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Albumin in decompensated cirrhosis : Future concepts and prospects

This article discusses the latest progress in the pathogenesis of liver cirrhosis and the potential role of albumin therapy .
Zhang Chenxi Huang Yan Cao Zhujun Geng Jiawei Xie Qing 200025 Department of Infectious Disease , Ruijin Hospital , Shanghai Jiaotong University School of Medicine , China
Supported by : Shanghai Municipal Key Clinical Specialty ( Infectious Diseases ) ( shslczdzk01103 ), National Natural Science Foundation of China ( 81770587 , 82070604 , 82000588 ), Thirteen Five- Year National Science and Technology Major Project of the Ministry of Science and Technology of China ( 2017ZX10203201-008 , 2018ZX09201016-003-001 , 2017ZX10202202-005-004 )
Liver cirrhosis is characterised by long-term inflammation in the liver , extracellular matrix remodelling and persistent collagen deposition . 1 With the progression of the disease , portal venous pressure gradually increases , which manifests clinically as ascites , jaundice , coagulopathy , and oedema , etc . Acute decompensation ( AD ) refers to complications such as hepatic encephalopathy , upper gastrointestinal bleeding , hepatorenal syndrome ( HRS ) and spontaneous bacterial peritonitis , and is the main cause of hospitalisation . Liver failure and / or extrahepatic organ ( such as kidney and brain ) failure in AD patients with cirrhosis is known as acute-on-chronic liver failure ( ACLF ), which is the most common cause of death in patients with liver cirrhosis . Albumin , as a plasma volume expander , has been used for many years to improve the vascular insufficiency , prevent spontaneous peritonitis and HRS , and treat HRS concomitantly with vasoconstrictors , 2 and it is widely used for treating liver cirrhosis and its complications . This article discusses the latest progress in the pathogenesis of liver cirrhosis and the potential role of albumin therapy .
Pathogenesis of AD and ACLF Systemic inflammation The levels of inflammatory molecules such as C-reactive protein ( CRP ), proinflammatory cytokines , anti-inflammatory cytokines and chemokines , and oxidative stress in the peripheral blood during the compensatory stage , decompensated stage and ACLF gradually increase , 3 indicating that ACLF has systemic inflammatory characteristics that might be related to bacterial infection , bacterial toxins entering the blood , necrotic apoptosis of hepatocytes and inflammatory necrosis , etc . 4 The former releases pathogen-associated molecular patterns ( PAMPs ), whereas the latter triggers damage-associated molecular patterns ( DAMPs ). Both are recognised by PRRs to produce inflammatory molecules , vasodilators and reactive oxygen species to mediate systemic inflammatory responses . In this respect , ACLF has the same characteristics as sepsis .
Immunoparalysis The monocytes of patients with ACLF demonstrate the characteristics of ‘ immunoparalysis ’ when stimulated by PAMPs and inhibit the induction of inflammatory signals of immune cells mediated by lipopolysaccharide-related TLR4 and reduce inflammatory responses . 5 The frequency of myeloidderived suppressor cells ( M-MDSCs ) in ACLF increases , which leads to the inhibition of
T cell proliferation , reduced tumour necrosis factor ( TNF ) -α and interleukin ( IL ) -6 production , and the reduction of phagocytosis of E . coli . 6 In addition , HLA-DR expression on monocytes in ACLF decreases , and phagocytosis and oxidative bursts are impaired , while glutamine synthetase inhibition can improve phagocytosis and inflammatory responses . 7 In summary , the immune function of neutrophils and monocytes in ACLF is inhibited , resistance to bacteria decreases and bacterial infection is more likely to occur .
Immunopathology hypothesis and cell energy crisis hypothesis Bacterial infection in patients with sepsis results in cytokine release , which activates innate immune cells to release cytokines , proteases and reactive oxygen species to resist bacterial invasion , and excessive inflammation will cause tissue damage . 8 The systemic inflammation in AD and ACLF might cause tissue damage in a similar way , leading to organ dysfunction or organ failure , but there is not sufficient evidence to support this hypothesis . Systemic inflammation in sepsis requires nutrients and much energy to produce inflammatory factors and maintain immune activities such as respiratory bursts and cell migration . The body prioritises the immune tissues in distribution of nutrients , whereas non-immune tissues adapt to this change by reducing energy demand . 9 Enhanced proteolysis and lipolysis were demonstrated in ACLF blood compared with AD , and mitochondrial oxidase was inhibited significantly , 10 which indicated that inflammation promoted systemic consistent metabolic changes . This mechanism might play a vital role in the occurrence and development of organ failure ( Figure 1 ).
Mechanism of albumin therapy Function of albumin The main direct function of albumin is maintaining plasma colloid osmotic pressure . 11 , 12 However , in recent years , increasing attention has been paid to the multifunctional characteristics of albumin . Apart from its extensive transport function , its antioxidant activity neutralises free copper and iron to limit oxidative stress damage . The free sulfhydryl group on its Cys-34 residue has reductive activity and is a free radical scavenger of reactive oxygen species and nitrides and an important source of reducing sulfhydryl groups in the glutathione redox system in vivo . In addition , albumin , as an immune modulatory molecule , can be delivered to TLR4 by binding to proinflammatory mediators such as lipopolysaccharide to activate innate immunity
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