What is the management plan for a patient with acute intermittent porphyria (AIP) during an acute attack?

Management of Acute Intermittent Porphyria During an Acute Attack

Immediately discontinue all porphyrinogenic drugs and initiate intravenous hemin (3-4 mg/kg/day) along with IV dextrose as the definitive treatment for acute attacks, with hospitalization required for patients presenting with severe abdominal pain, vomiting, or hypertension. 1, 2

Immediate Actions During Acute Attack

Drug Discontinuation and Trigger Removal

• Stop all potentially porphyrinogenic medications immediately upon suspicion, even before biochemical confirmation is obtained 1, 3
• Remove other precipitating factors including alcohol, fasting states, and infections 1
• Consult porphyria drug databases before introducing any new medications during the acute phase 1

Definitive Pharmacologic Treatment

• Administer intravenous hemin (PANHEMATIN) at 3-4 mg/kg/day as the treatment of choice for acute attacks 1, 2
• Hemin should be initiated early in the acute phase to prevent neurologic sequelae 4, 5
• In clinical trials, 85.5% of patients (141/165 treatment courses) experienced clinical response defined by symptom improvement and pain reduction 2
• All patients demonstrated chemical response with normalization of urinary ALA and PBG levels 2
• Administer hemin via central venous access when possible, as it can cause phlebitis in peripheral veins 2

Supportive Carbohydrate Therapy

• Provide intravenous dextrose (glucose) to suppress hepatic heme synthesis 1, 3, 4
• While oral glucose tablets or concentrated dextrose solutions have been used by some patients in early attack stages, there are no clear clinical data showing benefit 6
• Outpatient prophylactic dextrose infusions offer no proven benefit 6

Symptomatic Management

Pain Control

• Provide aggressive analgesic therapy for severe abdominal pain, which occurs in 90% of patients 1, 4
• Opioid analgesics are often required, but monitor for dependence in patients with chronic pain 6
• Refer patients with chronic pain to pain management specialists for optimal treatment 6

Autonomic Dysfunction Management

• Administer antiemetics for nausea and vomiting 1, 3
• Monitor and treat hypertension and tachycardia, which are common autonomic manifestations 4, 7
• Correct hyponatremia, which occurs in 25-60% of acute attacks 3

Neurologic Complications

• Monitor for peripheral neuropathy, which can progress rapidly to flaccid quadriparesis within days 5, 7
• Assess for respiratory muscle weakness requiring mechanical ventilation 7
• For seizures, use gabapentin or propofol rather than conventional antiepileptics, as many are porphyrinogenic 7
• Obtain nerve conduction studies if motor weakness develops 5

Hospitalization Criteria

Patients with severe abdominal pain, vomiting, and hypertension require inpatient hospital management as they can deteriorate rapidly and are not candidates for outpatient therapy. 1

Additional indications for intensive care include:

• Development of motor neuropathy or bulbar symptoms 5, 7
• Respiratory compromise requiring ventilatory support 7
• Severe hyponatremia or encephalopathy 4, 8
• Seizures or altered mental status 7, 8

Diagnostic Confirmation During Attack

Biochemical Testing

• Measure urinary porphobilinogen (PBG) and aminolevulinic acid (ALA) levels 6, 4
• During an acute attack, PBG/creatinine ratio is typically increased to more than 10 times the upper limit of normal 6
• If measured by mass spectrometry, expect results above 10 μmol/mmol creatinine 6
• More than fivefold elevation of urinary PBG together with typical symptoms is sufficient to start treatment 4
• The PBG/ALA ratio in urine is approximately 2:1 in AIP patients with normal renal function 6

Important Diagnostic Pitfalls

• If urinary PBG is normal during symptoms, acute porphyria is excluded as the cause (assuming proper sample handling) 6
• Hemin treatment may lower or normalize PBG excretion if sampling occurs during or shortly after therapy 6
• Screening tests for PBG have low specificity and sensitivity and must be confirmed by quantitative assays 6

Alternative Treatment for Resource-Limited Settings

• In developing countries where hemin is unavailable, hemodialysis has been used successfully for severe attacks 5
• One case report documented improvement in abdominal pain, myalgia, and motor function after 4-6 hours of daily hemodialysis for 6 days 5
• This should be considered only when hemin cannot be obtained, as hemin remains the standard of care 5

Monitoring During Acute Treatment

Clinical Parameters

• Assess pain severity and neurologic function daily 2, 4
• Monitor vital signs for autonomic dysfunction (blood pressure, heart rate) 4, 7
• Evaluate muscle strength and respiratory function if neuropathy develops 5, 7

Laboratory Monitoring

• Check serum sodium levels to detect and correct hyponatremia 3, 8
• Measure liver function tests, as aminotransferases are elevated in approximately 13% of patients during attacks 3
• Follow urinary ALA and PBG levels to assess biochemical response 2, 4

Post-Attack Follow-Up

After hospitalization for an acute attack, schedule a follow-up visit within one month for reassessment. 6

This visit should include:

• Review of precipitating factors and reinforcement of avoidance strategies 6, 1
• Assessment for residual neurologic deficits requiring physical therapy 5
• Evaluation for need for prophylactic therapy if this represents the fourth or more attack per year 1, 3
• Psychiatric evaluation if recurrent attacks are affecting quality of life 6

Prevention of Future Attacks

Patient Education

• Counsel all newly diagnosed patients about avoiding known precipitating factors 6, 1
• Provide access to online porphyria drug databases for medication safety checking 1, 3
• Educate about maintaining adequate caloric intake and avoiding prolonged fasting 3
• Advise complete avoidance of alcohol and smoking 1, 3

Prophylactic Therapy Indications

Patients experiencing 4 or more attacks per year are candidates for prophylactic hemin infusions administered weekly, bimonthly, or monthly. 1, 3

• Single prophylactic hemin infusions can be given at varying intervals 6
• Less frequent than weekly dosing may not be effective since heme is metabolized rapidly 1
• Alternative prophylactic option is subcutaneous givosiran (RNAi therapeutic targeting hepatic ALAS1) 6, 3

Menstrual-Related Attacks in Women

• For cyclic attacks related to the menstrual cycle (typically during luteal phase), consider 6:
  • GnRH analogue therapy initiated during days 1-3 of cycle
  • Switching to low-dose hormonal contraceptive (avoiding high-dose progestins)
  • Prophylactic hemin infusions during luteal phase
• Measure serum progesterone at symptom onset to identify luteal phase attacks 6
• Oophorectomy and hysterectomy should not be performed unless there is another indication 6

Iron Overload Monitoring with Chronic Hemin Use

• Measure serum ferritin every 3-6 months or after every ~12 doses in patients receiving prophylactic or frequent hemin treatment 1
• Hemin contains 9% iron by weight and can lead to iron overload 1
• Begin therapeutic phlebotomy when ferritin exceeds 1000 ng/mL, with goal of reducing to ~150 ng/mL 1

Definitive Treatment for Refractory Disease

Orthotopic liver transplantation is curative and should be considered for patients with severe, disabling, intractable attacks refractory to hemin therapy. 6, 1, 3

• Liver transplantation is associated with morbidity and mortality and is considered treatment of last resort 6
• Patients with advanced neuropathy, quadriplegia, and respiratory paralysis are poor transplant candidates 6
• Combined liver-kidney transplantation may benefit patients with both recurrent attacks and end-stage renal disease 6, 1, 3

Long-Term Complication Screening

All patients with confirmed AIP require at least annual monitoring including 1, 3:

• Liver function tests and complete blood count 1
• Metabolic panel with estimated glomerular filtration rate (eGFR) for renal function 1, 3
• Serum ferritin (especially if receiving hemin) 1
• Hepatocellular carcinoma screening with liver imaging at 6-12 month intervals after age 50 for patients with recurrent attacks or past symptoms 6, 3
• Blood pressure monitoring, as aggressive hypertension treatment may help prevent renal damage 3