About erythropoietic protoporphyria

What is erythropoietic protoporphyria?

Erythropoietic protoporphyria (EPP) is a rare inherited metabolic disorder characterized by a deficiency of the enzyme ferrochelatase (FECH). Due to abnormally low levels of this enzyme, excessive amounts of protoporphyrin accumulate in the bone marrow, blood plasma, and red blood cells. The major symptom of this disorder is hypersensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights (photosensitivity). After exposure to light, the skin may become itchy and red. Affected individuals may also experience a burning sensation on their skin. The hands, arms, and face are the most commonly affected areas. Some people with erythropoietic protoporphyria may also have complications related to liver and gallbladder function. Erythropoietic protoporphyria is inherited as an autosomal dominant genetic trait with poor penetrance.

Erythropoietic protoporphyria is one of a group of disorders known as the porphyrias. The porphyrias are all characterized by abnormally high levels of particular chemicals (porphyrins) in the body due to deficiencies of certain enzymes essential to the synthesis of hemoglobin. There are at least seven types of porphyria. The symptoms associated with the various types of porphyria differ, depending upon the specific enzyme that is deficient. It is important to note that people who have one type of porphyria do not develop any of the other types.

What are the symptoms for erythropoietic protoporphyria?

A few minutes of exposure to the sun induces pruritus symptom was found in the erythropoietic protoporphyria condition

The most common symptom of erythropoietic protoporphyria and X-linked protoporphyria is severe Pain on sun exposure. Some patients may also be sensitive to some types of artificial light. When the skin is exposed to sun, patients first develop tingling, itching, and/or Burning of the skin. These symptoms serve as warning signs as longer exposure can result in severe pain. Affected individuals may also have an abnormal accumulation of body fluid under affected areas (edema) and/or persistent Redness or Inflammation of the skin (erythema). In rare cases, affected areas of the skin may develop sac-like Lesions (blisters) and scar if exposure to sunlight is prolonged. However, scarring and/or discoloring of the skin is uncommon and rarely severe. These affected areas of skin may become abnormally thick. The severity and degree of symptoms is different from case to case. Some patients may only be able to tolerate a few minutes of sun exposure while others may be able to tolerate longer sun exposure without symptoms. The amount of sun tolerated may also be different based on weather conditions. Symptoms are often seen during infancy; however, in some cases, it may not occur until adolescence or rarely in adulthood.

In some affected individuals, the flow of bile through the gallbladder and bile ducts (biliary system) may be interrupted (cholestasis) causing gallstones (cholelithiasis) to form. In turn, such stones can cause obstruction and/or Inflammation of the gallbladder (cholecystitis). Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring transplantation. As liver transplantation does not cure EPP or XLP, a bone marrow transplant following liver transplant may be necessary in some cases.

Symptoms usually start in childhood but diagnosis is often delayed since Blistering is not common and, because the porphyrins are insoluble, they cannot be detected on urinanalysis. The diagnosis is made upon finding increased levels of the protoporphyrin in the plasma or red blood cells in both EPP and XLP. Genetic testing is useful to confirm the diagnosis.

Patients with EPP and XLP may also have mild anemia (low blood counts). In many cases, this may be due to low iron stores. They may also have high levels of liver enzymes on blood tests.

What are the causes for erythropoietic protoporphyria?

EPP is a rare genetic disorder caused by genetic changes in the FECH gene. The FECH gene is responsible for providing instructions for the body to create an enzyme called ferrochelatase. This enzyme is involved in a long process to make heme, a chemical that functions to transport oxygen around the body. Without enough of the enzyme, ferrochelatase, the body is not able to finish converting a heme precursor called protoporphyrin into heme, causing buildup of protoporphyrins in certain tissues in the body (i.e., the plasma, red blood cells, and the liver). These protoporphyrins also build up in the superficial blood vessels under the skin. These protoporphyrins are highly sensitive to sunlight. When they absorb sunlight, it results in a reaction which causes severe pain and inflammation resulting in symptoms of EPP.

EPP is inherited, or passed down through the generations, in an autosomal recessive manner. Everyone has two copies of the FECH gene, one inherited from the mother and one from the father. Most individuals with EPP have a different gene change on each copy of the FECH genes. On one copy, the change, called a mutation, has stopped this copy of the gene from working properly. On the other copy, there is a small change called a “low-expression allele” or a polymorphism. This alteration still affects the way the FECH gene works; it produces less ferrochelatase enzyme than normal. This small change is common in the general population, with up to 10% of Caucasians with one copy of this change. This alteration will not cause EPP by itself, and people who have the alteration on each copy of the FECH gene will NOT develop EPP. But when someone inherits the small alteration from one parent and a mutation from the other, they will develop EPP, because there will not be enough enzyme made. Most patients with EPP have the low-expression alteration on one copy of the FECH gene and a mutation on the other copy. The risk for patients with EPP to have a child who also has the condition depends on the genetic changes in their partner.

Some patients with symptoms of EPP have a genetic change in a different gene called ALAS2, a gene located on the X chromosome. When a patient has a genetic change in this gene, the condition is referred to as X-linked protoporphyria (XLP). XLP is passed down through families in an X-linked manner. Males have one X chromosome and one Y chromosome, while females have two X chromosomes.This means that males have only one copy of the ALAS2 gene and females have two copies of the ALAS2 gene. When a male has a mutation is his single copy of ALAS2, he is expected to have symptoms of XLP. In a woman with a mutation in one of her ALAS2 genes, the second functioning copy of the gene can help compensate and may lead to less severe symptoms or no symptoms at all. It is not possible to predict or control the severity of disease in females. Men with XLP pass on their X chromosome to their daughters and their Y chromosome to their sons. Therefore, a man with XLP with pass on his genetic change to all his daughters, and none of his sons. For a female with XLP, she will pass on the X chromosome with the genetic change 50% of the time. Thus, in each pregnancy, there is a 50% chance of having a child with a mutation in ALAS2.

Genetic counseling is recommended for affected individuals and their families.

What are the treatments for erythropoietic protoporphyria?

Avoidance of sunlight will be of benefit to individuals with EPP. The use of sun protective clothing such as long sleeves, hats, and sunglasses will also benefit patients. Tanning creams which increase skin pigmentation or sunscreens which contain physical reflecting agents may be beneficial to some patients. Individuals with EPP and XLP may also benefit from window tinting or using films to cover the windows in their car or house. Before tinting or shading car windows, affected individuals should check with their local Registry of Motor Vehicles to ensure that such measures do not violate any local codes.

In EPP, a high potency form of Lumitene (oral beta-carotene) has been used to improve an affected individual’s tolerance of sunlight. While some patients report improvement, recent studies show that there is no data to support the benefit of this treatment.

In 2019, the Food and Drug Administration (FDA) approved Scenesse (afamelanotide) for the treatment of adult patients with EPP. Scenesse is an injectable implant and works by increasing skin pigmentation which provides protection and improves sun tolerance. Scenesse was available in Europe for a period of time before its approval in the United States.

When iron deficiency is present, iron supplements may be given. A drug called Prevalite (cholestyramine) or activated charcoal maybe prescribed to interrupt the circulation of protoporphyrin through the liver and intestines in patients with liver disease.

In addition, individuals with high levels of protoporphyrin in the plasma and red blood cells should be observed closely by a physician for possible liver malfunction that could eventually lead to liver failure.

Liver transplantation has been performed as a life-saving measure in patients with EPP and XLP related liver failure. Bone marrow transplant can also be performed after liver transplant to prevent further damage to the liver.

EPP and XLP patients should take vitamin D supplements as they are likely to have low vitamin D levels since they avoid sunlight. They should also receive vaccination against hepatitis A and B to prevent other causes of liver damage.

Patients should be seen at least yearly to monitor protoporphyrin levels, anemia, liver enzymes, iron and vitamin D levels.

Other treatment is symptomatic and supportive.

What are the risk factors for erythropoietic protoporphyria?

Most forms of erythropoietic protoporphyria are inherited.

The risk factors of erythropoietic protoporphyria include:

  • Porphyria can occur if you inherit a defective gene from one of your parents (autosomal dominant pattern) or inherit a defective gene from both parents (autosomal recessive pattern).

Environmental factors may also trigger the development of signs and symptoms in porphyria.

Triggers factors include:

  • Certain medications, including hormone drugs
  • Exposure to sunlight
  • Dieting or fasting
  • Recreational drugs
  • Emotional stress
  • Smoking
  • Physical stress, such as infections or other illnesses
  • Alcohol use
  • Puberty and after menopause in women
  • Menstrual hormones ― acute porphyria attacks are rare before

A few minutes of exposure to the sun induces pruritus, erythema, swelling and pain,Scarring of the skin,Edema of the hands, face, and feet, rarely with blistering and petechiae,Skin thickening
Porphyria,Pruritus,Erythema,Lichenification,Hypopigmentation,Hyperpigmentation,Edema,Liver failure
Sunscreens,Afamelanotide,Proferrin,Probiotics,Beta carotene

Is there a cure/medications for erythropoietic protoporphyria?

Although there is no cure for Erythropoietic protoporphyria, the symptoms can usually be managed by limiting exposure to daytime sun and some types of artificial lighting.

  • Avoiding exposure to artificial lighting: Avoiding artificial lighting, especially fluorescent lighting, can be the best way to protect yourself from developing the disease.
  • Using sunscreens: Non-nano zinc oxide sunscreen is one of the best sunscreens to use for your skin. It provides uniform protection between 290-400 nm and some protection up to 700 nm.
  • Sun protective clothing: Wearing protective clothes with zinc oxide in their fabrics can also be very helpful.Window films
  • Some patients gradually build a protective layer of melanin by regularly exposing themselves for short times to ultraviolet radiation.
  • Over-the-counter drugs: Some over-the-counter drugs like Proferrin are oral heme supplements that may work similarly to Hematin, B. subtilis (a gram-positive soil probiotic) produces ferrochelatase, which may be able to convert some of the protoporphyrin in the intestine into heme, and Beta carotene, though a recent meta-analysis of carotene treatment has called its effectiveness into question.
  • Off-label therapies: Ursodeoxycholic acid, Hematin, Plasmapheresis, Cholestyramine, etc. can help.

Bone marrow transplantation, liver transplantation, acetylcysteine, extracorporeal albumin dialysis, parenteral iron and transfusion of erythrocytes are alternative plans for treatment of EEP.

A few minutes of exposure to the sun induces pruritus, erythema, swelling and pain,Scarring of the skin,Edema of the hands, face, and feet, rarely with blistering and petechiae,Skin thickening
Porphyria,Pruritus,Erythema,Lichenification,Hypopigmentation,Hyperpigmentation,Edema,Liver failure
Sunscreens,Afamelanotide,Proferrin,Probiotics,Beta carotene

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