Differential diagnosis

A high index of suspicion for AIP should be maintained for any patient with symptoms that are prominent for AIP, particularly abdominal pain, when initial clinical evaluation does not support another cause.1

Due to their non-specificity, the clinical features of AIP are not sufficient to confirm a diagnosis of AIP; thus, differential diagnosis should begin promptly.

Challenges with Diagnosis

A delay in diagnosis of acute intermittent porphyria is common because of variable non-specific symptoms. Manisha Balwani, MS, MD, Associate Professor and Robert Desnick, Ph.D, MD, Dean for Genetics and Genomic Medicine at the Icahn School of Medicine at Mount Sinai discuss the challenge of identifying AIP patients, common misdiagnoses, and the consequences of untreated or poorly treated AIP.

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Differential diagnosis of AIP ATTACKS:
Common clinical conditions mimicked by an acute porphyric attack2

  • Dysmetabolic/endocrine conditions

    • Acute hypoadrenalism (Addisonian crisis)
    • Acute hypoparathyroidism and hypocalcemic crisis
    • Pheochromocytoma
  • Neuropsychiatric conditions

    • Guillain–Barré syndrome
    • Emicrania
    • Acute psychotic attack
    • Delirium
    • Acute panic attack
    • Epilepsy
    • Acute myopathies
  • Cardiovascular conditions

    • Hypertensive crisis
    • Tachyarrhythmia
  • Hematological conditions

    • Acute hemolytic crisis
    • Acute drepanocyte crisis
  • Gastroenterological conditions

    Acute gastroenteritis with vomiting

Caution:
Untreated or inappropriately treated AIP attacks

Individuals with undiagnosed or inappropriately treated AIP may suffer serious, potentially fatal consequences, including1:

  • Peripheral neuropathy
  • Paresis
  • Respiratory and bulbar paralysis
  • Chronic arterial hypertension
  • Renal impairment
  • Chronic liver damage
  • Hepatocellular carcinoma
  • Chronic neuropathic pain
  • Death resulting from cardiac arrhythmia or paralysis during an attack

Therefore, a prompt diagnosis is critical.

Diagnostic testing for AIP

AIP can be readily diagnosed by laboratory testing, especially at or near the time of symptoms when large amounts of porphyrin precursors (i.e., porphobilinogen and δ-aminolevulinic acid) and porphyrins accumulate in the body. 1,3,4

1
PORPHOBILINOGEN (PBG) urine test

Once AIP is suspected in a symptomatic patient, the diagnosis should be confirmed immediately with a PBG urine test. Any significant delay in testing could delay appropriate treatment and result in serious consequences.1

Urinary PBG level is markedly increased 20-200 mg/L in patients with acute attacks of AIP and is never markedly increased in diseases other than acute porphyrias. Thus, the test is both sensitive and specific, and it will confirm the initial diagnosis when done at or near the time of symptoms.1,5


2
Second-line testing

If a patient’s PBG level is increased, additional tests, some on the same urine sample, should be done to determine the precise acute porphyria. The following combined laboratory findings indicate AIP1:

  • δ-aminolevulinic acid (ALA) levels: increased
  • Urine porphyrin levels, mostly uroporphyrin: markedly increased
  • Erythrocyte PBG deaminase levels: decreased by ≈50%
  • Fecal porphyrin levels: normal or slightly increased
  • Plasma porphyrin levels: normal or slightly increased

Interpreting second-line tests
Second-line tests should be interpreted carefully, as they may lack sensitivity and/or specificity.1


3
Genetic confirmation of AIP

Once biochemical studies have confirmed the diagnosis of AIP, DNA analysis can identify the disease-causing genetic mutation(s).1

DNA analysis is also important for identification of asymptomatic carrier family members who may be at risk for developing acute attacks in the future.1

Watch this video to hear Robert Desnick, Ph.D, MD, Dean for Genetics and Genomic Medicine at the Icahn School of Medicine at Mount Sinai discuss how to properly test a patient for AIP, some potential pitfalls that can be encountered during the testing process, and how to avoid them.

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CONSULT WITH A PORPHYRIA EXPERT

The American Porphyria Foundation (APF) can put physicians in touch with a porphyria specialist to consult on suspected or confirmed cases of porphyria. Some specialists are also available for clinical consultation with patients. Contact the APF at 713-266-9617 for more information.

Diagnostic challenge:
What would you do?

Challenge yourself with
an interactive case study

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, Biolcati G, Guida CC, Rocchi E. A challenging diagnosis for potential fatal diseases: recommendations for diagnosing acute porphyrias. Eur J Intern Med. 2014;25:497-505.
  3. American Porphyria Foundation. Porphyrins and porphyria diagnosis. Website: www.porphyriafoundation.com. Published 2010-2017. Accessed September 20, 2018.
  4. American Porphyria Foundation. Testing for porphyria. Website: www.porphyriafoundation.com. Published 2010-2017. Accessed September 20, 2018.
  5. American Porphyria Foundation. First-line tests. Website: www.porphyriafoundation.com. Published 2010-2017. Accessed September 20, 2018.