What is the recommended initial screening test for suspected porphyria?

Screening Test for Porphyria

The recommended initial screening test for suspected acute porphyria is quantitative measurement of urinary porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) in a random spot urine sample, normalized to creatinine. 1, 2

First-Line Testing Approach

For Acute Neurovisceral Symptoms

• Measure urinary PBG and ALA together with creatinine on a random (preferably morning) spot urine sample 1, 2
• PBG is the highly specific diagnostic marker for acute porphyria attacks 1
• During acute attacks, both ALA and PBG are elevated at least 5-fold above the upper limit of normal, with PBG/creatinine ratio typically >10 times the upper limit 2, 3
• Normal PBG during symptoms effectively rules out acute porphyria (with the rare exception of ALAD deficiency porphyria where only ALA is elevated) 1, 2, 3

For Cutaneous Symptoms

• Plasma porphyrin fluorescence emission spectroscopy is the first-line test 1, 4
• Add random urine sample for total urinary porphyrins (TUP) 4
• Whole blood porphyrin analysis is essential to identify erythropoietic protoporphyria 4

Critical Pre-Analytical Requirements

• Protect all samples from light by wrapping collection tubes in aluminum foil, as porphyrins are photosensitive 1, 2
• PBG begins to degrade within 24 hours at room temperature 1
• Use spot urine samples; 24-hour urine collections are not recommended 1, 2
• Results must be normalized to urinary creatinine 1
• Interpret with caution if urinary creatinine is below 2 mmol/L, as results may appear falsely elevated 1

What NOT to Do: Common Pitfalls

• Do not use urinary total porphyrins as a first-line test for acute porphyria—this is unhelpful and misleading 1
• Do not rely on qualitative screening tests (Watson-Schwartz or Hoesch tests) alone due to low specificity and sensitivity 1, 2, 5, 6
• If qualitative tests are used in emergency settings, results must be confirmed by quantitative assays 1, 6
• Do not collect 24-hour urine samples when spot urine is sufficient 1, 2

Interpretation Framework

If PBG is Significantly Elevated (>5-10x Upper Limit of Normal):

• Acute porphyria is confirmed 2, 3
• Proceed to genetic testing to identify the specific type (HMBS, CPOX, PPOX genes) 2

If Both ALA and PBG are Normal During Symptoms:

• Acute hepatic porphyria is effectively ruled out 2, 3
• The only exception is extremely rare ALAD deficiency porphyria, where PBG is normal but ALA and coproporphyrin III are significantly increased 1, 3

If Only ALA is Elevated:

• Consider lead intoxication or hereditary tyrosinemia, which can present with similar symptoms 1
• ALA is less specific than PBG for acute porphyria 1

Methodological Considerations

• Modern mass spectrometry methods are more sensitive with lower limits of normal compared to traditional ion-exchange chromatography 1
• Be aware of method-specific reference ranges when interpreting results 1
• Colorimetric methods have known false negatives (methenamine hippurate) and false positives (tienam, penicillin) 1

Special Circumstances

• In patients on hemin treatment, PBG excretion may be lower or normalized if sampling occurs during or shortly after treatment 1
• In acute intermittent porphyria patients with severe chronic kidney disease, the PBG/ALA ratio increases due to impaired glomerular filtration 1
• Very dilute urine samples may lead to false-negative results if not normalized to creatinine 1