Precipitating factors

AIP is caused by a deficiency of the enzyme porphobilinogen (PBG) deaminase in the heme biosynthetic pathway. This enzyme deficiency “predisposes” patients to the effects of precipitating factors that can increase the demand for hepatic heme and lead to a chemical buildup that may cause symptoms to develop.1

Causes of Acute Intermittent Porphyria

The heme biosynthetic pathway can function with half-normal activity of the PBG enzyme. However, with certain precipitating factors, this pathway can become overactivated and can cause an AIP attack. Specialists in the treatment of AIP, Manisha Balwani, MS, MD, Associate Professor and Robert Desnick, Ph.D, MD, Dean for Genetics and Genomic Medicine from the Icahn School of Medicine at Mount Sinai describe the pathogenesis of AIP.

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Patient characteristics commonly associated with AIP

Gender:

  • AIP attacks are 4 to 5 times more common in women than in men.2
  • In women, attacks occur during reproductive years, most commonly in their 30s and often during the luteal phase of the menstrual cycle.1, 2, 3

Family history and genetics:

  • AIP is a genetic disease, so a parent and possibly siblings of the patient will have the enzyme deficiency.4
  • Because AIP is an autosomal dominant condition with low penetrance, 80% to 90% of individuals with the enzyme deficiency never have symptomatic disease.4
  • A positive family history of AIP or unexplained symptoms should heighten the suspicion of AIP, but an absent family history should not remove suspicion.

Common triggers

AIP attacks are usually due to the additive effects of several factors,1 including:

  • Psychological stress4
  • Use of certain prescription drugs, and often newly prescribed drugs1,2,4
  • Cigarette smoking1
  • Dehydration4
  • Use of alcohol or illicit drugs such as amphetamines or cocaine and derivatives2,8
  • Fasting, crash dieting, or a low-carbohydrate diet1,3
  • Metabolic stress induced by exhaustion; acute viral or bacterial infection; surgery; or labor, delivery, or post-delivery periods1,2,3
  • Endogenous steroid hormones, particularly estrogen and progesterone, especially during the luteal phase of the menstrual cycle or as a result of hormone replacement therapy1,3,5

Medications and weight-loss diets:
common triggers

In 90 patients diagnosed with AIP in a recent observational study 6:

37%

Reported that medications triggered acute attacks

22%

Reported that weight-loss diets triggered acute attacks

Be aware!

Many drugs that are commonly prescribed to treat signs and symptoms of AIP actually increase the demand for hepatic heme and induce ALA synthase. These drugs may therefore exacerbate attacks and should be avoided.1,7 These drugs include1,5:

  • Some anti-infectives such as sulfonamides, erythromycin, and rifampin
  • Some sedatives such as barbiturates and some benzodiazepines
  • Some anti-epileptics such as phenytoin and carbamazepine

Lists of unsafe, possibly unsafe, and safe drugs for individuals with AIP are continuously updated.

Go to: http://www.porphyriafoundation.com/drug-database

References

  1. Anderson KE, Bloomer JR, Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR, Desnick RJ. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142:439-450.
  2. Ventura P, Cappellini MD, Rocchi E. The acute porphyrias: A diagnostic and therapeutic challenge in internal and emergency medicine. Intern Emerg Med. 2009;4:297-308.
  3. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014; 4:977-1006.
  4. Gonzalez-Arriaza HL, Bostwick JM. Acute porphyrias: A case report and review. Am J Psych. 2003;160(3);450-458.
  5. Crimlisk HL. The little imitator—porphyria: A neuropsychiatric disorder. J Neurol Neurosurg Psychiatry. 1997;62:319-328.
  6. Bonkovsky HL, Maddukuri MD, Yazici C, Anderson KE, Bissell DM, Bloomer JR, Phillips JD, Naik H, Peter I, Baillargeon G, Bossi K, Gandolfo L, Light C, Bishop D, Desnick RJ. Acute porphyrias in the USA: Features of 108 subjects from Porphyrias Consortium. Am J Med. 2014;127:1233-1241.
  7. Stein P, Badminton M, Barth J, Rees D, Stewart MF. Best practices guidelines on clinical management of acute attacks of porphyria and their complications. Ann Clin Biochem. 2013;50:217-223.
  8. Thadani H, Deacon A, Peters T. Diagnosis and management of porphyria. BMJ. 2000;320:1647-1651.
Diagnosing AIP

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