Thursday, September 29, 2016

Do you know about EPP or 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 it is 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.
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.  

Additional Reading about EPP and below that is more info on XLP:
Erythropoietic Protoporphyria
NORD gratefully acknowledges Micheline M. Mathews-Roth, MD, Associate Professor of Medicine, Harvard Medical School, for assistance in the preparation of this report.
Synonyms of Erythropoietic Protoporphyria
  • EPP
  • Erythrohepatic Protoporphyria
  • Protoporphyria
General Discussion
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.
Signs & Symptoms
The most common symptom of erythropoietic protoporphyria is hypersensitivity of the skin to sunlight and some types of artificial light (photosensitivity), with pain, itching, and/or burning of the skin occurring after exposure to sunlight and occasionally to fluorescent light. Affected individuals may also exhibit abnormal accumulations 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 (vesicles or bullae), scar, and/or become discolored (hyperpigmentation) 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. In addition, in some cases, affected individuals may also exhibit malformations of the nails. The severity and degree of photosensitivity is different from case to case. Photosensitivity is often seen during infancy; however, in some cases, it may not occur until adolescence or 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.
Symptoms usually start in childhood but diagnosis is often delayed since blistering is not common and, because the porphyrins are insoluble, they usually escape detection on urinanalysis. The diagnosis is made upon finding increased levels of the protoporphyrin in the plasma or red blood cells.
Causes
Erythropoietic protoporphyria is a rare disorder inherited as an autosomal dominant genetic trait with poor penetrance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.
The symptoms of erythropoietic protoporphyria develop due to excessive levels of a chemical called protoporphyrin that accumulates in certain tissues of the body (i.e., the plasma, red blood cells, and the liver). Excessive protoporphyrin levels occur as the result of abnormally low levels of the enzyme ferrochelatase (FECH).
There are several different allelic variants of erythropoietic protoporphyria. An allele is any of a series of two or more genes that may occupy the same position (locus) on a specific chromosome. Symptoms of these allelic variants of erythropoietic protoporphyria are predominantly the same; however, one type may be inherited as an autosomal recessive genetic trait.
The gene that is responsible for regulating the production of the enzyme ferrochelatase (FECH) has been located on the long arm of chromosome 18 (18q21.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q”.
Some people who have inherited this defective gene may have slightly elevated levels of protoporphyrin in the body but will not exhibit the symptoms of erythropoietic protoporphyria.
Affected Populations
Erythropoietic protoporphyria is a very rare inherited disorder that affects males and females in equal numbers. It is estimated that the disorder occurs in about 1 in about 74,300 individuals. The onset of symptoms affecting the skin usually occurs in infancy; however, in some cases, onset may not occur until adolescence or adulthood. More than 300 cases of EPP have been reported in the medical literature.
Related Disorders
Symptoms of the following disorders can be similar to those of EPP. Comparisons may be useful for a differential diagnosis:
There are several other types of porphyrias, all of which involve deficiencies of specific enzymes. Most of the symptoms of these porphyrias are not similar to the symptoms found in erythropoietic protoporphyria. Individuals with porphyria cutanea tarda and congenital erythropoietic porphyria may develop skin lesions; however, these lesions do not resemble the skin lesions found in EPP. It is important to note that individuals with one type of porphyria do not develop any of the other types. In addition, there are skin disorders characterized by hypersensitivity to artificial light and sunlight besides EPP, such as xeroderma pigmentosum and epidermolysis bullosa. The skin lesions in these disorders do not resemble the skin lesions in EPP. (For more information on these disorders, choose “Porphyria and Epidermolysis Bullosa” as your search terms in the Rare Disease Database.)
Xeroderma pigmentosum (XP) is a group of rare inherited skin disorders characterized by hypersensitivity of sunlight and some types of artificial light, with skin blistering occurring after such exposure. In some cases, pain and blistering may occur immediately after contact with sunlight or artificial light. Acute sunburn and persistent redness or inflammation of the skin (erythema) are also early symptoms of xeroderma pigmentosum. In most cases, these symptoms may be apparent immediately after birth or occur within the next three years. Other skin symptoms of xeroderma pigmentosum may include discolorations of the skin, weak and fragile skin, and/or scarring of the skin. Xeroderma pigmentosum also affects the eyes; the most common symptom being an extreme intolerance to light (photophobia). Additional symptoms may include some neurological impairments, short stature, an increased susceptibility to some forms of cancer (e.g., skin cancer). There are several types of xeroderma pigmentosum; in most cases, XP is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose “Xeroderma Pigmentosum” as your search terms in the Rare Disease Database).
Diagnosis
The diagnosis of erythropoietic protoporphyria (EPP) may be made by a thorough clinical evaluation, characteristic physical findings, and specialized laboratory tests. EPP is usually diagnosed during infancy or early childhood, due to characteristic skin symptoms. The diagnosis may be confirmed by testing the red blood cells (erythrocytes) for increased levels of protoporphyrin.
Standard Therapies
Treatment
Avoidance of sunlight will be of benefit to individuals with erythropoietic protoporphyria. The use of topical sunscreens, double layers of clothing, long sleeves, hats, and sunglasses will also benefit photosensitive individuals. Individuals with EPP may also benefit from window tinting or using vinyls or 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 erythropoietic protoporphyria, a high potency form of oral beta-carotene (Lumitene, Tishcon) may be given to improve an affected individual's tolerance of sunlight. For more information on this treatment, contact the organizations listed at the end of this report (i.e., American Porphyria Foundation and the EPPREF) and Mr. George McShane of the Tishcon Corp. (1-800-848-8442). In some cases, the drug cholestyramine may be given to alleviate skin symptoms and lower the protoporphyrin levels in the body.
When iron deficiency is present, iron supplements may be given. A type of bile acid (chenodeoxycholic acid) may be prescribed to help the liver dispose of excess protoporphyrin, and activated charcoal or cholestyramine may be used to interrupt the circulation of protoporphyrin through the liver and intestines.
Estrogens and drugs that can impair bile flow should be given cautiously under the supervision of a physician. 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.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Investigational Therapies
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
For information about clinical trials sponsored by private sources, contact:
The orphan product L-Cysteine is being tested for the prevention and reduction of photosensitivity in erythropoietic protoporphyria. More research is needed to determine the long-term safety and effectiveness of this drug for the treatment EPP. For more information, contact:
Micheline M. Mathews-Roth, M.D.
Channing Laboratory
Harvard Medical School
181 Longwood Ave
Boston, MA 02115-5804
Red blood cell transfusions have also been used to treat some people with EPP. In some affected individuals with severe liver disease, liver transplantations have been performed. Extreme caution should be used by physicians considering these treatment options; each particular case should be evaluated on its own merits.

Tuesday, September 27, 2016

Hereditary Coproporphyria. (HCP) Porphyria Expert Dr. Bissell

Hereditary Coproporphyria.

Authors

Source

GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
2012 Dec 13 [updated 2015 Jul 1].

Excerpt

CLINICAL CHARACTERISTICS:

Hereditary coproporphyria (HCP) is an acute (hepatic) porphyria in which the acute symptoms are neurovisceral and occur in discrete episodes. Attacks typically start in the abdomen with low-grade pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting. In some individuals, the pain is predominantly in the back or extremities. When an acute attack is untreated, a motor neuropathy may develop over a period of days or a few weeks. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Some individuals experience respiratory insufficiency due to loss of innervation of the diaphragm and muscles of respiration. Acute attacks are associated commonly with use of certain medications, caloric deprivation, and changes in female reproductive hormones. About 20% of those with an acute attack also experience photosensitivity associated with bullae and skin fragility.

DIAGNOSIS/TESTING:

The most sensitive and specific biochemical screening test for any one of the acute porphyrias (including HCP) during an acute attack is a striking increase in urinary porphobilinogen (PBG). Quantitative analysis of porphyrins in both urine and feces is essential to distinguish between the different acute porphyrias and establish the diagnosis of HCP. Identification of a heterozygous pathogenic variant inCPOX (encoding the enzyme coproporphyrinogen-III oxidase) confirms the diagnosis and enables family studies.

MANAGEMENT:

Treatment of manifestations: Acute attacks are treated by discontinuation of any medications thought to induce attacks, management of dehydration and/or hyponatremia, administration of carbohydrate, and infusion of hematin. Treatment of symptoms and complications should be with medications known to be safe in acute porphyria (see www.drugs-porphyria.org). A minority of affected individuals experience repeat acute attacks, in which case management strategies include suppression of ovulation in females, prophylactic use of hematin, and liver transplantation when attacks and neurologic complications persist despite multiple courses of hematin. Prevention of primary manifestations: Agents or circumstances that may trigger an acute attack (including use of oral contraception in women) are avoided. Suppression of menses using a GnRH agonist (leuprolide, nafarelin, and others) may help CPOX heterozygotes who experience monthly exacerbations. Prevention of secondary complications: In CPOX heterozygotes undergoing surgery, intravenous glucose is provided in the perioperative period and non-barbiturate agents are used for induction of anesthesia. Agents/circumstances to avoid: Fasting, use of female reproductive hormones, and certain drugs including barbiturates and phenytoin. Evaluation of relatives at risk: If the family-specific CPOXpathogenic variant is known, clarification of the genetic status of relatives at risk allows early diagnosis of heterozygotes and education regarding how to avoid risk factors known to be associated with acute attacks.

GENETIC COUNSELING:

HCP is inherited in an autosomal dominant manner with reduced penetrance. Most individuals with HCP have an affected parent; the proportion with a de novo pathogenic variant is unknown. Each child of an individual with HCP has a 50% chance of inheriting the CPOX pathogenic variant. Because of reduced penetrance, many individuals with a CPOX pathogenic variant have no signs or symptoms of HCP. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in an affected family member is known.
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                                              "Remember....Research is the key to your cure!"

Monday, September 26, 2016

PCT- Clinical Presentations

Porphyria cutanea tarda (PCT) is a term encompassing a group of acquired and familial disorders in which activity of the heme synthetic enzyme uroporphyrinogen decarboxylase (UROD) is deficient. Approximately 80% of all cases of porphyria cutanea tarda are acquired; 20% are familial, although the ratio may vary among different geographic regions and ethnic groups.
Familial porphyria cutanea tarda most often arises from autosomal dominant inheritance of a single mutation of the UROD gene. Human UROD has been mapped to band 1p34. To date, 121 UROD mutations are listed by the Human Genome Mutation Database. A rare recessive familial type of porphyria cutanea tarda in which both UROD alleles are mutated is termed hepatoerythropoietic porphyria. Familial porphyria cutanea tarda without detectable UROD mutations has been reported.
The common acquired form, sporadic porphyria cutanea tarda, occurs in individuals whose UROD DNA sequences are normal, but who may have other genetically determined susceptibilities to inhibition of UROD activity. Acquired porphyria in large populations exposed to polyhalogenated aromatic hydrocarbon hepatotoxins has been referred to as "epidemic” porphyria cutanea tarda. Hepatic tumors producing excess porphyrins are rare causes of porphyria cutanea tarda–like disorders.
Clinical expression of both sporadic and familial porphyria cutanea tarda most often requires exposure to environmental or infectious agents or the presence of coexisting conditions that adversely affect hepatocytes and result in hepatic siderosis. Ethanol intake, estrogen therapies, hemochromatosis genes, and hepatitis and human immunodeficiency viral infections are among these contributory factors.The increased oxidative stress associated with all of these factors has been shown to reduce hepatic expression of the gene encoding hepcidin, a regulator of iron absorption and metabolism, thus increasing iron absorption and iron overload. Excess iron facilitates formation of toxic oxygen species, thus amplifying porphyrinogenesis by catalyzing formation of oxidative inhibitors of UROD enzyme activity.Accumulating porphyrins in hepatocytes may then further down-regulate hepcidin gene expression.   Most patients with porphyria cutanea tarda have increased iron burden; iron-reduction therapies can lead to clinical and biochemical remissions; subsequent reaccumulation of iron stores may lead to symptomatic recurrence.
Reduced UROD activity causes polycarboxylated porphyrinogen intermediaries of heme synthesis to accumulate in hepatocytes; these excess substrates then undergo iron-facilitated spontaneous oxidization to photoactive porphyrins. Porphyrin by-products of the pathway exit the hepatocytes, are distributed throughout the body in blood plasma, mediate photooxidative chemical reactions causing skin lesions, and yield the abnormal excretory porphyrin profiles that characterize porphyria cutanea tarda. Partial oxidation of uroporphyrinogen to the UROD inhibitor uroporphomethene occurs in murine porphyria cutanea tarda models and has been suggested as a pathogenic mechanism in the human disease.[9] Reduction of hepatic UROD activity to approximately 25% of normal, most often reflecting effects of multiple genetic and/or exogenous inhibitory factors, is required for clinical disease expression.

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

Monday, September 19, 2016

Lina Rebeiz and her personal journey with AIP

  My porphyria symptoms started right after orientation of my freshman year of college. The pain started in my lower back and quickly moved to my abdomen, and within an hour I was curled up in my bed crying. My initial thought was that this must be food poisoning, and that my Resident Advisor's suggestion to go to the ER was ridiculous. When I woke up the next day, the pain had doubled and I began vomiting uncontrollably. I went directly to our student health and wellness center, where I was given Urinary Tract Infection (UTI) medication and advised to visit the ER if my symptoms worsened.
As the pain continued to intensify, I could not believe that this sensation was humanly possible. As soon as I thought the pain had reached its absolute limit, it would double. I finally decided to go to the ER, where I waited hours before being seen, only to be told that I should hydrate and relax for my ‘UTI’ to go away. Nevertheless, because of the intensity of my pain, I was admitted to the hospital overnight while the doctors ran tests. When everything came back negative, I was sent home and told to go about my life normally. My parents, who had come to visit me while I was in the hospital, both scratched their heads at my weird symptoms. Though they are both physicians, they could not think of what could possibly be causing this misery.

After being discharged from the hospital un-diagnosed, I returned to the health and wellness center every day (sometimes multiple times a day) in the hopes that somebody would figure out what was wrong with me. I couldn’t go to the hospital because they had already discharged me without a diagnosis. The pain was too unbearable to attend class, my parents made me feel guilty for staying home to rest, and everyone considered me an over-dramatic hypochondriac. Doctors repeated appendicitis and UTI tests, and every day they would tell me again that nothing was wrong with me. When I would call my parents crying, they would insist that I should trust the doctors and just relax. Unsure of what to do, I stopped going to class altogether because standing up and walking a few feet felt like running a marathon.

        Over the course of a few weeks I lost more than 20 pounds; anything I tried to consume or drink (including water) would instantly be thrown up. After a month of being told that the symptoms were in my head, I started to believe the doctors. I stopped talking to my friends because I could not explain what was wrong with me; I stopped calling my parents and just retreated into my room until I eventually started getting better on my own.

        Several months later, while on winter vacation with my family, my symptoms returned with a vengeance after I started taking birth control pills. My family, convinced that I had suffered something traumatic that I didn’t want to share, insisted that I should take a break from school until I got better. I knew that this suggestion was ridiculous, and that there had to be something physically wrong with me. But without any medical evidence nobody believed me, and so we kept ignoring my symptoms.
After another two weeks, I again became malnourished -- but this time I also became delusional. My blood pressure had risen so high and my sodium had dropped so low that I suffered two seizures. During this episode, all I remember is the recurring feeling of insanity. I experienced mild hallucinations paired with strong delusions, and I always felt confused and scared. I had a constant feeling of worry, but not about anything concrete. Though it sound ridiculous now, I felt like something abstract, perhaps a monster, was out to get me.

It was during this episode that I was finally diagnosed. After the seizures, I was being treated at Tufts Medical Center, where my dad works; I am sure that without his stature as head of the otolaryngology department I would have been ignored once more. It took a whole team of doctors to figure out what was causing my symptoms; with the seizures and the PRES syndrome that followed, we finally had proof that these symptoms could not have been psychosomatic. With a stroke of luck, they sent out the test for Porphyria, and within a week the results came back positive.

When I received Panhematin, I bounced back within two days. After months of hell, I cannot put into words how relieved I was to receive an official diagnosis, and to start treatment. Now, having a diagnosis of Acute Intermittent Porphyria, I am confident that my symptoms will never be as extreme as they were then. I still do have sporadic attacks, but I am now able to recognize them and receive treatment early on. Though every day I wake up and wonder if that dull ache in my stomach, or that abstract feeling of anxiety means that a full-blown attack is coming, I have learned to manage the pain and to take it one day at a time.

Friday, September 16, 2016

Learning about Porphyria

Learning about Porphyria

To view entire link:  https://www.genome.gov/19016728/learning-about-porphyria/

What is porphyria?

The porphyrias are a group of different diseases, each caused by a specific abnormality in the heme production process. Heme is a chemical compound that contains iron and gives blood its red color. The essential functions of heme depend on its ability to bind oxygen. Heme is incorporated into hemoglobin, a protein that enables red blood cells to carry oxygen from the lungs to all parts of the body. Heme also plays a role in the liver where it assists in breaking down chemicals (including some drugs and hormones) so that they are easily removed from the body.
Heme is produced in the bone marrow and liver through a complex process controlled by eight different enzymes. As this production process of heme progresses, several different intermediate compounds (heme precursors) are created and modified. If one of the essential enzymes in heme production is deficient, certain precursors may accumulate in tissues (especially in the bone marrow or liver), appear in excess in the blood, and get excreted in the urine or stool. The specific precursors that accumulate depend on which enzyme is deficient. Porphyria results in a deficiency or inactivity of a specific enzyme in the heme production process, with resulting accumulation of heme precursors.

What are the signs and symptoms of porphyria?

The signs and symptoms of porphyria vary among types. Some types of porphyria (called cutaneous porphyria) cause the skin to become overly sensitive to sunlight. Areas of the skin exposed to the sun develop redness, blistering and often scarring.
The symptoms of other types of porphyria (called acute porphyrias) affect the nervous system. These symptoms include chest and abdominal pain, emotional and mental disorders, seizures and muscle weakness. These symptoms often appear quickly and last from days to weeks. Some porphyrias have a combination of acute symptoms and symptoms that affect the skin.
Environmental factors can trigger the signs and symptoms of porphyria. These include:
  • Alcohol
  • Smoking
  • Certain drugs, hormones
  • Exposure to sunlight
  • Stress
  • Dieting and fasting

How is porphyria diagnosed?

Porphyria is diagnosed through blood, urine, and stool tests, especially at or near the time of symptoms. Diagnosis may be difficult because the range of symptoms is common to many disorders and interpretation of the tests may be complex. A large number of tests are available, however, but results among laboratories are not always reliable.

How is porphyria treated?

Each form of porphyria is treated differently. Treatment may involve treating with heme, giving medicines to relieve the symptoms, or drawing blood. People who have severe attacks may need to be hospitalized.

What do we know about porphyria and heredity?

Most of the porphyrias are inherited conditions. The genes for all the enzymes in the heme pathway have been identified. Some forms of porphyria result from inheriting one altered gene from one parent (autosomal dominant). Other forms result from inheriting two altered genes, one from each parent (autosomal recessive). Each type of porphyria carries a different risk that individuals in an affected family will have the disease or transmit it to their children.
Porphyria cutanea tarda (PCT) is a type of porphyria that is most often not inherited. Eighty percent of individuals with PCT have an acquired disease that becomes active when factors such as iron, alcohol, hepatitis C virus (HCV), HIV, estrogens (such as those used in oral contraceptives and prostate cancer treatment), and possibly smoking, combine to cause an enzyme deficiency in the liver. Hemochromatosis, an iron overload disorder, can also predispose individuals to PCT. Twenty percent of individuals with PCT have an inherited form of the disease. Many individuals with the inherited form of PCT never develop symptoms.
If you or someone you know has porphyria, we recommend that you contact a genetics clinic to discuss this information with a genetics professional. To find a genetics clinic near you, contact your primary doctor for a referral.

What triggers a porphyria attack?

Porphyria can be triggered by drugs (barbiturates, tranquilizers, birth control pills, sedatives), chemicals, fasting, smoking, drinking alcohol, infections, emotional and physical stress, menstrual hormones, and exposure to the sun. Attacks of porphyria can develop over hours or days and last for days or weeks.

How is porphyria classified?

The porphyrias have several different classification systems. The most accurate classification is by the specific enzyme deficiency. Another classification system distinguishes porphyrias that cause neurologic symptoms (acute porphyrias) from those that cause photosensitivity (cutaneous porphyrias). A third classification system is based on whether the excess precursors originate primarily in the liver (hepatic porphyrias) or primarily in the bone marrow (erythropoietic porphyrias). Some porphyrias are classified as more than one of these categories.

What are the cutaneous porphyrias?

The cutaneous porphyrias affect the skin. People with cutaneous porphyria develop blisters, itching, and swelling of their skin when it is exposed to sunlight. The cutaneous porphyrias include the following types:
Also called congenital porphyria. This is a rare disorder that mainly affects the skin. It results from low levels of the enzyme responsible for the fourth step in heme production. It is inherited in an autosomal recessive pattern.

An uncommon disorder that mainly affects the skin. It results from reduced levels of the enzyme responsible for the eighth and final step in heme production. The inheritance of this condition is not fully understood. Most cases are probably inherited in an autosomal dominant pattern, however, it shows autosomal recessive inheritance in a small number of families.

A rare disorder that mainly affects the skin. It results from very low levels of the enzyme responsible for the fifth step in heme production. It is inherited in an autosomal recessive pattern.

A rare disorder that can have symptoms of acute porphyria and symptoms that affect the skin. It results from low levels of the enzyme responsible for the sixth step in heme production. It is inherited in an autosomal dominant pattern.

The most common type of porphyria. It occurs in an estimated 1 in 25,000 people, including both inherited and sporadic (noninherited) cases. An estimated 80 percent of porphyria cutanea tarda cases are sporadic. It results from low levels of the enzyme responsible for the fifth step in heme production. When this condition is inherited, it occurs in an autosomal dominant pattern.

A disorder that can have symptoms of acute porphyria and symptoms that affect the skin. It results from low levels of the enzyme responsible for the seventh step in heme production. It is inherited in an autosomal dominant pattern.

What are the acute porphyrias?

The acute porphyrias affect the nervous system. Symptoms of acute porphyria include pain in the chest, abdomen, limbs, or back; muscle numbness, tingling, paralysis, or cramping; vomiting; constipation; and personality changes or mental disorders. These symptoms appear intermittently. The acute porphyrias include the following types:
This is probably the most common porphyria with acute (severe but usually not long-lasting) symptoms. It results from low levels of the enzyme responsible for the third step in heme production. It is inherited in an autosomal dominant pattern.

A very rare disorder that results from low levels of the enzyme responsible for the second step in heme production. It is inherited in an autosomal recessive pattern.

NHGRI Clinical Research in Porphyria

Currently, NHGRI is not conducting research on Porphyria.

Additional Resources for Porphyria

Foundations and Associations

Online Resources for Specific Porphyrias

Cutaneous Porphyrias
Information from the National Library of Medicine
Acute Porphrias
Information from the National Library of Medicine

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