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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 2  |  Issue : 3  |  Page : 49-53

Research Progress on Sepsis-Related Liver Injury


1 Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
2 Department of Critical Care Medicine, The Cancer Hospital of Harbin Medical University, Harbin 150081, China

Date of Submission08-Oct-2020
Date of Acceptance24-Nov-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
Kai-Jiang Yu
Department of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, No.23 Youzheng Street, Harbin 150001, Heilongjiang Province; Institute of Critical Care Medicine in Sino Russian Medical Research Center of Harbin Medical University, Harbin 150081
China
Prof. Ming-Yan Zhao
Department of Critical Care Medicine, the First Affiliated Hospital of Harbin Medical University, No.23 Youzheng Street, Harbin 150001, Heilongjiang Province
China
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DOI: 10.4103/jtccm.jtccm_27_20

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  Abstract 


Liver injury is one of the most common critical clinical illnesses and is one of the manifestations of multiple organ dysfunction induced by sepsis. The liver plays a central role in the development of sepsis. The role of the liver in removing bacteria and regulating immune inflammation is crucial, and the liver is the target of sepsis-related injuries. However, the mechanism of liver injury in sepsis is still not clear. This review discusses the pathophysiology, clinical manifestations, and treatment of sepsis-related liver injury.
Liver injury, pathophysiological mechanism, sepsis, sepsis-related liver injury

Keywords: Liver injury, pathophysiological mechanism, sepsis, sepsis-related liver injury


How to cite this article:
Kang K, Li NN, Gao Y, Du X, Zhang XY, Zhao MY, Yu KJ. Research Progress on Sepsis-Related Liver Injury. J Transl Crit Care Med 2020;2:49-53

How to cite this URL:
Kang K, Li NN, Gao Y, Du X, Zhang XY, Zhao MY, Yu KJ. Research Progress on Sepsis-Related Liver Injury. J Transl Crit Care Med [serial online] 2020 [cited 2021 Apr 18];2:49-53. Available from: http://www.tccmjournal.com/text.asp?2020/2/3/49/305796

FNx01Kai Kang and Na-Na Li: contributed equally to this work




Sepsis is a disease characterized by abnormal host regulatory functions caused by microbial infections and includes inflammatory factor cascade release, endothelial dysfunction, cell apoptosis, immunosuppression, and ultimately multiorgan dysfunction, which progressively leads to the main cause of death in patients in the intensive care unit.[1] Sepsis is a systemic disease that can present with various complications, including cardiac dysfunction,[2] kidney injury,[3] liver injury,[3] and brain injury.[4] As the largest reticuloendothelial system in the body, the liver has special physiological functions and plays an important role in the pathogenesis of sepsis, and it is also the organ that is the most vulnerable to sepsis.[5],[6] Early damage to liver function marks the stage of the disease known as multiple organ dysfunction syndrome (MODS). A study showed that the incidence of secondary liver injury in septic patients was approximately 30%, whereas the mortality rate was as high as approximately 60%. Liver injury is a high-risk factor for death in patients with sepsis, but the pathogenesis of liver injury secondary to sepsis is not fully understood. This review will discuss the pathophysiological mechanism, clinical manifestations, and treatment of the liver in the development of sepsis and provide a theoretical basis for the study of new methods for the treatment of sepsis.


  The Pathophysiological Mechanism of Liver Injury in Sepsis Top


Cytokine storm

The main pathogens associated with sepsis are Gram-negative bacilli. Lipopolysaccharide (LPS) is a compound composed of lipids and polysaccharides on the cell walls of these bacteria that has a wide range of biological activities and can induce the release of various inflammatory mediators by stimulating monocytes and macrophages. More Gram-negative bacilli accumulate in the human intestine than in any other part of the body and then first enters the body through the liver. LPS plays an important role in the pathogenesis of liver injury in sepsis,[7] which can induce intracellular signaling, the expression of inflammatory factors and cytotoxicity, thereby inducing hepatocyte apoptosis and necrosis.[8],[9] LPS can directly cause liver injury and exacerbate the development of some liver diseases.[10] LPS can induce hepatic inflammation by activating liver macrophages (called Kupffer cells) and triggering an inflammatory response in the liver, leading to the release of inflammatory factors such as interleukin (IL)-1 β, tumor necrosis factor-α (TNF-α), IL-6, and IL-18[11] and resulting in liver damage. IL-1 β activates phosphorylation of the JAK-STAT signaling pathway, which in turn damages the liver.[12] TNF-α causes liver damage through the nuclear factor-κB signaling pathway.[13] TNF-α is considered to be the core inflammatory factor that causes multi-organ damage in the development and progression of sepsis. As the most important pro-inflammatory factors, TNF-α and IL-1 β play synergistic roles in the initiation of inflammation.[14] IL-6 is a type of cytokine produced by macrophages and other immune cells. IL-6 maintains the immune response and participates in the acute phase of inflammation, and it is an important part of the body's immune response to infection. It has been reported in the literature that IL-6 is an important factor involved in the response to sepsis and liver injury, involving multiple levels of the immune cascade. In addition, IL-18 is a major factor leading to liver injury.[15] IL-18 leads to increased TNF-α levels and exacerbates the degree of liver damage. The excessive release of pro-inflammatory factors can cause damage to the functions of multiple organs in the body, while the secretion of anti-inflammatory factors protects organs to a certain extent. There is a certain balance between pro-and anti-inflammatory factors, and the inflammatory response stabilizes. A lack of balance may lead to a systemic inflammatory response. The imbalance between inflammatory factors and anti-inflammatory factors directly leads to uncontrolled and diffuse inflammatory responses, which can damage liver functions. The balance determines the severity of the infection and is strongly related to the prognosis of the patient.

Ischemia and hypoxia

The liver is an important organ involved in the metabolism of many substances, and the body is in a state of high metabolic activity during sepsis. During sepsis, a variety of hormones and neurological and humoral factors can cause hypermetabolism in the liver, such as increased protein synthesis and breakdown and enhanced gluconeogenesis, resulting in the liver consuming more oxygen than it can supply. At this point, hepatic blood flow does not decrease over time, and the liver also undergoes relative ischemia and hypoxia. During severe infection and low perfusion in tissues and organs, the release of large amounts of inflammatory mediators and cytokines can cause hepatic microangiomotor dysfunction, resulting in blood stasis, liver sinus fibrin deposition, and microvascularization, whereas low liver perfusion can cause hepatic cell ischemia and hypoxia, leading to liver damage.[16] When sepsis occurs, the liver participates in the inflammatory response through a variety of intrahepatic cells, such as Kupffer cells, hepatocytes, and sinusoidal endothelial cells. Moreover, the activation of hepatic sinusoidal endothelial cells can cause the accumulation of neutrophils and platelets, leading to the deposition of fibrin and the formation of microthrombi, thus causing or exacerbating hypoperfusion injury of the liver. The blood flow to the superior mesenteric artery and hepatic microcirculation are significantly reduced during shock. Even after fluid resuscitation, the major blood flow is significantly increased, but perfusion of the liver microvasculature only slightly increases; however, during septic shock, the organism first supplies blood to vital organs, the blood flow to the gastrointestinal tract and liver is reduced, and the blood flow to the portal vein is also reduced, causing ischemia and hypoxia in liver tissue. In general, the dual blood supply to the portal vein and hepatic artery allows the liver to maintain a relative level of tolerance to ischemic injury. However, when sepsis is accompanied by shock, the blood perfusion level of the liver tends to decrease significantly, making the liver highly susceptible to ischemic injury. Patients with sepsis suffer from tissue hypoxia, which affects blood flow and oxygen supply to the distal organs and may eventually lead to MODS.[17],[18]

Oxidative free radicals and lipid peroxidation

During sepsis, the body can produce excess reactive oxygen and reactive nitrogen species, which can lead to lipid, DNA and protein peroxidation. Patients with sepsis have significantly elevated levels of oxidative stress, as indicated by increased levels of free radicals and lipid peroxides and decreased antioxidant capacity.[18] Lipid peroxidation damages cell membranes and mitochondrial membranes, ultimately leading to cell apoptosis and necrosis.[19] Excessive reactive oxygen species (ROS) production in mitochondria mediates oxidative stress and loss of cell function and eventually leads to apoptosis or necrosis. Excessive ROS can induce lipid peroxidation and damage organelle or cell membranes so that endoenzymes (such as transaminases) can be released to the extracellular environment;[20] excessive ROS also lead to the death of intestinal epithelial cells during the progression of sepsis, exacerbating the inflammatory response and damaging the intestinal barrier.[21] Similarly, ROS can activate a variety of intracellular signaling pathways, ultimately leading to activation of the innate immune system.[22] In addition, oxidized proteins and lipids stimulate macrophages to release inflammatory factors by activating membrane receptors that activate multiple pathways. In addition to the excessive production of ROS, sepsis can lead to a decline in anti-oxidant enzyme activity in the body, resulting in a redox imbalance.

Energy metabolism disorder

The liver is affected the earliest and most severely by sepsis-induced energy metabolism disorder. Both the  Cori cycle More Details and the alanine-glucose cycle occur in the mitochondria of hepatocytes. The liver is an important energy metabolic center in the human body. In sepsis-induced organ failure, the inflammatory response and subsequent oxidative stress stimulate mitochondrial changes leading to mitochondrial dysfunction and apoptosis.[23],[24] During sepsis, the membrane integrity of liver cells is damaged by mitochondrial injury, the integrity of the respiratory chain is also damaged, and the function of related membrane proteins is reduced, which can cause dysfunctional liver energy metabolism and detoxification, leading to liver dysfunction and even liver failure.[25]

Intestinal bacteria/endotoxin translocation

The cellular targets of LPS in the liver include Kupffer cells, sinusoidal endothelial cells, stellate cells, neutrophils, and hepatocytes. Intestinal ischemia and hypoxia lead to damage to the gastrointestinal mucosa, loss of barrier function, gastrointestinal bacterial translocation, and large amounts of bacterial products and endotoxins entering the human liver through the portal vein, which is also an important factor leading to liver damage. Large doses of endotoxin disrupt the cytoskeletal structure of Kupffer cells, causing a decrease in phagocytosis and clearance by Kupffer cells, further exacerbating liver injury.[26]

Platelet activating factor

(1) Platelet activating factor (PAF) can directly lead to cell apoptosis. (2) Tissue ischemia-reperfusion can promote the release of PAF, leading to the closure of TWIK-related acid-sensitive potassium ion channels and L-type calcium ion channels, reducing calcium flow, inducing negative inotropic action, and dystonia, and ultimately leading to apoptosis. (3) Excessive release of PAF can also lead to the release of a large amount of ROS/RNS and opening of the mitochondrial permeability transition pore, which leads to the release of cytochrome C, increased calcium ions in the mitochondria, and the release of caspase, thus damaging the mitochondrial membrane and leading to cell apoptosis.

Immune disorder

The sepsis-induced immune response leads to increased morbidity and mortality.[27] The liver becomes the most active organ associated with LPS metabolism and the most common target of immune injury.[10] After infection, blood-borne LPS is released into the bloodstream in large quantities. This phenomenon can be recognized by the cell membrane receptors of neutrophils and macrophages, which stimulate downstream signals, produce a large number of inflammatory mediators, and promote immune cells to prevent inflammation, which in turn leads to serious defects related to immune cells. The literature has reported that IL-6 is an important factor involved in the response to sepsis and liver injury and is associated with multiple levels of immune cascade reactions.

Other factors

Sepsis involves the upregulated expression of cox-2, a sharp decrease in protein C, an increase in NO production, an increase in intracellular Ca2+ flux, poor infection control, improper treatment of organ dysfunction, the unreasonable use of drugs, and the synergistic effects of the previously described mechanisms. In addition, as sepsis involves other organs, it adds to the burden on the liver, creating a vicious cycle and further exacerbating liver damage.


  Clinical Manifestations of Septic Liver Injury Top


In sepsis, due to ischemia, hypoxia and the production of excessive free radicals in the body, the attack of oxygen-free radicals on the liver cell membrane leads to impairments in membrane protein functions and the destruction of both the cell and mitochondrial membrane, leading to impairments in the absorption, transportation, and secretion of bilirubin in the liver. Hepatic dysfunction during sepsis is mainly characterized by cholestasis, steatosis, hepatocyte injury, and the loss of regeneration. Patients with elevated bilirubin as their main manifestation are more likely to suffer from multi-organ dysfunction and are less likely to recover from liver function abnormalities than patients with normal bilirubin. The liver is the place where proteins, various enzymes, and bile are synthesized and secreted. Measurement of enzymes, proteins, and bilirubin synthesized by liver cells can reflect the degree of hepatocyte injury, bile metabolism, and other functions. There are indicators, including alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin, albumin, bile acid, serum prealbumin, that can reflect liver function and to some extent, damage. ALT is a protein that mainly exists in liver cells. It is present throughout the liver and has very low expression in the blood. Under normal conditions, a small amount is released into the blood, and serum ALT activity can be significantly increased. When liver cell necrosis occurs due to a variety of reasons, ALT is released into the blood in large amounts, which is highly sensitive and can serve as a marker of acute liver cell injury.[28]


  Treatment of Septic Liver Injury Top


According to the 2012 sepsis guidelines,[29] the treatment of sepsis with hepatic insufficiency should focus on eradicating the infection and treating sepsis and its complications. All patients were monitored for signs of life, such as blood pressure and blood culture-related tests. Moreover, patients were given positive fluid resuscitation, treatments against infection and shock, and treatments for liver protection, increased immunity (albumin), and the support of other symptoms. Organ support therapy, such as ventilator-assisted breathing, polymyxin-hemoperfusion,[30] and in vitro liver support, can be administered when patients develop organ failure. Patients with stable vital signs and good gastrointestinal functions are recommended to receive enteral nutrition as early as possible.[31] Furthermore, changes in patient blood glucose are closely monitored, and the patients are treated with continuous and moderate infusion of insulin in the early course of the disease. Reducing blood glucose can reduce the degree of oxidative stress and effectively reduce the incidence of cholestasis in patients with severe sepsis.[32],[33] During treatment, clinicians should also be aware of the possibility of medications causing or exacerbating liver damage.

In conclusion, the liver plays an important regulatory role in the process of sepsis and the maintenance of homeostasis. Therefore, correcting liver dysfunction and reducing liver damage is essential for improving patient prognosis and survival.[34],[35] Basic and clinical research will further explore the pathogenesis of septic liver injury to help improve the prevention and treatment of sepsis-related liver injury, thereby reducing morbidity and mortality.

Financial support and sponsorship

The National Natural Science Foundation of China (Nos. 81770276, 81772045 and 81902000), Nn10 program of Harbin Medical University Cancer Hospital and Scientific research project of Heilongjiang health and Family Planning Commission (No. 2018086).

Conflicts of interest

There are no conflicts of interest.



 
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