Is there any co-morbidity known with HAE?

Jun 24, 2015

Dr C: First of all, we would like to wish you all Happy Memorial Day. We honor all those who have served.

By co-morbidity, our questioner is referring to whether there are any other diseases that are linked to HAE. In HAE due to C1 inhibitor deficiency, patients show excessive activation of several pathways, including the kallikrein-kinin (also known as contact system), complement, fibrinolytic, and coagulation systems. We know that contact system activation leads to the generation of bradykinin which is the cause of the swelling attacks. While there are no clearly defined co-morbidities with HAE type I&II, there has been speculation that there may be risks for development of autoimmune disease due to the absence of complement inhibition. Bruce would you like to comment of this?

Dr. Z: A relationship between HAE and autoimmune diseases has been suspected for a long time. Dr. Michael Frank’s group reported an association between HAE and autoimmune and immunoregulatory diseases in 1986. Out of 157 HAE patients, they found 19 (12%) who had clinical immunoregulatory diseases including: glomerulonephritis (5); Sjogren’s syndrome (3); inflammatory bowel disease (3); thyroiditis (2); systemic lupus erythematosus (1); drug-induced lupus (1); rheumatoid arthritis (1); juvenile rheumatoid arthritis with IgA deficiency (1); incipient pernicious anemia (1); and sicca syndrome (1).

Dr. C: In addition to inflammatory bowel diseases like Crohns, we have also seen reports of greater then expected associations with celiac disease as well as intussusception (in which a part of the intestine folds into another section of intestine). There have also been reports of renal disease in HAE patients. This brings up the possibility of linkage with other genes causing disease. Any thoughts here?

Dr. Z: I’m not aware of any gene linkage relationships between HAE and autoimmune diseases. However there is a lot of data linking complement abnormalities to the development of autoimmune diseases, and this could be responsible the relationship.

Dr C: What about the reported association between pancreatitis and HAE? Do you think that this is real or could abdominal angioedema be confused with angioedema?

Dr. Z: I think that’s a fair question, but difficult to answer. The swelling in HAE could itself cause blockage of the pancreatic duct. There’s also suggestion that pancreatitis might be associated with the use of anabolic androgens such as danazol rather than HAE itself.

Dr. C: This introduces a very important topic. We do know that the anabolic androgens have been helpful as a prophylactic therapy for HAE type I&II. In the past they were literally all we had to work with. Anabolic androgens however have been associated with significant side effects, including problems like hypertension, hepatitis and virilization in women among many others. These side effects in exposed patients could be the reason for developing ‘co-morbidities’.

Dr. Z: Related to this a controversial issue has been whether HAE itself or androgens impact the lipid profile or even atherosclerosis. It’s very hard to show differences in risk in a relatively small patient group.

Dr C: I think that this is yet another area where we expect the HAE Registry to provide better information. We do not wish to forget our patients affected by HAE with nl C1 inhibitor. Unfortunately until we make better progress defining diagnostic testing and genetic markers for this group of patients this among many other questions remain unanswered.

I would like to thank you for your time and thoughtful answers. I look forward to our next discussion of the ‘Question of the Week’.

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