The Diabetes Mimic: a Primer on Addison’s Disease
In 1849, Dr. Addison described a series of anemia cases across adult males who developed weakness, hyperpigmentation, and experienced severe weight loss.1,2 Upon performing autopsies of the patients post-mortem, all were found to have a diseased condition of the suprarenal capsules.1 At the time the functions of the supernal glands were “almost or altogether unknown,” making it difficult to deduce a cause of the disease.1 Adding to the confusion was the bizarre progression of the condition, where patients struggled to “fix a date to his earliest feeling…before it became so extreme.”1 The disease, which would later be named Addison’s Disease (AD), was believed to have “resisted all remedial efforts, and sooner or later ended terminally.”1 In 1950, adrenal cortical hormones were discovered by Edward Calvin Kendall, Tadeus Reichstein, and Philip Showalter Hench, a discovery that they would later be jointly be awarded the Nobel Prize in Physiology or Medicine.3 Research on these hormones, which include the glucocorticoid cortisol and the mineralocorticoid aldosterone, would be foundational to our modern understanding of how cortisol and aldosterone deficiency that characterizes AD contributes to the manifestation of the common symptoms.4
While a number of risk factors like tuberculosis and primary hypothyroidism can contribute to the onset of AD, the leading cause of AD in the developed world is autoimmune adrenalitis.5 In autoimmune adrenalitis, we see the destruction of adrenocortical cells mediated by T lymphocytes, resulting in adrenocortical atrophy.5,6 AD remains subclinical until 90% of the adrenal glands have been destroyed, leading to symptoms of adrenal failure.6 As a result, the adrenal glands do not produce enough cortisol and sometimes also do not produce enough aldosterone. Cortisol is important in the body’s response to stress and helps regulate the body’s usage of proteins, carbohydrates, and fats.4 It is also responsible for maintaining blood pressure and controlling inflammation, which is why in the absence of sufficient cortisol, as seen in AD, one ends up with chronic weight loss, exhaustion, and an irregular pulse.4 The secondary hormone that is often lacking in AD patients is aldosterone, which maintains the salt-water balance in the blood to maintain blood pressure.4 Low levels of aldosterone make it difficult for the kidneys to retain salt and water, causing blood pressure to drop. AD often manifests in two forms: (1) primary adrenal insufficiency, where there is a problem with the adrenal glands themselves and (2) secondary adrenal insufficiency, where the problem originates upstream at the pituitary.4
The pathogenesis of autoimmune diseases like autoimmune AD is known to be the result of an interplay between genetic, immune, and environmental factors. There are current studies that try to link patterns in human behaviour with susceptibility to autoimmune disease. One of these studies looks at the impact of month of birth on the development of autoimmune AD. It is an extension of previous studies that have shown that babies born in the autumn/winter months are more prone to type 1 diabetes and autoimmune thyroid disease.7 In the AD-specific study, researchers examined two cohorts in UK and Poland and found a December peak and May trough, and January peak and July trough, respectively.7 They proposed that being born in the winter months had a protective effect because of exposure to seasonal viral infections in the perinatal period coupled with vitamin D deficiency due to lack of sun exposure. The winter months are characterized by viral infections like norovirus, rotavirus, and influenza, which hijack the host cell’s machinery to replicate its own proteins. These infections result in early priming of the immune system for winter babies, which influence disease risk in people who carry alleles that make them genetically susceptible to developing autoimmune AD.7 The other hypothesis is based on vitamin D signaling, which has been shown to have a regulatory role in both the innate and adaptive immunity in humans. It is known that there are interactions between the vitamin D receptor and AD susceptibility genes like CYP27B1 suggesting that a change in vitamin D status may affect the expression of these risk genes.7
Early diagnosis is crucial for individuals with AD because the survival of patients who are diagnosed and treated is comparable to the common population.8 However, for patients who do not receive steroid treatment, the survival rate is less than two years.8 The current standard of treatment is the administration of corticosteroids and glucocorticoids to replace the deficient cortisol and aldosterone in the body. AD patients need to closely monitor their weight, blood pressure, electrolytes, and stress level to ensure that they inject a sufficient amount of these steroids much like how an insulin-dependent diabetic patient needs to track their glucose levels to adjust accordingly for the amount of insulin needed.8 Specifically, glucocorticoid administration needs to be adjusted for stress (i.e. surgery or emotional stimulus), and mineralocorticoids need to be adjusted for salt loss (i.e. in the summer when there is salt loss from excessive perspiration).
The treatment of AD places a huge demand on the individual to “do the thinking” for their adrenal cortical hormones. Sometimes, it is difficult for people to predict these hormonal fluctuations, which results in a serious medical emergency known as an Addisonian crisis.9 It is characterized by a drop in cortisol that results in extreme weakness, vomiting, and a large drop in blood pressure that can progress to shock, seizures, and coma if not treated in time (Figure 1). AD support groups have developed emergency protocols like bracelets that help identify the individual’s condition and kits that allow for the injection of intravenous cortisol in case of an emergency.2 These strategies can determine life or death of a patient.
Figure 1: The Addison Crisis Pathway.
Many of the symptoms associated with AD, such as fatigue, weight change, and polyuria are very similar to diabetes. Especially since AD tends to manifest in their 30s and 50s, many people do not seek medical attention for these symptoms because they see it as part of the normal process of aging. Hopefully, with the continued efforts of awareness and support groups, people will be more educated about the symptoms and risk factors for AD so they can get diagnosed earlier to prevent the onset of a life-threatening Addisonian crisis. If the current research into the autoimmune causes of AD speaks to anything, it is that the development of this condition is seemingly random. This further reinforces the importance of looking at potential rare disease causes for these common disease symptoms.
Works Cited:
1. Bishop PMF. The History of the Discovery of Addison’s Disease. Proceedings of the Royal Society of Medicine. 1950;43(1):35-42.
2. Killinger D. Emergency Procedures. 2017. Available at http://www.addisonsociety.ca/emergency-procedures.html.
3. Shifrin A. The History of the Adrenal Gland. 2012. Available at http://www.adrenaltumors.org/history.
4. Web MD. Understanding Addison’s Disease – the Basics. 2017. Available at http://www.webmd.com/a-to-z-guides/understanding-addisons-disease-basics#1.
5. Zelissen PMJ, Bast EJEG, Croughs RJM. Associated Autoimmunity in Addison’s Disease. Journal of Autoimmunity. 1995;8(1):121-130. Doi: http://dx.doi.org/10.1006/jaut.1995.0009.
6. Neto RAB, Carvalho JF. Diagnosis and classification of Addison’s disease (autoimmune adrenalitis). Autoimmunity Reviews. 2014;13(4-5):408-411. Doi: http://dx.doi.org/10.1016/j.autrev.2014.01.025.
7. Pazderska A, Fichna M, Mitchell AL, Napier CM, Gan E, Ruchata M, Santibanez-Koref M, Pearce SH. Impact of Month of Birth on the Risk of Development of Autoimmune Addison’s Disease. Journal of Clinical Endocrinology & Metabolism. 2016;101(11):4214-4218. Doi: https://doi.org/10.1210/jc/2016-2392.
8. Shoenfeld Y, Cervera R, Gershwin ME, Diagnostic criteria in autoimmune diseases. Totowa: N.J.; 2008.
9. Cafasso J, Stoltzfus S, Kim S. Addisonian Crisis (Acute Adrenal Crisis). Available at http://www.healthline.com/health/acute-adrenal-crisis.
Cite This Article:
Zhang B., Chan G., Palczewski K., Lewis K., Ho J. The Diabetes Mimic: a Primer on Addison’s Disease. Illustrated by B. Yiu. Rare Disease Review. February 2018. DOI:10.13140/RG.2.2.18873.88166.
