What is the management and treatment of acute intermittent porphyria (AIP)?

Acute Intermittent Porphyria: Comprehensive Management

Diagnosis

Diagnose AIP immediately with a random urine sample measuring ALA, PBG, porphyrins, and creatinine—during an acute attack, both ALA and PBG will be elevated at least 5-fold above the upper limit of normal, typically exceeding 10 times normal or >10 μmol/mmol creatinine by mass spectrometry. 1

Key Diagnostic Points

• Do not use urine porphyrins alone as a screening test—mild elevations (secondary porphyrinurias) lead to frequent misdiagnosis 1
• A 24-hour urine collection is unnecessary; random samples are sufficient due to markedly elevated levels during attacks 1
• Testing remains positive for days to months after an acute attack in AIP, though levels may fall quickly in HCP or VP 1
• In asymptomatic periods, 15-44% of sporadic AIP patients may have normal ALA and PBG 1
• If only ALA is elevated with normal PBG, check lead levels and urine organic acids to exclude lead poisoning and hereditary tyrosinemia 1

Confirmatory Testing

• Perform genetic testing by sequencing HMBS, CPOX, and PPOX genes to determine the specific AHP type 1
• Genetic confirmation is most useful during the quiescent phase after biochemical diagnosis 2

Acute Attack Management

Immediately discontinue all porphyrinogenic drugs and initiate intravenous hemin at 3-4 mg/kg/day—this is the definitive treatment that must be started early, along with IV dextrose to suppress hepatic heme synthesis. 3, 4

Hospitalization Criteria

• Patients with severe abdominal pain, vomiting, and hypertension require inpatient management as they can deteriorate rapidly with respiratory failure necessitating ventilator support 3, 5
• These patients are not candidates for outpatient therapy 3

Hemin Administration

• Administer PANHEMATIN at 3-4 mg/kg/day IV once or twice daily for 3-4 days 4
• Clinical response occurs in 85.5% of treatment courses, defined by symptom improvement and pain reduction 4
• Chemical response (normalization of urinary ALA and PBG) occurs in all patients 4
• Hemin should be given via peripherally inserted central catheter 1

Adjunctive Acute Treatment

• Provide IV dextrose (carbohydrate loading of 300g minimum for 72 hours) when hemin is unavailable or for mild attacks 4, 6
• Aggressive symptomatic management with analgesics for severe abdominal pain 3
• Antiemetics for nausea and vomiting 3
• For seizures, use gabapentin or propofol rather than conventional antiepileptics which may be porphyrinogenic 5
• Treat autonomic dysfunction, polyneuropathy, and encephalopathy symptomatically 2
• Adequate fluid therapy and nutrition 2

Prevention of Recurrent Attacks

Patients experiencing 4 or more attacks per year are candidates for prophylactic hemin infusions administered weekly, bimonthly, or monthly—less frequent than weekly dosing may be ineffective since heme is metabolized rapidly. 3, 7

Prophylaxis Strategies

• Single prophylactic infusions at varying intervals (weekly or once/twice during luteal phase for menstrual-related attacks) 7
• For menstrual cycle-related attacks, administer hemin during the luteal phase 7

Avoidance of Triggering Factors

• All patients must avoid porphyrinogenic drugs, fasting, alcohol, and smoking 3, 7
• Consult publicly available drug databases (provide patients with safe drug lists) before starting any new medications 3, 8
• Maintain adequate caloric intake and avoid fasting 7
• Manage stress appropriately 7
• Be cautious with hormonal treatments, especially progestins, which trigger attacks 7

Monitoring and Complications

Iron Overload Monitoring

• Measure serum ferritin every 3-6 months or after every ~12 doses in patients receiving prophylactic or frequent hemin 3
• Hemin contains 9% iron by weight and causes iron overload 3
• Begin therapeutic phlebotomy when ferritin exceeds 1000 ng/mL, with goal of reducing to ~150 ng/mL 3

Annual Monitoring Requirements

• Liver enzymes, creatinine and eGFR 1
• Liver ultrasound and α-fetoprotein every 6 months for HCC screening 1
• Comprehensive metabolic panel, plasma homocysteine 1
• Urinalysis with urinary protein-to-creatinine ratio 1
• B12/folate, amylase/lipase 1
• Complete blood count and ferritin 1

Long-Term Complications

• Chronic kidney disease occurs in up to 59% of symptomatic AIP patients 9
• Hypertension requires optimal control to decrease additional CKD risk 1
• Hepatocellular carcinoma risk is increased—screen all confirmed AIP patients 3
• Chronic neuropathy affects 35% of recurrent attack patients 1
• 65% of recurrent attack patients report chronic symptoms (pain, fatigue, anxiety, nausea), with 46% experiencing daily symptoms 1

Patient Classification and Follow-Up

Classify all AIP patients into four subgroups to determine management intensity: latent genetic mutation carriers, asymptomatic high excretors (ASHE), sporadic attack patients, and recurrent attack patients. 3, 7

Follow-Up Frequency

• Recurrent attack patients: frequent monitoring with close follow-up 7
• Sporadic attack patients: annual follow-up 7
• Asymptomatic high excretors: annual monitoring for CKD and HCC risk 1
• Latent carriers: education and genetic counseling 3

Perioperative Management

• Administer IV fluids containing dextrose routinely to all fasting AIP patients, including latent cases 3
• Pre-procedure evaluation must include medication review and anesthesia planning using safe agents 3

Special Populations

Women of Reproductive Age

• Pre-conception evaluation is recommended 7
• High-risk obstetrical care is necessary during pregnancy 7
• Careful contraceptive selection—progestin-containing contraceptives may trigger attacks 7

Definitive Treatment

Orthotopic liver transplantation is curative and should be considered for patients with severe, disabling attacks or attacks refractory to hemin therapy. 3, 7

• Combined liver-kidney transplantation benefits patients with both recurrent attacks and end-stage renal disease 3, 7
• Transplantation results in significant improvement in clinical symptoms attributed to increased ALA and PBG clearance 1

Genetic Counseling

• All heterozygotes (symptomatic, ASHE, or latent) should receive genetic counseling about autosomal dominant inheritance 3
• Mutation screening for family members with education about precipitating factors 2
• Provide special identification cards listing safe medications 8

Common Pitfalls

• Avoid misdiagnosing based on mild urinary porphyrin elevations alone—these secondary porphyrinurias are common and non-specific 1
• Do not delay hemin treatment waiting for genetic confirmation—biochemical diagnosis with typical symptoms is sufficient to start treatment 2
• Remember that 15-44% of asymptomatic AIP patients have normal urine studies, requiring repeat testing during attacks 1
• AIP diagnosis is frequently delayed by an average of 15 years—maintain high suspicion in any woman of childbearing age with unexplained recurrent severe abdominal pain 1