What are the diagnostic steps for porphyria?

Diagnostic Approach to Porphyria

The definitive diagnosis of porphyria requires biochemical testing to demonstrate typical patterns of heme precursors in urine, feces, and blood before proceeding to genetic testing, as clinical features alone are insufficient for diagnosis. 1, 2

Initial Diagnostic Steps

• For suspected acute neurovisceral porphyria, collect a random urine sample for quantitative measurement of porphobilinogen (PBG) and δ-aminolevulinic acid (ALA), protecting all samples from light by covering collection tubes with aluminum foil 2
• Use morning or spot urine samples normalized to creatinine excretion rather than 24-hour collections for suspected acute neurovisceral porphyria 2
• Normal PBG/ALA levels during symptoms effectively rule out acute porphyria (ALAD deficiency porphyria, VP, HCP, and AIP) 1, 2
• Significantly elevated PBG (>10× upper limit of normal) confirms acute porphyria attack 2, 3

Diagnostic Algorithm by Porphyria Type

For Acute Neurovisceral Porphyrias:

• Measure urinary PBG and ALA in a random urine sample during symptoms 1, 4
• If PBG is significantly increased, diagnose acute porphyria 1
• Further differentiate between AIP, VP, HCP, and ALAD deficiency by analyzing:
  • Urine porphyrin excretion patterns 4
  • Plasma porphyrin fluorescence emission spectroscopy 4
  • Fecal porphyrin patterns (particularly helpful for VP and HCP) 5
• Genetic testing should only follow biochemical confirmation, analyzing genes specific to the suspected type: HMBS (for AIP), PPOX (for VP), CPOX (for HCP), or ALAD (for ALAD deficiency) 2

For Cutaneous Porphyrias:

• Collect EDTA blood sample for plasma porphyrin fluorescence emission spectroscopy 4
• Obtain random urine sample for total urinary porphyrins (TUP) 4
• Collect whole blood for porphyrin analysis to identify protoporphyria 4
• For PCT (most common cutaneous porphyria):
  • Check for characteristic red to brown urine in natural light and pink to red in fluorescent light 6
  • Measure porphyrin levels in 24-hour urine collection for confirmation 6
• For EPP, analyze FECH gene and intronic variant c.315-48T>C 2

Sample Collection and Handling

• Protect all samples from light by covering collection tubes with aluminum foil 2, 4
• For urine samples, assess concentration by measuring creatinine, and request repeat if urine creatinine <2 mmol/L 4
• Collect fecal samples only if first-line tests are positive or if clinical symptoms persist 4

Common Pitfalls to Avoid

• Performing genetic testing without prior biochemical confirmation can lead to false diagnoses 2
• Relying on urinary total porphyrins alone for diagnosing acute porphyria is misleading 2
• Failing to protect samples from light exposure can cause falsely low results 2, 4
• Secondary elevated urinary or blood porphyrins can occur in patients without porphyria (e.g., liver diseases, iron deficiency) 3
• Not recognizing that the most common porphyria, PCT, is usually sporadic (only 20% have pathogenic UROD variants) 2

Confirmation and Specialized Testing

• For acute porphyrias, hematin treatment requires confirmation of diagnosis through quantitative PBG measurement 7
• Enzyme assays are helpful in supporting the diagnosis and identifying family members with latent disease 8
• For latent porphyria or family history investigation, contact a specialist porphyria laboratory for advice 4
• Differentiation between specific types of porphyria often requires analysis of porphyrin patterns in multiple sample types (urine, plasma, feces) 1, 5