Introduction
Chronic hepatitis B (CHB) is a chronic disease that progresses to liver fibrosis and cirrhosis[1]. It is the leading cause of liver cirrhosis in Asian populations. Portal hypertension is the leading cause of mortality and morbidity in patients with liver cirrhosis. Portal hypertension is a condition in which the portal pressure gradient between the portal vein and the inferior vena cava exceeds 5 mmHg. The main factors that cause this pressure increase are fibrosis and regenerating nodules in the sinusoids, which cause an increase in intrahepatic vascular resistance, while the portal pressure gradient is increased by the addition of vasoconstriction resulting from sinusoidal endothelial dysfunction. The body develops collaterals to reduce the increase in portal pressure and balance it with systemic pressure. When the hepatic venous pressure gradient increases to 10 mmHg or more, varices develop in the portal and caval venous systems at the esophagogastric junction[2]. The increase in hepatic venous pressure gradient causes variceal bleeding, vasodilation in splanchnic arterioles, and a decrease in arterial blood flow in the systemic circulation, leading to systemic hypotension[2]. In contrast, renal vasoconstriction develops with the neurohumoral contribution of the renin-angiotensin-aldosterone system, causing water and sodium retention in the body[2]. As a result of this complex pathogenesis, portal hypertension can be the main trigger for the development of serious complications such as variceal bleeding, ascites, hepatic encephalopathy (HE), hepatorenal syndrome, hepato-pulmonary syndrome, porto-pulmonary syndrome, and hepatic hydrothorax, which may develop during decompensation of cirrhosis. Spontaneous or therapeutic portosystemic shunts cause toxins such as intestinal ammonia and bacterial metabolites to pass directly into the caval system without passing through the portal system, leading to HE. In the management of portal hypertension, nonselective beta-blockers are the first-line medical treatment to reduce portal pressure and its complications. A recent meta-analysis reported that in addition to propranolol, carvedilol was effective in preventing decompensation and improving survival in patients with compensated cirrhosis[3]. In select patients with liver cirrhosis who had recurrent variceal bleeding and were unresponsive to endoscopic band ligation therapy and prophylaxis, trans-jugular intrahepatic portosystemic shunt (TIPS) placement can improve control of cirrhosis complications such as variceal bleeding and ascites and also improve survival in selected patients with liver cirrhosis who failed medical therapy to reduce portal pressure[4]. The preventive TIPS (pTIPS) strategy was demonstrated in a meta-analysis conducted at the Baveno VII workshop on 1327 participants with Child-Pugh score B decompensated cirrhosis and variceal bleeding. In this meta-analysis, pTIPS was compared with medications and endoscopy, resulting in improved bleeding and ascites control and increased 1-year survival in both subgroups[5]. A recent meta-analysis of 12 trials comparing TIPS with standard care for the prevention of refractory ascites and recurrent variceal bleeding showed that TIPS reduced the incidence of further decompensation (hazard ratio: 0.44; 95%CI: 0.37–0.54) and improved survival (2-year cumulative survival probability for TIPS = 0.71 vs standard care 0.63; P = 0.0001)[6]. In this editorial, Zhao et al[7] demonstrated that changes in gut microbiota (GM) in patients with portal hypertension may influence the development of HE. This study analyzed the changes in GM composition before and after TIPS in Chinese patients with liver cirrhosis and portal hypertension secondary to the hepatitis B virus (HBV), showing that patients without HE exhibited higher GM-related synergism than those with HE. The present study highlighted the need for further discussion of our awareness that GM synergy may predict HE risk after TIPS placement.
Trans-jugular intrahepatic portocaval shunt
TIPS is recommended to reduce portal pressure and reduce the risk of rebleeding in decompensated cirrhotic patients with acute variceal bleeding that cannot be controlled by medical and endoscopic band ligation or in decompensated cirrhotic patients with successful endoscopic band ligation but with recurrent variceal bleeding at any time during hospitalization[9]. To manage complications like HE, the decision to perform TIPS should be made with a multidisciplinary approach led by a hepatologist in collaboration with interventional radiology, transplant surgery, nephrology, cardiology, chest diseases, and hematology. The importance of this multidisciplinary approach is emphasized by the protocol specified in Advancing Liver Therapeutic Approaches (ALTA). The ALTA protocol has simplified the management of patients with TIPS by simplifying the complex classification of TIPS indications, new procedural techniques, TIPS stent technology, and TIPS indications[10]. The probability of developing HE is very high in patients with spontaneous or therapeutic shunts. HE is a brain dysfunction that occurs in patients with liver cirrhosis due to severe hepatocellular insufficiency or the presence of portal-to-systemic shunts. The presence of spontaneous portal-to-systemic shunts (SPSS) may also be responsible for the chronic course of HE. Overt HE is seen in 30%-40% of patients with liver cirrhosis during the natural history of their disease[11]. However, it is difficult to estimate the true epidemiology. A total of 46%-70% of cirrhotic patients with refractory HE have SPSSs on radiological imaging. HE prevalence rates are estimated to be much higher in cirrhotic patients with TIPS and spontaneous or surgical shunts[12-14]. Although medical treatments such as lactulose, rifaximin, and L-ornithine L-aspartate are used in to treat HE, they have their own contradictory aspects. The aim is to reverse the evolving change in consciousness and to provide symptom relief rather than to provide curative treatment to the patient. Options for recurrent/persistent HE include fecal transplantation, TIPS revision, and closure of possible splenorenal shunts[10].
GM
GM has a close relationship with the brain and other systemic organs. GM and a series of metabolites affect the brain through various pathways, such as blood circulation, neuronal transmission, or neurohumoral transmission. It is critical to better understand the synergistic pathway within the gut-brain axis (GBA)[15]. In this editorial by Zhao et al[7], they analyzed the changes in GM in patients with liver cirrhosis secondary to CHB and recurrent variceal bleeding after TIPS and presented how certain bacterial species may shape the host GBA. They also aimed to estimate the contribution of the GM changes to the development of HE and evaluated the bacterial composition that may affect host immunity and nerve functions between the HE group and the non-HE group after TIPS. No significant difference was observed in GM abundance between the two groups. However, although it is not clear how bacteria, their products, or metabolites trigger HE between the two groups, the exact mechanism of action and signaling pathways could not be determined. However, the changes in GM in patients with TIPS and the pathogenic microorganisms in the HE group were reported. Haemophilus and Eggerthella abundance increased in the HE group after TIPS placement, while Anaerostipes, Dialister, Butyricicoccus, and Oscillospira decreased. Eggerthella, Streptococcus, and Bilophila abundance increased in the non-HE group, while Roseburia and Ruminococcus decreased. On the other hand, pathogenic Morganella bacteria were seen in the HE group but not in the non-HE group. In another animal experiment study, Staphylococcaceae, Enterobacteriaceae, and Lactobacillaceae abundance was present in the large intestine of HE mice, while Staphylococcaceae, Streptococcaceae, and Enterobacteriaceae species had higher abundance in the small intestine. In addition, TNF-α and IL-1β concentrations were higher in the circulation in these mice and were associated with systemic inflammation[16]. In another study, Enterobacteriaceae, Fusobacteriaceae, and Veillonellaceae were detected in cirrhotic patients with HE, while serum IL-2, IL-13, and IL-23 concentrations were higher and positively correlated[17]. These increased proinflammatory cytokines correlated with the severity of HE and were independent of the stage of liver cirrhosis and the amount of ammonia[18]. The blood-brain barrier does not allow the passage of microorganisms, metabolites, and cytokines in the circulation due to its tight junctions, but proinflammatory cytokines such as TNF-α, ILs, and interferon disrupt the expression of endothelial tight junction proteins, destroy cerebrovascular endothelial cells, activate astrocytes for the inflammatory process, and change their expression and transport pathways in the blood-brain barrier. This situation disrupts the integrity of the blood-brain barrier and further increases surface permeability. This proinflammatory signal initiated by systemic inflammation crosses the damaged blood-brain barrier and forms the basis of the neuroinflammatory response that develops in the brain[18]. Considering that innate immunity affects GBA in this way, it is necessary to consider a very complex spectrum.
Li et al[19] showed that GM abundance was changed in patients with CHB compared to patients without CHB. This showed that there is an interaction between the liver and intestine, which can affect the brain and other systems. Supported by animal and human studies, GM changes as HBV-associated liver fibrosis begins and progresses. Therefore, evaluating GM changes after TIPS may not be meaningful alone. However, since the cohort was of the same standard in the study design, it was very important to evaluate GM changes in HE after TIPS. This study showed that GM is quite important and can be affected by manipulative procedures. Zhao et al[7] reported that bypassing the portal flow in patients with therapeutic shunts is not the only factor that predisposes patients to HE and that GM may also affect HE through its metabolites and proinflammatory cytokines.
Determining whether microbiota is a suitable disease biomarker and comprehending the temporal and causal links between GM and HE development are critical. Translational methods and larger-scale clinical trials are unquestionably required to assess the effectiveness of microbial therapies in patients, such as probiotics and rifaximin therapy. It is established that the portal system raises the risk of developing HE by entering the systemic circulation right after the shunt. However, this is not seen in every shunted patient, while HE is seen in some shunted patients. The importance of GM can be better understood by early analysis and early treatment of GM. Studying the mechanisms underlying a certain immunological or neurological effect that occurs in the presence or absence of a particular bacterial species or in particular pathogenic conditions will need the use of this methodology. In this instance, the study highlights the need for further research to determine whether and how certain bacterial products or metabolites play a role in the development or maintenance of a disease. The aim of future research should be to identify the precise mechanisms behind the GM-induced pro- and anti-inflammatory responses[15]. For that reason, it will become even more crucial to understand the precise functions of specific bacterial compounds and metabolites within the central nervous system and how they enter the system.
