Psychological stress is defined as a “state in which homeostasis is actually threatened or perceived to be so”, whereas homeostasis represents the complex and dynamic equilibrium between all systems functioning in a living organism [1, 2]. The above definition and context excludes psychiatric disorders that may impair the integrative capacities of the individual. Thus, in the following chapter, psychiatric disorders resulting from stressful events are excluded. The idea that stressful events can influence the individual’s health and disease emerged in ancient times but only recent advances in the field of psychoneuroimmunology have led to a new perspective on this issue. The scientific community in this area has documented the effects and interactions between psychological stress and the well-being of a living organism. Within the last two-three decades, several studies revealed different interactions between neuroendocrine systems, such as the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), and various pathologies. In particular, human and animal studies indicate that liver disease is heavily influenced by chronic psychological stress. The effects of chronic viral hepatitis on liver parenchyma are well known, however the idea that real-life events, independent from the disease itself, can influence the course of this disease, is relatively new.
Central stress mechanism, HPA axis, glucocorticoids (GCs) and the SNS
Currently, it is widely acknowledged that a central stress mechanism exists, composed of different brain structures such as the lateral prefrontal cortex and the medial prefrontal structures, which in turn are connected with the amygdala and the paraventricular nucleus (PVN) of the hypothalamus [3]. Output from these structures is projected onto the pontomedullary nuclei and the pituitary gland. The signals from this central system are conveyed to the SNS components regulated through autonomic neuromediators such as norepinephrine and epinephrine [4].
The neuroendocrine component is represented by the functional axis composed from the hypothalamus, the pituitary and the adrenal glands (the HPA axis), regulated through circulating GCs [2, 5]. Pituitary hormones (prolactin and growth hormone), along with the adrenocorticotropic hormone, and neuropeptide Y and opioids are actively released during stressful events. They directly influence cellular- and antibody-mediated immune responses [6, 7]. The HPA axis represents the anatomical and functional system that regulates GC secretion and plays a major role in the adaptive responses to stress. This system is under direct neural control, receiving sympathetic innervation through short and long feedback circuits from the hypothalamus and other central structures. Hence, the HPA axis is deeply interconnected with the SNS. These two systems are key components of the stress system and are major regulators of basal homeostasis. The corticotrophin-releasing hormone (CRH) and noradrenergic neurons of the central stress system are in close relation through a two-way feedback mechanism that assures inter-regulated levels of production of norepinephrine (noradrenaline) and CRH [8, 9].
The central stress-related components are located in the hypothalamus and the brainstem, and include neurons located in the parvocellular area, which secrete CRH; the arginine vasopressin (AVP) neurons of the hypothalamic PVN; the CRH neurons located in the paragigantocellular and parabrachial nuclei of the medulla, and other mostly noradrenergic neurons located in different areas of the pons and medulla.
Central, hypothalamic CRH functions as a regulator and activator of the HPA axis. CRH, however, is also secreted peripherally at inflammatory sites (peripheral or immune CRH) and influences the immune system directly, through local modulatory actions. The HPA axis drives the secretion of GCs by the adrenal cortex, exerting mostly anti-inflammatory effects, which oppose the pro-inflammatory effects of the peripheral/local CRH. CRH is released in inflammation areas, while plasmatic concentrations remain low, thus proving its local effect in the inflammatory process [10].
The hypothalamic stress components’ activity is up-regulated by the serotoninergic and cholinergic systems, and their activity is inhibited by the opioid-peptide and the gamma-aminobutiric acid-benzodiazepine systems. Substance P stimulates the central noradrenergic system, while inhibiting hypothalamic CRH-secreting neurons [11-13]. In addition, cytokines also play an important role in the neuroendocrine-immune system interactions. Interleukin (IL)-1, IL-6 and tumor necrosis factor alpha (TNF)-alpha are released during immune mediated or inflammatory reactions, thus activating central components of the stress circuitry [14-16]. Primarily, the HPA axis is stimulated by IL-1, while IL-6 and TNF-alpha play a secondary role [17, 18].
Role of the HPA axis in acute and chronic liver inflammation
As already stated above, the activation of the HPA axis represents a key element of the normal response to stress factors. The end result of this stimulation is the active secretion of GCs from the adrenal cortex, which is a natural process designed to improve survival chances in a fight-or-flight scenario, usually associated with the notion of “exterior stress”. This process, however, is involved in the control of the inflammatory response, which, in turn, can also interact by stimulation of the vagal afferents and thus activation of the HPA axis.
Patients with chronic liver diseases, such as chronic viral hepatitis, express delayed cortisol clearance and altered cortisol binding at plasma level. Elevated plasma cytokine levels are common in chronic inflammatory diseases, and chronic exposure to high levels of circulating cytokines is associated with HPA axis failure or dysfunction [19]. Experimental data suggest that chronic liver injury results in elevated TNF-alpha and IL-6 levels. This includes as well more specific cellular alterations at hypothalamic level, such as mRNA depletion and impaired protein expression resulting in decreased levels of secreted CRH, which in turn impairs the activation of HPA axis mechanisms [20]. Thus, lower levels of circulating GCs, consecutive to the independent action of an exterior stressor, may be a promoter of hepatic inflammation, concomitant to the usual viral effects.
In a rodent model, acute inflammatory injury of the liver results in a rapid activation of the HPA axis, with consecutive rises in circulating GCs levels. When the physiological effects of GCs are inhibited, the inflammatory response is enhanced, resulting in an increased mortality rate [21]. This in turn can be prevented by the administration of exogenous GCs [22]. The protective effect of GCs can partially be attributed to the fact that they induce the release of IL-10 at hepatic level, particularly by the liver-specific macrophage system, the Kupffer cells. These cells produce a number of inflammatory mediators, such as IL-1, IL-6, TNF-alpha and the nitric oxide, all of them up-regulated during liver inflammation.
These effects are attributed to indirect mechanisms, as they interfere with the production of proinflammatory transcription factors such as (NF)-kB and the activator protein AP-1, or to direct mechanisms which operate at the level of mRNA stability and gene transcription. Liao et al. studied the effects of corticosterone, at both normal and stress levels, on an isolated perfused rat liver [23]. These authors observed that the GCs increased the release of TNF-alpha and IL-6. Later studies provided evidence that psychological stress itself can have the exact effect, possibly by following the same pathways [24]. The hepatic levels of inflammatory cytokines and compounds are differently influenced by GCs, as TNF-alpha seems to be the first to be altered, followed by IL-1 and IL-6.
The hepatitis C virus (HCV) was directly linked to the recruitment of cellular effectors implicated in liver inflammation. Chemokines, being important mediators of liver inflammation, have an increased expression during HCV infection. Dexamethasone, a form of synthetic GC, is routinely used in pretreatment phases. It was shown to attenuate endotoxins expression and cytokine secretion by immune cells during liver inflammation. We can therefore suggest a theoretical link between endogenous GCs and chemokine levels during chronic viral hepatitis, and their balance under chronic stress. Another critical component of the immune system is represented by T cells. In the liver, they are actively involved in the initiation, propagation and maintenance of the inflammatory disease. GCs were proven to specifically interact with T-cell proliferation in the liver, adrenal steroids being regulators of the T helper (Th) lymphocyte cytokine secretion. Activation of the HPA axis under stress impairs the release of Th1 cytokines, thus shifting the profile towards Th2 dominance, as documented by Iwakabe et al., in a restrain-stress model in rodents [25].
Circulating GCs induce T cell apoptosis. During the course of viral hepatitis, increased GCs levels at a hepatic level, following HPA activation, correlate with lower levels of activated T-cells at the same level. Tamada et al. proved that the administration of dexamethasone increases the production of IL-4 by hepatic natural killer (NK) 1.11-positive T cells, demonstrating that this cellular line is resistant to apoptosis induced by GCs. This study further supports the theory that HPA may actively regulate the Th1/Th2 balance during acute or chronic stress exposure [26].
Expansion of liver natural killer T cells and the up-regulation of the Fas antigen on hepatocytes follow the increase of endogenous GCs, as shown by Chida et al., employing inescapable electric foot shock in rats [27]. Restrain stress, another standardized stress model in animal studies, was found to increase the proportion of NK cells in the mouse liver through increased HPA activity and higher than normal GC concentrations [28]. Recent studies indicate that monocyte chemotactic protein (MCP-1) and macrophage inflammatory protein (MIP-2) along with other chemokines, direct NK cells towards inflammation sites, thus suggesting that GCs may influence this sub-population through down-regulation of these mediators [29].
The parasympathetic nervous system and hepatic inflammation
Recently, the main component of the parasympathetic feedback loop mechanism that regulates liver inflammation was identified as the “cholinergic anti-inflammatory pathway”. According to this theory, efferent vagus nerve fibers exist and supplement the normal afferent pathways that sent information to the central nervous system from the hepatic site. It was shown that acetylcholine, the principle vagal neurotransmitter, inhibits the release of TNF-alpha, IL-1beta, IL-6 and IL-18, in lipopolysaccharide-stimulated human macrophage cultures. This effect was proven to be dependent to the nicotinic acetylcholine receptor alpha 7 subunit [30-33].
Studies on transplanted and denervated livers show that inflammatory and immune components are severely impaired by the lack of sympathetic and parasympathetic innervations [33, 34]. Cholinergic nerves are organized as bundles in the vicinity of portal vessels [35]. Some of these fibers are adjacent to hepatic cells within the portal spaces, ending as Held prominences. By proving the existence of acetylcholinesterase-positive ganglia cells in the portal spaces situated in the vicinity of the hepatic hill, studies demonstrated their efferent origin, without excluding a sensory component in some cases [36, 37]. In normal liver, acetylcholine influences metabolic functions, including gluconeogenesis, through muscarinic M3 receptors. In cirrhotic liver, research has found numerous acetylcholine nerve fibers, which have connections to miofibroblasts and mastocytes. Nerve terminals within the cirrhotic nodules and these connections with fibroblasts can be found close to periseptal sinusoids [36-38].
The influence of psychosocial stress on chronic viral hepatitis
Not many clinical studies have evaluated the relationship between viral hepatitis B or C and stress response in a real-life settings. A number of studies did however underline different interactions between the primary anatomical and functional systems in the human body and the intrinsic mechanisms regulating hepatic inflammation, the main morphological change encountered during the course of chronic viral liver infection [39,40]. A clinical study by Nagano et al. indicated a correlation between psychosocial stress and the severity of chronic hepatitis C [41]. This study assessed levels of perceived stressor events through standardized stress questionnaires specifically designed to provide information regarding personality types. Type 1 personality subjects (principal traits being low sense of control, object dependence of loss, unfulfilled need for acceptance and altruism) are prone to disease due to the nature of their personal traits, being likely to be affected throughout chronic stress.
Both type 1 personality traits as well as psychosocial stress was positively correlated with the severity of chronic hepatitis C. Stress levels were assessed based on the Grossarth-Maticek theory, which states that type 1 personality subjects are prone to developing chronic diseases. The severity of chronic hepatitis C was assessed through the levels of alanine transaminase (ALT), platelet counts, albumin and total bilirubin levels. These serum determinations were used to determine if patients still had chronic hepatitis, or the disease further progressed into cirrhosis. Platelet count and serum albumin levels were positively correlated with levels of stress, and also proved to be good assessors for the severity of chronic hepatitis. Aspartate transaminase (AST) values were strongly correlated with stress levels and type 1 personality types, thus establishing a connection between stress and the severity of chronic hepatitis C.
A link between chronic hepatitis B, depression scores and psychosocial stressors were assessed in a group of 50 surface antigen of the Hepatitis B Virus (HbsAg)-positive Korean immigrants [42]. Depression scores, psychosocial factors and social support were evaluated and compared with biological markers of liver dysfunction, including ALT and AST, albumin levels and prothrombin time. These routine clinic follow-up values were correlated with scores obtained from short form Beck Depression Inventory questionnaires. Higher scores were significantly associated with elevated levels of both AST and ALT; however albumin and prothrombin time levels did not correlate with stress scores.
Psychological implications of HCV diagnosis were evaluated by a number of studies. Muzaffar et al. proved that the diagnosis of HCV is considered more stressful than divorce or material loss or house relocation. This study included 98 patients infected with HCV and 100 controls and compared stress and anxiety levels regarding the diagnosis of HCV with other life-changing events including death of a close relative, loss of marital or material status or move to another city [43]. A study by Castera et al. concluded that the psychological impact of chronic hepatitis C and emotional burden of such diagnoses are considerable, even when liver disease is insignificant [44].
Psychosocial stress and vaccination against hepatitis B
Hepatitis B currently represents a major health burden in many areas around the globe. The possibility of an effective vaccination is vital for controlling the effects hepatitis B viruses may have on exposed populations. Current studies estimate that a proportion of over 90% of healthy subjects respond well to vaccination; however, the remaining 10% may not possess protective antibody titers at the end of the vaccination period [45].
Chronic environmental stress exposure is common in several social settings, such as academic mediums, with extensive examination periods, or unfulfilled marriages and job-related distress. These situations were shown to have a negative impact on all components of the immune response. This relationship can best be described by studying the effects stressors have on vaccination outcome, as this procedure clearly reflects the efficiency of the innate immune system against disease. Clinical studies which take into account stress exposure when assessing vaccination protection against hepatitis B are especially useful both for quantifying the effects of psychological stress on the immune response, and naturally for determining the optimum clinical settings for a successful vaccination campaign.
Burns et al. evaluated the stress and coping level of 265 first-year medical school undergraduates who completed the standard three-dose recombinant hepatitis B vaccination program [46]. Test questionnaires were given to the participants, assessing life events of the past 12 months as well as coping types through the brief cope questionnaire and a short survey on individual health behaviors. Then their serum antibody levels were determined quantitatively. They found an inverse correlation between stress questionnaire scores and antibody titers (higher stress levels translated in lower antibody titers), while determining that coping and acceptance coping are significant predictors for antibody status. A higher antibody status post-vaccination was also noticed in subjects that had adequate sleeping patterns and were regularly practicing physical exercises. Another study examined 84 graduate students who received standard hepatitis B vaccination series. Subjects underwent a battery of questionnaires, and blood samples were evaluated [47].
Their results showed that higher scores, measuring a positive dispositional affect (a sense of well-being and fulfillment), positively correlated with greater antibody response to hepatitis B vaccination. Physical activity also proved to provide a protective role. On the other hand, a short, acute stressor may enhance the immune response and antibody production post-vaccination. This effect is however less studied than the exposure to chronic stress, which, usually coupled with a sedentary lifestyle, was unanimously associated with worse post-vaccination antibody titers [48]. The general consensus of these studies is that further research should overcome obvious limitations such as retrospective design or small cohorts, and that experimental models can be devised in order to assess antibody status after hepatitis B vaccination.
Conclusion
Recent evidence indicates a strong correlation between stressors and the progression and outcome of liver inflammatory diseases, such as chronic viral hepatitis. The influence stress has on the immune system ultimately leads to an alteration of several cellular pathways which in turn regulate liver metabolism and inflammation. In the past forty years, animal studies as well as human retrospective analyses have tried to uncover these interactions with various degrees of success. Recent advances were made in understanding the wide-ranging interactions between stress, infection, and/or inflammation and ultimately the onset and progress of viral infections.
Clinical implications are profound, as translational studies deciphering intrinsic cellular mechanisms and pathways lead the way to a better understanding of viral liver infection, thus improving the standard of care in this pathology. Ultimately, acknowledging the role stress plays on viral liver infections will influence the quality of life for these patients; decrease the hospitalization times and the inherent burden on the healthcare systems worldwide. Further studies are needed in order to fully understand the complex interactions between the social environment and the evolution of chronic viral hepatitis.
Nonstandard abbreviations: ALT, Aspartate transaminase; AST, Alanine transaminase; CRH, Corticotrophin-releasing hormone; GC, Glucocorticoid; HCV, Hepatitis C virus; HPA, Hypothalamic-pituitary-adrenal; IL, Interleukin; NK, Natural killer; Th, T helper; TNF, Tumor necrosis factor
Author(s) Affiliation
CC Vere, CT Streba, I Rogoveanu, AG Ionescu & LAM Streba – Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349, Romania
Corresponding Author: Costin Teodor Streba, St. Petru Rares No 2, 200349, Craiova, Romania. Email: costinstreba@gmail.com
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