Overview
Acute Intermittent Porphyria (AIP)
1. Clinical Overview
Summary
Acute Intermittent Porphyria (AIP) is an autosomal dominant disorder of heme biosynthesis caused by deficiency of porphobilinogen deaminase. Accumulation of porphyrin precursors (ALA, PBG) causes neurovisceral attacks triggered by drugs, fasting, or hormonal changes.
Key Facts
| Aspect | Detail |
|---|---|
| Inheritance | Autosomal dominant |
| Enzyme Defect | Porphobilinogen (PBG) deaminase (50% activity) |
| Key Finding | Elevated urinary PBG during attack |
| Classic Feature | Port-wine coloured urine |
| Treatment | Haem arginate + glucose loading |
Clinical Pearls - The 5 Ps
- Painful abdomen - severe, colicky, mimics surgical abdomen
- Port-wine urine - darkens on standing (oxidation of PBG)
- Polyneuropathy - motor > sensory, may cause paralysis
- Psychological - confusion, anxiety, psychosis
- Precipitated by drugs - P450 inducers, fasting, hormones
2. Epidemiology
Demographics
| Factor | Detail |
|---|---|
| Prevalence | 1-2 per 100,000 |
| Gender | Females > Males (hormonal triggers) |
| Peak age | 18-40 years |
| Penetrance | ~10-20% carriers develop symptoms |
Triggers
| Category | Examples |
|---|---|
| Drugs | Barbiturates, sulfonamides, rifampicin, phenytoin, alcohol |
| Hormones | Progesterone, menstrual cycle, OCP |
| Metabolic | Fasting, low carbohydrate diets |
| Stress | Infection, surgery |
| Smoking |
3. Pathophysiology
Heme Biosynthesis Defect
Glycine + Succinyl-CoA
↓ (ALAS - rate-limiting)
δ-Aminolevulinic Acid (ALA)
↓
Porphobilinogen (PBG)
↓ (PBG Deaminase - DEFICIENT in AIP)
████ BLOCK ████
↓
ALA + PBG ACCUMULATE
↓
NEUROTOXICITY (autonomic, motor, CNS)
↓
ACUTE ATTACK
Why Triggers Cause Attacks
- P450 inducers → ↑ demand for heme → ↑ ALAS activity → more ALA/PBG production
- Fasting → ↓ glucose → ↑ ALAS → same effect
- Progesterone → induces ALAS
4. Clinical Presentation
Acute Attack Features
| System | Manifestations |
|---|---|
| GI | Severe abdominal pain (colicky), vomiting, constipation |
| Neurological | Motor neuropathy, weakness, paralysis |
| Psychiatric | Confusion, anxiety, depression, psychosis |
| Autonomic | Tachycardia, hypertension, sweating |
| Urinary | Dark/red urine (port-wine) |
| Electrolytes | Hyponatraemia (SIADH) |
Danger Signs
| Sign | Concern |
|---|---|
| Respiratory weakness | May need ventilation |
| Bulbar weakness | Aspiration risk |
| Seizures | Usually due to hyponatraemia |
| Quadriparesis | Severe motor neuropathy |
5. Clinical Examination
Findings During Attack
| Finding | Notes |
|---|---|
| Tachycardia | Autonomic dysfunction |
| Hypertension | Common |
| Abdominal tenderness | Often NO peritonism (soft) |
| Reduced reflexes | Motor neuropathy |
| Proximal weakness | Motor predominant |
| Confusion | CNS involvement |
Key Point
- Normal abdomen on exam despite severe pain - no guarding = think AIP
6. Investigations
Diagnostic Tests
| Test | Finding | Notes |
|---|---|---|
| Urine PBG (spot) | ELEVATED (x20-100 normal) | Gold standard during attack |
| Urine ALA | Elevated | |
| Urine colour | Port-wine, darkens on standing | Classic |
Supporting Tests
| Test | Purpose |
|---|---|
| FBC, U&E | Hyponatraemia common |
| LFTs | May be deranged |
| Genetic testing | HMBS gene mutation |
| Erythrocyte PBG deaminase | Reduced (but overlaps with carriers) |
Exclude Surgical Abdomen
- AXR, CT usually normal
- Lactate normal
- No peritonism
7. Management
Acute Attack Management
| Step | Intervention |
|---|---|
| 1. Stop triggers | Identify and stop precipitating drugs |
| 2. IV glucose | 10% dextrose infusion (300-500g/day) |
| 3. Haem arginate | 3mg/kg/day IV for 4 days |
| 4. Analgesia | Opioids safe (pethidine traditionally used) |
| 5. Antiemetics | Ondansetron, prochlorperazine safe |
| 6. Monitor | Hyponatraemia, respiratory function |
Safe Drugs
| Category | Examples |
|---|---|
| Analgesia | Morphine, fentanyl, paracetamol |
| Antiemetics | Ondansetron |
| Sedation | Benzodiazepines (short-acting) |
| Antibiotics | Penicillins, cephalosporins |
Unsafe Drugs (Avoid)
| Category | Examples |
|---|---|
| Anticonvulsants | Phenytoin, barbiturates, valproate |
| Antibiotics | Sulfonamides, rifampicin |
| Others | Alcohol, hormones, ergots |
Prevention
| Measure | Details |
|---|---|
| Avoid triggers | Drug list, avoid fasting |
| Regular carbohydrate | Avoid low-carb diets |
| Hormonal | GnRH analogues if menstrual trigger |
| Prophylactic haem arginate | For frequent attacks |
| Givosiran | New RNAi therapy (reduces ALAS1) |
8. Complications
| Complication | Notes |
|---|---|
| Respiratory failure | Motor neuropathy |
| Bulbar paralysis | Aspiration |
| Chronic pain | Between attacks |
| Hyponatraemia | SIADH |
| Hepatocellular carcinoma | Long-term risk (screen annually >0y) |
| Chronic kidney disease | Long-term |
9. Prognosis & Outcomes
| Factor | Outcome |
|---|---|
| With treatment | Most attacks resolve in days |
| Motor neuropathy | May take months to recover |
| Long-term | Generally good if triggers avoided |
| HCC risk | Annual liver USS recommended >0 years |
10. Evidence & Guidelines
| Organisation | Key Points |
|---|---|
| British Porphyria Association | Drug lists, patient support |
| EPNET | European porphyria network |
| NICE | Givosiran recommendation |
11. Patient / Layperson Explanation
What is AIP? It's a rare inherited condition affecting how your body makes a substance called heme (part of haemoglobin). When triggered, your body makes too much of certain chemicals that affect your nerves and cause symptoms.
What are the symptoms of an attack?
- Severe tummy pain
- Nausea and vomiting
- Dark red ("port wine") urine
- Weakness in arms/legs
- Confusion or anxiety
- Fast heartbeat
What causes attacks?
- Certain medications (we'll give you a list of safe ones)
- Not eating (fasting or low-carb diets)
- Alcohol
- Hormonal changes (periods, pregnancy)
- Infections
How is it treated?
- During attack: IV drip with sugar solution and a medication called haem arginate
- Prevention: Avoid triggers, keep a list of safe medications
- New treatments: A drug called givosiran can prevent attacks
What can I do?
- Carry a card explaining your condition
- Keep a list of safe medications
- Don't fast or skip meals
- Avoid alcohol
- Tell doctors before any surgery or new medication
12. References
- British Porphyria Association. www.porphyria.org.uk
- Anderson KE, et al. Recommendations for the diagnosis and treatment of AIP. Ann Intern Med. 2005.
- Balwani M, et al. Givosiran in AIP. NEJM. 2020.