While we as clinicians often excel at focusing on the primary diagnosis, especially in the case of a rare disorder, it is important that we also treat all other comorbidities with care; this is because we know that comorbidities are often aggravated by the primary diagnosis and vice versa. 

This becomes more urgent as patients get older. Many studies tell us that older individuals are more likely to have a combination of comorbidities. The danger here is that we spend so much time and attention on the primary diagnosis at the expense of all others. Rather, medicine should be practiced holistically, and the more efficiently we treat all diseases in a patient, both primary and secondary, the greater our chances of restoring quality of life and providing a sense of normalcy.

Hereditary angioedema (HAE) is a deeply inconvenient, unpredictable disease because of the propensity of attacks, which can be debilitating in nature. These swellings can take place in various parts of the body, resulting in significant pain and discomfort. There is a hidden cost to this: if individuals with hereditary angioedema cannot predict when their next attack will be, or how severe, can they really plan for anything of significance at all? Many patients are no longer able to meaningfully participate in work/social events, contributing to poor psychological health. 

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In Clinical and Translational Allergy, Björkman and colleagues conducted a study in which they investigated the comorbidities commonly associated with hereditary angioedema. In their study, they drew a direct link between the activation of the complement, contact, and coagulation systems in hereditary angioedema and many of the comorbidities associated with this disorder. This explains why it is common for patients with hereditary angioedema to also be diagnosed with other autoimmune disorders, such as autoimmune thyroiditis, allergic disease, and asthma. 

Read more about hereditary angioedema etiology 

In addition, treatments commonly prescribed as prophylaxis against hereditary angioedema “may change the risk of various comorbid conditions,” Björkman and colleagues wrote. Attenuated androgens, one of the many prophylactic treatments for hereditary angioedema, are associated with an increase in atherogenic indices, which can lead to myocardial infarction, stroke, and deep vein thrombosis. Studies have also uncovered links to liver cell adenoma and carcinoma. 

This presents clinicians with an inescapable dilemma. If both the pathology and treatment of hereditary angioedema are associated with an increased risk of comorbidities, and the subsequent presence of comorbidities weakens the body’s ability to defend against other diseases, are we merely going in circles, playing catchup to problems we have indirectly caused? 

Before we get ahead of ourselves, let’s first look at the comorbidities commonly associated with hereditary angioedema as uncovered by Björkman and colleagues. 

Comorbidities in Hereditary Angioedema 

The research team conducted their study by contacting physicians treating hereditary angioedema in Sweden. Using the National Population Register at Statistics Sweden, they recruited an impressive number of control individuals—2383, about 10 controls per patient (n=239). The researchers then calculated the odds ratios with 95% confidence intervals to compare both groups by disease categories.

The first comorbidity they found to have a higher prevalence among patients with hereditary angioedema than the control was cardiovascular disease—particularly hyperlipidemia, hypertension, and thromboembolic events. Hence, some clinicians routinely prescribe antihypertensive drugs and lipid-lowering therapy to reduce the risk of cardiovascular disease in this patient population.

In addition, Björkman et al discovered that patients with autoimmune diseases had increased autoimmune disease-related mortality from the second to the seventh decade of life. Among the more common autoimmune conditions associated with hereditary angioedema, irrespective of sex, are autoimmune hypothyroidism and systemic lupus erythematosus. 

The researchers also identified a notable association between hereditary angioedema and allergy/asthma; however, no statistically significant association with cancer was found, although chronic inflammation is known to be a contributing risk to the development of cancer. 

How should we process this information, and should any of it impact treatment? Due to the potentially life-threatening implications of hereditary angioedema, it is not medically sound to stop treatment/prophylaxis on the off-chance that it may halt or slow down the development of comorbidities. If anything, this study should alert physicians about the increased risks of dangerous comorbidities, particularly thromboembolic events, among patients with hereditary angioedema. 

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It appears that the risk of polypharmacy may be difficult to avoid completely. A reasonable approach is to treat hereditary angioedema according to the highest standards available, while keeping an eye on possible comorbidities that can significantly decrease quality of life. Unfortunately, the human body rarely presents with one disease at a time. Careful monitoring, medical education, and the early recognition of warning signs are keys to the successful management of individuals with hereditary angioedema. 

Ironically, scientists have discovered that some therapeutic strategies employed in treating hereditary angioedema “should be considered for the treatment of COVID-19,” Xu and colleagues wrote in the World Allergy Organizational Journal. This is based on the idea that drugs acting on the kinin-kallikrein pathway may offer benefits for both conditions, especially in patients with acute respiratory distress syndrome. Scientists are now conducting further studies to examine the relationship between hereditary angioedema and COVID-19, including how their etiologies intersect. 


Björkman LS, Persson B, Aronsson D, Skattum L, Nordenfelt P, Egesten A. Comorbidities in hereditary angioedema—a population-based cohort studyClin Transl Allergy. 2022;12(3):e12135. doi:10.1002/clt2.12135

Xu Y, Liu S, Zhang Y, Zhi Y. Does hereditary angioedema make COVID-19 worse? World Allergy Organ J. 2020;13(9):100454. doi:10.1016/j.waojou.2020.100454