Diagnosis of the Porphyrias

  • Jan 3, 2020
  • Purple Light

First-line Testing for the Acute Porphyrias

Table 1. First-line Testing for Patients in Whom Acute Porphyria is Suspected

Symptoms Test Laboratories
Acute attacks of severe abdominal pain, nausea, vomiting, rapid heartbeat and other symptoms. Spot or 24 hour urine delta-aminolevulinic acid (ALA) and porphobilinogen (PBG)* UTMB, ARUP, Mount Sinai**, Mayo, Quest, LabCorp
Blistering skin photosensitivity (with or without acute attack symptoms) Plasma total porphyrins UTMB, ARUP, Mayo, Quest, LabCorp

*Take sample when symptoms are present

Acute porphyrias

An acute porphyria should be suspected if patient presents with neurolvisceral signs and symptoms. The first-line screening test is measurement of urinary porphobilinogen (PBG). PBG is markedly increased in all patients during acute porphyria attacks and not markedly elevated in other medical conditions that can present with similar symptoms. Therefore, this test is both sensitive and specific for diagnosing an acute porphyria. An exception is ADP, in which ALA is elevated but not PBG. However, the condition is not usually under consideration because of its extreme rarity.

Measurement of PBG is often combined with ALA and total urine porphyrins. In some patients with acute porphyria, urinary porphyrins may remain increased longer than ALA and PBG. However, mild increases in urinary porphyrins can occur in other medical conditions and is therefore much less specific than increases in ALA and PBG. In urgent situations, a “stat” PBG for diagnosis is not available through any of the large reference labs. While the report is pending, initial management of the patient should be tailored to the possibility of acute porphyria, correcting fluid and electrolyte imbalances, pain control, and avoidance of medications that could worsen an attack (such as phenytoin for seizures). Patients with progressive neurological signs should be started on intravenous hemin. Intravenous dextrose can be administered while hemin is being prepared but should not cause a delay of hemin infusion.

If urine ALA and PBG are normal during an attack, it essentially rules out an acute porphyria. If urine ALA and PBG are markedly increased, a diagnosis of an acute porphyria is confirmed and further testing is needed to identify the type of acute porphyria. A minor (~2-fold) elevation in urine porphyrins (especially coproporphyrin) with normal ALA and PBG is nonspecific and may not require further testing.

Table 2. Second-line Biochemical Testing for Acute Porphyrias: Laboratory Findings to Differentiate Between AIP, HCP and VP.

Acute Porphyria HMBS activity in RBCs Urine PBG Urine ALA Urine porphyrins Fecal porphyrins Plasma porphyrins
AIP Decreased in ~90% of cases elevated elevated Markedly increased; mostly uroporphyrin Normal or slightly increased Normal or slightly increased
HCP normal elevated elevated Markedly increased; mostly coproporphyrin Markedly increased; mostly coproporphyrin III Normal or slightly increased
VP normal elevated elevated Markedly increased; mostly coproporphyrin III Markedly increased; mostly protoporphyrin Markedly increased; Fluorescence peak (at neutral pH) at ~626nm
ADP normal normal elevated Markedly increased; mostly coproporphyrin III Normal or slightly increased Normal or slightly increased

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

Cutaneous porphyrias

The screening tests vary by specific symptoms for the cutaneous porphyrias. Total plasma porphyrins should be done for blistering skin photosensitivity. If this test is normal, cutaneous porphyrias that cause blistering skin lesions are effectively excluded. Further testing may be needed if total plasma porphyrins are increased. For suspected EPP/XLP, which has non-blistering photosensitivity, an erythrocyte protoporphyrin test is more specific. Urine ALA and PBG testing is not informative for any of the cutaneous porphyrias.

Table 3. Testing for Cutaneous Porphyrias: Laboratory Findings to Differentiate Between CEP, PCT, and EPP/XLP

Porphyria Urine porphyrins Erythrocyte porphyrins Plasma fluorescence emission peak Laboratories
CEP Increased; mostly uro- and coproporphyrin I Increased; mostly Zn-proto, copro-, and uroporphyrin 615-620nm UTMB, ARUP, Mayo, Quest, LabCorp
PCT & HEP Increased; mostly uro- and heptacarboxylate porphyrin normal 615-620nm
EPP normal Increased; mostly protoporphyrin; free-proto significantly greater than Zn-protoporphyrin 626-634nm UTMB, ARUP, Mayo
XLP normal Increased; mostly protoporphyrin; free-proto equal to Zn-protoporphyrin 626-634nm

For all the porphyrias genetic testing is recommended to confirm the diagnosis as well as biochemical testing. The following table lists the causative genes for each type of porphyria.

Table 4 Genes Responsible for the Porphyrias

Porphyria Enzyme Name Gene Symbol Laboratories that do Genetic Testing
AIP Hydroxymethylbilane synthase HMBS Mount Sinai Genetic Testing Lab, Mayo Clinic Molecular Genetics Lab
VP Protoporphyrinogen oxidase PPOX
HCP Coproporphyringen-III oxidase CPOX
CEP Uroporphyrinogen III synthase UROS
PCT & HEP Uroporphyrinogen decarboxylase UROD
EPP Ferrochelatase FECH
XLP 5-aminolevulinate synthase 2 ALAS2

**The Mount Sinai Lab only tests for urine ALA and PBG