There are six major porphyrias, and each one is associated with a different enzyme deficiency. Most porphyrias are inherited in an autosomal dominant fashion, with one normal and one affected gene. This results in about a 50% reduction in the activity of the heme-related enzyme. Enough heme is synthesized to prevent the affected person from becoming anemic, but a large excess of one or more precursors is produced.
Porphyrias may be classified according to:
- The affected enzyme
- The part of the body where the excess porphyrins are produced
- Hepatic - associated with the liver
- Erythropoietic - associated with red blood cell production or
- The signs and symptoms of the disease (neurological/psychiatric, cutaneous, or both).
Those porphyrias that cause neurological/psychiatric symptoms present with acute attacks that may last for days or weeks. They are associated with abdominal pain, nausea, constipation, depression, confusion, hallucinations, and seizures. Attacks may be triggered by a variety of drugs (such as anticonvulsants, antibiotics, and hormones) and environmental factors (such as dietary changes, stress, and exposure to toxic substances).
The cutaneous porphyrias are associated with photosensitivity. Sunlight exposure, even through a glass window, has a toxic effect on the patients skin. This may cause redness, swelling, and a burning sensation in some patients, while in others it leads to blistering, skin thickening, hyperpigmentation, and in some cases scarring.
Acute attack porphyrias (neurological/psychiatric) include:
- Acute intermittent porphyria (AIP), the most common of the neurological porphyrias
- Variegate porphyria (VP), which includes both neurological symptoms and photosensitivity
- Hereditary coproporphyria (HCP), which may present with neurological symptoms, photosensitivity, or both
Cutaneous porphyrias include:
- Porphyria cutanea tarda (PCT), the most common porphyria; it is unlike the other porphyrias. Most cases are due to an acquired enzyme deficiency that is triggered by liver dysfunction.
- Protoporphyria (also called erythropoietic protoporphyria), typically begins in childhood or adolescence; sun-exposed skin turns red accompanied by burning and itching, but scarring is uncommon.
- Congenital erythropoietic porphyria (CEP), a very rare autosomal recessive disorder; over time, extreme photosensitivity leads to extensive and severe scarring of light-exposed areas.
In rare cases, a patient may have two different porphyrias or a homozygous deficiency of one enzyme that produces a more severe form of porphyria.
Clinical laboratories measure porphyrins and their precursors in urine, blood, and feces. These tests are listed below:
- Delta-aminolevulinic acid (ALA) in urine
- Porphobilinogen (PBG) in urine
- Porphyrins including uroporphyrins, coproporphyrins, and protoporphyrins in urine, feces, or blood
- Zinc protoporphyrin (or free erythrocyte protoporphyrin), one test for protoporphyrins in red blood cells
Specialized laboratories may offer testing for one or more of the affected enzymes. The most commonly measured enzyme is porphobilinogen deaminase (PBG-D) in red blood cells, which tests for patients with acute intermittent porphyria. A few research laboratories offer genetic testing for specific gene mutations that cause one of the porphyrias, but this remains primarily a research tool.
How is the sample collected for testing?The sample collected depends on the porphyrin tests being ordered. It may be one or more of the following:
- A blood sample obtained by inserting a needle into a vein in the arm
- A random or 24-hour urine collection (urine must be protected from light during collection)
- A fresh stool sample that is not contaminated with urine or water
Is any test preparation needed to ensure the quality of the sample?No test preparation is needed.
How is it used?
Porphyrin testing is used to help diagnose and sometimes to monitor porphyrias. Since the symptoms associated with these disorders may also be seen in a variety of other conditions, testing is also used to help rule out the presence of a porphyria in someone who presents with neurologic/psychiatric or cutaneous symptoms.
For acute attacks, porphobilinogen (PBG) and urine porphyrins may be ordered on a random urine sample. If these are abnormal, they are followed by delta-Aminolevulinic Acid (ALA), PBG, and/or porphyrin testing on a 24-hour urine sample. Fecal porphyrins may be ordered to help distinguish between VP and HCP.
For cutaneous porphyrias, whole blood and urine porphyrins are the most frequently ordered tests. They are used to help diagnose a porphyria and may be used to monitor a porphyria. Enzyme testing, such as PBG deaminase, may be ordered to help detect latent porphyrias in family members of a patient with a diagnosed porphyria.
When is it ordered?
Tests for PBG and porphyrins may be ordered on a random urine specimen when a patient has symptoms that suggest an acute porphyria, such as abdominal pain, nausea, constipation, peripheral neuropathy (tingling, numbness, or pain in the hands and feet), muscle weakness, urinary retention, confusion, and hallucinations. When the initial tests are abnormal, these tests should be repeated on a 24-hour urine collection to determine how much PBG, ALA, and porphyrins are being excreted. Fecal porphyrin testing may be ordered to help distinguish between porphyrias.
Depending upon the patient’s age and symptoms, a test for urine porphyrins and/or the free erythrocyte protoporphyrin test should be ordered when a patient presents with blisters, scarring, redness, or other skin lesions in sun-exposed areas. A positive urine test is followed by analysis of a 24-hour urine collection to determine which porphyrins are present.
Enzyme testing is most commonly ordered to confirm the diagnosis of acute intermittent porphyria (porphobilinogen deaminase in red blood cells). This test is especially helpful in identifying family members of a known patient who have inherited the disease but have not yet developed signs or symptoms. Some reference laboratories can measure porphyrins in plasma, bile or other fluids, but this is not usually necessary to make a diagnosis.
What does the test result mean?
Care must be taken when interpreting porphyrin test results. Some porphyrins or their precursors may be mildly to moderately elevated in patients with other diseases or conditions. In addition, levels of ALA, PBG and porphyrins may fall to near normal levels between acute attacks of a neurologic porphyria. While negative test results mean that it is unlikely that a patient’s symptoms are caused by a porphyria, positive initial tests should be confirmed with follow-up testing.
ALA and PBG are significantly increased in most patients with an acute porphyria. ALA is less specific than PBG, as it may be elevated in other conditions as well. Specific porphyrins are elevated in each of the porphyrias, and the pattern of elevation (which porphyrin is elevated in which sample) determines the diagnosis. Urine, blood, and stool porphyrins may be increased up to several-fold in a variety of other conditions. Interpretation of the patterns can be difficult. It should be done by a physician or laboratory scientist with expertise in the area.
An abnormal enzyme test or the detection of a gene mutation indicates that a family member has inherited a porphyria. However, enzyme and gene tests cannot determine whether that individual will develop signs and symptoms of porphyria or, if they do, how severe it is likely to be. Fortunately, the majority of gene carriers never have an attack.
Results seen with specific porphyrias include:
Type of Porphyria Urine ALA and PBG* Urine porphyrins Fecal porphyrins Red Blood Cell Porphyrins Acute intermittent porphyria Normal Increased URO* Normal Normal Variegate porphyria Increased Increased COPRO Increased PROTO, COPRO Normal Hereditary coproporphyria Increased Increased COPRO Increased COPRO Normal Porphyria curtanea tarda Normal Increased URO, 7-carboxyl Increased Isocoproporphyrin Normal Protoporphyria Normal Normal Increased PROTO Increased PROTO (zinc protoporhyrin) Congenital erythropoietic porphyria Normal
Increased URO, COPRO
Increased URO, COPRO Increased COPRO Increased URO, COPRO URO = Uroporphyrins; COPRO = Coproporphyrins; PROTO = Protoporphyrins * May be increased only during acute attack
Is there anything else I should know?
A variety of drugs, alcohol, and other environmental factors such as diets, stress, and illness, can trigger acute attacks of a neurologic porphyria in those with latent or inactive disease. By the same token, sun exposure will induce skin lesions in patients with a cutaneous porphyria. Lifestyle modification to avoid aggravating factors is the most effective way to minimize the impact of a porphyria.
Will latent porphyria affect my health?In most cases, the answer is no, and the porphyria remains dormant. It is important, however, to have your latent porphyria identified if you have a family history so that your doctor can tailor any medical treatments to avoid drugs and situations that might trigger your porphyria.
Can porphyrin tests be done at home?
Why does the doctor need a 24-hour urine sample if a random sample has already been tested?