Physicians in Canada need better education about the multiple biological assays used to diagnose hereditary angioedema caused by C1 inhibitor deficiency (C1-INH-HAE), which will increase their confidence and access to relevant tests, a study shows.
Most cases of hereditary angioedema are caused by low levels of a malfunctioning plasma C1 inhibitor (C1-INH), caused by mutations in the the SERPING1 gene. In normal circumstances, this protein regulates the production of bradykinin, an inflammatory protein that controls the permeability of blood vessels.
However, when C1-INH is absent or functioning poorly, bradykinin increases and vessels become too permeable to fluid, causing severe swelling under the skin (edema).
The disease presentation, however, is widely variable among patients. Patients with lower C1-INH levels tend to have more severe disease. Also, some HAE patients have a normal C1-INH, but mutations in other proteins affecting bradykinin production.
That’s why it is important for physicians to be able to distinguish between C1-INH-HAE and HAE that doesn’t involve C1-inhibitor, as well as between different degrees of C1-INH-HAE.
In this study, surveys were given to Canadian physicians who treat HAE and laboratories where diagnostic tests are performed in order to get a better sense of the availability and knowledge about diagnostic tests for C1-INH-HAE.
Both surveys were conducted by the Canadian Hereditary Angioedema Network (CHAEN), a non-profit organization dedicated to providing care for HAE patients in Canada. The first survey obtained results from 29 physicians who are CHAEN members, the second from 17 laboratories in Canada and two in the U.S. where Canadian doctors report sending some samples.
A number of tests are available to help diagnose C1-INH-HAE, including genetic tests of the SERPING1 gene, measures of C1-INH activity, and measures of C1-INH levels.
C1-INH function can be tested directly with a chromogenic (color-based) assay and antibody-based assays. Immunologic assays also can be used to detect C1-INH, C4, or C1q. Detecting C1-INH directly can provide information about the mutant protein product and distinguish between subtypes of C1-INH-HAE.
C4 is a downstream target of C1-mediated degradation, so measuring its levels can give some indication of C1-inhibitor activity.
C1q levels are typically normal in HAE, but are often dysregulated in acquired angioedema (AAE), in which a misbehaving immune system, rather than an inherited mutation, causes angioedema. Testing for C1q can help to distinguish between these disorders.
Genetic testing, such as sequencing the SERPING1 gene, also can be used to diagnose C1-INH-HAE, particularly in infants, in whom C1-INH is not yet expressed.
Both physicians and laboratories were asked about whether these tests were available or provided by them. Laboratories also were asked about the specific methods they use for these assays, and physicians were asked about their confidence in lab results.
C1-INH functional assays were available to 93% of responding CHAEN physicians. However, confidence in this assay was relatively low; 41% said they did not trust the results, citing concerns about the handling and storage of samples, as well as the sensitivity and specificity (the chance of getting a false positive or negative, respectively) of different assays.
Assays measuring C1-INH levels were available to 93% of CHAEN physicians, and confidence in this assay was high; 96% said they were confident in this assay. This is likely because more samples were processed locally, and degradation of samples is less of a concern in these assays.
Antigenic C4 assays also were widely available and trusted, with 100% of responding physicians having access to and being confident in this assay.
However, since measuring C4 is an indirect and imperfect test of C1-INH activity, “it is important to keep in mind that a low antigenic C4 is only indicative of C1-INH-HAE, but it is not always conclusive because of the presence of [C4 mutations] in healthy individuals,” researchers wrote. Antigenic C4 also can appear normal in nearly one quarter of patients with C1-INH-HAE.
C1q tests were not as broadly available, with only 83% of physicians reporting having access to them. Confidence in these tests was mixed; 52% reported being confident, but 24% were not confident in them. (The remaining respondents had never used the test.) This test is likely less well-known and less available in Canada because AAE is less prevalent than HAE.
Genetic testing was available to only 35% of respondents, which is too few for any conclusions to be drawn about physicians’ attitudes. The researchers speculate this may change as costs for genetic testing continue to decrease.
“The results of both surveys indicate the need for better education and information exchange amongst physicians treating HAE, about various assays available in Canada, their performance and relevance in proper diagnosis of HAE, creation of local laboratory expertise to eliminate sample processing issues and, overall, improve confidence and access to various tests,” investigators concluded.