“I was diagnosed with C1 deficiency last year, at the same time they diagnosed me with B cell lymphoma. Is this common or rare?”

Sep 8, 2015

Dr. C:  First of all I would like to wish our readers a Happy Labor Day. In answer to our reader’s question, it is indeed very rare to have these two conditions simultaneously diagnosed but not, in all likelihood, a coincidence. It is probable that our reader has a condition that is even more unusual than HAE, namely acquired C1 inhibitor deficiency or ACID. Patients with ACID usually present in older age with bouts of angioedema that resemble the attacks seen in HAE. The laboratory will include low C4 and C1 inhibitor levels both for the protein and functionally—just like HAE type I. An astute clinician would be disturbed however by the lack of family history (although 25% of HAE I&II can be spontaneous) on top of the late onset of swelling. They would want to ‘dig further’ with other specific laboratory testing for this disorder. A cause would also need to be looked for—in other words why this was ‘acquired’. The two leading culprits are an autoantibody to the C1 inhibitor protein and/or alymphoreticular malignancy—including commonly a B cell lymphoma. Marc, would you like to discuss the diagnosis of ACID?

Dr. R: While it requires confirmatory lab testing, this presentation is suggestive of Acquired C1INH Deficiency (sometimes called Acquired Angioedema or AAE), a condition that appears to be even rarer than Hereditary C1INH Deficiency (HAE).  Angioedema symptoms of AAE typically start later in life (after the age of 40) and are usually associated with either a lymphoproliferative or autoimmune disorder.  The most common disorders causing AAE are lymphatic malignancies (i.e. Lymphoma) or monoclonal gammopathy of undetermined significance (MGUS), which is the presence of an abnormal protein detected in the bloodstream that is sometimes pre-malignant.  AAE symptoms are similar to HAE symptoms, though AAE usually causes fewer abdominal attacks and more facial attacks but this is highly variable from person to person. AAE swelling symptoms do not respond to antihistamines and corticosteroids and appear to be bradykinin-mediated. The major complement laboratory difference between AAE and HAE is that the C1q level is often low in AAE along with a low C1INH level and function – this feature along with the later age of onset and the presence of an underlying lymphoproliferative or autoimmune condition are the primary ways to distinguish AAE from HAE.

Dr. C: Bruce, do you have any thoughts why a lymphoma or a monoclonal gammopathy would cause an acquired deficiency of C1 inhibitor?

Dr. Z: As our readers are aware, C1 inhibitor deficiency in HAE results from mutations in SERPING1, the gene that codes for C1 inhibitor. The consequence of this is that the HAE patients do not produce sufficient amounts of the functional C1 inhibitor protein. In contrast, patients with ACID have an entirely normal biosynthetic capacity to make C1 inhibitor. The issue in ACID is that the C1 inhibitor that is produced is rapidly destroyed. C1 inhibitor acts as a suicide inactivator, meaning that every time it inhibits a protease, one molecule of C1 inhibitor is destroyed. For reasons that have still not been fully worked out, some monoclonal gammopathies or tumors cause continuous activation of proteases that are inactivated by C1 inhibitor. The C1 inhibitor autoantibody that can be linked to some cases of ACID has itself been shown to be capable of destabilizing the inhibitor-protease complex, leading to additional activation. Ultimately, this results in the C1 inhibitor level falling, which leads to activation of the contact system, generation of bradykinin and angioedema.

Dr. C: ACID is sometimes referred to as the “canary in the coal mine”. Could you explain this?

Dr. Z: Sure. One of the goals in treating cancer is to find the tumor at an early stage when it is most treatable. Tumors that lead to ACID are sometimes identified through the workup of the angioedema long before the tumor itself becomes manifest. I would mention that my experience has been different than Marc’s. I’ve found that patients with ACID have abdominal attacks as frequently as do HAE patients. I also strongly prefer calling this ACID rather than AAE. Most forms of angioedema are acquired, so the terminology acquired angioedema seems meaningless to me.

Dr. C: Physicians often use the C1q to differentiate between HAE and ACID. What do you think about this Bruce?

Dr. Z: We presume that the low C1q results from rapid turnover of the complement proteases C1r and C1s. So in the same way that C1 inhibitor can be consumed, complement C1 becomes consumed. I do agree with Marc that this test is not infallible and must be considered as part of the larger whole.

Dr. C: The management of ACID a bit different then HAE. Marc, can you speak to the treatment of ACID?

Dr. R: Once the diagnosis is established, AAE treatment typically includes 2 steps:  1) treatment of the underlying condition (i.e. Lymphoma) if indicated, and 2) Use of bradykinin-targeted drugs to treat or prevent angioedema attacks. Currently none of the bradykinin-targeted drugs FDA-approved for HAE have been rigorously studied or approved for AAE, but based on experience and published reports, these drugs are often effective and may be prescribed off-label by physicians who treat AAE.

Dr. C: Amicar and tranexamic acid seem to be helpful in prophylaxis where it is not too effective in HAE I&II (although helpful in HAE with normal C1 inhibitor). Acutely Firazyr and Kalbitor are both effective. In ACID the C1 inhibitor is “chewed up” so fast that Cinryze as prophylaxis or C1 inhibitor acutely may notwork well. On a positive note treatment of the cause of the C1 inhibitor consumption – i.e. the B cell lymphoma often can cure the swelling. There have been several reports of this with Rituximib for B cell lymphoma and even in a case with an autoantibody. Bruce or Marc any thoughts here?

Dr. Z: I certainly agree with you and Marc that treating the underlying disease, if possible, is always the best strategy.  There was actually a report of a patient with ACID getting worse with C1 inhibitor concentrate. So, one needs to be careful here. Interestingly, rituximab may lead to a prolonged remission in ACID. The problem we have is that this disease is rare enough that much of the experience is anecdotal rather than based on clinical trials.

Dr. C:  Thank you, Bruce and Marc. I hope that this has been helpful for both our reader posing the question as well as others who maybe affected by ACID. We look forward to our next ‘Question of the Week’.

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