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From the Townsend Letter
December 2007


Review and Commentary:
Liver Disease and Cirrhosis
by Robert A. Anderson, MD, FAAFP, FACPM, ABHM

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Psychoneuroimmunoendocrinology describes the unity of mental, neurological, hormonal, and immunological functions, addressing the impact of cognitive images of the mind (whatever its elusive definition) on the central nervous, endocrine, and immune systems. It encompasses biofeedback and voluntary controls, impacts on physiology of thought and belief, past/present stress, placebos, social relationships, and "energy medicine." This column highlights clinical applications of cogent studies from these arenas of holistic medicine in the new millennium.

Liver Disease and Cirrhosis

Hepatitis B Vaccination
This study investigated whether expression of the emotional aspect of traumatic experiences influences the immune response to a hepatitis B vaccination program. Forty medical students who tested negative for hepatitis B antibodies were randomly assigned to write about personal traumatic events or benign control topics during four consecutive daily sessions. The day after completion of the writing, participants were given their first hepatitis B vaccination, with booster injections at one and four months after the writing. Blood was collected before each vaccination and at a six-month follow-up. Compared with the benign-writing control group, participants in the traumatic emotional expression group showed significantly higher antibody levels against hepatitis B at the four- and six-month follow-up periods (p<.05). Other immune changes evident immediately after writing were significantly lower numbers of circulating T helper lymphocytes (p<.05) and basophils (p<.01) in the treatment group. The mean skin conductance levels fell significantly in the trauma-writing group over the four days of writing vs. a rise in the controls (p<.05).

Petrie KJ, Booth RJ, Pennebaker JW, et al. Disclosure of trauma and immune response to a hepatitis B vaccination program. J Consult Clin Psychol. 1995 Oct; 63(5):787-92.

COMMENT: The finding that a writing intervention influences immune responses provides further support for a link between emotional disclosure and health. In this study, the immune protection against hepatitis B appeared to be enhanced in those medical students who wrote about their past emotional traumas. Numerous studies utilizing the Pennebaker approach have demonstrated the benefit for immune strengthening and long-lasting improvement of functionality in asthma and rheumatoid arthritis as a result of providing the opportunity to express strong feelings about past emotionally traumatic events. Conversely, one could perhaps assume that failure to express extant strong feelings about these traumatic events might be detrimental to the immune system.

Stress and Hepatitis B Vaccine Responses
Each of a series of three hepatitis B (Hep B) inoculations was given to 48 second-year medical students on the third day of three days of exams to study the effect of academic stress on the ability to generate an immune response to a primary antigen. Those students who seroconverted after the first injection (25%) were significantly less stressed and anxious than those who did not seroconvert at that time. In addition, students who reported greater social support demonstrated a stronger immune response to the vaccine at the time of the third inoculation, as measured by antibody titers to Hep B surface antigen (HBsAg), and the blastogenic response to a HBsAg peptide.

Glaser R, Kiecolt-Glaser JK, Bonneau RH, et al. Stress-induced modulation of the immune response to recombinant hepatitis B vaccine. Psychosom Med. 1992 Jan-Feb; 54(1):22-9.

COMMENT: Ron Glaser and Janice Kiecolt-Glaser at Ohio State have made a career of demonstrating the effects of stress on a variety of conditions. This study involved hepatitis B vaccine responses that were down-regulated at times of stress and enhanced with psychosocial support. Most practitioners can identify with the stress of tests in medical school. Can we write prescriptions for managing stress more efficiently or for improving social support? Usually not, but the topic can be raised with patients, in much the same fashion as we would talk to patients about smoking. And we can offer them relaxation training or refer them for it with the portent of enhancing immune responses.

The Holmes Stress Scale and Liver Histopathology
Certain behaviors can have an influence on the cause and progression of liver disorders. To clarify the relation between histopathological change of the liver and psychosocial stress, behavioral traits, and psychological state, 14 patients with fatty liver were compared with 16 patients with chronic hepatitis. Both groups were alcohol-induced without other causes, and both consumed the same amounts of alcohol. By morphometric methods, fat deposit ratio and degree of liver damage (DLD) (which reflects lobular fibrosis), inflammatory cell infiltration, and necrosis were evaluated. Holmes Life Change Unit scores from the Social Readjustment Rating Scale were significantly higher in chronic hepatitis cases than in fatty liver patients (p<0.001). DLD was significantly correlated with Life Change Units (p<0.01).

Fukudo S, Suzuki J, Tanaka Y, et al. Impact of stress on alcoholic liver injury; a histopathological study. J Psychosom Res. 1989; 33(4):515-21.

COMMENT: These data leave the strong implication that psychosocial stress is one of the aggravating factors for fibrosis and inflammatory change of the liver that has been previously damaged by alcohol in man, similar to findings in the rat liver following stress. The response to stress is all too commonly expressed emotionally as intensely inflamed responses including anger, irritation, and rage. Could there be a connection between inflammatory emotional responses and tissue inflammation? It has not been shown definitively to my knowledge, but several varieties of studies have hinted at the possibility. The probable link is the elevated level of catecholamine synthesis in persons involved with intense and continued emotional turmoil, which, in turn, raises degradation products, the detoxification of which increases free radical production.

Hepatitis Causes Stress
Using a 100-mm visual analogue scale, 185 patients with compensated chronic hepatitis C (CHC) were asked to self-grade the degree of stress caused by the learning of their CHC diagnosis and the perceived severity of their disease. Learning of CHC diagnosis was considered a major stressful event (mean stress score 72), significantly less than death of a loved-one (89, p<0.0001) and divorce (78, p<0.007), but more stressful than job dismissal (68, p<0.04) and home removal (26, p<0.0001). CHC was considered a severe disease (74), after AIDS (94, p<0.001) and cancer (91, p<0.001), but above diabetes (66, p<0.001) and hypertension (62, p<0.001). Perceived CHC severity was not related to the actual severity of liver disease, rated according to the Metavir fibrosis score.

Castera L, Constant A, Bernard PH, et al. Psychological impact of chronic hepatitis C: comparison with other stressful life events and chronic diseases. World J Gastroenterol. 2006 Mar 14; 12(10):1545-50.

COMMENT: These data show the considerable psychological and emotional burden incurred with a diagnosis of CHC, even in the absence of significant liver disease. Often we think of stress inducing susceptibility to various illnesses and diseases. The opposite is also true as shown here. Practitioners might be well advised to be aware of the stressful nature of revealing a diagnosis of serious illness, particularly those that bear the stigmata of chronicity and incurability. This can be taken into account when announcing a diagnosis of chronic hepatitis and other life-threatening diseases and addressed in effective ways to reduce its negative effects.

Stress, Hypothalamic-Pituitary-Adrenal Axis, and Liver Disease
Early reports on the detrimental effects of psychosocial stress on liver disease were largely anecdotal. This is a review of evidence from the last two decades demonstrating how stress exacerbates liver diseases. The principal effectors of the activated hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoids, can exert a facilitative effect on the hepatic inflammatory response and "even increase the risk of developing hepatocellular carcinoma." For certain liver diseases, defective HPA axis activation probably contributed to the exacerbation of the liver disease. The efferent sympathetic/adrenomedullary system mainly contributes to the stress-induced exacerbation of liver diseases via its catecholamine neurotransmitters. In contrast, the efferent parasympathetic nervous system elicits an inhibitory effect on the development of hepatic inflammation.

Chida Y, Sudo N, Kubo C. Does stress exacerbate liver diseases? J Gastroenterol Hepatol. 2006 Jan; 21(1 Pt 2):202-8.

COMMENT: The pathophysiological interaction between stress and the liver appears to be regulated by the complex, dynamic networks of both the endocrine and autonomic nervous systems (both sympathetic and parasympathetic). The implication, of course, is that psychosocial support to patients with chronic liver diseases is an important part of treatment. The sympathetic adrenomedullary limb of the autonomic nervous system is down-regulated by biofeedback, meditation, social support, and relaxation therapies of all sorts. The glococorticoid axis also is also favorably modulated by these same practices. The vast majority of conventional practitioners are either unaware of these influences or consciously downplay them, because they do not fully accept the scientific evidence. They may also be too busy to take on a newly expanded worldview of the whole-person approach to health and disease.

Personality and Severity of Hepatitis
This cross-sectional study examined the association between the severity of chronic hepatitis C and the type 1 personality, strongly associated in the European Grossarth-Maticek studies to be related to the incidence of cancer and mortality. Sixty-nine patients with chronic hepatitis C who completed the Stress Inventory, a self-report questionnaire to measure psychosocial stress and personality, were classified into three groups according to hepatitis severity: group A, chronic hepatitis C with a normal serum alanine aminotransferase (ALT) level; group B, chronic hepatitis C with an elevated ALT level; and group C, liver cirrhosis. Each of four scales related to the type 1 personality - low sense of control, object dependence of loss, unfulfilled need for acceptance, and altruism - was significantly and positively associated with hepatitis severity. The type 1 score, calculated as the average of these scales, was also strongly related to hepatitis severity (p<0.0001), which persisted unchanged after adjustment for age, sex, education level, smoking, drinking, and duration.

Nagano J, Nagase S, Sudo N, Kubo C. Psychosocial stress, personality, and the severity of chronic hepatitis C. Psychosomatics. 2004 Mar-Apr;45(2):100-6.

COMMENT: Chronic psychosocial stress relevant to the type 1 personality may influence the course of chronic hepatitis C. This study proves correlation but not necessarily causation. The personality test instruments were administered by hepatitis subjects who presumably knew the severity of their disease. The study therefore is less credible than a study of a large population whose subjects complete psychological evaluations before becoming ill. Nonetheless, the association of this Grossarth-Maticek type 1 personality with hepatitis severity was very strong. One looks forward to a totally prospective study of populations who might be at risk for chronic hepatitis.

More on Psychological Stress and Immune Responses
Psychological stress affects immune function and predicts infectious disease susceptibility. But not all individuals who are stressed develop disease. In this article, the authors report on a series of studies from their laboratory describing inter-individual variability of immune responses to psychological stress. In their initial experimental investigations, they were able to demonstrate that acute laboratory stress alters both quantitative and functional components of cellular immunity. Individuals differ substantially in the magnitude of these immune responses. These differences were found to be predicted by inter-individual variability in stress-induced sympathetic nervous system activation. Further investigation revealed that individuals vary consistently in the magnitude of their immune responses to stress, making it conceivable that individual differences in immune reactivity provide a vulnerability factor, mediating relationships between stress and disease. In support of this possibility, the authors have recently reported initial evidence that individual differences in the magnitude of stress-induced reduction of immune function are often clinically significant and related to an immune response relevant for protection against infection, antibody response to hepatitis B vaccination.

Marsland AL, Bachen EA, Cohen S et al. Stress, immune reactivity, and susceptibility to infectious disease. Physiol Behav. 2002 Dec;77(4-5):711-6.

COMMENT: This editorial type comment doesn't tell us much new, but emphasizes that there is great variation in individual responses to stress, quantifiable in large measure by monitoring sympathetic nervous system responses. The chief benefit of relaxation training is the elicitation of voluntary controls over the sympathetic nervous system.

The psychological term that precisely applies here is equanimity. I'm reminded of that famous poem by Rudyard Kipling: "If you can keep your head when all about you are losing theirs and blaming it on you; if you can trust yourself when all men doubt you, . . . you'll be a man, my son!" So often it's not the initial insult that is so devastating, but rather the high tension response for lack of equanimity. Relaxation is teachable and learnable, and in a world where stress seems to be multiplying logarithmically, we need to pay attention to the learning of this skill.

Robert A. Anderson, MD, FAAFP, FACPM, ABHM
614 Daniels Drive NE
East Wenatchee, Washington 98802-4036

Robert Anderson is a retired family physician who has authored five major books: Stress Power!, Wellness Medicine, The Complete Self-Care Guide to Holistic Medicine (co-author), Clinician's Guide to Holistic Medicine (McGraw Hill, 2001), and The Scientific Basis for Holistic Medicine, (6th edition 2004, available from American Health Press, Anderson was the founding president of the American Board of Holistic Medicine, past president of the AHMA, and former Assistant Clinical Professor of Family Medicine at the University of Washington. He is currently an Adjunct Instructor in Family Medicine at Bastyr University.


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