Overview of the Porphyrias

Disorder Definitions

The porphyrias are inherited genetic conditions, which means that people with a porphyria have changes to certain genes that affect their body’s ability to regulate itself.  When genes are copied, either to make new cells or to make a child, sometimes the body makes an imperfect copy.  There can be little changes in the genes, called mutations, which can occur randomly.  Sometimes these changes do not make any difference in how well the gene works, but other times they can keep the gene from working properly (referred to as mutations) and are disease causing.

In the porphyrias, these mutations are in the genes involved in a certain chemical pathway, called the heme biosynthetic pathway. Heme is a compound that the body needs to make hemoglobin and there are several steps to make this compound in the body. Each type of porphyria is caused by a defect in a specific enzyme in the heme biosynthetic pathway. Without these enzymes working properly, the body is not able to finish making heme and it causes a buildup of other compounds, called porphyrins. It is the buildup of different types of porphyrins that causes the different types of porphyria.

Most commonly the porphyrias are divided into the “acute“ and “cutaneous” porphyrias, depending on the primary symptoms. The acute porphyrias [acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and ALA-dehydratase deficiency porphyria (ALD)] present with sudden attacks of severe stomach pain that last for several days; VP and HCP may also have skin symptoms 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 accumulate, 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)].

The Acute Porphyrias

There are four types of acute porphyrias; acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), and δ-aminolevulinic acid dehydratase porphyria (ADP), and they have similar symptoms. These are genetic disorders that are very rare and may be difficult to diagnose for this reason. It is estimated that about 1 in 10,000 Europeans or people of European ancestry have a mutation in one of the genes that cause AIP, VP or HCP. These mutations have been found in all races and many other ethnicities in addition to Europeans.

Approximately 80-90% of individuals who carry a gene mutation for acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria, remain asymptomatic, and others may have only one or a few acute attacks throughout life. The most frequent symptom is severe abdominal pain and is often accompanied by nausea, vomiting, and constipation. Other symptoms may include heart palpitations, seizures, and hallucinations. People with VP and HCP may also have skin symptoms of blistering after sun exposure.

The Cutaneous Porphyrias

All but one of the cutaneous porphyrias cause skin blistering and fragility on sun-exposed areas of the body, most commonly the backs of the hands, forearms, face, ears and neck. The cutaneous porphyrias are porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and X-linked protoporphyria (XLP).

CEP and HEP occur in childhood with severe blistering skin lesions. PCT occurs in adulthood generally and less severe blistering skin lesions after sun exposure. Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) have the same symptoms of painful, but nonblistering, reactions to sunlight. There can also be swelling and redness of the sun exposed areas of the skin with EPP and XLP. 

Each type of porphyria is caused by a mutation, or change, in the gene coding for a specific enzyme in the heme pathway. PCT is unique as it is the only porphyria where most patients do not have mutations in a gene, but instead have acquired, or sporadic, PCT.    

Types of porphyria, their patterns of inheritance, and the enzyme that is deficient in each.

Type Inheritance Deficient Enzyme Gene

ALA-Dehydratase Porphyria (ADP)

Autosomal recessive ALA-Dehydratase ALAD

Acute Intermittent Porphyria (AIP)

Autosomal dominant Hydroxymethylbilane synthase (Porphobilinogen deaminase)

HMBS

Congenital Erythropoietic Porphyria (CEP)

Autosomal recessive Uroporphyrinogen III synthase UROS

Porphyria Cutanea Tarda (PCT), familial form

Autosomal dominant Uroporphyrinogen decarboxylase UROD

Hepatoerythropoietic Porphyria (HEP)

Autosomal recessive Uroporphyrinogen decarboxylase UROD

Hereditary Coproporphyria (HCP)

Autosomal dominant Coproporphyrinogen oxidase CPOX

Variegate Porphyria (VP)

Autosomal dominant Protoporphyrinogen oxidase PPOX

Erythropoietic Protoporphyria (EPP)
X-linked Protoporphyria (XLP)

Autosomal recessive

X-linked

Ferrochelatase

δ-Aminolevulinate synthase 2

FECH

ALAS2

The inherited porphyrias are either autosomal dominant (inherited from one parent), autosomal recessive (inherited from both parents), or X-linked (the gene is located on the X-chromosome). "Autosomal" genes always occur in pairs, with one coming from each parent. Individuals with an autosomal dominant form of porphyria have one mutated gene paired with a normal gene, and there is a 50% chance with each pregnancy that the mutated gene will be passed to a child. 

Individuals with an autosomal recessive type of porphyria have mutations on both copies of a specific gene, one passed to them from each of their parents. Each of their children will inherit one mutated gene for that porphyria, and the child will be a “carrier” but will not have symptoms.

In X-linked disorders, the gene is located on one of the sex chromosomes, called the X-chromosome. Females have two X-chromosomes, and males have one X-chromosome and one Y-chromosome. Both males and females will likely have symptoms from a mutated gene on the X-chromosome, but females, with a normal gene on the other X-chromosome, usually are less severely affected than males. The risk for children depends on the gender of the affected parent. A female with an X-linked gene mutation will have a 50% risk of passing that mutation to any of her children with each pregnancy. However, a male will pass the mutation to all of his daughters but none of his sons.

There are many laboratory tests available for the porphyrias, and the right tests to order depend on the type of porphyria the doctor suspects. 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.

DNA testing to identify the specific mutation in an individual’s porphyria-causing gene is also recommended. Before requesting DNA testing, it is helpful that patients have biochemical testing. 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 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 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.

FAQ: Are the diagnostic tests the same of all the porphyrias?

Porphyrias Defined

Definitions of the different types of porphyrias

 

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  • Acute Intermittent Porphyria
  • Hereditary Coproporphyria
  • Variegate Porphyria
  • Aminolevulinate-dehydratase
    Deficiency Porphyria
  • Porphyria Cutanea Tarda
  • Hepatoerythropoietic Porphyria
  • Congenital Erythropoietic Porphyria
  • Erythropoietic Protoporphyria
    and X-Linked Protoporphyria

What is Acute Intermittent Porphyria?

Acute Intermittent Porphyria (AIP) is an inherited genetic condition. The genetic mutations that cause AIP are in the HMBS gene. They result in the production of partially defective hydroxymethylbilane synthase enzymes (also called porphobilinogen deaminase) and decrease the overall functional capacity of this enzyme. Without enough of this enzyme capacity, the body is not able to convert the chemical porphobilinogen (PBG) into hydroxymethylbilane, the first tetra-pyrrole of the heme biosynthetic pathway. In concert with other factors that increase the activity of ALA synthase-1, the first and normally rate-controlling enzyme of the heme biosynthetic pathway, the defect in HMBS leas to a build up in delta-aminolevulinic acid (ALA) and PBG to much higher levels than usual. These chemicals are toxic to nerves and their abnormal buildup can lead to symptomatic episodes called acute attacks. The vast majority (>90%) of people with AIP mutations never develop acute attacks, highlighting the importance of other host and environmental factors in the development of clinical disease.

When patients do suffer an acute attack, they will usually experience severe abdominal pain first and foremost. This is often extremely painful and patients may need to go to the urgent care, emergency rooms or other acute care facilities for help. Because these attacks will often not involve any obvious visible signs of acute illness, such as fever, healthcare providers such as ER staff may not fully understand how much pain patients are experiencing, may think that patients are malingering or are seeking narcotics, and may not know how to diagnose or treat acute attacks, if they lack experience in the evaluation and management of patients with acute porphyria. It is very important for patients to speak with their local hospital and health care provider to make sure a plan is in place before an attack so they are able to receive care as quickly as possible when such attacks do occur.

Patients can also a variety of other symptoms related to nerve damage from high levels of ALA and PBG. This can include numbness, weakness, nausea, constipation, confusion, restlessness, hallucination, seizures, and difficulty with urination during acute attacks. These symptoms can be very severe and hard to treat if health care providers do not know to suspect acute attacks of AIP, or have no experience in its evaluation and management. It is important for family members of AIP patients to get tested even if they have never had an attack before. If they do have a mutation in one of their copies of the HMBS gene, knowing this will allow their doctor to give them the appropriate care if any symptoms arise.

Patients with AIP, especially those with chronic overproduction of ALA, are likely to have been misdiagnosed with acute appendicitis or acute cholecystitis or other intra-abdominal disorders and to have undergo exploratory laparotomies, of with removal of normal appendices or gall bladders without gall stones or acute inflammation. Such surgeries do not prvent further acute attacks, which are due to metabolic disorders that do not have surgical cures. Long-term, patients with AIP also are at increased risk for development of systemic arterial hypertension [high blood pressure], development of chronic kidney disease and kidney failure, development of chronic liver disease, and also have an increased risk of developing liver cancer, called hepatocellular carcinoma.

How is Acute Intermittent Porphyria diagnosed?

There are two things to consider when it comes to AIP diagnosis: 1) who is at risk for developing acute attacks of AIP and 2) who is experiencing acute attacks. Genetic testing is used to determine who is at risk for acute attacks and biochemical testing is used to determine who is experiencing symptoms from acute attacks. Biochemical testing is typically done on blood or urine samples, while genetic tests are done from blood, or saliva samples or from buccal swabs.

Biochemical: Acute attacks of AIP are due to abnormally high levels of ALA and PBG, which cause damage to nerves in the body. These two “biomarkers” can be accurately measured in the urine. It is not necessary for 24 hour or other timed urine samples to be obtained; a single, random urine, with measurement of ALA, PBG, and creatinine will provide diagnostic results. It is best to take samples during an acute attack (e.g. when someone is having abdominal pain, etc), when the levels of both ALA and PBG should be very high (>5X normal). In patients who experience only one or a few attacks in their lifetime, ALA and PBG levels may be normal outside of attack periods. However, in patients who experience frequent, recurrent acute attacks, ALA and PBG levels are usually elevated even in between attacks. It is not necessary for urine samples to have preservatives added, nor that they be handled in very special ways. It is better if they are collected in amber containers or if the containers are wrapped in aluminum foil and if they are kept refrigerated after collection and until the time of chemical analysis. However, even at room temperature, the decrease in levels of ALA and PBG in urine is only about 5-10% per week.

Genetic: A blood sample is used to look at a person’s genes and whether mutations exist that can cause disease in specific genes. The gene that causes AIP is called HMBS. People who have disease-causing mutations in the HMBS gene are at risk for developing acute attacks, though more than 90% of mutation carriers will never experience acute attacks of AIP. If a patient has a mutation, their immediate family members should be tested for that same mutation as well. This includes their parents, their siblings, and any children they may have. This will allow all family members to receive appropriate care and counseling. Because of this, genetic testing is recommended for patients who already have the diagnosis confirmed with very high ALA and PBG levels.

Also see FAQ: What diagnostic tests are available?

What are treatments for Acute Intermittent Porphyria?

Acute attacks in AIP are triggered when the need for heme production in the body, and in particular the liver is increased. This occurs in a number of settings. A mainstain of AIP management is avoidance of these types of triggers that can induce acute attacks.

One known trigger is progesterone, a hormone which naturally increases in women during their menstrual cycle. Female AIP patients are more likely to have attacks in the second half of their menstrual cycle, when their uterine lining is thickening but before it begins to shed (when they begin bleeding). Very frequent premenstrual attacks can be prevented by a gonadotropin-releasing hormone (GnRH) analogue administered with expert guidance.

Prolonged starvation states is also known to induce liver heme production. Thus dieting can be a trigger and patients should avoid prolonged fasting and crash dieting. Patients with AIP should eat a balanced diet. If weight loss is desired, it is advisable to do this in a slow and gradual manner.

Most drugs are processed, or metabolized by the liver, in a process that requires heme. This is why drugs can be another trigger, especially barbiturates, sulfonamide antibiotics, anti-seizure drugs, and oral contraceptives (progesterone in particular). There is an online drug database to check which medications may be unsafe for people with AIP. The American Porphyria Foundation offers a mobile phone app that pulls up this information online (porphyriadrugs.com).

During an attack, patients may often need to be hospitalized. This will allow them to receive medications to handle their pain and IV fluids if they are unable to stop vomiting or are too nauseous to eat. If the attack was triggered by using drugs for a long time, the muscles which control breathing may be weak and the patient may need respiratory support.

Patients can receive heme therapy through an IV. Panhematin is an FDA approved medication which can help decrease the severity and length of the attack, and is more effective the earlier they receive it.

Patients with recurrent attacks of AIP, more than two per year, and/or with chronic symptoms and signs, such as neuropathic pain, anxiety, delirium, etc, should be offered a trial of givosiran [Givlaari, Alnylam Pharmaceuticals]. Givosiran is an siRNA that selectively and specifically down-regulates hepatic ALA synthase-1, the first and normally rate-controlling enzyme of the heme biosynthetic pathway. Uncontrolled up-regulation of ALA synthase-1 is required for acute porphyric attacks and for the overproduction of ALA and PBG, the former being the chief neurotoxin. In a recent pivotal international, phase-three, placebo-controlled trial of givosiran in patients with AIP with frequent attacks [more than two in the preceding 6 months], givosiran proved highly effective in decreasing the number and severity of acute attacks and in decreasing the need for hospitalizations and administration of IV heme. A limitation to broad use of givosiran is likely to be its high cost and more limited availability, compared to the other treatments outlined above.

How is AIP Inherited?

AIP is an autosomal dominant condition. Autosomal means that the defect is not on the chromosomes that determine sex, and dominant means that you only need to inherit one mutated gene to manifest the disease. The gene that causes AIP is called HMBS.

Most AIP patients have one mutated copy and one normal copy. It is random which of these two copies are inherited, so this means that each child of an AIP patient will have a 50% chance of inheriting the mutated copy and 50% chance of inheriting the working copy. Children who are found not to harbor the mutation of their parents with AIP can be assured that they will never develop AIP nor pass the genetic defect on to their children.

What is Hereditary Coproporphyria (HCP)?

HCP is an inherited genetic condition in the heme biosynthesis pathway but it is rarer than AIP. In HCP, the gene responsible is CPOX which produces the enzyme coproporphyinogen oxidase. Defects in coproporphyrinogen oxidase puts the body, and the liver specifically, at risk for abnormal accumulation of porphyrin precursors ALA and PBG which can cause symptoms indistinguishable from acute attacks of AIP. However, the acute attacks can be milder in people with HCP when compared to AIP. Patients with HCP have the same slight increased risk of liver cancer that AIP patients have. As in AIP, >90% of patients with HCP mutations will not develop symptoms.

Unlike AIP, other porphyrins which are sensitive to sunlight exposure also accumulate in HCP. This is why people with HCP can also have blistering skin lesions on sun exposed areas. The blistering is typically on the back of the hands and face.

How is Hereditary Coproporphyria diagnosed?

As with AIP, there are two things to consider when it comes to HCP diagnosis: 1) who is at risk for developing acute attacks of HCP and 2) who is experiencing acute attacks. Genetic testing is used to determine who is at risk for acute attacks and biochemical testing is used to determine who is experiencing symptoms from acute attacks.

Biochemical: Acute attacks of HCP are due to abnormally high levels of ALA and PBG, which cause damage to nerves in the body. These two “biomarkers” can be accurately measured in the urine. It is best to take samples during an acute attack (e.g. when someone is having abdominal pain, etc), when the levels of both ALA and PBG should be very high (>5X normal). In patients who experience only one or a few attacks in their lifetime, ALA and PBG levels may be normal outside of attack periods. However, in patients who experience frequent, recurrent acute attacks, ALA and PBG levels are usually elevated even in between attacks.

To distinguish HCP from AIP it is useful to also check the different types of porphyrins in the urine. Elevated porphyrins (not the porphyrin precursors ALA and PBG) are responsible for the blistering skin lesions in HCP. Porphyrins in the blood and stool should also be measured. Please note that slight elevations in porphyrins, particularly in the urine is seen in a number of conditions other than porphyria and is not diagnostic.

Genetic: A blood sample is used to look at a person’s genes and whether mutations exist that can cause disease in specific genes. The gene that causes HCP is called CPOX. People who have disease-causing mutations in the CPOX gene are at risk for developing acute attacks, though more than 90% of mutation carriers will never experience acute attacks of HCP. If a patient has a mutation, their immediate family members should be tested for that same mutation as well. This includes their parents, their siblings, and any children they may have. This will allow all family members to receive appropriate care and counseling. Because of this, genetic testing is recommended for patients who already have the diagnosis confirmed with very high ALA and PBG levels.

What are treatments for Hereditary Coproporphyria?

The treatments  and preventive measures are the same as in AIP. In addition, patients with blistering from sun exposure will need to protect themselves from sunlight.

How is HCP Inherited?

HCP is an autosomal dominant condition. Autosomal means that the defect is not on the chromosomes that determine sex, and dominant means that you only need to inherit one mutated gene to manifest the disease. The gene that causes HCP is called CPOX.

Most HCP patients have one mutated copy and one normal copy. It is random which of these two copies are inherited, so this means that each child of an HCP patient will have a 50% chance of inheriting the mutated copy and 50% chance of inheriting the working copy.

What is Variegate Porphyria (VP)?

VP is an inherited genetic condition with similar clinical signs and symptoms as AIP, but is rarer than AIP. VP is especially common in South African individuals of Dutch ancestry, where it has been estimated that 3 in 1,000 of the Caucasian population is affected. In VP, the gene responsible is PPOX which produces the enzyme protoporphyrinogen oxidase, Defects in protoporphyrinogen oxidase puts the body, and the liver specifically, at risk for abnormal accumulation of porphyrin precursors ALA and PBG which can cause symptoms indistinguishable from acute attacks of AIP. However, the acute attacks can be milder in people with VP when compared to AIP. Patients with VP have the same slight increased risk of liver cancer that AIP patients have. As in AIP, >90% of patients with VP mutations will not develop symptoms.

Unlike AIP, other porphyrins which are sensitive to sunlight exposure also accumulate in VP. This is why people with VP can also have blistering skin lesions on sun exposed areas. The blistering is typically on the back of the hands and face. The occurrence of blistering skin lesions are much more common in VP than in HCP and are not easily treated. The only effective preventive measure is use of protective clothing and avoidance of prolonged sun exposure.

How is Variegate Porphyria diagnosed?

As with AIP, there are two things to consider when it comes to VP diagnosis: 1) who is at risk for developing acute attacks of VP and 2) who is experiencing acute attacks. Genetic testing is used to determine who is at risk for acute attacks and biochemical testing is used to determine who is experiencing symptoms from acute attacks.

Biochemical: Acute attacks of VP are due to abnormally high levels of ALA and PBG, which cause damage to nerves in the body. These two “biomarkers” can be accurately measured in the urine. It is best to take samples during an acute attack (e.g. when someone is having abdominal pain, etc), when the levels of both ALA and PBG should be very high (>5X normal). In patients who experience only one or a few attacks in their lifetime, ALA and PBG levels may be normal outside of attack periods. However, in patients who experience frequent, recurrent acute attacks, ALA and PBG levels are usually elevated even in between attacks.

To distinguish VP from AIP it is useful to also check the different types of porphyrins in the urine. Elevated porphyrins (not the porphyrin precursors ALA and PBG) are responsible for the blistering skin lesions in VP. Porphyrins in the blood and stool should also be measured. Please note that slight elevations in porphyrins, particularly in the urine is seen in a number of conditions other than porphyria and is not diagnostic.

Genetic: A blood sample is used to look at a person’s genes and whether mutations exist that can cause disease in specific genes. The gene that causes VP is called PPOX. People who have disease-causing mutations in the PPOX gene are at risk for developing acute attacks, though more than 90% of mutation carriers will never experience acute attacks of VP. If a patient has a mutation, their immediate family members should be tested for that same mutation as well. This includes their parents, their siblings, and any children they may have. This will allow all family members to receive appropriate care and counseling. Because of this, genetic testing is recommended for patients who already have the diagnosis confirmed with very high ALA and PBG levels.

What are treatments for Variegate Porphyria?

The treatments and preventive measures are the same as in AIP. In addition patients with blistering from sun exposure will need to protect themselves from sunlight by using sun protective clothing and avoiding prolonged sun exposure.

How is Variegate Porphyria Inherited?

VP is an autosomal dominant condition. Autosomal means that the defect is not on the chromosomes that determine sex, and dominant means that you only need to inherit one mutated gene to manifest the disease. The gene that causes VP is called PPOX.

Most VP patients have one mutated copy and one normal copy. It is random which of these two copies are inherited, so this means that each child of an VP patient will have a 50% chance of inheriting the mutated copy and 50% chance of inheriting the working copy.

What is δ-Aminolevulinic Acid Dehydratase Porphyria (ADP)?

ADP is more severe than the other acute porphyrias and can present in childhood. It is an inherited genetic condition, but is extremely rare. Only ~10 cases have been reported worldwide and all of the reported cases have been males, in contrast to the other acute porphyrias where more women have symptoms. In ADP, the gene responsible is ALAD which produces the enzyme δ-aminolevulinic acid dehydratase. Normally, the activity of this enzyme is high, much higher than that of ALA synthase-1 the enzyme immediately preceding ALAD, or HMBS, the enzyme immediately after ALAD. When activity of ALAD is severely deficient [less than ~ 10% of normal], ALA builds up and can cause symptoms similar to those seen in AIP.

How is δ-Aminolevulinic Acid Dehydratase Porphyria diagnosed?

Biochemical testing means looking for “biomarkers” in the blood or urine. To diagnose ADP, measurements of porphobilinogen (PBG), aminolevulinic acid (ALA), and total porphyrins in the urine should be done. Also porphyrins in the blood should be measured. The level of PBG in the body can vary so the best time to take samples is during an acute attack (e.g. when someone is having abdominal pain, etc). Slight elevations in porphyrins are not diagnostic of ADP; the levels need to be very high.

What are treatments for δ-Aminolevulinic Acid Dehydratase Porphyria?

Due to its extreme rarity, there are few consensus recommendations regarding the management of ADP. Most authorities recommend the same general measures as for AIP, HCP, or VP. Use of IV heme in ADP has not been very effective, and its place in therapy is uncertain. In contrast to AIP, liver transplantation has not proven to be of certain benefit in ADP, but recent results in a Dutch patient indicate that also decreasing ALA overproduction from the bone marrow by hypertransfusions, to decrease bone marrow red blood cell production, is effective.

Givosiran may also be worthy of trial; there is thus far no clinical experience with its use in ADP. It is presumed that combined liver and bone marrow transplantation would likely be curative or highly ameliorative for ADP, but this also would entail great risks of complications. It has not yet been tried in ADP.

How is δ-Aminolevulinic Acid Dehydratase Porphyria Inherited?

ADP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive means that both copies of the gene are mutated. The gene that causes ADP is called ALAD.

What is Porphyria Cutanea Tarda (PCT)

Porphyria cutanea tarda (PCT) is the most common type of porphyria, with a prevalence of approximately 1 case for every 20,000 people. PCT is caused by low levels of the enzyme uroporphyrinogen decarboxylase (UROD), the fifth step in heme production. There are two types of PCT, one is inherited and called Familial PCT, and the other is not inherited and called Sporadic PCT. The sporadic type is more common. Developing PCT symptoms, of either type, requires other factors to be present causing the activity of this enzyme to drop to less than 20% of normal. The organ most affected in people with PCT is the liver. Some of these other risk factors include; excessive alcohol use, smoking, use of oral estrogens (birth control pills, hormone replacement therapy, etc.), hepatitis C infection, HIV (human immunodeficiency virus) infection, and a disease called hemochromatosis which causes iron overload.

Patients with PCT are generally adults that develop skin blisters on sun-exposed areas, such as the back of the hands and face and. The skin may also become fragile and/or peel after minor bumping or injury. People with PCT can also have increased hair growth, as well as darkening and thickening of the skin. Acute attacks that are seen in patients with AIP do NOT occur in patients with PCT.

Abnormal liver function tests can be seen in patients with PCT, but they are usually mild. PCT is often associated with hepatitis C infection, which also causes liver complications. However, liver tests are generally abnormal even in PCT patients without hepatitis C infection. Progression to cirrhosis and even liver cancer has been reported in some patients.

How is Porphyria Cutanea Tarda Diagnosed?

There are two types of testing; biochemical- meaning looking for “biomarkers” in the blood or urine, or genetic- meaning looking at the sequence of the UROD gene to see where the mutation is.

Biochemical: To diagnose PCT, measurements of total porphyrins in the urine or blood should be done at a reference laboratory. These levels are generally very high in people with PCT.

Genetic: A blood sample is used to make DNA to look at a person’s genes and by doing this it is possible to see if their genes have changes that can cause disease, called mutations. The gene that causes the familial form of PCT is called UROD. Genetic testing is recommended for all patients with PCT in addition to biochemical testing to help establish the type of PCT, sporadic versus familial form.

If a patient has a mutation, their immediate family members should be tested for that same mutation; including their parents, siblings, and children. This will allow all family members to receive appropriate counseling even though many people with a mutation in the UROD gene will not have symptoms of PCT.

What are treatments for Porphyria Cutanea Tarda?

Treatment and management are the same for both types of PCT. They can be treated either with regularly scheduled phlebotomies (like giving blood to a blood bank), or with a low dose of the drug hydroxychloroquine, a medication normally given for malaria. In addition, patients should be tested to see if they have any of the infections listed above and treated accordingly. Other susceptible factors including alcohol use, smoking, estrogen exposure should be avoided. PCT is the most treatable of the porphyrias; however, some patients can have relapse of symptoms after completing treatment. Treatment is the same for recurrences.

How is Porphyria Cutanea Tarda Inherited?

As mentioned above, only the familial form of PCT can be inherited, and even in this form patients with PCT may not have any family members with symptoms. Familial PCT is an autosomal dominant condition. Autosomal means that the defect is not on the chromosomes that determine sex, and dominant means that you only need to inherit one mutated gene to manifest the disease. The gene responsible for familial PCT is called UROD.

Genes are inherited randomly, so a parent has an equal chance of passing on either copy of each gene. Since most Familial PCT patients have one mutated copy and one normal copy, this means that each of their children will have a 50% chance of inheriting the mutated copy and 50% chance of inheriting the working copy.

What is Hepatoerythropoietic Porphyria (HEP)?

HEP is caused by low levels of the same enzyme that causes PCT, called uroporphyrinogen decarboxylase (UROD). In Familial PCT, there is only one mutated copy of the UROD gene, the other copy is normal. In HEP both copies of the UROD gene have mutations, one from the mother and one from the father. The symptoms of HEP resemble Congenital Erythropoietic Porphyria (CEP), with symptoms of skin blistering that usually begin in infancy or early childhood. HEP is a more severe form of PCT.

Skin photosensitivity (sun sensitivity) in HEP results in severe blistering and scarring. Increased hair growth (hypertrichosis) on sun-exposed skin, and reddish-colored urine due to the high levels of porphyrins are common.

HEP is caused by a deficiency of the enzyme uroporphyrinogen decarboxylase, due to the inheritance of mutations in both copies of a person’s URO-decarboxylase genes.

Who gets Hepatoerythropoietic Porphyria diagnosed?

HEP is a very rare type of autosomal recessive porphyria. For a child to be affected, he/she must have received a mutated gene from each parent. This means each parent of an affected individual has Familial PCT, however, they may not know they have it since not all gene carriers develop symptoms.

How is Hepatoerythropoietic Porphyria diagnosed?

There are two types of testing; biochemical, meaning looking for “biomarkers” in the blood or urine, and genetic, meaning looking at the gene we know causes the disease directly from a blood sample.

Biochemical: To diagnose HEP the tests that need to be done are to measure the levels of total porphyrins in the urine or blood. These levels are generally very high in people with HEP.

Genetic: A blood sample is used to look at a person’s genes and by doing this it is possible to see if their genes have changes that can cause disease, called mutations. The gene that causes HEP is called UROD. Genetic testing is recommended for all patients even if they have a biochemical diagnosis.

Once the UROD mutations have been found, the patient’s immediate family members should be tested for the same mutations. This includes their parents, their siblings, and any children they may have. This will allow all family members to receive appropriate counseling even though many people with one mutation in the UROD gene will not have symptoms of Familial PCT.

What are treatments for Hepatoerythropoietic Porphyria?

The standard treatments for PCT: regularly scheduled phlebotomies (removal of certain amounts of blood), or low doses of hydroxychloroquine, are generally less effective in HEP but can still be attempted. The main way to manage symptoms is avoidance and/or protection from sunlight.

How is Hepatoerythropoietic Porphyria inherited?

HEP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive means that patients who have HEP have inherited two mutated copies of the UROD gene, one from each of their parents. When someone with HEP has children, all their children will have Familial PCT since they will inherit one copy of the mutated UROD gene. The children will not necessarily develop symptoms of PCT but should be counseled accordingly.

What is Congenital Erythropoietic Porphyria (CEP)?

Congenital erythropoietic porphyria (CEP) is a very rare inherited metabolic disorder resulting from the deficient function of a specific enzyme, uroporphyrinogen III synthase (URO-synthase), in the heme biosynthetic pathway. Due to the impaired function of this enzyme, excessive amounts of particular porphyrins accumulate, particularly in the bone marrow, plasma, red blood cells, urine, teeth, and bones. The two major symptoms of this disorder are: 1) marked sensitivity of the skin to sunlight and some types of artificial light, such as fluorescent lights, in all patients, and 2) anemia which in severely affected patients requires chronic red blood cell transfusions. These patients are transfusion-dependent and may benefit from bone marrow transplantation. In less severely affected patients, the red blood cells have a shortened life-span, and mild anemia may result.

After exposure to sunlight, the photo-activated porphyrins in the skin cause blistering and the fluid-filled sacs can rupture, and the ruptured lesions often get infected. These infected lesions can lead to scarring, bone loss, and deformities. The hands, arms, and face are the most commonly affected areas. Increased hair growth (hypertrichosis) on sun-exposed skin, brownish-colored teeth (erythrodontia), and reddish-colored urine are common. There may be bone fragility due to expansion of the bone marrow and vitamin deficiencies, especially vitamin D. The spleen can be enlarged, particularly in anemic patients with CEP.

How is Congenital Erythropoietic Porphyria inherited?

CEP is inherited as an autosomal recessive genetic disorder. Recessive disorders occur when an individual inherits two copies of an abnormal gene for the same trait or disease, one from each parent. Typically, there is no family history of the disease, and neither parent has symptoms, but each carries a defective gene that they can pass to their children. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. If an individual receives one normal gene and one disease-causing gene, the person will be a carrier for the disease, and will not have any symptoms.

How is Congenital Erythropoietic Porphyria diagnosed?

The diagnosis of CEP may be suspected when reddish-colored urine is noted at birth in the diaper or later in life. This finding, or the occurrence of skin blisters on sun or light exposure, should lead to a clinical evaluation and specialized laboratory tests. The diagnosis can be made by testing the urine for markedly elevated levels of the porphyrins, uroporphyrin I and coproporphyrin I. Diagnostic confirmation requires the demonstration of the URO-synthase enzyme deficiency and/or the specific alterations in the URO-synthase gene. For genetic testing, DNA is extraction from a blood sample and is used to look at the URO-synthase gene to see if there are DNA changes that that can cause the disease, called mutations. Genetic testing is recommended for all patients, as the specific mutation(s) provides information about the severity of the disease.

Once the UROS mutations have been identified, family members can be tested to determine who carries the disease-causing gene. Prenatal and preimplantation genetic diagnoses are available for subsequent pregnancies in CEP families, if the underlying genetic mutations are known. Other reproductive options are available to avoid the birth of an affected child.

What are treatments for Congenital Erythropoietic Porphyria?

Avoiding exposure to sunlight is the most important way to manage symptoms for patients with CEP. Patients need to wear protective clothing, and have windows tinted in their cars and homes. Blood transfusions to correct anemia are required in severe cases, to reduce porphyrin production by the marrow. In severely affected, transfusion-dependent patients, a successful bone marrow transplant will replace the CEP marrow and correct the metabolic defect. Patients who have successful bone marrow transplants no longer have sun-sensitivity.

What is Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP)?

EPP is a rare genetic disorder caused by the decreased activity of an enzyme called ferrochelatase, which results from mutations in the FECH gene. Decreased levels of this enzyme result in the excessive accumulation of protoporphyrin in the bone marrow, plasma and red blood cells. About 10% of patients with symptoms of EPP have a mutation in a different gene called ALAS2, and the disorder is called X-linked Protoporhyria.

EPP and XLP, typically present in childhood and combined, are the third most common porphyria, with an estimated incidence of about 2 to 5 in 1,000,000.

Both EPP and XLP result in excess production of protoporphyrin in the bone marrow, which is taken up in the blood stream and transported to the liver and blood vessels. These protoporphyrins also build up in the superficial blood vessels under the skin. Protoporphyrins are highly sensitive to sunlight and on absorption of sunlight, they release certain chemicals which cause severe pain and inflammation resulting in symptoms of EPP/XLP.

As protoporphyrin deposits in the liver, some patients with EPP/XLP may also have complications related to liver and gallbladder function. Rarely, affected individuals may also develop liver damage that, in very severe cases, may lead to liver failure requiring transplantation. As liver transplantation does not cure EPP or XLP, a bone marrow transplant following liver transplant may be necessary in some cases.

The most common symptom in EPP/XLP is severe pain on exposure to sunlight. Patients first experience tingling, itching or burning which severe as warning signs to avoid sun exposure. With ongoing exposure, patients develop severe pain which may be followed by swelling or redness. The most common areas affected include are the back of the hands and face. Blistering or scarring is rare in EPP/XLP patients and the diagnosis is often delayed as there are often no visible signs in between phototoxic episodes.

The amount of sunlight tolerance varies between patients with some able to tolerate only a few minutes and others who can stay out in the sun for much longer. Sun tolerance also depends on weather conditions.

How is Erythropoietic Protoporphyria or X-Linked Protoporphyria diagnosed?

There are two types of testing; biochemical, meaning looking for “biomarkers” in the blood or urine, and genetic, meaning looking at the gene we know causes the disease directly from a blood sample.

Biochemical: To diagnose EPP/XLP the tests that need to be done are to measure the levels of protoporphyrin in the blood. These levels are generally very high in people with EPP/XLP.

Genetic: A blood sample is used to look at a person’s genes and by doing this it is possible to see if their genes have changes that can cause disease, called mutations.  The gene that causes EPP is called FECH, and the gene that causes XLP is called ALAS2. Genetic testing is recommended for all patients even if they have a biochemical diagnosis.

What are treatments for Erythropoietic Protoporphyria and X-Linked Protoporphyria?

The primary mode of management for EPP/XLP is avoidance of sunlight or use of protective clothing and gear. Treatment with pharmaceutical grade β-carotene (Lumitene, Tishcon) and cysteine have been used in the past but studies suggest that there is no evidence that these are effective.

Anti-itch treatments like cortisone or antihistamines do not help the symptoms of EPP/XLP Iron and Vitamin D levels can be low in patients with EPP and XLP so these should be checked and supplemented accordingly. To protect the liver from further injury, Hepatitis A and B vaccinations are recommended, as is the avoidance of large amounts of alcohol and medications which may be harmful to the liver.

Liver failure can appear suddenly and progress quickly in some patients. It is generally treated with a combination of plasmapheresis (liquid from the blood, called plasma, is separated from the other components of the blood), blood transfusions, infusions of Panhematin (the treatment usually given for the acute porphryias), the medications like cholestyramine, vitamin E, and ursodeoxycholic acid. The level of protoporphyrin in the blood should be followed closely during treatment. Liver transplantation is sometimes necessary.  It is not yet possible to predict which patients will develop liver failure. 

Recently, Scenesse (Afamelonotide) was approved by the FDA for the treatment of EPP and XLP. Scenesse works by increasing pigmentation (darkening) of the skin and also has anti-oxidant properties. This drug is in the form of an implant which is inserted in the fat just below the skin and given every two months. The implant dissolves by itself and does not need to be removed. Studies have shown that patients on Scenesse were able to tolerate more sunlight without pain and that it was safe to use long term.

Another potential treatment (MT-7117) is currently being tested for EPP/XLP. This drug is in the form of a pill taken by mouth. It also increases skin pigmentation and studies to test its effectiveness are ongoing.

How is Erythropoietic Protoporphyria inherited?

EPP is an autosomal recessive condition. Autosomal means that the defect is not on the chromosomes that determine sex, and recessive which means that patients who have EPP have inherited two mutated copies of the FECH gene, one from each parent.  All children of an EPP patient will inherit one of the mutated copies of the FECH gene.

How is X-Linked Protoporphyria inherited?

XLP is an X-linked inherited genetic disorder. This means that the defect is on the X chromosome. Females have two copies of the X chromosome, while males have only one copy. The gene that causes XLP is called ALAS2. Because females have two copies of the X chromosome, they have one mutated copy of ALAS2 and one working copy. A random process in the body causes one X chromosome to be turned off. For this reason, females can present with a varying degree of symptoms ranging from no symptoms to severe XLP symptoms. There is no way to predict this ahead of time. Therefore it is important for family members of XLP patients to be tested for this mutation so that they can receive appropriate counseling.

Genes are inherited randomly, so each parent has an equal chance of passing on either one of their sex chromosomes. If the father has XLP, each of his children has a 50% chance of inheriting his X chromosome (which has the mutated gene) and a 50% chance of inheriting his Y chromosome (which does not have the gene).  If they have inherited the X chromosome, they will be female and have one mutated copy of ALAS2. If they have inherited the Y chromosome, they will be male and not have XLP.

If a father has XLP, all of his daughters will have XLP but none of his sons will be affected.