What is the management and treatment of acute intermittent porphyria?

Acute Intermittent Porphyria: Comprehensive Overview

Pathophysiology and Epidemiology

Acute intermittent porphyria (AIP) is an autosomal dominant inherited disorder caused by ~50% deficiency of hydroxymethylbilane synthase (porphobilinogen deaminase), the third enzyme in heme biosynthesis, leading to toxic accumulation of porphyrin precursors (ALA and PBG) that cause neurovisceral symptoms. 1

• The enzyme deficiency results in compensatory upregulation of ALAS1 (the rate-limiting first enzyme), which when triggered by precipitating factors, causes massive overproduction of the neurotoxic precursors ALA and PBG 1
• Prevalence of symptomatic AIP is approximately 1 in 100,000, but genetic studies reveal pathogenic variants occur in 1 in 1,300 to 1 in 1,785 individuals, indicating most carriers remain asymptomatic (>90% penetrance is low) 1, 2
• Approximately 90% of symptomatic patients are women, with attacks occurring primarily during childbearing years (ages 15-50), rarely before menarche or after menopause 1, 2

Clinical Presentation

Acute attacks present with severe abdominal pain without peritoneal signs or imaging abnormalities, accompanied by autonomic dysfunction (tachycardia, hypertension), nausea, vomiting, constipation, and potentially life-threatening neurological complications including motor neuropathy, seizures, and psychiatric symptoms. 1

Attack Symptoms

• Severe generalized abdominal pain is the hallmark symptom, often mimicking acute abdomen or bowel obstruction but without peritoneal signs 1, 3
• Autonomic manifestations: tachycardia, hypertension, sweating 1
• Neurological: peripheral neuropathy (can progress to quadriplegia), seizures, confusion, hallucinations 1, 3
• Hyponatremia from SIADH is common and can precipitate seizures 1

Chronic Manifestations

• Contrary to the name "intermittent," most symptomatic patients experience chronic symptoms between attacks, not just during acute exacerbations 4, 5
• Chronic symptoms include persistent abdominal pain, fatigue, muscle pain, insomnia, and neuropathy (tingling, numbness) reported in 85% of sporadic attack patients and 46% of latent patients 4
• Quality of life is significantly impaired even in patients with infrequent attacks, with impact on pain, anxiety-depression, and mobility domains 4

Patient Classification

The 2017 Hepatology guidelines classify AIP patients into four management subgroups: 1

1. Latent carriers: Asymptomatic with normal urinary ALA/PBG levels
2. Asymptomatic high excretors (ASHE): No attacks but biochemically active (ALA/PBG ≥4× upper limit normal), representing ~10% of AHP patients
3. Sporadic attack patients: <4 attacks per year (majority of symptomatic patients)
4. Recurrent attack patients: ≥4 attacks per year (~3-5% of symptomatic patients, with markedly deteriorated quality of life)

Diagnosis

Screen all women aged 15-50 years with unexplained recurrent severe abdominal pain using random urine porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) corrected to creatinine—this is the screening test of choice. 1, 6

Diagnostic Algorithm

• During acute attack: Urinary PBG is markedly elevated (typically >10× normal); ALA is also elevated but usually less than PBG 1, 7
• All patients with elevated urinary PBG and/or ALA should initially be presumed to have AHP 1
• After biochemical confirmation: Perform genetic testing for pathogenic variants in HMBS, CPOX, PPOX, and ALAD genes to confirm AIP type 1, 6
• Diagnosis is often delayed >15 years from initial presentation due to nonspecific symptoms 1

Common Diagnostic Pitfall

• Do not rely on plasma or urinary porphyrins for acute attack diagnosis—these are not sensitive or specific; PBG and ALA are the definitive tests 1

Acute Attack Management

Immediately administer intravenous hemin 3-4 mg/kg once daily for 4 days, preferably via high-flow central vein (PICC or port), along with aggressive pain control, antiemetics, and IV dextrose. 6, 7

Immediate Treatment Steps

1. Discontinue all porphyrinogenic medications and precipitating factors immediately 6
2. IV hemin (PANHEMATIN): 3-4 mg/kg/day once daily for typically 4 days via central access 6, 7
   • Clinical response occurs in 85.5% of treatment courses with symptom improvement and pain reduction 7
   • Chemical response (normalization of ALA/PBG) occurs in 100% of patients 7
   • Most patients experience rapid clinical response after hemin infusion 7
3. IV carbohydrate loading: Administer IV dextrose (high carbohydrate intake of 300g minimum for 72 hours if oral intake tolerated) 6, 7
4. Aggressive pain management: Use appropriate opioid analgesics as needed (most non-opioid analgesics are porphyrinogenic) 6
5. Antiemetics: For nausea and vomiting control 6
6. Correct electrolyte abnormalities: Particularly hyponatremia from SIADH 1

Critical Caveat

• Hemin must be administered via high-flow central vein to prevent phlebitis and thrombosis; peripheral administration risks vascular complications 6, 7
• Consult porphyria drug safety databases before administering any medication, as many common drugs are porphyrinogenic 6

Precipitating Factors to Avoid

Identify and eliminate all precipitating factors: cytochrome P450-inducing drugs, alcohol, smoking, fasting/caloric restriction, hormonal fluctuations (menstrual cycle, pregnancy), infections, and physical/psychological stress. 1, 6

Specific Triggers

• Medications: Barbiturates, sulfonamides, anticonvulsants (phenytoin, carbamazepine), estrogens, many antibiotics 1, 6
• Nutritional: Fasting, low-calorie diets, low-carbohydrate intake 1
• Hormonal: Menstrual cycle (progesterone surge in luteal phase), pregnancy, oral contraceptives 1
• Lifestyle: Alcohol consumption, smoking, psychological stress 1, 8
• Medical: Infections, acute illnesses, surgery 6

Prophylactic Treatment for Recurrent Attacks

For patients with ≥4 attacks per year, initiate prophylactic therapy with either scheduled IV hemin infusions or subcutaneous givosiran (RNA interference therapy targeting ALAS1). 1, 6

Prophylaxis Options

• Scheduled IV hemin: Regular infusions to prevent attacks 6
• Givosiran (subcutaneous): RNA interference therapy that reduces ALAS1 expression, approved for recurrent attack prevention 1, 6
• For menstrual-associated attacks: Consider GnRH agonists for hormonal suppression 6

When to Consider Liver Transplantation

• Liver transplantation is curative but reserved for patients with intractable symptoms who have failed all other treatment options 1

Long-Term Complications and Monitoring

Patients with recurrent attacks face significantly increased risk of hepatocellular carcinoma, chronic kidney disease, systemic hypertension, and permanent peripheral neuropathy—requiring lifelong surveillance. 1, 2, 6

Surveillance Protocol

• Hepatocellular carcinoma screening: Regular liver imaging and AFP monitoring, as HCC risk is markedly elevated 1, 2, 6
• Renal function: Monitor for chronic kidney disease, which is the earliest long-term complication in sporadic attack patients 1, 2, 4
• Blood pressure: Screen for systemic arterial hypertension 1, 2, 6
• Neurological assessment: Monitor for chronic neuropathy and permanent nerve damage 1, 2, 6

Monitoring Frequency by Patient Subgroup

• Recurrent attack patients: Close, frequent monitoring with multidisciplinary care 1
• Sporadic attack patients: Regular monitoring even if attacks are infrequent, as chronic symptoms and complications occur regardless of attack frequency 4
• ASHE patients: Periodic surveillance as they may develop attacks 1
• Latent carriers: Genetic counseling and education about avoiding precipitating factors; no routine biochemical monitoring needed unless symptoms develop 1

Prognosis

Among symptomatic AIP patients, >90% experience only 1 or few attacks in their lifetime, but the 3-5% with recurrent attacks have markedly deteriorated quality of life and substantially higher risk of long-term complications including HCC, chronic renal disease, and permanent neuropathy. 1, 2

• Even patients with sporadic attacks (not recurrent) experience chronic symptoms and impaired quality of life, requiring regular monitoring and proper pain management 4
• AIP is not truly "intermittent" in most symptomatic patients—it manifests as a chronic disease with acute exacerbations 4, 5
• Hemin therapy is not curative; symptoms generally return after discontinuation, though some patients experience prolonged remission 7
• Some neurological symptoms may improve weeks to months after therapy, even if no immediate response was noted 7