Porphyria is not a single disease but a group of eight inherited genetic disorders that differ considerably from each other. A common feature in all porphyrias is the accumulation in the body of porphyrins or porphyrin precursors. Although these are normal body chemicals, they normally do not accumulate. Precisely which of these chemicals builds up depends on the type of porphyria.
The terms porphyrin and porphyria are derived from the Greek word porphyrus, meaning purple. Urine from some porphyria patients may be reddish-purple in color due to the presence of excess porphyrins and related substances in the urine, and the urine may darken after exposure to light.
Porphyria arises as a result of a malfunction in one of the eight steps in the body's synthesis of a complex molecule called heme. Heme is essential for the transport of oxygen to cells in the body. If any step in the synthesis of heme is blocked, an intermediate chemical accumulates in the cell, resulting in oxygen depletion. Those intermediate chemicals, known as porphyrins or porphyrin precursors, are the substances of which heme is composed. Each type of porphyria represents a deficiency of a specific enzyme needed for the synthesis of heme.
Most commonly the porphyrias are divided into the “acute” and “cutaneous” porphyrias, depending on the primary symptoms. The acute porphyrias 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 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), which are characterized by episodes of debilitating attacks. 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 has 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.
The porphyrias are rare diseases. Taken together, all forms of porphyria afflict fewer than 200,000 people in the United States. Based on European studies, the prevalence of the most common porphyria, Porphyria Cutanea Tarda (PCT), is 1 in 10,000; the most common acute porphyria, Acute Intermittent Porphyria (AlP), is about 1 in 20,000; and the most common erythropoietic porphyria, Erythropoietic Protoporphyria (EPP), is estimated at 1 in 50,000 to 75,000. Congenital Erythropoietic Porphyria (CEP) is extremely rare with prevalence estimates of 1 in 1,000,000 or less. Only 9 cases of ALAD-deficiency porphyria (ADP) are documented.
SIGNS AND SYMPTOMS
The signs and symptoms and vary significantly from one type of Porphyria to the next. Because the symptoms of the various porphyrias may resemble symptoms of other disorders, diagnosis may be difficult. The onset, severity and type of symptoms can vary greatly in individuals with a specific type of porphyria. This variation may depend on, in part, the amount of residual enzyme activity in each individual. Individuals with more significant enzyme deficiency may have more severe symptoms and earlier onset. Individuals with partial deficiency will have milder symptoms, and some individuals will not develop any symptoms (asymptomatic). It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their medical team about their specific case, associated symptoms and overall prognosis.
Acute Intermittent Porphyria
Abdominal pain is the most common complaint in Acute Intermittent Porphyria. In addition, some of the following symptoms occur with varying frequency: pain in the arms and leg, generalized weakness, vomiting, confusion, constipation, tachycardia, fluctuating blood pressure, urinary retention, psychosis, hallucinations, and seizures. The muscle weakness may progress to respiratory paralysis, necessitating artificial respiration. Porphobilinogen (PBG) and Aminolevulenic Acid (ALA), porphyrin precursors, are elevated during the attack but may be consistently high in some patients. Urine may exhibit a purple-red color. Unlike other forms of porphyria, sun sensitivity is not present in this type.
Variegate Porphyria is characterized by abrasions, blisters, and erosions of the skin which are commonly seen during the second and third decade. These lesions tend to heal slowly, often leaving pigmented or slightly depressed scars. The patients experience sensitivity to light and fragility of skin exposed to the sun. Although in many patients’ manifestations remain limited to the skin, episodes similar to those of acute porphyria are not uncommon. Therefore, the symptoms, drugs, precautionary measures, and treatment described for Acute Intermittent Porphyria are applicable to Variegate Porphyria.
The large amounts of coproporphyrin present in hereditary coproporphyrin makes the patient sensitive to sunlight, but skin disease is rarely severe in this type of porphyria. Clinically it resembles Variegate Porphyria except that a larger percentage of affected individuals exhibit few symptoms. Other symptoms are similar to those listed for Acute Intermittent Porphyria.
Erythropoietic Protoporphyria can have mild to severe light sensitivity and burning on exposure to the sunlight. Usually, the symptoms subside in twelve to twenty-four hours and heal without significant scarring or discoloration to the skin. The skin lesions may also progress to a chronic stage persisting for weeks and healing with a superficial scar. These manifestations generally begin in childhood. They are more severe in the summer and can recur throughout life. Affected skin, at times, exhibits the fragility or blister formation seen in other photosensitizing types of porphyria. Hepatobiliary dysfunction may be associated with significant liver damage.
Porphyria Cutanea Tarda
In Porphyria Cutanea Tarda, exposed skin shows abnormalities similar to those found in Variegate Porphyria. They range from slight fragility of the skin to persistent scarring and disfiguration. Due to fragility of the skin, minor trauma may induce blister formation. Areas of increased and decreased pigment content may be noted on the skin. Blistering of light exposed skin and increased hair growth, especially on the face, are also characteristic.
Congenital Erythropoietic Porphyria
This is a very rare disease with approximately 150 patients reported in the world. Congenital Erythropoietic Porphyria is often manifested shortly after birth with dark urine and sunlight sensitivity causing blistering and skin fragility. Later, brownish, fluorescent teeth, increased hair growth, and pronounced scarring may occur. In some cases, loss of fingers and toes and cartilage from ears or nose may be noted.
ALA-D porphyria symptoms usually arise from effects on the nervous system and/or the skin. Sometimes, the cause of the nervous system symptoms is not clear. Skin manifestations include burning, blistering, and scarring of the sun exposed areas. The disease usually manifests after puberty, and more commonly occurs in women. The most common symptom is severe abdominal pain. Other characteristics are nausea, vomiting, rapid heart rate, increased blood pressure, confusion and/or seizures, and the passing of ALA (delta- aminolevulinic acid) in the urine.
Porphyria is diagnosed through blood, urine, and stool tests, and increasingly by DNA (genetic testing).
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 porphobilinogen (PBG) and aminolevulinic acid (ALA). 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.
Please see Testing Options for detailed information.
The prevalence of porphyria remains unknown, but clinicians suggest that a range of 1 per 500-50,000 of population is probable. Some forms of porphyria are more common in specific populations including, for example, in Finland.
Treatment is specific to the type of porphyria.
The basic defect cannot presently be treated, but significant effort is being directed toward treating the underlying mechanisms that cause symptoms.
Some people who are identified as having inherited an acute porphyria do not have symptoms. It is important for those people, as well as for those who have symptoms, to be aware of preventive measures that may help them avoid episodes of porphyria symptoms. These preventive measures include avoidance of certain drugs and alcohol for some types of porphyria. For some people, they may also include avoidance of exposure to sunlight because sun sensitivity can occur with some types of porphyria.
Some of the drugs that affected individuals may need to avoid include barbiturates, tranquilizers, birth control pills, sedatives, and alcohol. The Safe/Unsafe Drug List offers a complete assessment of the potential of drugs to provoke attacks of acute porphyria and is intended for use by healthcare professionals.
An orphan drug formerly known as Panhematin (hemin for injection), is approved for use as a treatment for various forms of acute porphyria and is administered intravenously. It is extremely potent, and its use typically follows a period of glucose therapy that has not produced the desired results. See Treatment Options