Hepatitis B-related hepatocellular carcinoma and stress: untangling the host immune response from clinical outcomes

Figures & data

Table 1. Types and tools to measure stress.

A. Types of acute and chronic stress
	Acute	Chronic
Psysiologic stressors on the liver
Alcohol	Yes	Yes
Metabolic	No	Yes
Viral	Yes	Yes
Psychosocial stressors
Employment or personal finance challenges	Yes	Yes
Impaired quality of life from medical condition	Yes	Yes
Interpersonal conflicts	Yes	Yes
Psychological disorders (anxiety and depression)	Yes	Yes
B. Common tools to measure psychosocial stress
Instruments	Description
GHQ−12	Screening instrument to measure mental health disorders and stress burden
LDQoL instrument	Validated questionnaire to gauge quality of life in those with chronic liver disease
PHQ-9	Screens depressive symptoms via nine self-reported items
PSS	Measures self-reported stress levels

Table 1A illustrates the types of acute and chronic types of stress. Physiologic causes focus on stressors on the liver. Table 1B highlights common instruments used to measure psychosocial stress.

GHQ-12: General health questionnaire; LDQoL: Liver disease quality of life; PHQ-9: Patient health questionnaire; PSS: Perceived stress scale.

Figure 1. Hepatocyte injury-inflammation cycle from pathophysiological stressors.

Alcohol, fat and viral infection are established hepatic stressors. Psychosocial stress may also lead to a similar pattern of hepatic injury. Pathophysiological stressors can trigger an oxidative stress reaction via overproduction of ROS and RNS. These oxidative species can precipitate NF-κB-mediated inflammatory pathways, leading to release of pro-inflammatory cytokines and recruitment of phagocytic cells (neutrophils and monocytes) and lymphocytes. This inflammatory milieu within the liver can lead to continued hepatocyte injury.

RNS: Reactive nitrogen species; ROS: Reactive oxygen species.

Figure 2. Proposed mechanisms of hepatic injury from chronic psychological stress.

Chronic stress can promote release of NE via SAM system, activating innate immune cells possessing adrenergic receptors and leading to production of pro-inflammatory cytokines. Chronic stimulation of the HPA axis from psychosocial stress can decrease its sensitivity to negative feedback loops, leading amplification of pro-inflammatory cytokines by Kupffer cells. Both chronic glucocorticoid production and NE release can also stimulate hepatocytes to produce hydroxyl free radicals.

HPA: Hypothalamic–pituitary–adrenal; NE: Norepinephrine; SAM: Sympathetic adrenomedullary system.