What is being tested?

Porphyrins are a group of compounds defined by their chemical structure. These compounds are by-products of haem synthesis and are normally present at low concentrations in blood and other body fluids. Porphyrin tests measure porphyrins and their precursors in urine, blood, and/or stool.

Haem is an iron-containing pigment that is a part of haemoglobin and a number of their proteins. It consists of an organic portion (protoporphyrin) bound to an iron atom. The synthesis of haem is a step-by-step process that requires the action of eight different enzymes. If there is a deficiency in one of these enzymes, the process is disrupted and intermediate porphyrins such as uroporphyrin, coproporphyrin, and protoporphyrin build up in the body's fluid and tissues. The precursors that accumulate depend on which enzyme is deficient, and they can exert toxic effects on the body.

Porphyrin tests are assays that are used to help diagnose, and sometimes monitor a group of disorders called porphyrias.

There are seven major porphyrias, and each one is associated with a different enzyme deficiency. Most porphyrias are inherited, resulting from a gene mutation usually in an autosomal dominant fashion, with one normal and one affected gene. This results in about a 50% reduction in the activity of the haem-related enzyme. Enough haem is synthesised to prevent the affected person from becoming anaemic, but a large excess of one or more precursors is produced.

Porphyrias may be classified according to the:

• affected enzyme
• part of the body where the excess porphyrins are produced (hepatic - associated with the liver or erythropoietic - associated with red blood cell production), or
• 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 patient’s 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
• Delta-aminolevulinic Acid (ALA) dehydratase porphyria (ADP), which is very rare (less than 10 cases worldwide to date)

Cutaneous porphyrias include:

• Porphyria cutanea tarda (PCT), the most common porphyria; unlike the other porphyrias, most cases are due to an acquired enzyme deficiency which is triggered by liver dysfunction.
• Protoporphyria (also called erythropoietic protoporphyria), which 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.

Individual Tests
Clinical laboratories measure porphyrins and their precursors in urine, blood, and faeces. These tests are listed below:

• Delta-aminolaevulinic acid (ALA) in urine
• Porphobilinogen (PBG) in urine
• Porphyrins in urine, faeces or blood

Specialised 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. Genetic testing for specific gene mutations that cause porphyrias, is becoming more common and replacing measurement of the affected enzymes in many cases.

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), urine porphyrins and possibly delta-aminolaevulinic acid (ALA), may be ordered on a random urine sample The urine should be collected whilst symptoms are occurring as levels may only be abnormal at this time. Faecal porphyrins may be ordered to help distinguish between variegate porphyria (VP) and hereditary coproporphyria (HCP).

For cutaneous porphyrias, whole blood, plasma and urine porphyrins are the most frequently ordered tests. They are used to help diagnose a porphyria, and may be used to monitor treatment.

When is it requested?

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. Faecal porphyrin testing may be ordered to help distinguish between porphyrias.

Depending upon the patient’s age and symptoms, a test for urine and blood porphyrins should be ordered when a patient presents with blisters, scarring, redness, or other skin lesions in sun-exposed areas.

When an individual has been diagnosed with a porphyria, testing may be performed on a regular basis to monitor the condition.

Genetic testing or enzyme testing may be ordered to confirm the diagnosis of porphyria and to identify family members of a known patient who may have inherited the disease but have not yet developed signs or symptoms.

What does the 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, and this 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:

_{*May be increased only during acute attack
URO=uroporphyrins; COPRO=coproporphyrins; PROTO=protoporphyrins}

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 minimise the impact of a porphyria.

Common questions

• 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.

More information

RCPA Manual: Porphyrins - faeces

RCPA Manual: Porphyrin - urine

RCPA Manual: Porphyrins - red cell