measure C4 complement level to differentiate hereditary from ace angioedema

This patient is presenting with isolated angioedema involving the lips, tongue, and supraglottic airway that has required orotracheal intubation. The two most likely causes of the isolated angioedema based on this patient’s history are ACE inhibitor-induced angioedema and hereditary angioedema based on his family history.

ACE inhibitors are a common cause of angioedema, but there are no tests that definitively establish the diagnosis of ACE inhibitor-induced angioedema. This is a diagnosis of exclusion that is characterized by no further recurrence of angioedema symptoms after the ACE inhibitor has been discontinued for several months. In patients taking an ACE inhibitor who present with isolated angioedema but who also have risk factors for other hereditary and acquired angioedema disorders (like this case), the recommended approach is to screen for these alternate causes of bradykinin-mediated angioedema by serum complement protein levels, specifically C4 (choice A is correct; choice C is incorrect). This approach to diagnosis is based on the observation that ACE inhibitor use can unmask previously asymptomatic hereditary and acquired angioedema disorders. C4 screening is important for all patients taking an ACE inhibitor with risk factors for alternate etiologies, but it remains debatable whether further screening is warranted in all patients taking an ACE inhibitor without any additional risk factors at the time of first angioedema presentation. In addition to family history, other risk factors that should prompt complement screening include a personal history of lymphoma or monoclonal gammopathy of unknown significance.

The typical and most efficient approach to screening is to start with complement C4 levels. C4 levels are decreased in the most common forms of heredity and acquired angioedema not due to ACE inhibitors. In contrast, C4 levels are normal in the setting of ACE inhibitor angioedema. If the C4 level is low, then further diagnostic workup should be pursued and referral to allergy specialists should be considered. Broad evaluation with testing for C1 inhibitor levels, functional assays, and C1q levels is generally reserved only for patients with a low C4 level because the broad, empiric approach fails to add meaningful diagnostic value in the acute setting above the high performance of the C4 level as a screening test.

Another diagnostic consideration in the setting of angioedema is anaphylaxis or other forms of mast cell-mediated disorders. However, this case is less consistent with this diagnosis because the patient is presenting with isolated angioedema 10 h after symptom onset. The diagnostic criteria for anaphylaxis highlight the acute onset of an illness (minutes to several hours), while it is more typical of bradykinin-induced angioedema to present over a longer period of time (hours to days). This patient also does not have any additional signs or symptoms of anaphylaxis, with a notable absence of GI l symptoms, hypotension, urticarial rash, itching, evidence of bronchospasm, and exposure to known or likely allergens. A tryptase level is sometimes measured in cases where the diagnosis of anaphylaxis is considered, but tryptase is highly unlikely to be informative in this case. Even if this patient’s original presentation was due to mast cell-mediated anaphylaxis, a tryptase level is highly unlikely to aid in this diagnosis given that the patient is presenting 10 h after the onset of symptoms (choice D is incorrect). Tryptase levels typically peak within 90 min of symptom onset and then decline quickly with a half-life of 2 h, and they are more likely to reach high levels of elevation in anaphylaxis associated with shock and hypotension.

Elevated total IgE levels can reflect an underlying allergic disorder but are neither specific nor sensitive for the disorders that cause isolated angioedema (choice B is incorrect). In this case, an elevated total IgE would neither confirm nor refute a diagnosis of ACE inhibitor-induced angioedema, other hereditary or acquired angioedema disorders, or anaphylaxis; thus, this test is not the most appropriate next step for this patient. Total IgE levels are most useful in the diagnostic evaluation for a small number of disorders that are associated with marked IgE elevation, including allergic bronchopulmonary aspergillosis and parasitic infections.123456

A 52-year-old man with a history of diabetes mellitus, treated by metformin, and hypertension, treated by lisinopril, presents to the ED with acute onset lip and tongue swelling. The symptoms began 10 h prior to presentation and have progressed. He has no GI symptoms, itching, or rashes. He has no known allergies and reports no new exposures to foods or insect stings. His mother has a history of one episode of angioedema attributed to use of an angiotensin-converting enzyme (ACE) inhibitor. His temperature is normal, heart rate is 95/min, respiratory rate is 25/min, BP is 137/90 mm Hg, and pulse oximetry is 96% while breathing ambient air. On exam, he has inspiratory stridor without expiratory stridor or wheezing. He is intubated due to the degree of upper airway compromise. A CT scan of the neck after intubation is limited due to endotracheal tube but demonstrates diffuse soft tissue swelling of the lips, tongue, and supraglottis without evidence of focal fluid collection or mass.

In addition to stopping the lisinopril, what is the most appropriate next step for this patient?

Footnotes

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  5. Rosenbaum S, Wilkerson RG, Winters ME, Vilke GM, Wu MYC. Clinical practice statement: what is the emergency department management of patients with angioedema secondary to an ACE-inhibitor? J Emerg Med. 2021;61(1):105-112. PubMed ↩

  6. Zuraw BL, Bernstein JA, Lang DM, et al; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology. A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol. 2013;131(6):1491-1493. PubMed ↩