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Acute intermittent porphyria

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acute intermittent porphyria diagnosis management GeneReviews

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https://www.ncbi.nlm.nih.gov/sites/books/NBK1193

Acute intermittent porphyria (AIP)

AIP is an autosomal-dominant acute hepatic porphyria caused by reduced activity of hydroxymethylbilane synthase (HMBS), also called porphobilinogen deaminase. The defect increases hepatic production of the neurotoxic heme precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG).
Most mutation carriers never develop symptoms. Attacks usually begin after puberty, are more common in women, and do not cause photosensitivity or blistering skin lesions.

Clinical presentation: acute neurovisceral attack

Think of AIP in unexplained severe abdominal pain with neurologic or psychiatric features.
  • Severe, diffuse abdominal pain, often with a soft abdomen and few peritoneal signs
  • Constipation, nausea, vomiting
  • Autonomic features: tachycardia, hypertension, sweating
  • Peripheral motor neuropathy, weakness, neuropathic pain. Severe disease can progress to paralysis and respiratory failure.
  • Neuropsychiatric features: anxiety, insomnia, confusion, hallucinations, seizures
  • Hyponatremia, often related to SIADH, vomiting, or renal salt loss
  • Urine may become red, brown, or dark after standing in light or air, but this is not always present.

Common precipitants

Attacks can be provoked by increased hepatic heme synthesis:
  • Porphyrinogenic medications, especially some enzyme-inducing antiseizure drugs and other unsafe drugs
  • Fasting, crash dieting, low-carbohydrate intake
  • Alcohol, smoking
  • Infection, surgery, physiologic stress
  • Progesterone exposure or the luteal phase of the menstrual cycle
Medication safety should be checked against a specialized porphyria drug database before prescribing.

Diagnosis

During suspected acute symptoms, obtain a spot urine PBG, normalized to creatinine, without waiting for a 24-hour urine specimen. A markedly elevated PBG supports an acute hepatic porphyria attack. Urinary ALA is also elevated.
Then:
  1. Confirm and classify the porphyria with biochemical testing, including urine ALA/PBG and porphyrin studies as appropriate.
  2. Use HMBS genetic testing to confirm AIP and identify relatives eligible for cascade testing.
A pathogenic HMBS variant alone does not prove that current symptoms are an acute attack. The clinical syndrome plus elevated urinary PBG is needed. GeneReviews describes an attack as compatible manifestations lasting over 24 hours with a urine PBG-to-creatinine ratio at least 10 times the upper limit of normal.

Acute management

Treat a suspected severe attack urgently in hospital, preferably with porphyria-specialist input.
  • Stop possible triggers and unsafe medications.
  • IV hemin/heme, generally 3-4 mg/kg daily for 4 days, is the main specific treatment for significant attacks. Start early, especially with uncontrolled pain, hyponatremia, weakness, or neurologic manifestations.
  • Give adequate carbohydrate intake. For mild attacks or while awaiting hemin, oral carbohydrate or carefully selected IV dextrose may suppress hepatic ALA synthase activity. Avoid hypotonic dextrose-only fluids because they can worsen hyponatremia.
  • Manage pain, nausea/vomiting, blood pressure, seizures, and electrolyte abnormalities with agents known to be safe in acute porphyria.
  • Monitor for motor weakness and respiratory compromise. ICU care may be required.
Hemin is more effective than glucose alone for a substantial acute attack. The American Porphyria Foundation emergency guidance advises hospital management for symptomatic attacks and monitoring for respiratory impairment.

Preventing recurrent attacks

  • Avoid triggers, fasting, alcohol excess, and unsafe drugs.
  • Maintain regular carbohydrate intake during illness.
  • Genetic counseling and targeted testing for relatives.
  • For frequent attacks, specialist options include givosiran, an RNA-interference therapy that lowers hepatic ALAS1 expression, prophylactic hemin in selected cases, and hormonal strategies for clearly cyclical attacks.

Long-term follow-up

Symptomatic AIP is associated with increased risks of hypertension, chronic kidney disease, and hepatocellular carcinoma, particularly later in adulthood. Periodic blood pressure, renal assessment, and specialist-directed liver surveillance are appropriate.
Emergency warning: severe abdominal pain with weakness, seizures, confusion, dark urine, low sodium, breathing difficulty, or new paralysis needs emergency assessment. Do not self-treat a possible AIP attack with fasting or unverified medications.
Textbook sources: Harrison’s Principles of Internal Medicine, 22e, p. 3390; Yamada’s Textbook of Gastroenterology, 7e, p. 2026.
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