Diagnosis and Management of Acute Intermittent Porphyria and Variegate Porphyria

Initial Biochemical Testing

The American Association for the Study of Liver Diseases recommends collecting a spot urine sample for quantitative porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) measurement, normalized to urine creatinine, as the essential first-line test to confirm or exclude acute porphyria during symptomatic episodes 1, 2, 3
During acute attacks, expect PBG elevation >10-fold above the upper limit of normal, which confirms an acute porphyria attack 3
In Acute Intermittent Porphyria (AIP) and Variegate Porphyria (VP), urine PBG is typically elevated more than ALA, helping to distinguish these from other metabolic disorders 1, 2, 4
Normal urine PBG during symptomatic episodes effectively excludes AIP, VP, and Hereditary Coproporphyria (HCP) as the cause, with the rare exception of very dilute urine samples 1, 2, 3

Protect all samples from light by wrapping tubes in aluminum foil to prevent falsely low results from photodegradation 3
Refrigerate or freeze samples promptly, as PBG degrades within 24 hours at room temperature, though short delays are unlikely to cause false-negatives 1, 3
Interpret results cautiously if urinary creatinine is below 2 mmol/L, as this indicates dilute urine that may yield falsely elevated results when normalized 3

In VP, urine PBG and ALA levels may be less elevated during attacks than in AIP and are more likely to normalize between acute episodes, whereas in AIP they often remain elevated for months to years 1, 2, 5
Examine sun-exposed skin for chronic cutaneous blistering, milia, pigmented areas, and scars, which occur in VP but not in AIP 1, 2, 6

Once biochemical diagnosis is established, perform gene sequencing to identify the specific mutation, sequencing HMBS for AIP and PPOX for VP 1, 2, 4
Genetic testing should not be used as first-line screening because most mutation carriers never develop symptomatic disease, and there are no common mutations except founder mutations in Scandinavia (AIP) and South Africa (VP) 1, 2, 5

Obtain complete blood count and ferritin levels at baseline and at least yearly, as iron deficiency is common in young women and should be treated 1, 2, 6
Check comprehensive metabolic panel including electrolytes, as hyponatremia occurs in 25-60% of symptomatic cases during attacks and should resolve after recovery 1, 2, 6
Measure baseline estimated glomerular filtration rate (eGFR), as both AIP and VP pose risk for chronic tubulointerstitial nephropathy and focal cortical atrophy 1, 2, 6

Avoid using urinary total porphyrins as a first-line test, as it is unhelpful and misleading for diagnosing acute porphyrias 5, 7
Do not rely on qualitative PBG screening tests due to low specificity and sensitivity; always confirm with quantitative assays 5
Be aware that hemin treatment rapidly lowers PBG levels, so collect urine for PBG and ALA before initiating hemin therapy whenever possible 5