The in vitro effect of antioxidants on immune phenotype in alcohol-related liver disease (ALD)

Abstract

Intro Excessive alcohol consumption is associated with the development of alcohol-related liver disease (ALD). Alcoholic hepatitis (AH) is a clinical syndrome characterised by jaundice and coagulopathy in patients with a history of heavy alcohol intake. It is part of the ALD spectrum, which also includes fatty liver disease and cirrhosis (1). Alcohol may be metabolised by the liver to acetaldehyde in 2 ways; via alcohol dehydrogenase (ADH) for limited quantities, or by cytochrome p450 for more excessive alcohol intake. Both of these pathways ultimately generate reactive oxygen species (ROS) which promote a microenvironment of oxidative stress, contributing to liver damage (2, 3, 4). Infection is a common complication of AH that may prove fatal (5) and is likely related to the associated immune dysfunction; in that the immune system is activated and primed, but ineffective. Mechanisms of immune dysfunction are multifactorial but suggestive of a chronic inflammatory state. A leaky gut allows PAMPs and DAMPs to cross the portal circulation and stimulate the immune cells (6). Monocytes, neutrophils and T cells have been studied in line with non-infectious liver disease, and changes in their phenotype, function and/or role have been described. Monocytes demonstrate a skewed phenotype (7), neutrophils have reduced phagocytic capacity (8) and T cells portray an exhausted phenotype (9). Oxidative stress often results in tissue damage and is known to impact on the immune system if not counterbalanced by antioxidants (10). The subsequent pro-inflammatory state has been described in the context of liver injury (11). Alcohol metabolism is known to result in oxidative stress and is described in patients with ALD and AH. However, further work is required to assess if this imbalanced redox state is influential in immune dysfunction and infection risk. It would be appropriate to target the oxidative pathways in these patients to assess any improvement in immune function and response to infection. Antioxidants Trace elements are a group of minerals, present in living tissues at small volumes, some of which are nutritionally fundamental to basic cellular and immunological function (12). A vital role of these trace elements is their capacity to act as cofactors of antioxidant enzymes, making their role essential in context of oxidative stress. Zinc (Zn) and selenium (Se) are widely described in their capacity to support the immune system and promote tissue repair. Zinc (Zn) is involved in over 300 enzymatic systems and is crucial for immune cell development and function, as well as playing a key role in wound healing and synthesis of DNA (22). Selenium (Se) is an essential micronutrient that is known to have an impact on various arms of the immune system (23) alongside fulfilling its pivotal role in protecting against oxidative stress (16). Reduced serum levels of trace elements is established in chronic liver disease (26, 27), often due to malnutrition (16, 17), and decreased intake and/or absorption of Zn has been described in patients with liver cirrhosis (21). Preliminary data from over 300 patients with ALD and AH have confirmed deficiencies in Zn and Se compared to healthy volunteers (HV) (figure; Dhanda, unpublished). There is no single cause of trace element deficiency, but is often due to altered gut absorption and reduced dietary intake. What remains unknown is the effect of trace element deficiency on immune function and infection risk in ALD and AH. Supplementation of trace elements, including Zn and Se, has been shown to positively influence immune function in multiple patient groups (17-19). In addition to Zn and Se, N-acetylcysteine (NAC) is an anti-oxidant precursor utilised during intracellular stress (14). NAC is known to have a protective effect in liver injury and has demonstrated a positive impact in patients with non-alcoholic fatty liver disease (20). A clinical trial of combination glucocorticosteroids and NAC therapy in AH demonstrated a reduced infection rate, but did not reduce mortality (21) – this suggests that NAC supplementation may improve the immune phenotype in AH patients. Conclusion Oxidative stress is a result of alcohol metabolism which results in tissue damage, and may influential in the capacity of the immune system to fight infection. Impaired immune function and increased infection risk is described in patients with AH; where there is increased oxidative stress post alcohol metabolism and low levels of trace elements to counterbalance this microenvironment. Targeting the imbalanced redox state by promoting antioxidants in this patient cohort may result in improved immune function and reduce the infection risk, thereby resulting in improved clinical outcomes.