Porphyrias

Indications for Testing

Diagnostic testing for porphyrias should be performed in individuals who present with severe, diffuse neuropathic abdominal pain and accompanying symptoms and in individuals with cutaneous photosensitivity. Certain tests are also indicated for treatment monitoring.

Classification

Laboratory Testing

Diagnosis

Initial Testing

Porphobilinogen

PBG measurement is the initial test recommended when AIP, HCP, or VP is suspected on the basis of clinical symptoms, particularly during an acute attack. If PBG is increased, acute porphyria is diagnosed and treatment should begin immediately.  During an episode, the urinary PBG level is at least 10-fold the normal reference range  and can easily identify an acute porphyria. An increased PBG level also excludes PCT. Because PBG excretion is high, random urine collection is sufficient during attacks; a 24-hour collection unnecessarily delays diagnosis.  Fecal porphyrin testing to differentiate type should follow a positive PBG result.

Negative results in symptomatic patients rule out AIP, HCP, and VP.  If results are negative for asymptomatic patients, testing should be repeated during an attack because PBG excretion may be less elevated between attacks.  When blistering cutaneous symptoms are present in addition to neurologic and abdominal symptoms, or when HCP or VP is suspected, urine porphyrin analysis should be performed concurrently with PBG measurement to ensure a diagnosis of HCP or VP is not overlooked, given that PBG levels can return to normal when acute symptoms subside. 

Urine Porphyrin Fractionation and Quantitation

Urine porphyrin fractionation and quantitation is the initial test used to evaluate patients for porphyrias that manifest with blistering cutaneous photosensitivity. Excretion is elevated in all active cases, and the resulting excretion pattern can determine whether the diagnosis is PCT, CEP, or either HCP or VP. Significantly increased coproporphyrin suggests HCP or VP, even if PBG is negative. Urine tests are irrelevant to the diagnosis of EPP, except to exclude other types of porphyria, because protoporphyrins are not excreted in urine. 

Erythrocyte Porphyrin

Erythrocyte porphyrin analysis is the first-line test for evaluating patients for suspected protoporphyrias (EPP or XLP), which are characterized by elevated protoporphyrin levels. Testing should differentiate total, free, and zinc protoporphyrins.  Patients with EPP have less zinc protoporphyrin in the erythrocytes than do those with XLP.

Secondary Testing

Fecal Porphyrins

Once a diagnosis of acute porphyria has been made, porphyrin analysis of stool can be used to differentiate among the specific types; samples should be collected before treatment. Fecal porphyrin excretion is normal or slightly elevated in AIP; excretion of coproporphyrin III is markedly increased in HCP, and both coproporphyrin and protoporphyrin excretion is increased in VP.   Fecal porphyrin analysis also can support the initial findings of erythrocyte porphyrin analysis. 

Total Plasma Porphyrins

Total plasma porphyrin analysis is useful as a confirmatory test. Plasma porphyrin testing can be used to help differentiate VP from other porphyria types, identify protoporphyria, and monitor PCT.

Erythrocyte Porphyrins​

Erythrocyte porphyrin analysis is used as a first-line test in the diagnosis of protoporphyria. It can also be used as secondary testing to differentiate PCT from HEP and CEP. Concentrations are normal or mildly increased in PCT and are noticeably elevated in CEP.  Erythrocyte zinc protoporphyrin concentrations are increased in HEP but normal in PCT. 

Aminolevulinic Acid

If strong clinical suspicion exists despite a negative PBG result, measuring ALA to identify ADP may be indicated. Negative PBG excretion with substantially elevated ALA suggests ADP. ALA dehydratase testing in blood and molecular testing can be used to confirm ADP. ALA may also be increased in lead intoxication and hereditary tyrosinemia type I. 

Enzyme and Variant Analysis

After laboratory testing has identified the type of porphyria, additional testing of enzymes and/or variants may help confirm the diagnosis. Erythrocyte PBG deaminase testing is optional for suspected AIP ; patients with AIP may have a 50% decrease in PBG deaminase concentrations, whereas patients with HCP and VP will have normal concentrations.  However, normal erythrocyte PBG deaminase activity does not exclude AIP. Genetic testing can identify the variant or variants associated with the porphyria type. Variant testing is not necessary to confirm the biochemical diagnosis, but it can be helpful in identifying family members with the same disorder. The following table shows associations between genes, enzymes, and particular types of porphyria.

Diagnostic Patterns

Porphyria types are diagnosed based on the test result patterns, as shown in the following table.

Monitoring

Patients with any of the acute porphyrias and sporadic or recurrent attacks should be monitored annually at a minimum and should undergo follow-up 1 month after hospitalization; annual tests should include PBG and ALA measurement, a CBC, a metabolic panel, and a hepatic function panel.  Ferritin and iron testing and liver imaging should be performed every 3 months.  Because of the additional risk for hepatocellular carcinoma (HCC), serum alpha-fetoprotein measurements should be performed every 6 months for patients older than 50 years. 

Treatment of PCT should be monitored with serum ferritin or plasma or urine porphyrin testing, depending on therapy type.  Patients with EPP or XLP should have a CBC, ferritin test, and liver function test performed annually, along with erythrocyte and plasma porphyrin measurements and serum 25-hydroxy vitamin D testing.