Berger disease

Psychoneuroimmunoendocrinology describes the unity of mental, neurological, hormonal and immunological functions with its many potential applications. PNIE addresses the impact of cognitive images of the mind (whatever its elusive definition) on the central nervous system and consequent interactions with endocrine and immune systems. It encompasses many arenas, including biofeedback and voluntary controls, impacts of thought and belief on physiology, past and present effects of stress on mental, emotional and physical function, placebo effects, effects of social relationships on health and disease, and impacts of "energy medicine" on personal function and that of others. This column highlights the impact of cogent studies from these arenas on the understanding of holistic medicine in the new millennium.

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Hostility, pro-inflammatory factors and acute coronary syndromes

Review. The acute coronary syndrome is triggered in 3 stages: * plaque instability involves pro-inflammatory cytokine (IL-1, IL-6, TNF-[alpha]) and chemoattractant (MCP-1, interleukin-8) induction of leukocytes to the endothelium, and CD40L-CD40 co-stimulation activating plaque monocytes (macrophages). Macrophages then produce matrix metalloproteinases that disintegrate extra-cellular plaque matrix, causing coronary plaque instability. Acute stress, hostility, depression and vital exhaustion (VE) have been associated with recruitment and elevation of pro-inflammatory cytokines and leukocyte. * Extraplaque factors promoting rupture: Neuro-endocrinological factors (norepinephrine) and cytokines induce vasoconstriction and elevated BP, both provoking a vulnerable plaque to rupture. Hostility/anger and acute stress elevate catecholamines leading to vasoconstriction and elevated BP. * Superimposed thrombosis at a ruptured site: Increases in coagulation factors and reductions in anticoagulation factors (e.g. C-reactive protein) induced by inflammatory factors enhance platelet aggregation, a key stage in thrombosis. Hostility, depression and VE have been positively correlated with platelet aggregation. Thrombosis can lead to severe coronary occlusion, clinically manifested as an acute coronary syndrome.

Gidron Y, Gilutz H, Berger R. Huleihel M. Molecular and cellular interface between behavior and acute coronary syndromes. Cardiovasc Res 2002 Oct; 56(1):15-21

Comment: Psychoimmunoneurological processes may, at least in part, contribute to the pathogenesis of the acute coronary syndrome. The italicized sentences are entry points where "psychological" factors may influence the process; the pro-inflammatory cytokines mentioned here including interleukin-1, interleukin-6 and tumor necrosis factor-alpha appear to increase under stress. This chain of events may endure due to lack of neuroendocrine-to-immune negative feedback stemming from cortisol resistance. The entire picture is not yet clear; what is apparent is that profound effects on the immune and inflammatory systems derive from the experience of stress.

Hostility, tumor necrosis factor and atherosclerotic cardiovascular disease

Aggression, hostility, and anger significantly predict morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD) which is believed to be an inflammatory disease processed characterized by increased expression of a number of proinflammatory cytokines, such as tumor necrosis factor (TNF)-[alpha]. In 62 healthy, non-smoking men age 18-45, after controlling for age, race, education, and alcohol use, scores on the hostility (p=0.013), physical aggression (p=0.010), and verbal aggression (p=0.034) subscales, and the total score (p=0.007) of the Buss-Perry Aggression Questionnaire were positively associated with stimulated TNF-[alpha] expression.

Suarez EC, Lewis JG, Kuhn C. The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-alpha by blood monocytes from normal men. Brain Behav Immun 2002 Dec; 16(6): 675-84

Comment: The results suggest that hostility and aggression are associated with an increased expression of TNF-[alpha], a cytokine implicated in ASCVD. The attitude of hostility often leads to intense expression of anger and rage, with abrupt increases in epinephrine and proinflammatory cytokines, quickly elevating blood pressure and exposing plaque to sudden rupture. Indeed, numerous case reports and studies have linked bouts of rage with acute coronary events. The acute biochemical and physiological changes of anger are superimposed on the plaque whose "cap" has been weakened in the inflammatory process.

Negative emotions and proinflammatory cytokines

Negative affect and lack of supportive interpersonal relationships loom large in the modulation of immune dysregulation. Immune dysregulation may be one core mechanism for a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type II diabetes, certain cancers, and frailty and functional decline. Production of proinflammatory cytokines that influence these and other conditions can be stimulated directly by negative emotions and indirectly by prolonged infection. The ability to unwind after stressful encounters down-regulates the total stress burden. Prolonged intrusive ruminations following a stressful trauma appear to provide one avenue for persistent immune downregulation including reduced natural killer cell activity. Higher salivary immune responses are associated with days of more positive mood. Higher social support is robustly associated with higher NK cell activity and mitogenic leukocyte responsiveness in those under stress, whereas chronically abrasive close personal relationships are seen to provoke persistent immune downregulation. Differences in perceptions to the same event provoke different endocrine and immune responses. Benefits of disclosure-based interventions vary depending on the degree to which subjects become emotionally and cognitively involved in the process, reorganize the meaning of the traumatic event, and reduce avoidance of the issue.

Kiecolt-Glaser JK, McGuire L, Robles TF, Glaser R. Psychoneuro-immunology: psychological influences on immune function and health. J Consult Clin Psychol 2002 Jun; 70(3):537-47

Comment: The Ronald Glaser and Janice Kiecolt-Glaser research at Ohio State has made great progress toward synthesizing a coherent theory of stress, physiological and physiological effects, interventions, and reduction of risk for many chronic conditions. In scores of controlled studies, it is now apparent that negative mood is associated with higher risk of immune-related diseases; that interventions including verbal and written disclosure reduce risk; and that lack of resolution of stressful issues is associated with ongoing increased risks of a panoply of cardiovascular, metabolic and degenerative diseases. No body system appears to be excluded from the disease risks associated with the downstream effects of unmanaged stress. This means the approach to disease management must look at the whole array of effects, addressing them all.

Dermatoses and the mind

It is only recently that Western physicians are rediscovering the link between thought and health. The spectrum of causative factors in inflammatory dermatoses are often multifactorial. Stress and negative thoughts are major factors in dermatological conditions. This summary begins with some basic information on the pathways by which thoughts affect health. Practical methods of intervention include meditation, journal writing, affirmations, prayer, biofeedback and hypnosis.

Bilkis MR, Mark KA. Mind-body medicine. Practical applications in dermatology. Arch Dermatol 1998 Nov; 134(11):1437-41

Comment: In the 1930s, 40s and 50s, Walter Cannon, Hans Selye and Flanders Dunbar explored homeostasis and the early understanding of the mechanisms by which stress affected emotional, physiological and pathological responses in animals and humans. In the 1950s, more sophisticated research opened the arena of "psychosomatic medicine" with more precise essential research by Harold Wolff and his followers at Cornell. I have previously cited in this column studies and case histories such as the urticaria-prone subject who developed hives immediately on getting in touch with his anger on thinking about situations in which he was being symbolically pummeled (J Am Med Assoc 1950; 143:1396). Then in the early 1980s with Robert Ader's demonstration of the conditionability of immune cells, the experimental fields of Psychoneuro-immunology and Psychneuroimmunoendocrinology were launched. This summary by Bilkis and Mark nicely delineates the credible evidence for efficacy of meditation, relaxation techniques, affirmations, journaling, biofeedback and hypnosis in managing and mitigating the pervasive effects of stress and resulting tension. I first summarized many of these techniques in 1978, introducing the concept of the good news about stress: i.e. bringing awareness about stress into the light of day to be able to accept, manage and mitigate it to the benefit of better health. Subsequent research has corroborated early attempts to formulate proactive coherent stress management programs.

Gingival health and stress

Fifty-two medical student volunteers underwent a dental examination four weeks before taking a major exam and again just before the examination itself. 6/26 exam subjects and 1/26 control student developed severe inflammation and deteriorated gingivitis at the site of teeth that had been healthy at baseline (p=0.014).

Deinzer R et al. Increase in gingival inflammation under academic stress. J Clin Periodontol 1998 May; 25(5):431-3

Comment: These results further support the hypothesis that psychological stress is a significant risk factor for periodontal inflammation. This clinical study, without looking at which inflammatory cytokines were actually involved, tells us that inflammation and susceptibility to infection accompanied the run-up to the major examination. Many of us who went through these experiences in medical school remember how stressful it often was. Practitioners who see patients with similar immunological and inflammatory changes would do well to ask about precipitating circumstances rather than merely addressing the presenting changes which are actually only symptoms of something more profound going on.

Immunity and stress

Stimuli (cold, heat, fear, hunger, physical injury) at low levels (low stress) increase cellular immune responses more than humoral immune responses. This increases susceptibility to cell-mediated autoimmunityincluding arthritis, and increases resistance to pathogenic organisms including mycobacterium tuberculosis, Hansen's bacillus and the leishmaniasis protozoan. High stress increases humoral immunity more than cellular immunity and favors susceptibility to pathogenic organisms and resistance to autoimmune disorders. Adrenal steroids increase humoral immunity and decrease cellular immune responses.

Mason D. Genetic variation in the stress response: Susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol Today 1991 Jan; 12:57-60 [Editorial]

Comment: Mason distinguishes the effects of low-level and high-level stress. The cellular immune responses, he believes, respond more powerfully with low-level stress, building resistance to infectious organisms and entraining autoimmune mechanisms. The humoral responses (immune globulins, cytokines, etc.) are more greatly stimulated by high stress, building resistance to autoimmunity and susceptibility to infections; steroids aggravate the latter scenario. This theoretical dichotomy is an over-simplification, but still bears some relationship to reality. And since cortisol levels are elevated in subacute and chronic stress, susceptibility to pathogens is a practical consideration.

Immunity and stress

The relationship between adrenocortical function and immunity is complex. In addition to the well-known detrimental effects of large, pharmacological dosages of glucocorticoids upon the immune process, there is impressive evidence that physiological amounts of cortisol, a principal glucocorticoid produced by the human adrenal cortex, are necessary for the development and maintenance of normal immunity. Differentiating between physiological and pharmacological dosages and effects is important. There is increasing awareness not only that the immune process provides protection against infection, but also that its impairment seems to be involved in the development of autoimmune disorders, malignancies and the acquired immunodeficiency syndrome (AIDS).

Jefferies WM. Cortisol and immunity. Med Hypotheses 1991 Mar; 34(3):198-208.

Comment: This early comment by Jefferies, who propounded the theory of identifying persons whose states of fatigue and depression were due to depleted adrenal reserve without frank Addison's disease, amplifies the comment above about the complexities of adrenal hormone/immune interactions. The stress story is likewise very complex; in acute states, physiological responses to stress are life-saving; in chronic states, continued high-levels responses to stress are counterproductive. Biofeedback, meditation and relaxation methods can be of enormous benefit in the chronic stress state, allowing equilibration of appropriate responses to minimize inflammation and promote late stages of healing.

Immunity and stress

This meta-analysis of stress/immunity literature demonstrated a very significant inverse relationship of stress to immune function including decreased proliferative response to mitogens Con-A and PHA (p<.001); NK cell activity (p<.001); numbers of WBCs (p<.001); immunoglobulins IgA and IgM (p<.01); and antibody titers to herpes virus (p<.001). Stress of interpersonal events was significantly more important than stress of nonsocial events.

Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med 1993 JulAug; 55(4):364-79

Comment: This meta-analysis bears out individual studies demonstrating a consistent relationship of stress to altered cellular and humoral responses. Flexibility on the part of the host in crafting responses to stress would appear to be enhanced by training in relaxation processes and the cultivation of emotional equanimity. No evidence has yet been presented to document any disadvantage in mounting a wholly adequate acute inflammatory response to trauma and acute injury in persons who have become expert in managing their own tension and emotional/physiological responses. In fact, there is evidence in the opposite direction: persons with a highly trained relaxation response appear to do better under acute, adverse stressful circumstances.

Inflammation and stress

Molecular and biochemical bases for CNS-immune interactions include cytokines which activate immune function and also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of adaptive behaviors after injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin releasing hormone neurons (CRH) to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. CRH not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the CNS may coordinate both behavioral and immunological adaptation during stressful situations. The pathophysiological perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific CNS pathways (e.g. the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacological means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history.

Sternberg EM, Chrousos GP, Wilder RL, Gold PW. The stress response and the regulation of inflammatory disease. Ann Intern Med 1992 Nov 15; 117(10):854-66

Comment: These concepts suggest that agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune. While this summary was suggesting that the agents which might accomplish this would be pharmacological, PNIE observers suspect that hypothalamic influences on the HPA (hypothalamic-pituitary-adrenal) axis can also be generated by psychological "agents"--meditation, biofeedback, progressive relaxation and hypnosis--which elaborate relaxation responses, affecting the adrenal-medullary-autonomic axis as well.

Inflammation and stress

In response to psychological or certain physiological stressors, an inflammatory process may occur through release of neuropeptides (especially substance P or other inflammatory mediators) from sensory nerves and the activation of mast cells and other inflammatory cells. Central neuropeptides, including corticotropin releasing factor and perhaps substance P as well, initiate a systemic stress mobilization response by activating the sympathetic nervous system, hypothalamic pituitary axis, and the renin angiotensin system, thus releasing stress hormones (i.e., catecholamines, corticosteroids, growth hormone, glucagon, and renin) which, together with cytokines induced by stress, initiate the acute phase response (APR) and the induction of acute phase proteins, essential mediators of inflammation. Central nervous system norepinephrine may also induce the APR by macrophage activation and cytokine release. The increase in lipids with stress may also be a factor in macrophage activation and lipopolysaccharide release which may induce cytokines from hepatic Kupffer cells, subsequent to an enhanced absorption from the gastrointestinal tract during psychological stress. The brain may initiate or inhibit the inflammatory process which is embedded within the psychological stress response which evolved later in human evolution. Moreover, the same neuropeptides (i.e., CRF and possibly substance P) mediate both stress and inflammation. Cytokines evoked by either a stress or inflammatory response may utilize similar somatosensory pathways to signal the brain. Repeated episodes of acute or chronic psychogenic stress may produce chronic inflammatory changes which may result in atherosclerosis in the arteries or chronic inflammatory changes in other organs as well.

Black PH. Stress and the inflammatory response: A review of neurogenic inflammation. Brain Behav Immun 2002 Dec; 16(6):622-53

Comment: The interactions of stress and inflammation mechanisms are well mapped in this review. What is clear is the integral way in which stress, or at least the perception of it, neuropeptide and hormone responses, the hypothalamic-pituitary-adrenal axis and inflammatory activators all interact with numerous complex feedback loops. Although not demonstrated, a global look at numerous studies of the interaction of voluntary controls of the relaxation centers of the brain and downstream physiological and biochemical activity demonstrate that a centered personality state imbuing greater levels of relaxation more optimally equilibrates inflammatory responses, favoring greater acute phase inflammatory responses for healing while decreasing chronic inflammatory responses to reduce autoimmunity and induction of inflammatory disease.

Autoimmunity and psychological states

This Harvard review of the relationship of psychological states and the immune system confirms the importance of paying attention to the mind-brain-immune axis. The authors point out the strong evidence for far-reaching interactions between psychoneurology and autoimmunity, chiefly lupus erythematosus and rheumatoid arthritis. Research confirms a relationship of stress to the onset and course of autoimmune disorders. The various interactions are bi-directional, as evidenced by the autoimmune-mediated neuropsychiatric manifestations of systemic lupus. The authors suggest that the exploration of the role of the various neurotransmitters and neuromodulators of the stress response will shed much light on the therapeutic implications in these diseases.

Rogers MP, Fozdar M. Psychoneuroimmunology of autoimmune disorders. Adv Neuroimmunol 1996; 6(2):169-77

Comment: This fairly recent summary tends to confirm the validity of research in which onset and exacerbations of autoimmune disease appear to be strongly related to subjects' perceptions of stress at a short prior interval of time. Because of potentially extremely broad applications, the teaching of stress management skills to appropriate populations including school children, could even be considered a public health measure. Education has much greater potential for improvement of the general health of a society than the principal narrow focus of allopathic and osteopathic teaching institutions on disease treatment.

Immunity and emotional expression

In this report, results from a series of studies are summarized in support of a general theory of inhibition and psychosomatics. According to this view, to inhibit thoughts, feelings, or behaviors is associated with physiological work. In the short term, inhibition results in increased autonomic nervous system activity. Over time, inhibition serves as a cumulative stressor that increases the probability of psychosomatic disease. Actively avoiding thoughts and feelings surrounding a trauma and / or not discussing a trauma is a particularly insidious form of inhibition. The results from recent surveys and research studies indicate that: (a) childhood traumatic experiences, particularly those never discussed, are highly correlated with current health problems; (b) recent traumas that are not discussed are linked with increased health problems and ruminations about the traumas; (c) requiring individuals to confront earlier traumas in writing improves health and immune system functioning; (d) actively talking about upsetting experiences is associated with immediate reductions in selected autonomic activity.

Pennebaker JW, Susman JR. Disclosure of traumas and psychosomatic processes. Soc Sci Med 1988; 26(3):327-32

Comment: Implications of these findings for disclosure, trauma, and disease are substantial. James Pennebaker has pioneered the research linking the key concepts in this summary. The emphasis here is the therapeutic immune system benefit and reductions in risk of health problems which obtain with self-disclosure and sharing of upsetting experiences. Close friends, spouses and significant others can be appropriate active listeners to allow this avoidance energy to be dissipated. Even more to the point, counselors, physicians and others in the helping professions can invite clients and patients into the self-disclosure process by creating the right climate where it can happen. The therapeutic benefits can scarcely be comprehended.

Self-disclosure and natural killer cell activity

In 43 male recruited undergraduates classified as high or low on the Cook-Medley Hostility scale, the increase in NK cell cytotoxicity in those from the high hostility group (highest quartile) randomly assigned to verbal self-disclosure of a significant life trauma or stress was significantly greater than that of high hostility controls who engaged in a non-disclosure discussion (p<0.001), comparing baseline to post-self-disclosure 35 minutes later. High hostility disclosing subjects also had a greater rise in NK cytotoxicity than low hostility disclosing subjects (p<.05). The effect of self-disclosure on NK cell activity was moderated by an individual's level of cynical hostility. The greater short term enhancement in NK cell activity observed for hostile persons may be a correlate of a more pronounced acute arousal response elicited by the self-disclosure task.

Christensen AJ, Edwards DL, Wiebe JS et al. Effect of verbal self-disclosure on natural killer cell activity: moderating influence of cynical hostility. Psychosom Med 1996 Mar-Apr; 58(2):150-5

Comment: Extrapolation of the conclusion in this study would prompt the highlighting of encouragement for self-disclosure, especially for persons known to have or appearing to have a high degree of attitudinal hostility. Natural killer cell populations and activity are known to have important anti-viral and anti-tumor activity. As part of their therapeutic processes they interact with tumor-necrosis-factor-a, interleukins and interferons, all important elements in the body's immune and inflammatory response patterns. The attitude of hostility appears to be specifically related to the downstream emotional complex recognized as irritation, anger and rage. I have sought a broader term applying to negative attitudes in general: the word that fits is oppugnence. Oppugnence might be referred to as the descriptor of generic negative attitudes. This is the attitude which says "I'm not o.k., you're not o.k.," contrasting to "I'm o.k., you're o.k." as the starting point for unconditional love so essential in therapeutic relationships. While negative attitudes are certainly normal and almost universally experienced, they do appear to be related to undesirable conditions. For instance, overdone and unresolved experiences of grief, depression, anger and anxiety are all associated with poor survival after myocardial infarction. The attitude of oppugnence provokes adverse bodily reactivity at psychological and physiological levels and should perhaps be categorized as pro-inflammatory.

Rheumatoid arthritis and emotional expression

In 51 volunteers with moderately severe to severe rheumatoid arthritis, disease severity index evaluated by a blinded rheumatologist fell 28% over 4 months in those randomly assigned at baseline to write for 20 minutes a day for 3 consecutive days about the most emotionally stressful event of their lives (p=.001) v. no change in routinely treated controls who wrote about emotionally neutral topics. These gains were beyond those attributable to the standard medical care that all participants were receiving.

Smyth JM et al. Effects of writing about stressful experiences on symptom reduction in patients with asthma or rheumatoid arthritis: a randomized trial. JAMA 1999 Apr 14; 281(14):1304-9

Comment: Rheumatoid arthritis is regularly classified in textbooks as an autoimmune disease. Inflammation is a major consideration central to the understanding of this disease process. Although Smyth et al. did not study concomitant changes in immune complexes, cytokines and other biochemical inflammatory elements, the clinical connection demonstrated by the disparity in emotional/mental participation by the improved group vs. the lack of change in controls who were not emotionally involved in their writing expression is noteworthy. Counselors and psychotherapists have long noted benefits following self-disclosure of emotionally loaded elements of one's experience. Improvement in immune and inflammatory status, previously shown by healthy subjects writing about their traumas (see above), have been shown here objectively in a well defined disease entity. Release of feelings was highly therapeutic. Perhaps this has been empirically recognized by the Roman Catholic tradition of the confessional.

Robert Anderson is a retired family physician. In mid-career, his practice took on a more holistic nature as decades passed. He has authored five major books, Stress Power! (1978), Wellness Medicine (1987), The Complete Self-Care Guide to Holistic Medicine (1999) (co-author), Clinician's Guide to Holistic Medicine (McGraw Hill, 2001), and The Scientific Basis for Holistic Medicine, (6th edition), newly available from American Health Press, nhf@msn.com. Anderson was the founding president of the American Board of Holistic Medicine, past president of the American Holistic Medical Association, former Assistant Clinical Professor of Family Medicine at the University of Washington and currently Adjunct Instructor in Family Medicine at Bastyr University.

by Robert A. Anderson, MD

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