Acute Intermittent Porphyria (AIP)

Overview

Genetics and Enzyme Defect

Glycine + Succinyl-CoA → ALA (via ALAS1) → PBG (via ALAD) → Hydroxymethylbilane (via PBGD ← deficient here) → Uroporphyrinogen III → ... → Heme

Pathophysiology

1. Baseline enzyme insufficiency: All carriers have ~50% PBGD activity (consistent with heterozygous dominant inheritance). Homozygous deficiency would presumably be lethal.
2. Precipitant-driven ALAS1 induction: The rate-limiting enzyme of heme synthesis, ALAS1 (delta-aminolevulinic acid synthase 1), is normally feedback-regulated by free hepatic heme. When a precipitant (drug, hormone, fasting) depletes free heme or directly upregulates ALAS1 via nuclear receptor signaling (e.g., pregnane X receptor, constitutive androstane receptor), the flux of ALA and PBG through the pathway increases dramatically.
3. Bottleneck at PBGD: The elevated flux exceeds the reduced PBGD capacity, causing accumulation of ALA and PBG in plasma, urine, and tissues.
4. Neurotoxicity: ALA (structurally similar to GABA) is directly neurotoxic and disrupts the peripheral, autonomic, and central nervous systems. The pathogenesis of neurological disease is not fully resolved, but elevated ALA and PBG are always present during attacks.
5. Hyperhomocysteinemia: A secondary effect - reduced heme availability impairs the heme-dependent enzyme cystathionine-beta-synthase, elevating homocysteine. - Goldman-Cecil Medicine

Precipitating Factors (Triggers)

Clinical Features

The Acute Attack

• Severe, generalized abdominal pain (95% of patients), often colicky, radiating to back/buttocks/thighs
• Nausea, vomiting, constipation or diarrhea (up to 90%)
• No abdominal rigidity (important clue - pain without peritoneal signs)
• Abdominal distension

• Tachycardia, hypertension, sweating (sympathetic overactivity)
• Urinary retention

• Peripheral neuropathy - predominantly motor (50-70%)
• Proximal limb weakness, flaccid quadriplegia in severe cases
• Diaphragmatic weakness, respiratory paralysis (life-threatening)
• Cranial nerve involvement: optic atrophy, facial palsy, dysphagia
• Seizures (10-20%)

• Agitation, anxiety, hallucinations, depression, confusion, psychosis

Chronic/Long-term Complications

• Hypertension and chronic renal disease (up to 59% of symptomatic patients develop CKD)
• Hepatocellular carcinoma - markedly increased risk; hepatic imaging recommended every 6 months
• Neuropathy, fatigue, chronic pain, depression/anxiety
• Hyperhomocysteinemia

Diagnosis

During an Acute Attack

Between Attacks (Asymptomatic)

• Urinary PBG/ALA may be normal
• RBC PBGD enzyme activity (reduced to ~50%) - confirms carrier status in ~88%
• HMBS gene mutation analysis in leukocyte DNA - definitive; also enables family screening

Differential Diagnosis

• Variegate porphyria (VP) - elevated fecal protoporphyrin, plasma peak at 625-627 nm
• Hereditary coproporphyria (HCP) - elevated fecal coproporphyrin III
• ALA dehydratase deficiency porphyria (ALAD) - autosomal recessive, elevated ALA but normal/slight PBG, resembles AIP clinically
• Abdominal emergencies (appendicitis, bowel obstruction - no peritoneal signs in AIP)
• Lead poisoning (elevated ALA, normal PBG)
• Guillain-Barre syndrome (motor neuropathy)

Treatment

Acute Attack Management

• Remove and avoid all precipitating drugs/factors
• IV fluids and electrolyte correction (especially hyponatremia)
• Narcotic analgesics (opioids) for abdominal pain
• Phenothiazines (e.g., chlorpromazine) for nausea, vomiting, anxiety
• Benzodiazepines (low dose, probably safe) for insomnia/agitation
• Chloral hydrate for insomnia
• Respiratory monitoring; ICU if motor neuropathy progresses

• IV glucose ≥300 g/day suppresses ALAS1 by providing caloric substrate
• Effective in mild attacks when hemin is unavailable
• Not adequate for severe attacks with paresis or hyponatremia

• Standard regimen: 3-4 mg/kg/day for 4 days
• Available as: lyophilized hemin (Panhematin), heme arginate (Orphan Europe, preferred in Europe - more stable, less phlebitis), or heme albumin
• Repletes the free hepatic heme pool, suppresses ALAS1, reduces ALA and PBG production
• FDA approved since 1984
• Early treatment produces best outcomes; recovery from motor neuropathy may take months to years if delayed

Long-term/Prophylactic Therapy

• FDA and EMA approved in 2019 for acute hepatic porphyrias
• Mechanism: siRNA that silences hepatic ALAS1 mRNA, reducing ALA and PBG production at source
• Dose: 2.5 mg/kg subcutaneously once monthly
• Phase 3 trial showed significant reduction in attack frequency, reduced hemin utilization, improved daily pain scores
• Currently first-line for patients with recurrent attacks - Harrison's 22E (2025)

• GnRH analogue (e.g., leuprolide) - prevents ovulation and progesterone production; effective for perimenstrual attacks
• Prophylactic hemin infusions
• Givosiran

Advanced/Refractory Cases

• Corrects the hepatic enzyme defect - the liver is the principal site of ALA/PBG overproduction
• Indicated for severe, disabling, treatment-refractory attacks
• Results in normalization of urinary PBG/ALA, no further attacks, improvement in neuropathy
• Associated with significant morbidity/mortality - last resort
• Some patients with both recurrent attacks and end-stage renal disease have benefited from combined liver-kidney transplantation

• Under investigation (promising early results)

Summary Table: AIP vs. Other Acute Porphyrias

• Harrison's Principles of Internal Medicine, 22nd Ed. (2025)
• Goldman-Cecil Medicine, International Ed.
• Thompson & Thompson Genetics & Genomics in Medicine, 9th Ed.
• Andrews' Diseases of the Skin, Clinical Dermatology
• Yamada's Textbook of Gastroenterology, 7th Ed.