I remember a wonderful lecture at UCSF, about 30 years ago, by Dr. Dennis Burkitt, on “Diseases of Civilization”. Dr. Burkitt was a missionary doctor in the bush in what at the time was Rhodesia (today’s Zimbabwe). He was also an extraordinarily astute clinical observer (he was the first to describe a hitherto unknown cancer, aptly called Burkitt’s lymphoma). At the end of the lecture, somebody asked whether Africans in the bush, being free of modern world stress, are healthier. Dr. Burkitt retorted that wondering every night whether that was the night the lion was going to have you for lunch is hardly an anxiety-free thought. The message was that stress recognizes no boundaries of geography, education, income, sex, or national origin.


What is stress?

To paraphrase Potter Stewart, a supreme court justice who grappled with the definition of pornography: “I know it when I see it.” But there is a more “scientific” definition: “Psychological stress occurs when an individual perceives that environmental demands tax or exceed his or her adaptive capacity.” Interestingly, an elaboration of this definition includes two elements: high psychological demands coupled with low decision latitude. In other words, stress as we commonly understand it, high and unrelenting demand, is not enough. It is the lack of control, the feeling of helplessness, which tips the scale to the feeling of stress.


Can psychological stress cause disease?

I have to admit, being a firm believer in the physical causes of disease, I was highly skeptical. I readily admitted that stress could exacerbate disease; I have seen countless cases of acute asthma attacks or acute MI precipitated by acute psychological stress. But chronic, low-intensity stress? I wanted to see hard evidence.

The title of a recent article, and an accompanying commentary in the JAMA, “Job Strain and Risk of Acute Recurrent Coronary Heart Disease Events”, tweaked my curiosity. The authors followed 206 patients who have had an MI, for a period of 2.5 years following their initial episode. After statistically adjusting for 26 potentially confounding factors (smoking history, hypertension, high LDL, etc.), they concluded that job strain increased the risk of recurrent coronary heart disease or CHD by 100%!


How can it happen?

There are many theories, but the most plausible and the best documented is the stress hormone theory. We have two systems that get activated during stress: the HPA (hypothalamic-pituitary-adrenocortical axis) and the SAM (sympathetic-adrenal-medullary) systems. HPA secretes cortisol, SAM secretes epinephrine a.k.a. adrenaline. Both are known as stress hormones.

If stress is so common in life, how is it that evolution allowed the hormonal response to stress to be so deleterious? And the answer is it didn’t. Besides facilitating the fight or flight response, they increase innate immunity, our first line of defense against pathological invaders, and decrease the inflammatory response. But all this is true for acute stress (e.g., the lion is coming at you). Chronic stress is something quite different. For reasons yet unknown, chronic stress causes a decrease of the immune response and an increase of the inflammatory response—exactly the opposite effects of acute stress. Whatever the reasons may be, the effect is destructive. As an example, coronary heart disease is basically an inflammatory process, and chronic stress aids and abets it. Furthermore, macrophages, which are white blood cells that are central to the formation of a coronary plaque, were recently discovered to secrete their own adrenaline, adding insult to injury.

Does a low dose of NSAID (non-steroidal anti-inflammatory drugs) to prevent CHD make sense now?


What other diseases are associated with stress?

Depression is the most obvious one. To cite some compelling statistics, approximately 20-25% of persons who experience major stressful events develop depression. And when a cohort of depressed persons was examined, it was found that 50-80% have had a major “life event” in the preceding 3-6 months. To close the loop, most depressed individuals suffer from a depressed immune response and from chronic, low-grade inflammation. Based on this, we still cannot conclude that there is a cause and effect relationship here; but it is an intriguing correlation nonetheless.

HIV/AIDS has also been suggested to progress faster, even when taking anti-HIV medications, if the patient is under chronic stress. Again, one should’t be surprised if the explanation will turn out to be a depressed immune response.


In conclusion

On the biological level, this is yet another demonstration of the mind-body relationship. In fact, a whole field of research called psychoneuroimmunology (I know, it’s a mouthful, but if you break it up to its component words, psycho-neuro-immunology, it makes sense) is thriving and is uncovering new connections between brain, mind, and immune response on an almost daily basis.

On the clinical level, the strengthening evidence of the effect of stress on health and disease suggests new modalities and approaches to treatment.

What is most intriguing and potentially far-reaching are the societal consequences. Now that we accrue more and more evidence on the effects of stress on health, it would make economic sense to pay attention to the work environment. An enlightened manager would insist on stress reduction in the workplace in order to increase productivity. Conversely, could a company be found liable if an employee is subjected to an abusive supervisor and suffers a heart attack? The medical evidence is already here.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.