What are the diagnostic criteria and management options for acute intermittent porphyria (AIP)?

Diagnosis of Acute Intermittent Porphyria

Order a spot urine sample for quantitative porphobilinogen (PBG) and delta-aminolevulinic acid (ALA), normalized to creatinine, as the essential first-line test when AIP is suspected—this single test confirms or excludes the diagnosis during symptomatic episodes. 1, 2

When to Suspect AIP

Suspect AIP in patients presenting with:

• Recurrent severe abdominal pain without identifiable cause, especially in women aged 15-50 years 3
• Neuropsychiatric manifestations including peripheral neuropathy (primarily motor with proximal weakness), autonomic dysfunction (tachycardia, hypertension), mental status changes, or seizures 1, 4
• Hyponatremia (occurs in 25-60% of acute attacks) 2, 3, 5
• Symptoms triggered by specific medications (cytochrome P450 inducers), fasting, alcohol, stress, or hormonal changes 1

Critical First-Line Diagnostic Test

Collect a random spot urine sample for quantitative PBG and ALA measurement during symptomatic episodes 1, 2:

• PBG >10 mg/g creatinine (or >5-fold above upper limit of normal) confirms acute hepatic porphyria 1, 2
• During acute attacks, expect PBG elevation >10-fold above normal, with mean increases of 50-fold 6
• Normal urine PBG during symptomatic episodes effectively excludes AIP as the cause of current symptoms 2, 3

Sample Handling Requirements

Protect all samples from light by wrapping tubes in aluminum foil to prevent photodegradation of porphyrins 1, 2:

• Refrigerate or freeze samples promptly, as PBG degrades within 24 hours at room temperature 1, 2
• Interpret results cautiously if urinary creatinine is below 2 mmol/L, as dilute urine may yield falsely elevated results when normalized 1, 2
• Collect the sample before initiating hemin treatment whenever possible, as hemin rapidly lowers PBG levels 1, 2

Critical Pitfall to Avoid

Do not order urinary total porphyrins as a first-line screening test—this is unhelpful and misleading for diagnosing acute porphyrias 1, 2. The American Association for the Study of Liver Diseases explicitly states that total porphyrins should not be used for screening 1.

Confirmatory Genetic Testing

Once biochemical diagnosis is established with elevated PBG:

• Perform gene sequencing of HMBS (hydroxymethylbilane synthase) to confirm AIP and identify the specific mutation 1, 2
• Genetic testing identifies 95-99% of cases when whole-gene sequencing is performed 1
• Do not use genetic testing as first-line screening, as most mutation carriers (>90%) never develop symptomatic disease—penetrance is only ~1% in unselected carriers 1

Screen first-degree family members with genetic testing once the familial pathogenic variant is identified 1.

Baseline Laboratory Evaluation After Diagnosis

Once AIP is confirmed, obtain the following baseline tests 1, 2:

• Complete blood count and ferritin (iron deficiency is common in young women and should be treated) 2
• Comprehensive metabolic panel including electrolytes (hyponatremia requires monitoring) 2, 3
• Liver enzymes (AST, ALT, alkaline phosphatase) 1
• Creatinine and estimated glomerular filtration rate (eGFR) (AIP poses risk for chronic tubulointerstitial nephropathy) 1, 2, 3
• Liver ultrasound and alpha-fetoprotein every 6 months after age 50 for hepatocellular carcinoma screening 1

Diagnostic Accuracy During Remission

Important limitation: Urinary PBG identifies only 85% of AIP patients during remission (asymptomatic periods) 6:

• In 15-44% of patients with sporadic AIP, urine ALA and PBG can be normal when asymptomatic 1
• If clinical suspicion remains high but initial testing is normal, repeat testing during an acute attack for confirmatory diagnosis 1
• Mutation analysis is needed to definitively exclude or confirm AIP diagnosis in patients with indeterminate biochemical results during remission 6, 7

Patient Classification for Monitoring

The American Association for the Study of Liver Diseases classifies AIP patients into four subgroups that determine follow-up frequency 1, 3:

1. Latent genetic carriers: Asymptomatic with normal ALA/PBG
2. Asymptomatic high excretors: No attacks but ALA/PBG ≥4× upper limit of normal
3. Sporadic attack patients: <4 attacks per year
4. Recurrent attack patients: ≥4 attacks per year (3-5% of symptomatic patients)

All confirmed AIP patients require at least annual monitoring including liver enzymes, creatinine, and eGFR 1, 3.

Acute Attack Management

For moderate to severe attacks, immediate hemin treatment is recommended 8:

• Dose: 3-4 mg/kg/day IV for 3-14 days (standard clinical practice dose) 8
• Infuse over at least 30 minutes via high-flow central vein (peripherally inserted central catheter or port preferred) to minimize thrombophlebitis risk 1, 8
• Clinical benefit depends on prompt administration—symptom relief typically requires 48-72 hours 1

For mild attacks (mild pain, no vomiting, no paralysis, no hyponatremia, no seizures), a trial of glucose therapy (approximately 300 g/day IV carbohydrate loading) is recommended while awaiting hemin or if hemin is unavailable 1, 8.