What is Acute Intermittent Porphyria (AIP)?

What is Acute Intermittent Porphyria (AIP)?

Acute Intermittent Porphyria (AIP) is an autosomal dominant inherited disorder of heme biosynthesis caused by deficiency of hydroxymethylbilane synthase (HMBS), resulting in accumulation of neurotoxic porphyrin precursors (δ-aminolevulinic acid and porphobilinogen) that cause acute neurovisceral attacks. 1

Pathophysiology

AIP results from pathogenic variants in the HMBS gene that cause at least 50% reduction in enzyme activity. 1 When triggering factors increase hepatic heme demand, the decreased free heme induces ALAS1 (the first and rate-limiting enzyme in heme biosynthesis) through negative feedback. 1 Due to the half-normal HMBS enzyme activity, this marked ALAS1 induction leads to excessive production and accumulation of the neurotoxic precursors ALA and PBG, which are always markedly elevated during acute attacks. 1

Epidemiology and Genetics

• The prevalence of pathogenic variants for AIP is between 1 in 1,300 and 1 in 1,785, much higher than previously believed. 1
• Symptomatic AIP affects approximately 1 in 100,000 patients. 1
• Penetrance is low—over 90% of heterozygotes for disease-causing mutations remain asymptomatic for life. 1
• Approximately 90% of patients with symptomatic AIP are women, and attacks are rare before menarche or after menopause. 1

Clinical Presentation

Acute Neurovisceral Attacks

The hallmark presentation includes: 1

• Severe acute abdominal pain (most common)
• Nausea and vomiting
• Constipation
• Muscle weakness
• Peripheral and autonomic neuropathy
• Tachycardia and hypertension
• Neuropsychiatric symptoms and altered mental status 2
• Dark or reddish urine (from porphyrin precursors) 3

Attack Patterns

• Over 90% of symptomatic patients experience only 1 or a few acute attacks in their lifetimes. 1
• An estimated 3-5% of patients experience recurrent attacks (≥4 per year). 1
• Attacks are often precipitated by triggering factors including certain drugs, stress, fasting, alcohol, smoking, hormones (particularly progesterone during the luteal phase), and infections. 1, 3

Chronic Manifestations in Recurrent Disease

Patients with recurrent attacks face significant morbidity: 1

• Over 50% report chronic neurologic symptoms between attacks
• 35% have diagnosed neuropathy
• Markedly impaired quality of life
• Higher risk of hepatocellular carcinoma (HCC)
• Chronic renal failure

Diagnostic Approach

Biochemical Testing

The diagnostic hallmark is markedly elevated urinary porphobilinogen (PBG) and δ-aminolevulinic acid (ALA) during acute attacks. 1 In AIP specifically, urine PBG is typically elevated more than ALA. 1

Genetic Testing

Following biochemical confirmation, genetic testing for HMBS pathogenic variants should be performed to determine the specific AHP subtype and enable family screening. 1

Clinical Suspicion Triggers

Consider AIP screening in women aged 15-50 years with unexplained, recurrent severe abdominal pain without clear etiology after initial workup. 1 The diagnosis is frequently delayed by an average of 15 years from symptom onset, as AIP mimics common surgical conditions like appendicitis, cholecystitis, and pancreatitis. 1, 2

Common Diagnostic Pitfalls

• Hyponatremia is frequently present and may be marked, sometimes leading to altered mental status. 2
• The nonspecific symptoms often lead to extensive diagnostic workups or unnecessary surgical interventions if AIP is not considered. 1, 2
• AIP can present with ileus and bowel distension, further mimicking surgical emergencies. 3

Treatment of Acute Attacks

Immediate Management

The standard of care includes: 4, 5

• Intravenous hemin (3-4 mg/kg/day) is the primary treatment, achieving clinical response in 85.5% of treatment courses. 4
• Intravenous dextrose (high carbohydrate intake) to suppress ALAS1 induction 4, 3
• Immediate discontinuation of all porphyrinogenic drugs and precipitating factors 6
• Analgesics and antiemetics for symptom control 6

Treatment Efficacy

In clinical studies, hemin treatment produced clinical response (improvement of symptoms and pain reduction) in 73-90% of acute attacks, with all patients demonstrating chemical response (normalization of urinary ALA and PBG). 4

Long-term Management and Complications

Patients require regular monitoring for: 6

• Liver enzymes and hepatocellular carcinoma screening (due to increased HCC risk)
• Creatinine, eGFR, and blood pressure (chronic kidney disease and hypertension risk)
• Neurologic examination for peripheral neuropathy
• Bone health (osteoporosis and vitamin D deficiency risk)

Prophylactic hemin infusion may be effective in patients with recurrent attacks, though it can induce tolerance and carries risks of thromboembolic disease and hepatic siderosis with frequent use. 5 Orthotopic liver transplantation remains the only curative treatment for patients with severe recurrent attacks. 5