Liver Cirrhosis and Complications

**175**

**1. Introduction**

**Chapter 11**

**Abstract**

Spontaneous Bacterial Peritonitis:

*Rebeca Pérez-Cabeza De Vaca, Balasubramaniyan Vairappan,* 

Physiopathological Mechanism

*Tomás Cortés Espinoza, Juan Antonio Suárez Cuenca,* 

*Cuauhtemoc Licona Cassani, Brenda Maldonado Arriaga,* 

*Chrisitan Navarro Gerrard, Diana Selene Morgan Penagos,* 

Changes in intestinal permeability have been determined to influence secondary inflammatory reactions and clinical manifestations such as spontaneous bacterial peritonitis (SBP) secondary to cirrhosis. As of yet, no in-depth exploration of the changes in the microbiota and how this influences cirrhosis to differ from clinically more severe cases than others has not begun. However, at the level of pathophysiological mechanism, it must be taken into account that due to the abuse of substances such as alcohol and chronic fatty liver disease, changes in the bacterial composition and intestinal permeability are induced. This set of changes in the bacterial composition (microbiome) and modification of the intestinal permeability could be related to the presence of ascites and spontaneous peritonitis secondary to cirrhosis, being of relevance the knowledge of the mechanisms underlying this phenomenon, as well as clinical manifestation. Prophylaxis and antibiotic treatment of SBP requires clinical knowledge for the treatment decisions based mainly on the presence of ascitic fluid, accompanied of risk factors, laboratory indexes such as PMN count and culture results, in order to determine the kind of molecule that will help to the SBP recovery or to amelioration symptoms, always taking care of not exceed

*Paul Mondragón Terán and Victoria Chagoya De Sanchez*

the antibiotic consumption and restoring the microbiome imbalance.

**Keywords:** bacteria, peritonitis, microbiome, cirrhosis, gut permeability

In cirrhotic patients with ascites, spontaneous bacterial peritonitis (SBP), an ominous complication, occurs recurrently with an annual increase rate of 69% [1]. Furthermore, in cirrhosis with portal hypertension, SBP is a key hallmark feature in developing hepatic encephalopathy, variceal bleeding, hepatorenal syndrome and increased mortality [2]. Also, intestinal barrier dysfunction is pondered central in the pathogenesis of cirrhotic complications. In health, intestinal barrier function is

and Clinical Manifestations

#### **Chapter 11**

## Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations

*Rebeca Pérez-Cabeza De Vaca, Balasubramaniyan Vairappan, Tomás Cortés Espinoza, Juan Antonio Suárez Cuenca, Cuauhtemoc Licona Cassani, Brenda Maldonado Arriaga, Chrisitan Navarro Gerrard, Diana Selene Morgan Penagos, Paul Mondragón Terán and Victoria Chagoya De Sanchez*

### **Abstract**

Changes in intestinal permeability have been determined to influence secondary inflammatory reactions and clinical manifestations such as spontaneous bacterial peritonitis (SBP) secondary to cirrhosis. As of yet, no in-depth exploration of the changes in the microbiota and how this influences cirrhosis to differ from clinically more severe cases than others has not begun. However, at the level of pathophysiological mechanism, it must be taken into account that due to the abuse of substances such as alcohol and chronic fatty liver disease, changes in the bacterial composition and intestinal permeability are induced. This set of changes in the bacterial composition (microbiome) and modification of the intestinal permeability could be related to the presence of ascites and spontaneous peritonitis secondary to cirrhosis, being of relevance the knowledge of the mechanisms underlying this phenomenon, as well as clinical manifestation. Prophylaxis and antibiotic treatment of SBP requires clinical knowledge for the treatment decisions based mainly on the presence of ascitic fluid, accompanied of risk factors, laboratory indexes such as PMN count and culture results, in order to determine the kind of molecule that will help to the SBP recovery or to amelioration symptoms, always taking care of not exceed the antibiotic consumption and restoring the microbiome imbalance.

**Keywords:** bacteria, peritonitis, microbiome, cirrhosis, gut permeability

#### **1. Introduction**

In cirrhotic patients with ascites, spontaneous bacterial peritonitis (SBP), an ominous complication, occurs recurrently with an annual increase rate of 69% [1]. Furthermore, in cirrhosis with portal hypertension, SBP is a key hallmark feature in developing hepatic encephalopathy, variceal bleeding, hepatorenal syndrome and increased mortality [2]. Also, intestinal barrier dysfunction is pondered central in the pathogenesis of cirrhotic complications. In health, intestinal barrier function is

crucial against extensive and continuous exposure of the liver to the gut microbiota and their products and metabolites. Thus, gut microbiome sets the stage for the gutliver axis [3]. Nevertheless, in cirrhosis, intestinal barrier dysfunction, increased permeability and extensive inflammation occurs due to SBP. The intestinal barrier consists of several layers, including mucus layer, intestinal epithelial cells, lamina propria and Peyer's patches. They determine the extent to which gut microbes and their products (endotoxin) can access the host vasculature [4].

Therefore, the intestinal vascular barrier is considered an important layer controlling the entry of gut bacterial products into the portal circulation and liver [5]. Gut microbiota may therefore have a prime role in a pathologic loop, which regulates portal hypertension, and thus have a role in the cirrhosis development.

SBP is a frequent and severe complication in cirrhotic patients with ascites. On the other hand, cirrhotic complication initiates dysregulation of intestinal AMP and bacterial overgrowth, which triggers mucosal inflammation. The proinflammatory cytokine milieu in the intestinal lumen plays a critical role in disrupting the tight junction protein integrity, leading to BT. Bacterial endotoxin and harmful pathogenic bacterial species translocate to the liver through portal vein further exacerbate the already prevalent hepatic inflammation and fibrosis in the liver, causing a cyclic progression of liver injury. Pathogenic bacteria and endotoxins also translocate to blood causes systemic inflammatory responses induced by cytokines, chemokines and interferons resulting cytokine storm syndrome and hemodynamic abnormalities, thereby promotes liver injury followed by multiorgan failure and eventually it causes death.

#### **2. The pathophysiological mechanism involved in spontaneous bacterial peritonitis in cirrhosis: loss of permeability and gut microbiota**

Peritonitis occurs in patients with cirrhosis and ascites, in the absence of any other intra-abdominal cause of infection, such as an abscess or intestinal perforation. The spontaneous bacterial peritonitis (SBP) is defined as an infection of the ascites fluid, which produces an inflammatory reaction of the peritoneum and as previously described. It has been associated with intestinal dysbiosis, since it leads to dysfunction of the intestinal barrier that can cause bacterial translocation of very small quantities of viable or dead bacteria, constituting a physiologically important reinforcement for the immune system. Bacterial translocation is defined as the passage of bacteria or bacterial products that go from the intestine to the mesenteric lymph nodes.

#### **2.1 Bacterial translocation**

Due to the close anatomical and physiological connections between the liver and gut, barrier dysfunction results in translocation of viable bacteria and its product to the liver via the portal circulation, thereby causing liver dysfunction. Several experimental studies showed that cirrhotic patients had increased intestinal permeability which might be a critical contributing factor to cirrhosis development [6, 7]. In addition, microbial overgrowth has been observed in intrahepatic cholestatic patients [8]. Bacterial infections such as SBP and bacteraemia are associated with the four-fold increased death rate in cirrhotic patients [9]. In this context, it was observed that the presence of bacterial DNA in the blood and ascitic fluid of cirrhotic patients developed poor prognosis compared to cirrhotic patients who had negative for bacterial DNA [10]. Bacterial translocation (BT) initiates a cycle of dysfunctional immune activation, and systemic inflammatory response, facilitating

**177**

*receptor; TNF-tumor necrosis factor.*

**Figure 1.**

*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations*

the worsening of pre-existing hepatic and hemodynamic abnormalities in cirrhosis [11]. Identification of bacterial DNA has been associated with worsening of intrahepatic endothelial dysfunction and extra-hepatic (peripheral) vasodilation [12]. Further, lipopolysaccharide-binding protein (LBP) is a surrogate marker for BT, correlated with systemic hemodynamic abnormalities in cirrhotic patients [13]. Endotoxemia has been closely associated with hyperdynamic circulation, coagulopathy, portal hypertension, renal and cardiac dysfunction in cirrhosis [14]. Furthermore, systemic inflammatory response syndrome (SIRS) with bacterial infection shows an increased risk of 67% in cirrhotic patients suggesting that SIRS

Bacterial dysbiosis is characterized by the pathogenic shift in quantity or quality from the symbiotic state existing between the host and indigenous bacteria [16, 17]. A marked alteration has been observed in the small intestinal microbiota in patients with cirrhosis compared to normal individuals. A ratio of autochthonous to non-autochthonous bacterial taxa is referred to as cirrhosis dysbiosis ratio (CDR). Patients with cirrhosis were shown to exhibit a lower CDR [16]. The pathogenic shift in the proportion of bacterial taxa is also associated with decompensation of cirrhosis. The disruption of microbial balance in cirrhosis leads to accumulation of harmful bacterial metabolites that damage the intestinal epithelial barrier [16]. Gut dysbiosis also leads to intestinal immune system dysregulation by changing the composition of short-chain fatty acids produced by the microbiota [17]. This immune dysregulation with functional proinflammatory switch

*The pathophysiological mechanism associated with BT and SBP in decompensated cirrhosis. SBP is a frequent and severe complication in cirrhotic patients with ascites. On the other hand, cirrhotic complication initiates dysregulation of intestinal AMP and bacterial overgrowth, which triggers mucosal inflammation. The proinflammatory cytokine milieu in the intestinal lumen plays a critical role in disrupting the tight junction protein integrity, leading to BT. Bacterial endotoxin and harmful pathogenic bacterial species translocate to the liver through portal vein further exacerbate the already prevalent hepatic inflammation and fibrosis in the liver, causing a cyclic progression of liver injury. Pathogenic bacteria and endotoxins also translocate to blood causes systemic inflammatory responses induced by cytokines, chemokines and interferons resulting cytokine storm syndrome and hemodynamic abnormalities, thereby promotes liver injury followed by multiorgan failure and eventually it causes death. Note: AMP-anti microbial peptides; BT-bacterial translocation; IFN-Interferon; IL-interleukin; IJP-tight junction protein; SBP-spontaneous bacterial peritonitis; TLR-toll-like* 

*DOI: http://dx.doi.org/10.5772/intechopen.96910*

**2.2 Gut dysbiosis**

also contributing to cirrhosis prognosis **Figure 1** [15].

*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations DOI: http://dx.doi.org/10.5772/intechopen.96910*

the worsening of pre-existing hepatic and hemodynamic abnormalities in cirrhosis [11]. Identification of bacterial DNA has been associated with worsening of intrahepatic endothelial dysfunction and extra-hepatic (peripheral) vasodilation [12]. Further, lipopolysaccharide-binding protein (LBP) is a surrogate marker for BT, correlated with systemic hemodynamic abnormalities in cirrhotic patients [13]. Endotoxemia has been closely associated with hyperdynamic circulation, coagulopathy, portal hypertension, renal and cardiac dysfunction in cirrhosis [14]. Furthermore, systemic inflammatory response syndrome (SIRS) with bacterial infection shows an increased risk of 67% in cirrhotic patients suggesting that SIRS also contributing to cirrhosis prognosis **Figure 1** [15].

#### **2.2 Gut dysbiosis**

*Advances in Hepatology*

causes death.

lymph nodes.

**2.1 Bacterial translocation**

crucial against extensive and continuous exposure of the liver to the gut microbiota and their products and metabolites. Thus, gut microbiome sets the stage for the gutliver axis [3]. Nevertheless, in cirrhosis, intestinal barrier dysfunction, increased permeability and extensive inflammation occurs due to SBP. The intestinal barrier consists of several layers, including mucus layer, intestinal epithelial cells, lamina propria and Peyer's patches. They determine the extent to which gut microbes and

Therefore, the intestinal vascular barrier is considered an important layer controlling the entry of gut bacterial products into the portal circulation and liver [5]. Gut microbiota may therefore have a prime role in a pathologic loop, which regulates portal hypertension, and thus have a role in the cirrhosis development. SBP is a frequent and severe complication in cirrhotic patients with ascites. On the other hand, cirrhotic complication initiates dysregulation of intestinal AMP and bacterial overgrowth, which triggers mucosal inflammation. The proinflammatory cytokine milieu in the intestinal lumen plays a critical role in disrupting the tight junction protein integrity, leading to BT. Bacterial endotoxin and harmful pathogenic bacterial species translocate to the liver through portal vein further exacerbate the already prevalent hepatic inflammation and fibrosis in the liver, causing a cyclic progression of liver injury. Pathogenic bacteria and endotoxins also translocate to blood causes systemic inflammatory responses induced by cytokines, chemokines and interferons resulting cytokine storm syndrome and hemodynamic abnormalities, thereby promotes liver injury followed by multiorgan failure and eventually it

**2. The pathophysiological mechanism involved in spontaneous bacterial peritonitis in cirrhosis: loss of permeability and gut microbiota**

Peritonitis occurs in patients with cirrhosis and ascites, in the absence of any other intra-abdominal cause of infection, such as an abscess or intestinal perforation. The spontaneous bacterial peritonitis (SBP) is defined as an infection of the ascites fluid, which produces an inflammatory reaction of the peritoneum and as previously described. It has been associated with intestinal dysbiosis, since it leads to dysfunction of the intestinal barrier that can cause bacterial translocation of very small quantities of viable or dead bacteria, constituting a physiologically important reinforcement for the immune system. Bacterial translocation is defined as the passage of bacteria or bacterial products that go from the intestine to the mesenteric

Due to the close anatomical and physiological connections between the liver and gut, barrier dysfunction results in translocation of viable bacteria and its product to the liver via the portal circulation, thereby causing liver dysfunction. Several experimental studies showed that cirrhotic patients had increased intestinal permeability which might be a critical contributing factor to cirrhosis development [6, 7]. In addition, microbial overgrowth has been observed in intrahepatic cholestatic patients [8]. Bacterial infections such as SBP and bacteraemia are associated with the four-fold increased death rate in cirrhotic patients [9]. In this context, it was observed that the presence of bacterial DNA in the blood and ascitic fluid of cirrhotic patients developed poor prognosis compared to cirrhotic patients who had negative for bacterial DNA [10]. Bacterial translocation (BT) initiates a cycle of dysfunctional immune activation, and systemic inflammatory response, facilitating

their products (endotoxin) can access the host vasculature [4].

**176**

Bacterial dysbiosis is characterized by the pathogenic shift in quantity or quality from the symbiotic state existing between the host and indigenous bacteria [16, 17]. A marked alteration has been observed in the small intestinal microbiota in patients with cirrhosis compared to normal individuals. A ratio of autochthonous to non-autochthonous bacterial taxa is referred to as cirrhosis dysbiosis ratio (CDR). Patients with cirrhosis were shown to exhibit a lower CDR [16]. The pathogenic shift in the proportion of bacterial taxa is also associated with decompensation of cirrhosis. The disruption of microbial balance in cirrhosis leads to accumulation of harmful bacterial metabolites that damage the intestinal epithelial barrier [16]. Gut dysbiosis also leads to intestinal immune system dysregulation by changing the composition of short-chain fatty acids produced by the microbiota [17]. This immune dysregulation with functional proinflammatory switch

#### **Figure 1.**

*The pathophysiological mechanism associated with BT and SBP in decompensated cirrhosis. SBP is a frequent and severe complication in cirrhotic patients with ascites. On the other hand, cirrhotic complication initiates dysregulation of intestinal AMP and bacterial overgrowth, which triggers mucosal inflammation. The proinflammatory cytokine milieu in the intestinal lumen plays a critical role in disrupting the tight junction protein integrity, leading to BT. Bacterial endotoxin and harmful pathogenic bacterial species translocate to the liver through portal vein further exacerbate the already prevalent hepatic inflammation and fibrosis in the liver, causing a cyclic progression of liver injury. Pathogenic bacteria and endotoxins also translocate to blood causes systemic inflammatory responses induced by cytokines, chemokines and interferons resulting cytokine storm syndrome and hemodynamic abnormalities, thereby promotes liver injury followed by multiorgan failure and eventually it causes death. Note: AMP-anti microbial peptides; BT-bacterial translocation; IFN-Interferon; IL-interleukin; IJP-tight junction protein; SBP-spontaneous bacterial peritonitis; TLR-toll-like receptor; TNF-tumor necrosis factor.*

contributes to mucosal barrier dysfunction and BT [17] and thus, bile acids (BA) derangement, which plays a causal role in the gut dysbiosis.

In cirrhotic patients, intraluminal BA reduction was shown to increase deconjugation by enteric bacteria [18]. Moreover, defect in intestinal BA concentration accelerates BT and develops susceptibility to bacterial endotoxin [19]. Intestinal dysmotility is another important contributor to the development of SBP in cirrhotic patients [20].

#### **2.3 Tight junctions and intestinal permeability**

Increased intestinal permeability exerts a pivotal role in the pathogenesis of SBP in cirrhosis following elevated systemic endotoxemia. Moreover, a significant association was found between elevated portal pressure and gastro-duodenal and intestinal permeability in cirrhosis [21]. Specific ultrastructural and functional alterations in the intestinal mucosa have been identified in cirrhosis patients associated with increased intestinal permeability to BT [22]. The intestinal barrier comprises tight junction (TJ) proteins that allow specific passage of gut bacterial products and metabolites, thus maintaining intestinal structural integrity and regulating intestinal permeability following SBP [23]. Zona occludens (ZO-1), occludin and claudins are the major integral transmembrane proteins composed of TJ and maintaining the intestinal permeability [24]. The TJ proteins expression and turnover are predisposed by oxidative stress and inflammation following SBP in cirrhosis, consequently, disruption of the intestinal barrier allows bacterial endotoxin from the intestinal lumen to pass into the portal circulation and thus reaches the liver culminating hepatic complications (**Figure 1**). Significant alterations in occludin were observed in intestine of both compensated decompensated cirrhotic patients compared to healthy subjects [6, 7]. Notably, the reduction in intestinal occludin expression was associated with elevated endotoxins levels and severe variceal bleeding [6]. We found significantly decreased hepatic ZO 1 levels in patients with cirrhosis and HCC [25]. Furthermore, our rodent experimental data show evidence that in cirrhosis and HCC, diminished hepatic expression of ZO-1 and occludin was correlated with BT [25, 26].

#### **2.4 Small intestinal bacterial overgrowth (SIBO)**

Small intestinal bacterial overgrowth (SIBO) induced by prolonged gastric and small intestinal transit of bacterial products and metabolites. It is a condition in which colonic bacterial translocate into the small intestine [27]. The process of bacterial dysbiosis, coupled with SIBO, is well documented in cirrhosis [16, 28]. Increased proportion of the gram-negative Bacteroides species and the grampositive *Enterococcus spp.* were identified in the small intestine of patients with alcoholic liver disease [28]. SIBO is also accompanied by a decrease in *Lactobacillus spp.*, which is regarded as beneficial to the host [29]. SIBO coupled with bacterial dysbiosis (**Figure 1**) leads to accumulation of bacterial endotoxins such as LPS, an specific PAMP (Pathogen Associated Molecular Patterns), which in turn results in the induction of inflammatory response culminating in intestinal epithelial damage and gut permeability [30] this mechanism will be explained deeply ahead in this chapter. Cirrhotic patients who use proton pump inhibitors are vulnerable to SBP, due to intestinal overgrowth of *Enterococcus spp*. [31, 32]. Antimicrobial peptides (AMP) are considered the first line of defence to counter bacterial overgrowth and maintain bacterial symbiosis, which are primarily produced by paneth cells and intestinal epithelial cells [33]. Decreased AMP was pronounced in the ileum, which was associated with increased BT in cirrhosis [34]. Also, human and experimental

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*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations*

ALD attributed to decreased AMP expression [33, 35]. Regenerating family member 3 alpha [Reg3A] belongs to the C-type lectin family is one of the important AMP in regulating intestinal inflammation [36] and facilitating the repair of gut mucosa in rodent models. Moreover, our recent study shows that Reg3A protein expression was significantly reduced in cirrhotic mice small intestine [37]. We also found significantly decreased Lactobacillus and increased *Bacteroides* and *Enterococcus* 16 s rRNA levels in the liver and small intestine of cirrhotic mice [37]. This reduced intestinal Reg3A expression was associated with an increased E*nterococcus* translocation to rodent cirrhotic liver. Similarly, Darnaud et al., observed that Reg3A overexpression in colitis mice attenuated intestinal inflammation and restricted BT [36]. Moreover, Reg3A expression protected against dextran sulphate sodium (DSS)-induced intestinal inflammation, intestinal permeability and BT in mice [36]. In addition, intestinal Reg3A has been reported to promote the enrichments of *Lactobacilli sp* [38] and depletion of *Bacteroidetes* population [36], indicating Reg3A could be a critical factor in restricting BT by averting bacterial dysbiosis. Cathelin-related antimicrobial peptide (CRAMP) is an AMP produced by intestinal epithelial cells exhibits potent antibiotic activity against various strains of gramnegative bacteria [39]. Deficiency of CRAMP expression correlated with impaired microbial clearance and elevated proinflammatory cytokine response in glial cells exposed to bacterial endotoxins [40]. We found CRAMP cellular expression in the small intestine of cirrhotic mice albeit, no significant difference between control

Inflammation and oxidative stress are other key players contributing to mucosal damage and cirrhosis progression by triggering cytokine productions. Activation of Kupffer cells and the recruitment of proinflammatory monocyte subsets could propagate both intra-hepatic and extra-hepatic (systemic) inflammation [41, 42]. Of note, the cirrhotic patients with bacterial infections exhibited elevated systemic levels of inflammatory and pyrogenic cytokines IL-6 and TNF-α compared to septicemia patients without cirrhosis [43]. IL-6 levels in cirrhotic patients correlated with immune cell activation, organ failure, and portal hypertension [14, 44]. Moreover, soluble TNF-α receptor levels in hepatic venous and portal venous blood correlated with endotoxin concentration as well as hemodynamic derangements in cirrhosis [45]. Hence endotoxin-induced proinflammatory cytokines serve as important mediators of SIRS induced-hemodynamic abnormalities in cirrhosis. In this context, our experimental data show evidence that significantly elevated ascitic fluid cytokine concentrations in cirrhotic mice [37]. Gastrointestinal tract inflammation was contemplated as a major mediator of TJ disruption. Decreased TJ proteins ZO-1 and occludin were reported in gastric carcinoma with inflammation [46]. In cirrhosis with SBP, intestinal barrier disruption has been precipitated by inflammation [26]. Proinflammatory cytokines such as TNF alpha, IL-I beta and IFN gamma trigger barrier damage on the gut epithelium by inducing endocytosis of TJ proteins and increased expression of myosin light chain kinase protein, thereby causing TJ permeability [17, 26]. Intestinal mucosa covered by the mucus layer provides a first line of defence mechanism against harmful bacteria and endotoxin from invading the microvillus environment [30]. Inflammatory mediators, LPS and growth factors affect the secretion of mucin, which is present in the mucus layer. In particular, nuclear factor-κB [NF-κB] binds with the specific site of the promoter region of mucin and affect its secretion [47]. Therefore, modulation of bacterial adherence to the gut mucosal surface by intestinal mucus results in loss of gut barrier function [48]. In this context, a previous experimental study

*DOI: http://dx.doi.org/10.5772/intechopen.96910*

and cirrhotic mice [37].

**2.5 Inflammation in spontaneous bacterial peritonitis**

*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations DOI: http://dx.doi.org/10.5772/intechopen.96910*

ALD attributed to decreased AMP expression [33, 35]. Regenerating family member 3 alpha [Reg3A] belongs to the C-type lectin family is one of the important AMP in regulating intestinal inflammation [36] and facilitating the repair of gut mucosa in rodent models. Moreover, our recent study shows that Reg3A protein expression was significantly reduced in cirrhotic mice small intestine [37]. We also found significantly decreased Lactobacillus and increased *Bacteroides* and *Enterococcus* 16 s rRNA levels in the liver and small intestine of cirrhotic mice [37]. This reduced intestinal Reg3A expression was associated with an increased E*nterococcus* translocation to rodent cirrhotic liver. Similarly, Darnaud et al., observed that Reg3A overexpression in colitis mice attenuated intestinal inflammation and restricted BT [36]. Moreover, Reg3A expression protected against dextran sulphate sodium (DSS)-induced intestinal inflammation, intestinal permeability and BT in mice [36]. In addition, intestinal Reg3A has been reported to promote the enrichments of *Lactobacilli sp* [38] and depletion of *Bacteroidetes* population [36], indicating Reg3A could be a critical factor in restricting BT by averting bacterial dysbiosis. Cathelin-related antimicrobial peptide (CRAMP) is an AMP produced by intestinal epithelial cells exhibits potent antibiotic activity against various strains of gramnegative bacteria [39]. Deficiency of CRAMP expression correlated with impaired microbial clearance and elevated proinflammatory cytokine response in glial cells exposed to bacterial endotoxins [40]. We found CRAMP cellular expression in the small intestine of cirrhotic mice albeit, no significant difference between control and cirrhotic mice [37].

#### **2.5 Inflammation in spontaneous bacterial peritonitis**

Inflammation and oxidative stress are other key players contributing to mucosal damage and cirrhosis progression by triggering cytokine productions. Activation of Kupffer cells and the recruitment of proinflammatory monocyte subsets could propagate both intra-hepatic and extra-hepatic (systemic) inflammation [41, 42]. Of note, the cirrhotic patients with bacterial infections exhibited elevated systemic levels of inflammatory and pyrogenic cytokines IL-6 and TNF-α compared to septicemia patients without cirrhosis [43]. IL-6 levels in cirrhotic patients correlated with immune cell activation, organ failure, and portal hypertension [14, 44]. Moreover, soluble TNF-α receptor levels in hepatic venous and portal venous blood correlated with endotoxin concentration as well as hemodynamic derangements in cirrhosis [45]. Hence endotoxin-induced proinflammatory cytokines serve as important mediators of SIRS induced-hemodynamic abnormalities in cirrhosis. In this context, our experimental data show evidence that significantly elevated ascitic fluid cytokine concentrations in cirrhotic mice [37]. Gastrointestinal tract inflammation was contemplated as a major mediator of TJ disruption. Decreased TJ proteins ZO-1 and occludin were reported in gastric carcinoma with inflammation [46]. In cirrhosis with SBP, intestinal barrier disruption has been precipitated by inflammation [26]. Proinflammatory cytokines such as TNF alpha, IL-I beta and IFN gamma trigger barrier damage on the gut epithelium by inducing endocytosis of TJ proteins and increased expression of myosin light chain kinase protein, thereby causing TJ permeability [17, 26]. Intestinal mucosa covered by the mucus layer provides a first line of defence mechanism against harmful bacteria and endotoxin from invading the microvillus environment [30]. Inflammatory mediators, LPS and growth factors affect the secretion of mucin, which is present in the mucus layer. In particular, nuclear factor-κB [NF-κB] binds with the specific site of the promoter region of mucin and affect its secretion [47]. Therefore, modulation of bacterial adherence to the gut mucosal surface by intestinal mucus results in loss of gut barrier function [48]. In this context, a previous experimental study

*Advances in Hepatology*

patients [20].

contributes to mucosal barrier dysfunction and BT [17] and thus, bile acids (BA)

In cirrhotic patients, intraluminal BA reduction was shown to increase deconjugation by enteric bacteria [18]. Moreover, defect in intestinal BA concentration accelerates BT and develops susceptibility to bacterial endotoxin [19]. Intestinal dysmotility is another important contributor to the development of SBP in cirrhotic

Increased intestinal permeability exerts a pivotal role in the pathogenesis of SBP in cirrhosis following elevated systemic endotoxemia. Moreover, a significant association was found between elevated portal pressure and gastro-duodenal and intestinal permeability in cirrhosis [21]. Specific ultrastructural and functional alterations in the intestinal mucosa have been identified in cirrhosis patients associated with increased intestinal permeability to BT [22]. The intestinal barrier comprises tight junction (TJ) proteins that allow specific passage of gut bacterial products and metabolites, thus maintaining intestinal structural integrity and regulating intestinal permeability following SBP [23]. Zona occludens (ZO-1), occludin and claudins are the major integral transmembrane proteins composed of TJ and maintaining the intestinal permeability [24]. The TJ proteins expression and turnover are predisposed by oxidative stress and inflammation following SBP in cirrhosis, consequently, disruption of the intestinal barrier allows bacterial endotoxin from the intestinal lumen to pass into the portal circulation and thus reaches the liver culminating hepatic complications (**Figure 1**). Significant alterations in occludin were observed in intestine of both compensated decompensated cirrhotic patients compared to healthy subjects [6, 7]. Notably, the reduction in intestinal occludin expression was associated with elevated endotoxins levels and severe variceal bleeding [6]. We found significantly decreased hepatic ZO 1 levels in patients with cirrhosis and HCC [25]. Furthermore, our rodent experimental data show evidence that in cirrhosis and HCC, diminished hepatic expression of ZO-1

Small intestinal bacterial overgrowth (SIBO) induced by prolonged gastric and small intestinal transit of bacterial products and metabolites. It is a condition in which colonic bacterial translocate into the small intestine [27]. The process of bacterial dysbiosis, coupled with SIBO, is well documented in cirrhosis [16, 28]. Increased proportion of the gram-negative Bacteroides species and the grampositive *Enterococcus spp.* were identified in the small intestine of patients with alcoholic liver disease [28]. SIBO is also accompanied by a decrease in *Lactobacillus spp.*, which is regarded as beneficial to the host [29]. SIBO coupled with bacterial dysbiosis (**Figure 1**) leads to accumulation of bacterial endotoxins such as LPS, an specific PAMP (Pathogen Associated Molecular Patterns), which in turn results in the induction of inflammatory response culminating in intestinal epithelial damage and gut permeability [30] this mechanism will be explained deeply ahead in this chapter. Cirrhotic patients who use proton pump inhibitors are vulnerable to SBP, due to intestinal overgrowth of *Enterococcus spp*. [31, 32]. Antimicrobial peptides (AMP) are considered the first line of defence to counter bacterial overgrowth and maintain bacterial symbiosis, which are primarily produced by paneth cells and intestinal epithelial cells [33]. Decreased AMP was pronounced in the ileum, which was associated with increased BT in cirrhosis [34]. Also, human and experimental

derangement, which plays a causal role in the gut dysbiosis.

**2.3 Tight junctions and intestinal permeability**

and occludin was correlated with BT [25, 26].

**2.4 Small intestinal bacterial overgrowth (SIBO)**

**178**

#### *Advances in Hepatology*

shows evidence in cirrhotic rats ileum that increased mucin 2&3 mRNA expression compared to control [49]. Moreover, increased mucus content in the small intestine was found following chronic alcohol supplementation to rats [30].

In cirrhosis, SBP is a major precipitating factor initiates gut-liver axis dysfunction. It is mainly due to the fact that intestinal microbiota dysbiosis, bacterial overgrowth and bacterial translocation [4], which originates intestinal mucosal dysfunction and damage at the systemic immune cell functions [50]. Moreover, inflammation and oxidative stress are other contributing factors that can influence the barrier function of both the small and the large intestine and probably result in the occurrence of SBP in cirrhosis.

#### **2.6 Microbiota in spontaneous bacterial peritonitis consequence**

The gut microbiota plays a key role in spontaneous bacterial peritonitis due to intestinal dysbiosis and bacterial translocation. A study conducted by Lachar & Bajaj, 2016, demonstrated that patients with spontaneous bacterial peritonitis presented intestinal dysbiosis, and thus concluded that it can be a useful quantitative index to describe the microbiome alterations that accompany the progression and complications of cirrhosis [51].

The term microbiota refers to the community of living microorganisms that reside in a specific ecological niche. In the gastrointestinal tract, the microbiota is a dynamic system that maintains a symbiotic relationship with the intestinal mucosa. This relationship imparts metabolic, protective and immune functions that contribute to the well-being of the host, which are modified by environmental factors. Additionally, it participates in metabolic processes that connect the intestine with liver, muscle and brain [52, 53]. The eubiosis microbiota comprises a balance between symbiotic microorganisms [bacteria with homeostasis-promoting functions] and pathobionts [commensal bacteria with the ability to induce pathology]. However, the dysregulation of this balance can determine a state of dysbiosis [54] (**Figure 2A**). Therefore, alterations in the intestinal microbiota are important in the pathogenesis of several complications that arise in liver disease, such as spontaneous bacterial peritonitis. This is usually caused by the presence of one or more species of aerobic and anaerobic enteric bacteria that act in synergy [55–59] (**Figure 2B**).

The most common microorganisms associated with this disorder are Gramnegative bacteria, such as *Escherichia coli* and *Klebsiella* species, and infections by Gram-positive bacteria such as *Staphylococcus*. Gram negative bacilli, especially *Escherichia coli*, which are found in low concentrations in the small intestine of healthy subjects, these are increased as jejunal microbiota in many cirrhotic patients, especially in those patients with more advanced cirrhosis and a greater decrease in the intestinal motility. *Escherichia coli* is known to be the main cause of SBP and is more frequently isolated in ascites fluid, in previous studies it has been described that the isolation rate is 66.6%. An increase in endotoxin levels in patients with advanced cirrhosis has been shown to promote the production of multiple pro-inflammatory elements, so the activation of this cytokine cascade in spontaneous bacterial peritonitis has been associated with greater complications leading to death [60–62].

In recent years the prevalence of Gram-positive bacteria in SBP has increased. In addition, there is a growing resistance to multiple drugs such as quinolones, which is of particular importance since norfloxacin represents the antimicrobial of choice for SBP. But this has changed dramatically, as multidrug resistant organisms (MDRO) have been described [63]. A study carried out by Mücke *et al.*

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prophylaxis [64].

**Figure 2.**

**diagnostic**

*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations*

demonstrated that the presence of MDRO and quinolone-resistant Gram-

*The role of the gut microbiota in spontaneous bacterial peritonitis. (A) Ecology of the gut microbiota. Ecological community in balance of symbiotic microorganisms (anti-inflammatory species) and pathobionts (pro-inflammatory species) that share a certain niche and are considered an important factor in health or disease. (B) Bacterial translocation in spontaneous bacterial peritonitis. From the intestinal lumen, in a state of dysbiosis, bacteria (gram-negative bacilli of enteric origin and to a lesser extent gram-positive) cross the intestinal barrier and infect the mesenteric lymph nodes, a process known as bacterial translocation, and from there they reach the blood circulation through of the lymphatic pathway leading to the hepatosplenic and systemic circulation. Which leads to the development of an inflammatory reaction in the mesenteric lymph nodes themselves with the release of pro-inflammatory cytokines. TRL-4 is responsible for the production of* 

**3. Clinical manifestations of spontaneous bacterial peritonitis and** 

Patients with liver cirrhosis (LC) and ascites are at a high risk of developing bacterial infections, spontaneous bacterial peritonitis [SBP] can be a life-threatening infection in these patients [69]. The diagnosis of SBP is based on the patient's signs and symptoms, in addition to the findings at diagnostic paracentesis in a patient with ascites fluid. The patient with peritonitis may have symptoms such as abdominal pain, nausea, vomiting, diarrhea and signs of a systemic inflammatory response (hyper or hypothermia, chills, altered white blood cell count, tachycardia, and/or

lance for the use of the correct use of antimicrobials.

*TNF-*α *in response to endotoxin, while Th1 cells release interferon* γ*.*

negative bacteria (QR-GNB) has been associated with the failure of antimicrobial

There is great concern worldwide about the increase in antimicrobial resistance, which has now been associated with SBP. Appropriate antimicrobial therapy should be administered as soon as possible, as inappropriate administration increases hospital mortality. Unfortunately, it has been reported that treatment protocols still support the use of third-generation cephalosporins as a first line of therapy [65–67]. In a meta-analysis carried out by Iogna *et al.*, showed that there is significant uncertainty about the choice of antimicrobial therapy that is best in people with SBP. It is important to highlight that the short-term mortality from spontaneous bacterial peritonitis (SBP) is high, approximately 25% [68]. Therefore, having the result of the culture, and an antimicrobial regimen with a narrower spectrum should be started. Based on these findings, it is essential to perform a microbiological surveil-

*DOI: http://dx.doi.org/10.5772/intechopen.96910*

*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations DOI: http://dx.doi.org/10.5772/intechopen.96910*

#### **Figure 2.**

*Advances in Hepatology*

the occurrence of SBP in cirrhosis.

and complications of cirrhosis [51].

shows evidence in cirrhotic rats ileum that increased mucin 2&3 mRNA expression compared to control [49]. Moreover, increased mucus content in the small intestine

In cirrhosis, SBP is a major precipitating factor initiates gut-liver axis dysfunc-

The gut microbiota plays a key role in spontaneous bacterial peritonitis due to intestinal dysbiosis and bacterial translocation. A study conducted by Lachar & Bajaj, 2016, demonstrated that patients with spontaneous bacterial peritonitis presented intestinal dysbiosis, and thus concluded that it can be a useful quantitative index to describe the microbiome alterations that accompany the progression

The term microbiota refers to the community of living microorganisms that reside in a specific ecological niche. In the gastrointestinal tract, the microbiota is a dynamic system that maintains a symbiotic relationship with the intestinal mucosa. This relationship imparts metabolic, protective and immune functions that contribute to the well-being of the host, which are modified by environmental factors. Additionally, it participates in metabolic processes that connect the intestine with liver, muscle and brain [52, 53]. The eubiosis microbiota comprises a balance between symbiotic microorganisms [bacteria with homeostasis-promoting functions] and pathobionts [commensal bacteria with the ability to induce pathology]. However, the dysregulation of this balance can determine a state of dysbiosis [54] (**Figure 2A**). Therefore, alterations in the intestinal microbiota are important in the pathogenesis of several complications that arise in liver disease, such as spontaneous bacterial peritonitis. This is usually caused by the presence of one or more species of aerobic and anaerobic enteric bacteria that act in synergy [55–59]

The most common microorganisms associated with this disorder are Gramnegative bacteria, such as *Escherichia coli* and *Klebsiella* species, and infections by Gram-positive bacteria such as *Staphylococcus*. Gram negative bacilli, especially *Escherichia coli*, which are found in low concentrations in the small intestine of healthy subjects, these are increased as jejunal microbiota in many cirrhotic patients, especially in those patients with more advanced cirrhosis and a greater decrease in the intestinal motility. *Escherichia coli* is known to be the main cause of SBP and is more frequently isolated in ascites fluid, in previous studies it has been described that the isolation rate is 66.6%. An increase in endotoxin levels in patients with advanced cirrhosis has been shown to promote the production of multiple pro-inflammatory elements, so the activation of this cytokine cascade in spontaneous bacterial peritonitis has been associated with greater complications

In recent years the prevalence of Gram-positive bacteria in SBP has increased. In addition, there is a growing resistance to multiple drugs such as quinolones, which is of particular importance since norfloxacin represents the antimicrobial of choice for SBP. But this has changed dramatically, as multidrug resistant organisms (MDRO) have been described [63]. A study carried out by Mücke *et al.*

tion. It is mainly due to the fact that intestinal microbiota dysbiosis, bacterial overgrowth and bacterial translocation [4], which originates intestinal mucosal dysfunction and damage at the systemic immune cell functions [50]. Moreover, inflammation and oxidative stress are other contributing factors that can influence the barrier function of both the small and the large intestine and probably result in

was found following chronic alcohol supplementation to rats [30].

**2.6 Microbiota in spontaneous bacterial peritonitis consequence**

**180**

(**Figure 2B**).

leading to death [60–62].

*The role of the gut microbiota in spontaneous bacterial peritonitis. (A) Ecology of the gut microbiota. Ecological community in balance of symbiotic microorganisms (anti-inflammatory species) and pathobionts (pro-inflammatory species) that share a certain niche and are considered an important factor in health or disease. (B) Bacterial translocation in spontaneous bacterial peritonitis. From the intestinal lumen, in a state of dysbiosis, bacteria (gram-negative bacilli of enteric origin and to a lesser extent gram-positive) cross the intestinal barrier and infect the mesenteric lymph nodes, a process known as bacterial translocation, and from there they reach the blood circulation through of the lymphatic pathway leading to the hepatosplenic and systemic circulation. Which leads to the development of an inflammatory reaction in the mesenteric lymph nodes themselves with the release of pro-inflammatory cytokines. TRL-4 is responsible for the production of TNF-*α *in response to endotoxin, while Th1 cells release interferon* γ*.*

demonstrated that the presence of MDRO and quinolone-resistant Gramnegative bacteria (QR-GNB) has been associated with the failure of antimicrobial prophylaxis [64].

There is great concern worldwide about the increase in antimicrobial resistance, which has now been associated with SBP. Appropriate antimicrobial therapy should be administered as soon as possible, as inappropriate administration increases hospital mortality. Unfortunately, it has been reported that treatment protocols still support the use of third-generation cephalosporins as a first line of therapy [65–67]. In a meta-analysis carried out by Iogna *et al.*, showed that there is significant uncertainty about the choice of antimicrobial therapy that is best in people with SBP. It is important to highlight that the short-term mortality from spontaneous bacterial peritonitis (SBP) is high, approximately 25% [68]. Therefore, having the result of the culture, and an antimicrobial regimen with a narrower spectrum should be started. Based on these findings, it is essential to perform a microbiological surveillance for the use of the correct use of antimicrobials.

#### **3. Clinical manifestations of spontaneous bacterial peritonitis and diagnostic**

Patients with liver cirrhosis (LC) and ascites are at a high risk of developing bacterial infections, spontaneous bacterial peritonitis [SBP] can be a life-threatening infection in these patients [69]. The diagnosis of SBP is based on the patient's signs and symptoms, in addition to the findings at diagnostic paracentesis in a patient with ascites fluid. The patient with peritonitis may have symptoms such as abdominal pain, nausea, vomiting, diarrhea and signs of a systemic inflammatory response (hyper or hypothermia, chills, altered white blood cell count, tachycardia, and/or

tachypnea), also presenting with worsening of liver function, hepatic encephalopathy, shock, kidney failure and gastrointestinal bleeding. However, it is important to note that SBP can be asymptomatic particularly in outpatients [70].

Diagnostic paracentesis should be performed in all patients who present symptoms is extremely important, as the PMN count in the ascitic fluid plays an essential role in obtaining a diagnosis of SBP [71]. However, clinical signs and symptoms are occasionally absent in patients with SBP [72]. The diagnosis of SBP is confirmed based on a PMN count of >250 cells/mm3 in the ascitic fluid cell analysis (**Figure 3**). The cutoff value of 250 PMN cells/mm3 has the greatest sensitivity, whereas 500 PMN cells/mm3 exhibits the greatest specificity [73].

The gold standard for ascitic neutrophil count is manual microscopy, but it is labor intensive and associated with interobserver variability, time and costs. In most places this has been substituted with automated counts based on flow cytometry for counting and differentiating cells. This technique has been documented to have high linearity with manual microscopy and thus sensitivity and specificity close to 100% [74].

#### **3.1 Clinical manifestations of spontaneous bacterial peritonitis.**

For Spontaneous bacterial peritonitis (SBP) the diagnosis is established based on positive ascitic fluid bacterial cultures and the detection of an elevated absolute fluid polymorphonuclear neutrophil (PMN) count in the ascites (>250/mm3 ) without an evident intra-abdominal surgically treatable source of infection (**Figure 3**). In addition, ascitic fluid cultures are negative in approximately 10–60% of patients with clinical manifestations of SBP [75].

The Secondary Bacterial Peritonitis, that differs of Spontaneous bacterial peritonitis (SBP) consists of ascitic fluid infection due to intraabdominal infections, for example, perforation of gastrointestinal tract or abscess. It is much less frequent, but has still high mortality rate compared with SBP in patients with LC [76].

#### **Figure 3.**

*Recommended empirical antibiotic treatment for SBP. Community-acquired agents are treated with 3rd generation Cephalosporins, Amoxicilin/Clavulanic acid, Ciprofloxacin, Ofloxacin or Piperacilin/Tazobactam. Health care associated and nosocomial agents are treated with Piperacilin/Tazobactam or a Carbapenem antibiotic. For profilaxis of SPB, Norfloxacin is the agent of choice. (Figure adapted from [66]). \*In case of multidrug resistant organism.*

**183**

**Figure 4.**

*ascites (>250/mm3*

*PD catheter during exchanges.*

*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations*

Non-neutrocytic bacterial ascites or Bacterascites: is an ascitic fluid polymorphonuclear -neutrophil (PMN) count below 250/μL and a positive ascitic fluid culture results in the absence of an evident intra-abdominal, surgically treatable source of infection. It is a different clinical entity than spontaneous bacterial peritonitis (SBP), which is characterized by a neutrophil reaction in ascites regardless of the bacterial culture result. Bacterascites is prevalent in 8–11% of all patients with cirrhosis and ascites, and the clinical significance seems to vary according to how

Even though the spectrum of this chapter does not contemplate treatment modalities we thought it best to give an updated brief view of the treatment involved in SBP in an easy diagram (**Figure 4**). First step is to acknowledge and apply the indication of a paracentesis, which are the following according to multiple clinical practice guidelines: All patients with new onset grade 2 or 3 of ascites, in those hospitalized for worsening of ascites or any complication of cirrhosis. Other indications are new onset of ascites, any patient admitted to the hospital with preexisting ascites, regardless of the reason for admission and ascites who has signs of clinical deterioration [78]. Once the diagnosis of SBP is made the treatment modalities must be applied as soon as possible (**Figure 4**). These empiric treatment schemes should also be administered if the patient has a diagnosis of culturenegative neutrocyte ascites and monomicrobial non-neutrocytic bacterial ascites or bacterial ascites. Particularly the treatment decision differs from the community acquired SBP from the nosocomial one, considering the risk factors, other comorbidities treatment and the previous use of antibiotic (3 months at least) to prescribe the specific drug, because the microbiome involucrate in each case requires a different antibiotic. For example, the use of 3rd. generation cephalosporines in community acquired SBP, not such as the treatment suggested in the nosocomial acquired

*DOI: http://dx.doi.org/10.5772/intechopen.96910*

the infection was acquired [77].

**3.2 Treatment of spontaneous bacterial peritonitis**

SPB that the carbapenem is indicated as first therapeutic option.

*Diagnostic algorithm of SBP. The diagnosis of SBP is established based on positive ascitic fluid bacterial cultures and the detection of an elevated absolute fluid polymorphonuclear neutrophil (PMN) count in the* 

*peritonitis associated with peritoneal dialysis, where bacteria can enter the body through the open ends of the* 

*) without an evident intra-abdominal surgically treatable source of infection, except in* 

*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations DOI: http://dx.doi.org/10.5772/intechopen.96910*

Non-neutrocytic bacterial ascites or Bacterascites: is an ascitic fluid polymorphonuclear -neutrophil (PMN) count below 250/μL and a positive ascitic fluid culture results in the absence of an evident intra-abdominal, surgically treatable source of infection. It is a different clinical entity than spontaneous bacterial peritonitis (SBP), which is characterized by a neutrophil reaction in ascites regardless of the bacterial culture result. Bacterascites is prevalent in 8–11% of all patients with cirrhosis and ascites, and the clinical significance seems to vary according to how the infection was acquired [77].

#### **3.2 Treatment of spontaneous bacterial peritonitis**

Even though the spectrum of this chapter does not contemplate treatment modalities we thought it best to give an updated brief view of the treatment involved in SBP in an easy diagram (**Figure 4**). First step is to acknowledge and apply the indication of a paracentesis, which are the following according to multiple clinical practice guidelines: All patients with new onset grade 2 or 3 of ascites, in those hospitalized for worsening of ascites or any complication of cirrhosis. Other indications are new onset of ascites, any patient admitted to the hospital with preexisting ascites, regardless of the reason for admission and ascites who has signs of clinical deterioration [78]. Once the diagnosis of SBP is made the treatment modalities must be applied as soon as possible (**Figure 4**). These empiric treatment schemes should also be administered if the patient has a diagnosis of culturenegative neutrocyte ascites and monomicrobial non-neutrocytic bacterial ascites or bacterial ascites. Particularly the treatment decision differs from the community acquired SBP from the nosocomial one, considering the risk factors, other comorbidities treatment and the previous use of antibiotic (3 months at least) to prescribe the specific drug, because the microbiome involucrate in each case requires a different antibiotic. For example, the use of 3rd. generation cephalosporines in community acquired SBP, not such as the treatment suggested in the nosocomial acquired SPB that the carbapenem is indicated as first therapeutic option.

#### **Figure 4.**

*Advances in Hepatology*

specificity close to 100% [74].

with clinical manifestations of SBP [75].

tachypnea), also presenting with worsening of liver function, hepatic encephalopathy, shock, kidney failure and gastrointestinal bleeding. However, it is important to

Diagnostic paracentesis should be performed in all patients who present symptoms is extremely important, as the PMN count in the ascitic fluid plays an essential role in obtaining a diagnosis of SBP [71]. However, clinical signs and symptoms are occasionally absent in patients with SBP [72]. The diagnosis of SBP is confirmed based on a PMN count of >250 cells/mm3 in the ascitic fluid cell analysis (**Figure 3**). The cutoff value of 250 PMN cells/mm3 has the greatest sensitivity, whereas 500 PMN cells/mm3 exhibits the greatest specificity [73]. The gold standard for ascitic neutrophil count is manual microscopy, but it is labor intensive and associated with interobserver variability, time and costs. In most places this has been substituted with automated counts based on flow cytometry for counting and differentiating cells. This technique has been documented to have high linearity with manual microscopy and thus sensitivity and

note that SBP can be asymptomatic particularly in outpatients [70].

**3.1 Clinical manifestations of spontaneous bacterial peritonitis.**

For Spontaneous bacterial peritonitis (SBP) the diagnosis is established based on positive ascitic fluid bacterial cultures and the detection of an elevated absolute fluid polymorphonuclear neutrophil (PMN) count in the ascites (>250/mm3

out an evident intra-abdominal surgically treatable source of infection (**Figure 3**). In addition, ascitic fluid cultures are negative in approximately 10–60% of patients

The Secondary Bacterial Peritonitis, that differs of Spontaneous bacterial peritonitis (SBP) consists of ascitic fluid infection due to intraabdominal infections, for example, perforation of gastrointestinal tract or abscess. It is much less frequent,

but has still high mortality rate compared with SBP in patients with LC [76].

*Recommended empirical antibiotic treatment for SBP. Community-acquired agents are treated with 3rd generation Cephalosporins, Amoxicilin/Clavulanic acid, Ciprofloxacin, Ofloxacin or Piperacilin/Tazobactam. Health care associated and nosocomial agents are treated with Piperacilin/Tazobactam or a Carbapenem antibiotic. For profilaxis of SPB, Norfloxacin is the agent of choice. (Figure adapted from [66]). \*In case of* 

) with-

**182**

**Figure 3.**

*multidrug resistant organism.*

*Diagnostic algorithm of SBP. The diagnosis of SBP is established based on positive ascitic fluid bacterial cultures and the detection of an elevated absolute fluid polymorphonuclear neutrophil (PMN) count in the ascites (>250/mm3 ) without an evident intra-abdominal surgically treatable source of infection, except in peritonitis associated with peritoneal dialysis, where bacteria can enter the body through the open ends of the PD catheter during exchanges.*

The efficacy of antibiotic therapy should ideally be revised doing a second paracentesis at 48 hours from the starting treatment. One should suspect either resistance to antibiotics, secondary bacterial peritonitis or fungal peritonitis if the patient exhibits worsening clinical signs and symptoms or does not have a marked reduction in the leucocyte count of at least 25% [78, 79]. In addition to the antibiotics administered it is vital to administer albumin 1.5 g/kg body weight at diagnosis followed by 1 g/kg on day three. This in order to significantly decrease the incidence of type 1 Hepatorenal syndrome and mortality in up to 30% of the cases [78].

Another important topic is the prophylaxis of SBP in high risk patients which in which in summary are three: (1) Patients with acute gastrointestinal hemorrhage; (2) Patients with less than 15 g/L of ascitic fluid protein; (3) Patients with previous history of SBP. For the prophylaxis of SBP in high risk patients the recommended prophylaxis schemes are with norfloxacin [79]. Healthcare providers must be very conscious when they are considering the use of prophylactic antibiotics balancing the risks of generating gastrointestinal complications secondary to gut dysbiosis *vs* the benefits of preventing an event of SBP. As healthcare workers one must avoid the abuse of antibiotic use, it is important to know and apply these indications, and imperative to be clear in which antibiotic can be used in these specific cases, and avoid the use of broad spectrum antibiotics.

#### **4. Conclusions**

In cirrhotic patients, the intestinal barrier dysfunction increased permeability, and extensive inflammation occurs due to Spontaneous Bacterial Peritonitis. Clinically, the SBP is a frequent and severe complication in cirrhotic patients with ascites. It is well documented that bacterial endotoxin and harmful pathogenic bacterial species translocate to the liver through portal vein further exacerbate the already prevalent hepatic inflammation and fibrosis driven by hepatocytes destruction and loss of biochemical functionality, thereby these phenomena promote liver injury followed by multiorgan failure and eventually death in a high percentage of cirrhotic patients.

In this analysis were described that microbiota plays an essential role in this pathological process, but it is also related to gut permeability loss due to previous treatments or the inflammation sustained signalling by hepatic lesion immunological response.

Clinically, a flux for diagnostic and treatment was proposed for SBP, that includes de analysis of ascitic fluid and polymorphonuclear cells as consequence.

It is suggested that there is a lot of task to do in public health, in order to control the self-medication and the excess of antibiotic therapy, in order to avoid microbiota dysbiosis and SBP.

#### **Acknowledgements**

Programa Presupuestal E015 de Investigación y Desarrollo Tecnológico en Salud, ISSSTE.

**185**

Mexico

*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations*

Rebeca Pérez-Cabeza De Vaca1,6\*, Balasubramaniyan Vairappan2

Education and Research (JIPMER), Pondicherry, India

Fisiología Celular, UNAM, Mexico City, Mexico

provided the original work is properly cited.

\*Address all correspondence to: esderebk@gmail.com

, Juan Antonio Suárez Cuenca4

1 Biomedical Research Division, Centro Médico Nacional "20 de Noviembre"

2 Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical

Centro Médico Nacional "20 de Noviembre" ISSSTE, Mexico City, Mexico

, Brenda Maldonado Arriaga4

, Diana Selene Morgan Penagos3

and Victoria Chagoya De Sanchez6

3 Department of Gastroenterology, Clínica de Enfermedad Inflamatoria Intestinal,

4 Laboratorio de Metabolismo Experimental e Investigación Clínica, Coordinación de Investigación, Centro Médico Nacional "20 de Noviembre" ISSSTE, Mexico City,

5 Centro de Biotecnología-FEMSA, Tecnológico de Monterrey, Monterrey, Mexico

6 Departamento de Biología Celular y Desarrollo, Laboratorio 305-Sur, Instituto de

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

,

,

,

,

*DOI: http://dx.doi.org/10.5772/intechopen.96910*

**Author details**

Tomás Cortés Espinoza<sup>3</sup>

Paul Mondragón Terán4

Cuauhtemoc Licona Cassani5

ISSSTE, Mexico City, Mexico

Chrisitan Navarro Gerrard3

#### **Conflict of interest**

The authors declare no conflict of interest.

### **Author details**

*Advances in Hepatology*

30% of the cases [78].

**4. Conclusions**

cirrhotic patients.

logical response.

biota dysbiosis and SBP.

**Acknowledgements**

**Conflict of interest**

The authors declare no conflict of interest.

Salud, ISSSTE.

The efficacy of antibiotic therapy should ideally be revised doing a second paracentesis at 48 hours from the starting treatment. One should suspect either resistance to antibiotics, secondary bacterial peritonitis or fungal peritonitis if the patient exhibits worsening clinical signs and symptoms or does not have a marked reduction in the leucocyte count of at least 25% [78, 79]. In addition to the antibiotics administered it is vital to administer albumin 1.5 g/kg body weight at diagnosis followed by 1 g/kg on day three. This in order to significantly decrease the incidence of type 1 Hepatorenal syndrome and mortality in up to

Another important topic is the prophylaxis of SBP in high risk patients which in which in summary are three: (1) Patients with acute gastrointestinal hemorrhage; (2) Patients with less than 15 g/L of ascitic fluid protein; (3) Patients with previous history of SBP. For the prophylaxis of SBP in high risk patients the recommended prophylaxis schemes are with norfloxacin [79]. Healthcare providers must be very conscious when they are considering the use of prophylactic antibiotics balancing the risks of generating gastrointestinal complications secondary to gut dysbiosis *vs* the benefits of preventing an event of SBP. As healthcare workers one must avoid the abuse of antibiotic use, it is important to know and apply these indications, and imperative to be clear in which antibiotic can be used in these

In cirrhotic patients, the intestinal barrier dysfunction increased permeability,

In this analysis were described that microbiota plays an essential role in this pathological process, but it is also related to gut permeability loss due to previous treatments or the inflammation sustained signalling by hepatic lesion immuno-

Clinically, a flux for diagnostic and treatment was proposed for SBP, that includes de analysis of ascitic fluid and polymorphonuclear cells as consequence. It is suggested that there is a lot of task to do in public health, in order to control the self-medication and the excess of antibiotic therapy, in order to avoid micro-

Programa Presupuestal E015 de Investigación y Desarrollo Tecnológico en

and extensive inflammation occurs due to Spontaneous Bacterial Peritonitis. Clinically, the SBP is a frequent and severe complication in cirrhotic patients with ascites. It is well documented that bacterial endotoxin and harmful pathogenic bacterial species translocate to the liver through portal vein further exacerbate the already prevalent hepatic inflammation and fibrosis driven by hepatocytes destruction and loss of biochemical functionality, thereby these phenomena promote liver injury followed by multiorgan failure and eventually death in a high percentage of

specific cases, and avoid the use of broad spectrum antibiotics.

**184**

Rebeca Pérez-Cabeza De Vaca1,6\*, Balasubramaniyan Vairappan2 , Tomás Cortés Espinoza<sup>3</sup> , Juan Antonio Suárez Cuenca4 , Cuauhtemoc Licona Cassani5 , Brenda Maldonado Arriaga4 , Chrisitan Navarro Gerrard3 , Diana Selene Morgan Penagos3 , Paul Mondragón Terán4 and Victoria Chagoya De Sanchez6

1 Biomedical Research Division, Centro Médico Nacional "20 de Noviembre" ISSSTE, Mexico City, Mexico

2 Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India

3 Department of Gastroenterology, Clínica de Enfermedad Inflamatoria Intestinal, Centro Médico Nacional "20 de Noviembre" ISSSTE, Mexico City, Mexico

4 Laboratorio de Metabolismo Experimental e Investigación Clínica, Coordinación de Investigación, Centro Médico Nacional "20 de Noviembre" ISSSTE, Mexico City, Mexico

5 Centro de Biotecnología-FEMSA, Tecnológico de Monterrey, Monterrey, Mexico

6 Departamento de Biología Celular y Desarrollo, Laboratorio 305-Sur, Instituto de Fisiología Celular, UNAM, Mexico City, Mexico

\*Address all correspondence to: esderebk@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Spontaneous Bacterial Peritonitis: Physiopathological Mechanism and Clinical Manifestations DOI: http://dx.doi.org/10.5772/intechopen.96910*

*The Cochrane database of systematic reviews*. 2019;9[9]:CD013120. DOI:10.1002/14651858.CD013120.pub2

*Advances in Hepatology*

Orvosi hetilap. 2017;158[2]:50-57. DOI:10.1556/650.2017.30637

Rüschenbaum, S., Queck, A., Göttig, S., Vermehren, A., Weiler, N., Welker, M. W., Reinheimer, C., Hogardt, M., Vermehren, J., Herrmann, E., Kempf, V., Zeuzem, S., & Lange, C. M. Quinolone and Multidrug Resistance Predicts Failure of Antibiotic Prophylaxis of Spontaneous Bacterial Peritonitis. *Clinical infectious diseases : an official publication of the Infectious Diseases Society of America*. 2020;70[9]:1916- 1924. DOI:10.1093/cid/ciz540

[65] Friedrich, K., Nüssle, S., Rehlen, T., Stremmel, W., Mischnik, A., & Eisenbach, C. Microbiology and resistance in first episodes of spontaneous bacterial peritonitis: implications for management and prognosis. Journal of gastroenterology and hepatology. 2016;31[6]:1191-1195.

[66] Li, Y. T., Yu, C. B., Huang, J. R., Qin, Z. J., & Li, L. J. Pathogen profile and drug resistance analysis of spontaneous

[67] Fiore, M., Gentile, I., Maraolo, A. E., Leone, S., Simeon, V., Chiodini, P., Pace, M. C., Gustot, T., & Taccone, F. S. Are third-generation cephalosporins still the empirical antibiotic treatment of community-acquired spontaneous bacterial peritonitis? A systematic review and meta-analysis. European journal of gastroenterology & hepatology. 2018;30[3]:329-336. DOI:10.1097/MEG.0000000000001057

[68] Iogna Prat, L., Wilson, P., Freeman, S. C., Sutton, A. J., Cooper, N. J., Roccarina, D., Benmassaoud, A., Plaz Torres, M. C., Hawkins, N., Cowlin, M., Milne, E. J., Thorburn, D., Pavlov, C. S., Davidson, B. R., Tsochatzis, E., & Gurusamy, K. S. Antibiotic treatment for spontaneous bacterial peritonitis in people with decompensated liver cirrhosis: a network meta-analysis.

peritonitis in cirrhotic patients. World journal of gastroenterology. 2015;21[36]:10409-10417. DOI:10.3748/

DOI:10.1111/jgh.13266

wjg.v21.i36.10409

[58] Dever, J. B., & Sheikh, M. Y. Review article: spontaneous bacterial peritonitis--bacteriology, diagnosis, treatment, risk factors and prevention.

Alimentary pharmacology & therapeutics. 2015;41[11]:1116-1131.

[59] Gómez-Hurtado, I., Such, J., & Francés, R. Microbiome and bacterial translocation in cirrhosis. Microbioma y traslocación bacteriana en la cirrosis. Gastroenterologia y hepatología. 2016;39[10]:687-696. DOI:10.1016/j.

[60] Ascione, T., Di Flumeri, G., Boccia, G., & De Caro, F. Infections in patients affected by liver cirrhosis: an update. Le infezioni in medicina. 2017;25[2]:91-97.

[61] Kajihara, M., Koido, S., Kanai, T., Ito, Z., Matsumoto, Y., Takakura, K., Saruta, M., Kato, K., Odamaki, T., Xiao, J. Z., Sato, N., & Ohkusa, T. Characterisation of blood microbiota in patients with liver cirrhosis. European journal of gastroenterology & hepatology. 2019;31[12]:1577-1583. DOI:10.1097/MEG.0000000000001494

[62] Duah, A., & Nkrumah, K. N. Prevalence and predictors for spontaneous bacterial peritonitis in cirrhotic patients with ascites admitted at medical block in Korle-Bu Teaching Hospital, Ghana. *The Pan African medical journal*. 2019;33:35. DOI:10.11604/pamj.2019.33.35.18029

[63] De Mattos, A. A., Costabeber, A. M., Lionço, L. C., & Tovo, C. V. Multi-resistant bacteria in spontaneous bacterial peritonitis: a new step in management?. World journal of gastroenterology. 2014;20[39]:14079- 14086. DOI:10.3748/wjg.v20.i39.14079

[64] Mücke, M. M., Mayer, A., Kessel, J., Mücke, V. T., Bon, D., Schwarzkopf, K.,

DOI:10.1111/apt.13172

gastrohep.2015.10.013

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[69] Shizuma T. Spontaneous bacterial and fungal peritonitis in patients with liver cirrhosis: A literature review. World J Hepatol 2018; 10[2]: 254-266.

[70] The European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol [2018].

[71] Wiest R., Krag A., Gerbes A. "Spontaneous bacterial peritonitis: recent guidelines and beyond," Gut, vol. 61, no. 2, pp. 297-310, 2012.

[72] Moore K. P., Aithal G. P. "Guidelines on the management of ascites in cirrhosis," Gut, vol. 55, no. S6, pp. vi1– vi12, 2006.

[73] Garcia-Tsao G., Conn H. O., Lerner E. "The diagnosis of bacterial peritonitis: comparison of pH, lactate concentration and leukocyte count," Hepatology, vol. 5, no. 1, pp. 91-96, 1985.

[74] Van de Geijn GM, Van Gent M, Van Pul-Bom N, Beunis MH, van Tilburg AJ, Njo TL. A new flow cytometric method for differential cell counting in ascitic fluid. Cytometry B Clin Cytom 2016;90:506-511.

[75] Enomoto H., Shin-ichi I., Matsuhisa A., Nishiguchi S. Diagnosis of Spontaneous Bacterial Peritonitis and an In Situ Hybridization Approach to Detect an "Unidentified" Pathogen, International Journal of Hepatology, Volume 2014, Article ID 634617, 7 pages.

[76] Krastev N, Djurkov V, Murdjeva M, Akrabova P, Karparova T, Penkov V, Kiprin G, Asenov K. Diagnosis of spontaneous and secondary bacterial peritonitis in patients with hepatic

cirrhosis and ascites. Khirurgiia [Sofiia] 2013; [3]: 20-25

[77] Oey RC, Van Buuren HR, De Jong DM, Erler NS, De Man RA. Bacterascites: A study of clinical features, microbiological findings, and clinical significance. Liver Int. 2018;38:2199-2209.

[78] Angeli P, Bernardi M, Villanueva C, Francoz C, Mookerjee RP, Trebicka J, et al. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018;69[2]:406-60.

[79] Xu X, Duan Z, Ding H, Li W, Jia J, Wei L, et al. Chinese guidelines on the management of ascites and its related complications in cirrhosis. Hepatol Int. 2019;13[1]:1-21.

**193**

**Chapter 12**

**Abstract**

Hepatorenal Syndrome

*Arshpal Gill, Ra'ed Nassar, Ruby Sangha,* 

*Rachelle Hamadi and Suzanne El-Sayegh*

*Mohammed Abureesh, Dhineshreddy Gurala, Zeeshan Zia,* 

Hepatorenal Syndrome (HRS) is an important condition for clinicians to be aware of in the presence of cirrhosis. In simple terms, HRS is defined as a relative rise in creatinine and relative drop in serum glomerular filtration rate (GFR) alongside renal plasma flow (RPF) in the absence of other competing etiologies of acute kidney injury (AKI) in patients with hepatic cirrhosis. It represents the end stage complication of decompensated cirrhosis in the presence of severe portal hypertension, in the absence of prerenal azotemia, acute tubular necrosis or others. It is a diagnosis of exclusion. The recognition of HRS is of paramount importance for clinicians as it carries a high mortality rate and is an indication for transplantation. Recent advances in understanding the pathophysiology of the disease improved treatment approaches, but the overall prognosis remains poor, with Type I HRS having an average survival under 2 weeks. Generally speaking, AKI and renal failure in cirrhotic patients carry a very high mortality rate, with up to 60% mortality rate for patients with renal failure and cirrhosis and 86.6% of overall mortality rates of patients admitted to the intensive care unit. Of the various etiologies of renal failure in cirrhosis, HRS carries a poor prognosis among cirrhotic patients with acute kidney injury. HRS continues to pose a diagnostic challenge. AKI can be either pre-renal, intrarenal or postrenal. Prerenal causes include hypovolemia, infection, use of vasodilators and functional due to decreased blood flow to the kidney, intra-renal such as glomerulopathy, acute tubular necrosis and post-renal such as obstruction. Patients with cirrhosis are susceptible to developing renal impairment. HRS may be classified as Type 1 or rapidly progressive disease, and Type 2 or slowly progressive disease. There are other types of HRS, but this chapter will focus on Type 1 HRS and Type 2 HRS. HRS is considered a functional etiology of acute kidney injury as there is an apparent lack of nephrological parenchymal damage. It is one several possibilities for acute kidney injury in patients with both acute and chronic liver disease. Acute kidney injury (AKI) is one of the most severe complications that could occur with cirrhosis. Up to 50% of hospitalized patients with cirrhosis can suffer from acute kidney injury, and as mentioned earlier an AKI in the presence of cirrhosis in a hospitalized patient has been associated with nearly a 3.5-fold increase in mortality. The definition of HRS will be discussed in this chapter, but it is characterized specifically as a form of acute kidney injury that occurs in patients with advanced liver cirrhosis which results in a reduction in renal blood flow, unresponsive to fluids this occurs in the setting of portal hypertension and splanchnic vasodilation. This chapter will discuss the incidence of HRS, recognizing HRS, focusing mainly on HRS Type I and Type II, recognizing competing etiologies

of renal impairment in cirrhotic patients, and the management HRS.

#### **Chapter 12**

## Hepatorenal Syndrome

*Arshpal Gill, Ra'ed Nassar, Ruby Sangha, Mohammed Abureesh, Dhineshreddy Gurala, Zeeshan Zia, Rachelle Hamadi and Suzanne El-Sayegh*

#### **Abstract**

Hepatorenal Syndrome (HRS) is an important condition for clinicians to be aware of in the presence of cirrhosis. In simple terms, HRS is defined as a relative rise in creatinine and relative drop in serum glomerular filtration rate (GFR) alongside renal plasma flow (RPF) in the absence of other competing etiologies of acute kidney injury (AKI) in patients with hepatic cirrhosis. It represents the end stage complication of decompensated cirrhosis in the presence of severe portal hypertension, in the absence of prerenal azotemia, acute tubular necrosis or others. It is a diagnosis of exclusion. The recognition of HRS is of paramount importance for clinicians as it carries a high mortality rate and is an indication for transplantation. Recent advances in understanding the pathophysiology of the disease improved treatment approaches, but the overall prognosis remains poor, with Type I HRS having an average survival under 2 weeks. Generally speaking, AKI and renal failure in cirrhotic patients carry a very high mortality rate, with up to 60% mortality rate for patients with renal failure and cirrhosis and 86.6% of overall mortality rates of patients admitted to the intensive care unit. Of the various etiologies of renal failure in cirrhosis, HRS carries a poor prognosis among cirrhotic patients with acute kidney injury. HRS continues to pose a diagnostic challenge. AKI can be either pre-renal, intrarenal or postrenal. Prerenal causes include hypovolemia, infection, use of vasodilators and functional due to decreased blood flow to the kidney, intra-renal such as glomerulopathy, acute tubular necrosis and post-renal such as obstruction. Patients with cirrhosis are susceptible to developing renal impairment. HRS may be classified as Type 1 or rapidly progressive disease, and Type 2 or slowly progressive disease. There are other types of HRS, but this chapter will focus on Type 1 HRS and Type 2 HRS. HRS is considered a functional etiology of acute kidney injury as there is an apparent lack of nephrological parenchymal damage. It is one several possibilities for acute kidney injury in patients with both acute and chronic liver disease. Acute kidney injury (AKI) is one of the most severe complications that could occur with cirrhosis. Up to 50% of hospitalized patients with cirrhosis can suffer from acute kidney injury, and as mentioned earlier an AKI in the presence of cirrhosis in a hospitalized patient has been associated with nearly a 3.5-fold increase in mortality. The definition of HRS will be discussed in this chapter, but it is characterized specifically as a form of acute kidney injury that occurs in patients with advanced liver cirrhosis which results in a reduction in renal blood flow, unresponsive to fluids this occurs in the setting of portal hypertension and splanchnic vasodilation. This chapter will discuss the incidence of HRS, recognizing HRS, focusing mainly on HRS Type I and Type II, recognizing competing etiologies of renal impairment in cirrhotic patients, and the management HRS.

#### **Keywords:** Hepatorenal Syndrome, Cirrhosis, Kidney Injury

#### **1. Introduction**

Hepatorenal Syndrome (HRS) is an important condition for clinicians to be aware of in the presence of cirrhosis. In simple terms, HRS is defined as a relative rise in creatinine and relative drop in serum glomerular filtration rate (GFR) alongside renal plasma flow (RPF) in the absence of other competing etiologies of acute kidney injury (AKI) in patients with hepatic cirrhosis [1–7]. It represents the end stage complication of decompensated cirrhosis in the presence of severe portal hypertension, in the absence of prerenal azotemia, acute tubular necrosis or others. It is a diagnosis of exclusion [2]. The recognition of HRS is of paramount importance for clinicians as it carries a high mortality rate. Recent advances in understanding the pathophysiology of the disease improved treatment approaches, but the overall prognosis remains poor, with Type I HRS having an average survival under 2 weeks [3]. Generally speaking, AKI and renal failure in cirrhotic patients carry a very high mortality rate, with up to 60% mortality rate for patients with renal failure and cirrhosis and 86.6% of overall mortality rates of patients admitted to the intensive care unit [4, 5]. Of the various etiologies of renal failure in cirrhosis, HRS carries a poor prognosis among cirrhotic patients with AKI.

HRS continues to pose a diagnostic challenge. AKI is relatively frequent, seen in about 20% of patients with cirrhosis [8]. AKI can be either pre-renal, intrarenal or postrenal. Prerenal causes include hypovolemia, infection, use of vasodilators and functional due to decreased blood flow to the kidney, intra-renal such as glomerulopathy, acute tubular necrosis and post-renal such as obstruction. Patients with cirrhosis are susceptible to developing renal impairment. HRS may be classified as type 1 or rapidly progressive disease, and type 2 or slowly progressive disease. There are other types of HRS [9], but this chapter will focus on type 1 HRS and type 2 HRS. HRS is considered a functional etiology of AKI as there is an apparent lack of nephrological parenchymal damage. This is one of several possibilities of AKI in patients with both acute and chronic liver disease.

AKI is one of the most severe complications that could occur with cirrhosis. Up to 50% of hospitalized patients with cirrhosis can suffer from AKI, and as mentioned earlier an AKI in the presence of cirrhosis in a hospitalized patient has been associated with nearly a 3.5-fold increase in mortality [6].

The definition of HRS will be discussed in this chapter, but it is characterized specifically as a form of AKI that occurs in patients with advanced liver cirrhosis which results in a reduction in renal blood flow, unresponsive to fluids this occurs in the setting of portal hypertension and splanchnic vasodilation [7].

This chapter will discuss the incidence, definitions and management of HRS, focusing mainly on HRS type I and type II.

#### **2. Frequency of acute kidney injury in cirrhosis**

AKI is a common entity in cirrhotic patients at baseline. It is also commonly seen in general hospitalized patients, both with and without cirrhosis. This fundamentally means that a clinician should be able to distinguish various etiologies of AKI establish the reason for AKI in each cirrhotic patient so that management can be conducted appropriately.

As mentioned before, the frequency of AKI in patients with underlying liver pathology can be as high as 50%. One study looked at hospitalized patients with

**195**

a diagnosis.

*Hepatorenal Syndrome*

15–40% [13–15].

*DOI: http://dx.doi.org/10.5772/intechopen.97698*

cirrhosis. Of these patients, 19% found to have an AKI, out of these 23% found to have HRS [10]. "The AKI was divided into pre-renal, intrinsic, and post-renal. Pre-renal injury was the most common form of AKI which represented 68% of patients with AKI. The pre-renal injury was usually volume responsive, while HRS is non-volume responsive. In most cases, the injury was volume responsive and therefore less likely HRS [11, 12]. Although HRS is not always the most common cause of renal impairment in cirrhosis; renal impairment itself is commonly seen as the frequency of AKI in cirrhosis can vary in the literature from approximately

The etiologies of AKI in cirrhosis vary, and the prognosis that each etiology carries also varies. One large prospective study found that hypovolemia and infections were in fact the most common culprits of AKI in cirrhosis, with HRS being identified in 13% of cases [16]. The definition of HRS is important as it can guide clinicians into decision making. For instance, if the etiology of an AKI in cirrhosis is reversible and will not cause significant long-term impairment, the urgency for immediate transplantation dissipates. Conversely, if there is the development of

While there are varying figures reported in the literature on the frequency of AKI in the cirrhotic population, it is evident that it is a common entity. Not all AKI in cirrhosis is considered HRS and defining HRS as the specific cause of renal

As stated previously, HRS is defined as renal impairment that occurs in patients who have clinically established cirrhosis or have significant liver impairment. The most widely used definition is the relative rise in creatinine and the relative drop in serum GFR and renal plasma flow in the absence of other causes of AKI like prerenal, renal or post-renal. Given its poor prognosis, HRS was formerly associated with the term terminal functional renal failure [17]. In theory, since there is no intrinsic kidney pathology, upon reversing the hepatic dysfunction either medically or via transplantation, there should be resolution of HRS. In intrinsic renal pathologies, this would not be the case. Before considering HRS, clinicians should rule out other

Differentiating HRS from other etiologies of AKI in cirrhotic patients is clinically of high importance because of the pronounced difference in management and prognosis. Patients with liver cirrhosis are prone to have acute, subacute and chronic kidney disease through a variety of mechanisms. Clinicians should have a broad differential diagnosis when approaching patients with AKI as there is no definitive test for HRS yet [18]. It is therefore necessary to rule out other differential diagnosis before a diagnosis of HRS is made. Identification of risk factors and careful assessment of the renal system are the mainstay to make such

Cirrhotic patients may have a certain level of renal insufficiency at baseline since

some etiologies of cirrhosis can directly or indirectly lead to renal insufficiency. For instance, patients with non-alcoholic fatty liver disease have higher incidence of obesity and associated diabetes and diabetic nephropathy. Also, both glomerulonephritis and vasculitis can occur in patients with liver cirrhosis secondary to viral

HRS, there may be urgent indication for transplantation.

**4. Competing etiologies of hepatorenal syndrome**

**3. Defining hepato-renal syndrome**

competing etiologies.

impairment in cirrhosis represents another challenge for clinicians.

#### *Hepatorenal Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97698*

*Advances in Hepatology*

**1. Introduction**

**Keywords:** Hepatorenal Syndrome, Cirrhosis, Kidney Injury

HRS carries a poor prognosis among cirrhotic patients with AKI.

patients with both acute and chronic liver disease.

focusing mainly on HRS type I and type II.

associated with nearly a 3.5-fold increase in mortality [6].

**2. Frequency of acute kidney injury in cirrhosis**

the setting of portal hypertension and splanchnic vasodilation [7].

Hepatorenal Syndrome (HRS) is an important condition for clinicians to be aware of in the presence of cirrhosis. In simple terms, HRS is defined as a relative rise in creatinine and relative drop in serum glomerular filtration rate (GFR) alongside renal plasma flow (RPF) in the absence of other competing etiologies of acute kidney injury (AKI) in patients with hepatic cirrhosis [1–7]. It represents the end stage complication of decompensated cirrhosis in the presence of severe portal hypertension, in the absence of prerenal azotemia, acute tubular necrosis or others. It is a diagnosis of exclusion [2]. The recognition of HRS is of paramount importance for clinicians as it carries a high mortality rate. Recent advances in understanding the pathophysiology of the disease improved treatment approaches, but the overall prognosis remains poor, with Type I HRS having an average survival under 2 weeks [3]. Generally speaking, AKI and renal failure in cirrhotic patients carry a very high mortality rate, with up to 60% mortality rate for patients with renal failure and cirrhosis and 86.6% of overall mortality rates of patients admitted to the intensive care unit [4, 5]. Of the various etiologies of renal failure in cirrhosis,

HRS continues to pose a diagnostic challenge. AKI is relatively frequent, seen in about 20% of patients with cirrhosis [8]. AKI can be either pre-renal, intrarenal or postrenal. Prerenal causes include hypovolemia, infection, use of vasodilators and functional due to decreased blood flow to the kidney, intra-renal such as glomerulopathy, acute tubular necrosis and post-renal such as obstruction. Patients with cirrhosis are susceptible to developing renal impairment. HRS may be classified as type 1 or rapidly progressive disease, and type 2 or slowly progressive disease. There are other types of HRS [9], but this chapter will focus on type 1 HRS and type 2 HRS. HRS is considered a functional etiology of AKI as there is an apparent lack of nephrological parenchymal damage. This is one of several possibilities of AKI in

AKI is one of the most severe complications that could occur with cirrhosis. Up to 50% of hospitalized patients with cirrhosis can suffer from AKI, and as mentioned earlier an AKI in the presence of cirrhosis in a hospitalized patient has been

The definition of HRS will be discussed in this chapter, but it is characterized specifically as a form of AKI that occurs in patients with advanced liver cirrhosis which results in a reduction in renal blood flow, unresponsive to fluids this occurs in

This chapter will discuss the incidence, definitions and management of HRS,

AKI is a common entity in cirrhotic patients at baseline. It is also commonly seen in general hospitalized patients, both with and without cirrhosis. This fundamentally means that a clinician should be able to distinguish various etiologies of AKI establish the reason for AKI in each cirrhotic patient so that management can be

As mentioned before, the frequency of AKI in patients with underlying liver pathology can be as high as 50%. One study looked at hospitalized patients with

**194**

conducted appropriately.

cirrhosis. Of these patients, 19% found to have an AKI, out of these 23% found to have HRS [10]. "The AKI was divided into pre-renal, intrinsic, and post-renal. Pre-renal injury was the most common form of AKI which represented 68% of patients with AKI. The pre-renal injury was usually volume responsive, while HRS is non-volume responsive. In most cases, the injury was volume responsive and therefore less likely HRS [11, 12]. Although HRS is not always the most common cause of renal impairment in cirrhosis; renal impairment itself is commonly seen as the frequency of AKI in cirrhosis can vary in the literature from approximately 15–40% [13–15].

The etiologies of AKI in cirrhosis vary, and the prognosis that each etiology carries also varies. One large prospective study found that hypovolemia and infections were in fact the most common culprits of AKI in cirrhosis, with HRS being identified in 13% of cases [16]. The definition of HRS is important as it can guide clinicians into decision making. For instance, if the etiology of an AKI in cirrhosis is reversible and will not cause significant long-term impairment, the urgency for immediate transplantation dissipates. Conversely, if there is the development of HRS, there may be urgent indication for transplantation.

While there are varying figures reported in the literature on the frequency of AKI in the cirrhotic population, it is evident that it is a common entity. Not all AKI in cirrhosis is considered HRS and defining HRS as the specific cause of renal impairment in cirrhosis represents another challenge for clinicians.

#### **3. Defining hepato-renal syndrome**

As stated previously, HRS is defined as renal impairment that occurs in patients who have clinically established cirrhosis or have significant liver impairment. The most widely used definition is the relative rise in creatinine and the relative drop in serum GFR and renal plasma flow in the absence of other causes of AKI like prerenal, renal or post-renal. Given its poor prognosis, HRS was formerly associated with the term terminal functional renal failure [17]. In theory, since there is no intrinsic kidney pathology, upon reversing the hepatic dysfunction either medically or via transplantation, there should be resolution of HRS. In intrinsic renal pathologies, this would not be the case. Before considering HRS, clinicians should rule out other competing etiologies.

#### **4. Competing etiologies of hepatorenal syndrome**

Differentiating HRS from other etiologies of AKI in cirrhotic patients is clinically of high importance because of the pronounced difference in management and prognosis. Patients with liver cirrhosis are prone to have acute, subacute and chronic kidney disease through a variety of mechanisms. Clinicians should have a broad differential diagnosis when approaching patients with AKI as there is no definitive test for HRS yet [18]. It is therefore necessary to rule out other differential diagnosis before a diagnosis of HRS is made. Identification of risk factors and careful assessment of the renal system are the mainstay to make such a diagnosis.

Cirrhotic patients may have a certain level of renal insufficiency at baseline since some etiologies of cirrhosis can directly or indirectly lead to renal insufficiency. For instance, patients with non-alcoholic fatty liver disease have higher incidence of obesity and associated diabetes and diabetic nephropathy. Also, both glomerulonephritis and vasculitis can occur in patients with liver cirrhosis secondary to viral

hepatitis [2]. These are just a few examples of how one pathology can affect both the hepatic and renal system.

Given the wide spectrum of possibilities, when approaching a renal impairment in a patient with cirrhosis, a systematic approach can be of benefit to clinicians to assess the nature of renal impairment. Causes of AKI and renal failure in cirrhotic patients can be summarized in four main categories.

#### **4.1 Hypovolemia-induced renal failure**

This is usually due to hemorrhage related to gastrointestinal bleed or fluid loss associated with excessive diuresis or diarrhea induced by excessive laxatives use [19]. Also, can be secondary to different infectious etiologies including spontaneous bacterial peritonitis. In any of these cases, renal failure will occur soon after any of the mentioned hypovolemic events [16, 19]. Due to the fact that patients with worsening liver cirrhosis will have decreased intravascular volume and mean arterial resistance [17], hypovolemia should be considered as a frequent component of AKI in those patients [16]. The management of hypovolemia induced renal failure is to address the volume status.

#### **4.2 Parenchymal renal disease**

By definition HRS is a purely functional disease and it does not induce renal parenchymal damage. However, any parenchymal renal disease can occur in both cirrhotic patients and non-cirrhotic patients. The presence of proteinuria, hematuria or both is associated with glomerular disease. Differentiating HRS from acute Tubular Necrosis (ATN) remains difficult. While the presence of muddy brown casts favors ATN, other urinary indexes like fractional excretion of sodium (FeNa) can be misleading due to the prolonged use of diuretics in cirrhotic patients. Granular casts can be seen in both ATN and HRS [19].

#### **4.3 Drug induced renal disease**

Drug-induced tubular/tubulointerstitial injury is a common cause of AKI especially with the consideration ill patients such as those with cirrhosis will inevitably need medications. There are various pathways and in which a drug can cause renal injury [20]. Some examples can include aminoglycosides, vancomycin, and even administration of contrast needed for imaging studies.

#### **4.4 Hepatorenal syndrome**

HRS is a diagnosis of exclusion based on the previously mentioned criteria. This chart simplifies the definition based on the criteria set forth by the International Ascites Club [21, 22].

The key factor in diagnosing HRS is the absence of improvement of kidney function despite discontinuation of potential nephrotoxic agents, and a trial of fluid repletion. Essentially HRS appears as a non-volume responsive pre-renal injury. This is why it is essential to rule out all other possible AKI systematically (**Table 1**).

#### *4.4.1 Diagnosis*

AKI stage 1 is defined as the increase in serum creatinine (sCr) of >0.3 mg/dl within 48 hours or a > 50% percentage increase in sCr from a known or presumed

**197**

*Hepatorenal Syndrome*

• Low GFR

of diuretic **Additional criteria**

• Exclusion of shock

parecnyhmal disease

*DOI: http://dx.doi.org/10.5772/intechopen.97698*

• Chronic or acute liver failure with signs of portal hypertension

• Low urine sodium (<10mmol/l), serum sodium <130mmol/l • Less than 50 red blood cells per hpf on urine microscopy

**Defining hepatorenal syndrome**

volume < 0.5 cc/kg for 6 hours.

• Urine volume less than 0.5 liters per day

which helps differentiate HRS type I and HRS type II.

ment of HRS.

**Table 1.**

*4.4.1.1 HRS type I*

period [23].

*4.4.1.2 HRS type II*

AKI and lasts for less than 90 days.

persist for more than 90 days [9, 23].

more challenging than expected.

baseline in the past 3 months which occurred within the past 7 days or urine

*Defining Hepatorenal Syndrome. Adopted from International Ascites Club and in [21, 22].*

• Protienuria less than 0.5 grams per day with exclusion of obsrtuvtive uropathy and exclusion of

• Failure of renal function improve with 1.5 liter isotonic volume - exapnsion and/or with discontiuation

Changes in the definition of AKI in patients with cirrhosis has changed over time and has been replaced by the ICA (International Club of Ascites) AKI criteria [4, 23]. One of the most important changes was the removal of cutoff values of sCr for diagnosis of HRS in the setting of AKI, allowing earlier recognition and treat-

Major diagnostic criteria include cirrhosis with ascites, presence of renal failure

HRS type 1, renal failure is acute based on the KDIGO guidelines, increase in serum creatinine by ≥0.3 mg/dL within 48 hours; Increase in serum creatinine to ≥1.5 times baseline (i.e. 50% above baseline), which is known or presumed to have occurred within the prior 7 days; or urine volume < 0.5 mL/kg/h over a 6-hour

Type 2 HRS renal failure decline in renal function progresses more slowly, usually Cr >1.5. Diagnosis of HRS-type 2 be made either in the context of chronic kidney disease (CKD), that is, in a patient with cirrhosis and a GFR <60 ml/min per 1.73 m2 for >3 months (HRS-CKD) in whom other causes have been excluded, or in the context of AKI, defined as a renal dysfunction that does not meet criteria for

KDIGO guidelines define CKD as abnormalities in kidney structure or function (GFR <60 ml/min/1.72 m2) that persist for more than 90 days, and acute kidney disease (AKD), as AKI or as abnormalities in kidney structure or function that

A recent proposal in the European association for the study of the liver guidelines suggested that HRS-2 should be referred to as HRS-NAKI (hepato-renal syndrome non-acute kidney injury) [24]. This is due to many reasons. HRS 2 is poorly defined and is more of an assumption that chronic abnormalities in serum creatinine without a definite timeline, thus arriving at a new definition of HRS-2 is

#### **Defining hepatorenal syndrome**


*Advances in Hepatology*

hepatic and renal system.

to address the volume status.

**4.2 Parenchymal renal disease**

**4.3 Drug induced renal disease**

**4.4 Hepatorenal syndrome**

Ascites Club [21, 22].

patients can be summarized in four main categories.

Granular casts can be seen in both ATN and HRS [19].

administration of contrast needed for imaging studies.

**4.1 Hypovolemia-induced renal failure**

hepatitis [2]. These are just a few examples of how one pathology can affect both the

Given the wide spectrum of possibilities, when approaching a renal impairment in a patient with cirrhosis, a systematic approach can be of benefit to clinicians to assess the nature of renal impairment. Causes of AKI and renal failure in cirrhotic

This is usually due to hemorrhage related to gastrointestinal bleed or fluid loss associated with excessive diuresis or diarrhea induced by excessive laxatives use [19]. Also, can be secondary to different infectious etiologies including spontaneous bacterial peritonitis. In any of these cases, renal failure will occur soon after any of the mentioned hypovolemic events [16, 19]. Due to the fact that patients with worsening liver cirrhosis will have decreased intravascular volume and mean arterial resistance [17], hypovolemia should be considered as a frequent component of AKI in those patients [16]. The management of hypovolemia induced renal failure is

By definition HRS is a purely functional disease and it does not induce renal parenchymal damage. However, any parenchymal renal disease can occur in both cirrhotic patients and non-cirrhotic patients. The presence of proteinuria, hematuria or both is associated with glomerular disease. Differentiating HRS from acute Tubular Necrosis (ATN) remains difficult. While the presence of muddy brown casts favors ATN, other urinary indexes like fractional excretion of sodium (FeNa) can be misleading due to the prolonged use of diuretics in cirrhotic patients.

Drug-induced tubular/tubulointerstitial injury is a common cause of AKI especially with the consideration ill patients such as those with cirrhosis will inevitably need medications. There are various pathways and in which a drug can cause renal injury [20]. Some examples can include aminoglycosides, vancomycin, and even

HRS is a diagnosis of exclusion based on the previously mentioned criteria. This chart simplifies the definition based on the criteria set forth by the International

The key factor in diagnosing HRS is the absence of improvement of kidney function despite discontinuation of potential nephrotoxic agents, and a trial of fluid repletion. Essentially HRS appears as a non-volume responsive pre-renal injury. This is why it is essential to rule out all other possible AKI systematically

AKI stage 1 is defined as the increase in serum creatinine (sCr) of >0.3 mg/dl within 48 hours or a > 50% percentage increase in sCr from a known or presumed

**196**

(**Table 1**).

*4.4.1 Diagnosis*


#### **Additional criteria**


#### **Table 1.**

*Defining Hepatorenal Syndrome. Adopted from International Ascites Club and in [21, 22].*

baseline in the past 3 months which occurred within the past 7 days or urine volume < 0.5 cc/kg for 6 hours.

Changes in the definition of AKI in patients with cirrhosis has changed over time and has been replaced by the ICA (International Club of Ascites) AKI criteria [4, 23]. One of the most important changes was the removal of cutoff values of sCr for diagnosis of HRS in the setting of AKI, allowing earlier recognition and treatment of HRS.

Major diagnostic criteria include cirrhosis with ascites, presence of renal failure which helps differentiate HRS type I and HRS type II.

#### *4.4.1.1 HRS type I*

HRS type 1, renal failure is acute based on the KDIGO guidelines, increase in serum creatinine by ≥0.3 mg/dL within 48 hours; Increase in serum creatinine to ≥1.5 times baseline (i.e. 50% above baseline), which is known or presumed to have occurred within the prior 7 days; or urine volume < 0.5 mL/kg/h over a 6-hour period [23].

#### *4.4.1.2 HRS type II*

Type 2 HRS renal failure decline in renal function progresses more slowly, usually Cr >1.5. Diagnosis of HRS-type 2 be made either in the context of chronic kidney disease (CKD), that is, in a patient with cirrhosis and a GFR <60 ml/min per 1.73 m2 for >3 months (HRS-CKD) in whom other causes have been excluded, or in the context of AKI, defined as a renal dysfunction that does not meet criteria for AKI and lasts for less than 90 days.

KDIGO guidelines define CKD as abnormalities in kidney structure or function (GFR <60 ml/min/1.72 m2) that persist for more than 90 days, and acute kidney disease (AKD), as AKI or as abnormalities in kidney structure or function that persist for more than 90 days [9, 23].

A recent proposal in the European association for the study of the liver guidelines suggested that HRS-2 should be referred to as HRS-NAKI (hepato-renal syndrome non-acute kidney injury) [24]. This is due to many reasons. HRS 2 is poorly defined and is more of an assumption that chronic abnormalities in serum creatinine without a definite timeline, thus arriving at a new definition of HRS-2 is more challenging than expected.

#### *Advances in Hepatology*

It is proposed that the diagnosis of HRS-NAKI be made either in the context of CKD, that is in a patient with cirrhosis and a decrease in GFR greater than 3 months (HRS-CKD) or in the context of AKD, defined as a renal dysfunction that does not meet criteria for AKI and lasts for less than 90 days underlying factors such as diabetes, arterial hypertension causing nonalcoholic steatohepatitis which eventually lead to cirrhosis can simultaneously affect the kidneys causing CKD as well [23].

The new nomenclature may enable clinicians to define the presence of HRS-AKI superimposed on CKD in a patient with structural damage of the kidney, as evidenced by previous abnormal biopsy, renal ultrasonography or by significant proteinuria.

In the context of the new definition of HRS-AKI on CKD: HRS-AKI, there would be no evidence of chronic structural damage. For HRS-AKI on CKD in which there would be evidence of chronic structural damage such as chronic proteinuria and/or abnormal renal ultrasonography but with a high suspicion of HRS-AKI.

Other diagnostic criteria for hepatorenal syndrome include:


#### *4.4.2 Challenges in diagnosing hepatorenal syndrome*

Although the definition of HRS appears straightforward, there are many clinical challenges to consider when making a diagnosis. For instance, the usefulness of creatinine measurement in patients with cirrhosis may be limited for many reasons such as assay interference with bilirubin, reduced creatinine production in liver failure patients, muscle wasting and malnutrition [25].

Also using the urine output in patients with cirrhosis is limited as it can affected by other factors, for example decreased urine can be a normal in hypovolemic patients as they retain sodium or it can be simply increased secondary to the use of diuretics, [26, 27] despite that urine output remain a factor to look for, as was demonstrated by, Amathieu et al. who showed that reduction in urine output is associated with worse prognosis and 3-fold increased in hospital mortality [28].

These are just a few examples of how clinicians must use sound judgment when attempting to make a diagnosis of HRS. As mentioned earlier, it is important to stratify causes as it would impact both management and possibly the urgency for transplantation.

#### **4.5 ATN versus HRS**

Differentiating ATN and HRS can also pose a challenge to clinicians. Pre-renal azotemia represents the leading cause of AKI in patients with cirrhosis, good history and physical examination of patients warranted to exclude causes of hypovolemia as discussed above.

Urine studies have been also sought to be helpful, with structural etiologies such as ATN, tubular injury limits sodium reabsorption and fraction excretion of sodium (FENa) is increased, typically by greater than 2–3%, using these cutoffs has been challenging owing to the fact that all patients with advanced cirrhosis have chronic

**199**

*Hepatorenal Syndrome*

**Table 2.**

including HRS [31].

*DOI: http://dx.doi.org/10.5772/intechopen.97698*

FeNa has been excluded from HRS definitions.

**4.6 The role of biomarkers in diagnosing HRS**

AKI-HRS and ATN in patients with cirrhosis [30].

**5. Management of hepatorenal syndrome**

**6. Vasopressin analogues (terlipressin)**

renal hypoperfusion and have an FENa less than 1%, even in the absence of AKI [29]. Other studies such as urinary sodium (less than 40 milliequivalents per liter), low urine osmolality are suggestive of ATN although their use in HRS has been limited. The fraction excretion of urea (FEUrea) is superior to FeNA in differentiating AKI-HRS from ATN, obtaining such tests is very important in HRS as most patients with HRS are on diuretics. Urinary sodium is known to be affected by use of diuretic which can falsely elevate the urine sodium. That is one main reason why

**Hepatorenal syndrome type 1 Hepatorenal syndrome type II**

Median survival <2 weeks Median survival 6 months

*Comparing Types of Hepatorenal Syndrome. Adopted from KDIGO guidelines [9, 21, 23].*

Rapid, progressive Insidious

Novel urine biomarkers of tubular injury have long been sought to differentiate

There are many biomarkers released by tubular injury. Among these, NGAL has been the most widely studied biomarker in patients with cirrhosis and showed the greatest diagnostic accuracy in differentiating ATN from AKI-HRS [9]. Cut-off of 0.2% has been widely used in distinguishing HRS from ATN [9]. Urinary NGAL seems to be superior to plasma concentrations and performs better when measured after the two-day volume challenge recommended in the management of any AKI

At the current time human studies rely on expert adjudication for differentiating ATN from AKI-HRS owing to the limited availability of renal biomarkers and

HRS is one of the many causes of AKI in individuals with both acute and chronic liver disease. After correctly making a diagnosis of HRS, clinicians must address the underlying etiology of HRS. Patients that develop usually have cirrhosis, alcoholic hepatitis, liver failure, or fulminant hepatic failure from any etiology. Management of HRS is usually supportive, with the definitive treatment being reversal of the underlying liver pathology. In several patients, this means liver transplantation. First line treatment of supportive management for HRS is using vasoconstrictors in combination with albumin to combat splanchnic arterial vasodilation [32]. The goal of treatment is to improve hemodynamic dysfunction by combatting the decreased circulating volume and increasing mean arterial pressure. The most common vasoconstrictors used are vasopressin analogues (terlipressin), norepinephrine, and somatostatin analogues such as octreotide and midodrine.

The vasopressin analogue Terilpressin is noted to have a greater affinity for the vasopressin 1 receptors in the splanchnic bed, it has been found to improve kidney

restricted use of kidney biopsies in such a high risk population.


**Table 2.**

*Advances in Hepatology*

proteinuria.

tinuation of diuretics.

It is proposed that the diagnosis of HRS-NAKI be made either in the context of CKD, that is in a patient with cirrhosis and a decrease in GFR greater than 3 months (HRS-CKD) or in the context of AKD, defined as a renal dysfunction that does not meet criteria for AKI and lasts for less than 90 days underlying factors such as diabetes, arterial hypertension causing nonalcoholic steatohepatitis which eventually lead to cirrhosis can simultaneously affect the kidneys causing CKD as well [23]. The new nomenclature may enable clinicians to define the presence of HRS-AKI superimposed on CKD in a patient with structural damage of the kidney, as evidenced by previous abnormal biopsy, renal ultrasonography or by significant

In the context of the new definition of HRS-AKI on CKD: HRS-AKI, there would be no evidence of chronic structural damage. For HRS-AKI on CKD in which there would be evidence of chronic structural damage such as chronic proteinuria and/or

1.Failure of response to 48-hour volume expansion with albumin and discon-

3.Absence of macroscopic indication of structural kidney injury such as of proteinuria less than 500 mg per day, microhematuria (less than 50 red blood cells per high powered field) and normal kidney ultrasound [9, 21, 23] (**Table 2**).

Although the definition of HRS appears straightforward, there are many clinical

Also using the urine output in patients with cirrhosis is limited as it can affected

Differentiating ATN and HRS can also pose a challenge to clinicians. Pre-renal azotemia represents the leading cause of AKI in patients with cirrhosis, good history and physical examination of patients warranted to exclude causes of hypovole-

Urine studies have been also sought to be helpful, with structural etiologies such as ATN, tubular injury limits sodium reabsorption and fraction excretion of sodium (FENa) is increased, typically by greater than 2–3%, using these cutoffs has been challenging owing to the fact that all patients with advanced cirrhosis have chronic

challenges to consider when making a diagnosis. For instance, the usefulness of creatinine measurement in patients with cirrhosis may be limited for many reasons such as assay interference with bilirubin, reduced creatinine production in liver

by other factors, for example decreased urine can be a normal in hypovolemic patients as they retain sodium or it can be simply increased secondary to the use of diuretics, [26, 27] despite that urine output remain a factor to look for, as was demonstrated by, Amathieu et al. who showed that reduction in urine output is associated with worse prognosis and 3-fold increased in hospital mortality [28]. These are just a few examples of how clinicians must use sound judgment when attempting to make a diagnosis of HRS. As mentioned earlier, it is important to stratify causes as it would impact both management and possibly the urgency for

abnormal renal ultrasonography but with a high suspicion of HRS-AKI. Other diagnostic criteria for hepatorenal syndrome include:

2.Absence of current use of nephrotoxic medications.

*4.4.2 Challenges in diagnosing hepatorenal syndrome*

failure patients, muscle wasting and malnutrition [25].

**198**

transplantation.

**4.5 ATN versus HRS**

mia as discussed above.

*Comparing Types of Hepatorenal Syndrome. Adopted from KDIGO guidelines [9, 21, 23].*

renal hypoperfusion and have an FENa less than 1%, even in the absence of AKI [29]. Other studies such as urinary sodium (less than 40 milliequivalents per liter), low urine osmolality are suggestive of ATN although their use in HRS has been limited.

The fraction excretion of urea (FEUrea) is superior to FeNA in differentiating AKI-HRS from ATN, obtaining such tests is very important in HRS as most patients with HRS are on diuretics. Urinary sodium is known to be affected by use of diuretic which can falsely elevate the urine sodium. That is one main reason why FeNa has been excluded from HRS definitions.

#### **4.6 The role of biomarkers in diagnosing HRS**

Novel urine biomarkers of tubular injury have long been sought to differentiate AKI-HRS and ATN in patients with cirrhosis [30].

There are many biomarkers released by tubular injury. Among these, NGAL has been the most widely studied biomarker in patients with cirrhosis and showed the greatest diagnostic accuracy in differentiating ATN from AKI-HRS [9]. Cut-off of 0.2% has been widely used in distinguishing HRS from ATN [9]. Urinary NGAL seems to be superior to plasma concentrations and performs better when measured after the two-day volume challenge recommended in the management of any AKI including HRS [31].

At the current time human studies rely on expert adjudication for differentiating ATN from AKI-HRS owing to the limited availability of renal biomarkers and restricted use of kidney biopsies in such a high risk population.

#### **5. Management of hepatorenal syndrome**

HRS is one of the many causes of AKI in individuals with both acute and chronic liver disease. After correctly making a diagnosis of HRS, clinicians must address the underlying etiology of HRS. Patients that develop usually have cirrhosis, alcoholic hepatitis, liver failure, or fulminant hepatic failure from any etiology. Management of HRS is usually supportive, with the definitive treatment being reversal of the underlying liver pathology. In several patients, this means liver transplantation.

First line treatment of supportive management for HRS is using vasoconstrictors in combination with albumin to combat splanchnic arterial vasodilation [32]. The goal of treatment is to improve hemodynamic dysfunction by combatting the decreased circulating volume and increasing mean arterial pressure. The most common vasoconstrictors used are vasopressin analogues (terlipressin), norepinephrine, and somatostatin analogues such as octreotide and midodrine.

#### **6. Vasopressin analogues (terlipressin)**

The vasopressin analogue Terilpressin is noted to have a greater affinity for the vasopressin 1 receptors in the splanchnic bed, it has been found to improve kidney function in patients with HRS with a decreased incidence of ischemia as compared to vasopressin [33]. Studies have demonstrated that continuous administration of Terlipressin is better tolerated and associated with fewer adverse effects as compared to intermittent bolus administration [34]. Continuous infusion of terlipressin in an outpatient setting has also been reported to be an effective, safe option of HRS treatment as a bridge to transplant [35, 36]. Terlipressin is considered as the first treatment of choice of HRS in Europe. Despite this fact, it is not currently approved by the Food and Drug Administration for use in the United States and Canada as a clear benefit of treatment in HSR has not been established.

Terlipressin was proven to be more effective than placebo in treating HRS type 1 although terlipressin use was associated with more adverse events such abdominal pain, nausea, diarrhea and respiratory failure [37].

#### **7. Norepinephrine**

While Terilpressin is the traditional first choice for HRS, norepinephrine is another option clinician can use as vasoconstrictive therapy. One large metaanalysis looking at randomized control trials in HRS compared the efficacy of various constrictive therapies. Terlipressin did demonstrate the most effective pressor to reverse HRS, but had an increased risk of adverse events. Norepinephrine was nearly as efficacious as Terlipressin, and although it was not able to provide the survival benefit as Terlipressin did have a better safety profile [38, 39].

#### **8. Role of albumin**

Albumin has a role in maintaining plasma oncotic pressure and detoxification. One of the few indications for albumin administration is HRS; with existing studies in the literature that report the efficacy of albumin in the treatment of HRS [40]. Although albumin has been proven to help in HRS, the optimal treatment dose has not yet been established in guidelines. One large meta-analysis study did demonstrate a benefit with albumin, but optimal treatment dose with albumin has yet to be established. The study did demonstrate that a cumulative dose predicts a successful response to therapy [41].

Current recommendation is to use both albumin with Terlipressin as it has been shown that it improves its beneficial effect when compared to using terlipressin alone or placebo [34, 42].

#### **9. Transjugular intrahepatic portosystemic shunt**

Transjugular intrahepatic portosystemic shunt (TIPS) is a treatment option for those patients who fail to respond to pharmacologic therapy. TIPS reduces portal pressures by placing a stent between the portal and hepatic vein. This decreases portal pressure and vascular resistance by reducing endothelin-1 [43, 44]. This procedure has shown to improve kidney function in patients with HRS with a reduction in serum blood urea nitrogen, serum creatinine, and urinary sodium excretion [45, 46]. Although the TIPS procedure does improve elements of HRS, it was shown that there is limited evidence of survival benefit in patients with HRS [47] in addition to risk of development of hepatic encephalopathy which remains the greatest concern for clinicians. This is due to the portosystemic bypass shunt which results in bypassing the livers detoxifying function.

**201**

**13. Conclusion**

*Hepatorenal Syndrome*

*DOI: http://dx.doi.org/10.5772/intechopen.97698*

Renal replacement therapy (RRT) is an option for patients with HRS who progress to kidney failure and is most commonly done in patients awaiting liver transplant, or those with an acute reversible event. The role of RRT remains unclear due to lack of survival benefits as similar short term and long-term survival rates have been demonstrated as compared with non RRT treated patients [48].

HRS is an important entity in liver transplantation. Firstly, many patients waiting for liver transplant will develop HRS. This is owing to the fact that the indication for liver transplant is often advanced cirrhosis or decompensated cirrhosis with ascites. These conditions may also predispose for HRS. The 1-year probability of developing HRS in the presence of ascites is 20%, and the 5-year probability is 40%. The patient population at highest risk of complications are those with fluid reten-

Secondly, in patients who have HRS the therapies mentioned above such as vasoconstrictors are used often as a bridge to transplantation. Therapies discussed above including vasoconstrictors may help, but the definitive treatment in HRS patients is often a transplant. Aggressive supportive care is unable to improve the recovery of

tion, which is seen in advanced and decompensated cirrhosis [49, 50].

The concept of addressing HRS with a Simultaneous Liver and Kidney Transplant (SLKT) would seem to address both organ dysfunctions. However, HRS has the potential to be reversed by liver transplantation alone, and thus SLKT is not routinely considered in HRS. As mentioned in earlier sections, HRS is associated with many renal pathologies and it is possible for patients with HRS to develop endstage renal disease after liver transplant alone. Long wait times for liver transplantation has led to a rise in the incidence of pre-transplantation renal dysfunction. The prolonged HRS and long-term RRT can lead to permanent renal damage. The permanent renal injury may lead to a decline in renal function that may not be

HRS is not an uncommon entity in cirrhotic patients. It remains a challenge both diagnostically and in terms of management. Although there are many causes of renal impairment in the setting of cirrhosis, HRS is unique as the kidneys do not have an organic injury; rather they are a victim of poor circulation seen in advanced liver disease. Any renal impairment has the potential to increase mortality in the cirrhosis population, but HRS in particular is endangering to patients. There are two common forms of HRS, type 1 and type 2, and they can be generally distinguished based on acuity. There appears to be promise in the ease of diagnosis, with the advent of possible biomarkers; however, the present diagnosis is one of exclusion and can often be of challenge for clinicians. The management is mostly supportive care, with albumin and pressor playing a prominent role. The definitive treatment is addressing the underlying liver pathology, which often

kidney function in less than 50% of patients with HRS [50].

**12. Simultaneous liver and kidney transplant**

adequate after liver transplant alone [42, 50].

**10. Renal replacement therapy**

**11. Liver transplantation**

#### **10. Renal replacement therapy**

*Advances in Hepatology*

**7. Norepinephrine**

**8. Role of albumin**

ful response to therapy [41].

alone or placebo [34, 42].

ing the livers detoxifying function.

function in patients with HRS with a decreased incidence of ischemia as compared to vasopressin [33]. Studies have demonstrated that continuous administration of Terlipressin is better tolerated and associated with fewer adverse effects as compared to intermittent bolus administration [34]. Continuous infusion of terlipressin in an outpatient setting has also been reported to be an effective, safe option of HRS treatment as a bridge to transplant [35, 36]. Terlipressin is considered as the first treatment of choice of HRS in Europe. Despite this fact, it is not currently approved by the Food and Drug Administration for use in the United States and Canada as a

Terlipressin was proven to be more effective than placebo in treating HRS type 1 although terlipressin use was associated with more adverse events such abdominal

While Terilpressin is the traditional first choice for HRS, norepinephrine is another option clinician can use as vasoconstrictive therapy. One large metaanalysis looking at randomized control trials in HRS compared the efficacy of various constrictive therapies. Terlipressin did demonstrate the most effective pressor to reverse HRS, but had an increased risk of adverse events. Norepinephrine was nearly as efficacious as Terlipressin, and although it was not able to provide the

Albumin has a role in maintaining plasma oncotic pressure and detoxification. One of the few indications for albumin administration is HRS; with existing studies in the literature that report the efficacy of albumin in the treatment of HRS [40]. Although albumin has been proven to help in HRS, the optimal treatment dose has not yet been established in guidelines. One large meta-analysis study did demonstrate a benefit with albumin, but optimal treatment dose with albumin has yet to be established. The study did demonstrate that a cumulative dose predicts a success-

Current recommendation is to use both albumin with Terlipressin as it has been shown that it improves its beneficial effect when compared to using terlipressin

Transjugular intrahepatic portosystemic shunt (TIPS) is a treatment option for those patients who fail to respond to pharmacologic therapy. TIPS reduces portal pressures by placing a stent between the portal and hepatic vein. This decreases portal pressure and vascular resistance by reducing endothelin-1 [43, 44]. This procedure has shown to improve kidney function in patients with HRS with a reduction in serum blood urea nitrogen, serum creatinine, and urinary sodium excretion [45, 46]. Although the TIPS procedure does improve elements of HRS, it was shown that there is limited evidence of survival benefit in patients with HRS [47] in addition to risk of development of hepatic encephalopathy which remains the greatest concern for clinicians. This is due to the portosystemic bypass shunt which results in bypass-

survival benefit as Terlipressin did have a better safety profile [38, 39].

**9. Transjugular intrahepatic portosystemic shunt**

clear benefit of treatment in HSR has not been established.

pain, nausea, diarrhea and respiratory failure [37].

**200**

Renal replacement therapy (RRT) is an option for patients with HRS who progress to kidney failure and is most commonly done in patients awaiting liver transplant, or those with an acute reversible event. The role of RRT remains unclear due to lack of survival benefits as similar short term and long-term survival rates have been demonstrated as compared with non RRT treated patients [48].

#### **11. Liver transplantation**

HRS is an important entity in liver transplantation. Firstly, many patients waiting for liver transplant will develop HRS. This is owing to the fact that the indication for liver transplant is often advanced cirrhosis or decompensated cirrhosis with ascites. These conditions may also predispose for HRS. The 1-year probability of developing HRS in the presence of ascites is 20%, and the 5-year probability is 40%. The patient population at highest risk of complications are those with fluid retention, which is seen in advanced and decompensated cirrhosis [49, 50].

Secondly, in patients who have HRS the therapies mentioned above such as vasoconstrictors are used often as a bridge to transplantation. Therapies discussed above including vasoconstrictors may help, but the definitive treatment in HRS patients is often a transplant. Aggressive supportive care is unable to improve the recovery of kidney function in less than 50% of patients with HRS [50].

#### **12. Simultaneous liver and kidney transplant**

The concept of addressing HRS with a Simultaneous Liver and Kidney Transplant (SLKT) would seem to address both organ dysfunctions. However, HRS has the potential to be reversed by liver transplantation alone, and thus SLKT is not routinely considered in HRS. As mentioned in earlier sections, HRS is associated with many renal pathologies and it is possible for patients with HRS to develop endstage renal disease after liver transplant alone. Long wait times for liver transplantation has led to a rise in the incidence of pre-transplantation renal dysfunction. The prolonged HRS and long-term RRT can lead to permanent renal damage. The permanent renal injury may lead to a decline in renal function that may not be adequate after liver transplant alone [42, 50].

#### **13. Conclusion**

HRS is not an uncommon entity in cirrhotic patients. It remains a challenge both diagnostically and in terms of management. Although there are many causes of renal impairment in the setting of cirrhosis, HRS is unique as the kidneys do not have an organic injury; rather they are a victim of poor circulation seen in advanced liver disease. Any renal impairment has the potential to increase mortality in the cirrhosis population, but HRS in particular is endangering to patients. There are two common forms of HRS, type 1 and type 2, and they can be generally distinguished based on acuity. There appears to be promise in the ease of diagnosis, with the advent of possible biomarkers; however, the present diagnosis is one of exclusion and can often be of challenge for clinicians. The management is mostly supportive care, with albumin and pressor playing a prominent role. The definitive treatment is addressing the underlying liver pathology, which often

means liver transplantation. In some instances, there may be a simultaneous transplantation of the kidney and liver.

### **Abbreviations**


### **Author details**

Arshpal Gill1 \*, Ra'ed Nassar1 , Ruby Sangha<sup>2</sup> , Mohammed Abureesh1 , Dhineshreddy Gurala1 , Zeeshan Zia1 , Rachelle Hamadi1 and Suzanne El-Sayegh1

1 Hofstra/Northwell School of Medicine, Staten Island University Hospital, Staten Island, New York, United States

2 Upstate Medical University, New York, United States

\*Address all correspondence to: arshgillmd@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**203**

*Hepatorenal Syndrome*

Jan 1. PMID: 24388293.

PMID: 28613606.

30606404.

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### **References**

*Advances in Hepatology*

**Abbreviations**

transplantation of the kidney and liver.

HRS hepatorenal syndrome GFR glomerular filtration rate AKI acute kidney injury ATN acute tubular necrosis CKD chronic kidney disease

AKD acute kidney disease

FENa fraction excretion of sodium FEUrea The fraction excretion of urea RRT Renal replacement therapy

**202**

**Author details**

Dhineshreddy Gurala1

\*, Ra'ed Nassar1

Staten Island, New York, United States

provided the original work is properly cited.

, Ruby Sangha<sup>2</sup>

1 Hofstra/Northwell School of Medicine, Staten Island University Hospital,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

means liver transplantation. In some instances, there may be a simultaneous

HRS-NAKI hepato-renal syndrome non-acute kidney injury

SLKT Simultaneous Liver and Kidney Transplant

, Zeeshan Zia1

2 Upstate Medical University, New York, United States

\*Address all correspondence to: arshgillmd@gmail.com

, Mohammed Abureesh1

, Rachelle Hamadi1

,

and Suzanne El-Sayegh1

Arshpal Gill1

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May 7. PMID: 23665185.

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2006 Jul 12. PMID: 17699328.

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gut.47.2.288. PMID: 10896924; PMCID:

[47] Song, T., Rössle, M., He, F., Liu, F., Guo, X., & Qi, X. (2018). Transjugular intrahepatic portosystemic shunt for hepatorenal syndrome: A systematic review and meta-analysis. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of

[46] Guevara M, Ginès P, Bandi JC, Gilabert R, Sort P, Jiménez W, Garcia-Pagan JC, Bosch J, Arroyo V, Rodés J. Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems. Hepatology. 1998 Aug;28(2):416-422. doi: 10.1002/ hep.510280219. PMID: 9696006.

Jun 25. PMID: 23811307.

PMID: 20308721.

PMC1727992.

18.1552575

[37] Wong, F., Pappas, S. C., Curry, M. P., Reddy, K. R., Rubin, R. A., Porayko, M. K., Gonzalez, S. A., Mumtaz, K., Lim, N., Simonetto, D. A., Sharma, P., Sanyal, A. J., Mayo, M. J., Frederick, R. T., Escalante, S., Jamil, K., & CONFIRM Study Investigators (2021). Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome. The New England journal of medicine, *384*(9), 818-828. https://doi.org/10.1056/

[38] Zheng JN, Han YJ, Zou TT, Zhou YJ, Sun DQ, Zhong JH, Braddock M, Zheng MH. Comparative efficacy of vasoconstrictor therapies for type 1 hepatorenal syndrome: a network meta-analysis. Expert Rev Gastroenterol Hepatol. 2017 Nov;11(11):1009-1018. doi: 10.1080/17474124.2017.1356223. Epub 2017 Jul 27. PMID: 28708431.

[39] Nanda A, Reddy R, Safraz H, Salameh H, Singal AK. Pharmacological Therapies for Hepatorenal Syndrome: A Systematic Review and Meta-Analysis. J Clin Gastroenterol. 2018 Apr;52(4): 360-367. doi: 10.1097/MCG.0000000 000000913. PMID: 28991106.

[40] Valerio C, Theocharidou E, Davenport A, Agarwal B. Human albumin solution for patients with cirrhosis and acute on chronic liver failure: Beyond simple volume

expansion. World J Hepatol. 2016 Mar 8;8(7):345-54. doi: 10.4254/wjh. v8.i7.345. PMID: 26981172; PMCID:

[41] Salerno F, Navickis RJ, Wilkes MM. Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis. BMC Gastroenterol. 2015 Nov 25;15:167. doi: 10.1186/s12876-015- 0389-9. PMID: 26606982; PMCID:

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[48] Zhang Z, Maddukuri G, Jaipaul N, Cai CX. Role of renal replacement therapy in patients with type 1 hepatorenal syndrome receiving combination treatment of vasoconstrictor plus albumin. J Crit Care. 2015 Oct;30(5):969-974. doi: 10.1016/j.jcrc.2015.05.006. Epub 2015 May 19. PMID: 26051980.

[49] Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology. 2008 Dec;48(6):2064-2077. doi: 10.1002/hep.22605. PMID: 19003880.

[50] Modi RM, Patel N, Metwally SN, Mumtaz K. Outcomes of liver transplantation in patients with hepatorenal syndrome. World J Hepatol. 2016 Aug 28;8(24):999-1011. doi: 10.4254/wjh.v8.i24.999. PMID: 27648152; PMCID: PMC5002501.

**209**

**Chapter 13**

**Abstract**

Cirrhosis

*Anıl Delik and Yakup Ülger*

Treatment Approach in Patients

Chronic liver disease and decompensated cirrhosis are the major causes of morbidity and mortality in the world. According to current data, deaths due to liver cirrhosis constitute 2.4% of the total deaths worldwide. Cirrhosis is characterized by hepatocellular damage that leads to fibrosis and regenerative nodules in the liver. The most common causes of cirrhosis include alcohol consumption, hepatitis C, hepatitis B, and non-alcoholic fatty liver disease. Dysbiosis and intestinal bacterial overgrowth play a role in the development of complications of cirrhosis through translocation. In liver cirrhosis, ascites, gastrointestinal variceal bleeding, spontaneous bacterial peritonitis infection, hepatic encephalopathy, hepatorenal syndrome, hepatocelluler carcinoma are the most common complications. In addition, there are refractory ascites, hyponatremia, acute on-chronic liver failure, relative adrenal insufficiency, cirrhotic cardiomyopathy, hepatopulmonary syndrome and portopulmonary hypertension. In the primary prophylaxis of variceal bleeding, non-selective beta blockers or endoscopic variceal ligation are recommended for medium and large variceal veins. In current medical treatment, vasoactive agents, antibiotics, blood transfusion, endoscopic band ligation are the standard approach in the treatment of acute variceal bleeding. Sodiumrestricted diet, diuretics and large-volume paracentesis are recommended in the management of ascites. In the treatment of hepatic encephalopathy, lactulose, branched chain amino acids, rifaximin and L-ornithine L-aspartate can be used. New therapeutic approaches such as ornithine phenyl acetate spherical carbon and fecal microbiota transplantation have shown beneficial effects on hepatic encephalopathy symptoms. In addition to their antioxidative, anti-proliferative and anti-inflammatory properties, statins have been shown to reduce the risk of decompensation and death by reducing portal pressure in compensated cirrhosis. In the treatment of liver failure, some artificial liver devices such as molecular adsorbent recirculating system, the single albumin dialysis system, fractionated plasma separation and adsorption are used until transplantation or regeneration. The purpose of this chapter is to review the most up-to-date information on liver cirrhosis and to explain the complications assessment, current management and

with Decompensated Liver

potential treatment strategies in decompensated cirrhosis.

**Keywords:** advanced liver disease, ascites, gastrointestinal bleeding, hepatic encephelopathy, acute on chronic liver failure, therapy

#### **Chapter 13**

## Treatment Approach in Patients with Decompensated Liver Cirrhosis

*Anıl Delik and Yakup Ülger*

#### **Abstract**

Chronic liver disease and decompensated cirrhosis are the major causes of morbidity and mortality in the world. According to current data, deaths due to liver cirrhosis constitute 2.4% of the total deaths worldwide. Cirrhosis is characterized by hepatocellular damage that leads to fibrosis and regenerative nodules in the liver. The most common causes of cirrhosis include alcohol consumption, hepatitis C, hepatitis B, and non-alcoholic fatty liver disease. Dysbiosis and intestinal bacterial overgrowth play a role in the development of complications of cirrhosis through translocation. In liver cirrhosis, ascites, gastrointestinal variceal bleeding, spontaneous bacterial peritonitis infection, hepatic encephalopathy, hepatorenal syndrome, hepatocelluler carcinoma are the most common complications. In addition, there are refractory ascites, hyponatremia, acute on-chronic liver failure, relative adrenal insufficiency, cirrhotic cardiomyopathy, hepatopulmonary syndrome and portopulmonary hypertension. In the primary prophylaxis of variceal bleeding, non-selective beta blockers or endoscopic variceal ligation are recommended for medium and large variceal veins. In current medical treatment, vasoactive agents, antibiotics, blood transfusion, endoscopic band ligation are the standard approach in the treatment of acute variceal bleeding. Sodiumrestricted diet, diuretics and large-volume paracentesis are recommended in the management of ascites. In the treatment of hepatic encephalopathy, lactulose, branched chain amino acids, rifaximin and L-ornithine L-aspartate can be used. New therapeutic approaches such as ornithine phenyl acetate spherical carbon and fecal microbiota transplantation have shown beneficial effects on hepatic encephalopathy symptoms. In addition to their antioxidative, anti-proliferative and anti-inflammatory properties, statins have been shown to reduce the risk of decompensation and death by reducing portal pressure in compensated cirrhosis. In the treatment of liver failure, some artificial liver devices such as molecular adsorbent recirculating system, the single albumin dialysis system, fractionated plasma separation and adsorption are used until transplantation or regeneration. The purpose of this chapter is to review the most up-to-date information on liver cirrhosis and to explain the complications assessment, current management and potential treatment strategies in decompensated cirrhosis.

**Keywords:** advanced liver disease, ascites, gastrointestinal bleeding, hepatic encephelopathy, acute on chronic liver failure, therapy

#### **1. Introduction**

Decompensated cirrhosis is characterized by the development of complications related to portal hypertension (PHT) such as variceal bleeding, ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), hepatorenal syndrome (HRS), or hepatopulmunary syndrome (HPS) in the presence of cirrhosis [1]. The mortality rate in patients with decompensated cirrhosis is 10 times higher than in the normal population. In cirrhosis, PHT occurs due to increased plasma volume, cardiac output and imbalance of biochemical parameters (such as vasoconstrictors, vasodilators, vascular endothelial growth factor, and nitric oxide) [2]. The incidence of cirrhosis is 26 per 100,000 in Europe, and the incidence in Asia ranges from 16.5 per 100,000 in East Asia to 23.6 per 100,000 in Southeast Asia [3]. It causes 1.2 million deaths due to complications of cirrhosis and 790.000 deaths due to liver cancer, accounting for 3.5% of all deaths worldwide [4]. Chronic liver disease epidemiology, hepatitis B (HBV) incidence and complications decrease with HBV vaccination and antiviral treatment programs. In addition, chronic hepatitis C (HCV) infection reduces the risk of cirrhosis and HCC development with directacting antiviral (DAA) treatment. Non-alcoholic fatty liver disease (NAFLD) increases due to obesity and metabolic syndrome. Similarly, alcohol consumption accounts for approximately 27% of liver-related death causes in the world. NAFLD has the highest mortality rate in western countries [5]. Asymptomatic cirrhotic patients develop decompensated cirrhosis at a rate of 5–7% each year [6]. The development of decompensation causes dysfunction in multiple organs and systems, leading to systemic disease [7]. Although many factors play a role in the background of cirrhosis pathophysiology, mainly according to the peripheral vasodilation hypothesis, arterial vasodilation in the splanchnic circulatory system in cirrhosis leads to the activation of compensatory vasoconstrictor systems (such as renal angiotensin aldosterone axis, sympathetic nervous system and activation of water retention systems). Changes in saliva and intestinal microbiome in cirrhosis have been found to be associated with the development of intestinal bacterial overgrowth, dysbiosis, increased intestinal permeability, and decompensating complications from portal tract intestinal translocation [8]. Treatment strategy in decompensated cirrhosis patients should be aimed at preventing the progression of cirrhosis before complications occur. The ultimate treatment for decompensated cirrhosis should be aimed at regressing fibrosis by suppressing inflammation, normalizing liver cell number and function by regulating portal and arterial circulation, and restoring liver integrity [9].

#### **2. Treatment of complications in decompensated cirrhosis**

#### **2.1 Ascites**

Ascites is the abnormal accumulation of fluid in the abdominal cavity and is the most common cause of decompensation in cirrhosis. The basis for the formation of ascites is renal sodium uptake due to activation of sodium-sparing systems such as the renin angiotensin aldosterone system (RAAS) and the sympathetic nervous system [10]. Extra cellular volume increase and decreased effective volume secondary to splanchnic arterial vasodilation are the main determinants of these changes. There are 5 different phases of the ascites development process. The first phase pre-ascites does not cause a decrease in effective blood volume due to hyperdynamic circulation accompanying splanchnic arterial vasodilation, cardiac output and increase in plasma volume. Blood pressure, kidney function, renin

**211**

**Table 1.**

**Grading of ascites**

*Treatment Approach in Patients with Decompensated Liver Cirrhosis*

activity, noradrenaline and anti-diuretic hormone (ADH) levels remain normal. In the second phase, there is a moderate decrease in sodium excretion unrelated to the sympathetic nervous system and RAAS activation [11]. In the third phase, RAAS and activation of the sympathetic nervous system cause sodium retention as a result of an increase in splanchnic arterial vasodilation. In the fourth phase, plasma renin activity, noradrenaline and ADH levels increase significantly, decreasing the renal perfusion and glomerular filtration rate (GFR) and decreasing the osmotic free water excretion ability of the kidneys leads to dilutional hyponatremia. In the fifth phase, severe systemic vasodilation and a decrease in cardiac output cause left ventricular systolic dysfunction in cirrhosis patients and type 2 hepatorenal syndrome

It is classified as uncomplicated ascites and refractory ascites according to the recommendation of the international ascites club (IAC). Ascites is considered uncomplicated if not associated with infection or hepatorenal syndrome (**Table 1**). Refractory ascites are defined as non-regressing at least one degree of regression with diuretic therapy and dietary sodium restriction, or early recurrence after large-volume paracentesis. There are two subtypes, diuretic resistance and diuretic intractable. Type 1 subtype has resistance to optimal dose diuretics. The second

The management of uncomplicated acids according to the European association for the study of the liver (EASL) guidelines depends on the degree of clinical symptoms. Diuretics and low sodium diet are not needed in patients with grade 1 ascite. Grade 2 ascite patients can be treated on an outpatient basis using sodium restriction and diuretics. Daily sodium intake should be determined as 80–120 mmol/d. A very low sodium restrictive diet should be avoided (<40 mmol/d). Bed rest is not required due to the lack of data on the activation of sodium-sparing systems and the negative effect of vertical posture on renal perfusion. It can lead to the progression of muscle atrophy [15]. The diuretic agents preferred in the treatment of ascites are aldosterone antagonists (spironolactone, carnenone, potassium canrenoate etc). They not only inhibit sodium and water retention, but also suppress potassium excretion and reduce the synthesis of permeases in the collecting tubules and distal tubules of the

aldosterone-sensitive kidney. In addition, loop diuretics are used. It inhibits sodium reabsorption along the emerging branch of the henle ring. Loop diuretics are not recommended as monotherapy because of their lower efficacy and higher

Grade 1 A small amount of acid that can only be demonstrated by ultrasonography

number of complications compared to aldosterone antagonists [16].

**Findings**

Grade 2 Moderate acid in the abdomen Grade 3 Massive, common acid

*Grading ascites according to the amount of intraabdominal ascites.*

*DOI: http://dx.doi.org/10.5772/intechopen.96155*

develops [12, 13].

*2.1.1 Classification of ascites*

subtype is due to insufficient diuretic dose [14].

*2.1.2 Ascites treatment in cirrhosis patients*

*2.1.2.1 Uncomplicated ascites treatment*

#### *Treatment Approach in Patients with Decompensated Liver Cirrhosis DOI: http://dx.doi.org/10.5772/intechopen.96155*

activity, noradrenaline and anti-diuretic hormone (ADH) levels remain normal. In the second phase, there is a moderate decrease in sodium excretion unrelated to the sympathetic nervous system and RAAS activation [11]. In the third phase, RAAS and activation of the sympathetic nervous system cause sodium retention as a result of an increase in splanchnic arterial vasodilation. In the fourth phase, plasma renin activity, noradrenaline and ADH levels increase significantly, decreasing the renal perfusion and glomerular filtration rate (GFR) and decreasing the osmotic free water excretion ability of the kidneys leads to dilutional hyponatremia. In the fifth phase, severe systemic vasodilation and a decrease in cardiac output cause left ventricular systolic dysfunction in cirrhosis patients and type 2 hepatorenal syndrome develops [12, 13].

#### *2.1.1 Classification of ascites*

*Advances in Hepatology*

**1. Introduction**

Decompensated cirrhosis is characterized by the development of complications related to portal hypertension (PHT) such as variceal bleeding, ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), hepatorenal syndrome (HRS), or hepatopulmunary syndrome (HPS) in the presence of cirrhosis [1]. The mortality rate in patients with decompensated cirrhosis is 10 times higher than in the normal population. In cirrhosis, PHT occurs due to increased plasma volume, cardiac output and imbalance of biochemical parameters (such as vasoconstrictors, vasodilators, vascular endothelial growth factor, and nitric oxide) [2]. The incidence of cirrhosis is 26 per 100,000 in Europe, and the incidence in Asia ranges from 16.5 per 100,000 in East Asia to 23.6 per 100,000 in Southeast Asia [3]. It causes 1.2 million deaths due to complications of cirrhosis and 790.000 deaths due to liver cancer, accounting for 3.5% of all deaths worldwide [4]. Chronic liver disease epidemiology, hepatitis B (HBV) incidence and complications decrease with HBV vaccination and antiviral treatment programs. In addition, chronic hepatitis C (HCV) infection reduces the risk of cirrhosis and HCC development with directacting antiviral (DAA) treatment. Non-alcoholic fatty liver disease (NAFLD) increases due to obesity and metabolic syndrome. Similarly, alcohol consumption accounts for approximately 27% of liver-related death causes in the world. NAFLD has the highest mortality rate in western countries [5]. Asymptomatic cirrhotic patients develop decompensated cirrhosis at a rate of 5–7% each year [6]. The development of decompensation causes dysfunction in multiple organs and systems, leading to systemic disease [7]. Although many factors play a role in the background of cirrhosis pathophysiology, mainly according to the peripheral vasodilation hypothesis, arterial vasodilation in the splanchnic circulatory system in cirrhosis leads to the activation of compensatory vasoconstrictor systems (such as renal angiotensin aldosterone axis, sympathetic nervous system and activation of water retention systems). Changes in saliva and intestinal microbiome in cirrhosis have been found to be associated with the development of intestinal bacterial overgrowth, dysbiosis, increased intestinal permeability, and decompensating complications from portal tract intestinal translocation [8]. Treatment strategy in decompensated cirrhosis patients should be aimed at preventing the progression of cirrhosis before complications occur. The ultimate treatment for decompensated cirrhosis should be aimed at regressing fibrosis by suppressing inflammation, normalizing liver cell number and function by regulating portal and arterial

**210**

**2.1 Ascites**

circulation, and restoring liver integrity [9].

**2. Treatment of complications in decompensated cirrhosis**

Ascites is the abnormal accumulation of fluid in the abdominal cavity and is the most common cause of decompensation in cirrhosis. The basis for the formation of ascites is renal sodium uptake due to activation of sodium-sparing systems such as the renin angiotensin aldosterone system (RAAS) and the sympathetic nervous system [10]. Extra cellular volume increase and decreased effective volume secondary to splanchnic arterial vasodilation are the main determinants of these changes. There are 5 different phases of the ascites development process. The first phase pre-ascites does not cause a decrease in effective blood volume due to hyperdynamic circulation accompanying splanchnic arterial vasodilation, cardiac output and increase in plasma volume. Blood pressure, kidney function, renin

It is classified as uncomplicated ascites and refractory ascites according to the recommendation of the international ascites club (IAC). Ascites is considered uncomplicated if not associated with infection or hepatorenal syndrome (**Table 1**).

Refractory ascites are defined as non-regressing at least one degree of regression with diuretic therapy and dietary sodium restriction, or early recurrence after large-volume paracentesis. There are two subtypes, diuretic resistance and diuretic intractable. Type 1 subtype has resistance to optimal dose diuretics. The second subtype is due to insufficient diuretic dose [14].

#### *2.1.2 Ascites treatment in cirrhosis patients*

#### *2.1.2.1 Uncomplicated ascites treatment*

The management of uncomplicated acids according to the European association for the study of the liver (EASL) guidelines depends on the degree of clinical symptoms. Diuretics and low sodium diet are not needed in patients with grade 1 ascite. Grade 2 ascite patients can be treated on an outpatient basis using sodium restriction and diuretics. Daily sodium intake should be determined as 80–120 mmol/d. A very low sodium restrictive diet should be avoided (<40 mmol/d). Bed rest is not required due to the lack of data on the activation of sodium-sparing systems and the negative effect of vertical posture on renal perfusion. It can lead to the progression of muscle atrophy [15]. The diuretic agents preferred in the treatment of ascites are aldosterone antagonists (spironolactone, carnenone, potassium canrenoate etc). They not only inhibit sodium and water retention, but also suppress potassium excretion and reduce the synthesis of permeases in the collecting tubules and distal tubules of the aldosterone-sensitive kidney. In addition, loop diuretics are used. It inhibits sodium reabsorption along the emerging branch of the henle ring. Loop diuretics are not recommended as monotherapy because of their lower efficacy and higher number of complications compared to aldosterone antagonists [16].


**Table 1.** *Grading ascites according to the amount of intraabdominal ascites.* Sequential administration of aldosterone antagonists and loop diuretics in the first phase of acid therapy and a combination of these drugs if recurrence occurs. Initial treatment starts with 100–200 mg/d spironolactone administration, then 20–40 mg furosemide is added within two weeks in case of no effect. In the followup, daily doses can be increased to 400 mg and 160 mg, respectively. The second recommended method is the combination of diuretic agents and it is recommended to increase the dose of spironolactone and furosemide gradually to 400 mg and 160 mg/d [17]. Daily diuresis and weight monitoring is required to prevent hypovolemia, hyponatremia and acute kidney damage. The reduction in body weight should not exceed 500 g/day in patients without peripheral edema and 1000 g/day in patients with this [18]. In cirrhosis patients with second degree uncomplicated acid, it is possible to achieve 90% success with a combination of diuretic therapy and low sodium diet. Even if a small amount of fluid remains in the abdomen, the effect is considered sufficient, but peripheral edema should not be. It is recommended that the dose of diuretic be reduced to the lowest effective dose after the treatment goal is reached [19]. Diuretic-related side effects may occur during the first weeks of treatment. It often causes fluid electrolyte imbalance such as dehydration, hypovolemic hypoosmolar hyponatremia, hypokalemia or hyperkalemia. It can also cause possible complications such as HE, gynecomastia, muscle cramps, and acute kidney damage. Aldosterone antagonists may cause hypovolemic hypoosmolar hyponatremia, especially with the use of thiazide group diuretics in elderly patients with cirrhotic acid. This group of agents inhibit reabsorption of sodium and chlorine in distal folded tubules. Hypovolemic hypoosmolar hyponatremia is characterized by a serum sodium level below 130 mmol/L, low plasma osmolarity and simultaneous reduction in extracellular fluid volume. It can lead to weakness, apathy, irritability, dizziness, hypotension, nausea and vomiting in the clinic [20]. The development of severe hyponatremia (serum sodium level < 125 mmol/L), the presence of signs of HE worsening, muscle cramps, and acute kidney damage necessitate discontinuation of the drug. Loop diuretics can cause hypokalemia (serum potassium level less than 3 mmol/L), aldosterone antagonists can cause hyperkalemia (more than 6 mmol/L). In this case, diuretics should be discontinued.

Large volume paracentesis (LVP) is the preferred method in patients with third degree ascites. Removal of more than 5–6 L of acid fluid with LVP (albumin infusion 8 g/L acites removed), diuretic agents and a low sodium diet are recommended. Paracentesis with plasma support should be performed under sterile conditions using disposable material to prevent effective blood volume reduction after paracentesis circulatory impairment (PPCD). The procedure may cause very low local complications, especially bleeding. Clinical symptoms of PPCD are renal failure, dilutional hyponatremia, HE and decreased survival. Artificial plasma expanders such as dextran-70 (8 g/L ascites removed) or polygeline (150 ml/L), saline solution (170 ml/L) to prevent these complications (if less than 5 L ascites are discharged) only 20% albumin-like effect. Polygeline prions are not used in many countries due to the potential risk of contamination. Dextran carries the risk of severe allergic reactions and kidney failure.

According to recent studies, a reduction in short-term mortality has been reported in patients who underwent LVP. According to a meta-analysis, PPCD due to large volume paracentesis has been shown to be associated with acid recurrence, dilutional hyponatremia, development of hepatorenal syndrome, and high mortality [21]. The diagnosis of PPCD is made 5 days after LVP when the plasma renin concentration is 50% higher or 4 ng/ml compared to the basal value. Albumin infusion can prevent this complication with its increased oncotic pressure, anti-inflammatory and antioxidant properties. Alternative concentrated

**213**

*Treatment Approach in Patients with Decompensated Liver Cirrhosis*

in patients with ascites due to an increased risk of renal failure [13].

due to the development of diuretic-related complications.

sodium should be less than the sodium intake.

potassium <3 mmol/L or > 6 mmol/L [23, 24].

ascites reinfussion therapy (CART) is in the form of intravenous and reinfusion of proteins collected by concentrating and filtering acid fluid to maintain serum

Since nonsteroidal anti-inflammatory drug (NSAIDs) inhibit prostaglandin synthesis and cause sodium retention, hyponatremia and acute kidney damage, they should not be used in acidic patients. Angiotensin converting enzyme inhibitors, angiotensin 2 antagonists or alpha 1 adrenergic receptor blockers are not used

The definition of refractory ascites is in the form of refractory ascites that cannot be mobilized with medical treatment or early recurrence (after LVP) according to the criteria of the IAC. Refractory ascites is associated with a poor prognosis. Average survival is about 6 months. These patients should be referred to transplant centers for transplantation. Diuretic resistant ascites: an acid that does not respond to sodium restriction and diuretic therapy or whose early recurrence cannot be prevented. Diuretic intractable ascites: Ascites that prevent the use of diuretics at effective doses and cannot be mobilized or early recurrence cannot be prevented

The duration of treatment should be salt restricted diet (less than 90 mmol/d) and at least one week of intensive diuretic therapy spirinolactone 400 mg/d, furosemide 160 mg/d. Lack of responce weight loss of less than 0.8 kg in 4 days and urine

Early acid development: Reappearance of Grade 2 or 3 acid within 4 weeks is the development of drug-induced HE in the absence of other predisposing factors, diuretic-induced renal failure, in patients with ascites serum creatinine level increases above 2 mg/dl. Diuretic-induced encephalopathy: The development of

Diuretic induced renal failure: an increase in serum creatinine level to >2 mg/ dl (177 lmol/L) in patients with ascites. It is defined as a serum sodium level falling below 125 mmol/L. Diuretic-induced hypo or hyperkalemia is defined as serum

First-line therapy combined with albumin infusion (8 g/L ascites removed)

should be repeated every 2–3 weeks for LVP, and diuretics are only recommended when sodium concentration in urine is >30 mmol/d. Clonidine (alpha 2 presynaptic receptor agonist) may be considered to increase the effectiveness of the diuretic response and reduce the need for diuretics. Midodrine (alpha 1 receptor agonist) increases sodium excretion by decreasing plasma renin activity in patients with refractory ascites without azotemia. According to the metaanalysis results, it was shown that midodrine is effective therapeutically but does not have a statistically significant effect on survival [25]. The addition of clonidine or midodrine to diuretic therapy in resistant acids is not recommended according to current guidelines [13]. Despite controversial data on the use of non-selective beta-blockers (NSBBs) refractory ascites, high doses of NSBBs should be avoided in refractory ascites or circulatory dysfunction. (systolic blood pressure < 90 mmol Hg, serum sodium <130 mEq/L, sepsis, bleeding, AKI, SBP) (such as; propranolol >80 mg/d). Followed by an attempt at re-introduction of beta-blocker therapy after recovery. According to EASL, carvedilol is not recommended in this case. Terlipressin stimulates specific V1 receptors in arterial muscle cells, causing the arteries to contract. Reduced splanchnic vasodilation decreases the portal pressure and increases the effective blood volume and renal

hepatic encephalopathy in the absence of any other precipitating factors.

*DOI: http://dx.doi.org/10.5772/intechopen.96155*

albumin level [22].

*2.1.2.2 Refractory ascites*

#### *Treatment Approach in Patients with Decompensated Liver Cirrhosis DOI: http://dx.doi.org/10.5772/intechopen.96155*

ascites reinfussion therapy (CART) is in the form of intravenous and reinfusion of proteins collected by concentrating and filtering acid fluid to maintain serum albumin level [22].

Since nonsteroidal anti-inflammatory drug (NSAIDs) inhibit prostaglandin synthesis and cause sodium retention, hyponatremia and acute kidney damage, they should not be used in acidic patients. Angiotensin converting enzyme inhibitors, angiotensin 2 antagonists or alpha 1 adrenergic receptor blockers are not used in patients with ascites due to an increased risk of renal failure [13].

#### *2.1.2.2 Refractory ascites*

*Advances in Hepatology*

In this case, diuretics should be discontinued.

reactions and kidney failure.

Large volume paracentesis (LVP) is the preferred method in patients with third degree ascites. Removal of more than 5–6 L of acid fluid with LVP (albumin infusion 8 g/L acites removed), diuretic agents and a low sodium diet are recommended. Paracentesis with plasma support should be performed under sterile conditions using disposable material to prevent effective blood volume reduction after paracentesis circulatory impairment (PPCD). The procedure may cause very low local complications, especially bleeding. Clinical symptoms of PPCD are renal failure, dilutional hyponatremia, HE and decreased survival. Artificial plasma expanders such as dextran-70 (8 g/L ascites removed) or polygeline (150 ml/L), saline solution (170 ml/L) to prevent these complications (if less than 5 L ascites are discharged) only 20% albumin-like effect. Polygeline prions are not used in many countries due to the potential risk of contamination. Dextran carries the risk of severe allergic

According to recent studies, a reduction in short-term mortality has been reported in patients who underwent LVP. According to a meta-analysis, PPCD due to large volume paracentesis has been shown to be associated with acid recurrence, dilutional hyponatremia, development of hepatorenal syndrome, and high mortality [21]. The diagnosis of PPCD is made 5 days after LVP when the plasma renin concentration is 50% higher or 4 ng/ml compared to the basal value. Albumin infusion can prevent this complication with its increased oncotic pressure, anti-inflammatory and antioxidant properties. Alternative concentrated

Sequential administration of aldosterone antagonists and loop diuretics in the first phase of acid therapy and a combination of these drugs if recurrence occurs. Initial treatment starts with 100–200 mg/d spironolactone administration, then 20–40 mg furosemide is added within two weeks in case of no effect. In the followup, daily doses can be increased to 400 mg and 160 mg, respectively. The second recommended method is the combination of diuretic agents and it is recommended to increase the dose of spironolactone and furosemide gradually to 400 mg and 160 mg/d [17]. Daily diuresis and weight monitoring is required to prevent hypovolemia, hyponatremia and acute kidney damage. The reduction in body weight should not exceed 500 g/day in patients without peripheral edema and 1000 g/day in patients with this [18]. In cirrhosis patients with second degree uncomplicated acid, it is possible to achieve 90% success with a combination of diuretic therapy and low sodium diet. Even if a small amount of fluid remains in the abdomen, the effect is considered sufficient, but peripheral edema should not be. It is recommended that the dose of diuretic be reduced to the lowest effective dose after the treatment goal is reached [19]. Diuretic-related side effects may occur during the first weeks of treatment. It often causes fluid electrolyte imbalance such as dehydration, hypovolemic hypoosmolar hyponatremia, hypokalemia or hyperkalemia. It can also cause possible complications such as HE, gynecomastia, muscle cramps, and acute kidney damage. Aldosterone antagonists may cause hypovolemic hypoosmolar hyponatremia, especially with the use of thiazide group diuretics in elderly patients with cirrhotic acid. This group of agents inhibit reabsorption of sodium and chlorine in distal folded tubules. Hypovolemic hypoosmolar hyponatremia is characterized by a serum sodium level below 130 mmol/L, low plasma osmolarity and simultaneous reduction in extracellular fluid volume. It can lead to weakness, apathy, irritability, dizziness, hypotension, nausea and vomiting in the clinic [20]. The development of severe hyponatremia (serum sodium level < 125 mmol/L), the presence of signs of HE worsening, muscle cramps, and acute kidney damage necessitate discontinuation of the drug. Loop diuretics can cause hypokalemia (serum potassium level less than 3 mmol/L), aldosterone antagonists can cause hyperkalemia (more than 6 mmol/L).

**212**

The definition of refractory ascites is in the form of refractory ascites that cannot be mobilized with medical treatment or early recurrence (after LVP) according to the criteria of the IAC. Refractory ascites is associated with a poor prognosis. Average survival is about 6 months. These patients should be referred to transplant centers for transplantation. Diuretic resistant ascites: an acid that does not respond to sodium restriction and diuretic therapy or whose early recurrence cannot be prevented. Diuretic intractable ascites: Ascites that prevent the use of diuretics at effective doses and cannot be mobilized or early recurrence cannot be prevented due to the development of diuretic-related complications.

The duration of treatment should be salt restricted diet (less than 90 mmol/d) and at least one week of intensive diuretic therapy spirinolactone 400 mg/d, furosemide 160 mg/d. Lack of responce weight loss of less than 0.8 kg in 4 days and urine sodium should be less than the sodium intake.

Early acid development: Reappearance of Grade 2 or 3 acid within 4 weeks is the development of drug-induced HE in the absence of other predisposing factors, diuretic-induced renal failure, in patients with ascites serum creatinine level increases above 2 mg/dl. Diuretic-induced encephalopathy: The development of hepatic encephalopathy in the absence of any other precipitating factors.

Diuretic induced renal failure: an increase in serum creatinine level to >2 mg/ dl (177 lmol/L) in patients with ascites. It is defined as a serum sodium level falling below 125 mmol/L. Diuretic-induced hypo or hyperkalemia is defined as serum potassium <3 mmol/L or > 6 mmol/L [23, 24].

First-line therapy combined with albumin infusion (8 g/L ascites removed) should be repeated every 2–3 weeks for LVP, and diuretics are only recommended when sodium concentration in urine is >30 mmol/d. Clonidine (alpha 2 presynaptic receptor agonist) may be considered to increase the effectiveness of the diuretic response and reduce the need for diuretics. Midodrine (alpha 1 receptor agonist) increases sodium excretion by decreasing plasma renin activity in patients with refractory ascites without azotemia. According to the metaanalysis results, it was shown that midodrine is effective therapeutically but does not have a statistically significant effect on survival [25]. The addition of clonidine or midodrine to diuretic therapy in resistant acids is not recommended according to current guidelines [13]. Despite controversial data on the use of non-selective beta-blockers (NSBBs) refractory ascites, high doses of NSBBs should be avoided in refractory ascites or circulatory dysfunction. (systolic blood pressure < 90 mmol Hg, serum sodium <130 mEq/L, sepsis, bleeding, AKI, SBP) (such as; propranolol >80 mg/d). Followed by an attempt at re-introduction of beta-blocker therapy after recovery. According to EASL, carvedilol is not recommended in this case. Terlipressin stimulates specific V1 receptors in arterial muscle cells, causing the arteries to contract. Reduced splanchnic vasodilation decreases the portal pressure and increases the effective blood volume and renal


*MELD Model for End-Stage Liver disease, INR international normalized ratio, GFR glomerular filtration rate, HE hepatic encephelopathy, E/A: Echocardiographic E wave velocity, A wave velocity.*

#### **Table 2.**

*Factors negatively affecting the result in transjugular intrahepatic portosystemic shunt (TIPS).*

perfusion pressure with a positive effect on hyperdynamic circulation, decreases plasma renin activity and noradrenaline level, and increases renal glomerular filtration rate and sodium excretion.

It has been shown that resistant acids can be successfully treated with transjugular intrahepatic portosystemic shunt (TIPS) [26]. TIPS improves cardiovascular function by causing a decrease in portal pressure, increased renal blood flow and glomerular filtration rate. According to current guidelines, cases where LVP is contraindicated (uncooperative patient, skin infection at the puncture site, pregnancy, severe abdominal distension, severe coagulopathy) and TIPS is recommended only when LVP is not effective. Diuretic and salt restriction after TIPS, close clinical monitoring is recommended until the acid regresses. The reason for this is the high mortality in decompensated cirrhotic patients and the development of HE associated with TIPS [27]. Patients undergoing TIPS should be selected carefully. TIPS is not recommended for patients with CTP C [23, 28] (**Table 2**).

The use of polytetrafluoroethylene (PTFE) stents is recommended for patients with TIPS dysfunction and high risk of HE. If the patient has contraindications for TIPS, implantation of a permanent peritoneal catheter may be an alternative. In addition, although the automatic low flow pump (alfa pump system) can reduce the need for paracentesis in patients with cirrhosis and refractory ascites, it remains unclear whether it has a significant advantage over LVP in improving survival. It is currently not considered a standard of medical care, but theoretically TIPS can serve as a bridge for liver transplantation in patients with contraindications [29].

#### **2.2 Gastrointestinal bleeding**

Gastrointestinal varices develop as a result of the dilation of abnormally enlarged submucosal veins in the digestive system as a result of PHT. The most important complication of PHT causing morbidity and mortality is gastrointestinal variceal bleeding. The most common gastrointestinal variceal type is esophageal varices 42.7% in CTP A, 70.7% in CTP B, and 75.5% in CTP C [30]. The prevalence of variceal veins increases with the severity of liver disease. Variceal veins can be in the form of esophagus, stomach or ectopic variceal (**Table 3**). Esophageal variceal incidence in cirrhosis patients is 5% in the first year and 28% in the third year. Small esophageal varices can progress to large varices at a rate of 10–12% annually. The risk of variceal bleeding is 5% annually in small variceal and 15% in large variceal veins (**Table 4**). Early mortality (6 weeks) rate after esophageal variceal bleeding is approximately 20%.

**215**

be repeated every 2 years.

*2.2.1 Non-bleeding variceal treatment*

*Treatment Approach in Patients with Decompensated Liver Cirrhosis*

**Esophageal varices Stomach varices**

2 Covering 1/3 of a lumen 2 GOV-2

**Grade Class of modified paquet No By anatomical location** 1 Lying on top of the mucosa 1 GOV-1 (most common type)

3 Covering 50% of the lumen 3 İsolated gastric varise- type 1

*Esophageal varices according to the modified Paquet classification and gastric varices according to anatomical* 

3 Increased varices wall tension and enlarged capillaries in the varices wall (red wale sign)

4 Isolated gastric varise-type 2

Endoscopy is the gold standard in the diagnosis of gastrointestinal variceal veins. Endoscopic ultrasonography (EUS) can be used to detect gastric varices, to evaluate the anatomical structure, and to evaluate the response to treatment with endoscopic variceal ligation [31]. Temporary elastography to predict PHT clinically, platelet count, spleen size, MR elastography, splenic stiffness are the most commonly used non-invasive parameters in cirrhotic patients. If the liver stiffness measured by transient elastography is <20 kPa and the thrombocyte count is>150.000 uL, the probability of high risk variceal is less than 5% [32]. Esophageal varices are the most common gastrointestinal varices. Endoscopy is recommended for all newly diagnosed cirrhosis patients. Endoscopy is recommended every 3 years in compensated cirrhotic patients without variceal veins, but if the patient has other predisposing factors such as HCV, alcohol use, obesity, endoscopic screening should

NSBBs (propranolol, nodolol), carvedilol, or endoscopic band ligation are recommended for patients with moderate or large variceal veins for primary prophylaxis. Primary prophylaxis should be initiated after the detection of small variceal veins with red sign, medium and large variceal veins, small variceal veins in patients with CTP C. NSBBs are recommended for patients with small variceal or CTP C with red wale marks. Patients with moderate to large variceal veins should be treated with NSBBs or endoscopic band ligations. Although there is no contraindication for ascites NSBBs, caution should be exercised in severe or refractory ascites cases and high dose NSBBs should be avoided. The EASL guideline does not recommend the use of carvedilol. NSBBs should be discontinued in patients with

*DOI: http://dx.doi.org/10.5772/intechopen.96155*

*GOV: gastroesophageal varices.*

**No of risk Factors of risk**

*Risk factors for varices bleeding.*

1 Hepatic venous pressure gradient>12 mm Hg 2 Medium and Large varices (varices veins>5 mm)

4 Small varices veins in patients with CTP C

*CTP: child turcotte pugh, DS: decompansated cirrhosis.*

5 Other factors (Coagulopathy, infection, presence of DS)

**Table 3.**

**Table 4.**

*classification.*

*Treatment Approach in Patients with Decompensated Liver Cirrhosis DOI: http://dx.doi.org/10.5772/intechopen.96155*


#### **Table 3.**

*Advances in Hepatology*

**No. Factors**

**Table 2.**

**2.** INR value >2

**4.** Serum creatinine >1.9 mg/dl

**6.** Recurrent HE (stage 2 and above) **7.** Diastolic diysfunction (E/A ratio ≤ 1)

**5.** GFR <90 ml/min and platelet count <125.000

filtration rate and sodium excretion.

**2.2 Gastrointestinal bleeding**

perfusion pressure with a positive effect on hyperdynamic circulation, decreases plasma renin activity and noradrenaline level, and increases renal glomerular

*MELD Model for End-Stage Liver disease, INR international normalized ratio, GFR glomerular filtration rate, HE* 

not recommended for patients with CTP C [23, 28] (**Table 2**).

**1.** MELD score > 25 and portasystemic pressure gradient <8 mm Hg

**3.** Ttotal serum bilirubin value >3 mg/dl and platelet count <75.000

*hepatic encephelopathy, E/A: Echocardiographic E wave velocity, A wave velocity.*

*Factors negatively affecting the result in transjugular intrahepatic portosystemic shunt (TIPS).*

It has been shown that resistant acids can be successfully treated with transjugular intrahepatic portosystemic shunt (TIPS) [26]. TIPS improves cardiovascular function by causing a decrease in portal pressure, increased renal blood flow and glomerular filtration rate. According to current guidelines, cases where LVP is contraindicated (uncooperative patient, skin infection at the puncture site, pregnancy, severe abdominal distension, severe coagulopathy) and TIPS is recommended only when LVP is not effective. Diuretic and salt restriction after TIPS, close clinical monitoring is recommended until the acid regresses. The reason for this is the high mortality in decompensated cirrhotic patients and the development of HE associated with TIPS [27]. Patients undergoing TIPS should be selected carefully. TIPS is

The use of polytetrafluoroethylene (PTFE) stents is recommended for patients with TIPS dysfunction and high risk of HE. If the patient has contraindications for TIPS, implantation of a permanent peritoneal catheter may be an alternative. In addition, although the automatic low flow pump (alfa pump system) can reduce the need for paracentesis in patients with cirrhosis and refractory ascites, it remains unclear whether it has a significant advantage over LVP in improving survival. It is currently not considered a standard of medical care, but theoretically TIPS can serve as a bridge for liver transplantation in patients with contraindications [29].

Gastrointestinal varices develop as a result of the dilation of abnormally enlarged submucosal veins in the digestive system as a result of PHT. The most important complication of PHT causing morbidity and mortality is gastrointestinal variceal bleeding. The most common gastrointestinal variceal type is esophageal varices 42.7% in CTP A, 70.7% in CTP B, and 75.5% in CTP C [30]. The prevalence of variceal veins increases with the severity of liver disease. Variceal veins can be in the form of esophagus, stomach or ectopic variceal (**Table 3**). Esophageal variceal incidence in cirrhosis patients is 5% in the first year and 28% in the third year. Small esophageal varices can progress to large varices at a rate of 10–12% annually. The risk of variceal bleeding is 5% annually in small variceal and 15% in large variceal veins (**Table 4**). Early mortality (6 weeks) rate after esophageal variceal bleeding is

**214**

approximately 20%.

*Esophageal varices according to the modified Paquet classification and gastric varices according to anatomical classification.*


#### **Table 4.** *Risk factors for varices bleeding.*

Endoscopy is the gold standard in the diagnosis of gastrointestinal variceal veins. Endoscopic ultrasonography (EUS) can be used to detect gastric varices, to evaluate the anatomical structure, and to evaluate the response to treatment with endoscopic variceal ligation [31]. Temporary elastography to predict PHT clinically, platelet count, spleen size, MR elastography, splenic stiffness are the most commonly used non-invasive parameters in cirrhotic patients. If the liver stiffness measured by transient elastography is <20 kPa and the thrombocyte count is>150.000 uL, the probability of high risk variceal is less than 5% [32]. Esophageal varices are the most common gastrointestinal varices. Endoscopy is recommended for all newly diagnosed cirrhosis patients. Endoscopy is recommended every 3 years in compensated cirrhotic patients without variceal veins, but if the patient has other predisposing factors such as HCV, alcohol use, obesity, endoscopic screening should be repeated every 2 years.

#### *2.2.1 Non-bleeding variceal treatment*

NSBBs (propranolol, nodolol), carvedilol, or endoscopic band ligation are recommended for patients with moderate or large variceal veins for primary prophylaxis. Primary prophylaxis should be initiated after the detection of small variceal veins with red sign, medium and large variceal veins, small variceal veins in patients with CTP C. NSBBs are recommended for patients with small variceal or CTP C with red wale marks. Patients with moderate to large variceal veins should be treated with NSBBs or endoscopic band ligations. Although there is no contraindication for ascites NSBBs, caution should be exercised in severe or refractory ascites cases and high dose NSBBs should be avoided. The EASL guideline does not recommend the use of carvedilol. NSBBs should be discontinued in patients with

progressive hypotension (systolic blood pressure < 90 mm Hg), bleeding, sepsis, SBP and acute kidney injury. Endoscopic band ligation is recommended if the patient has NSBBs intolerance or contraindications. The NSBBs + EBL combination is recommended as it reduces the risk of bleeding compared to monotherapy [23, 32]. Primary prophylaxis of gastric varices NSBBs can be used in primary prophylaxis in the prevention of cardiofundal varices.

#### *2.2.2 Treatment in acute variceal bleeding*

Endoscopy should be performed within 12 hours after admission and when the patient is hemodynamically stable. Initially, the patient should be evaluated hemodynamically. Early TIPS should be considered in cases of resuscitation, vasoactive drugs, antibiotic therapy, early endoscopic evaluation, and endoscopic treatment (such as endoscopic band ligation) insufficiency.

Hemoglobin target should be kept between 7–9 g/dl. Antibiotic therapy (ceftriaxone 1 g/24 h, max. 7 days) has been associated with decreased mortality, reduced re-bleeding, and reduced hospital stay. Vasoactive drugs reduce portal blood flow. The use of agents such as octreotide, somatostatin and terlipressin is recommended in all main guidelines. When variceal bleeding is suspected, it should be started early and should be continued for 2–5 days. NSBBs should be initiated after stopping vasoactive drugs. Octireotide (somatostatin analogue) initially 50 microgram IV bolus, then 50 micrograms/hr. infusion 2–5 days. Somatostatin initially 250 microgram IV bolus, then 250 microgram/hr. 2–5 days.

Terlipressin (an analogue of vasopressin) initially 2 mg IV every 4 fours untill control of bleeding, maintenance therapy 1 mg IV every hours to prevent rebleeding 2–5 days. Among the vasoactive agents, terlipressin was only associated with reduced mortality [33]. Endoscopic intervention (such as, endoscopic band ligation) constitutes the basis of treatment in variceal bleeding. Endoscopy should be performed within 24 hours after resuscitation.

Combination of NSBBs and endoscopic band ligation is first choice for preventing re-bleeding. In patients with high failure of endoscopic treatment or risk of re-bleeding (CTP C or endoscopic active bleeding CTP B, if bleeding recurs despite vasoactive drugs), an early TIPS within 72 hours may be beneficial in selected patients. TIPS is the recommended salvage therapy for recurrent bleeding despite NSBB and endoscopic band ligation treatment. Propranolol 20-40 mg orally, 2 times/day, the treatment goal should not be below the resting heart rate 55–60/min and systolic blood pressure < 90 mm Hg. Nadolol 20–40 mg/day oral, once/day. Endoscopic band ligation should be done at intervals of 1–4 weeks until variceal veins are eradicated. Endoscopy is recommended every 6 to 12 months after eradication [31].

Treatment of gastric varices endoscopic band ligation, cyanoacrylate injection, endoscopic ultrasound guided coil placement, TIPS and BRTO treatments require a multi-disciplinary approach. Patients with acute gastric variceal bleeding are initially performed similarly to esophageal varices (a restrictive transfusion policy, vasoactive drug infusion, and antibiotic prophylaxis). NSBBs can be used in primary prophylaxis to prevent cardio fundal varices. In the endoscopic treatment of gastric varices, mainly cyanoacrylate adhesives, fibrin and thrombin therapy, use of sclerosing agents such as endoscopic band ligation and alcohol are among the treatment options [34].

Endoscopic band ligation or cyanoacrylate glue injection are recommended treatments for bleeding GOV2 varices. In the secondary prophylaxis of GOV1 variceal bleeding, the combination of NSBBs and endoscopic variceal treatment (endoscopic band ligation or cyanoacrylate injection) is the first-line treatment to prevent re-bleeding. High dose NSBBs (propranolol>160 mg/d, nadolol>80 mg/d)

**217**

*Treatment Approach in Patients with Decompensated Liver Cirrhosis*

hepatorenal syndrome (HRS) dose should be reduced [35].

should be avoided in patients with refractory ascites SBP. With refractory ascites and systolic blood pressure < 90 mm Hg, serum sodium level < 130 meq/L or

It is an adhesive hemostatic powder. It forms a mechanical barrier that covers the bleeding area by contacting with blood or tissue. Its effect lasts about 24 hours [36]. There are case reports of the use of hemospray as a salvage therapy in the failure of cyanoacrylate injection [37]. There is little evidence to support its current use in

Balloon tamponade is a short-term measure. Sengstaken Blakemore (SB) tube, Minnesota tube, Linton-Nachlas tube. Because of the high risk of re-bleeding when the balloon is lowered and its complications, it should be considered as a temporary measure until definitive control of bleeding is achieved [38]. While the success rate with the use of balloon tamponade in gastric varices is 88%, the complication rate has been reported as 10% [39]. Complications include esophageal ulcers, necrosis, esophageal rupture, and aspiration pneumonia. Consequently, it is recommended that its use be limited to temporary control until a more precise method is applied [34]. TIPS is a shunt created by placing a stent between the portal vein and hepatic vein to reduce portal pressure. If variceal bleeding of the patient cannot be controlled due to medical and endoscopic treatment, early TIPS (24 hours) should be considered [31, 40]. Complications caused by TIPS include HE, heart failure and stent stenosis. Heart failure, severe pulmonary hypertension, severe tricuspid valve insufficiency, sepsis, unresolved bile duct obstruction are among the absolute contraindications for TIPS. Relative contraindications are portal vein thrombosis, hepatoma, uncorrected coagulopathy, and severe thrombocytopenia (<20,000 uL). Cardio fundal is increasingly used as a first-line treatment for the control of bleed-

Balloon occluded retrograde transvenous obliteration (BRTO): It is an interventional radiology technique performed by accessing gastric varices through a gastrorenal shunt and injecting the variceal sclerosing agent. The current recommendation for BRTO can be applied as a salvage therapy in cases where TIPS such as advanced liver failure or HE is contraindicated. The main side effect of BRTO can be stated as causing vascular damage due to sclerosing substance and progression of esophageal varices in case of accidental displacement of the balloon. TIPS or BRTO is not recommended for primary prophylaxis in fundal varices without bleeding. However, fundal variceal veins are the first step treatments to prevent re-bleeding. Cyanoacrylate injection is recommended instead of TIPS in patients at high risk of

HE is a complication of liver failure characterized by reversible neuropsychiatric

symptoms and signs ranging from disorientation to coma. High portosystemic shunting is an important cause of morbidity in acute and chronic liver diseases. It is the second most common complication of decompensated cirrhosis after acid. In addition, HE is the most common cause of hospitalization in decompensated cirrhosis patients. The incidence of symptomatic HE ranges from 30–40% and minimal encephalopathy from 20–80% [43, 44]. Although the pathogenesis of HE is not fully understood, ammonia toxicity is an important factor in its development, but inflammation (proinflammatory cytokines, TNF alpha, ınterleukin 1, ınterleukin 6) oxidative stress, changes in intestinal microbiota play a role [45, 46]. Intestinal flora changes play an important role in the development of HE. Ammonia, which is a product of intestinal metabolism in liver cirrhosis, cannot be effectively converted into urea in the liver. Serum ammonia level rises due to the passage of portal blood

*DOI: http://dx.doi.org/10.5772/intechopen.96155*

active varices bleeding.

ing from varices (GOV2, IGV1) [41].

advanced liver dysfunction and HE [42].

**2.3 Hepatic encephalopathy**

#### *Treatment Approach in Patients with Decompensated Liver Cirrhosis DOI: http://dx.doi.org/10.5772/intechopen.96155*

*Advances in Hepatology*

progressive hypotension (systolic blood pressure < 90 mm Hg), bleeding, sepsis, SBP and acute kidney injury. Endoscopic band ligation is recommended if the patient has NSBBs intolerance or contraindications. The NSBBs + EBL combination is recommended as it reduces the risk of bleeding compared to monotherapy [23, 32]. Primary prophylaxis of gastric varices NSBBs can be used in primary

Endoscopy should be performed within 12 hours after admission and when the patient is hemodynamically stable. Initially, the patient should be evaluated hemodynamically. Early TIPS should be considered in cases of resuscitation, vasoactive drugs, antibiotic therapy, early endoscopic evaluation, and endoscopic treatment

Hemoglobin target should be kept between 7–9 g/dl. Antibiotic therapy (ceftriaxone 1 g/24 h, max. 7 days) has been associated with decreased mortality, reduced re-bleeding, and reduced hospital stay. Vasoactive drugs reduce portal blood flow. The use of agents such as octreotide, somatostatin and terlipressin is recommended in all main guidelines. When variceal bleeding is suspected, it should be started early and should be continued for 2–5 days. NSBBs should be initiated after stopping vasoactive drugs. Octireotide (somatostatin analogue) initially 50 microgram IV bolus, then 50 micrograms/hr. infusion 2–5 days. Somatostatin initially 250

Terlipressin (an analogue of vasopressin) initially 2 mg IV every 4 fours untill

Combination of NSBBs and endoscopic band ligation is first choice for preventing re-bleeding. In patients with high failure of endoscopic treatment or risk of re-bleeding (CTP C or endoscopic active bleeding CTP B, if bleeding recurs despite vasoactive drugs), an early TIPS within 72 hours may be beneficial in selected patients. TIPS is the recommended salvage therapy for recurrent bleeding despite NSBB and endoscopic band ligation treatment. Propranolol 20-40 mg orally, 2 times/day, the treatment goal should not be below the resting heart rate 55–60/min and systolic blood pressure < 90 mm Hg. Nadolol 20–40 mg/day oral, once/day. Endoscopic band ligation should be done at intervals of 1–4 weeks until variceal veins are eradicated.

control of bleeding, maintenance therapy 1 mg IV every hours to prevent rebleeding 2–5 days. Among the vasoactive agents, terlipressin was only associated with reduced mortality [33]. Endoscopic intervention (such as, endoscopic band ligation) constitutes the basis of treatment in variceal bleeding. Endoscopy should

Endoscopy is recommended every 6 to 12 months after eradication [31].

Treatment of gastric varices endoscopic band ligation, cyanoacrylate injection, endoscopic ultrasound guided coil placement, TIPS and BRTO treatments require a multi-disciplinary approach. Patients with acute gastric variceal bleeding are initially performed similarly to esophageal varices (a restrictive transfusion policy, vasoactive drug infusion, and antibiotic prophylaxis). NSBBs can be used in primary prophylaxis to prevent cardio fundal varices. In the endoscopic treatment of gastric varices, mainly cyanoacrylate adhesives, fibrin and thrombin therapy, use of sclerosing agents such as endoscopic band ligation and alcohol are among the

Endoscopic band ligation or cyanoacrylate glue injection are recommended treatments for bleeding GOV2 varices. In the secondary prophylaxis of GOV1 variceal bleeding, the combination of NSBBs and endoscopic variceal treatment (endoscopic band ligation or cyanoacrylate injection) is the first-line treatment to prevent re-bleeding. High dose NSBBs (propranolol>160 mg/d, nadolol>80 mg/d)

prophylaxis in the prevention of cardiofundal varices.

(such as endoscopic band ligation) insufficiency.

microgram IV bolus, then 250 microgram/hr. 2–5 days.

be performed within 24 hours after resuscitation.

*2.2.2 Treatment in acute variceal bleeding*

**216**

treatment options [34].

should be avoided in patients with refractory ascites SBP. With refractory ascites and systolic blood pressure < 90 mm Hg, serum sodium level < 130 meq/L or hepatorenal syndrome (HRS) dose should be reduced [35].

It is an adhesive hemostatic powder. It forms a mechanical barrier that covers the bleeding area by contacting with blood or tissue. Its effect lasts about 24 hours [36]. There are case reports of the use of hemospray as a salvage therapy in the failure of cyanoacrylate injection [37]. There is little evidence to support its current use in active varices bleeding.

Balloon tamponade is a short-term measure. Sengstaken Blakemore (SB) tube, Minnesota tube, Linton-Nachlas tube. Because of the high risk of re-bleeding when the balloon is lowered and its complications, it should be considered as a temporary measure until definitive control of bleeding is achieved [38]. While the success rate with the use of balloon tamponade in gastric varices is 88%, the complication rate has been reported as 10% [39]. Complications include esophageal ulcers, necrosis, esophageal rupture, and aspiration pneumonia. Consequently, it is recommended that its use be limited to temporary control until a more precise method is applied [34].

TIPS is a shunt created by placing a stent between the portal vein and hepatic vein to reduce portal pressure. If variceal bleeding of the patient cannot be controlled due to medical and endoscopic treatment, early TIPS (24 hours) should be considered [31, 40]. Complications caused by TIPS include HE, heart failure and stent stenosis. Heart failure, severe pulmonary hypertension, severe tricuspid valve insufficiency, sepsis, unresolved bile duct obstruction are among the absolute contraindications for TIPS. Relative contraindications are portal vein thrombosis, hepatoma, uncorrected coagulopathy, and severe thrombocytopenia (<20,000 uL). Cardio fundal is increasingly used as a first-line treatment for the control of bleeding from varices (GOV2, IGV1) [41].

Balloon occluded retrograde transvenous obliteration (BRTO): It is an interventional radiology technique performed by accessing gastric varices through a gastrorenal shunt and injecting the variceal sclerosing agent. The current recommendation for BRTO can be applied as a salvage therapy in cases where TIPS such as advanced liver failure or HE is contraindicated. The main side effect of BRTO can be stated as causing vascular damage due to sclerosing substance and progression of esophageal varices in case of accidental displacement of the balloon. TIPS or BRTO is not recommended for primary prophylaxis in fundal varices without bleeding. However, fundal variceal veins are the first step treatments to prevent re-bleeding. Cyanoacrylate injection is recommended instead of TIPS in patients at high risk of advanced liver dysfunction and HE [42].

#### **2.3 Hepatic encephalopathy**

HE is a complication of liver failure characterized by reversible neuropsychiatric symptoms and signs ranging from disorientation to coma. High portosystemic shunting is an important cause of morbidity in acute and chronic liver diseases. It is the second most common complication of decompensated cirrhosis after acid. In addition, HE is the most common cause of hospitalization in decompensated cirrhosis patients. The incidence of symptomatic HE ranges from 30–40% and minimal encephalopathy from 20–80% [43, 44]. Although the pathogenesis of HE is not fully understood, ammonia toxicity is an important factor in its development, but inflammation (proinflammatory cytokines, TNF alpha, ınterleukin 1, ınterleukin 6) oxidative stress, changes in intestinal microbiota play a role [45, 46]. Intestinal flora changes play an important role in the development of HE. Ammonia, which is a product of intestinal metabolism in liver cirrhosis, cannot be effectively converted into urea in the liver. Serum ammonia level rises due to the passage of portal blood

to the systemic circulation and the blood passes to the brain barrier. Astrocytes are neuroglial cells responsible for protecting the blood brain barrier and detoxifying it by converting ammonia to glutamine. Glutamine increase leads to astrocyte swelling, morphological changes and cell dysfunction [47]. Increased production of ammonia during HE triggers in the clinic (GIS bleeding, hypovolemia, hypokalemia, acidosis, diabetes, excessive diuresis, excessive protein intake), impaired ammonia excretion (constipation, renal failure, sarcopenia, portosystemic shunt, zinc deficiency, branched chain amino acid deficiency) and Increased neurotoxicity (infection, drug/substance abuse, hyponatremia, hyperglycemia).

Studies have shown a decrease in bile acid production in advanced stage liver disease, an increase in more pathogenic bacteria such as enterobacteia, and a decrease in protective bacteria such as lachnospiraceae [48]. Regarding the importance of gut-liver-brain axis in HE, it has been shown that patients with HE have more systemic inflammation, dysbiosis, hyperammonemia and neuronal/astrocytic dysfunction compared to controls and patients with cirrhosis without HE [49]. According to a recent meta-analysis, it has been reported that a decrease in serum ammonia and endotoxin levels can improve and prevent HE [50]. It has been shown that HE patients who underwent fecal microbiota transplantation (FMT) had fewer HE attacks and hospitalizations. In addition, albumin infusion can reduce the frequency and severity of HE in liver cirrhosis [51].

Current guidelines for the clinical management of HE suggest lactulosis and rifaximine as first-line therapy [44]. In HE patients, care needs to be initiated for a change in consciousness, which includes securing the airway, hemodynamic stabilization, and ensuring patient safety to prevent physical injury. Intubation is recommended in patients with HE 3 or above, Glasgow score (GCS) < 8, but this is not possible in many hospitals. Protection of the airway and close monitoring is recommended. CT scan is recommended to evaluate the causes of mental changes. Infection bleeding, constipation, dehydration, sedative drugs, alcohol intoxication, or electrolyte disturbances should be identified and corrected. The goal of many treatments is to reduce ammonia levels.

In the treatment of hepatic encephalopathy, lactulose, branched chain amino acids, rifaximine, and L-ornithine L-aspartate can be used. The current treatment in HE as the first step is lactulose 20 g/30 ml-30 g/45 ml orally 3–4 times a day, if not oral, similar dose nasogastric or 300 ml enema can be given 3–4 times a day. As a side effect, diarrhea is seen as abdominal swelling and taste disturbance. In the second step treatment, rifaximine 400–500 mg can be taken orally twice a day. An important side effect is the road. It is reported that percutaneous endoscopic gastrostomy, which has not yet been approved by food and drug administration (FDA), can be used in the third step.

Lactulose and rifaximine are recommended as primary care in the prevention of recurrent HE (**Figure 1**). Probiotics and fecal microbiota transplantation are included. There is no evidence yet for the use of probiotics in acute HE [52]. L ornithine L-Aspartate (LOLA) is a substrate for the urea cycle. It can be used in HE and other hyperammonemia conditions. According to a recent meta-analysis, it is reported that HE LOLA has a positive effect on decompensation and mortality.

The american association for the study of liver diseases (AASLD) and EASL guidelines suggest that LOLA oral therapy is not effective. The potential beneficial effect of LOLA remains unclear [53]. Osmotic laxatives, non-absorbable disaccharides lactulose and lactitol are recommended as first-line therapy. Lactulose is likely to increase intestinal transit, acidifying the intestinal environment, reducing ammonia production in the intestine, increasing fecal excretion and decreasing ammonia absorption. As an antimicrobial agent, Rifaximine is a semi-synthetic non-aminoglycoside substance effective against gram-positive, negative aerobic,

**219**

*Treatment Approach in Patients with Decompensated Liver Cirrhosis*

anerobic enteric bacteria. It inhibits bacterial RNA synthesis. Rifaximine + lactulose

In patients with recurrent HE, an improvement in FMT coordination has been shown to result in an improvement in the fecal microbiome profile with a decrease in the incidence of HE [54]. Other new treatments are changed to brain gamma-aminobutyric acid (GABA) receptors. Therapies focusing on *E. coli* are some of the new methods that are actively researched in HE but not currently close to clinical use.

Hepatorenal syndrome (HRS) is one of the most important complications in cirrhosis patients. In patients with cirrhotic portal hypertension in the pathophysiology of HRS, systemic and splanchnic vasodilation, bacterial translocation, inflammation, nitric oxide, increased prostacyclin, decrease in effective arterial blood volume (GIS bleeding, diuretics, lactulose, non-steroids, radiocontrast agent, oral intake failure) may cause hypovolemia. It causes vasoconstriction in renal artery tracts with RAAS and activation of sympathetic nervous system to decrease renal blood flow and HRS develops. It is evaluated in two groups in cirrhotic patients. (HRS AKI and non-HRS AKI) (**Table 5**). HRS AKI, decompensated cirrhosis is characterized by prerenal azotemia in patients with severe portal hypertension, nephrotoxicity, and worsening of renal functions in the absence of intrinsic renal disease. Non-HRS AKI may result from prerenal hypoperfusion bile acid nephropathy, nephrotoxicity, or acute parenchymal injury [55]. Although the best treatment option for HRS is liver transplantation, the basis of medical therapy is vasoconstrictor agents, such as terlipressin noradrenaline and dopamine in combi-

has been shown to increase recovery in HE and decrease mortality.

*Hepatic encephalopathy (HE) pathogenesis and treatment approaches.*

**2.4 Hepatorenal syndrome**

**Figure 1.**

nation with albumin [56].

*DOI: http://dx.doi.org/10.5772/intechopen.96155*

*Treatment Approach in Patients with Decompensated Liver Cirrhosis DOI: http://dx.doi.org/10.5772/intechopen.96155*

**Figure 1.**

*Advances in Hepatology*

to the systemic circulation and the blood passes to the brain barrier. Astrocytes are neuroglial cells responsible for protecting the blood brain barrier and detoxifying it by converting ammonia to glutamine. Glutamine increase leads to astrocyte swelling, morphological changes and cell dysfunction [47]. Increased production of ammonia during HE triggers in the clinic (GIS bleeding, hypovolemia, hypokalemia, acidosis, diabetes, excessive diuresis, excessive protein intake), impaired ammonia excretion (constipation, renal failure, sarcopenia, portosystemic shunt, zinc deficiency, branched chain amino acid deficiency) and Increased neurotoxicity

Studies have shown a decrease in bile acid production in advanced stage liver disease, an increase in more pathogenic bacteria such as enterobacteia, and a decrease in protective bacteria such as lachnospiraceae [48]. Regarding the importance of gut-liver-brain axis in HE, it has been shown that patients with HE have more systemic inflammation, dysbiosis, hyperammonemia and neuronal/astrocytic dysfunction compared to controls and patients with cirrhosis without HE [49]. According to a recent meta-analysis, it has been reported that a decrease in serum ammonia and endotoxin levels can improve and prevent HE [50]. It has been shown that HE patients who underwent fecal microbiota transplantation (FMT) had fewer HE attacks and hospitalizations. In addition, albumin infusion can reduce the

Current guidelines for the clinical management of HE suggest lactulosis and rifaximine as first-line therapy [44]. In HE patients, care needs to be initiated for a change in consciousness, which includes securing the airway, hemodynamic stabilization, and ensuring patient safety to prevent physical injury. Intubation is recommended in patients with HE 3 or above, Glasgow score (GCS) < 8, but this is not possible in many hospitals. Protection of the airway and close monitoring is recommended. CT scan is recommended to evaluate the causes of mental changes. Infection bleeding, constipation, dehydration, sedative drugs, alcohol intoxication, or electrolyte disturbances should be identified and corrected. The goal of many

In the treatment of hepatic encephalopathy, lactulose, branched chain amino acids, rifaximine, and L-ornithine L-aspartate can be used. The current treatment in HE as the first step is lactulose 20 g/30 ml-30 g/45 ml orally 3–4 times a day, if not oral, similar dose nasogastric or 300 ml enema can be given 3–4 times a day. As a side effect, diarrhea is seen as abdominal swelling and taste disturbance. In the second step treatment, rifaximine 400–500 mg can be taken orally twice a day. An important side effect is the road. It is reported that percutaneous endoscopic gastrostomy, which has not yet been approved by food and drug administration

Lactulose and rifaximine are recommended as primary care in the prevention of recurrent HE (**Figure 1**). Probiotics and fecal microbiota transplantation are included. There is no evidence yet for the use of probiotics in acute HE [52]. L ornithine L-Aspartate (LOLA) is a substrate for the urea cycle. It can be used in HE and other hyperammonemia conditions. According to a recent meta-analysis, it is reported that HE LOLA has a positive effect on decompensation and mortality. The american association for the study of liver diseases (AASLD) and EASL guidelines suggest that LOLA oral therapy is not effective. The potential beneficial effect of LOLA remains unclear [53]. Osmotic laxatives, non-absorbable disaccharides lactulose and lactitol are recommended as first-line therapy. Lactulose is likely to increase intestinal transit, acidifying the intestinal environment, reducing ammonia production in the intestine, increasing fecal excretion and decreasing ammonia absorption. As an antimicrobial agent, Rifaximine is a semi-synthetic non-aminoglycoside substance effective against gram-positive, negative aerobic,

(infection, drug/substance abuse, hyponatremia, hyperglycemia).

frequency and severity of HE in liver cirrhosis [51].

treatments is to reduce ammonia levels.

(FDA), can be used in the third step.

**218**

*Hepatic encephalopathy (HE) pathogenesis and treatment approaches.*

anerobic enteric bacteria. It inhibits bacterial RNA synthesis. Rifaximine + lactulose has been shown to increase recovery in HE and decrease mortality.

In patients with recurrent HE, an improvement in FMT coordination has been shown to result in an improvement in the fecal microbiome profile with a decrease in the incidence of HE [54]. Other new treatments are changed to brain gamma-aminobutyric acid (GABA) receptors. Therapies focusing on *E. coli* are some of the new methods that are actively researched in HE but not currently close to clinical use.

#### **2.4 Hepatorenal syndrome**

Hepatorenal syndrome (HRS) is one of the most important complications in cirrhosis patients. In patients with cirrhotic portal hypertension in the pathophysiology of HRS, systemic and splanchnic vasodilation, bacterial translocation, inflammation, nitric oxide, increased prostacyclin, decrease in effective arterial blood volume (GIS bleeding, diuretics, lactulose, non-steroids, radiocontrast agent, oral intake failure) may cause hypovolemia. It causes vasoconstriction in renal artery tracts with RAAS and activation of sympathetic nervous system to decrease renal blood flow and HRS develops. It is evaluated in two groups in cirrhotic patients. (HRS AKI and non-HRS AKI) (**Table 5**). HRS AKI, decompensated cirrhosis is characterized by prerenal azotemia in patients with severe portal hypertension, nephrotoxicity, and worsening of renal functions in the absence of intrinsic renal disease. Non-HRS AKI may result from prerenal hypoperfusion bile acid nephropathy, nephrotoxicity, or acute parenchymal injury [55]. Although the best treatment option for HRS is liver transplantation, the basis of medical therapy is vasoconstrictor agents, such as terlipressin noradrenaline and dopamine in combination with albumin [56].


#### **Table 5.**

*Classification of Hepatorenal syndrome subtypes in cirrhosis.*

In patients followed up with HRS in the intensive care unit, initial treatment is recommended as a combination of norepinephrine and albumin. (norepinephrine intravenously continuous infusion 0.5–3 mg/hr, albumin intravenous bolus 1 g/kg per day for at least two days). Terlipressin albumin combination is recommended as the initial therapy in HRS patients outside the intensive care unit. Terlipressin 1–2 mg is recommended as an intravenous bolus every 4 to 6 hours. Albumin is given for 2 days as intravenous bolus (1 gr/kg per day). During follow-up, terlipressin treatment is recommended as 25–50 g/day until discontinuation. TIPS therapy until liver transplantation can sometimes be successful in specially selected patients who are unresponsive to medical therapy [57–59].

#### **2.5 Hepatopulmonary syndrome**

Hepatopulmonary syndrome (HPS) is the most common cause of respiratory failure in patients with chronic liver disease. It is characterized by a gas exchange abnormality caused by intrapulmonary vascular dilatations (IPVD) in liver patients. Its incidence ranges from 4–47%. The pathogenesis of HPS includes a complex pathogenetic mechanism such as increased nitric oxide production, angiogenesis, intrapulmonary shunt and ventilation perfusion mismatch. Clinical consequences of hypoxemia can be seen together with progressive dyspnea, cyanosis, clubbing, platypnea and orthodoxy, and chronic pulmonary comorbidity (COPD, asthma bronchiale, idiopathic pulmonary fibrosis, restrictive lung disease).

Hepatopulmonary syndrome diagnostic criteria are partial oxygen pressure < 80 mmHg or alveolar-arterial oxygen gradient ≥15 mmHg (PO2 gradient) (or > 20 mmHg over 65 years of age). Detection of intrapulmonary vascular dilatation (Contrasted ECO cardıography or lung perfusion scan with radioactive albumin). Liver transplantation is the only successful treatment that alters the natural history of HPS and improves arterial hypoxemia. There is no effective treatment support for HPS other than long-term oxygen support [60–62].

#### **2.6 Acute on chronic liver failure**

Acute on chronic liver failure (ACLF) is a clinical sudden hepatic decompensation syndrome associated with one or more extra hepatic organ failure, increased mortality, observed in patients with pre-existing chronic liver disease. Hepatic causes include alcohol-related liver damage, drug-induced hepatic damage, viral hepatitis (A, B, C, D, and E), hypoxic damage or liver surgeries, including TIPS, in the etiology of pre-existing liver disease precipitating events. Extrahepatic causes are

**221**

transplant facilities.

*LVP: large volume paracentesis.*

**Figure 2.**

treatment of associated complications.

**2.7 Gut microbiota relationship in decompensated cirrhosis**

*Treatment Approach in Patients with Decompensated Liver Cirrhosis*

bacterial infection and major surgical interventions. In patients with chronic liver disease, acute triggering agents trigger inflammatory cytokine cascade by causing hepatocyte damage, leading to further liver damage decompensation, multi-organ failure and death in the presence of insufficient hepatocyte regeneration [63, 64]. It consists of prevention of triggering factors that lead to acute decompensation, supportive therapy, early initiation of specific therapy and management of complications (**Figure 2**). All patients should be followed, preferably in a center with liver

*Treatment approaches in organ failure due to acute on chronic liver failure (ACLF), AKI: Acute kidney* ı*njury, KDIGO: kidney disease improving globai outcomes, HE: Hepatic encephalopathy, HRS: Hepatorenal syndrome,* 

The essence of ACLF treatment is based on supportive treatment of organ failure in intensive care conditions. Liver transplantation is a good long-term effective treatment for selected patients. Potential treatment alternatives that will improve patient survival are highly awaited. There is currently no specific effective treatment for their patients. Therefore, treatment is based on organ support and

Cirrhosis is associated with an altered immune response in the stool, potentially due to dysbiosis in the intestinal mucosa. Patients with cirrhosis have an altered gut-liver axis associated with changes in gut microbiota composition and function, associated with liver disease severity, intestinal barrier disorder, and changes in intestinal and systemic inflammation. Microbiota is one of the organs most exposed to intestinal toxins through the liver portal system. The gut microbiota is the first line of defense against toxic bacterial products in protecting the host's mucosal barrier integrity. Firmicutes, bacteroidetes, actinobacteria, proteobacteria, verrucomicrobia and

*DOI: http://dx.doi.org/10.5772/intechopen.96155*

#### *Treatment Approach in Patients with Decompensated Liver Cirrhosis DOI: http://dx.doi.org/10.5772/intechopen.96155*

**Figure 2.**

*Advances in Hepatology*

**Table 5.**

**HRS subtypes according to the new classification**

In patients followed up with HRS in the intensive care unit, initial treatment is recommended as a combination of norepinephrine and albumin. (norepinephrine intravenously continuous infusion 0.5–3 mg/hr, albumin intravenous bolus 1 g/kg per day for at least two days). Terlipressin albumin combination is recommended as the initial therapy in HRS patients outside the intensive care unit. Terlipressin 1–2 mg is recommended as an intravenous bolus every 4 to 6 hours. Albumin is given for 2 days as intravenous bolus (1 gr/kg per day). During follow-up, terlipressin treatment is recommended as 25–50 g/day until discontinuation. TIPS therapy until liver transplantation can sometimes be successful in specially selected patients

*HRS AKI Hepatorenal sendrom acute kidney injury, NRS NAKI hepatorenal sendrom non acute kidney injury sCr,* 

Urine amount ≤ 0.5 ml/kg B.W. ≥6 h or

sCr ≥ 50% according to basal value, increase within 3 months

<50% increase in sCr basal value within 3 months in outpatients

in the absence of other structural causes

**Criteria**

HRS AKI sCr ≥ 0.3 mg/dl increase up to 48 hours and/or

HRS NAKI eGFR <60 ml/min 1.73 m2

*serum creatinine, eGFR estimated glomerular filtration rate.*

*Classification of Hepatorenal syndrome subtypes in cirrhosis.*

Hepatopulmonary syndrome (HPS) is the most common cause of respiratory failure in patients with chronic liver disease. It is characterized by a gas exchange abnormality caused by intrapulmonary vascular dilatations (IPVD) in liver patients. Its incidence ranges from 4–47%. The pathogenesis of HPS includes a complex pathogenetic mechanism such as increased nitric oxide production, angiogenesis, intrapulmonary shunt and ventilation perfusion mismatch. Clinical consequences of hypoxemia can be seen together with progressive dyspnea, cyanosis, clubbing, platypnea and orthodoxy, and chronic pulmonary comorbidity (COPD, asthma

bronchiale, idiopathic pulmonary fibrosis, restrictive lung disease).

support for HPS other than long-term oxygen support [60–62].

Hepatopulmonary syndrome diagnostic criteria are partial oxygen pressure < 80 mmHg or alveolar-arterial oxygen gradient ≥15 mmHg (PO2 gradient) (or > 20 mmHg over 65 years of age). Detection of intrapulmonary vascular dilatation (Contrasted ECO cardıography or lung perfusion scan with radioactive albumin). Liver transplantation is the only successful treatment that alters the natural history of HPS and improves arterial hypoxemia. There is no effective treatment

Acute on chronic liver failure (ACLF) is a clinical sudden hepatic decompensation syndrome associated with one or more extra hepatic organ failure, increased mortality, observed in patients with pre-existing chronic liver disease. Hepatic causes include alcohol-related liver damage, drug-induced hepatic damage, viral hepatitis (A, B, C, D, and E), hypoxic damage or liver surgeries, including TIPS, in the etiology of pre-existing liver disease precipitating events. Extrahepatic causes are

who are unresponsive to medical therapy [57–59].

**2.5 Hepatopulmonary syndrome**

**2.6 Acute on chronic liver failure**

**220**

*Treatment approaches in organ failure due to acute on chronic liver failure (ACLF), AKI: Acute kidney* ı*njury, KDIGO: kidney disease improving globai outcomes, HE: Hepatic encephalopathy, HRS: Hepatorenal syndrome, LVP: large volume paracentesis.*

bacterial infection and major surgical interventions. In patients with chronic liver disease, acute triggering agents trigger inflammatory cytokine cascade by causing hepatocyte damage, leading to further liver damage decompensation, multi-organ failure and death in the presence of insufficient hepatocyte regeneration [63, 64].

It consists of prevention of triggering factors that lead to acute decompensation, supportive therapy, early initiation of specific therapy and management of complications (**Figure 2**). All patients should be followed, preferably in a center with liver transplant facilities.

The essence of ACLF treatment is based on supportive treatment of organ failure in intensive care conditions. Liver transplantation is a good long-term effective treatment for selected patients. Potential treatment alternatives that will improve patient survival are highly awaited. There is currently no specific effective treatment for their patients. Therefore, treatment is based on organ support and treatment of associated complications.

#### **2.7 Gut microbiota relationship in decompensated cirrhosis**

Cirrhosis is associated with an altered immune response in the stool, potentially due to dysbiosis in the intestinal mucosa. Patients with cirrhosis have an altered gut-liver axis associated with changes in gut microbiota composition and function, associated with liver disease severity, intestinal barrier disorder, and changes in intestinal and systemic inflammation. Microbiota is one of the organs most exposed to intestinal toxins through the liver portal system. The gut microbiota is the first line of defense against toxic bacterial products in protecting the host's mucosal barrier integrity. Firmicutes, bacteroidetes, actinobacteria, proteobacteria, verrucomicrobia and

fusobacteria are the main intestinal bacteria in the gastrointestinal flora. Firmicutes and bacteroidetes make up 90% of all bacteria [65]. Gastrointestinal system microbiota plays an important role in providing intestinal epithelial permeability and barrier function in NAFLD/NASH. Toxic bacterial products such as lipopolysaccharides bind to the CD14 receptor with Toll-like receptors (TLR), and stress-activated protein kinase, JNK, P38, interferon regulatory factor 3, nuclear factor JB play a role in the NASH process by initiating inflammatory cascade [66, 67]. In animal models, it has been shown that feeding mice with impaired intestinal barrier function with a diet containing high saturated fat, fructose and cholesterol leads to more severe steatohepatitis development compared to the control group [68]. Nutrition with a high fat diet; Atrophy in epithelial cell microvilli, disruption in the tight junction between cells, bacterial overgrowth in the small intestine (SIBO) is more severe in NASH than in NAFLD. Change in intestinal barrier function; Lipopolysaccharide and toxic bacterial products (other organic compounds such as ethanol, acetone, butanoic acid) cause the liver to be exposed to higher levels of inflammatory bacterial metabolites [69].

#### **2.8 Artificial liver support systems**

Artificial liver support systems (ALSS) are used to provide recovery in patients with acute liver failure (ALF) and acute-chronic liver failure and to act as a bridge until transplantation. There are two main types of devices, artificial and bioartificial. Artificial liver devices are detoxification of blood or plasma, removal of physical and chemical gradients, removal of toxic and metabolic wastes by means of albumin. There are artificial liver support systems used today, such as Molecular adsorbent recirculating system (MARS), single - pass albumin dialysis (SPAD), Prometheus, selective plasma filtration therapy and hemodiafiltration. There was no difference between Prometheus and standard medical treatment in terms of survival. The role of TPE2 in patients with ALF plasmapheresis ACLF is not known. Prospective studies are needed on this issue. Its effectiveness in hemodialysis patients with ALF and ACLF remains unclear. The effect of MARS therapy on ACLF and ALF survival has not been demonstrated [70, 71].

#### **3. Conclusions**

Portal hypertension has an important place in complications and deaths related to cirrhosis. Non-selective beta blockers occupy an important place in the medical treatment of portal hypertension, but their potential side effects limit their use. New agents that suppress fibrosis, tissue damage and angiogenesis are needed in cirrhosis. Statins and PPARα/y agonists may be an alternative in this regard. Intestinal microbiota (systemic inflammation, dysbiosis, increased intestinal permeability, endotoxemia, impaired intestinal motility, bacterial overgrowth, increased production of short-chain fatty acids and changes in metabolism) play an important role in the pathogenesis of liver diseases. Dysbiosis plays a key role in the development of cirrhosis-related complications. Moreover, modulation of the microbiome with current and future therapeutic strategies is thought to be the cornerstone of cirrhosis management. It is predicted that the microbiota will play an important role in developing new prognostic and therapeutic strategies in cirrhotic patients.

**223**

**Author details**

Adana, Turkey

Anıl Delik\* and Yakup Ülger

Department of Gastroenterology, Faculty of Medicine, Çukurova University,

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: anildelik@gmail.com

provided the original work is properly cited.

*Treatment Approach in Patients with Decompensated Liver Cirrhosis*

*DOI: http://dx.doi.org/10.5772/intechopen.96155*

### **Conflict of interest**

The authors declare no conflict of interest.

*Treatment Approach in Patients with Decompensated Liver Cirrhosis DOI: http://dx.doi.org/10.5772/intechopen.96155*

*Advances in Hepatology*

**2.8 Artificial liver support systems**

and ALF survival has not been demonstrated [70, 71].

fusobacteria are the main intestinal bacteria in the gastrointestinal flora. Firmicutes and bacteroidetes make up 90% of all bacteria [65]. Gastrointestinal system microbiota plays an important role in providing intestinal epithelial permeability and barrier function in NAFLD/NASH. Toxic bacterial products such as lipopolysaccharides bind to the CD14 receptor with Toll-like receptors (TLR), and stress-activated protein kinase, JNK, P38, interferon regulatory factor 3, nuclear factor JB play a role in the NASH process by initiating inflammatory cascade [66, 67]. In animal models, it has been shown that feeding mice with impaired intestinal barrier function with a diet containing high saturated fat, fructose and cholesterol leads to more severe steatohepatitis development compared to the control group [68]. Nutrition with a high fat diet; Atrophy in epithelial cell microvilli, disruption in the tight junction between cells, bacterial overgrowth in the small intestine (SIBO) is more severe in NASH than in NAFLD. Change in intestinal barrier function; Lipopolysaccharide and toxic bacterial products (other organic compounds such as ethanol, acetone, butanoic acid) cause the liver to be exposed to higher levels of inflammatory bacterial metabolites [69].

Artificial liver support systems (ALSS) are used to provide recovery in patients with acute liver failure (ALF) and acute-chronic liver failure and to act as a bridge until transplantation. There are two main types of devices, artificial and bioartificial. Artificial liver devices are detoxification of blood or plasma, removal of physical and chemical gradients, removal of toxic and metabolic wastes by means of albumin. There are artificial liver support systems used today, such as Molecular adsorbent recirculating system (MARS), single - pass albumin dialysis (SPAD), Prometheus, selective plasma filtration therapy and hemodiafiltration. There was no difference between Prometheus and standard medical treatment in terms of survival. The role of TPE2 in patients with ALF plasmapheresis ACLF is not known. Prospective studies are needed on this issue. Its effectiveness in hemodialysis patients with ALF and ACLF remains unclear. The effect of MARS therapy on ACLF

Portal hypertension has an important place in complications and deaths related to cirrhosis. Non-selective beta blockers occupy an important place in the medical treatment of portal hypertension, but their potential side effects limit their use. New agents that suppress fibrosis, tissue damage and angiogenesis are needed in cirrhosis. Statins and PPARα/y agonists may be an alternative in this regard. Intestinal microbiota (systemic inflammation, dysbiosis, increased intestinal permeability, endotoxemia, impaired intestinal motility, bacterial overgrowth, increased production of short-chain fatty acids and changes in metabolism) play an important role in the pathogenesis of liver diseases. Dysbiosis plays a key role in the development of cirrhosis-related complications. Moreover, modulation of the microbiome with current and future therapeutic strategies is thought to be the cornerstone of cirrhosis management. It is predicted that the microbiota will play an important role in

developing new prognostic and therapeutic strategies in cirrhotic patients.

**222**

**Conflict of interest**

The authors declare no conflict of interest.

**3. Conclusions**

#### **Author details**

Anıl Delik\* and Yakup Ülger Department of Gastroenterology, Faculty of Medicine, Çukurova University, Adana, Turkey

\*Address all correspondence to: anildelik@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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hbpd.2018.01.005

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10.1080/03007995.2018.1552575

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[47] Iwasa M., Takei Y. Pathophysiology

Ammonia toxicity and hyponatremia: Management of hepatic encephalopathy. Hepatology Research, 2015:45(12), 1155-1162. doi:10.1111/hepr.12495

[48] Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441-9. DOİ.org/10.1002/

[49] Ahluwalia V, Betrapally NS, Hylemon PB. Impaired gut-liver-brain axis in patients with cirrhosis. Sci Rep 2016;6:26800. DOI: 10.1038/srep26800

[50] Cao Q, Yu CB, ang SG, et al. Effect of probiotic treatment on cirrhotic patients with minimal

and management of hepatic encephalopathy 2014 update:

jceh.2014.10.001

#### *Treatment Approach in Patients with Decompensated Liver Cirrhosis DOI: http://dx.doi.org/10.5772/intechopen.96155*

[43] Dharel N, Bajaj JS. Definition and nomenclature of hepatic encephalopathy. J Clin Exp Hepatol. 2015;5:S37-S41. DOI: 10.1016/j. jceh.2014.10.001

*Advances in Hepatology*

gie.2006.08.023

cmh.2020.0022

10.1002/hep.28906

gutjnl-2015-309262]

[30] Kovalak M, Lake J, Mattek N, Eisen G, Lieberman D, Zaman A. Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database. Gastrointest Endosc. 2007;65:82-88. DOI: 10.1016/j.

Mostafa I, Devière J. Early application of haemostatic powder added to standard management for oesophagogastric variceal bleeding: a randomised trial. Gut 2018 [PMID: 29730601 DOI: 10.1136/gutjnl-2017-314653]

[37] Holster IL, Poley JW, Kuipers EJ, Tjwa ET. Controlling gastric variceal bleeding with endoscopically applied hemostatic powder (Hemospray™). J Hepatol 2012; 57: 1397-1398 [PMID: 22864337 DOI: 10.1016/j.

jhep.2012.07.024]

[38] Carbonell N, Pauwels A, Serfaty L, Fourdan O, Lévy VG, Poupon R. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 2004; 40: 652-659 [PMID: 15349904 DOI: 10.1002/hep.20339]

[39] Panés J, Terés J, Bosch J,

Rodés J. Efficacy of balloon tamponade in treatment of bleeding gastric and esophageal varices. Results in 151 consecutive episodes. Dig Dis Sci 1988; 33: 454-459 [PMID: 3280273] DOI: 10.1097/MD.0000000000013437

[40] de Franchis R; Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63:743- 752. DOI: 10.1016/j.jhep.2015.05.022

[41] Vine, Louisa J., Mohsan Subhani, and Juan G. Acevedo. "Update on management of gastric varices." World Journal of Hepatology 11.3 :2019: 250.

Transjugular Intrahepatic Portosystemic Shunt with Covered Stent and Balloon-Occluded Retrograde Transvenous Obliteration in Managing Isolated Gastric Varices. Korean J Radiol 2017; 18: 345-354 [PMID: 28246514 DOI:

DOI: 10.4254/wjh.v11.i3.250

[42] Kim SK, Lee KA, Sauk S, Korenblat K. Comparison of

10.3348/kjr.2017.18.2.345].

[31] Lesmana, CRA, Raharjo, M, Gani, RA. Managing liver cirrhotic complications: Overview of esophageal and gastric varices. Clinical and molecular hepatology. 2020;26(4): 444. DOI:https://doi.org/10.3350/

[32] Garcia-Tsao, Guadalupe, et al. "Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association

for the study of liver diseases." Hepatology 65.1 :2017: 310-335. DOI:

[33] Zhou X, Tripathi D, Song T, Shao L, Han B, Zhu J, Han D, Liu F, Qi X. Terlipressin for the treatment of acute variceal bleeding: A

systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2018; 97: e13437 [PMID: 30508958 DOI: 10.1097/ MD.0000000000013437]

[34] Tripathi D, Stanley AJ, Hayes PC, Patch D, Millson C, Mehrzad H, etal Clinical Services and Standards Committee of the British Society of Gastroenterology. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut 2015; 64: 1680- 1704 [PMID: 25887380 DOI: 10.1136/

[35] McAvoy NC, Plevris JN, Hayes PC. Human thrombin for the treatment of gastric and ectopic varices. World J Gastroenterol 2012; 18: 5912-5917 [PMID: 23139607 DOI: 10.3748/wjg.v18.

[36] Ibrahim M, El-Mikkawy A, Abdel Hamid M, Abdalla H, Lemmers A,

**226**

i41.5912]

[44] Vilstrup H., Amodio P., Bajaj J., Cordoba J., Ferenci P., Mullen K. D., Wong P. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology, 2014:60(2), 715- 735. doi:10.1016/j.jhep.2014.05.042

[45] Tranah T., Paolino A., Shawcross D. Pathophysiological mechanisms of hepatic encephalopathy: Pathophysiological mechanisms. Clinical Liver Disease, 2015:5(3), 59-63. doi:10.1002/cld.445

[46] Butt Z., Jadoon N., Salaria O., Mushtaq K., Riaz I., Shahzad A., Sarwar S. Diabetes mellitus and decompensated cirrhosis: Risk of hepatic encephalopathy in different age groups. Journal of Diabetes, 2013:5(4), 449-455. doi:10.1111/1753-0407.12067

[47] Iwasa M., Takei Y. Pathophysiology and management of hepatic encephalopathy 2014 update: Ammonia toxicity and hyponatremia: Management of hepatic encephalopathy. Hepatology Research, 2015:45(12), 1155-1162. doi:10.1111/hepr.12495

[48] Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004;39:1441-9. DOİ.org/10.1002/ hep.20194

[49] Ahluwalia V, Betrapally NS, Hylemon PB. Impaired gut-liver-brain axis in patients with cirrhosis. Sci Rep 2016;6:26800. DOI: 10.1038/srep26800

[50] Cao Q, Yu CB, ang SG, et al. Effect of probiotic treatment on cirrhotic patients with minimal

hepatic encephalopathy: a metaanalysis. HepatobiliaryPancreat Dis Int 2018;17(1):9-16. DOI: 10.1016/j. hbpd.2018.01.005

[51] Bai Z., Bernardi M., Yoshida EM., Li, H., Guo, X., Méndez-Sánchez, N. et al. Albumin infusion may decrease the incidence and severity of overt hepatic encephalopathy in liver cirrhosis. Aging (Albany NY), 2019:11(19), 8502. DOI: 10.18632/aging.102335.

[52] Dalal R, McGee RG, Riordan SM, et al. Probiotics for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;2:CD008716. DOI: 10.1002/14651858.CD008716.pub3

[53] Rose CF, Amodio P, Bajaj JS, Dhiman RK, Montagnese S, taylor-Robinson SD, et al. Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. Journal of Hepatology . 2020;73:1526-1547. DOI:https://doi. org/10.1016/j.jhep.2020.07.013

[54] Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology. 2017;66:1727-1738. DOI: 10.1002/hep.29306

[55] Amin AA, Alabsawy EI, Jalan R, davenport A. Epidemiology, Pathophysiology, and Management of Hepatorenal Syndrome. Seminars in Nephrology. 2019;39:1:17-30. DOI: 10.1016/j.semnephrol.2018.10.002.

[56] Zhang, J., Rössle, M., Zhou, X., Deng, J., Liu, L., Qi, X. Terlipressin for the treatment of hepatorenal syndrome: an overview of current evidence. Current medical research and opinion. 2019;35(5): 859-868. DOI: 10.1080/03007995.2018.1552575

[57] Rajesh, S., George, T., Philips, C. A., Ahamed, R., Kumbar, S., Mohan, N. et al. Transjugular intrahepatic

portosystemic shunt in cirrhosis: An exhaustive critical update. World Journal of Gastroenterology. 2020:26(37); 5561. DOİ: 10.3748/wjg. v26.i37.556.

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**229**

**Chapter 14**

**Abstract**

Therapy that Targets Growth

for Liver Cirrhosis Treatment

*Halyna Kuznietsova and Olexandr Ogloblya*

and *in vivo* models, are also presented.

**1. Introduction**

Factor Receptors: Novel Approach

The background of liver fibrous degeneration is excessive cell proliferation including hepatic stellate cells, inflammatory cells, fibroblasts and myofibroblasts. Often it is the consequence of increased growth factors and/or their receptors expression. Key contributors to the liver cell proliferation are EGFR, FGFR, PDGFR, VEGFR, TGFβR, the increased expression of which is indicated on *in vitro* and *in vivo* models of liver fibrosis and in patients who experienced fibrosis-accompanied liver diseases. Elimination of growth factors/suppression of their receptors is associated with the weakening/elimination of certain processes responsible for fibrogenesis. This chapter represents the evidences of the efficacy of growth factor receptors signaling downregulation for the suppression of liver fibrosis and cirrhosis and their individual manifestations. The data on established and experimental therapeutics – specific and multikinase growth factor receptor inhibitors which demonstrated antifibrotic and anticirrhotic activity under *in vitro*

**Keywords:** EGFR, VEGFR, PDGFR, FGFR, TGFβR, tyrosine kinase inhibitors

If organs with high regenerative capacity undergo chronic injury and inflammation, their healing often occurs abnormally - due to replacement of the damaged elements with connective tissue. The most striking example of such distorted regeneration is the development of liver fibrosis and cirrhosis on the background of its chronic damage. Fibrosis is an "exceeding" healing accompanied with the formation of an excessive amount of connective tissue incorporated into liver parenchyma due to extracellular matrix (ECM) overproduction and/or its incomplete degradation. The main etiological factors of liver fibrosis and cirrhosis are alcohol, storage diseases, hepatitis viruses, hepatotoxic drugs, cholestasis, and autoimmune reactions. The trigger of fibrogenesis is chronic injury accompanied by an inflammatory component, which causes the activation and expansion of mesenchymal cells (including fibroblasts, myofibroblasts, smooth muscle cells) and increased synthesis of ECM molecules, predominantly collagen. Cells involved into the inflammation actively produce soluble factors like pro-inflammatory cytokines, endothelins, growth factors, reactive oxygen and nitrogen species, which also promote fibrogenesis [1, 2]. The final stage of organ's fibrosis is cirrhosis - the

#### **Chapter 14**

*Advances in Hepatology*

v26.i37.556.

portosystemic shunt in cirrhosis: An exhaustive critical update. World Journal of Gastroenterology. 2020:26(37); 5561. DOİ: 10.3748/wjg. [65] Zhou D, Fan JG. Gut microbiota and energy balance: role in obesity. Proc Nutr Soc. 2015;74:227-234. DOİ:

[66] Bajaj JS. Altered Microbiota in Cirrhosis and its relationship to the Development of infection. Clinical Liver Disease, 2019:14(3), 107. DOI: 10.1002/

[67] Zheng, R., Wang, G., Pang, Z., Ran, N., Gu, Y., Guan, X. et al. Liver cirrhosis contributes to the disorder of gut microbiota in patients with hepatocellular carcinoma. Cancer Medicine. 2020. Jun;9(12):4232-4250.

[68] Rahman K, Desai C, Iyer SS, et al. Loss of junctional adhesion molecule A promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology. 2016;151:733-746 e712. DOİ: 10.1053/j.

[69] Mao JW, Tang HY, Zhao T, et al. Intestinal mucosal barrier dysfunction

[70] Larsen, FS. Artificial liver support in acute and acute-on-chronic liver failure. Current opinion in critical care, 2019;25(2):187-191. DOI: 10.1097/

[71] Tandon, R., and Froghi, S. Artificial

Gastroenterology and Hepatology. 2020.

liver support systems. Journal of

participates in the progress of nonalcoholic fatty liver disease. Int J Clin Exp Pathol. 2015;8:3648-3658.

MCC.0000000000000584

DOİ: 10.1111/jgh.15255.

DOİ: 10.1002/cam4.3045.

gastro.2016.06.022

PMID: 26097546

10.1017/S0029665114001700.

cld.827.

[58] Bruce AR. Hepatorenal syndrome. UpToDate. 2020. www.uptodate.com/ contents/hepatorenal-syndrome

[59] Angeli P, Garcia-Tsao G, Nadim MK, Parikh CR. News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the ınternatıonal club of ascites (ıCA) consensus document. 2019;71:811-822.

[60] Krowka MJ, Fallon MB, Kawut SM, et al. International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome and Portopulmonary Hypertension. Transplantation 2016; 100:1440. DOI: 10.1097/ TP.0000000000001229

[61] Nayyar D, Man HS, Granton J, et al. Proposed management algorithm for severe hypoxemia after liver

transplantation in the hepatopulmonary syndrome. Am J Transplant 2015; 15:903. DOI: 10.1111/ajt.13177

[62] Zhao H, Liu F, Yue Z, et al. Clinical efficacy of transjugular intrahepatic portosystemic shunt in the treatment of hepatopulmonary syndrome. Medicine (Baltimore) 2017; 96:e9080. DOİ: 10.1097/MD.0000000000009080

[63] Arroyo V, Moreau R, Jalan R. Acuteon-Chronic Liver Failure. New England journal of Medicine. 2020;382:2137- 2145. DOI: 10.1056/NEJMra1914900

[64] Zaccherini G, Weiss E, Moreau R. Acute-on-Chronic liver failure: Definitions pathophysiology and principles of treatment. JHEP Reports. 2020;100176. DOI: 10.1016/j.

jhepr.2020.100176

DOI: 10.1016/j.jhep.2019.07.002

**228**

## Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment

*Halyna Kuznietsova and Olexandr Ogloblya*

#### **Abstract**

The background of liver fibrous degeneration is excessive cell proliferation including hepatic stellate cells, inflammatory cells, fibroblasts and myofibroblasts. Often it is the consequence of increased growth factors and/or their receptors expression. Key contributors to the liver cell proliferation are EGFR, FGFR, PDGFR, VEGFR, TGFβR, the increased expression of which is indicated on *in vitro* and *in vivo* models of liver fibrosis and in patients who experienced fibrosis-accompanied liver diseases. Elimination of growth factors/suppression of their receptors is associated with the weakening/elimination of certain processes responsible for fibrogenesis. This chapter represents the evidences of the efficacy of growth factor receptors signaling downregulation for the suppression of liver fibrosis and cirrhosis and their individual manifestations. The data on established and experimental therapeutics – specific and multikinase growth factor receptor inhibitors which demonstrated antifibrotic and anticirrhotic activity under *in vitro* and *in vivo* models, are also presented.

**Keywords:** EGFR, VEGFR, PDGFR, FGFR, TGFβR, tyrosine kinase inhibitors

#### **1. Introduction**

If organs with high regenerative capacity undergo chronic injury and inflammation, their healing often occurs abnormally - due to replacement of the damaged elements with connective tissue. The most striking example of such distorted regeneration is the development of liver fibrosis and cirrhosis on the background of its chronic damage. Fibrosis is an "exceeding" healing accompanied with the formation of an excessive amount of connective tissue incorporated into liver parenchyma due to extracellular matrix (ECM) overproduction and/or its incomplete degradation.

The main etiological factors of liver fibrosis and cirrhosis are alcohol, storage diseases, hepatitis viruses, hepatotoxic drugs, cholestasis, and autoimmune reactions. The trigger of fibrogenesis is chronic injury accompanied by an inflammatory component, which causes the activation and expansion of mesenchymal cells (including fibroblasts, myofibroblasts, smooth muscle cells) and increased synthesis of ECM molecules, predominantly collagen. Cells involved into the inflammation actively produce soluble factors like pro-inflammatory cytokines, endothelins, growth factors, reactive oxygen and nitrogen species, which also promote fibrogenesis [1, 2]. The final stage of organ's fibrosis is cirrhosis - the

irreversible replacement of a significant part of that by connective tissue, which leads to the organ's failure. The main cells which "trigger" liver fibrosis are hepatic stellate cells (HSC). Under liver injury and if being stimulated with cytokines produced by inflammatory cells, Kupffer cells and hepatocytes, HSCs are activated and transformed into myofibroblasts. The latters are able to migrate to the damaged area and produce a reduced number of matrix metalloproteinases (MMPs) and an increased number of their tissue inhibitors (TIMPs) and ECM proteins, causing the growth of connective tissue in liver and accumulation of fibrillar matrix into Disse spaces. Thick bundles of newly synthesized collagen fibers in the Disse spaces between hepatocytes are surrounded by fibroblasts, macrophages, HSCs, lymphocytes, polymorphonuclear leukocytes, eosinophils and plasmatic cells. These cells produce ROS, inflammatory mediators and growth factors, thus maintaining liver inflammation and promoting substantial disorders followed by cirrhosis development [3].

Cirrhosis is the endpoint of many liver diseases and causes the development of serious complications with possible fatal outcome. Those include: liver failure, gastrointestinal bleeding, portal hypertension, i.e. increased pressure in the portal vein, and hepatic coma. Thus, mortality from liver cirrhosis within 1 year after diagnosis varies from 1 to 57%, depending on the stage [4] and reaches more than 1.2 million deaths annually [5].

#### **2. The role of growth factors and their receptors in fibrogenesis**

Growth factor receptors are tightly involved in the pathogenesis of chronic inflammation due to their signaling close relationship with the major proinflammatory pathways. Those include, in particular, nuclear factor kappa B (NFκB), p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt), Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathways, which are activated not only by proinflammatory cytokines, but also by individual growth factors, such as transforming growth factor beta (TGFβ), TGFα, hepatocytes growth factor (HGF), epidermal growth factor (EGF), insulin-like growth factor (IGF) [6–9], associated with the "start" of regenerative processes.

The main proinflammatory pathways are also profibrogenic ones. Thus, NF-κB signaling provides not only survival and inflammatory reaction of Kupffer cells, but also survival, inflammatory response and activation of HSCs. Constitutive activity of this pathway in HSCs and/or hepatic myofibroblasts stimulates fibrous degeneration of the liver due to direct profibrogenic and antiapoptotic effects and by stimulating the secretion of cytokines - macrophage attractants [10]. Another proinflammatory pathway, STAT3, is involved in the control of MMPs and TIMPs transcription, TGF-β1 and ECM molecules synthesis and secretion, myofibroblasts proliferation and resistance to apoptosis, thus enhancing tissue regeneration. Activation of this pathway is observed in many tissues due to their fibrosis [11]. The PI3K/Akt pathway, in addition to its significant role in apoptosis inhibition and cell proliferation and survival, may promote epithelial-mesenchymal transition, thus contributing to fibrogenesis [12] (**Figure 1**). Furthermore, this pathway could be activated by EGF receptor (EGFR), the ligands of which are ones of the main profibrogenic growth factors [13]. P38 MAPK pathway is the one, the effects of the main profibrogenic cytokine TGF-β1 are realized through [14].

Macrophages and neutrophils, the first responders on damage and inducers of acute inflammation, also produce cytokines and chemokines, which serve as mitogens and chemoattractants for endothelial, epithelial and mesenchymal cells

**231**

**Figure 1.**

*Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment*

(myofibroblasts, HSCs) migrating to the cites of injury. With the chronicity of the inflammatory process, these cells are activated and secrete profibrogenic cytokines and growth factors such as TGF-β1, interleukin 13 (IL-13) and platelet-derived growth factor (PDGF), which further activate macrophages and fibroblasts and promote proliferation of those in addition to epithelial cells. Wound/injury healing also includes ECM synthesis and remodeling. Under chronic inflammation, this process is violated: the synthesis of ECM molecules prevails on their cleavage, lead-

Impaired activity of protein kinases, in particular growth factor receptors such as EGFR, vaso-endothelial growth factor receptor (VEGFR), PDGF receptor (PDGFR), fibroblast growth factor receptor (FGFR), play a significant role in development of numerous non-malignant liver diseases, including diseases associated with its fibrous degeneration [16]. Thus, PDGF is the most important cytokine responsible for the proliferation of HSCs; PDGF, VEGF and FGF2 induce their migration, TGF-β causes HSCs transformation to myofibroblasts, stimulates synthesis of ECM by those and inhibits its degradation. Inhibition of these growth factors receptors downregulates mentioned processes [17]. Furthermore, an excessive proliferation of cholangiocytes which express numerous cytokines, chemokines and growth factors is one of the main mechanisms of fibrogenesis. The proliferating cholangiocytes also involve myofibroblasts, fibroblasts and immune cells in this process [18, 19]. Therefore, activation of biliary proliferation (called ductular reaction)

ing to accumulation of those, which called fibrosis [15].

*The role of growth factor receptors in liver fibrogenesis.*

contributes a lot in the initiation and progression of liver fibrosis.

**3. Growth factor receptors as the targets of antifibrotic therapy**

There is no specific remedy for the liver fibrosis to date. Some compounds having therapeutic activity against liver fibrosis are undergoing preclinical and I-II phases of clinical trials. They include: (1) the monoclonal antibodies and low molecule inhibitors of key signaling pathways involved in the regulation of inflammation, HSCs life cycle and collagen metabolism [20]; (2) the broad-spectrum agents

*DOI: http://dx.doi.org/10.5772/intechopen.96552*

*Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment DOI: http://dx.doi.org/10.5772/intechopen.96552*

#### **Figure 1.**

*Advances in Hepatology*

cirrhosis development [3].

1.2 million deaths annually [5].

regenerative processes.

irreversible replacement of a significant part of that by connective tissue, which leads to the organ's failure. The main cells which "trigger" liver fibrosis are hepatic stellate cells (HSC). Under liver injury and if being stimulated with cytokines produced by inflammatory cells, Kupffer cells and hepatocytes, HSCs are activated and transformed into myofibroblasts. The latters are able to migrate to the damaged area and produce a reduced number of matrix metalloproteinases (MMPs) and an increased number of their tissue inhibitors (TIMPs) and ECM proteins, causing the growth of connective tissue in liver and accumulation of fibrillar matrix into Disse spaces. Thick bundles of newly synthesized collagen fibers in the Disse spaces between hepatocytes are surrounded by fibroblasts, macrophages, HSCs, lymphocytes, polymorphonuclear leukocytes, eosinophils and plasmatic cells. These cells produce ROS, inflammatory mediators and growth factors, thus maintaining liver inflammation and promoting substantial disorders followed by

Cirrhosis is the endpoint of many liver diseases and causes the development of serious complications with possible fatal outcome. Those include: liver failure, gastrointestinal bleeding, portal hypertension, i.e. increased pressure in the portal vein, and hepatic coma. Thus, mortality from liver cirrhosis within 1 year after diagnosis varies from 1 to 57%, depending on the stage [4] and reaches more than

**2. The role of growth factors and their receptors in fibrogenesis**

Growth factor receptors are tightly involved in the pathogenesis of chronic inflammation due to their signaling close relationship with the major proinflammatory pathways. Those include, in particular, nuclear factor kappa B (NFκB), p38 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt), Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathways, which are activated not only by proinflammatory cytokines, but also by individual growth factors, such as transforming growth factor beta (TGFβ), TGFα, hepatocytes growth factor (HGF), epidermal growth factor (EGF), insulin-like growth factor (IGF) [6–9], associated with the "start" of

The main proinflammatory pathways are also profibrogenic ones. Thus, NF-κB signaling provides not only survival and inflammatory reaction of Kupffer cells, but also survival, inflammatory response and activation of HSCs. Constitutive activity of this pathway in HSCs and/or hepatic myofibroblasts stimulates fibrous degeneration of the liver due to direct profibrogenic and antiapoptotic effects and by stimulating the secretion of cytokines - macrophage attractants [10]. Another proinflammatory pathway, STAT3, is involved in the control of MMPs and TIMPs transcription, TGF-β1 and ECM molecules synthesis and secretion, myofibroblasts proliferation and resistance to apoptosis, thus enhancing tissue regeneration. Activation of this pathway is observed in many tissues due to their fibrosis [11]. The PI3K/Akt pathway, in addition to its significant role in apoptosis inhibition and cell proliferation and survival, may promote epithelial-mesenchymal transition, thus contributing to fibrogenesis [12] (**Figure 1**). Furthermore, this pathway could be activated by EGF receptor (EGFR), the ligands of which are ones of the main profibrogenic growth factors [13]. P38 MAPK pathway is the one, the effects of the

main profibrogenic cytokine TGF-β1 are realized through [14].

Macrophages and neutrophils, the first responders on damage and inducers of acute inflammation, also produce cytokines and chemokines, which serve as mitogens and chemoattractants for endothelial, epithelial and mesenchymal cells

**230**

*The role of growth factor receptors in liver fibrogenesis.*

(myofibroblasts, HSCs) migrating to the cites of injury. With the chronicity of the inflammatory process, these cells are activated and secrete profibrogenic cytokines and growth factors such as TGF-β1, interleukin 13 (IL-13) and platelet-derived growth factor (PDGF), which further activate macrophages and fibroblasts and promote proliferation of those in addition to epithelial cells. Wound/injury healing also includes ECM synthesis and remodeling. Under chronic inflammation, this process is violated: the synthesis of ECM molecules prevails on their cleavage, leading to accumulation of those, which called fibrosis [15].

Impaired activity of protein kinases, in particular growth factor receptors such as EGFR, vaso-endothelial growth factor receptor (VEGFR), PDGF receptor (PDGFR), fibroblast growth factor receptor (FGFR), play a significant role in development of numerous non-malignant liver diseases, including diseases associated with its fibrous degeneration [16]. Thus, PDGF is the most important cytokine responsible for the proliferation of HSCs; PDGF, VEGF and FGF2 induce their migration, TGF-β causes HSCs transformation to myofibroblasts, stimulates synthesis of ECM by those and inhibits its degradation. Inhibition of these growth factors receptors downregulates mentioned processes [17]. Furthermore, an excessive proliferation of cholangiocytes which express numerous cytokines, chemokines and growth factors is one of the main mechanisms of fibrogenesis. The proliferating cholangiocytes also involve myofibroblasts, fibroblasts and immune cells in this process [18, 19]. Therefore, activation of biliary proliferation (called ductular reaction) contributes a lot in the initiation and progression of liver fibrosis.

#### **3. Growth factor receptors as the targets of antifibrotic therapy**

There is no specific remedy for the liver fibrosis to date. Some compounds having therapeutic activity against liver fibrosis are undergoing preclinical and I-II phases of clinical trials. They include: (1) the monoclonal antibodies and low molecule inhibitors of key signaling pathways involved in the regulation of inflammation, HSCs life cycle and collagen metabolism [20]; (2) the broad-spectrum agents

#### *Advances in Hepatology*

exhibiting antioxidant, anti-inflammatory, hepatoprotective, antilipotoxic activities such as ursolic, ursodeoxycholic and 24-norursodeoxycholic acids, resveratrol, silymarin [3]. However, the last agents are rather supplements, the positive effect of which is observed only in combination with other therapeutics.

Cytostatics like methotrexate and azathioprine are actively used for the treatment of diseases accompanied by fibrosis. However, due to the nonspecificity of action, they cause the development of numerous side effects. Therefore, the idea of using selective inhibitors of excessive cell proliferation can be fruitful. Impaired activity of tyrosine kinases, in particular growth factor receptors EGFR, VEGFR, PDGFR, TGFβR, and FGFR, contributes significantly to liver diseases associated with its fibrous degeneration [16]. Therefore, these receptors may be potential targets for antifibrotic therapy [21]. Among approved and experimental therapeutics tyrosine kinase inhibitors (TKIs) possess the leading position.

#### **3.1 VEGFR**

VEGF is a key regulator of liver cells proliferation. An increased expression of this growth factor and its receptors by the biliary cells was noted under liver biliary pathologies, in particular polycystic liver disease and primary biliary cirrhosis (PBC) [22]. PBC patients also demonstrated over-expression of the angiogenic factors Ang-1, Ang-2 and tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) their effects are realized by, in the epitheliocytes and periportal hepatocytes [23], suggesting, therefore, their contribution in fibrosis development. VEGF has been shown to stimulate also proliferation of sinusoidal endothelial cells and activated HSCs *in vitro*, indicating that VEGF-VEGFR interaction in HSCs plays an important role in liver fibrogenesis [24]. VEGFR inhibitor sunitinib significantly reduced the inflammatory infiltrate and collagen expression under liver cirrhosis [25]. Another small molecule tyrosine kinase inhibitor vatalanib, which is effective against all VEGF receptors, inhibited CCl4-induced mice liver fibrosis, as evidenced by decrease of fibrous tissue accumulation and hepatic sinusoidal capillarization, and downregulation of α-smooth muscle actin (α-SMA), collagen I and TGF-β1 expression as well [26] (**Table 1**). Similar results were demonstrated for pan-VEGFR tyrosine kinase inhibitor PTK787/ZK222584 [27].

#### **3.2 EGFR**

The EGFR signaling plays an important role in proliferation of liver progenitor cells and their differentiation into hepatocytes or cholangiocytes during the hepatic regeneration. In liver samples of primary sclerosing cholangitic (PSC) patients, the upregulation of EGFR compared to that of healthy individuals was revealed. EGFR is also required for the induction of active pro-inflammatory response by the cholangiocytes [28]. Indeed, the panitumumab, anti-EGFR antibody, inhibited an excessive proliferation of the bile duct mucosa and accumulation of collagen fibers in chronic proliferative cholangitis [29]. In addition, anti-EGFR antibodies applied at bile duct ligation (BDL) model inhibited biliary epithelium hyperplasia and fibrosis. EGFR inhibitor erlotinib inhibited proliferation of the cholangiocytes and hepatocytes, and prevented activation of HSCs, which was demonstrated on different (CCl4-, diethylnitrosamine (DEN)- and BDL-induced) rat models [30]. EGFR inhibition also significantly reduced viability and ECM production in activated HSCs, inhibited their proliferation and α-SMA production, but did not affect parenchymal cells [31, 32]. Moreover, inhibition of EGFR signaling by erlotinib and other specific inhibitors effectively prevented the progression of cirrhosis and regressed fibrosis in some animals [33, 34] (**Table 1**).

**233**

**3.3 FGFR**

**Table 1.**

*Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment*

mucosa excessive proliferation and accumulation of collagen

activated HSCs

expression

collagen I and TGF-β1

decrease HSC migration

Decrease of vascular density, inflammatory infiltrate, α-SMA and collagen expression

Stimulation of HSCs autophagy and apoptosis, inhibition of HSCs proliferation and collagen

Induce of HSCs apoptosis, inhibition of HSCs activation, α-SMA, MMP-2, TIMP-1 expression

Depression of HSCs activation, proliferation, migration, α-SMA formation, induce of HSCs apoptosis, reduce collagen deposition in activated HSCs and in liver tissues

Depression of HSCs activation, contractility, migration, collagen deposition, inhibition of macrophage migration

Reduce portal

regression

*TKIs which demonstrated antifibrotic effects, their molecular targets and cellular effects.*

Decrease of HSCs proliferation

hypertension, NO effects on HSCs activation and fibrosis progression or

deposition

fibers

**Drug Target(s) Cellular effects Model/Patients References**

chronic proliferative cholangitis

DEN-, BDLinduced rats, CCl4-induced mice

CCl4-induced mice

CCl4-, TAAinduced mice

CCl4-induced rats

High fat diet-, BDL-, DENinduced mice

CCl4-induced mice

CCl4- and BDLinduced rats

CCl4-induced mice

BDL-, CCl4 induced mice

BDL-, CCl4-, TAA-induced mice

Liu et al. 2019 [35]

Fuchs et al. 2014 [36]

Kong et al. 2017 [26]

Kim et al. 2012 [37]

Tugues et al. 2007 [25]

Wang et al. 2010 [38]

Elshal et al. 2015 [39]

Liu et al. 2011 [40]

Acora et al. 2017 [41]

Uschner et al. 2018 [42]

Nakamura et al. 2014 [17]

FGF family includes 7 subfamilies of growth factors (1, 4, 8, 9, 10, 11, 19) and four isoforms of their receptors (FGFR1, FGFR2, FGFR3, FGFR4), and all of them are involved in liver injury and regeneration. There is coordinated regulation of

*DOI: http://dx.doi.org/10.5772/intechopen.96552*

Panitumumab EGFR Inhibition of bile duct

Erlotinib EGFR Reduce the number of

Vatalanib VEGFR Inhibition of α-SMA,

Imatinib PDGFR Induce of HSC apoptosis,

PDGFR, c-Kit

VEGFR2/3, PDGFR-β

PDGFR-β, FGFR

PDGFR, TGFβRII

VEGFR, FGFR

PDGFR-β and FGFR, TIE2

FGFR

Sunitinib VEGFR,

Sorafenib Raf,

Pazopanib VEGFR1,

Nilotinib BCR-ABL,

Nintedanib PDGFR,

Regorafenib VEGFR1–3,

Brivanib VEGFR,


*Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment DOI: http://dx.doi.org/10.5772/intechopen.96552*

#### **Table 1.**

*Advances in Hepatology*

**3.1 VEGFR**

**3.2 EGFR**

exhibiting antioxidant, anti-inflammatory, hepatoprotective, antilipotoxic activities such as ursolic, ursodeoxycholic and 24-norursodeoxycholic acids, resveratrol, silymarin [3]. However, the last agents are rather supplements, the positive effect of

Cytostatics like methotrexate and azathioprine are actively used for the treatment of diseases accompanied by fibrosis. However, due to the nonspecificity of action, they cause the development of numerous side effects. Therefore, the idea of using selective inhibitors of excessive cell proliferation can be fruitful. Impaired activity of tyrosine kinases, in particular growth factor receptors EGFR, VEGFR, PDGFR, TGFβR, and FGFR, contributes significantly to liver diseases associated with its fibrous degeneration [16]. Therefore, these receptors may be potential targets for antifibrotic therapy [21]. Among approved and experimental therapeutics tyrosine

VEGF is a key regulator of liver cells proliferation. An increased expression of this growth factor and its receptors by the biliary cells was noted under liver biliary pathologies, in particular polycystic liver disease and primary biliary cirrhosis (PBC) [22]. PBC patients also demonstrated over-expression of the angiogenic factors Ang-1, Ang-2 and tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) their effects are realized by, in the epitheliocytes and periportal hepatocytes [23], suggesting, therefore, their contribution in fibrosis development. VEGF has been shown to stimulate also proliferation of sinusoidal endothelial cells and activated HSCs *in vitro*, indicating that VEGF-VEGFR interaction in HSCs plays an important role in liver fibrogenesis [24]. VEGFR inhibitor sunitinib significantly reduced the inflammatory infiltrate and collagen expression under liver cirrhosis [25]. Another small molecule tyrosine kinase inhibitor vatalanib, which is effective against all VEGF receptors, inhibited CCl4-induced mice liver fibrosis, as evidenced by decrease of fibrous tissue accumulation and hepatic sinusoidal capillarization, and downregulation of α-smooth muscle actin (α-SMA), collagen I and TGF-β1 expression as well [26] (**Table 1**). Similar results were demonstrated for pan-VEGFR

The EGFR signaling plays an important role in proliferation of liver progenitor cells and their differentiation into hepatocytes or cholangiocytes during the hepatic regeneration. In liver samples of primary sclerosing cholangitic (PSC) patients, the upregulation of EGFR compared to that of healthy individuals was revealed. EGFR is also required for the induction of active pro-inflammatory response by the cholangiocytes [28]. Indeed, the panitumumab, anti-EGFR antibody, inhibited an excessive proliferation of the bile duct mucosa and accumulation of collagen fibers in chronic proliferative cholangitis [29]. In addition, anti-EGFR antibodies applied at bile duct ligation (BDL) model inhibited biliary epithelium hyperplasia and fibrosis. EGFR inhibitor erlotinib inhibited proliferation of the cholangiocytes and hepatocytes, and prevented activation of HSCs, which was demonstrated on different (CCl4-, diethylnitrosamine (DEN)- and BDL-induced) rat models [30]. EGFR inhibition also significantly reduced viability and ECM production in activated HSCs, inhibited their proliferation and α-SMA production, but did not affect parenchymal cells [31, 32]. Moreover, inhibition of EGFR signaling by erlotinib and other specific inhibitors effectively prevented the progression of cirrhosis and regressed

which is observed only in combination with other therapeutics.

kinase inhibitors (TKIs) possess the leading position.

tyrosine kinase inhibitor PTK787/ZK222584 [27].

fibrosis in some animals [33, 34] (**Table 1**).

**232**

*TKIs which demonstrated antifibrotic effects, their molecular targets and cellular effects.*

#### **3.3 FGFR**

FGF family includes 7 subfamilies of growth factors (1, 4, 8, 9, 10, 11, 19) and four isoforms of their receptors (FGFR1, FGFR2, FGFR3, FGFR4), and all of them are involved in liver injury and regeneration. There is coordinated regulation of

FGFR activation and FGFs secretion during liver injury and subsequent healing: hepatocyte-derived FGFs activate FGFRs on HSCs, and FGFs produced by HSCs activate FGFRs on hepatocytes [38]. FGF signaling during liver damage enhances liver regeneration, however, its chronic production can also lead to the abnormal regeneration with subsequent fibrosis development.

FGF2, a main FGFR1 binding partner, is a mitogen for HSCs. FGFR1 overexpression has been reported in human liver myofibroblasts and activated HSCs compared to the non-activated ones [37]. Then, FGF2 also induces chemotaxis and chemoinvasion by HSCs and may participate in the recruitment and activation of HSCs in acute liver injury. Thus, Yu et al. demonstrated, that chronic hepatic fibrosis is markedly reduced in FGF1/FGF2-deficient mice. However, the absence of FGF1 and FGF2 did not impair the total number of HSCs and their migration into the areas of injury, but overproduction of matrix components, especially collagen α1(I), by those, and therefore excessive fibrous tissue accumulation. The probable explanation is that FGF1 and FGF2 are not essential activating ligands for proliferation and migration of activated HSCs *in vivo*, but the important ones for fibrosis progression [43].

Furthermore, blockade of FGFR1 by small molecule inhibitors prevents HSCs activation (as evidenced by diminishing of α-SMA expression by those), inhibits their proliferation and release of the inflammatory cytokines by those both *in vitro* and *in vivo*. *In vivo* experiments also demonstrated that such inhibition significantly ameliorates CCl4-induced hepatic fibrosis in a rat model [44, 45].

The ability of FGFs to regulate HSCs proliferation, migration, and transdifferentiation makes FGFR signaling an attractive target for the treatment of hepatic fibrosis. Therapeutic agents which are developing now aim to inhibit FGFRs, to modulate FGF expression, are recombinant FGF proteins, therefore achieving to inhibit EGFR signaling in all levels [37].

#### **3.4 PDGFR**

PDGF is the most prominent cytokine that regulates HSCs activation, proliferation and migration. Primary producers of PDGF are platelets, vascular endothelial cells, pericytes and Kupffer cells. PDGFR, tyrosine kinase receptor, is primarily located in vascular endothelial cells, fibroblasts and Kupffer cells. Under the liver injury macrophages, injured endothelial cells and activated HSCs synthesize and secrete PDGF which stimulates proliferation of fibroblasts and vascular endothelial cells via autocrine and paracrine mechanisms. Additionally, PDGF promotes HSCs transformation into myofibroblasts and collagen production by those. Marked upregulation of PDGFR expression on the membranes of activated HSCs have been shown under various chronic liver diseases associated with its fibrosis. Hence, PDGFR overexpression contributes to HSCs activation by synthesized PDGF via the autocrine mechanism and enhances cellular chemotaxis [46]. Additionally, clinical studies demonstrated an excessive activation of PDGF and its downstream molecules, and association of those with the extent of fibrosis in patients with hepatic damage.

There are four PDGF subunits (A, B, C and D) and 2 types of PDGFRs (α and β), and all of them are involved in different stages of hepatic fibrogenesis. Thus, PDGF-B is elevated during the early stage of the disease and is the most potent factor associated with HSCs activation, whereas PDGF-C and -D levels continuously rise during the whole process of HSCs transformation into myofibroblasts and demonstrate relatively high level at the late stage of hepatic fibrosis. Then, quiescent HSCs express PDGFR-α only, and activated ones – predominantly PDGFR-β.

**235**

**3.5 TGF**β**R**

*Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment*

The latter is substantially upregulated, and together with PDGF-B and -D serves

Activated PDGFR induces many signaling pathways, which regulate cell proliferation, migration and survival. In particular, activated Ras system through MAPK signaling cascade regulates the expression of collagen type I, MMPs, TIMPs genes responsible for ECM synthesis and degradation; phospholipase Cγ (PLCγ) signaling contributes to HSCs mitosis; PDGFR-activated PI3K/Akt and JAK/STAT pathways promote cell migration, mediate metabolic regulation, stimulate cell growth and

Blocking of PDGF signaling has been suggested to inhibit HSCs proliferation and to ameliorate liver fibrogenesis, so the strategies aimed to regulate that have been explored in preclinical and clinical investigations. Application of PDGF isoform antagonists, blocking of PDGFR activation and its downstream pathway regulation are considered as those ones. Thus, sorafenib (a first-line oral chemotherapy drug towards advanced hepatocellular carcinoma (HCC)) is a multikinase inhibitor that targets Raf, VEGFR2/3, and PDGFR-β and has been demonstrated to be a potent antifibrotic agent. The mechanisms of its antifibrotic action were revealed on mice models (high fat diet-, BDL- and DEN- induced ones) and include HSCs autophagy and apoptosis induction (through activation of Akt/mTOR and MAPK signaling pathways), suppression of neovascularization and oxidative stress (through PDGF, STAT3 and mitochondrial respiration downregulation), and inhibition of collagen deposition [47]. Imatinib, another selective TKI, which specifically targets PDGFR, attenuates liver fibrosis and additionally inhibits PDGFR-β expression and decreases the levels of proinflammatory cytokines. The ability of imatinib to induce HSCs apoptosis and substantially decrease their migration could contribute a lot to antifibrotic activity of that and was proven *in vitro* and on CCl4- and thioacetamide (TAA)-induced mice models [35] (**Table 1**). Strong antifibrotic activity under cholestatic liver diseases has been demonstrated for small molecule roseotoxin B, and investigation of its possible mechanisms revealed its ability to block the PDGF-B/

The great potency of PDGFR inhibitors was demonstrated on numerous animal and *in vitro* models. However, it is difficult and often impossible to distinguish the antifibrotic activity from anticancer one due to analysis of clinical trials outcomes. The first reason is that these agents are tested as anti-HCC therapeutics, and outcomes important for anticancer assessment only (like overall survival, disease-free survival etc.) are considered. The second possible reason is strong stratification of HCC patients involved in clinical trial according to their cirrhotic stage, and, despite "anticancer-important" outcomes are monitored thoroughly, the level of cirrhosis is not reassessed. So anticancer activity of the chemicals might be accompanied with antifibrotic one, however, it should be checked additionally. Furthermore, due to high similarity of the homologous domains of PDGFR and VEGFR, applied TKIs like sorafenib, sunitinib and pazopanib could not only inhibit PDGFR activation but also downregulate VEGFR (**Table 1**). It could indicate the complex and therefore more powerful action of these drugs on liver fibrogenesis, but, on the other hand, could also lead to non-target cells impairment and additional toxicity [49].

TGF-β is a cytokine which plays a prominent role in transformation of HSCs to myofibroblasts. Indeed, many of TGF-β pathological effects could be related with its ability to regulate cell plasticity – change of cell phenotype and function due to genetic and epigenetic changes and cytoskeleton remodeling. One of the

*DOI: http://dx.doi.org/10.5772/intechopen.96552*

important role in hepatic fibrosis [46].

PDGFR-β pathway in HSCs directly [48].

inhibit cellular apoptosis.

#### *Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment DOI: http://dx.doi.org/10.5772/intechopen.96552*

The latter is substantially upregulated, and together with PDGF-B and -D serves important role in hepatic fibrosis [46].

Activated PDGFR induces many signaling pathways, which regulate cell proliferation, migration and survival. In particular, activated Ras system through MAPK signaling cascade regulates the expression of collagen type I, MMPs, TIMPs genes responsible for ECM synthesis and degradation; phospholipase Cγ (PLCγ) signaling contributes to HSCs mitosis; PDGFR-activated PI3K/Akt and JAK/STAT pathways promote cell migration, mediate metabolic regulation, stimulate cell growth and inhibit cellular apoptosis.

Blocking of PDGF signaling has been suggested to inhibit HSCs proliferation and to ameliorate liver fibrogenesis, so the strategies aimed to regulate that have been explored in preclinical and clinical investigations. Application of PDGF isoform antagonists, blocking of PDGFR activation and its downstream pathway regulation are considered as those ones. Thus, sorafenib (a first-line oral chemotherapy drug towards advanced hepatocellular carcinoma (HCC)) is a multikinase inhibitor that targets Raf, VEGFR2/3, and PDGFR-β and has been demonstrated to be a potent antifibrotic agent. The mechanisms of its antifibrotic action were revealed on mice models (high fat diet-, BDL- and DEN- induced ones) and include HSCs autophagy and apoptosis induction (through activation of Akt/mTOR and MAPK signaling pathways), suppression of neovascularization and oxidative stress (through PDGF, STAT3 and mitochondrial respiration downregulation), and inhibition of collagen deposition [47]. Imatinib, another selective TKI, which specifically targets PDGFR, attenuates liver fibrosis and additionally inhibits PDGFR-β expression and decreases the levels of proinflammatory cytokines. The ability of imatinib to induce HSCs apoptosis and substantially decrease their migration could contribute a lot to antifibrotic activity of that and was proven *in vitro* and on CCl4- and thioacetamide (TAA)-induced mice models [35] (**Table 1**). Strong antifibrotic activity under cholestatic liver diseases has been demonstrated for small molecule roseotoxin B, and investigation of its possible mechanisms revealed its ability to block the PDGF-B/ PDGFR-β pathway in HSCs directly [48].

The great potency of PDGFR inhibitors was demonstrated on numerous animal and *in vitro* models. However, it is difficult and often impossible to distinguish the antifibrotic activity from anticancer one due to analysis of clinical trials outcomes. The first reason is that these agents are tested as anti-HCC therapeutics, and outcomes important for anticancer assessment only (like overall survival, disease-free survival etc.) are considered. The second possible reason is strong stratification of HCC patients involved in clinical trial according to their cirrhotic stage, and, despite "anticancer-important" outcomes are monitored thoroughly, the level of cirrhosis is not reassessed. So anticancer activity of the chemicals might be accompanied with antifibrotic one, however, it should be checked additionally. Furthermore, due to high similarity of the homologous domains of PDGFR and VEGFR, applied TKIs like sorafenib, sunitinib and pazopanib could not only inhibit PDGFR activation but also downregulate VEGFR (**Table 1**). It could indicate the complex and therefore more powerful action of these drugs on liver fibrogenesis, but, on the other hand, could also lead to non-target cells impairment and additional toxicity [49].

#### **3.5 TGF**β**R**

*Advances in Hepatology*

fibrosis progression [43].

**3.4 PDGFR**

hepatic damage.

inhibit EGFR signaling in all levels [37].

FGFR activation and FGFs secretion during liver injury and subsequent healing: hepatocyte-derived FGFs activate FGFRs on HSCs, and FGFs produced by HSCs activate FGFRs on hepatocytes [38]. FGF signaling during liver damage enhances liver regeneration, however, its chronic production can also lead to the abnormal

FGF2, a main FGFR1 binding partner, is a mitogen for HSCs. FGFR1 overexpression has been reported in human liver myofibroblasts and activated HSCs compared to the non-activated ones [37]. Then, FGF2 also induces chemotaxis and chemoinvasion by HSCs and may participate in the recruitment and activation of HSCs in acute liver injury. Thus, Yu et al. demonstrated, that chronic hepatic fibrosis is markedly reduced in FGF1/FGF2-deficient mice. However, the absence of FGF1 and FGF2 did not impair the total number of HSCs and their migration into the areas of injury, but overproduction of matrix components, especially collagen α1(I), by those, and therefore excessive fibrous tissue accumulation. The probable explanation is that FGF1 and FGF2 are not essential activating ligands for proliferation and migration of activated HSCs *in vivo*, but the important ones for

Furthermore, blockade of FGFR1 by small molecule inhibitors prevents HSCs activation (as evidenced by diminishing of α-SMA expression by those), inhibits their proliferation and release of the inflammatory cytokines by those both *in vitro* and *in vivo*. *In vivo* experiments also demonstrated that such inhibition significantly

The ability of FGFs to regulate HSCs proliferation, migration, and transdifferentiation makes FGFR signaling an attractive target for the treatment of hepatic fibrosis. Therapeutic agents which are developing now aim to inhibit FGFRs, to modulate FGF expression, are recombinant FGF proteins, therefore achieving to

PDGF is the most prominent cytokine that regulates HSCs activation, proliferation and migration. Primary producers of PDGF are platelets, vascular endothelial cells, pericytes and Kupffer cells. PDGFR, tyrosine kinase receptor, is primarily located in vascular endothelial cells, fibroblasts and Kupffer cells. Under the liver injury macrophages, injured endothelial cells and activated HSCs synthesize and secrete PDGF which stimulates proliferation of fibroblasts and vascular endothelial cells via autocrine and paracrine mechanisms. Additionally, PDGF promotes HSCs transformation into myofibroblasts and collagen production by those. Marked upregulation of PDGFR expression on the membranes of activated HSCs have been shown under various chronic liver diseases associated with its fibrosis. Hence, PDGFR overexpression contributes to HSCs activation by synthesized PDGF via the autocrine mechanism and enhances cellular chemotaxis [46]. Additionally, clinical studies demonstrated an excessive activation of PDGF and its downstream molecules, and association of those with the extent of fibrosis in patients with

There are four PDGF subunits (A, B, C and D) and 2 types of PDGFRs (α and β), and all of them are involved in different stages of hepatic fibrogenesis. Thus, PDGF-B is elevated during the early stage of the disease and is the most potent factor associated with HSCs activation, whereas PDGF-C and -D levels continuously rise during the whole process of HSCs transformation into myofibroblasts and demonstrate relatively high level at the late stage of hepatic fibrosis. Then, quiescent HSCs express PDGFR-α only, and activated ones – predominantly PDGFR-β.

ameliorates CCl4-induced hepatic fibrosis in a rat model [44, 45].

regeneration with subsequent fibrosis development.

**234**

TGF-β is a cytokine which plays a prominent role in transformation of HSCs to myofibroblasts. Indeed, many of TGF-β pathological effects could be related with its ability to regulate cell plasticity – change of cell phenotype and function due to genetic and epigenetic changes and cytoskeleton remodeling. One of the

most striking events of cell plasticity is epithelial-mesenchymal transition (EMT). Activation of HSCs and their transformation to myofibroblasts is an example of that one. Moreover, another example of cell transformation caused by TGF-β is EMT in hepatocytes accompanied with loss of cell–cell contacts and polarity [50]. Actually, TGF-β stimulates almost of all liver cell populations (portal and resident fibroblasts, bone marrow-derived fibrocytes, endothelial cells, vascular smooth muscle cells, pericytes and cholangiocytes additionally to hepatocytes and HSCs) to change into a more fibroblastic phenotype [40] and to release profibrogenic transcriptional program manifested by upregulation of collagen expression [41] and disturbances in ECM turnover through imbalance between MMPs and TIMPs. TGF-β receptors (TGFβRI and TGFβRII) are Ser/Tre protein kinases expressed on the membranes of various cells including all above mentioned ones. TGF-β is secreted by these cells and regulates their activity by autocrine and paracrine mechanisms. Moreover, both monocyte-derived macrophages and Kupffer cells (liver resident macrophages) produce this cytokine and some other profibrogenic factors like PDGF and connective tissue growth factor (CTGF), contributing, therefore, to HSCs activation and transdifferentiation, and promoting fibrosis [39]. Thus, TGF-β plays a master role in the activation of HSCs to myofibroblasts. In fact, some of the previous factors stimulate the expression, production and activation of TGF-β, which is responsible finally for the activation of HSCs, and the higher the level of TGF-β the more expressed fibrotic changes in the tissue.

The main mediators of the TGF-β-induced fibrogenic transcriptional program are SMADs (*Caenorhabditis elegans* Sma genes and the *Drosophila* Mad, Mothers against decapentaplegic) [41] (**Figure 1**). Moreover, proteins enriched in TGFR signaling involve Src, cAMP response element-binding protein (CREBP) and others, and some of them belong to EGFR signaling, indicating the crosstalk between these pathways [51]. Additionally, TGF-β1 also mediates the role of FGF1 and FGF2 in the deposition of ECM, or FGF1 and FGF2 mediate the TGF-β activity, or both factors play independent roles through convergent signaling pathways *in vivo* [43].

#### **4. Multikinase inhibitors**

Some TKIs have been shown to release antifibrotic activity do not demonstrate exact specificity against their targets and could inhibit more than one receptor. So, it is difficult to explain the mechanism of their action precisely. Nevertheless, these agents attract the attention and reveal the antifibrotic potency even more than specific inhibitors because of multiplicity of mechanisms and downregulated signaling pathways, and therefore, ability to avoid drug resistance through the compensatory mechanisms and signaling crosstalk.

For example, multikinase TKI nilotinib, which is a breakpoint cluster region protein (Bcr)-tyrosine-protein kinase ABL (Abl) inhibitor, also significantly inhibited PDGFR and TGFβRII, which contributes to depression of HSCs activation, proliferation, migration, and α-SMA formation, induction of their apoptosis, reduce collagen deposition in activated HSCs and in liver tissues of CCl4- and BDL-induced rats experienced liver fibrosis [52]. Moreover, the effects of nilotinib also include diminished expression of VEGF and VEGFR, which, however, is expected due to high similarity of PDGFR and VEGFR kinase domains. These results indicated that nilotinib may represent a putative antifibrotic treatment due to its combined inhibition of non-receptor tyrosine kinases (nonRTK) (Abl) and RTK (PDGFR-β, TGFβRII and VEGFR) (**Table 1**).

Treatment of CCl4-induced fibrotic mice with nintedanib that blocks PDGFR, VEGFR and FGFR, in addition to depression of HSCs activation, contractility,

**237**

progression.

lished data, under consideration).

plicity of these drugs' targets.

**approach**

*Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment*

migration, and collagen deposition, inhibited macrophage migration, intrahepatic inflammation and angiogenesis as well [36]. Another oral multitargeted TKI pazopanib (approved for renal cell sarcoma treatment) directly inhibits PDGFRs, FGFRs, mast/stem cell growth factor receptor (KIT) and selectively suppresses VEGFR-mediated angiogenesis. The drug can halt liver fibrosis progression through modulating inflammatory cytokines, suppressing HSCs activation, inducing their apoptosis, and regulating angiogenesis [53]. Regorafenib could affect similar targets (VEGFR1–3, PDGFR-β and FGFR) and also potently inhibits another angiogenic RTK TIE2. This drug has recently been approved as a second-line therapy for HCC and demonstrated depression of cirrhotic-associated systemic changes and portal hypertension in HCC patients. Moreover, regorafenib might also be beneficial towards fibrosis and portal hypertension even in absence of HCC [42]. Despite regorafenib treatment had no direct observable effect on HSCs activation and fibrosis progression or regression (as evidenced by liver histopathology, α-SMA and hydroxyproline deposition), however, even its acute administration improved cirrhotic portal hypertension (BDL and CCl4 models of liver fibrosis) and also hemodynamic circulation in an animal model mimicking portal vein thrombosis [54] (**Table 1**). These findings might explain the anticirrhotic effects of the drug in HCC patients by normalization of liver blood circulation in fibrotic liver and therefore exhausting the inflammatory microenvironment which leads to fibrosis

Brivanib is a selective inhibitor of VEGFR and FGFR and also affects liver fibrosis through multiple signaling pathways. Nakamura et al. demonstrated that brivanib decreased HSCs proliferation induced by PDGF, VEGF and FGF treatment, and also abrogated the phosphorylation of PDGFRβ, which was confirmed *in vitro* and on BDL-, CCl4- and TAA-induced mice models and supported by histo-

Our team developed the set of multikinase inhibitors, and one of them (1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione, called MI1) demonstrated high inhibitory activity against EGFR, VEGFR1,2,3 (the most prominent results), FGF-R1, IGF1-R, spleen associated tyrosine kinase (Syk), 3-phosphoinositide-dependent protein kinase-1 (PDK1), and Src [55]. Besides anticancer and anti-inflammatory activity having been revealed in our previous investigations [56, 57], we showed that MI1 could inhibit liver fibrosis development on rat acute (3 days) and chronic (28 days) cholangitis models, as evidenced by substantially depleted connective tissue deposits in liver and improved liver general state (according to plasma biochemical tests). Moreover, antifibrotic effects of MI1 preserved through at least 28 days since the interventions were terminated (unpub-

Thus, multikinase inhibitors might be more potent antifibrotic treatments through their impact on several signaling pathways. However, this task should be explored in more detail because of high probability of adverse effects due to multi-

**5. Small molecule inhibitors of RTK signaling – "noncanonical"** 

Inhibitors of RTK signaling include not only molecules designed to block ATP-binding sites of the kinase, but also small therapeutic molecules with different activities, which, however, could additionally inhibit RTK. For example, natural antioxidant of polyphenol origin resveratrol despite of different therapeutic activities (anti-inflammatory, antitumor, antiaging, protective etc.) demonstrated also

pathological evidences of liver fibrosis alleviation [17] (**Table 1**).

*DOI: http://dx.doi.org/10.5772/intechopen.96552*

#### *Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment DOI: http://dx.doi.org/10.5772/intechopen.96552*

migration, and collagen deposition, inhibited macrophage migration, intrahepatic inflammation and angiogenesis as well [36]. Another oral multitargeted TKI pazopanib (approved for renal cell sarcoma treatment) directly inhibits PDGFRs, FGFRs, mast/stem cell growth factor receptor (KIT) and selectively suppresses VEGFR-mediated angiogenesis. The drug can halt liver fibrosis progression through modulating inflammatory cytokines, suppressing HSCs activation, inducing their apoptosis, and regulating angiogenesis [53]. Regorafenib could affect similar targets (VEGFR1–3, PDGFR-β and FGFR) and also potently inhibits another angiogenic RTK TIE2. This drug has recently been approved as a second-line therapy for HCC and demonstrated depression of cirrhotic-associated systemic changes and portal hypertension in HCC patients. Moreover, regorafenib might also be beneficial towards fibrosis and portal hypertension even in absence of HCC [42]. Despite regorafenib treatment had no direct observable effect on HSCs activation and fibrosis progression or regression (as evidenced by liver histopathology, α-SMA and hydroxyproline deposition), however, even its acute administration improved cirrhotic portal hypertension (BDL and CCl4 models of liver fibrosis) and also hemodynamic circulation in an animal model mimicking portal vein thrombosis [54] (**Table 1**). These findings might explain the anticirrhotic effects of the drug in HCC patients by normalization of liver blood circulation in fibrotic liver and therefore exhausting the inflammatory microenvironment which leads to fibrosis progression.

Brivanib is a selective inhibitor of VEGFR and FGFR and also affects liver fibrosis through multiple signaling pathways. Nakamura et al. demonstrated that brivanib decreased HSCs proliferation induced by PDGF, VEGF and FGF treatment, and also abrogated the phosphorylation of PDGFRβ, which was confirmed *in vitro* and on BDL-, CCl4- and TAA-induced mice models and supported by histopathological evidences of liver fibrosis alleviation [17] (**Table 1**).

Our team developed the set of multikinase inhibitors, and one of them (1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione, called MI1) demonstrated high inhibitory activity against EGFR, VEGFR1,2,3 (the most prominent results), FGF-R1, IGF1-R, spleen associated tyrosine kinase (Syk), 3-phosphoinositide-dependent protein kinase-1 (PDK1), and Src [55]. Besides anticancer and anti-inflammatory activity having been revealed in our previous investigations [56, 57], we showed that MI1 could inhibit liver fibrosis development on rat acute (3 days) and chronic (28 days) cholangitis models, as evidenced by substantially depleted connective tissue deposits in liver and improved liver general state (according to plasma biochemical tests). Moreover, antifibrotic effects of MI1 preserved through at least 28 days since the interventions were terminated (unpublished data, under consideration).

Thus, multikinase inhibitors might be more potent antifibrotic treatments through their impact on several signaling pathways. However, this task should be explored in more detail because of high probability of adverse effects due to multiplicity of these drugs' targets.

#### **5. Small molecule inhibitors of RTK signaling – "noncanonical" approach**

Inhibitors of RTK signaling include not only molecules designed to block ATP-binding sites of the kinase, but also small therapeutic molecules with different activities, which, however, could additionally inhibit RTK. For example, natural antioxidant of polyphenol origin resveratrol despite of different therapeutic activities (anti-inflammatory, antitumor, antiaging, protective etc.) demonstrated also

*Advances in Hepatology*

expressed fibrotic changes in the tissue.

**4. Multikinase inhibitors**

compensatory mechanisms and signaling crosstalk.

RTK (PDGFR-β, TGFβRII and VEGFR) (**Table 1**).

most striking events of cell plasticity is epithelial-mesenchymal transition (EMT). Activation of HSCs and their transformation to myofibroblasts is an example of that one. Moreover, another example of cell transformation caused by TGF-β is EMT in hepatocytes accompanied with loss of cell–cell contacts and polarity [50]. Actually, TGF-β stimulates almost of all liver cell populations (portal and resident fibroblasts, bone marrow-derived fibrocytes, endothelial cells, vascular smooth muscle cells, pericytes and cholangiocytes additionally to hepatocytes and HSCs) to change into a more fibroblastic phenotype [40] and to release profibrogenic transcriptional program manifested by upregulation of collagen expression [41] and disturbances in ECM turnover through imbalance between MMPs and TIMPs. TGF-β receptors (TGFβRI and TGFβRII) are Ser/Tre protein kinases expressed on the membranes of various cells including all above mentioned ones. TGF-β is secreted by these cells and regulates their activity by autocrine and paracrine mechanisms. Moreover, both monocyte-derived macrophages and Kupffer cells (liver resident macrophages) produce this cytokine and some other profibrogenic factors like PDGF and connective tissue growth factor (CTGF), contributing, therefore, to HSCs activation and transdifferentiation, and promoting fibrosis [39]. Thus, TGF-β plays a master role in the activation of HSCs to myofibroblasts. In fact, some of the previous factors stimulate the expression, production and activation of TGF-β, which is responsible finally for the activation of HSCs, and the higher the level of TGF-β the more

The main mediators of the TGF-β-induced fibrogenic transcriptional program are SMADs (*Caenorhabditis elegans* Sma genes and the *Drosophila* Mad, Mothers against decapentaplegic) [41] (**Figure 1**). Moreover, proteins enriched in TGFR signaling involve Src, cAMP response element-binding protein (CREBP) and others, and some of them belong to EGFR signaling, indicating the crosstalk between these pathways [51]. Additionally, TGF-β1 also mediates the role of FGF1 and FGF2 in the deposition of ECM, or FGF1 and FGF2 mediate the TGF-β activity, or both factors

Some TKIs have been shown to release antifibrotic activity do not demonstrate exact specificity against their targets and could inhibit more than one receptor. So, it is difficult to explain the mechanism of their action precisely. Nevertheless, these agents attract the attention and reveal the antifibrotic potency even more than specific inhibitors because of multiplicity of mechanisms and downregulated signaling pathways, and therefore, ability to avoid drug resistance through the

For example, multikinase TKI nilotinib, which is a breakpoint cluster region protein (Bcr)-tyrosine-protein kinase ABL (Abl) inhibitor, also significantly inhibited PDGFR and TGFβRII, which contributes to depression of HSCs activation, proliferation, migration, and α-SMA formation, induction of their apoptosis, reduce collagen deposition in activated HSCs and in liver tissues of CCl4- and BDL-induced rats experienced liver fibrosis [52]. Moreover, the effects of nilotinib also include diminished expression of VEGF and VEGFR, which, however, is expected due to high similarity of PDGFR and VEGFR kinase domains. These results indicated that nilotinib may represent a putative antifibrotic treatment due to its combined inhibition of non-receptor tyrosine kinases (nonRTK) (Abl) and

Treatment of CCl4-induced fibrotic mice with nintedanib that blocks PDGFR, VEGFR and FGFR, in addition to depression of HSCs activation, contractility,

play independent roles through convergent signaling pathways *in vivo* [43].

**236**

strong antifibrotic effect against liver cirrhosis (CCl4- model) [58]. The mechanisms of its action are different and include predominantly antioxidant capability, but also impact on gene expression and ability to modulate different signaling pathways through interaction with their key molecules. Among others, resveratrol could downregulate EGFR/Akt/ERK1/2 signaling pathway particularly by decrease of EGFR activation [59]. Furthermore, this polyphenol could scavenge VEGF, altering, therefore, its binding with VEGFR and activation of the latter [60]. Of course, this action could not be interpreted as direct impact on VEGFR. However, it deserves to be considered as an approach for modulation of this signaling activity on its initial stages.

Another plant-derived polyphenol curcumin among various types of biological activities (anticancer, antiviral, antioxidant, anti-inflammatory ones) had beneficial effects in animal models of liver injury and cirrhosis [61]. While studying the possible mechanisms of its action, substantial reduce of TGFβRII levels and its downstream molecules Smad2/3 phosphorylation in response to added TGF-β was found [62]. Furthermore, curcumin revealed anti-EGFR activity: firstly, it was able to inhibit directly the enzymatic activity of the EGFR intracellular domain, and, secondly, it could influence the cell membrane environment of the receptor [63, 64].

Ability to affect the membrane environment of the receptor and thus alter its binding with ligand and subsequent activation has been shown for biologically active indolic related compounds including melatonin, 3-indoleacetic acid, 5-hydroxytryptophol, and serotonin. These chemicals are proven to significantly inhibit VEGF-induced VEGFR2 activation in human umbilical vein endothelial cells through interacting with the cell surface components in a way that prevents VEGF from activating the receptor [65]. This property could contribute to the hepatoprotective and antifibrotic efficacy of melatonin realizing by inhibition of inflammation, HSCs proliferation and hepatocyte apoptosis [66]. The similar mechanism of RTK inhibition has been considered for natural cyclopeptide destruxin A5, that effectively downregulate PDGF-B-induced PDGFR-β signaling. Destruxin A5 does not bind to the ATP-binding pocket of PDGFR-β, so the inhibitory mechanism of that is distinct from the mechanism of "canonical" TKIs. It looks like this chemical selectively targets PDGF-β/PDGFR-β interaction interface and blocks this signaling [67].

However, some non-specific small molecules are able to inhibit RTK by "classical" mechanism – through binding to receptor and preventing its activation by ligand. A naturally occurring flavone 4′,5,7-trihydroxy-3′,5′-dimethoxyflavone (tricin) is one of them. Tricin affected HSCs *in vitro* exploring its potential as antifibrotic therapeutic, as evidenced by inhibiting of human HSC line LI90 and culture-activated HSCs proliferation and migration by that. This flavone reduced the phosphorylation of PDGFRβ and downstream signaling molecules ERK1/2 and Akt, which might be due to its TKI properties rather than inhibition of the direct binding between PDGF-B and its receptor [68]. Flavonoid quercetin was reported to exhibit a wide range of pharmacological properties, including its ability to attenuate liver fibrosis by multiple mechanisms involving several signaling pathways [69]. In particular, quercetin was found to suppress the phosphorylation of EGFR by direct binding with its ATP-binding site [70]. A powerful free radical scavenger carbon-based nanoparticle C60 fullerene could be considered as another unusual RTK inhibitor. It explores wide range of biological activities including antifibrotic and anticirrhotic ones [71–75] probably realized by its antioxidant capacity. However, we also demonstrated its ability to bind to ATP-binding pockets of EGFR and FGFR and to avoid interaction of those with ATP [75], which could be an alternative mechanism of this nanoparticle's antifibrotic action.

**239**

**Author details**

Halyna Kuznietsova\* and Olexandr Ogloblya

provided the original work is properly cited.

Taras Shevchenko National University of Kyiv, Kyiv, Ukraine

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: biophyz@gmail.com

*Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment*

Growth factor receptors, in particular EGFR, VEGFR, PDGFR, FGFR, and TGFβR are proven to be key regulators of various liver cell populations behavior under hepatic injury and reparation, and subsequent fibrosis development if "something has been going wrong". Upregulation of related signaling pathways has been shown in numerous *in vitro* and *in vivo* models, and for patients who experienced liver diseases accompanied by its fibrosis as well. Inhibiting of those by specific and non-specific compounds followed by fibrosis depression. Above mentioned suggests the potency of RTK inhibition as an antifibrotic treatment. However, all the clinical evidences dedicated to that are rather "concomitant" to TKIs anticancer activity because of predominant focus of these studies on the therapy of liver malignancies developed on cirrhotic background. However, we should remember that liver fibrosis and subsequent cirrhosis are severe high-morbidity diseases themselves. And our knowledge about mechanisms of liver fibrosis development and essential RTKs involvement in that, as well as our achievements in the field of liver

*DOI: http://dx.doi.org/10.5772/intechopen.96552*

fibrosis therapy by TKIs should not be neglected.

The authors declare that they have no conflict of interest.

**6. Conclusions**

**Conflict of interest**

*Therapy that Targets Growth Factor Receptors: Novel Approach for Liver Cirrhosis Treatment DOI: http://dx.doi.org/10.5772/intechopen.96552*

### **6. Conclusions**

*Advances in Hepatology*

initial stages.

the receptor [63, 64].

and blocks this signaling [67].

strong antifibrotic effect against liver cirrhosis (CCl4- model) [58]. The mechanisms of its action are different and include predominantly antioxidant capability, but also impact on gene expression and ability to modulate different signaling pathways through interaction with their key molecules. Among others, resveratrol could downregulate EGFR/Akt/ERK1/2 signaling pathway particularly by decrease of EGFR activation [59]. Furthermore, this polyphenol could scavenge VEGF, altering, therefore, its binding with VEGFR and activation of the latter [60]. Of course, this action could not be interpreted as direct impact on VEGFR. However, it deserves to be considered as an approach for modulation of this signaling activity on its

Another plant-derived polyphenol curcumin among various types of biological activities (anticancer, antiviral, antioxidant, anti-inflammatory ones) had beneficial effects in animal models of liver injury and cirrhosis [61]. While studying the possible mechanisms of its action, substantial reduce of TGFβRII levels and its downstream molecules Smad2/3 phosphorylation in response to added TGF-β was found [62]. Furthermore, curcumin revealed anti-EGFR activity: firstly, it was able to inhibit directly the enzymatic activity of the EGFR intracellular domain, and, secondly, it could influence the cell membrane environment of

Ability to affect the membrane environment of the receptor and thus alter its binding with ligand and subsequent activation has been shown for biologically active indolic related compounds including melatonin, 3-indoleacetic acid, 5-hydroxytryptophol, and serotonin. These chemicals are proven to significantly inhibit VEGF-induced VEGFR2 activation in human umbilical vein endothelial cells through interacting with the cell surface components in a way that prevents VEGF from activating the receptor [65]. This property could contribute to the hepatoprotective and antifibrotic efficacy of melatonin realizing by inhibition of inflammation, HSCs proliferation and hepatocyte apoptosis [66]. The similar mechanism of RTK inhibition has been considered for natural cyclopeptide destruxin A5, that effectively downregulate PDGF-B-induced PDGFR-β signaling. Destruxin A5 does not bind to the ATP-binding pocket of PDGFR-β, so the inhibitory mechanism of that is distinct from the mechanism of "canonical" TKIs. It looks like this chemical selectively targets PDGF-β/PDGFR-β interaction interface

However, some non-specific small molecules are able to inhibit RTK by "classical" mechanism – through binding to receptor and preventing its activation by ligand. A naturally occurring flavone 4′,5,7-trihydroxy-3′,5′-dimethoxyflavone (tricin) is one of them. Tricin affected HSCs *in vitro* exploring its potential as antifibrotic therapeutic, as evidenced by inhibiting of human HSC line LI90 and culture-activated HSCs proliferation and migration by that. This flavone reduced the phosphorylation of PDGFRβ and downstream signaling molecules ERK1/2 and Akt, which might be due to its TKI properties rather than inhibition of the direct binding between PDGF-B and its receptor [68]. Flavonoid quercetin was reported to exhibit a wide range of pharmacological properties, including its ability to attenuate liver fibrosis by multiple mechanisms involving several signaling pathways [69]. In particular, quercetin was found to suppress the phosphorylation of EGFR by direct binding with its ATP-binding site [70]. A powerful free radical scavenger carbon-based nanoparticle C60 fullerene could be considered as another unusual RTK inhibitor. It explores wide range of biological activities including antifibrotic and anticirrhotic ones [71–75] probably realized by its antioxidant capacity. However, we also demonstrated its ability to bind to ATP-binding pockets of EGFR and FGFR and to avoid interaction of those with ATP [75], which could be an alternative mechanism of this nanoparticle's

**238**

antifibrotic action.

Growth factor receptors, in particular EGFR, VEGFR, PDGFR, FGFR, and TGFβR are proven to be key regulators of various liver cell populations behavior under hepatic injury and reparation, and subsequent fibrosis development if "something has been going wrong". Upregulation of related signaling pathways has been shown in numerous *in vitro* and *in vivo* models, and for patients who experienced liver diseases accompanied by its fibrosis as well. Inhibiting of those by specific and non-specific compounds followed by fibrosis depression. Above mentioned suggests the potency of RTK inhibition as an antifibrotic treatment. However, all the clinical evidences dedicated to that are rather "concomitant" to TKIs anticancer activity because of predominant focus of these studies on the therapy of liver malignancies developed on cirrhotic background. However, we should remember that liver fibrosis and subsequent cirrhosis are severe high-morbidity diseases themselves. And our knowledge about mechanisms of liver fibrosis development and essential RTKs involvement in that, as well as our achievements in the field of liver fibrosis therapy by TKIs should not be neglected.

### **Conflict of interest**

The authors declare that they have no conflict of interest.

### **Author details**

Halyna Kuznietsova\* and Olexandr Ogloblya Taras Shevchenko National University of Kyiv, Kyiv, Ukraine

\*Address all correspondence to: biophyz@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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*Advances in Hepatology*

PMID: 23937051.

jat.1249

[59] Li W, Ma X, Li N,

yexcr.2016.11.002

[60] Hu WH, Duan R, Xia YT,

doi: 10.1021/acs. jafc.8b05977

[62] Yao QY, Xu BL, Wang JY,

[61] Vera-Ramirez L, Pérez-Lopez P, Varela-Lopez A, Ramirez-Tortosa M, Battino M, Quiles JL. Curcumin and liver disease. Biofactors.

2013;39(1):88100. doi: 10.1002/biof.1057

Liu HC, Zhang SC, Tu CT. Inhibition by curcumin of multiple sites of the transforming growth factor-beta1 signalling pathway ameliorates the progression of liver fibrosis induced

Xiong QP, Wang HY, Chan GK, Liu SY, Dong TT, Qin QW, Tsim KW. Binding of Resveratrol to Vascular Endothelial Growth Factor Suppresses Angiogenesis by Inhibiting the Receptor Signaling. J Agric Food Chem. 2019;67(4):1127-1137.

2016;2016:2145753. doi: 10.1155/2016/2145753

[57] Kuznietsova HM, Lynchak OV, Danylov MO, Kotliar IP, Rybal'chenko VK. [Effect of dihydropyrrol and maleimide derivatives on the state of the liver and colon in normal rats and those with colorectal carcinogenesis induced by dimethylhydrazine]. Ukr Biokhim Zh (1999). 2013;85(3):74-84. Ukrainian.

by carbon tetrachloride in rats. BMC Complement Altern Med. 2012;12:156.

[63] Starok M, Preira P, Vayssade M, Haupt K, Salomé L, Rossi C. EGFR Inhibition by Curcumin in Cancer Cells: A Dual Mode of Action.

Biomacromolecules. 2015;16(5):163442.

[64] Tang Y. Curcumin targets multiple pathways to halt hepatic stellate cell activation: updated mechanisms in vitro and in vivo. Dig Dis Sci. 2015;60(6):1554-1564. doi: 10.1007/

[65] Cerezo AB, Hornedo-Ortega R, Álvarez-Fernández MA, Troncoso AM, García-Parrilla MC. Inhibition of VEGFInduced VEGFR-2 Activation and HUVEC Migration by Melatonin and Other Bioactive Indolic Compounds. Nutrients. 2017;9(3):249. doi: 10.3390/

[66] Hu C, Zhao L, Tao J, Li L. Protective role of melatonin in early-stage and end-stage liver cirrhosis. J Cell Mol Med. 2019;23(11):7151-7162. doi: 10.1111/

[67] Wang X, Wu X, Zhang A, Wang S, Hu C, Chen W, Shen Y, Tan R, Sun Y, Xu Q. Targeting the PDGF-B/PDGFR-β

Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis. EBioMedicine. 2016;7:146-156. doi: 10.1016/j.ebiom.2016.03.042

Interface with Destruxin A5 to

[68] Seki N, Toh U, Kawaguchi K, Ninomiya M, Koketsu M, Watanabe K,

Shirouzu K, Yamana H. Tricin inhibits proliferation of human hepatic stellate cells in vitro by blocking tyrosine phosphorylation of PDGF receptor and its signaling pathways. J Cell Biochem. 2012;113(7):2346-2355. doi: 10.1002/

Aoki M, Fujii T, Nakamura A, Akagi Y, Kusukawa J, Kage M,

doi: 10.1021/acs.biomac.5b00229

s10620-014-3487-6

nu9030249

jcmm.14634

jcb.24107

doi: 10.1186/1472-6882-12-156

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Liu H, Dong Q, Zhang J, Yang C, Liu Y, Liang Q, Zhang S, Xu C, Song W, Tan S, Rong P, Wang W. Resveratrol inhibits Hexokinases II mediated glycolysis in non-small cell lung cancer via targeting Akt signaling pathway. Exp Cell Res. 2016;349(2):320-327. doi: 10.1016/j.

**244**

[70] Fridrich D, Teller N, Esselen M, Pahlke G, Marko D. Comparison of delphinidin, quercetin and (−)-epigallocatechin-3-gallate as inhibitors of the EGFR and the ErbB2 receptor phosphorylation. Mol Nutr Food Res. 2008;52(7):815-822. doi: 10.1002/mnfr.200800026

[71] Kuznietsova HM, Lynchak OV, Dziubenko NV, Osetskyi VL, Ogloblya OV, Prylutskyy YuI, Rybalchenko VK, Ritter U, Scharff P. Water-soluble C60 fullerenes reduce manifestations of acute cholangitis in rats. Appl Nanosci. 2019;9:601-608. Doi: 10.1007/s13204-018-0700-5

[72] Kuznietsova H, Lynchak O, Dziubenko N, Herheliuk T, Prylutskyy Y, Rybalchenko V, Ritter U. Water-soluble pristine C60 fullerene attenuates acetaminophen-induced liver injury. Bioimpacts. 2019;9(4):227-237. doi: 10.15171/bi.2019.28

[73] Kuznietsova HM, Dziubenko NV, Lynchak OV, Herheliuk TS, Zavalny DK, Remeniak OV, Prylutskyy YI, Ritter U. Effects of Pristine C60 Fullerenes on Liver and Pancreas in α-NaphthylisothiocyanateInduced Cholangitis. Dig Dis Sci. 2020;65(1):215- 224. doi: 10.1007/ s10620-019-05730-3

[74] Kuznietsova H, Dziubenko N, Herheliuk T, Prylutskyy Y, Tauscher E, Ritter U, Scharff P. WaterSoluble Pristine C60 Fullerene Inhibits Liver Alterations Associated with Hepatocellular Carcinoma in Rat. Pharmaceutics. 2020;12(9):794. doi: 10.3390/pharmaceutics12090794

[75] Kuznietsova H, Dziubenko N, Hurmach V, Chereschuk I, Motuziuk O, Ogloblya O, Prylutskyy Y. Water-Soluble Pristine C60 Fullerenes Inhibit Liver Fibrotic Alteration and Prevent Liver Cirrhosis in Rats. Oxid Med Cell Longev. 2020;2020:8061246. doi: 10.1155/2020/8061246

### *Edited by Luis Rodrigo, Ian Martins, Xiaozhong Guo and Xingshun Qi*

This book discusses clinical advances in hepatology, with a focus on metabolic diseases and chronic hepatitis C. The development of direct-acting antiviral (DAA) agents for the treatment of hepatitis C virus (HCV) infection in 2010 has completely transformed the management of this disease. This transformative nature of DAA therapy underpins the goal of the World Health Organization (WHO) to eliminate HCV infection as a public health threat by 2030. The advantages of using these therapies include high efficacy (sustained virological response rate >95%) with minimal side effects, good tolerability, easy drug administration (once-daily oral dosing) and short duration of treatment (8-12 weeks). The commercialization of second-generation DAA agents due to their high effectiveness, few side-effects and pangenotypic action. This transformative nature of DAA therapy underpins the goal of the WHO to eliminate HCV infection as a public health threat by 2030.

Published in London, UK © 2021 IntechOpen © Dr\_Microbe / iStock

Advances in Hepatology

Advances in Hepatology

*Edited by Luis Rodrigo, Ian Martins,* 

*Xiaozhong Guo and Xingshun Qi*