Diagnostic Approach for Acute Hepatic Porphyria

Diagnostic Algorithm

• The American Gastroenterological Association recommends genetic testing with sequencing of the four genes (HMBS, CPOX, PPOX, and ALAD) as the confirmatory test for acute hepatic porphyria once significantly elevated urinary PBG has been documented 1, 2
• Ensure PBG elevation is at least 5-fold above the upper limit of normal, which is diagnostic of an acute porphyria attack 1, 3
• During acute attacks, expect PBG elevation >10-fold above normal 3
• Verify that ALA is also elevated (except in rare ALAD porphyria where only ALA is elevated) 1

Genetic Testing

• Sequence HMBS gene to diagnose Acute Intermittent Porphyria (AIP) 3, 5
• Sequence CPOX gene to diagnose Hereditary Coproporphyria (HCP) 1
• Sequence PPOX gene to diagnose Variegate Porphyria (VP) 1, 3
• Sequence ALAD gene to diagnose ALAD porphyria (extremely rare) 1

Diagnostic Specificity and Sensitivity

• Whole-gene sequencing can identify 95-99% of cases 1, 5
• Genetic testing is the gold standard for confirmation due to its high detection rate 3

Clinical Considerations

• Examine sun-exposed skin for chronic cutaneous blistering, milia, pigmented areas, and scars, which occur in VP but not in AIP or HCP 3
• 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, 3

Family Screening

• First-degree family members should be screened with genetic testing to identify patients at risk for acute attacks once the familial pathogenic variant has been identified 1, 2
• Those who are mutation carriers should be counseled about trigger avoidance and monitored appropriately 2