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Diagnosis of the Porphyrias

Diagnosis of the 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
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
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

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