What is Erythropoietic Protoporphyria?
Erythropoietic protoporphyria (EPP) is a condition that a person is born with that leads to an excess of a substance called protoporphyrins in red blood cells. The accumulation of protoporphyrins can cause severe, painful sensitivity to sunlight that doesn’t result in blisters, and it can potentially harm the liver. It’s common for signs of EPP to first appear in early childhood, with immediate pain and crying when exposed to intense sunlight. The symptoms are often linked with the time of year, becoming more prominent in the spring and summer season.
EPP is a condition that lasts throughout a person’s life. After multiple reactions to sunlight, the skin often thickens, and wax-like scars may form on the face. In a few cases, the protoporphyrins gathered in the liver can lead to serious liver conditions like cirrhosis or liver failure. Though it’s rare, EPP can start showing signs in adulthood. In some situations, a form of EPP can develop due to an increase in cells with a mutation in the ferrochelatase, a key enzyme, especially in conditions affecting blood cells production or proliferation.
What Causes Erythropoietic Protoporphyria?
Erythropoietic protoporphyria (EPP) is caused by a mutation in a protein known as ferrochelatase. This protein acts as the last step in creating heme, a crucial part of our red blood cells, by combining iron (Fe+2) with a compound called protoporphyrin IX (PPIX). When someone has EPP, their body can’t make enough ferrochelatase, so PPIX builds up in red blood cells, plasma, the liver, and skin.
This is problematic because PPIX can react with oxygen, especially when exposed to light. This reaction releases energy and potentially creates harmful substances known as free radicals. These free radicals can cause damage to the skin, which is why people with EPP can develop skin problems when they are exposed to light.
Risk Factors and Frequency for Erythropoietic Protoporphyria
Erythropoietic protoporphyria, first thoroughly described in 1961, is a condition that is reported globally. Being the third most common type of porphyria in adults and the most common in children, it affects both males and females equally. This condition is found more frequently in East Asians than in Whites and is rarely seen in Africans. The rate at which it occurs in European countries differs.
Signs and Symptoms of Erythropoietic Protoporphyria
Erythropoietic protoporphyria (EPP) is a condition that generally starts showing symptoms in early childhood. Both boys and girls can be affected equally. Often, children with EPP are wrongly diagnosed as having severe swelling (primary angioedema) or allergic reactions. Symptoms usually begin with a strong reaction to sunlight, which can cause severe burning, tingling, and itching on sun-exposed skin areas like the nose, cheeks, and backs of the hands.
After exposure to the sun, other symptoms can develop, such as redness, swelling or blanching of the skin, which can last from minutes to days. If an individual with EPP spends too much time in the sun, they might develop small raised skin lesions (papulovesicles). Repeated sun exposure can also lead to changes to the fingernails, bruises, small purple spots (petechiae), and minor scars on the face, along with vertical grooving of the lips. The severity of these symptoms can vary and mostly depends on how much sun the person is exposed to, with milder symptoms in winter.
Kids with EPP have a higher risk of developing gallstones, and it’s considered a leading cause of gallstones in children.
In rare instances, EPP can lead to an uncommon type of liver disease (protoporphyric hepatopathy). This liver condition can happen if an individual with EPP has high levels of a substance called protoporphyrins in their body, leading to symptoms like yellowing skin and eyes (jaundice), nausea, pain in the upper right part of the belly, and throwing up. Persistent whopping, combined with a history of unexplained sensitivity to light, may point to EPP. This liver disease can worsen the skin symptoms because it leads to an increase in the amount of porphyrins, substances that make the skin sensitive to sunlight. Liver function tests could be constantly high in people with this chronic liver disease, even though people with EPP without complications often have normal liver function tests. In severe cases of this liver condition, individuals could develop nerve damage that affects their limbs and potentially leads to breathing difficulties.
People with EPP often avoid the sun, which can lead to a vitamin D deficiency and subsequently make them more prone to bone loss (osteoporosis). Some people might also have mild anemia, which means their red blood cells are smaller and carry less oxygen than normal. For reasons not entirely understood yet, pregnancy seems to lower the levels of protoporphyrins, which in turn improves the sensitivity to light.
Testing for Erythropoietic Protoporphyria
If you experience sudden sensitivity to sunlight without any blisters, your doctor might consider a condition called Erythropoietic Protoporphyria (EPP). This condition might be the reason for unexplained discomfort and a decrease in your overall wellbeing over a long period. Diagnosing EPP involves screening for the total level of protoporphyrins (a special type of protein related to hemoglobin, the molecule in our blood that carries oxygen) in your blood.
Normally, the total protoporphyrin level in your red blood cells should be around 80 mcg/dL. But, if you have EPP, this number could increase to 300 to 8000 mcg/dL – that’s 5 to 50 times higher than the normal range! Also, you are likely to have a higher quantity of metal-free protoporphyrin as compared to zinc protoporphyrin in your red blood cells. Interestingly, if you have EPP, your urine will normally have regular porphyrin levels unless you have liver complications.
To help avoid delayed diagnosis, doctors will look at the levels of porphyrins in your plasma, a component of your blood, at the same time they’re checking your red blood cell protoporphyrin.
Gene tests are especially important when dealing with EPP, unlike many other types of porphyria (a group of genetic disorders affecting the nervous system or skin), because they can identify any abnormal genes that might run in your family. Also, you may need to have regular liver function tests every 6-12 months to monitor your condition.
Other tests that may be necessary include a blood test to check for iron deficiency anemia and a vitamin D test. You might also need an ultrasound of your abdomen, or other imaging tests if doctors suspect you have gallstones.
In some cases, tests might reveal you have Osteoporosis or Osteopenia, conditions of weak or brittle bones, due to a lack of vitamin D. Very rarely, a tissue sample (a biopsy) from your skin or bone marrow might be needed, while a liver biopsy can be helpful to rule out other potential causes of chronic liver disease.
Treatment Options for Erythropoietic Protoporphyria
For individuals suffering from Erythropoietic Protoporphyria (EPP), a condition that makes skin overly sensitive to light, there is currently no definitive treatment to lower the levels of porphyrins – the substances causing this sensitivity – in the body. However, certain lifestyle measures can help manage this condition.
Those affected by EPP should significantly limit their exposure to sunlight or fluorescent light. This applies to both adults and children, and parents should teach their kids how to stay safe from sunlight. When stepping outdoors, protective clothing, broad-brimmed hats, and staying in shaded areas can all help to reduce the impact of light exposure. Applying broad-spectrum sunscreen is also essential. To further shield from light, car and home windows can be equipped with protective tinted glass.
Even indoor light, especially the ones used in operating rooms, can cause adverse reactions to people with EPP. So it is advisable to use light filters in such spaces. This becomes especially crucial during long surgical procedures, such as liver transplantation.
Afamelanotide, a lab-made version of a hormone that increases skin pigmentation, can also help in improving tolerance to sunlight, especially during the summer. Beta-carotene, another compound that increases sunlight tolerance, can also be used. However, it should be noted that a high intake of beta-carotene may increase the risk of lung cancer.
Treating extreme sensitivity to light has also seen varying levels of success with treatments like narrow-band UVB phototherapy and oral cysteine. Additionally, because people with EPP are advised to avoid sunlight, they may not get enough vitamin D. That’s why they may need supplements of calcium and vitamin D.
In acute instances when the patient is experiencing pain, certain over-the-counter or prescribed painkillers, or even cold compresses, may provide relief.
For patients who develop a rapidly worsening liver condition as a part of EPP, treatments may include intravenous hemin (to reduce plasma porphyrin level), plasmapheresis (a process to filter the blood), ursodeoxycholic acid, cholestyramine, vitamin-E, and addressing anemia. In severe cases where the liver is extensively damaged, a liver transplant may be necessary.
Bone marrow transplant is a relatively new treatment option that may be performed along with a liver transplant. This transplant approach can potentially prevent EPP from recurring, and even reverse or treat both light sensitivity and liver problems associated with EPP. This method seems promising because a substantial part of the heme production (the substance that ultimately leads to porphyrin build-up) occurs in the bone marrow. Therefore, replacing unhealthy bone marrow with healthy ones appears as a possibly curative strategy in some cases of EPP.
What else can Erythropoietic Protoporphyria be?
Here are some conditions that can cause skin reactions, especially when the skin is exposed to the sun:
- Phototoxic drug reaction: This might happen if you’ve recently started a new medication. You’d experience skin redness and discomfort almost right after exposure to the sun.
- Hydroa vacciniforme: This rare condition involves recurring outbreaks of fluid-filled blisters on sun-exposed areas of the skin, that heal leaving scar-like marks.
- Solar urticaria: Here, exposure to sunlight causes hives or skin inflammation akin to nettle rash. Like EPP, symptoms often show up within minutes and tend to be itchy rather than painful.
- Polymorphic light eruption: Also known as a sun allergy or sun poisoning, this common condition usually starts between childhood and early adulthood. It gives rise to itchy bumps, blisters, or raised patches on sun-exposed parts of the skin.
- Discoid lupus erythematosus: This condition causes flaky, red patches or lesions to appear on sun-exposed areas.
- Sunburn: This is a temporary skin inflammation in response to the ultraviolet radiation from sunlight or artificial light sources. Anyone can get sunburned, but you’re more prone if you have lighter skin pigmentation and hair and eye color.
Remember, it’s always a good idea to protect your skin from excessive sun exposure, and see a doctor if any suspicious skin changes occur.
What to expect with Erythropoietic Protoporphyria
Patients with EPP, or Erythropoietic Protoporphyria, typically have a normal life expectancy unless they develop liver disease due to the harmful effects of protoporphyrins – a type of natural compound that can cause liver dysfunction. EPP itself doesn’t typically shorten a person’s life, but it can have a significant impact on their quality of life.
This is because the condition can cause severe and sudden pain after exposure to sunlight, which may require the patient to make adjustments to their daily routines and even their job.
Possible Complications When Diagnosed with Erythropoietic Protoporphyria
The most severe problem resulting from EPP (Erythropoietic Protoporphyria) is a related liver disease, which could turn deadly. In more advanced stages of this liver disease, patients may experience peripheral neuropathy, a nerve condition that’s similar to what’s observed in acute porphyria, and could result in breathing failure. Additionally, repeated sun exposure could cause thickening of the skin or intense itching, particularly on the face and knuckles, and could lead to the disappearance of the white, crescent-shaped area of fingernails. Because patients with EPP typically avoid sunlight, they are at a higher risk of having a deficiency in vitamin-D, which could weaken bones, causing osteoporosis.
Common Problems:
- Protoporphyrin-related liver disease
- Peripheral neuropathy
- Respiratory failure
- Thickened skin or intense itching due to sun exposure
- Loss of fingernail lunulae
- Vitamin-D deficiency
- Osteoporosis
Preventing Erythropoietic Protoporphyria
It’s crucial for parents and patients to understand the nature of their disease and how they can take steps to safeguard themselves. Here’s one important tip: patients should limit their exposure to the sun as much as possible. It may be helpful to wear protective clothing such as long-sleeved shirts, wide-brimmed hats, and shoes (avoiding sandals). Gloves can also make a difference, especially during driving. Sunscreens that contain zinc dioxide or titanium dioxide are ideal because they provide broad protection against different types of sunlight: UVA, UVB, and even visible light.
During surgical procedures, we need to be extra careful as these patients are susceptible to burns from the intense lights in the operating rooms. These injuries can occur not only on the skin but also on internal organs. Therefore, it’s best to use light filters in the operating rooms to shield the patient. Moreover, patients may need to consider switching jobs or modifying their employment conditions based on their individual cases.
Genetic counseling is particularly important considering this disease, known as EPP, is inherited. This means it’s passed on from parents to their children through genes. When it comes to the likelihood of a child inheriting EPP, it depends on whether the other parent carries a specific genetic variant known as the hypomorphic IVS3-48T/C allele. This variant is more common in some populations than others. A genetic test for the other parent will help determine this likelihood. If the other parent does not have the EPP-causing mutation in their FECH genes, half of their children could inherit a severe mutation in the FECH gene from the affected parent. But these children will not have EPP because they also inherited a normal FECH gene from the other parent.
