Laboratory Diagnosis of the Porphyrias

First-line Testing

It is important to know that the same screening test (ie, first line test) is not suitable for all porphyrias. Therefore, testing must be tailored to the presenting symptoms and the type of porphyria suspected. Broadly speaking, the different porphyrias can be grouped into 3 categories when testing is being considered.

Table 1. First-line Testing is different for Acute Porphyrias, Blistering Cutaneous or Nonblistering Cutaneous Porphyria

*Obtain sample when symptoms are present, if possible

Acute porphyrias

An acute porphyria should be suspected if a patient presents with neurovisceral signs and symptoms and an initial evaluation excludes more common causes. The most important first-line screening test is measurement of urinary porphobilinogen (PBG). PBG is expected to be substantially increased in all patients during acute porphyria attacks but not in other medical conditions. Therefore, this test is both sensitive and specific for diagnosis of acute porphyria under most circumstances. An exception is ADP, in which ALA and porphyrins, but not PBG, are elevated.

Measurement of urine PBG should be combined with total urine porphyrins for first line testing. This is recommended even though porphyrin elevation is nonspecific, because porphyrins may remain increased longer than PBG in acute porphyrias (especially in HCP and VP). Also PBG is often less increased during attacks of HCP and VP than AIP. Urgent first line measurement of ALA is not essential, because ALA elevation from ADP or any other cause is always accompanied by increased porphyrins. Normal urine PBG and total porphyrins essentially rules out an acute porphyria as the cause of concurrent symptoms. However, slight elevations of PBG and porphyrins may not support a diagnosis of porphyria, especially with more sensitive methods that result in a narrow reference range.

A “stat” PBG is currently not available for rapid diagnosis of acute porphyria. While awaiting the report, initial management should be tailored to the possibility of acute porphyria, and include control of pain and other symptom, correcting fluid and electrolyte imbalances, and avoidance of medications that could worsen an attack (such as phenytoin for seizures). Patients with progressive neurological signs may be started on intravenous hemin before laboratory confirmation of acute porphyria is achieved, if the index of suspicion is high. Intravenous dextrose can be administered while hemin is being obtained but should not delay hemin administration.

This first line testing is inexpensive and can be done often, even when the index of suspicion for acute porphyrias is not high. When marked elevation in PBG establishes a diagnosis of either AIP, HCP or VP, more extensive second line biochemical and genetic testing can be justified to differentiate these conditions. Elevation in urine porphyrins without elevation in PBG also requires further evaluation by second line testing, to include urine ALA and plasma and fecal porphyrins, which if normal will exclude ADP, HCP and VP.

In a patient with known acute porphyria, the diagnosis of an attack is made on clinical grounds, and treatment can be initiated without waiting for urine PBG and porphyrin results. Recent experience suggests that patients on givosiran have many fewer attacks, but these are often not accompanied by elevations in urine ALA, PBG and porphyrins.

Table 2. Second-line Biochemical Testing for Acute Porphyrias: Laboratory Findings to Differentiate the four Acute Porphyrias

Labs that can be used for second-line testing include: UTMB, ARUP, Mayo, Quest, and LabCorp

Blistering cutaneous porphyrias

Total plasma or urine porphyrins are measured when porphyrias are considered as a possible cause of blistering skin photosensitivity. Normal results effectively exclude these cutaneous porphyrias. Further second line testing is needed if porphyrins are increased, because this finding is not specific, and porphyrinuria (especially coproporphyrinuria) is common in other diseases. If second line testing is negative, then porphyria is not present. If porphyria is present, the most likely possibility is PCT, which is the most common porphyria. But it is important to differentiate other porphyrias that can cause the same skin manifestations, and especially in adults are almost always initially misdiagnosed as PCT.

Table 3. Laboratory Findings to Differentiate PCT from other porphyrias that cause blistering skin lesions.

*Elevation in plasma porphyrins with or without blistering skin lesions are common in VP, but uncommon in HCP in the absence of skin lesions.

Nonblistering cutaneous porphyrias

This type of photosensitivity is immediate and painful and leaves little if any blistering or other skin damage. It occurs only in the protoporphyrias, namely erythropoietic protoporphyria (EPP) and the less common x-linked protoporphyria (XLP). Urine ALA, PBG and porphyrins are normal in these conditions, because protoporphyrin is insoluble in water and excreted only in bile. It is essential to measure erythrocyte total protoporphyrin to screen for EPP and XLP, and to remember that urine testing is not informative. Plasma porphyrins are less elevated than in other cutaneous porphyrias, and may even be normal. Some major laboratories do not offer the proper testing for EPP and XLP. At present, only the UTMB Porphyria Lab and Mayo Medical Laboratories are recommended.

Table 4. Laboratory Findings in the protoporphyria (EPP and XLP).

Genetic testing

Confirmation of the diagnosis by genetic testing is recommended for all porphyrias. Importantly, knowing the familial mutation(s) enables screening of family members who may be at risk for developing symptoms or may pass a pathogenic mutation to the next generation. If the type of porphyria has been proven biochemically, it is usually necessary to examine (usually by sequencing) only one gene to identify the responsible mutation. Once the familial mutation is known, the testing of family members can be targeted to that mutation.

Table 5. Genes Responsible for the Porphyrias