What is the management and treatment of acute intermittent porphyria?

Management and Treatment of Acute Intermittent Porphyria

Acute Attack Management

For acute attacks, immediately discontinue all porphyrinogenic drugs and initiate intravenous hemin therapy early, which is the treatment of choice, along with IV dextrose to suppress hepatic heme synthesis. 1, 2

Immediate Actions During Acute Attack

• Stop all potentially porphyrinogenic medications immediately upon suspicion of an acute attack, even before biochemical confirmation is obtained 2, 3
• Administer oral or intravenous dextrose (glucose) to suppress hepatic heme synthesis 2, 4
• Initiate intravenous hemin (PANHEMATIN) at 3-4 mg/kg/day as the definitive treatment for acute attacks 1, 5
• Provide aggressive symptomatic management with analgesics for severe abdominal pain and antiemetics for nausea/vomiting 2
• Monitor and correct hyponatremia, which occurs in 25-60% of acute attacks 2, 6

Hospitalization Criteria

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

Prevention of Recurrent Attacks

Prophylactic Hemin Therapy

Patients with 4 or more attacks per year are candidates for prophylactic hemin infusions administered weekly, bimonthly, or monthly, though weekly dosing is most effective given heme's rapid metabolism 1, 7

• Single prophylactic infusions can be given at varying intervals, but less frequent than weekly dosing may not be effective since heme is metabolized rapidly by heme oxygenase 1
• For patients experiencing prodromal symptoms, hemin can be administered "on demand" at an outpatient center to control symptoms and prevent hospitalization 1
• Reassess the need for ongoing prophylactic hemin after 6-12 months of repeated therapy by interrupting treatment and restarting if necessary 1

Monitoring for Iron Overload

Measure serum ferritin every 3-6 months or after every ~12 doses in patients receiving prophylactic or frequent hemin treatment, as hemin contains 9% iron by weight and can lead to iron overload 1

• Begin therapeutic phlebotomy when ferritin levels exceed 1000 ng/ml, with a goal of reducing serum ferritin to ~150 ng/ml 1
• Measure ferritin between attacks and before the next hemin dose to avoid acute phase effects 1

Avoidance of Triggering Factors

All patients must avoid porphyrinogenic drugs, fasting, alcohol, and smoking, which can precipitate attacks 1, 7

• Patients should consult publicly available drug databases before starting new medications 1
• Maintain adequate caloric intake and avoid prolonged fasting or crash dieting 1, 7
• Carbohydrate loading has no proven clinical benefit for preventing attacks and sustained high-carbohydrate diets are not recommended 1
• Patients with severe recurrent symptoms should completely avoid alcohol and smoking 1
• Medical alert bracelets are recommended for all AHP patients 1

Management of Cyclic Attacks in Women

For women with menstrual cycle-related attacks, consider GnRH analogues, low-dose hormonal contraceptives, or prophylactic hemin infusions administered weekly or once-twice during the luteal phase 1, 7

• Progestin-containing contraceptives may trigger attacks and should be avoided 7, 2, 6
• Pre-conception evaluation is recommended for all women planning pregnancy 7, 2, 6
• High-risk obstetrical care is necessary during pregnancy due to increased attack risk from hormonal changes 7, 2, 6

Perioperative Management

For patients undergoing surgery, administer IV fluids containing dextrose routinely to all AHP patients who are fasting, including latent cases 1

• Pre-procedure evaluation should include review of current medications and planning anesthesia using agents that are safe in AHPs 1
• For patients with frequently recurring attacks, consider prophylactic hemin infusion prior to surgery and postoperatively 1

Long-Term Monitoring and Complication Screening

All patients with confirmed AHP require at least annual monitoring including liver function tests, complete blood count, ferritin, metabolic panel with eGFR, and screening for complications 2, 6

Hepatic Monitoring

• Obtain liver function tests at baseline for all patients 1
• Serum aminotransferases are elevated in ~13% of patients during acute attacks and in some asymptomatic patients 1, 2
• Screen for hepatocellular carcinoma in all patients with confirmed AHP, as they carry increased risk 7, 2

Renal Monitoring

• Monitor for chronic kidney disease, typically chronic tubulointerstitial nephropathy or focal cortical atrophy 1, 7, 2
• Aggressively monitor and treat hypertension, which may help prevent renal damage 1, 7, 2
• Refer to a nephrologist if hypertension is not controlled by first-line treatment or when renal dysfunction is first recognized 1

Neurologic Evaluation

• Neurological consultation is useful for assessing positive neurological findings or unexplained symptoms 1
• Nerve conduction and electromyographic studies may detect chronic neuropathy as the cause of ongoing pain, sensory loss, or muscle weakness 1

Definitive Treatment Options

Orthotopic liver transplantation is curative and should be considered for patients with severe, disabling attacks or attacks refractory to hemin therapy 7, 2

• Combined liver-kidney transplantation may benefit patients with both recurrent attacks and end-stage renal disease 7, 2
• Renal transplantation benefits patients with advanced renal disease 7

Patient Classification for Management Intensity

The American Association for the Study of Liver Diseases classifies patients into four subgroups that determine follow-up frequency and management intensity 1, 7, 2, 6:

1. Latent genetic mutation carriers: Asymptomatic with normal urinary ALA and PBG levels
2. Asymptomatic high excretors (ASHE): No current attacks but biochemically active with urinary ALA and PBG ≥4 times upper limit of normal
3. Sporadic attack patients: Infrequent acute attacks (<4 per year) requiring annual follow-up
4. Recurrent attack patients: >4 attacks per year requiring closer monitoring and prophylactic therapy

Genetic Counseling

All heterozygotes, whether symptomatic, ASHE, or latent, should receive appropriate genetic counseling about inheritance 1

• Pregnancy is generally not avoided as it is usually well tolerated 1
• Treatment is available and prognosis favorable for offspring who inherit the familial mutation 1