FREQUENTLY ASKED QUESTIONS (FAQ) ABOUT THE PORPHYRIAS

Most porphyrias are inherited. However, one type, Porphyria Cutanea Tarda (PCT), may either be inherited (also referred to as “familial”) or “sporadic” due to various environmental factors. In each type of porphyria there is a deficiency of a specific enzyme. These enzymes are involved in the synthesis of heme, a substance important to many body functions which is found in large amounts in bone marrow and red blood cells (which contain hemoglobin), and which also has important functions in the liver, muscles, and other tissues. The type of porphyria present is determined by which enzyme is deficient; these enzyme deficiencies are usually inherited. Environmental factors, such as drugs, diet, and sun exposure can, depending on the type of porphyria, greatly influence the severity of symptoms.

The best way to classify a case of porphyria is to determine which enzyme is deficient, or not functioning properly. Normally these enzymes act in a sequence to make heme from simpler molecules. Heme is a vital substance for all body organs and consists of an iron atom surrounded by a porphyrin molecule. If a specific enzyme is not made properly or there is not enough of the enzyme, it cannot function properly and that step in the heme-making process cannot proceed.

Sometimes other classifications are useful. Most commonly the porphyrias are divided into the “acute” and “cutaneous” porphyrias, depending on the cardinal clinical features. The acute porphyrias [Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), and ALA-dehydratase Deficiency Porphyria (ALD)] present with attacks of severe abdominal pain that usually come on gradually over hours and last for several days; VP and HCP may also have skin manifestations of blistering after sun exposure. The cutaneous porphyrias present with blistering and scarring of the skin, pain, and/or redness and swelling in sun-exposed areas. The porphyrias may also be classified as “hepatic” or “erythropoietic”, depending on the organ where the porphyrins or their precursors, called ALA and PBG, are chiefly made:, the liver for the hepatic porphyrias [AIP, HCP, VP, Porphyria Cutanea Tarda (PCT), and Hepatoerythropoietic Porphyria (HEP)] or the bone marrow for the erythropoietic porphyrias [Congenital Erythropoietic Porphyria (CEP), Erythropoietic Protoporphyria (EPP), and X-Linked Protoporphyria (XLP)].

What diagnostic tests are available? Are the diagnostic tests the same for all porphyrias?

There are many laboratory tests available for the porphyrias, and the correct tests to order depend on the type of porphyria the doctor suspects. It is often difficult to decide which tests should be chosen, and the results may be difficult to interpret. The tests vary in sensitivity and specificity. If a test is “sensitive”, it is unlikely to be falsely negative (that is, fail to diagnose porphyria in a patient who has the disorder). If a test is “specific,” it is unlikely to be falsely positive (that is, diagnose porphyria in a patient who does not have the disorder). Certain tests are both sensitive and specific in patients who have symptoms that are suggestive of a porphyria. It is advisable to have the testing performed by a laboratory that has expertise in the clinical aspects of porphyria and can provide a valid interpretation of the test results. If testing has been performed in laboratories other than porphyria laboratories, consultation with a porphyria expert is advised before a final diagnosis is made.

When abdominal and neurological symptoms suggest an acute porphyria, the best screening tests are urinary aminolevulinic acid (ALA) and porphobilinogen (PBG). When there are cutaneous symptoms that suggest porphyria, the best screening test is a plasma porphyrin assay. If one of these screening tests is abnormal, more extensive testing, including urinary, fecal, and red blood cell porphyrins, are often indicated. Urinary, fecal, and red blood cell porphyrin measurements are not very useful for initial screening because they lack either sensitivity or specificity and, therefore, are often difficult to interpret. Measurement of heme biosynthetic enzymes in red blood cells or lymphocytes is not appropriate for screening unless it is part of a family study that is done after someone in the family is already known to have a specific enzyme deficiency. The table below summarizes the tests to be done for each type of porphyria.

 

Type of Porphyria		Most Common Symptoms	Biochemical Lab Tests	Labs to Use
Acute Porphyrias	Acute Intermittent Porphyria (AIP)	Acute attacks of severe abdominal pain, nausea, vomiting, rapid heartbeat and other symptoms. These attacks generally last for several days or longer and can be frequent or infrequent. They can be triggered by certain medications. Symptoms are very rare before puberty.	Urine Porphobilinogen (PBG) done during an acute attack	UTMB, ARUP, Mount Sinai**, Mayo, Quest, LabCorp
Variegate Porphyria (VP)	Same as in AIP. Also, can have blistering on sun exposed areas of the skin. Symptoms rare before puberty.	Urine PBG done during an acute attack Urine total porphyrins Plasma porphyrins and fluorescence emission peak at 626 nm* *Following excitation by light of 410 nm	UTMB, ARUP, Mayo, Quest, LabCorp
Hereditary Coproporphyria (HCP)	Same as VP, but skin blistering less common.	Urine PBG done during an acute attack Urine total porphyrins Plasma porphyrins Stool porphyrins	UTMB, ARUP, Mayo, Quest, LabCorp
Porphyria Cutanea Tarda (PCT)	Blistering and skin fragility (skin that tears easily) on the sun exposed areas. Rare in children.	Urine total porphyrins Plasma porphyrins	UTMB, ARUP, Mayo, Quest, LabCorp
Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP)	Severe pain on sun exposed areas of the skin, with swelling, lasting several days. Generally, there is no blistering. Symptoms usually start in infancy or childhood.	Erythrocyte protoporphyrin Plasma porphyrins	UTMB, ARUP or Mayo
Congenital Erythropoietic Porphyria (CEP)	Severe blistering on sun exposed areas of the skin that can result in infections and scarring. Generally, symptoms start at birth or in early childhood.	Urine total porphyrins Plasma porphyrins	UTMB, ARUP, Mayo, Quest, LabCorp *

**The Mount Sinai Lab only tests for urine PBG

NOTE –; To diagnose all of the porphyrias GENETIC TESTING is also recommended. Information on genetic testing can be found here.

However, many patients have not had an acute attack or are not symptomatic at present, so biochemical testing may be inconclusive. In contrast, DNA testing is the most accurate and reliable method for determining if a person has a specific porphyria and is considered the "gold standard" for the diagnosis of genetic disorders. If a known disease-causing mutation (or change) in the DNA sequence is found in a specific Porphyria-causing gene, the diagnosis of that Porphyria is confirmed. DNA analysis will detect more than 97% of known disease-causing mutations. DNA testing can be performed whether the patient is symptomatic or not. Once a mutation has been identified, DNA analysis can then be performed on other family members to determine if they have inherited that Porphyria, thus allowing identification of individuals who can be counseled about appropriate management in order to avoid or minimize disease complications.

Is the free genetic testing accurate?

This is offered at the present time by the Alnylam Act program. Certain criteria must be met. Testing is by Invitae, which provides very reliable results. Contact the American Porphyria Foundation to learn more about this no-charge testing. 301-APF-3635.

How can it be determined from saliva?

DNA is usually prepared from blood but can also be found in other body fluids including saliva.

What is a Variant of Unknown Significance?

Some differences, or variants, in DNA do not cause disease and are referred to as benign. Those that are known to cause disease are called pathogenic, or disease-causing. Variants of unknown significance are those that need further study to see if they are pathogenic or benign.

Is Enzyme Testing used?

Enzyme testing is used for some porphyrias, such as AIP, but is less reliable than DNA testing.

What are the names of the biochemical testing for blood and stool?

Porphyrins are measured in blood plasma (or serum), red blood cells, urine and stool. ALA and PBG are best measured in urine, because levels are higher than in plasma. But measurement of PBG in plasma is important for diagnosis of AHP in patients with advanced kidney disease.

There are Porphyria experts in the US and outside the US, including the Porphyria Centers in this Physicians Consortium. Information about other experts can be obtained by contacting the American Porphyria Foundation (www.porphyriafoundation.com). If a porphyria is suspected, any physician can order the appropriate tests. Since interpretation of these results may be difficult, it is best for the physician or healthcare professional to consult with a porphyria expert for an accurate interpretation of the results and, if necessary, advice about additional testing, treatment, or prevention and precautionary measures.

Depending on the type of porphyria you have, biochemical testing should be performed prior to genetic testing. For the acute porphyrias, the most important tests are urine delta-aminolevulinic acid and porphobilinogen, which are always elevated during acute porphyria attacks. In the cutaneous porphyrias, urine or plasma fractionated porphyrin testing is recommended. While all porphyrias are inherited, porphyria cutanea tarda can develop in the absence of a genetic mutation in the UROD gene.

Because all porphyrias are rare, it is very unlikely that more than one type of porphyria will occur in the same family, or that a person with one type of porphyria will have an additional type. However, patients with more than one type of porphyria have been reported.

The liver is affected differently for each type of porphyria. Please refer to the disorder definitions page about your type of porphyria for more information on how the liver is involved. Although the different types of porphyria affect the liver differently, liver function tests should be performed routinely (usually annually) on all individuals diagnosed with any type of porphyria.

Such a situation needs to be dealt with on an individual basis. Whether further testing is recommended depends on how the patient was initially diagnosed and how the porphyria expert made the decision that porphyria is not the diagnosis. The results of biochemical testing are sometimes interpreted incorrectly by a physician who is not an expert in porphyria. Review of the results of the biochemical testing by a porphyria expert may determine that the results are not consistent with what is typically seen in a patient with porphyria during an attack. The results of DNA analysis may also contribute to the porphyria expert saying that it is unlikely that the patient has porphyria. DNA analysis, although considered to be the “gold standard” for diagnosis, is not perfect in that the patient may have a mutation in a part of the porphyria gene that is not analyzed by routine testing or the patient has a mutation in a porphyria gene that was not analyzed. If a diagnosis of porphyria is still suspect, then it is recommended that the patient undergo additional biochemical testing at the time of an acute attack. Additionally, further testing may include DNA analysis for other acute porphyrias (if only one or two were tested).

Yes, we are conducting research about the porphyrias. For additional information about our studies and how to volunteer to participate, please contact the American Porphyria Foundation on 866-APF-3635.

None of the porphyrias are contagious. However, one of the major risk factors for development of acquired PCT, [PCT type 1] is infection with the hepatitis C virus [HCV]. A lesser risk factor for PCT type 1 is infection with the human immunodeficiency virus [HIV]. These common viral infections are contagious.

The heme biosynthetic pathway is one of the key metabolic pathways that leads from the simple building blocks of the amino acid glycine and the dicarboxylic acid succinic acid to the formation first of 5-aminolevulinic acid [ALA], then to the monopyrrole porphobilinogen [PBG], then to porphyrinogens and porphyrins [four pyrrole rings strung together and closed on themselves], and, in the eighth step, to the insertion of an iron atom into the center of the protoporphyrin ring to form heme. Nearly all cells of the human body contain heme, which is essential to carry out many essential functions. Heme functions mainly as a small molecule that binds to proteins to form a large class of proteins called ‘hemoproteins.’ Hemoglobin is one such essential hemoprotein; it is found mainly in developing and adult red blood cells, where it functions to carry oxygen absorbed from air in the lungs to cells and tissue throughout the body. Hemoglobin also functions to carry carbon dioxide, a waste product formed by the metabolic functions of most cells, from these cells back to the lungs, where the carbon dioxide is released into the expired air and where the hemoglobin again picks up more oxygen.

Most of the heme that is synthesized in the human body is made in developing red blood cells, to provide for the formation of heme for hemoglobin. In the erythropoietic porphyrias, the major site of the overproduction of heme precursors is the developing red blood cells. Thus, the name erythropoietic porphyria.

The other major organ where heme is made is the liver. When the major overproduction of heme precursors occurs in the liver, the disorder is called a hepatic porphyria.

For the pain of acute porphyric attacks, prompt treatment of underlying causes of the acute attacks, such as cessation of alcohol intake or stopping drugs or chemicals that can trigger acute attacks, treatment of intercurrent illnesses is essential. Maintenance of adequate nutrition and fluid intake is also important: during acute attacks, patients, who are mostly women between the ages of 15-50 years, often have nausea and vomiting and are unable to eat or drink adequate amounts of food and fluids. In particular, during attacks, an intake of carbohydrates and starches [at least 300 g of sugars/starches per day] is important. If the acute attacks are more severe, they should be treated also with intravenous heme, given at a daily dose of 3 mg/ kg body weight per day.

Acetaminophen [Tylenol and other brands] is the analgesic of first choice, because it is safe if used in amounts that do not exceed 3 grams per day [9 regular strength or 6 extra-strength tablets]. The addition of a phenothiazine, such as promethazine [Phenergan] or prochlorperazine [Compazine] can help to increase the effect of acetaminophen, can help to decrease nausea and vomiting, and can also decrease anxiety and agitation, which are frequent symptoms curing acute attacks. Narcotic analgesics, such as oxycodone, hydrocodone, meperidine, morphine, fentanyl, and others, may be needed for severe attacks. Because of their risks of adverse side effects, such as respiratory depression, constipation, nausea, gastro-esophageal motor dysfunction, narcotic analgesics are best used only for a short time [not more than 5 days]. A major and ongoing problem faced by too many patients with acute porphyrias is that they have been using narcotics chronically and have become addicted to them and thus will suffer withdrawal symptoms when they try to stop them. Patients who are chronically using narcotics should best be managed long-term by specialists in chronic pain management and with a goal of decreasing and stopping their use of chronic narcotics, benzodiazepines, and other habit-forming medications.

For the acute pain of a severe phototoxic reaction, as may occur in EPP or XLP, the key is avoidance of any further sun or strong light exposure and the use of ice packs/cold compresses on the most severely affected areas of the skin. Some patients seem to benefit from a short course of potent, anti-inflammatory medication, such as prednisone [in tapering doses of 30, 25, 20, 15, 10, 5 mg on 6 successive days] or methylprednisolone [Medrol dose pak]. Others may derive some benefit from a combination of H1 [diphenhydramine (Benadryl)] and H2- [cimetidine [Tagamet], famotidine (Pepcid)] antihistamine blockers or from combination histamine and serotonin blockade with cyproheptadine [Periactin].

It is not possible to provide a general or generic answer this question. This requires the thoughtful assessment of each patient by a board-certified specialist in general internal medicine, perhaps, in consultation with selected sub-specialists.

This depends upon the specific type of porphyria and the severity. For most patients, the life expectancy is similar to that of persons without porphyria. In the case of patients with acute hepatic porphyrias, especially those with chronic overproduction of ALA and PBG, there are increased risks of development of systemic arterial hypertension, chronic kidney disease, and, usually later in life [after age 50-55 years] development of hepatocellular carcinoma [primary liver cell cancer]. These conditions can be treated successfully, so such patients should be screened on a regular basis [at least once every 6 months] for the development of these complications. If they are found, they should be treated and controlled.

For most patients with porphyria, there is no contraindication to their having children. Women with an acute porphyria are more prone to have acute attacks during pregnancy and in the post-partum period, and these may require prompt and careful treatment. Such pregnancies are best monitored by an Ob-Gyn specialist with expertise in high-risk pregnancies. The risks of transmitting the genetic abnormalities that usually underlie the porphyrias to children are usually 50/50. If a child inherits an autosomal dominant mutation, such as one that causes AIP, from a parent, the odds that such a child will, in turn, pass the mutation on to his or her child [grandchild of the grandparent] is also 50/50.

There are different treatment options available for acute and cutaneous porphyrias.

Acute Porphyrias:
Treatment for acute attacks requiring hospitalization is hemin (Panhematin) which is given intravenously. During hospitalization, patients typically get one dose a day for about 4 days. In addition to hemin, patients may need intravenous fluids, medications to control nausea, high blood pressure and pain.

Patients who have recurrent (frequent) attacks may sometimes be recommended hemin infusions as an outpatient. This can be given on a regular schedule or when a patient is in early stages of an attack.

Recently a new drug called Givlaari (Givosiran) was approved for patients with acute hepatic porphyrias. This drug was tested in patients with recurrent attacks (> 4 attacks/year) to prevent attacks. Givosiran has not been tested for the management of acute attacks in the hospital.

In addition to these, patients with acute porphyria may develop chronic (daily) symptoms and may need medications to control pain, nausea and other symptoms

The choice of therapy may depend on the patients symptoms and should be made by the treating physician after a complete evaluation.

Cutaneous Porphyrias:
There are different types of cutaneous porphyrias, and the treatment varies by type.

EPP: The primary mode of symptom management for EPP patient has been sun avoidance. Medications such as beta-carotene, cysteine, vitamin C and others have been tried however there is no clear evidence that any of them are effective.

Scenesse (Afamelanotide ) was recently approved by the FDA for the treatment of EPP. This drug is administered in the subcutaneous tissue (just below the skin) through a large needle after numbing the area. The implant is administered once every 2 months and is bioresorbable (dissolves by itself ). This works by increasing the amount of melanin in the skin which makes the skin darker. In addition, this may have some anti-inflammatory properties. Studies show that patients taking this drug can spend longer time in the sun without pain.

There is another medication called MT 7117 in clinical trials for patients with EPP. This medication is in a pill form and is taken daily. It also works by increasing melanin in the skin and may have anti-inflammatory properties.

CEP: CEP is an extremely rare disorder and the symptoms are very variable. Some patients may require a bone marrow transplant, others may need ongoing blood transfusions and other supportive care. In addition, patients should avoid the sun to prevent symptoms and blister formation.

PCT: PCT is one of the most common porphyrias. The primary treatment is phlebotomy (bloodletting) till the blisters disappear and the urine and blood tests normalize. In addition, there is an oral medication chloroquine which can be used to control symptoms. In all cases of PCT, it’s important to treat the underlying factor contributing to the disease manifestations such as hepatitis C, HIV, excessive alcohol consumption etc.

It is important to remember that all patients respond differently to medications and treatment should be individualized to the patient.

Treatment during pregnancy should be administered only after careful evaluation of risk and benefit. For the acute porphyrias, hemin has been safely used during pregnancy and does not appear to impact the fetus. Givlaari has not been tested in pregnant women and should not be used in patients who are pregnant or planning a pregnancy. Scenesse has also not been tested in pregnant women and should not be used during pregnancy.