Guideline for Screening and Diagnosis of Acute Porphyria

Initial Screening Test

Quantitative measurement of urinary porphobilinogen (PBG) and 5‑aminolevulinic acid (ALA) in a random spot urine sample, normalized to creatinine, is the recommended first‑line screening for suspected acute porphyria. 1

Collect a random (preferably morning) spot urine sample and measure urinary PBG and ALA together with creatinine. 1, 2
PBG is a highly specific diagnostic marker for acute porphyria attacks. 3, 1
A normal PBG result during symptomatic periods effectively excludes acute porphyria, except in the rare ALAD‑deficiency form where only ALA is elevated. 1

Plasma porphyrin fluorescence emission spectroscopy is the first‑line test for porphyria presenting with skin manifestations. 4

All specimens must be protected from light (e.g., wrap collection tubes in aluminum foil) because porphyrins are photosensitive. 3, 1
PBG begins to degrade if the sample remains at room temperature for more than 24 hours; prompt refrigeration is advised. 3, 1
Spot urine collections are preferred; 24‑hour urine collections are not recommended for acute porphyria screening. 3, 1
Results must be normalized to urinary creatinine to account for urine concentration. 3, 1, 2
When urinary creatinine is < 2 mmol/L, interpret PBG/ALA results with caution because values may appear falsely elevated. 3, 1

Do not use total urinary porphyrins as a first‑line test for acute porphyria; this approach is misleading. 3, 1, 5
Do not rely solely on qualitative screening tests (e.g., Watson‑Schwartz or Hoesch) because of their low specificity and sensitivity. 1
If qualitative tests are employed in emergency settings, confirm abnormal results with quantitative assays. 4
Do not collect 24‑hour urine when a spot sample is sufficient. 3, 1

Normal PBG during symptoms rules out acute hepatic porphyria; the only exception is ALAD‑deficiency porphyria, where PBG remains normal but ALA and coproporphyrin III are markedly increased. 1, 4
Isolated elevation of ALA (with normal PBG) suggests alternative diagnoses such as lead intoxication or hereditary tyrosinemia; ALA is less specific for acute porphyria than PBG. 3, 1, 5

Modern mass‑spectrometry techniques provide greater sensitivity and lower limits of normal compared with traditional ion‑exchange chromatography. 3, 1, 5
Reference ranges are method‑specific; clinicians must use the appropriate range for the assay employed. 3, 1
Colorimetric assays are prone to false‑negative results (e.g., methenamine hippurate) and false‑positive results (e.g., certain antibiotics such as tienam and penicillin). 3, 1, 5

In patients receiving hemin therapy, urinary PBG excretion may be reduced or return to normal if sampling occurs during or shortly after treatment. 4
In individuals with severe chronic kidney disease, the PBG/ALA ratio tends to increase because of impaired glomerular filtration. 4
Very dilute urine samples can yield false‑negative findings unless results are corrected for creatinine concentration. 4, 2

The American Gastroenterological Association recommends that a negative urine porphyrin test does not rule out acute hepatic porphyria (AHP), and proper biochemical testing with urinary ALA and PBG levels is necessary to definitively exclude or confirm this diagnosis 6, 7
The European Association for the Study of the Liver discourages urine porphyrin testing alone for diagnosing acute porphyrias, as it leads to false negatives and false positives, and instead recommends testing urinary ALA and PBG measured together with creatinine in a random urine sample 7, 8, 9
The correct first-line test for diagnosing or excluding AHP during an acute attack is urinary ALA and PBG measured together with creatinine in a random urine sample, with a strength of evidence level of high 6, 7

The American Gastroenterological Association recommends measuring urinary ALA, PBG, and creatinine on a random urine sample, preferably morning spot urine, to diagnose AHP 6, 7
The European Association for the Study of the Liver recommends protecting the sample from light by wrapping the collection tube in aluminum foil, as porphyrins are photosensitive, and results should be normalized to creatinine excretion 7, 8, 9
During acute attacks, both ALA and PBG are elevated at least 5-fold above the upper limit of normal, with a strength of evidence level of moderate 6, 10

If PBG is significantly elevated (>5-10x upper limit of normal), acute porphyria is confirmed, with a strength of evidence level of high 6, 10
If both ALA and PBG are normal during symptoms, AHP is effectively ruled out, with the rare exception of ALAD deficiency porphyria, where only ALA is elevated, and a strength of evidence level of moderate 7, 10, 11

Once biochemical testing confirms AHP, genetic testing should identify the specific type by sequencing ALAD, HMBS, CPOX, and PPOX genes, with a strength of evidence level of high 6
First-degree family members require genetic screening once the pathogenic variant is identified, with a strength of evidence level of moderate 6

The American Gastroenterological Association recommends not relying on the Watson-Schwartz or Hoesch qualitative tests alone, and instead using quantitative ALA and PBG measurements, with a strength of evidence level of high 6
The European Association for the Study of the Liver recommends not collecting 24-hour urine samples, and instead using random spot urine, which is sufficient and preferred, with a strength of evidence level of moderate 7, 8