Workup for Acute Intermittent Porphyria and Variegate Porphyria
Begin with quantitative spot urine porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) normalized to creatinine—this is the essential first-line test that confirms or excludes acute porphyria during symptomatic episodes. 1, 2
Initial Biochemical Testing
Primary Diagnostic Tests
Collect a spot urine sample for quantitative PBG and ALA measurement, normalized to urine creatinine—a 24-hour collection is unnecessary and delays diagnosis 1, 2
During acute attacks, expect PBG elevation >10-fold above the upper limit of normal (typically >10 μmol/mmol creatinine by mass spectrometry), which confirms an acute porphyria attack 2
In AIP and VP, urine PBG is typically elevated more than ALA—this pattern helps distinguish these from other metabolic disorders 1
Normal urine PBG during symptomatic episodes effectively excludes AIP, VP, and HCP as the cause, with the rare exception of very dilute urine samples 1, 2
Critical Sample Handling
Protect all samples from light by wrapping tubes in aluminum foil to prevent falsely low results from photodegradation 2
Refrigerate or freeze samples promptly—PBG degrades within 24 hours at room temperature, though short delays are unlikely to cause false-negatives 1, 2
Interpret results cautiously if urinary creatinine is below 2 mmol/L, as this indicates dilute urine that may yield falsely elevated results when normalized 2
Plasma ALA and PBG can be used as alternatives to urine testing when urine collection is problematic, and may more accurately reflect the clinical course during acute attacks 1, 3
Distinguishing AIP from VP
Differentiating Tests
Obtain plasma fluorescence scanning and fecal porphyrin analysis with coproporphyrin isomer ratio to differentiate between AIP, VP, and HCP once elevated PBG is confirmed 4
Plasma fluorescence scanning is positive in 99% of VP patients but only 68% of AIP patients—a negative scan during an acute attack with elevated PBG strongly suggests AIP over VP 4
The wavelength of fluorescence emission peak and fecal coproporphyrin isomer ratio have high diagnostic specificity for distinguishing these conditions 4
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
Physical Examination Findings
Examine sun-exposed skin (especially dorsal hands and face) for chronic cutaneous blistering, milia, pigmented areas, and scars—these findings occur in VP but not in AIP 1
Perform a detailed neurologic assessment for peripheral motor and sensory deficits and cranial nerve abnormalities to establish baseline function and detect acute attack complications 1
Confirmatory Genetic Testing
Once biochemical diagnosis is established, perform gene sequencing to identify the specific mutation—sequence HMBS for AIP and PPOX for VP 1
If biochemical results are incomplete or not definitive, sequence all three genes (HMBS, CPOX, PPOX) as an acute hepatic porphyria panel 1
Genetic testing should not be used as first-line screening because most mutation carriers never develop symptomatic disease (penetrance ~1% for AIP), and there are no common mutations except founder mutations in Scandinavia (AIP) and South Africa (VP) 1
Mutation detection sensitivity is 98.1% for AIP and 100% for VP when both sequencing and gene-dosage analysis are performed 4
Once the familial mutation is identified, test first-degree relatives to identify at-risk carriers who require counseling about trigger avoidance 1
Baseline Laboratory Evaluation for Confirmed Cases
Hematologic and Metabolic Assessment
Obtain complete blood count and ferritin levels at baseline and at least yearly—iron deficiency is common in young women, causes chronic symptoms, and should be treated 1
Check comprehensive metabolic panel including electrolytes, as hyponatremia occurs in 25-60% of symptomatic cases during attacks and should resolve after recovery 1
Renal Function Monitoring
Measure baseline estimated glomerular filtration rate (eGFR)—both AIP and VP pose risk for chronic tubulointerstitial nephropathy and focal cortical atrophy 1
Monitor blood pressure aggressively, as chronic hypertension develops in some patients and may contribute to renal damage 1
Refer to nephrology if hypertension is not controlled by first-line treatment or when renal dysfunction is first recognized 1
Hepatic Assessment
Obtain liver function tests at baseline—serum aminotransferases are elevated in ~13% of patients during acute attacks and in some asymptomatic patients 1
After age 50, perform liver ultrasound and α-fetoprotein every 6 months due to increased hepatocellular carcinoma risk in both AIP and VP 1, 5
Important Diagnostic Pitfalls
Avoid using urinary total porphyrins as a first-line test—it is unhelpful and misleading for diagnosing acute porphyrias 1, 6
Do not rely on qualitative PBG screening tests (Watson-Schwartz or Hoesch tests) due to low specificity and sensitivity; always confirm with quantitative assays 1
Be aware that hemin treatment rapidly lowers PBG levels—collect urine for PBG and ALA before initiating hemin therapy whenever possible 1
In patients with recurrent attacks, PBG typically remains elevated even at baseline between attacks, so a modest increase (1.6- to 4.0-fold) during symptoms may still represent an acute attack 7, 3
Erythrocyte PBGD enzyme activity is decreased in only 84% of AIP patients and is normal in the variant form of AIP, making it unreliable as a standalone diagnostic test 7
During remission, urinary PBG identifies only 85% of AIP patients, so normal levels between attacks do not exclude the diagnosis if genetic testing confirms a pathogenic mutation 7