What is the diagnosis and management of Acute Intermittent Porphyria (AIP)?

Acute Intermittent Porphyria (AIP): Diagnosis and Management

What is AIP?

Acute Intermittent Porphyria is an autosomal dominant metabolic disorder caused by deficiency of hydroxymethylbilane synthase (HMBS), leading to accumulation of porphyrin precursors (ALA and PBG) that cause life-threatening neurovisceral attacks. 1 The disease has remarkably low penetrance—only approximately 1% of gene carriers ever develop symptomatic attacks, though this rises to over 20% in families with known symptomatic patients. 1

Clinical Presentation

Classic Attack Symptoms

• Severe abdominal pain without peritoneal signs is the hallmark symptom, occurring in 90% of acute attacks. 1, 2, 3
• Neuropsychiatric manifestations including peripheral neuropathy (primarily motor with flaccid paresis), autonomic dysfunction, mental status changes, seizures, or psychosis are characteristic. 1, 4, 2
• Hyponatremia occurs in 25-60% of acute attacks due to syndrome of inappropriate antidiuretic hormone secretion and hypovolemia. 1, 5, 4
• Tachycardia and hypertension from autonomic dysfunction are common during attacks. 1

High-Risk Population

• Women aged 15-50 years are most commonly affected, with attacks often triggered during the luteal phase of menstrual cycles. 1
• Attacks are precipitated by cytochrome P450-inducing medications, fasting, alcohol, stress, or hormonal changes. 1, 4

Diagnostic Algorithm

Step 1: Initial Biochemical Testing (During Symptomatic Episode)

Order a random spot urine sample for quantitative PBG and ALA, normalized to creatinine—this is the essential first-line test. 1, 5, 4

• PBG >10 mg/g creatinine (or >10-fold above upper limit of normal) confirms acute hepatic porphyria. 1, 5
• Normal PBG during symptomatic episodes effectively excludes AIP as the cause of current symptoms. 1, 5, 4
• In AIP, urine PBG is typically elevated more than ALA. 5

Critical Sample Handling

• Wrap all tubes in aluminum foil to protect from light and prevent photodegradation of porphyrins. 5, 4
• Refrigerate or freeze samples promptly, as PBG degrades within 24 hours at room temperature. 5, 4
• Interpret cautiously if urinary creatinine is below 2 mmol/L, as dilute urine may yield falsely elevated results. 5

Important Timing Considerations

• Collect urine BEFORE starting hemin treatment, as hemin rapidly lowers PBG levels. 1, 5
• In AIP, PBG can remain elevated for months to years after an acute attack, allowing delayed testing. 1
• When testing asymptomatic AIP patients, 15-44% may have normal urine ALA and PBG values, requiring repeat testing during an attack. 1

Step 2: Confirmatory Genetic Testing

Once biochemical testing confirms elevated PBG, perform gene sequencing of HMBS to identify the specific mutation. 1, 5, 4

• Whole-gene sequencing identifies 95-99% of AIP cases. 1
• Do NOT use genetic testing as first-line screening, as most mutation carriers never develop symptomatic disease. 1, 5, 4
• Screen first-degree family members with genetic testing once the familial pathogenic variant is identified. 1

Step 3: Baseline Laboratory Evaluation

After confirming AIP diagnosis, obtain: 1, 4

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

Common Diagnostic Pitfalls to Avoid

• Never use urinary total porphyrins as a first-line screening test—it is unhelpful and misleading, with mild elevations often incorrectly interpreted as indicating AIP. 1, 5, 6
• Avoid qualitative PBG screening tests (Hoesch or Watson-Schwartz) due to low specificity and sensitivity; always confirm with quantitative assays. 1, 5
• Do not rely on erythrocyte PBGD enzyme activity alone, as it is decreased in only 84% of AIP patients and can be normal in variant forms. 7

Management of Acute Attacks

Severe Attacks Requiring Hospitalization

Treat immediately with intravenous hemin at 3-4 mg/kg/day, given daily for 4 days, preferably into a high-flow central vein via PICC or central port. 1, 4

• Hemin rapidly down-regulates ALAS1 expression, stopping overproduction of ALA and PBG. 1
• Symptom relief typically requires 48-72 hours, though recovery from neurologic symptoms varies significantly. 1, 4
• Timely initiation decreases risk of long-term neurologic complications. 1
• Use heme bound to human serum albumin when available, as it causes less vein irritation. 1

Mild Attacks

For mild attacks, trial intravenous glucose therapy (approximately 300 g/day carbohydrate loading) while awaiting hemin or if hemin is unavailable. 1, 4

• Fasting induces ALAS1 expression, so adequate carbohydrate intake suppresses porphyrin precursor production. 1

Supportive Management

In addition to hemin, aggressively manage all acute attack complications: 1

• Stop all cytochrome P450-inducing medications immediately, as they directly up-regulate ALAS1. 1
• Treat severe pain aggressively with analgesics (avoid barbiturates and sulfonamides). 1
• Provide antiemetics for nausea and vomiting. 1
• Manage hypertension and tachycardia from autonomic dysfunction. 1
• Correct hyponatremia slowly if present, monitoring electrolytes closely. 1
• Monitor for and correct hypomagnesemia. 1
• For seizures, use gabapentin or propofol rather than conventional antiepileptics, which may worsen attacks. 3

Respiratory Failure

Peripheral polyneuropathy can progress to respiratory muscle weakness requiring mechanical ventilation and intensive care support. 3

Long-Term Management and Monitoring

Patient Classification

The American Gastroenterological Association classifies AIP patients into four subgroups: 1, 4

1. Latent genetic carriers (asymptomatic, normal PBG)
2. Asymptomatic high excretors (elevated PBG, no attacks)
3. Sporadic attack patients (few attacks in lifetime)
4. Recurrent attack patients (frequent attacks)

Annual Monitoring for All Confirmed AIP Patients

All confirmed AIP patients require at least annual monitoring including: 1, 4

• Liver enzymes
• Creatinine and eGFR (to monitor for chronic kidney disease)
• Comprehensive metabolic panel
• Liver ultrasound and alpha-fetoprotein every 6 months after age 50

Recurrent Attack Patients

Patients with recurrent attacks have high chronic disease burden including chronic nausea, fatigue, neuropathy, and kidney disease, with 65% reporting chronic symptoms and 46% reporting daily symptoms. 1

Counsel all AIP patients on long-term complications including neuropathy, chronic kidney disease, hypertension, and hepatocellular carcinoma. 1

Prognosis

With current management, prognosis is good, but physicians must remain aware of potentially fatal outcomes. 2 Early diagnosis and treatment prevent recurrent episodes and can be lifesaving. 8