NORD gratefully acknowledges Karl E. Anderson, MD, FACP, Galveston Porphyria Laboratory & Center, University of Texas Medical Branch/UTMB Health, for assistance in the preparation of this report.
Summary
Porphyrias are a group of at least eight related disorders that primarily affect the skin or the nervous system, and sometimes the liver and other organs. Porphyrias occur when there is an abnormality in the pathway for making heme, a chemical that is an essential component of many enzymes and other molecules, many of which interact with oxygen. Heme is made in all tissues, but especially the bone marrow and liver. Heme is made in a series of eight steps, with a specific enzyme responsible for each step. Disruption of the pathway to make heme can cause intermediates between these steps to accumulate and cause symptoms of porphyria. Intermediates late in the pathway are porphyrins, whereas those early in the pathway are called porphyrin precursors. Accumulation of porphyrin precursors is associated with effects on the nervous system, whereas excess porphyrins are activated by light and cause skin photosensitivity. Each major type of porphyria is due to an abnormality of a different enzyme in the pathway that produces heme.
There are two general categories of porphyria. In hepatic porphyrias, pathway intermediates accumulate initially in the liver, whereas in erythropoietic porphyrias they first originate in the bone marrow, before being transported in blood throughout the body. Erythropoietic porphyrias often begin to cause symptoms early in life, whereas hepatic porphyrias are manifest especially in adults.
Three clinical types of porphyria are readily distinguished but are not completely distinct (see table below). The acute porphyrias, also known as the acute hepatic porphyrias, mainly affect the nervous system. Symptoms include periodic attacks of abdominal pain, other gastrointestinal symptoms, mental changes and pain and weakness of the extremities. Blistering cutaneous porphyrias are chronic, with skin blistering, scarring and pigment changes after exposure to sunlight. Non-blistering cutaneous porphyrias cause much more acute, severe and painful reactions after sunlight exposure, which greatly alters behavior but causes few chronic skin changes.
All but one of the porphyrias are related to pathogenic variants (mutations) in genes for enzymes in the pathway to make heme and are inherited in families. However, many individuals with a familial mutation may never have symptoms. Other external and genetic factors may be necessary before symptoms occur, especially in hepatic porphyrias. These may include certain medications, alcohol use, changes in diet or exposure to certain hormones or chemicals. External causative factors predominate in the most common porphyria, porphyria cutanea tarda, and most cases occur in the absence of a familial mutation.
Diagnosis of porphyrias can be challenging because they are uncommon with symptoms that resemble other more common conditions. Diagnosis is based on clinical suspicion and confirmed by laboratory testing. Further confirmation by genetic testing is now widely available and facilitates screening of relatives. After diagnosis, management focusses on treatment of presenting symptoms and prevention of recurrences and long-term complications.
Introduction
This report provides a general overview of the types of porphyria. NORD has individual reports on each type.
ACUTE PORPHYRIAS
The acute (hepatic) porphyrias are characterized by episodes of abdominal pain (the most common symptom), constipation and other gastrointestinal symptoms, extremity pain and weakness and mental changes such as insomnia, anxiety, agitation, hallucinations, delusions and seizures. Examination often reveals rapid heart rate and hypertension. Attacks may last days or weeks. Other symptoms may include red or dark urine and urinary hesitancy. Weakness can progress to generalized paralysis and need for respiratory support. These severe symptoms can be life threatening especially if diagnosis and treatment are delayed. Effective treatments include intravenous infusion of heme and subcutaneous injection of givosiran, an interfering RNA therapeutic.
Acute Intermittent Porphyria (AIP)
Acute intermittent porphyria (AIP) is the most common of the acute porphyrias. Symptoms include periodic attacks, as described above. Long-term complications of AIP and other acute porphyrias may include progressive kidney damage, high blood pressure and liver cancer. Symptoms begin during adulthood in almost all patients and are more common in females. Photosensitivity occurs only in some individuals who develop advanced renal failure, which can elevate levels of porphyrins in plasma.
AIP patients have a mutation in the gene for porphobilinogen deaminase (PBGD), also known as hydroxymethylbilane synthase (HMBS). Most individuals who inherit a mutation that can cause AIP never have symptoms. Others may have only one or a few attacks in their lifetime, whereas a minority may have attacks that recur frequently. Chronic symptoms may persist between attacks.
Variegate Porphyria (VP)
Variegate porphyria (VP) is the second most common acute porphyria. Attacks are identical to those seen in AIP. Blistering skin lesions are often misdiagnosed as porphyria cutanea tarda (PCT), which is much more common than VP. Symptoms develop after puberty, as in AIP. VP patients have a mutation in the gene for protoporphyrinogen oxidase (PPOX). Many individuals with a PPOX gene mutation that can cause VP never develop symptoms.
Hereditary Coproporphyria (HCP)
HCP is less common than VP. Symptoms are like those seen in VP, except that skin manifestations are much less common. HCP patients have a mutation in the gene for coproporphyrinogen oxidase (CPOX). Many individuals with a pathogenic CPOX mutation never develop symptoms.
ALAD-Deficiency Porphyria (ADP)
ALAD porphyria (ADP) is extremely rare with only eight well documented cases. Why all cases have been males is unexplained. Symptoms occur mostly in attacks, as in AIP. Symptoms usually begin at or near puberty but can begin in childhood. Chronic neurological symptoms are seen in severe cases. In one case, onset in an adult was associated with a bone marrow disorder (polycythemia vera).
BLISTERING CUTANEOUS PORPHYRIAS
Porphyria Cutanea Tarda (PCT)
This hepatic porphyria is the most common of all porphyrias, and also the most readily treated. It is primarily an acquired, iron related disease in which there is inhibition of uroporphyrinogen decarboxylase (UROD), the fifth enzyme in the heme synthetic pathway, in the liver. A minority or patients have a predisposing UROD gene mutation and are classified as having familial PCT. Symptoms usually occur after age 40. Sun-exposed areas of the skin (most commonly the backs of the hands) can become friable and prone to blistering, scarring and excess hair growth. Other predisposing factors include chronic hepatitis C, HIV infection, alcohol, smoking, estrogens and excess iron. Some of these factors and PCT itself can lead to chronic liver disease and liver cancer. PCT responds well to treatment with phlebotomies (to reduce iron) or a low dose regimen of hydroxychloroquine. Treatment of hepatitis C, if present, is also highly effective.
Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)
The symptoms of the protoporphyrias (EEP and XLP) usually begin in infancy or early childhood. Sun exposure causes severe burning pain often within minutes of exposure. Patients learn to avoid sunlight and seldom develop blistering or scarring. Prolonged exposure to sunlight can lead to both cutaneous and systemic symptoms lasting for several days. Protoporphyrin is insoluble in water and is excreted in bile rather than urine. In less than 5% of patients, excess protoporphyrin can cause significant liver damage. Current treatment is sunlight avoidance and agents that increase skin melanin pigmentation.
Congenital Erythropoietic Porphyria (CEP)
Congenital erythropoietic porphyria (CEP) is very rare, with onset usually in early childhood or even in utero. The blistering skin manifestations are usually severe, but mild cases can resemble PCT. Facial hair growth is often increased. Porphyrins are deposited in bone and teeth. Anemia in severe cases may require red blood cell transfusion. An enlarged spleen is common. Repeated blistering, infection and scarring can lead to loss of fingers and facial features. Rare onset during adulthood is often related to development of a clonal bone marrow disease.
Hepatoerythropoietic Porphyria (HEP)
Hepatoerythropoietic porphyria (HEP) is caused by two mutations in the UROD gene and resembles CEP clinically. Unusually mild cases can resemble PCT. Symptoms usually begin in infancy or childhood.
Porphyria occurs when there is an alteration of one of the enzymes used to make the molecule heme. At least eight different enzymes are involved in making heme. A different gene is responsible for making each of these enzymes. Each type of porphyria is related to a different altered (mutated) gene responsible for one of the enzymes involved in the steps making the molecule heme. Most mutations cause decreased function of the affected enzyme, but mutations in one type of porphyria (XLP) cause an increase in enzyme activity.
Porphyrias are inherited in families. However, many people who inherit a mutated gene for one of the porphyrias have no symptoms. Especially in hepatic porphyrias, certain medications, chemical exposures or changes in diet may be necessary before someone with a gene mutation for porphyria develops symptoms of the disease. Unknown modifying genes also have effects especially in hepatic porphyrias.
The following table summarizes the pattern of inheritance and the enzyme that is altered in each type of porphyria:
Autosomal Dominant Inheritance
Dominant genetic disorders occur when only a single copy of a non-working or partially working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or, rarely, can be the result of a newly changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Dominant disorders can vary in severity from person to person. Sometimes, someone who inherits a non-working gene for a dominant condition will not have any symptoms of the condition but can still pass it on to a child who may develop symptoms.
Autosomal Recessive Inheritance
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass a non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
X-Linked Recessive Inheritance
X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and manifest mostly in males. Females that have a mutated gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. However, because one X chromosome is variably inactivated, some carrier females may develop symptoms. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease. X-linked protoporphyria (XLP) results from mutations that increase enzyme activity.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
The exact number of people who have porphyria is unknown, but it has been estimated that about 1 in 20,000 people may have some type of porphyria. Some forms of porphyria are more common in specific populations. For example, acute intermittent porphyria is more common in Sweden than other parts of the world. Porphyria cutanea tarda may be the most common type of porphyria, occurring in 1 in 25,000 people in the United States. Erythropoietic porphyria is the most common in children, with the highest incidence in the Netherlands of about 1 in 75,000.
Porphyria is diagnosed based on a clinical exam and symptoms, as well as blood, urine and stool tests. Molecular genetic (DNA) testing may be used to help confirm the diagnosis. Once someone in a family has been diagnosed with porphyria, other family members may be tested to see if they have inherited the condition.
Treatment
Effective treatment is available for most porphyrias. Porphyria cutanea tarda (PCT) is readily treated by phlebotomies (to reduce iron), low-dose hydroxychloroquine (to remove excess porphyrins from the liver) or by treating hepatitis C (if present). These treatments can normalize porphyrin levels, and most patients do not experience recurrence of PCT
Exacerbations of the acute porphyrias often require hospitalization for management of severe symptoms. Hemin is approved by the U.S. Food and Drug Administration (FDA) to treat acute attacks. Glucose loading may be helpful but is less effective than hemin. Givosiran, a long-acting interfering RNA drug, is approved by the FDA and is effective for prevention of frequently recurring attacks. GnRH analogues that interrupt ovulation can be used to prevent attacks related to the menstrual cycle in women. Liver transplantation is an effective option for acute porphyria patients who become unresponsive to other treatments.
Afamelanotide (a human melanocyte stimulating hormone analogue) is approved by the FDA for treatment of protoporphyrias. It increases skin melanin and can greatly increase sun tolerance in EPP and XLP patients but does not lower circulating levels of protoporphyrin. Patients with protoporphyrias learn to avoid painful reactions by avoiding sunlight. However, patients with blistering cutaneous porphyrias such as CEP have much less pain from sun exposure and are at risk for severe skin damage unless they learn to avoid sunlight. Marrow stem cell transplantation is effective in severe childhood cases of CEP.
Information on current clinical trials is posted on the Internet at https://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:
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Some current clinical trials also are posted on the following page on the NORD website:
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https://www.clinicaltrialsregister.eu/.
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
TEXTBOOKS
Anderson KE. Acute Intermittent Porphyria, ALA-Dehydratase-Deficient Porphyria,
Congenital Erythropoietic Porphyria, Porphyria Cutanea Tarda, Variegate Porphyria and
Hereditary Coproporphyria. In: NORD Guide to Rare Disorders. Lippincott Williams &
Wilkins. Philadelphia, PA. 2003:490-95.
Mathews-Roth MM. Erythropoietic Porphyria. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:495-96.
JOURNAL ARTICLES
Muschalek W, Hermasch MA, Poblete-Gutiérrez P, Frank J. The porphyrias. J Dtsch Dermatol Ges. 2022 Mar;20(3):316-331.
Marcacci M, Ricci A, Cuoghi C, Marchini S, Pietrangelo A, Ventura P. Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives. Orphanet J Rare Dis. 2022 Apr 7;17(1):160.
Gerischer LM, Scheibe F, Nümann A, Köhnlein M, Stölzel U, Meisel A. Acute porphyrias – a neurological perspective. Brain Behav. 2021 Nov;11(11): e2389. Epub 2021 Oct 17.
Di Pierro E, Granata F. Nutrients and porphyria: an intriguing crosstalk. Int J Mol Sci. 2020 May 14;21(10):3462.
Neeleman RA, Wensink D, Wagenmakers MAEM, Mijnhout GS, Friesema ECH, Langendonk JG. Diagnostic and therapeutic strategies for porphyrias. Neth J Med. 2020 Jul;78(4):149-160.
Yasuda M, Chen B, Desnick RJ. Recent advances on porphyria genetics: inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab. 2019 Nov;128(3):320-331. Epub 2018 Nov 30.
Balwani M. Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019 Nov;128(3):298-303. Epub 2019 Jan 24.
Stölzel U, Doss MO, Schuppan D. Clinical guide and update on porphyrias. Gastroenterology. 2019 Aug;157(2):365-381.e4. Epub 2019 May 11.
Singal AK. Porphyria cutanea tarda: Recent update. Mol Genet Metab. 2019 Nov;128(3):271-281. Epub 2019 Jan 18.
Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug 31;377(9):862-872.
INTERNET
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Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Porphyria Cutanea Tarda, MIM Number: 176100: Last edited: 06/28/2022. World Wide Web URL: https://www.omim.org/entry/176100 Accessed August 2, 2022.
Erwin A, Balwani M, Desnick RJ; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network. Congenital Erythropoietic Porphyria. 2013 Sep 12 [Updated 2021 Apr 15]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK154652/ Accessed August 2, 2022.
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