What is the diagnosis and treatment approach for a patient with suspected acute intermittent porphyria (AIP)?

Acute Intermittent Porphyria: Comprehensive Overview

Definition and Pathophysiology

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

• The enzyme deficiency predisposes patients to triggering factors (certain drugs, stress, fasting, alcohol, smoking, hormones) that increase hepatic heme demand, inducing ALAS1 (the rate-limiting enzyme) and causing marked accumulation of ALA and PBG 1
• The genetic prevalence is much higher than previously recognized: pathogenic variants occur in 1 in 1,300 to 1 in 1,785 individuals, though symptomatic disease affects only approximately 1 in 100,000 1
• Clinical penetrance is extremely low—over 90% of mutation carriers remain asymptomatic for life 1

Clinical Presentation

Demographics and Attack Patterns

• Approximately 90% of symptomatic patients are women, with attacks rare before menarche or after menopause 1
• Among symptomatic patients, more than 90% experience only 1 or a few acute attacks in their lifetime 1
• An estimated 3-5% develop recurrent attacks (defined as 4 or more per year), often triggered by progesterone during the luteal phase 1

Acute Attack Symptoms

The key clinical triad indicating possible AIP includes: (1) severe abdominal pain without peritoneal signs, (2) acute peripheral neuropathy, and (3) encephalopathy with seizures or psychosis. 2

• Abdominal symptoms: Severe paroxysmal abdominal pain, nausea, vomiting, constipation 1
• Autonomic dysfunction: Tachycardia, hypertension 1, 2
• Neurological manifestations: Motor and/or sensory polyneuropathy, muscle weakness, cranial nerve abnormalities 1, 2
• Psychiatric symptoms: Mental status changes, psychosis 2, 3
• Metabolic abnormalities: Hyponatremia 2, 4

Chronic Manifestations

• Over 50% of patients with recurrent attacks report chronic neurologic symptoms, and 35% have diagnosed neuropathy 1
• These patients experience markedly impaired quality of life and elevated risk for long-term complications 1

Diagnosis

When to Screen

Women aged 15-50 years with unexplained, recurrent severe abdominal pain without clear etiology after initial workup should be screened for AHP. 1

• Diagnosis is frequently delayed by an average of 15 years from symptom onset to diagnosis in the United States and Europe 1
• AIP should be considered in any patient (especially women of reproductive age) with the characteristic symptom triad 1, 2

Biochemical Testing

Initial diagnosis requires measurement of urinary PBG and ALA in a random urine sample corrected for creatinine. 1

• During an acute attack: PBG/creatinine ratio is typically increased more than 10 times the upper limit of normal 1
• Diagnostic threshold: More than fivefold elevation of urinary PBG with typical acute attack symptoms is sufficient to initiate treatment 2
• The PBG/ALA ratio in urine is approximately 2:1 in AIP patients with normal renal function 1
• If urinary PBG is normal during current symptoms, acute porphyria is excluded as the cause (assuming proper sample handling) 1

Common pitfall: Screening tests to detect PBG in urine have low specificity and sensitivity and are generally not recommended; if used in emergency settings, results must be confirmed by quantitative assay 1

Genetic Testing

• Following biochemical confirmation, genetic testing should determine the specific AHP type and identify the pathogenic HMBS variant 1
• Mutation screening should be offered to family members of confirmed cases 2

Differential Diagnosis

• ALAD deficiency porphyria (extremely rare, autosomal recessive) presents with elevated ALA but normal or near-normal PBG 5
• Lead poisoning and hereditary tyrosinemia should be excluded when elevated ALA is found 5

Patient Classification and Management Intensity

Patients should be classified into four subgroups that determine management intensity: 1

1. Latent genetic carriers: Asymptomatic with normal ALA and PBG levels
2. Asymptomatic high excretors (ASHE): No acute attacks but biochemically active (urinary ALA and PBG ≥4 times upper limit of normal), representing about 10% of AHP patients 1
3. Sporadic attack patients: Infrequent acute attacks (<4 per year), representing the majority of symptomatic patients 1
4. Recurrent attack patients: ≥4 attacks per year, representing 3-5% of symptomatic patients 1

Treatment of Acute Attacks

Immediate Management

The cornerstone of acute attack treatment is suppression of ALA and PBG production through: 3

1. Discontinuation of all porphyrinogenic drugs and precipitating factors 1, 2
2. Intravenous hemin administration (most effective treatment) 6, 2, 7
3. Adequate caloric support 2, 3
4. Symptomatic treatment 2

Hemin Therapy

Hemin (Panhematin) should be administered at 3-4 mg/kg/day intravenously for severe or moderate acute attacks. 6

• Hemin inhibits δ-aminolevulinic acid synthetase, limiting porphyrin/heme biosynthesis 6
• In clinical studies of 99 patients with acute porphyrias, hemin produced clinical response in 85.5% (141/165) of treatment courses, defined by symptom improvement and pain reduction 6
• All patients demonstrated chemical response with normalization of urinary ALA and PBG 6
• Clinical response is often rapid after hemin infusion 6
• Hemin therapy is not curative; symptoms generally return after discontinuation, though some patients experience prolonged remission 6

Important caveat: If sampling occurs during or shortly after hemin treatment, PBG excretion may be lower or normalized 1

Alternative Acute Treatment

• Carbohydrate loading (intravenous dextrose) should be used when hemin is unavailable or for mild attacks 5, 7
• High carbohydrate intake (300 g minimum for 72 hours) was used in clinical studies before hemin administration 6

Symptomatic Management

• Analgesics for severe abdominal pain 5
• Antiemetics for nausea and vomiting 5
• Treatment of autonomic dysfunction (tachycardia, hypertension) 2
• Management of peripheral neuropathy 2
• Treatment of encephalopathy and seizures 2
• Correction of hyponatremia 2

Prevention and Long-Term Management

For All Patients

• Education about avoiding precipitating factors (porphyrinogenic drugs, fasting, alcohol, smoking) 1, 2
• Access to online drug safety lists for porphyria 2
• Adequate nutrition and avoidance of fasting 2

For Recurrent Attack Patients (≥4 attacks/year)

Prophylactic treatment with intravenous hemin or subcutaneous givosiran should be considered for patients with 4 or more acute attacks per year. 8

• Lifestyle evaluation to identify and eliminate triggers 2
• Hormonal therapy evaluation in women (attacks often correlate with luteal phase) 2, 1
• Prophylactic heme therapy for prevention 2, 7
• Liver transplantation should be considered for patients with severe recurrent attacks refractory to other treatments 2, 7

Emerging Therapies

• Givosiran (siRNA therapy) down-regulates ALAS1 and represents a novel molecular approach 7
• Enzyme replacement therapy and liver gene therapy are under investigation 3

Long-Term Monitoring and Complications

All AIP patients require regular monitoring for chronic complications: 5

Monitoring Parameters

• Liver enzymes for hepatic function 5
• Creatinine and eGFR for renal function 5
• Blood pressure monitoring 5
• Neurological assessment for symptoms of neuropathy 5
• Hepatocellular carcinoma (HCC) screening in appropriate cases 5

Long-Term Complications

Patients with recurrent attacks face elevated risk for: 1, 5, 2

• Hepatocellular carcinoma 1, 2
• Chronic kidney disease and renal failure 1, 5, 2
• Chronic hypertension 1, 2
• Permanent peripheral neuropathy 1, 2
• Chronic pain syndrome 2

Asymptomatic High Excretors

• Individuals with elevated ALA and PBG who have never experienced acute attacks may be at increased risk for induced acute attacks, chronic renal or hepatic injury, and/or HCC compared to mutation carriers with normal ALA 1

Prognosis

• Currently, the prognosis for AIP patients is good, but physicians must remain aware of potentially fatal outcomes 2
• Neurological symptoms may improve weeks to months after therapy, even when little response was noted during treatment 6
• Some patients experience prolonged remission after hemin treatment 6
• The majority of symptomatic patients (>90%) experience only one or a few attacks in their lifetime and maintain good quality of life 1