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

Workup and Management of Acute Intermittent Porphyria (AIP)

The diagnosis of AIP requires measurement of urinary porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) levels, with genetic testing for HMBS gene mutations to confirm the diagnosis, while management includes intravenous hemin for acute attacks and consideration of givosiran for patients with recurrent attacks (≥4 per year).

Diagnostic Workup

Initial Screening

• Collect random urine sample to measure PBG, ALA, and creatinine levels 1, 2
  • During acute attacks, PBG and ALA are typically elevated at least 5-fold above upper limit of normal
  • Urine may turn dark when exposed to light due to PBG oxidation
• Watson-Schwartz test can be used for rapid detection of elevated urinary PBG 2

Confirmatory Testing

• Genetic testing for pathogenic variants in HMBS gene (for AIP) 1, 2
  • Should be performed after positive biochemical testing
  • Whole-gene sequencing identifies 95-99% of cases
  • First-degree family members should be screened once the familial pathogenic variant is identified

Important Considerations

• In patients with sporadic AIP, 15-44% may have normal urine ALA and PBG when asymptomatic 1
• Repeat testing during an acute attack may be necessary for diagnosis
• In patients with recurrent attacks, urine ALA and PBG are typically elevated even between attacks 1

Management

Acute Attack Management

1. First-line Treatment

   • Intravenous hemin: 3-4 mg/kg body weight once daily for 4 days 1, 2, 3
     • Preferably administered into a high-flow central vein
     • Heme bound to human serum albumin is preferred to reduce vein irritation
     • Collect urine for ALA, PBG, and creatinine before starting hemin

2. Supportive Care

   • Discontinue any potential triggering medications 1, 2
   • Carbohydrate loading: 300g/day orally or as 10% glucose intravenously 1, 2
   • Pain management: Aggressive treatment with safe analgesics 1, 2
   • Antiemetics for nausea and vomiting 1
   • Monitor and correct electrolyte abnormalities, particularly hyponatremia and hypomagnesemia 1, 2
   • Manage systemic arterial hypertension and tachycardia if present 1

Prevention and Management of Recurrent Attacks

1. Trigger Avoidance

   • Educate patients to avoid:
     • Porphyrinogenic medications
     • Alcohol consumption
     • Severe caloric restriction
     • Stress 2

2. Prophylactic Treatment Options

   • For patients with ≥4 attacks per year:
     • Givosiran (RNAi therapeutic targeting hepatic ALAS1) 1, 2
     • Prophylactic hemin infusions 2
   • For women with menstrual cycle-related attacks:
     • GnRH analogues with low-dose estrogen supplementation 2

3. Last Resort Options

   • Liver transplantation for severe, disabling, intractable attacks refractory to hemin therapy 2
   • Renal transplantation for AIP patients with advanced renal disease 2
   • Combined liver-kidney transplantation for patients with both recurrent attacks and end-stage renal disease 2

Long-term Monitoring

Regular Monitoring

• Patients with recurrent attacks: Every 3-6 months 2
• Patients with sporadic attacks: Annually 2
• Latent carriers: Every 1-3 years 2

Specific Monitoring Parameters

• Urinary ALA and PBG levels 1, 2
• Renal function (serum creatinine and eGFR) 2
• Liver enzymes 2
• Serum ferritin (in patients receiving prophylactic hemin) 2
• Hepatic ultrasound and alpha-fetoprotein every 6 months after age 50 for hepatocellular carcinoma screening 1, 2

Special Considerations

Pregnancy

• Pre-conception evaluation is recommended 2
• High-risk obstetrical care should be provided during pregnancy 2
• Hemin can be safely administered during pregnancy if needed 2

Quality of Life

• Psychiatric evaluation and pain management are essential components of care 2
• Address chronic symptoms including nausea, fatigue, anxiety, and insomnia 2

Complications to Monitor

• Chronic hypertension 1, 2
• Chronic kidney disease 1, 2
• Chronic pain syndrome 2
• Hepatocellular carcinoma (particularly in patients over 50 years) 1, 2

AIP diagnosis requires a high index of suspicion, especially in women aged 15-50 years with recurrent severe abdominal pain without peritoneal signs or abnormalities on imaging. Timely diagnosis and appropriate management are crucial to prevent neurological complications and improve quality of life.