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Monday, February 8, 2016

FACTS of EPP & XLP

Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)


Erythropoietic Protoporphyria (EPP) or Protoporphyria
Erythropoietic Protoporphyria is characterized by abnormally elevated levels of protoporphyrin IX in erythrocytes (red blood cells) and plasma (the fluid portion of circulating blood), and by sensitivity to visible light that is usually noticed in early childhood and occurs throughout life.  EPP can result either from mutations of the ferrochelatase gene (FECH), or less commonly the delta-aminolevulinic acid synthase-2 gene (ALAS2).  When EPP is due to an ALAS2 mutation it is termed X-linked protoporphyria (XLP), because that gene is found on the X chromosome. 
Protoporphyrin accumulates first in the bone marrow in EPP, and then in red blood cells, plasma and sometimes the liver. Protoporphyrin is excreted by the liver into the bile, after which it enters the intestine and is excreted in the feces. It is not soluble in water so is not excreted in the urine. 
EPP is the third most common type of porphyria, and the most common in childhood.  It causes very painful photosensitivity and can greatly impair quality of life.  Delay in diagnosis is greater than with any other type of porphyria. 
Swelling, burning, itching, and redness of the skin may appear during or after exposure to sunlight, including sunlight that passes through window glass. This can cause mild to severe burning pain on sun-exposed areas of the skin.  Usually, these symptoms subside in 12 to 24 hours and heal without significant scarring. Blistering and scarring are characteristic of other types of cutaneous porphyria but are unusual in EPP.  Skin manifestations generally begin early childhood and are more severe in the summer.
There is an increased risk of gallstones, which contain protoporphyrin. Excess protoporphyrin can also cause liver damage.  Less than 5% of EPP patients’ severe liver damage and a condition caused protoporphyric hepatopathy that sometimes requires liver transplantation. 
Diagnosis and Genetic Counseling
EPP should be suspected in anyone with non-blistering photosensitivity especially when is it prolonged and beginning in childhood.  It is easy to make a diagnosis, or rule it out, once it is suspected. 
The diagnosis of EPP is established by finding an abnormally high level of total erythrocyte protoporphyrin, and showing that this increase is mostly free protoporphyrin rather than zinc protoporphyrin.  There is considerable confusion about which test to order.  Sometimes laboratories have measured only zinc protoporphyrin and reported results incorrectly as “protoporphyrin” or “free erythrocyte protoporphyrin (FEP)”.  Laboratories that measure total erythrocyte protoporphyrin, free protoporphyrin and zinc protoporphyrin and report results reliably are:
  • Porphyria Laboratory and Center, University of Texas Medical Branch at Galveston, 1-409-772-4661
  • Mayo Medical Laboratories, 1-800-533-1710 
  • ARUP Laboratories

Porphyrins are almost always elevated in plasma in EPP, but may be normal in mild cases.  Fecal porphyrins may be normal or increased. 
An experienced biochemical laboratory can usually distinguish between patients with EPP and XLP, because the former have much less zinc protoporphyrin in their erythrocytes.  This can be explained because in the marrow the enzyme ferrochelatase not only normally makes heme (iron protoporphyrin) from protoporphyrin and iron, but can also make zinc protoporphyrin, especially when excess protoporphyrin is present or iron is deficient.  However, this does not replace DNA studies. 
Rarely, EPP develops in adults in the presence of a bone marrow disorder such as polycythemia vera, and is due to expansion of a clone of red blood cell precursors in the marrow that is deficient in ferrochelase. 
DNA studies are important for confirming the diagnosis of EPP and XLP and for genetic counseling.  This should be completed first in a person known to have the disease, and the information about the mutations in that individual used to guide testing of family members. 
When EPP is due to a FECH mutation the inheritance is described as autosomal recessive.  It is most common to find that one severe mutation is inherited from one parent and another weak mutation inherited from the other parent.  The weak mutation is quite common in normal Caucasians, rare in Blacks and even more common in Japanese and Chinese populations.  This mutation is sometime referred to as “hypomorphic” because it results in formation of a less than normal amount of ferrochelatase.  But is does not cause EPP unless it is paired with a severe mutation.  The severe mutation is characteristic for an EPP family and is present in all affected individuals.  “Carriers” of the severe mutation are not affected because they do not have the weak mutation.  Affected individuals and unaffected carriers can transmit the severe mutation to the next generation.  Some of their children will have EPP if the other parent has a copy of the weak mutation.  Rarely, the weak mutation is absent in an EPP family and two severe mutations are found, with at least one producing some ferrochelatase. 
In XLP, mutations of the ALAS2 gene, which is found on the X chromosome, causes an increase in the production of the enzyme ALAS2 in the bone marrow.  Several of these “gain of function” mutations have been described in different XLP families.  In XLP protoporphyrin production exceeds that needed for heme and hemoglobin formation.  Like hemophilia and other X linked genetic diseases, XLP is more common in men.  Women have two X chromosomes and are usually not affected because they have a normal as well as a mutated ALAS2 gene.  Men have only one X chromosome and will be affected if they inherit an ALAS2 mutation.  Women with an ALAS2mutation will, on average, pass that mutation to half of their daughters (who will usually be unaffected carriers) and to half of their sons (who will be affected). 
Treatment and Management
1.  Sunlight protection
Protection from sunlight is the mainstay of management of EPP, and this is necessary throughout life.  Disease severity and porphyrin levels in erythrocytes and plasma probably remain high and relatively constant throughout life in EPP.  However, this has been little studied and more longitudinal observations are needed.  Life style, employment, travel and recreation require adjustment in order to avoid painful reactions to sunlight and even from exposure to fluorescent lighting.  For these reasons EPP can substantially affect quality of life. 
Protective clothing, including broad-brimmed hats, long sleeves, gloves and trousers (rather than shorts), is beneficial.  Several manufacturers specialize on clothing made of closely woven fabrics for people with photosensitivity. 
2.  Beta-Carotene (Lumitene Tishcon)
Beta-carotene is an over the counter product that was originally developed in a purified form as a drug for the treatment of EPP, and was shown to be effective by Dr. Micheline Mathews-Roth at Harvard University and others.  The pharmaceutical grade formulation is now distributed by Tishcon as Lumitene, and can be ordered by calling 1-800-866-0978 or via the website www.epic4health.com.  Other products are less standardized and reliable and are not recommended. 
Beta-carotene provides protection by quenching reactive oxygen products that form when protoporphyrin is activated in the skin by light.  It is important to take an amount that is adequate to be protective.  For more information about Lumitene, including a recommended dosing schedule, please see the Lumitene section of this website.

3.  Other considerations
In an occasional patient, protoporphyrin causes liver problems, so monitoring liver function is important. EPP patients should also not use any drug or anesthetic which causes cholestasis (slowing down bile flow), and should also avoid alcohol. Women should avoid medications containing estrogen (birth-control pills, hormone replacement therapy), and men should avoid testosterone supplements, as these substances can also have deleterious effects on the liver of a person with EPP.
Consult a specialist.  Because EPP is a rare condition, most physicians are not knowledgeable about it.  Contact The American Porphyria Foundation, 713-266-9617 for contact with an expert and to provide further information.  A Medic Alert bracelet with instructions to contact a specialist if needed is a worthwhile precaution.
Yearly monitoring.  Testing to include erythrocyte total protoporphyrin, plasma porphyrin, complete blood counts, ferritin and liver function tests should be done yearly.  Porphyry levels are expected to be stable and liver tests to remain normal.  EPP patients may have evidence of iron deficiency, and an iron supplement may be advisable if the serum ferritin is below about 20 ng/mL. 
Vitamin D.  Because they avoid sunlight, EPP patients are likely to be deficient in vitamin D.  A vitamin D supplement with calcium is recommended for bone health. 
Liver protection.  It is important to avoid other causes of liver disease that might promote the development of liver complications from EPP.  Patients should avoid alcohol and other substances that might damage the liver, including many herbal preparations, and be vaccinated for hepatitis A and B. 
Surgical lights. Strong operating room lights can cause photosensitivity of the skin and even surfaces of internal organs.  Flexible membrane filters, such as CL5-200-X from Madico Co., are available to cover surgical lights and offer some protection.  This is especially important in EPP patients with liver failure, which causes even greater increases in protoporphyrin levels and photosensitivity. 
Drugs.  Drugs that are harmful in other porphyrias are not known to make EPP worse, but are best avoided as a precaution.  This may include estrogens and other drugs that might reduce bile formation.  A short course of a non-steroidal anti-inflammatory drug can provide some pain relief after an episode of photosensitivity, but can cause ulcerations of the digestive track especially with prolonged use. 
Laser treatment.  According to Dr. Roth, laser treatments for hair removal or eye surgery have not been a problem in EPP people.  But the doctor should be made aware of the diagnosis, and that laser output between 400 and 650 nanometers might be harmful. Before hair removal treatment, the doctor may irradiate a small area of the skin to be treated for the length of time it will take to do the hair removal to ascertain if the patient would react within the period of time that a reaction to sunlight would be expected in that patient.  
Children with EPP.  Avoiding sunlight can be difficult for children with EPP who have less sunlight tolerance than their friends.  Camp Discovery is an option for such children.  It provides a week-long summer camping experience of fishing, boating, swimming, water skiing, arts and crafts, and just plain fun for young people with skin disorders, and is sponsored by the American Academy of Dermatology.  Full scholarships, including transportation, are provided by the American Academy of Dermatology through generous donations of their members and other organizations. Members of the Academy are asked to recommend candidates for Camp Discovery, so ask your child's doctor about sending your child to Camp Discovery.
Disneyland and Disney World are responsive to people with sun sensitivity. They will provide a pass to enable you to enter attractions without waiting in line in the sun.
Disneyland
Go to "Town Hall" and explain your problem with photosensitivity. You should bring a physician's letter with you as well as an APF brochure explaining the type of Porphyria you have. The staff will ask you some questions about your limitations (e.g., whether or not you can climb stairs) and how many are in your group. Next time you return, be sure to bring the old card with you, as it will only take about half as long to go through the process on your next trip.
Disney World
Proceed to the "Guest Relations" office at any park (Magic Kingdom, EPCOT, etc.) and request the Special Assistance Pass.
Remember to bring a doctor's note and explanation of your condition, because it is not necessarily visible. People on duty may not be familiar with light sensitivity and its consequences.
Research Opportunities
Patients with EPP and XLP can participate in the research through the Porphyrias Consortium.  The American Porphyria Foundation has information on what research protocols are currently open. 
·         
The Porphyrias Consortium is conducting a Longitudinal Study to better define the natural history of the disease.  This study is currently open for enrollment of new patients. 
·         
The Porphyrias Consortium will be starting a pilot study soon on a drug that may lower porphyrin levels in EPP. 
·         
Clinuvel Pharmaceuticals is developing afamelanotide (Scenesse®) for the treatment of EPP.  This drug is given by injection and increases skin pigmentation.  Another study of this drug is expected to open within the next year. 
All patients with porphyria are encouraged to enter the Porphyrias Registry at the Porphyrias Consortium website.  A link to this website is found on the website of the American Porphyria Foundation.  Registration demonstrates to NIH that patients and their families think that research on porphyrias is important.  You can also ask that one of the 6 porphyria center in the Consortium contact you.  

Thursday, February 4, 2016

Write your Congressman EPP PATIENTS!!!

Write your Congressman

Your 300 letters to the FDA regarding EPP were VERY effective. We are gaining ground! EPP is now on their radar. BUT we need your help. Now we need everyone to contact their congressmen and urge them to contact the FDA directly.
Here is the link to find each of your congressmen with one easy search: https://www.opencongress.org/people/zipcodelookup.
You may submit your letters via mail OR email. The website shown above provides you with all contact information. Below we have provided a template letter you may use, or, better yet, please write one of your own. The more letters, the better! Thank you all!


"Remember...research is the key to your cure!!"
  
[Insert Date]

The Honorable _________________
[Insert your Congressman's address here]

Dear Mr. ________,
As a person who has been diagnosed with Erythropoietic Protoporphyria (EPP), I am very concerned that the FDA has not approved Afamelanotide, a revolutionary drug to treat EPP. EPP is a rare, extremely photosensitive disease that causes severe burning of the skin, liver damage, Vitamin D deficiency and other major health problems. In other words, sunlight causes children and adults to suffer, and no one can avoid sunlight. When we discovered this drug would allow us to drive to work without pain, spend a day in the sun with our families and even do simple acts like walk to our cars without burning severely, we began to demand that the FDA approve Afamelanotide.
The EMA approved Afamelanotide in Europe in October 2014. In fact, almost half of worldwide patients can receive Afamelanotide for EPP, while US citizens have no FDA approval and continue to suffer. Instead, EPP patients in the US are forced to travel at great expense to purchase the drug in Switzerland. The demand has escalated to the point that people are asking for Congressional and media help. Recently, NBC, ABC, CNN, FOX, Telemundo and a host of other networks reported on EPP and this new treatment.
The American Porphyria Foundation, their Scientific Advisory Board and Porphyria Research Consortium, who performed the research, all recommend that the FDA approve Afamelanotide. As of yet, the FDA has not assessed the data from the clinical trials. Clinuvel, the drug manufacturer, cannot file a New Drug Application until the FDA assesses the data and allows their filing.
Afamelanotide has a long, safe and effective history. This timeline purports the readiness for this drug to receive accelerated approval.
• Trials for EPP started in 2006. Since then, there have been five clinical trials. In all other indications, including healthy volunteers, there have been more than 15 trials. More than 1,000 patients have received the drug. This is extremely important in that EPP is considered an ultra-rare disease, therefore, the numbers herein mean that a large part of the EPP population has been tested with the drug.
• Since 2006, a total of 146 patients continuously have been on Afamelanotide on a compassionate basis as part of the Special Access Schemes in Switzerland and Italy. The FDA has never allowed patients to have Afamelanotide on a compassionate basis.
• The European Medicines Agency (EMA) approved Afamelanotide for EPP on October 24, 2014. The FDA is keenly aware that Afamelanotide was approved in Europe as FDA representatives attended the plenary session in September 2014 before the EMA approval. The European Medicines Agency took record time to assess the novel and challenging nature of EPP and the unusual mode of action of the drug.
Most important to all of the EPP community is the FDA has not allowed trials for children. Every FDA delay adds five years to these children ever having access to the drug. While we await FDA approval of Afamelanotide, the FDA has approved treatments for wrinkle cream and double chin. Meanwhile, the EPP community suffers with severe pain and liver damage when a tiny implant of Afamelanotide would provide us with a normal life.
Please ask the FDA to grant accelerated approval for Afamelanotide.

Sincerely,

[Your signature here]
[Insert your name here]
Age, [insert] years old
[Insert your address here: # Street
Town, State Zip Code]

  

Friday, January 29, 2016

Lifestyle and home remedies & Prevention

Lifestyle and home remedies

By Mayo Clinic Staff
If you have porphyria:
  • Learn what could trigger symptoms. Talk to your doctor about the type of porphyria you have and become familiar with possible symptom triggers and ways to avoid them.
  • Inform your health care providers. Tell all your health care providers that you have porphyria. This is particularly important because sometimes treatments, medications or surgery can trigger porphyria symptoms.
  • Wear a medical alert bracelet or necklace. Have information about your condition inscribed on a medical alert bracelet or necklace, and always wear it.
Although there's no way to prevent porphyria, if you have the disease, these steps may help prevent symptoms:
  • Avoid medications known to trigger acute attacks. Ask your doctor for a list of safe and unsafe drugs.
  • Don't use alcohol or illegal drugs.
  • Avoid fasting and dieting that involves severe calorie restriction.
  • Don't smoke.
  • Minimize sun exposure. When you're outdoors, wear protective clothing and use a broad-spectrum sunscreen with a high sun protection factor (SPF).
  • Treat infections and other illnesses promptly.
  • Take steps to reduce emotional stress.
Because porphyria is an inherited disorder, your siblings and other family members may want to consider genetic testing to determine if they have the disease.
            
                   "Remember....Research is the key to your cure!"

Wednesday, January 27, 2016

Meeting with the FDA March 7!! IMPORTANT

Meeting with the FDA   March 7!!
The APF is meeting with the FDA on March 7, 2016 to discuss the ACUTE PORPHYRIAS (AIP, HCP, VP). We ask that you and your family members please join us at this meeting to share your story and your needs.
This is a very difficult meeting to gain. Please come help us explain the patient needs, problems and difficulties. Note this is not the EPP meeting we are trying to schedule but an acute porphyria meeting.
Please contact the APF if you need any further information or assistance.



"Remember....Research is the key to your cure!"

Tests and diagnosis & Treatments and drugs

Tests and diagnosis

By Mayo Clinic Staff
Many signs and symptoms of porphyria are similar to those of other more common diseases. Also, because porphyria is rare, it can be more difficult to diagnosis. Lab tests are required to make a definitive diagnosis of porphyria and to determine which form of the disease you have.
If your doctor suspects porphyria, he or she may recommend these tests:
  • Urine test. If you have a form of acute porphyria, a urine test may reveal elevated levels of two substances: porphobilinogen (por-foe-bih-LIN-uh-jen) and delta-aminolevulinic (uh-me-no-lev-yoo-LIN-ik) acids, as well as other porphyrins.
  • Blood test. If you have a form of cutaneous porphyria, a blood test may show an elevation in the level of porphyrins in your blood plasma.
  • Stool sample test. Analysis of a stool sample may reveal elevated levels of some porphyrins that may not be detected in urine samples. This test may help your doctor determine your specific type of porphyria.
More tests may be needed to confirm the type of porphyria you have. Genetic testing may be suggested in the family of a person with porphyria.

    Treatments and drugs

    By Mayo Clinic Staff
    Treatment depends on the type of porphyria you have and is directed at relieving symptoms.

    Acute porphyrias

    Treatment of acute porphyrias focuses on providing rapid treatment of symptoms and preventing complications. This may require hospitalization in severe cases. Treatment may include:
    • Stopping medications that may have triggered symptoms
    • Medication to control pain, nausea and vomiting
    • Prompt treatment of infections or other illness that may have caused symptoms
    • Intravenous sugar (glucose) or sugar taken by mouth, if able, to maintain an adequate intake of carbohydrates
    • Intravenous fluids to combat dehydration
    • Injections of hemin, a medication that is a form of heme, to limit the body's production of porphyrin

    Cutaneous porphyrias

    Treatment of cutaneous porphyrias focuses on reducing exposure to sunlight and the amount of porphyrins in your body to help eliminate your symptoms. This may include:
    • Drawing blood (phlebotomy). Drawing a certain amount of blood from one of your veins reduces the iron in your body, which decreases porphyrins. You may need to have a phlebotomy repeated at regular intervals before cutaneous porphyria goes into remission.
    • Medication. Drugs used to treat malaria — hydroxychloroquine (Plaquenil) or, less often, chloroquine (Aralen) — can absorb excess porphyrins and help your body get rid of them more quickly than usual. These medications are generally used only in people who can't tolerate a phlebotomy.
    • Beta carotene. Long-term treatment of cutaneous porphyrias may include daily doses of prescription beta carotene. Beta carotene may increase your skin's tolerance to sunlight. Your doctor can tell you what kind of beta carotene will work best for porphyria photosensitivity.
    • Reducing or eliminating triggers. Triggers, such as certain medications or too much sunlight, which activated the disease, should be reduced or removed if possible, with guidance from your doctor.
    • Vitamin D. Supplements may be recommended to replace vitamin D deficiency caused by avoidance of sunlight.
  •                     "Remember....Research is the key to your cure!"

Monday, January 25, 2016

Preparing for your appointment

Preparing for your appointment

By Mayo Clinic Staff
If you have signs and symptoms of porphyria, you're likely to start by seeing your primary care provider. However, because porphyria can be difficult to diagnose, you may be referred to a doctor who specializes in blood disorders (hematologist).
Here's some information to help you get ready, and what to expect from your doctor.

What you can do

Before your appointment, make a list of:
  • Any symptoms you're experiencing, including any that may seem unrelated to the reason for your appointment
  • Key personal information, including any major stresses or recent life changes
  • All medications, vitamins or other supplements that you're taking, including dosages
Preparing a list of questions before your appointment will help you make the most of your time. For porphyria, some basic questions to ask your doctor include:
  • What's the most likely cause of my symptoms?
  • What are other possible causes?
  • What kinds of tests do I need? Do I need genetic testing?
  • How severe is my condition?
  • What's the best course of action?
  • What are the alternatives to the primary approach that you're suggesting?
  • I have another health condition. How can I best manage these together?
  • Are there any dietary restrictions I need to follow?
  • What precautions do I need to take when spending time outdoors?
  • Do I need to be concerned about taking medications in the future?
  • Are there any brochures or other printed material that I can have? What websites do you recommend?
  • Should my family members be screened?
  • Will I need a medical alert bracelet?
Don't hesitate to ask any other questions during your appointment.

What to expect from your doctor

Your doctor is likely to ask you a number of questions, such as:
  • When did you first begin experiencing symptoms?
  • Have your symptoms been continuous or occasional?
  • How severe are your symptoms?
  • What, if anything, seems to improve your symptoms?
  • What, if anything, appears to worsen your symptoms?
  • Do any family members have similar symptoms?
       
                        "Remember....Research is the key to your cure!"

Friday, January 22, 2016

Risk Factors & Complications of All Porphyrias by Mayo Clinic

Risk factors

By Mayo Clinic Staff
In addition to genetic risks, environmental factors may trigger the development of signs and symptoms in some types of porphyria. When exposed to the trigger, your body's demand for heme production increases. This overwhelms the deficient enzyme, setting in motion a process that causes signs and symptoms. Examples of triggers include:
  • Certain drugs (barbiturates or sulfonamide antibiotics or, less often, birth control pills, or some drugs that affect the mind or behavior, known as psychoactive drugs)
  • Chemicals
  • Dieting or fasting
  • Smoking
  • Physical stress, such as infections or other illnesses
  • Liver disease
  • Emotional stress
  • Alcohol use
  • Menstrual hormones
  • Sun exposure
  • Excess iron in your body

Complications

By Mayo Clinic Staff
Possible complications of porphyria include:
  • Dehydration. Vomiting due to an attack of acute porphyria can lead to dehydration, which may require that you receive fluids through a vein (intravenously).
  • Breathing difficulties. Acute porphyrias can cause muscle weakness and paralysis, which can cause breathing problems. If left untreated, they can also lead to respiratory failure.
  • Low sodium in your blood. Called hyponatremia, this is usually linked to problems with sodium and water handling in your body.
  • High blood pressure. Porphyrin buildup can damage your kidneys and may result in high blood pressure (hypertension).
  • Chronic kidney failure. Porphyrin buildup may cause your kidneys to gradually lose their ability to function.
  • Liver damage. Some forms of porphyria cause excessive porphyrins in your liver, which may lead to severe liver damage that can eventually require a liver transplant.
  • Permanent skin damage. When your skin heals after cutaneous porphyria, it may have an abnormal appearance and coloring. Scars may remain on your skin as well, and lasting skin problems may cause your hair to fall out.
                         "Remember....Research is the key to your cure!"