HAE Expert’s Approach to Diagnosing HAE: Clinical Criteria and Laboratory Evaluation
Physician/researcher and University of California at San Diego Professor of Medicine Bruce L. Zuraw has published a formidable body of Hereditary Angioedema (HAE) work that spans a wide range of topics including studies of molecular genetics, clinical syndrome, pathophysiology, and emergent therapies. Below we provide highlights and excerpts from Professor Zuraw’s work that elucidate his diagnostic approach.
Clinical Characteristics Suggesting HAE as a Potential Diagnosis:1
- The patient may or may not report a family history because up to 25 percent of new HAE cases result from de novo mutations.
- Age of onset is variable ranging from early childhood to adult; frequency worsening around puberty.
- Attacks may be preceded or accompanied by a non-pruritic, flat, erythematous mottling or erythema marginatum.
- Attacks are prolonged, typically increasing over the first 24 hours then slowly subsiding over the next 48-72 hours before full resolution is achieved.
- Angioedema does not respond to treatment with epinephrine, antihistamines, or corticosteroids.
Scientists recognize two forms of disease, but it is important for the clinician to note they are symptomatically indistinguishable. Type I HAE is characterized by low quantitative/antigenic and functional levels of C1-Inhibitor and affects about 85% of patients. Type II HAE affects the other 15% of patients whose tests reveal normal or elevated quantitative/antigenic levels of protein which is dysfunctional and results in a low C1-Inhibitor functional value.
While a patient history compatible with the clinical characteristics outlined above should lead the clinician to suspect HAE, a diagnosis requires laboratory confirmation of C1-Inhibitor deficiency.
- Professor Zuraw recommends that patients suspected of having HAE should be initially screened by measuring complement C4 antigenic levels which are typically low even when the patient is not swelling, and in most cases low during a swelling attack.
- If the C4 level is decreased (or in cases where it is normal, but most or all of the clinical criteria listed above are met), C1-Inhibitor antigenic and functional levels should be tested to confirm the HAE diagnosis.
- Because the test for C1-Inhibitor function used in the United States is insensitive and may not provide accurate information, in some cases it may be prudent to repeat the C4 and C1-Inhibitor functional levels during an attack of angioedema.3
Professor Zuraw notes that patients who are C1 inhibitor deficient, but have no family history and report onset of symptoms in the fourth decade of life or later should be screened for Acquired Angioedema. This can be accomplished by testing the C1q component because it is typically decreased in Acquired Angioedema, but normal in HAE. In Acquired Angioedema, C1 inhibitor deficiency is caused by either an underlying lymphoproliferative disease or an autoimmune process that produces a neutralizing autoantibody.
There is another form of familial angioedema that is not caused by C1-Inhibitor deficiency, only affects women, and is correlated with conditions creating high estrogen levels–for example, pregnancy or the use of oral contraceptives.4 Clinically, patients with familial angioedema are virtually indistinguishable from those with hereditary angioedema, except that a higher percentage of their attacks are facial.2 Further evaluation of these patients revealed a mutation in the gene for human coagulation Factor XII that results in a marked increase of Factor XII ‘s amidolytic activity. Researchers believe that enhanced FXII enzymatic plasma activity in female mutation carriers leads to enhanced kinin production, which results in angioedema.4 Transcription of Factor XII is positively regulated by estrogens, which may explain why only women are affected.4
When faced with an uncertain diagnosis, physicians may wish to contact the US HAE Association for recommendations on how to obtain more specialized testing such as measurement of C1-Inhibitor function by inhibition of hemolytic complement activity, or molecular diagnosis of the C1-Inhibitor mutation.
For a detailed typology of the various forms of angioedema, please see our Comprehensive Angioedema Typology and Description table.
- Zuraw BL. Hereditary angioedema. New England Journal of Medicine. 2008;359(10):1027
- Ibid, p. 1029
- Zuraw BL. Diagnosis and treatment of hereditary angioedema: an American approach. Transfusion and Apheresis Science 29 (2003) 241
- Cichon S et. al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet. 2006 Dec;79(6):1098-104