Is There a Role for Psychology in Ulcer Disease? ROBERT MURISON

Department of Biological and Medical Psychology

University of Bergen, Norway Abstract--The discovery of the importance of bacterial factors in the etiology of ulcer disease has led to a neglect of psychological factors. However, both earlier theoretical and empirical approaches implicating these factors are supported by more recent studies, both epidemiological and experimental. While not ignoring the unquestioned role of Helicobacter, it is important for future research to recognize the multi-factorial nature of ulcer disease by which several factors, including stress, bacteria and non-steroid antiinflammatory drugs, may interact to drive a pre-pathology (erosions or ulcerations) to a pathological state (ulcer). Calls for general eradication programs should be cautioned in the light of possible unwanted side effects.

DORINGTHELASTFEWDECADES,there have been marked changes in how both researchers and laymen view the relationship between mind and disease, but paradoxically the directions of these changes are at odds with one another. For the mainstream biomedical establishment, there has been a trend away from mind-body interactionism to greater focus on hard technology and finding the golden bullet, a process which inadvertently reinforces Cartesian dualism. For the layman, in contrast, there has been an increasing interest in socalled alternative approaches which emphasize treating mind and body as one. These latter are the foundation of a thriving industry (Diehl and Eisenberg, 2000) and represent the heritage of the holistic approaches of such writers as Alexander and Dunbar. These two opposing trends should be a wake-up call to biomedical professionals and educators alike and, indeed, recent commentaries suggest that some sections of the biomedical community are already sensitive to this issue (Rees and Weil, 2001). On the one hand, physicians need to be reminded of the importance of doctor-patient communications while educators in general must teach how to differentiate between "real" and "false" science. A failure to address this problem will inevitably lead to an increased disillusionment with medical science and a risk that inappropriate or even dangerous forms of treatment will be preferred. Just one example of this has been the dramatic developments in our approach to gastrointestinal disorders. On the one hand, there is increasing interest for a role for psychological factors in some diseases and disorders (for example inflammatory bowel disease), while for other disorders (gastric and duodenal ulcer) a role for psychological factors has been all but dismissed, as reflected in the decline in number of publications in that area Address for correspondence: Robert Murison, Department of Biological and Medical Psychology, University of Bergen,.A,rstadveien 21, N-5009 Bergen, Norway. Telephone: int + 47 55 586225; fax: int + 47 55 589872; email:

[email protected] Integrative Physiological and Behavioral Science, January-March 2001, Vol. 36, No. 1,75-83. 75

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(Levenstein, 2000). In this paper, it is argued that this dismissal is unwan'anted and potentially dangerous.

Historical background Peptic ulcer was until relatively recently a prototypic "psychosomatic" disorder, along with ulcerative colitis, bronchial asthma, essential hypertension, rheumatoid arthritis, thyrotoxicosis, and neurodermatitis. The term "psychosomatic" was earlier used to describe medical conditions that could be induced by psychological states, implying a uni-causal psychological etiology (Theorell, 2000). Later, with greater acceptance of the multi-causal nature of many, if not most, disease states, the term came to be used to describe medical conditions in which psychological factors were considered to contribute significantly to the development and time course of the disease. The point is underscored by Weiner: The fact remains, however, that no one today considers that psychological factors by themselves are the cause of this or any other disease. They may account for a variable proportion of its etiological and pathogenetic variance, but they do not by themselves determine the particular disease, any more than the etiology of gout is determined by any one, exclusive biochemical defect. (Weiner, 1977) The influence of the psyche on the soma, with consequences for disease risk and prognosis, might in practice be negligible (for example in the face of an overwhelmingly powerful pathogen) or highly significant (for example in the face of a less powerful pathogen). In passing, it should be noted that the term psychosomatic has been somewhat misused in recent years in some circles who use it synonymously with functional disorders, i.e. those in which there is no observable organic change. Functional disorders may be psychosomatic but psychosomatic also covers real organic perturbations. After all, the term functional only means that the organic etiology is unknown. Earlier psychosomatic approaches were grounded within the psychodynamic tradition and it is perhaps this emphasis which led to a general disillusionment amongst medical practitioners. The writings of Franz Alexander may seem archaic to many of us today, and there is no doubt that his emphasis on psychodynamic conflicts as such in ulcer disease etiology is problematic in the light of later observations (Alexander, 1987). However, he was neither the first nor the last to believe that ulcer disease is to s o m e extent influenced by psychological factors. Later work by Herbert Weiner and others demonstrated that risk of ulcer disease in both animals and humans could be predicted by behavioral, personality and physiological markers (Weiner, 1991a). And there are numerous reports of increased prevalence of ulcer disease in populations under conditions of severe psychological stress (Aoyama et al., 1998; Levenstein, 2000; Pomakov, Gueorgieva, Stantcheva, Tenev, and Rizov, 1993; Spicer, Stewart, and Winser, 1944). Parallel to this, a mountain of evidence was accumulating from animal models that both gastric and duodenal mucosal damage (erosions or ulcerations) induced by "psychogenic" stress was influenced by specific characteristics of the stressor, including predictability and controllability over the stressor, as well as by psychological characteristics of stressors to which the animal might previously have been exposed (Ader, 1971; Weiner, 1991 b; Weiss, 1984). For example, we have shown in a series of studies that the animals' vulnerability to gastric ulceration can be manipulated by earlier exposure to controllable and uncontrollable stressors (Overmier & Murison, 2000).

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Ulcerations and ulcer Somewhere along the line between Selye's early observations of "ulcers" in stressed animals and the 1990"s, the assumption was made that gastric ulcerations were models for peptic ulcer. Part of this was because of the documented association between stress and ulcer disease in humans, and partly because of the ubiquity of gastric erosions amongst mammals exposed to stress, including primates (Glavin et al., 1991; Tarara, Tarara & Suleman, 1995). Of particular appeal to many was the clear parallel between those factors influencing ulceration in stressed rats and those influencing disease outcome in humans (Ursin, Murison, & Knardahl, 1983). Selye's writings of course emphasized the consequences of stress for the stomach based on his observations of ulcerations in animals, and he did not hesitate to generalize these to human peptic ulcer (Selye, 1974). However, analogies between animal gastric erosions and human ulcer are questioned (Levenstein, 2000). In defense of the analogy, three points should born in mind. Firstly, ulcer disease in humans, like ulceration in animals, is related to stress in some way and to some extent. Secondly stress erosions in animals and ulcer in humans share some common predictors, e.g. levels of plasma pepsinogen (Ader, 1964; Mirsky, 1958). Thirdly, stress erosions or ulcerations in the animal stomach differ from ulcer in terms of the depth of the epithelial damage. It is difficult to understand how an ulcer can develop without first having been an ulceration--of some cause. That is, a deeper hole (ulcer) cannot appear without first having been a shallow hole (ulceration or erosion).

The rise of Helicobacter The world of ulcer research was irreversibly changed by the identification in the 1980's of a bacterium--known today as Helicobacter pylori (Hp)--that was present in the vast majority of peptic ulcer patients, and whose eradication was the most effective ever course of treatment (Marshall and Warren, 1984; Warren and Marshall, 1983). In passing, it should be noted that the first suggestion that microflora might be important for ulcer is over a century old (EUiott et al., 1998). Consequent to the reports of Helicobacter-induced gastritis, ulcer was re-defined as an infectious disease and was treated accordingly with triple therapy to eradicate the bacterium. Psychological factors were out. The observations and theories of several decades were deemed irrelevant, stupid, a distraction (Hyman, 1994). And in fact, we have to agree that from a clinical point of view, this is probably the case for the time being. If the clinicians can cure the vast majority of patients suffering from ulcer disease, why concern ourselves with its etiology? But if as research scientists we strive to understand the disease processes, the issue of psychological factors in ulcer and the observations reported earlier cannot be ignored unless we choose to regard them as fundamentally bad science. It is hard to believe that all those who accepted ulcer as psychosomatic were bad scientists. Moreover, the eradication of Helicobacter pyiori is revealing an increasing number of cases of ulcer disease unrelated to the bacterium (Peura, 2000).

What is the relationship between Helicobacter and ulcer? There are a number of possibilities concerning the relationship between Helicobacter and ulcer. The current dogma amongst most clinical gastroenterologists is that Helicobacter causes ulcer disease. That is, given Helicobacter, then ulcer. But numerous

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studies have shown that this is not true. Depending on which population is studied, we can generally say that the majority or a significant minority of the population lives happily with Helicobacter in their stomach, while only a small minority develops ulcer disease. Thus Helicobacter is not sufficient for disease. Other factors have to be involved, and the most likely here are use of non-steroid anti-inflammatory drugs (NSAIDs) use and life stress. The necessity of Helicobacter for ulcer disease is also in question. According to the Helicobacter dogma, an individual who develops an ulcer must be Helicobacter positive. Over several studies, the relationship between infection is far stronger for duodenal ulcer than for gastric ulcer (Henriksson, Edman, Held & Wadstrom, 1995; Hunt, 1996; Kuipers, Thijs & Festen, 1995) and the incidence of infection is less than 100% for both disorders. It is perfectly clear that there is an increased risk for ulcer associated with Helicobacter infection, but it is also clear that given Helicobacter infection, an individual has a vastly greater probability of not getting an ulcer than of getting one. More than 80% of infected individuals never develop ulcer (Mayer, 2000; Weiner and Shapiro, 1998). Even Marshall agrees that Koch's postulates have not been satisfied (Marshall, 1995). Ulcer therefore remains a multifactorial disease state and a heterogeneous phenomenon. For some individuals, Helicobacter will be the main factor, for others not. Other factors could include use of NSAIDs, alcohol, smoking and psychosocial factors, and it would be foolish to ignore the interactions both between these and between these and Helicobacter. In an elegant analysis of epidemiological data, Levenstein cautiously concludes that somewhere between 30 and 60 % of ulcers are influenced by psychosocial factors (Levenstein, 2000). Is there a n y t h i n g to learn f r o m a n i m a l m o d e l s o f stress a n d ulceration? Animal models have generally (but not exclusively) looked at stomach rather than duodenal damage and in psychobiological studies the animal of choice has been the rat. The rat stomach is not a human stomach, but there are a number of similarities both in structure and function which should make us cautious in throwing out analogies. Stress typically results in erosions or ulcerations rather than ulcer. Continuous intense stress in the rats will lead to true ulcer, but most researchers choose not to go this far because it represents unnecessary suffering for the animals. The other difference is often the superficial shape of the damage between the rodent and human pathology (or pre-pathology) in humans. In the rat, ulcerations are generally observed as longitudinal bleeding areas whereas the human ulcer is more focal. However, the stress ulcer in monkey looks more like the human rather than the rat state, yet is known to be caused by stress (Suleman, Tarara, Else, and Sayer, 1995). No doubt the stress ulcer in horses looks different again. The role of bacteria in animal ulcer remains unclear but a number of findings suggest that this is an area ripe for further systematic study in the light of the Helicobacter phenomenon. As long ago as 1968, reports were appearing that antibiotics reduced the amount of stress ulcerations in rats (Goldman and Rosoff, 1968; Rosoff and Goldman, 1968). The hypothesis presented was that bacteria (or bacterial products) entering the circulation from the gut leads to increased activation of the hypothalamus and vagus, which in turn mediates those changes in the stomach which lead to the formation of ulcer. Although these studies were little noticed at the time, we know today that activation of the immune system leads to increase of intedeukins which by stimulating vagal afferents will have central effects including on hypothalamus and vagal outflow (Milligan et al., 1997). Later, William Par6, one of the major contributors to this area, showed that germ-flee rats, while they do develop stress ulceration, do so to a significantly lesser extent than do

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I BACTERIALl FACTORS

(HP)

BACTEFIIAL FACTq (HF

I BACTERIAL FACT~FIS l (HF')

EROSIONS ~, ~

FIG. 1. Bacteria (e.g. Helicobacter), chemical agents (e.g. NSAID's) or stress may induce mucosal erosions (ulcerations) which may then be exacerbated by other factors to develop into ulcers.

"dirty" animals (Par6, Burken, Allen & Kluczynski, 1993). Whatever the role might be of bacteria in the ulceration process in rat models, it does not appear to be Helicobacterpylori which is relevant. Despite monumental efforts, the infection of rats with Helicobacter is notoriously difficult (but not impossible, and could conceivably happen in nature). There are some reports of Helicobacter species infection in laboratory animal colonies, but this does not include Helicobacter pylori. However, health monitoring in this area seems weak (Hansen et al., 2000). Some fascinating data have appeared from animal models which suggest that the role of gut micro-flora might not be as simple as fast proposed. Not only may bacteria effect the integrity of the mucosa (as in the Helicobacter dogma) but the integrity of the gut mucosa may effect the microfloral population. In the normal undamaged rat stomach, the bacteria

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NSAID c

STRESS II

EROSIONS

>[ ULCERS

BACTERIAL FACTORS (HP)

FIG. 2. Interactionsbetween the several factors are involved in the formation of ulcerations or erosions, and the developmentof these to ulcers.

are predominantly gram positive (Elliott et al., 1998). After acidic, cryogenic or chemical induction of mucosal injury, the nature of the microfloral population both around and contralateral to the damage changes to being predominantly gram negative. Mucosal healing is associated with an increase in the presence of the gram positive Lactobacillus, and finally the stomach resumes its normal micro-floral state. The bacterial colonization associated with the tissue damage was predominantly E. Coli and Enterococcus. The important point is that damage of the mucosa changes the bacterial flora and the ease for bacteria to colonize the mucosa. Studies have shown that it is easier to infect the rat stomach with Helicobacter after ulcer induction (Ross et al., 1992).

Alternative etiologies The current view of ulcer disease is that bacteria leads to ulcer. This uni-causal model is clearly inadequate to account for the data and requires modification. Equally, a simple stress model is inadequate. The heterogeneity of ulcer disease suggests several etiologies with weight on one or more factors--these including at least Helicobacter, psychosocial stress and NSAID use. A simple model would allow any one of these (the primary inducer) to first induce an erosion of the mucosa which may then be exacerbated by one or both of the two other factors (secondary amplifiers), effectively driving the ulceration to an ulcer

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(see figures la to lc). Of course it is possible that the primary inducer alone could cause an ulcer if sufficiently potent, but this suggests a potency outwith the ordinary. More likely, erosions caused by one factor are amplified by one or more others, exemplified in Figure 1. A more realistic model would involve complex interactions between these factors (Figure 2). Such interactions would, for example, involve the fact that individuals under pressure often (mistakenly) increase their use of NSAIDs. The immune response to bacterial colonization will itself stimulate the stress endocrine (hypothalamo-pituitary-adrenal) system via interleukins (Dunn, 1988) while the levels of cortisol will themselves influence the efficacy of the immune response. And of course the individual's visceral sensitivity and perception of gastrointestinal discomfort may lead to exacerbation of both stress and NSAID use. Such a vicious circle has been proposed as a important also for the functional gastrointestinal disorders (Berstad, 2000).

Conclusions Clearly Helicobacter is neither necessary nor sufficient for ulcer disease. From a pragmatic clinical point of view, this may seem to be irrelevant and for the majority of cases the cure is simple and cheap. From a scientific point of view, and also in the long term clinical perspective, the non-sovereignty of Helicobacter is crucial. Other factors--and there may be many of them--play a role in the disease etiology and it is essential to understand these for two reasons. Firstly, with a reduced prevalence of Helicobacter in the developed countries, the phenomenon of Helicobacter negative ulcer is and will necessarily continue to be more apparent (Peura, 2000). Only by maintaining an interest and research activity on the multi-causality of ulcer disease will we be able to face the problems which face us in the future. Secondly, there have been calls for widespread Helicobacter eradication programs aimed at general populations. Such a program is potentially dangerous. The vast majority of infected individuals suffer no ill-effects from the presence of the bacteria, and there could be a symbiotic relationship between the host and bacteria. Symbiosis is the rule rather than the exception with regard to body-born bacteria. Under particular circumstances, the symbiotic relationship may be disturbed, leading to disease. Potentially beneficial effects of Helicobacter are illustrated by an increase in gastro-esophogeal reflux disease following eradication therapy and an inverse relationship between the two disorders (el-Serag and Kuipers, 1998; Labenz et al., 1997; Williams and Pounder, 1999). The implication is that eradication may lead to undesirable side effects. Given that eradication on a global level may prove to be undesirable, the role played by factors other than Helicobacter needs to be better understood, and this includes factors commonly referred to as stress. Those human studies that have implicated stress as a direct causal factor in ulcer disease have involved high to extreme levels, for example war scenarios and natural disasters. Animal studies have however shown that exposure to stressors which in themselves do not induce ulcerations change the vulnerability of the organism to ulcerations induced by later stressors. That is, the organism is sensitized. Daily stress is unlikely to be a major causal factor in ulcer disease in the normal individual, but is likely important in severe conditions and in individuals sensitized by previous events.

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