What is a confirmatory test for acute hepatic porphyria in an adult patient with significantly elevated urinary Porphobilinogen (PBG) levels and a possible family history of porphyria?

Confirmatory Test for Acute Hepatic Porphyria with Elevated Urinary PBG

Genetic testing with sequencing of the four genes (HMBS, CPOX, PPOX, and ALAD) is the confirmatory test for acute hepatic porphyria once significantly elevated urinary PBG has been documented. 1

Diagnostic Algorithm After Elevated PBG

Step 1: Confirm Biochemical Diagnosis

• Ensure PBG elevation is at least 5-fold above the upper limit of normal, which is diagnostic of an acute porphyria attack 1, 2
• During acute attacks, expect PBG elevation >10-fold above normal 2
• Verify that ALA is also elevated (except in rare ALAD porphyria where only ALA is elevated) 1

Step 2: Proceed to Genetic Confirmation

Once biochemical testing confirms elevated PBG, genetic testing establishes the specific type of acute hepatic porphyria: 1

• Sequence HMBS gene → diagnoses Acute Intermittent Porphyria (AIP) 2, 3
• Sequence CPOX gene → diagnoses Hereditary Coproporphyria (HCP) 1
• Sequence PPOX gene → diagnoses Variegate Porphyria (VP) 1, 2
• Sequence ALAD gene → diagnoses ALAD porphyria (extremely rare) 1

Why Genetic Testing is the Confirmatory Test

The 2023 AGA guidelines explicitly state that genetic testing should be used to confirm the diagnosis of AHP in patients with positive biochemical testing 1. When whole-gene sequencing is performed, 95-99% of cases can be identified 1, 3. This high detection rate makes genetic testing the gold standard for confirmation 2.

Critical distinction: Genetic testing is NOT recommended for initial screening because most carriers of pathogenic variants never develop symptomatic disease (penetrance is only ~1% in unselected carriers) 2, 3. However, once biochemical evidence exists (elevated PBG), genetic testing becomes essential for confirmation 1.

Additional Tests to Distinguish AHP Subtypes

While awaiting genetic results, these tests help differentiate between AHP types:

Plasma Fluorescence Scanning

• Positive in 99% of VP patients 4
• Positive in only 68% of AIP patients and 29% of HCP patients 4
• The wavelength of fluorescence emission peak has high diagnostic specificity for differentiating AIP, HCP, and VP 4

Fecal Porphyrin Analysis

• The fecal coproporphyrin isomer ratio has high diagnostic specificity and sensitivity for differentiating between AIP, HCP, and VP 4
• Particularly useful when combined with plasma fluorescence scanning 4

Skin Examination

• Examine sun-exposed skin for chronic cutaneous blistering, milia, pigmented areas, and scars, which occur in VP but not in AIP or HCP 2
• This clinical finding can immediately suggest VP over other AHP types 2

Common Pitfalls to Avoid

Do not use genetic testing as first-line screening before confirming biochemical abnormalities, as this leads to identification of asymptomatic carriers who may never develop disease 2, 3

Do not rely on urinary porphyrins alone for diagnosis, as mild elevations (secondary porphyrinurias) are often incorrectly interpreted as indicating AHP and lead to erroneous overdiagnosis 1

Collect samples before hemin treatment whenever possible, as hemin rapidly lowers PBG levels and may complicate confirmation 2

Be aware of timing issues: In VP and HCP, PBG levels may normalize quickly after acute attacks, whereas in AIP they often remain elevated for months to years 1, 2. If testing occurs between attacks in VP/HCP patients, repeat testing during an acute episode may be necessary 1

Family Screening After Confirmation

Once the familial pathogenic variant has been identified through genetic testing, first-degree family members should be screened with genetic testing to identify patients at risk for acute attacks 1. Those who are mutation carriers should be counseled about trigger avoidance and monitored appropriately 1.