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DIAGNOSIS AND TESTING

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

Diagnostic Testing Laboratories

Biochemical Testing Laboratories:

The laboratories listed with a ** are overseen by a Porphyria expert who can consult with the referring physician about test results.

University of Texas Medical Branch**
Porphyria Center

Dr. Karl Anderson700 Harborside Drive
Galveston, TX 77555-1109
(409) 772-4661

ARUP Laboratories**
University of Utah

500 Chipeta Way
Salt Lake City, UT 84108
(801) 583-2787

Mount Sinai Biochemical Genetics Lab
For urine/plasma ALA and PBG testing only
1428 Madison Ave, Atran Building
Room 2-25
New York, NY 10029
(212) 241-7518

Quest Diagnostics
33608 Ortega Highway
San Juan Capistrano, CA 92690
(866) 697-8378

Mayo Clinic
Biochemical Genetics Laboratory

200 First Street SW
Rochester, MN 55905
Tel: (800) 533-1710 or (507) 266-2888
Fax: (507) 266-2888

Molecular Testing Laboratory:

Porphyria DNA Testing Laboratory
Robert J. Desnick, PhD, MD, Director
Dana O. Doheny, MS, CGC, Genetic Counselor
Telephone: 212-659-6779 (Office) or 866-322-7963 (toll-free)
Fax: 212-659-6780
E-mail: dana.doheny@mssm.edu