First-Line Screening Test for Porphyria
The first-line screening test for suspected porphyria is quantitative measurement of urinary porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) in a random spot urine sample, normalized to creatinine. 1, 2
Essential Testing Protocol
Collect a random spot urine sample (preferably morning urine) and measure both PBG and ALA together with creatinine—do not order a 24-hour urine collection, as it is unnecessary and not recommended. 1, 2
PBG is the most specific marker for acute porphyria; if significantly elevated (>10 times the upper limit of normal, or >10 μmol/mmol creatinine), it confirms an acute porphyria attack with high certainty. 1, 2
Normal PBG during acute symptoms effectively excludes acute porphyria (AIP, variegate porphyria, hereditary coproporphyria) as the cause, provided the sample was collected and handled properly. 1, 2
ALA must be measured alongside PBG because ALA alone is less specific—it can be elevated in lead poisoning and hereditary tyrosinemia, which may mimic acute porphyria symptoms. 1, 2
Critical Sample Handling Requirements
Protect all samples from light immediately by wrapping collection tubes in aluminum foil, as porphyrins are photosensitive and will degrade, causing falsely low or negative results. 1, 2, 3
Refrigerate or freeze samples promptly because PBG begins to decrease within 24 hours when kept at room temperature. 1, 2
Interpret results cautiously if urinary creatinine is below 2 mmol/L, as low creatinine concentrations can produce falsely elevated PBG/ALA ratios. 1, 2, 3
Normalize all results to urinary creatinine to account for urine concentration and ensure accurate interpretation. 1, 2
Common Diagnostic Pitfalls to Avoid
Never use urinary total porphyrins as a first-line screening test—this is the most common diagnostic error and is unhelpful and misleading for diagnosing acute porphyrias. 1, 2, 4
Do not rely on qualitative screening tests (Watson-Schwartz or Hoesch tests) alone due to low specificity and sensitivity; always confirm with quantitative assays. 2, 5, 3
Avoid colorimetric methods when possible, as they are prone to false-negative results (with methenamine hippurate) and false-positive results (with certain antibiotics like tienam and penicillin). 1
Be aware that mass spectrometry methods have lower reference limits (and correspondingly lower upper limits of normal) compared to traditional ion-exchange chromatography methods, which affects interpretation. 1, 2, 6
Interpretation Framework
During acute attacks, both ALA and PBG are elevated at least 5-fold (often >10-fold) above the upper limit of normal, making the diagnosis straightforward. 1, 2, 4
If PBG is significantly elevated (>5-10× upper limit of normal) during symptoms, acute porphyria is confirmed. 2, 4, 7
If both ALA and PBG are normal during acute symptoms, acute hepatic porphyria is effectively ruled out, with the rare exception of ALAD-deficiency porphyria where only ALA is elevated. 1, 2
Isolated elevation of ALA with normal PBG suggests alternative diagnoses such as lead intoxication or hereditary tyrosinemia rather than acute porphyria. 1, 2
Special Circumstances
Hemin treatment can lower or normalize PBG excretion if sampling occurs during or shortly after treatment, potentially causing false-negative results. 2, 4
Very dilute urine samples can yield false-negative findings unless results are corrected for creatinine concentration. 1, 2
In patients with chronic kidney disease, the PBG/ALA ratio tends to increase due to impaired glomerular filtration. 2
Next Steps After Positive Screening
Once biochemical testing confirms elevated ALA and PBG, genetic testing is mandatory to confirm the diagnosis and identify the specific type of acute hepatic porphyria by sequencing HMBS, CPOX, PPOX, and ALAD genes. 1, 2, 4
Genetic testing should not be used as first-line screening (except in Scandinavian populations with founder mutations) because most carriers of pathogenic variants never develop symptoms. 1, 2, 4