphyria (EPP) is a relatively mild form of porphyria
, although very painful, which arises from a deficiency in the enzyme ferrochelatase
, leading to abnormally high levels of protoporphyrin in the tissue. The severity varies significantly from individual to individual.
Both autosomal dominant and autosomal recessive
inheritance
have been reported with this disorder.
, manifesting itself as a burning and itching sensation on the surface of the skin. At times the itching sensations are almost unbearable. Rubbing the affected areas with ice can be the only relief, and that is only temporary. The usual anti-itch remedies, including cortisone anti-histamine topical preparations, and Calomine lotion generally provide little or no relief. If a patient presents with a history of anti-itch preparation inefficacy, EPP should be considered.
EPP usually first presents in childhood, and most often affects the face and the upper surfaces of the arms, hands, and feet and the exposed surfaces of the legs. Most patients, if the EPP is not as severe, manifest symptoms with onset of puberty when the male and female hormone levels elevate during sexual development and maintenance. More severe EPP can manifest in infancy. Exposure to even indoor light sources can cause the rash, and the infant, if clothed only in a diaper, will break out everywhere except under the diaper. EPP can be triggered through exposure to sun even though the patient is behind glass. Even the UV emissions from arc welding with the use of full protective mask have been known to trigger EPP.
Prolonged exposure to the sun can lead to edema and blistering. At times the immediate damage can be so severe that the individual can lose the skin in sheets. After many years, chronically sun-exposed skin may become thick and wrinkled if no beta carotene and other carotenoids and no lutein and other xanthophylls are ingested.
Another aspect of the painfulness of EPP is the painful abdomen, which may manifest as generalized pain, or may imitate an appendicitis. Some healthy appendices have been removed due to this mimic. Since porphyria is not that common, most doctors don't even think to do blood porphyrin levels when symptoms present. For doctors that are familiar with porphyria, it is generally considered insignificant and irrelevant compared to the possibility of a pending burst appendix, especially since porphyrin levels cannot be generally be received back immediately due to lab protocols.
Moderate and severe cases can present with pelvic and shoulder girdle muscle weakness. This is because porphyrins are poisonous to the body and produce nerve damage. Damage to nerves of the digestive system not only cause nerve pain in the abdominal area, but also cause slow movement of the bowels, especially the large bowel. Patients can therefore develop a larger than normal diameter of the large bowel, at times causing a condition called megacolon. The damage of nerves to the esophagus and to the stomach valve muscles (sphincters) can cause stomach reflux. One of the ironies of these digestive condition is that one of the medical treatments of these digestive conditions is Reglan, to which some porphyrics have a very strong adverse reaction.
Porphyrin neurotoxins are neurotropic and shut down the nerve trunks one by one until the individual has difficulty with fine motor tasks, like turning phonebook pages, has difficulty speaking (develops dystonic speech that is almost unintelligible), and develops difficulty breathing. The porphyrin neurotoxins have caused some patients to present to the Emergency Room not only in pain but also seeming to be neurotic, or even psychotic. Once glucose is infused, those episodes subside, and if they don't, healthy red blood cell infusion in whole also helps, due to the naturally occurring glucose in the infused blood. These patients will often present with a very enlarged spleen due to having to process defective red blood cells. At times poking around on the spleen can cause elevation of body temperature by at least two degrees Fahrenheit. The liver may also be tender.
People with EPP are also at increased risk to develop gallstones. In a small percentage of cases, protoporphyrin accumulates to toxic levels in the liver
, leading to liver failure
.
has been estimated somewhere between 1 in 75,000 and 1 in 200,000. An estimated 5,000-10,000 individuals worldwide have EPP.
s (with the exception of light-reflecting substances such as zinc oxide
) are of little use. Some individuals may decrease their sun sensitivity with daily doses of beta carotene, though a recent meta analysis of carotene treatment has called its effectiveness into question. Some patients gradually build a protective layer of melanin
by regularly exposing themselves for short times to ultraviolet radiation.
EPP is considered one of the least severe of the porphyrias. The ferrochetalase enzyme is the last step before actual heme production and then actual hemoglobin production. The steps before protoporphyrin production also have enzymes that produce intermediaries. If the very first enzyme in the production process is defective, that porphyria is generally the most severe. If the next enzyme in the step-wise process is the defective one, the porphyria is generally less severe, and-so-on until the ferrochetalase step. One thing to keep in mind is the fact that low blood sugar activates the cytochrome p450 system. The cytochrome p450 system is the system that contains the subsystem that produces the porphyrin ring. Therefore infusion of glucose into the blood stream to produce slightly higher than normal blood sugar produces relief. Transfusion of healthy blood cells in whole blood into the patient also gives relief. Protoporphyrins sometimes accumulate to toxic levels in the liver, causing liver failure; if this occurs, a liver transplant becomes necessary.
The individual symptoms of this condition are multiple, and many of those symptoms can occur in other conditions. Therefore other diagnoses are often made and the patient can go through life as an undiagnosed and untreated person with EPP.
s with a melanocyte-stimulating hormone
called afamelanotide
(SCENESSE®) (formerly CUV1647). In May 2010 afamelanotide (SCENESSE®) was approved by the Italian Medicines Agency (AIFA) for reimburement, for the treatment of EPP.
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
, although very painful, which arises from a deficiency in the enzyme ferrochelatase
Ferrochelatase
Ferrochelatase is an enzyme that catalyses the terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme. It catalyses the reaction:A ferrochelatase enzyme consists of 497 amino acid residues with a m.w...
, leading to abnormally high levels of protoporphyrin in the tissue. The severity varies significantly from individual to individual.
Both autosomal dominant and autosomal recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
inheritance
Inheritance
Inheritance is the practice of passing on property, titles, debts, rights and obligations upon the death of an individual. It has long played an important role in human societies...
have been reported with this disorder.
Presentation
A common symptom is very painful photosensitivityPhotosensitivity
Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
, manifesting itself as a burning and itching sensation on the surface of the skin. At times the itching sensations are almost unbearable. Rubbing the affected areas with ice can be the only relief, and that is only temporary. The usual anti-itch remedies, including cortisone anti-histamine topical preparations, and Calomine lotion generally provide little or no relief. If a patient presents with a history of anti-itch preparation inefficacy, EPP should be considered.
EPP usually first presents in childhood, and most often affects the face and the upper surfaces of the arms, hands, and feet and the exposed surfaces of the legs. Most patients, if the EPP is not as severe, manifest symptoms with onset of puberty when the male and female hormone levels elevate during sexual development and maintenance. More severe EPP can manifest in infancy. Exposure to even indoor light sources can cause the rash, and the infant, if clothed only in a diaper, will break out everywhere except under the diaper. EPP can be triggered through exposure to sun even though the patient is behind glass. Even the UV emissions from arc welding with the use of full protective mask have been known to trigger EPP.
Prolonged exposure to the sun can lead to edema and blistering. At times the immediate damage can be so severe that the individual can lose the skin in sheets. After many years, chronically sun-exposed skin may become thick and wrinkled if no beta carotene and other carotenoids and no lutein and other xanthophylls are ingested.
Another aspect of the painfulness of EPP is the painful abdomen, which may manifest as generalized pain, or may imitate an appendicitis. Some healthy appendices have been removed due to this mimic. Since porphyria is not that common, most doctors don't even think to do blood porphyrin levels when symptoms present. For doctors that are familiar with porphyria, it is generally considered insignificant and irrelevant compared to the possibility of a pending burst appendix, especially since porphyrin levels cannot be generally be received back immediately due to lab protocols.
Moderate and severe cases can present with pelvic and shoulder girdle muscle weakness. This is because porphyrins are poisonous to the body and produce nerve damage. Damage to nerves of the digestive system not only cause nerve pain in the abdominal area, but also cause slow movement of the bowels, especially the large bowel. Patients can therefore develop a larger than normal diameter of the large bowel, at times causing a condition called megacolon. The damage of nerves to the esophagus and to the stomach valve muscles (sphincters) can cause stomach reflux. One of the ironies of these digestive condition is that one of the medical treatments of these digestive conditions is Reglan, to which some porphyrics have a very strong adverse reaction.
Porphyrin neurotoxins are neurotropic and shut down the nerve trunks one by one until the individual has difficulty with fine motor tasks, like turning phonebook pages, has difficulty speaking (develops dystonic speech that is almost unintelligible), and develops difficulty breathing. The porphyrin neurotoxins have caused some patients to present to the Emergency Room not only in pain but also seeming to be neurotic, or even psychotic. Once glucose is infused, those episodes subside, and if they don't, healthy red blood cell infusion in whole also helps, due to the naturally occurring glucose in the infused blood. These patients will often present with a very enlarged spleen due to having to process defective red blood cells. At times poking around on the spleen can cause elevation of body temperature by at least two degrees Fahrenheit. The liver may also be tender.
People with EPP are also at increased risk to develop gallstones. In a small percentage of cases, protoporphyrin accumulates to toxic levels in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, leading to liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...
.
Prevalence
Case reports suggest that EPP is prevalent globally. The prevalencePrevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
has been estimated somewhere between 1 in 75,000 and 1 in 200,000. An estimated 5,000-10,000 individuals worldwide have EPP.
Treatment and prognosis
There is no cure for this disorder; however, symptoms can usually be managed by the simple expedient of limiting sun exposure. Protective clothing is also very helpful. Since the photosensitivity results from light in the visible spectrum, most sunscreenSunscreen
Sunblock is a lotion, spray, gel or other topical product that absorbs or reflects some of the sun's ultraviolet radiation on the skin exposed to sunlight and thus helps protect against sunburn...
s (with the exception of light-reflecting substances such as zinc oxide
Zinc oxide
Zinc oxide is an inorganic compound with the formula ZnO. It is a white powder that is insoluble in water. The powder is widely used as an additive into numerous materials and products including plastics, ceramics, glass, cement, rubber , lubricants, paints, ointments, adhesives, sealants,...
) are of little use. Some individuals may decrease their sun sensitivity with daily doses of beta carotene, though a recent meta analysis of carotene treatment has called its effectiveness into question. Some patients gradually build a protective layer of melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
by regularly exposing themselves for short times to ultraviolet radiation.
EPP is considered one of the least severe of the porphyrias. The ferrochetalase enzyme is the last step before actual heme production and then actual hemoglobin production. The steps before protoporphyrin production also have enzymes that produce intermediaries. If the very first enzyme in the production process is defective, that porphyria is generally the most severe. If the next enzyme in the step-wise process is the defective one, the porphyria is generally less severe, and-so-on until the ferrochetalase step. One thing to keep in mind is the fact that low blood sugar activates the cytochrome p450 system. The cytochrome p450 system is the system that contains the subsystem that produces the porphyrin ring. Therefore infusion of glucose into the blood stream to produce slightly higher than normal blood sugar produces relief. Transfusion of healthy blood cells in whole blood into the patient also gives relief. Protoporphyrins sometimes accumulate to toxic levels in the liver, causing liver failure; if this occurs, a liver transplant becomes necessary.
The individual symptoms of this condition are multiple, and many of those symptoms can occur in other conditions. Therefore other diagnoses are often made and the patient can go through life as an undiagnosed and untreated person with EPP.
Experimental treatments
Clinuvel Pharmaceuticals Ltd., an Australian pharmaceutical company, has successfully completed Phase III clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s with a melanocyte-stimulating hormone
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
called afamelanotide
Afamelanotide
Afamelanotide developed at the University of Arizona is a synthetic analog of the naturally-occurring melanocortin peptide hormone alpha-melanocyte stimulating hormone that has been shown to induce skin pigmentation through melanogenesis and thereby subsequently reduce sun damage to UV exposed...
(SCENESSE®) (formerly CUV1647). In May 2010 afamelanotide (SCENESSE®) was approved by the Italian Medicines Agency (AIFA) for reimburement, for the treatment of EPP.