What Tests Can Help Diagnose Porphyria?

Doctors can use various diagnostic tests to determine whether a patient’s symptoms are caused by porphyria or another disorder. Here is some information about the most common tests and how test results can help diagnose porphyria.

What is porphyria?

Porphyria is a group of eight different disorders all related to the formation of a molecule called heme in the body. Cells use heme to make hemoglobin, the molecule that carries oxygen in red blood cells.

Each of the eight types of porphyria is caused by a mutation in a different gene that codes for an enzyme that is necessary for heme production. Mutations in these genes result in lower heme production and a buildup of heme precursors called porphyrins.

These types are acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), variegate porphyria (VP), delta-aminolevulinic acid dehydratase (ALAD) porphyria (ADP), porphyria cutanea tarda (PCT), hepatoerythropoietic porphyria (HEP), congenital erythropoietic porphyria (CEP), and erythropoietic protoporphyria (EPP). A specific type of EPP is further classified as X-linked protoporphyria.

Porphyrias are often classified depending on whether their symptoms are more neurological (acute), cutaneous (skin), or a combination of both. After a physical examination of symptoms, physicians will order a series of tests to diagnose porphyria and its type.

Urine tests

Several urine tests can help diagnose porphyria, and can be done on a spot sample (single sample) or a 24-hour sample requiring the collection of urine over a 24-hour period. The 24-hour sampling helps to average out the concentrations of molecules that can vary throughout the day and interfere with test results.

Porphobilinogen (PBG)

Porphobilinogen (PBG) is a precursor of porphyrins. So PBG urine levels are higher than normal in nearly all cases of acute porphyria (except for ADP) but not in other conditions. PBG is, therefore, usually included in the first round of testing.

Urine PBG levels should be collected during an acute porphyria attack as this is when levels are usually the most elevated. Dehydration can increase PBG levels as much as three times the normal values. Therefore, PBG levels should be at least five times greater than normal for a positive diagnosis.

High levels of PBG in the urine point to a possible diagnosis of AIP, HCP, or VP. PBG levels in HCP and VP may not be as high as those in AIP and may not stay high as long. Further testing is necessary to differentiate between the three types.

Delta-aminolevulinic acid (ALA)

Like PBG, ALA is another precursor of porphyrins. Urine ALA levels may be measured along with PBG and total porphyrin urine levels or may be ordered following the results of those tests. High ALA levels occur in all four types of acute porphyria as well as in ADP, which is the rarest form of acute porphyria.

Patients with ADP will have high ALA levels but normal PBG levels. This can help doctors differentiate it from the other acute porphyrias, where both levels are high.

Total porphyrin

Total porphyrin urine tests are nonspecific and look for changes in porphyrin levels as a whole. The total porphyrin test is useful in combination with PBG and ALA urine tests for diagnosing acute porphyrias. Total porphyrins are usually investigated with urine PBG as first-line testing for acute porphyrias.

If total porphyrins are elevated but PBG and ALA are within the normal ranges, then medical symptoms may not be related to acute porphyria. Elevated total porphyrins and ALA levels but normal PBG levels point to ADP. PBG and total porphyrin elevations point to AIP, HCP, or VP.

Doctors can also use total porphyrin levels to investigate blistering cutaneous porphyrias. Total urine porphyrin levels are high in PCT, HEP, and CEP, and in VP and HCP, which can have acute as well as cutaneous symptoms.

Fractionated porphyrins

The fractionated porphyrin test is usually done after total porphyrins have been shown to be high. High-performance liquid chromatography (HPLC) is often used to separate the different types of porphyrins so that their levels can be measured. Physicians use the test to determine which porphyrins are the highest to diagnose the type of porphyria the patient might have.

Blood tests

Diagnostic tests for porphyria may also be conducted on blood samples.

Plasma (serum) tests

Plasma or serum tests can be used to look for elevated total porphyrin levels. Doctors use the plasma porphyrin test as the first line of testing for suspected cutaneous porphyria, as they will be elevated in all of these cases. Porphyrins fluoresce a reddish color when they are exposed to ultraviolet light. The fluorescence of the plasma samples can be measured with a spectrofluorometer. The wavelength with the highest peak can be used to differentiate between some of the cutaneous porphyrias. If needed, HPLC can also be performed to separate out the individual levels of porphyrins.

Erythrocyte porphyrins

The erythrocyte total porphyrin test measures the total amount of porphyrins in erythrocytes (red blood cells). The test is sometimes called the erythrocyte protoporphyrin test since protoporphyrin is the predominant porphyrin in red blood cells. Elevated levels of protoporphyrins can also be present in several other conditions, including lead poisoning, iron deficiency, and most conditions that affect red blood cells. In all of these conditions, the protoporphyrin is bound with the metal zinc. The only exception is EPP in which the protoporphyrin is not bound.

A method called ethanol extraction can determine whether high protoporphyrin levels are the result of EPP or another disorder.

Fecal tests

Total fecal porphyrin levels are also high in several forms of porphyria. HCP, VP, and to a lesser extent, PCT and EPP all lead to high levels of fecal porphyrins. If the total numbers of fecal porphyrins are high, then HPLC can be performed to understand which porphyrins are highest to differentiate between porphyrias. Fecal flow can vary throughout the day and so fecal samples are usually collected over a 24-hour period.

Genetic tests

Genetic testing will check a patient’s DNA for mutations causing porphyrias. Doctors may use genetic testing for a final diagnosis. Eight different genes that are implicated in porphyria are ALAD, ALAS2, CPOX, FECH, HMBS, PPOX, UROD, and UROS. A mutation in each is associated with one of the eight different types of porphyria.

Last updated: Nov. 3, 2020

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