**Meet the editor**

Dr. Xingshun Qi was born in July 1984 in Shenyang, China. He obtained his medical doctoral degree at the Fourth Military Medical University in Xi'an and completed his postdoctoral fellowship at the General Hospital of Shenyang Military Area in Shenyang, China. He is currently working at the Department of Gastroenterology of the General Hospital of Shenyang Military Area

as a vice chief physician. He served as a co–editor-in-chief of *AME Medical Journal*; an associate editor of *Annals of Hepatology*; a lead guest editor in *Gastroenterology Research and Practice, BioMed Research International*, and *Therapeutic Advances in Gastroenterology*; a guest editor in *Canadian Journal of Gastroenterology and Hepatology*; an editorial member of *World Journal of Hepatolog*y and *Cardiovascular & Hematological Disorders - Drug Targets*; and a column executive editor of *Journal of Translational Internal Medicine*. He has also served as a peer reviewer in more than 60 journals. According to the Scopus, his H-index is 26, and total number of citation is now 2235.

Contents

**Preface VII**

**Section 1 Chronic Liver Disease 1**

and Shuji Terai

**Hyponatremia 17**

Chapter 3 **Acute Kidney Injury in Cirrhosis 31**

**Section 3 Hepatocellular Carcinoma 81**

**Section 2 Liver Cirrhosis 15**

Chapter 1 **Intra-Abdominal Hypertension and Abdominal Compartment**

Hiroteru Kamimura, Tomoyuki Sugano, Ryoko Horigome, Naruhiro Kimura, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa

Andra Iulia Suceveanu, Roxana Popoiag, Laura Mazilu, Irinel Raluca Parepa, Andreea Gheorghe, Anca Stoian, Felix Voinea, Claudia

**Syndrome in Liver Diseases 3**

Chapter 2 **Management of Ascites Associated with Severe**

Voinea and Adrian Paul Suceveanu

Marco Antonio López Hernández

Chapter 4 **Portal Vein Thrombosis in Liver Cirrhosis 51**

Shuai Xue, Peisong Wang, Hui Han and Guang Chen

Chapter 5 **Predictors of 50 Day In-Hospital Mortality in Decompensated**

Chinmaya Kumar Bal, Ripu Daman and Vikram Bhatia

Chapter 6 **Stereotactic Body Radiation Therapy for Hepatocellular**

Hiroshi Doi, Hiroya Shiomi and Ryoong-Jin Oh

**Carcinoma in Cirrhotic Liver 83**

**Cirrhosis Patients with Spontaneous Bacterial Peritonitis 69**

## Contents

## **Preface XI**

#### **Section 2 Liver Cirrhosis 15**

Preface

has been dramatically updated.

with its merits and usefulness.

wife Jun Liu.

Chronic liver disease, which can progress to liver cirrhosis and even hepatocellular carcino‐ ma, is a major global burden. Long-term efforts have been made to understand the patho‐ genesis of chronic liver diseases, to optimize clinical decisions, and to improve the patients' prognosis. In recent years, the knowledge regarding management of chronic liver diseases

Under such a circumstance, I was very honored and excited to receive the invitation from IntechOpen in October 2017 to initiate an Open Access book project regarding the manage‐ ment of chronic liver diseases. After critical reviews, meticulous selection, repeated revi‐ sions, and great improvement, a total of 6 chapters, which are contributed by worldwide experts in the field of liver diseases, have been included in this book entitled *Management of Chronic Liver Diseases – Recent Advances*. The book is divided into 3 major sections according to the stage of liver diseases analyzed (i.e., chronic liver diseases, liver cirrhosis, and hepato‐ cellular carcinoma). In detail, it introduces the intra-abdominal hypertension and abdominal compartment syndrome in chronic liver diseases, ascites with hyponatremia, acute kidney injury, portal vein thrombosis, spontaneous bacterial peritonitis in liver cirrhosis, and the use of stereotactic body radiation therapy in hepatocellular carcinoma. Clinicians and inves‐ tigators who are interested in the management of chronic liver diseases will be acquainted

This is the first book that I have edited. Such an experience will be unforgettable in my life. Herein, I should acknowledge the great help from IntechOpen staff, including Ana Pantar (Senior Commissioning Editor), Anja Filipovic (Junior Commissioning Editor), Danijela Vla‐ dika (Publishing Process Manager), and Romina Rovan (Publishing Process Manager). Also, I deeply appreciate the support from all chapter authors. Finally, I dedicate this book to my

**Dr. Xingshun Qi**

China

Department of Gastroenterology

General Hospital of Shenyang Military Area

## Preface

Chronic liver disease, which can progress to liver cirrhosis and even hepatocellular carcino‐ ma, is a major global burden. Long-term efforts have been made to understand the patho‐ genesis of chronic liver diseases, to optimize clinical decisions, and to improve the patients' prognosis. In recent years, the knowledge regarding management of chronic liver diseases has been dramatically updated.

Under such a circumstance, I was very honored and excited to receive the invitation from IntechOpen in October 2017 to initiate an Open Access book project regarding the manage‐ ment of chronic liver diseases. After critical reviews, meticulous selection, repeated revi‐ sions, and great improvement, a total of 6 chapters, which are contributed by worldwide experts in the field of liver diseases, have been included in this book entitled *Management of Chronic Liver Diseases – Recent Advances*. The book is divided into 3 major sections according to the stage of liver diseases analyzed (i.e., chronic liver diseases, liver cirrhosis, and hepato‐ cellular carcinoma). In detail, it introduces the intra-abdominal hypertension and abdominal compartment syndrome in chronic liver diseases, ascites with hyponatremia, acute kidney injury, portal vein thrombosis, spontaneous bacterial peritonitis in liver cirrhosis, and the use of stereotactic body radiation therapy in hepatocellular carcinoma. Clinicians and inves‐ tigators who are interested in the management of chronic liver diseases will be acquainted with its merits and usefulness.

This is the first book that I have edited. Such an experience will be unforgettable in my life. Herein, I should acknowledge the great help from IntechOpen staff, including Ana Pantar (Senior Commissioning Editor), Anja Filipovic (Junior Commissioning Editor), Danijela Vla‐ dika (Publishing Process Manager), and Romina Rovan (Publishing Process Manager). Also, I deeply appreciate the support from all chapter authors. Finally, I dedicate this book to my wife Jun Liu.

> **Dr. Xingshun Qi** Department of Gastroenterology General Hospital of Shenyang Military Area China

**Section 1**

**Chronic Liver Disease**

**Section 1**

## **Chronic Liver Disease**

**Chapter 1**

**Provisional chapter**

**Intra-Abdominal Hypertension and Abdominal**

**Intra-Abdominal Hypertension and Abdominal**

DOI: 10.5772/intechopen.77061

Intra-abdominal hypertension (IAH) is defined as an intra-abdominal pressure (IAP) above 12 mmHg. Abdominal compartment syndrome (ACS) is defined as an IAP above 20 mmHg with evidence of organ failure. Moreover, IAH/ACS is a condition that can cause acute renal failure, respiratory failure, circulatory disease, gastrointestinal dysfunction, and liver failure due to elevated IAP. The incidence of IAH/ACS increases in the more critically ill patient and is associated with significantly increased morbidity and mortality. Ascites, blood, or tumors increase IAP. In liver cirrhosis, massive ascites is often encountered. Hence, preventing IAH/ACS conditions may improve outcomes of

**Keywords:** intra-abdominal hypertension (IAH), abdominal compartment syndrome

The pressure within the abdominal cavity is normally a little higher than the atmospheric pressure to less than 0 mmHg. Certain physiological conditions such as morbid obesity and pregnancy may be associated with chronic IAP elevations. However, even small increases in intra-abdominal pressure can have adverse effects on renal function, cardiac output, hepatic blood flow, respiratory mechanics, splanchnic perfusion, and intracranial pressure. IAP is

> © 2016 The Author(s). Licensee InTech. 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.

© 2018 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.

**Compartment Syndrome in Liver Diseases**

**Compartment Syndrome in Liver Diseases**

Hiroteru Kamimura, Tomoyuki Sugano, Ryoko Horigome, Naruhiro Kimura, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa and Shuji Terai

Hiroteru Kamimura, Tomoyuki Sugano, Ryoko Horigome, Naruhiro Kimura, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa and Shuji Terai

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77061

patients with liver disease.

(ACS), hepatorenal syndrome (HRS)

approximately 5–7 mmHg in critically ill adults.

**Abstract**

**1. Introduction**

#### **Intra-Abdominal Hypertension and Abdominal Compartment Syndrome in Liver Diseases Intra-Abdominal Hypertension and Abdominal Compartment Syndrome in Liver Diseases**

DOI: 10.5772/intechopen.77061

Hiroteru Kamimura, Tomoyuki Sugano, Ryoko Horigome, Naruhiro Kimura, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa and Shuji Terai Hiroteru Kamimura, Tomoyuki Sugano, Ryoko Horigome, Naruhiro Kimura, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa and Shuji Terai

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.77061

#### **Abstract**

Intra-abdominal hypertension (IAH) is defined as an intra-abdominal pressure (IAP) above 12 mmHg. Abdominal compartment syndrome (ACS) is defined as an IAP above 20 mmHg with evidence of organ failure. Moreover, IAH/ACS is a condition that can cause acute renal failure, respiratory failure, circulatory disease, gastrointestinal dysfunction, and liver failure due to elevated IAP. The incidence of IAH/ACS increases in the more critically ill patient and is associated with significantly increased morbidity and mortality. Ascites, blood, or tumors increase IAP. In liver cirrhosis, massive ascites is often encountered. Hence, preventing IAH/ACS conditions may improve outcomes of patients with liver disease.

**Keywords:** intra-abdominal hypertension (IAH), abdominal compartment syndrome (ACS), hepatorenal syndrome (HRS)

### **1. Introduction**

The pressure within the abdominal cavity is normally a little higher than the atmospheric pressure to less than 0 mmHg. Certain physiological conditions such as morbid obesity and pregnancy may be associated with chronic IAP elevations. However, even small increases in intra-abdominal pressure can have adverse effects on renal function, cardiac output, hepatic blood flow, respiratory mechanics, splanchnic perfusion, and intracranial pressure. IAP is approximately 5–7 mmHg in critically ill adults.

© 2016 The Author(s). Licensee InTech. 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. © 2018 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.

Wendt et al. firstly described oliguria in the presence of elevated intra-abdominal pressure in 1876 [1]. In 1947, Bradley published a seminal study of the renal effects of elevated IAP in humans [2]. Despite these early descriptions of the adverse effects of IAH, physicians are not careful about the significance of increased abdominal pressure.

Until recently, patients with ACS were not infrequently managed in the intensive care unit and typically presented with a tense distended abdomen, increased peak inspiratory airway pressure, severe hypercapnia, hypotension, and oliguria. Abdominal ascites occurs typically at the end stage of liver failure. Massive ascites also influences IAP and causes oliguria and acute kidney injury. Commonly, we recognize this symptom and confused it with hepatorenal syndrome (HRS). In such patients, we should take into account the elevation of renal parenchymal and renal vein pressures, as they are likely the mechanisms of renal impairment. Note that IAH/ACS and HRS are occurring simultaneously. Recently, Matsumoto et al. reported that renal vein dilation predicts poor outcome in patients with refractory cirrhotic ascites [3].

## **2. Pathophysiology of ACS**

The pathology of IAH/ACS is perfusion imbalance in multiple organs: compression of the portal system in the abdominal cavity, compression of the inferior vena cava system in retroperitoneal organs, compression of the diaphragm in the intrathoracic organ, and perfusion dysfunction of the brain circulation through increase of intrathoracic pressure [4].

The perfusion imbalance in the upper body originated from the abdominal cavity, which causes circulation impairment and further increased intrathoracic cavity pressure and retroperitoneal cavity. This imbalance presents a functional disorder that substantially affects multiple organs.

The World Society of Abdominal Compartment Syndrome classified IAH into grade I–IV and

Hyperacute IAH Elevated IAP for seconds Secondary to physical activity, coughing,

laughing, sneezing, straining, or defecation

http://dx.doi.org/10.5772/intechopen.77061

5

Pregnancy, morbid obesity, intra-abdominal

Secondary to trauma or intra-abdominal

hemorrhage

Intra-Abdominal Hypertension and Abdominal Compartment Syndrome in Liver Diseases

Medical patients

tumor, ascites

Burch et al. suggested that most patients with grade III and all patients with grade IV should

Due to the increased intrathoracic pressure, indirect measures of cardiac filling such as central venous pressure and pulmonary artery occlusion pressure give inaccurate results and can be increased despite profound intravascular volume depletion. The decrease in cardiac output caused by intra-abdominal hypertension is therefore exacerbated by hypovolemia [11].

Respiratory distress and failure: Initial signs of ACS include elevated peak airway pressures in intubated patients with decreased tidal volumes. The ensuing increase in intrathoracic pressure and hypoxic pulmonary vasoconstriction can lead to pulmonary hypertension [12].

ACS (**Table 2**) [9].

**Grading of IAH**

**Classification of IAH**

Acute IAH Elevated IAP that develops over hours and

Subacute IAH Elevated IAP that develops over days and can also lead to ACS

Chronic IAH Elevated IAP that develops over months or

years.

**Table 1.** Classification of intra-abdominal hypertension.

Grade I IAP 12-15 mmHg Grade II IAP 16-20 mmHg Grade III IAP 21-21 mmHg Grade IV IAP > 25 mmHg

can lead to rapid development of ACS

IAH, intra-abdominal hypertension; ACS, abdominal compartment syndrome.

**3.1. Cardiovascular**

**3.2. Respiratory**

undergo abdominal decompression [10].

**Table 2.** Grading of intra-abdominal hypertension.

**3. ACS results in non-abdominal organ failure**

ACS is similar to the compartment syndrome in muscular diseases. It is a circulatory disease caused by internal pressure of organs sectioned in a small wall of the compliance anatomically [5]. The normal IAP ranges from sub-atmospheric level to 0 mmHg. Certain physiological conditions, such as morbid obesity and pregnancy, may be associated with chronic IAP elevations. Moreover, IAH is defined as an IAP above 12 mmHg. ACS is defined as an IAP above 20 mmHg with evidence of organ failure [6]. IAP is the steady state of pressure concealed within the abdominal cavity. The normal IAP for critically ill patients are 5–7 mmHg range. Once, IAP have increased, patients become the state of IAH. IAH is recognized sustained IAP greater than to 12 mmHg. IAH may also be subclassified according to the duration of symptoms into one of the four groups. This fulminant example of IAH commonly leads to rapid development of ACS. With its development over a protracted time course, the abdominal wall adapts and progressively distends in response to increasing IAP, allowing time for the body to adapt physiologically. The clinical consideration of IAH subtypes is useful in prescribing patients at risk for ACS (**Table 1**) [6].

Primary ACS is characterized by the presence of acute or subacute IAH of relatively brief duration occurring as a result of an intra-abdominal cause such as severe acute pancreatitis, abdominal trauma, ruptured abdominal aortic aneurysm, and liver transplantation [7].

Secondary ACS is characterized by the presence of subacute or chronic IAH that develops massive fluid resuscitation such as an extra-abdominal cause such as sepsis, capillary leak, burns [8].

**Table 1.** Classification of intra-abdominal hypertension.

Wendt et al. firstly described oliguria in the presence of elevated intra-abdominal pressure in 1876 [1]. In 1947, Bradley published a seminal study of the renal effects of elevated IAP in humans [2]. Despite these early descriptions of the adverse effects of IAH, physicians are not

Until recently, patients with ACS were not infrequently managed in the intensive care unit and typically presented with a tense distended abdomen, increased peak inspiratory airway pressure, severe hypercapnia, hypotension, and oliguria. Abdominal ascites occurs typically at the end stage of liver failure. Massive ascites also influences IAP and causes oliguria and acute kidney injury. Commonly, we recognize this symptom and confused it with hepatorenal syndrome (HRS). In such patients, we should take into account the elevation of renal parenchymal and renal vein pressures, as they are likely the mechanisms of renal impairment. Note that IAH/ACS and HRS are occurring simultaneously. Recently, Matsumoto et al. reported that renal vein dilation predicts poor outcome in patients with refractory cirrhotic ascites [3].

The pathology of IAH/ACS is perfusion imbalance in multiple organs: compression of the portal system in the abdominal cavity, compression of the inferior vena cava system in retroperitoneal organs, compression of the diaphragm in the intrathoracic organ, and perfusion

The perfusion imbalance in the upper body originated from the abdominal cavity, which causes circulation impairment and further increased intrathoracic cavity pressure and retroperitoneal cavity. This imbalance presents a functional disorder that substantially affects multiple organs. ACS is similar to the compartment syndrome in muscular diseases. It is a circulatory disease caused by internal pressure of organs sectioned in a small wall of the compliance anatomically [5]. The normal IAP ranges from sub-atmospheric level to 0 mmHg. Certain physiological conditions, such as morbid obesity and pregnancy, may be associated with chronic IAP elevations. Moreover, IAH is defined as an IAP above 12 mmHg. ACS is defined as an IAP above 20 mmHg with evidence of organ failure [6]. IAP is the steady state of pressure concealed within the abdominal cavity. The normal IAP for critically ill patients are 5–7 mmHg range. Once, IAP have increased, patients become the state of IAH. IAH is recognized sustained IAP greater than to 12 mmHg. IAH may also be subclassified according to the duration of symptoms into one of the four groups. This fulminant example of IAH commonly leads to rapid development of ACS. With its development over a protracted time course, the abdominal wall adapts and progressively distends in response to increasing IAP, allowing time for the body to adapt physiologically. The clinical consideration

Primary ACS is characterized by the presence of acute or subacute IAH of relatively brief duration occurring as a result of an intra-abdominal cause such as severe acute pancreatitis, abdominal trauma, ruptured abdominal aortic aneurysm, and liver transplantation [7].

Secondary ACS is characterized by the presence of subacute or chronic IAH that develops massive fluid resuscitation such as an extra-abdominal cause such as sepsis, capillary leak, burns [8].

dysfunction of the brain circulation through increase of intrathoracic pressure [4].

of IAH subtypes is useful in prescribing patients at risk for ACS (**Table 1**) [6].

careful about the significance of increased abdominal pressure.

4 Management of Chronic Liver Diseases - Recent Advances

**2. Pathophysiology of ACS**

**Table 2.** Grading of intra-abdominal hypertension.

The World Society of Abdominal Compartment Syndrome classified IAH into grade I–IV and ACS (**Table 2**) [9].

Burch et al. suggested that most patients with grade III and all patients with grade IV should undergo abdominal decompression [10].

## **3. ACS results in non-abdominal organ failure**

#### **3.1. Cardiovascular**

Due to the increased intrathoracic pressure, indirect measures of cardiac filling such as central venous pressure and pulmonary artery occlusion pressure give inaccurate results and can be increased despite profound intravascular volume depletion. The decrease in cardiac output caused by intra-abdominal hypertension is therefore exacerbated by hypovolemia [11].

#### **3.2. Respiratory**

Respiratory distress and failure: Initial signs of ACS include elevated peak airway pressures in intubated patients with decreased tidal volumes. The ensuing increase in intrathoracic pressure and hypoxic pulmonary vasoconstriction can lead to pulmonary hypertension [12].

### **3.3. Neurological**

Intracranial perfusion pressure is decreased by increase in intracranial pressure (ICP) caused by venal perfusion defect, including renal failure. For increased ICP, decompressive laparotomy has been shown to reduce intractable elevated ICP in patients with IAH, and compression of the ureters is not thought to contribute to renal dysfunction, as the insertion of ureteric stents does not result in an improvement in urine output [13].

experimentally in 61% of the baseline value of 40 mmHg [16]. In MODS, there is gastrointestinal mucous membrane acidosis of which the IAP is expected to be at 10 mmHg is derived

Intra-Abdominal Hypertension and Abdominal Compartment Syndrome in Liver Diseases

http://dx.doi.org/10.5772/intechopen.77061

7

There are various methods of measuring intermittent IAP, such as invasive (direct, i.e., needle puncture of the abdomen during peritoneal dialysis or laparoscopy) and noninvasive (indirect, i.e., transduction of intravesicular or "bladder," gastric, colonic or uterine pressure via the balloon catheter). Noninvasive measurement of bladder internal pressure and intragastric

pressure are recommended. The internal bladder pressure are commonly related to IAP mea-

Intrabladder pressure monitoring estimated for IAP can be obtained either via a closed transducer technique or the closed Foley Manometer technique, which seems safe and does not

Discussions on IAP to become the adaptation standard of decompression is divided, but more than 25 mmHg is assumed to be a tentative adaptation standard clinically. However, recently, reports on gastrointestinal disorder due to impairment of IAP in the lower abdominal cavity need to be considered. The World Society of the Abdominal Compartment Syndrome sug-

sured directly in the range of 5–70 mmHg [6].

gested a management algorithm for IAH/ACS [20].

**6. ACS treatment**

alter the risk of UTI in patients with critical illness [19] (**Figure 1**).

**Figure 1.** Measurement of intra-abdominal pressure using bladder pressure measurements.

from ACS.

**5. Diagnosis of ACS**

## **4. Intra-abdominal organ failure in ACS**

## **4.1. Renal function disorder**

ACS is characterized by marked reduction in glomerular filtration rate (GFR) and renal plasma flow in the absence of other causes of renal failure. Moreover, changes in cardiac output, direct compression of the renal vessels or renal parenchyma with diminished renal blood flow, increase in renal vascular resistance, and distribution of blood from the renal cortex to the medulla are reported the mechanisms of renal dysfunction [14]. Bradley et al. are the first to report that animals become anuric with an IAP of 30 mmHg [2]. Additional factors that cause IAP to reach ACS range include reduction in cardiac output and elevated levels of catecholamines [15]. Renin, angiotensin, and inflammatory cytokines may also come into play, further worsening renal function.

#### **4.2. Liver function disorder**

Diebel et al. reported that the portal vein (PV) pressure decreased experimentally in 65% of patients with an IAP of 40 mmHg, and liver tissue microcirculation quantity decreases to 71% [16].

Liver dysfunction occurs due to decrease PV flow because of IAH. Furthermore, with cardiac dysfunction, liver ischemia becomes worse. Persistent IAP decrease the mean arterial blood pressure in the superior mesenteric artery (SMA) and PV flow by 50% [17].

Rasmussen et al. reported that an IAP of 25 mm Hg results in a 66% decrease in PV blood flow and a 6.5-fold increase in portal/hepatic vascular resistance compared to baseline levels [18].

Furthermore, in studies evaluating the effects of increased IAP on hepatocyte, the characteristics of the sinusoid should be expected to elucidate hepatic dysfunction from increased IAP.

### **4.3. Gastrointestinal functional disorder**

To determine the possibility of bacterial translocation (BT), of which there is failure of the mucous membrane barrier mechanism caused by decline in blood circulation in mucous membranes, pH in the mucous membrane declined as well. Besides, this phenomenon is regarded as the cause of multiple organ dysfunction syndrome (MODS) after ACS, but there is no direct proof. Even if the IAP is at 20 mmHg, blood flow to the intestinal mucosa decreases to 28% experimentally in 61% of the baseline value of 40 mmHg [16]. In MODS, there is gastrointestinal mucous membrane acidosis of which the IAP is expected to be at 10 mmHg is derived from ACS.

## **5. Diagnosis of ACS**

**3.3. Neurological**

Intracranial perfusion pressure is decreased by increase in intracranial pressure (ICP) caused by venal perfusion defect, including renal failure. For increased ICP, decompressive laparotomy has been shown to reduce intractable elevated ICP in patients with IAH, and compression of the ureters is not thought to contribute to renal dysfunction, as the insertion of ureteric

ACS is characterized by marked reduction in glomerular filtration rate (GFR) and renal plasma flow in the absence of other causes of renal failure. Moreover, changes in cardiac output, direct compression of the renal vessels or renal parenchyma with diminished renal blood flow, increase in renal vascular resistance, and distribution of blood from the renal cortex to the medulla are reported the mechanisms of renal dysfunction [14]. Bradley et al. are the first to report that animals become anuric with an IAP of 30 mmHg [2]. Additional factors that cause IAP to reach ACS range include reduction in cardiac output and elevated levels of catecholamines [15]. Renin, angiotensin, and inflammatory cytokines may also come into play, further worsening renal function.

Diebel et al. reported that the portal vein (PV) pressure decreased experimentally in 65% of patients with an IAP of 40 mmHg, and liver tissue microcirculation quantity decreases to 71% [16]. Liver dysfunction occurs due to decrease PV flow because of IAH. Furthermore, with cardiac dysfunction, liver ischemia becomes worse. Persistent IAP decrease the mean arterial blood

Rasmussen et al. reported that an IAP of 25 mm Hg results in a 66% decrease in PV blood flow and a 6.5-fold increase in portal/hepatic vascular resistance compared to baseline levels [18]. Furthermore, in studies evaluating the effects of increased IAP on hepatocyte, the characteristics of the sinusoid should be expected to elucidate hepatic dysfunction from increased IAP.

To determine the possibility of bacterial translocation (BT), of which there is failure of the mucous membrane barrier mechanism caused by decline in blood circulation in mucous membranes, pH in the mucous membrane declined as well. Besides, this phenomenon is regarded as the cause of multiple organ dysfunction syndrome (MODS) after ACS, but there is no direct proof. Even if the IAP is at 20 mmHg, blood flow to the intestinal mucosa decreases to 28%

pressure in the superior mesenteric artery (SMA) and PV flow by 50% [17].

stents does not result in an improvement in urine output [13].

**4. Intra-abdominal organ failure in ACS**

6 Management of Chronic Liver Diseases - Recent Advances

**4.1. Renal function disorder**

**4.2. Liver function disorder**

**4.3. Gastrointestinal functional disorder**

There are various methods of measuring intermittent IAP, such as invasive (direct, i.e., needle puncture of the abdomen during peritoneal dialysis or laparoscopy) and noninvasive (indirect, i.e., transduction of intravesicular or "bladder," gastric, colonic or uterine pressure via the balloon catheter). Noninvasive measurement of bladder internal pressure and intragastric

**Figure 1.** Measurement of intra-abdominal pressure using bladder pressure measurements.

pressure are recommended. The internal bladder pressure are commonly related to IAP measured directly in the range of 5–70 mmHg [6].

Intrabladder pressure monitoring estimated for IAP can be obtained either via a closed transducer technique or the closed Foley Manometer technique, which seems safe and does not alter the risk of UTI in patients with critical illness [19] (**Figure 1**).

## **6. ACS treatment**

Discussions on IAP to become the adaptation standard of decompression is divided, but more than 25 mmHg is assumed to be a tentative adaptation standard clinically. However, recently, reports on gastrointestinal disorder due to impairment of IAP in the lower abdominal cavity need to be considered. The World Society of the Abdominal Compartment Syndrome suggested a management algorithm for IAH/ACS [20].

An early indication of the open abdomen technique has been shown to reduce mortality [21]. Chen et al. reported that laparoscopy can be used as a safe alternative for ACS decompression [22].

The World Society of the Abdominal Compartment Syndrome has noted that correct fluid therapy and perfusion support during resuscitation form the cornerstone of medical management in patients with abdominal hypertension [23].

Pharmacologic therapy is less effective than drainage procedures. Agustí et al. reported that dobutamine restores intestinal mucosal blood flow in a porcine model of intra-abdominal hyperpressure [24].

If a patient experiences decompensation, ACS should be re-examined as a potential cause.

## **7. Possible involvement of IAH/ACS and HRS**

We reported an autopsy case with HRS and ACS diagnosed with a clinical and histopathological consideration of liver and kidney diseases. Further clinical studies are needed to improve the management of renal failure in patients with acute liver failure and advanced liver cirrhosis (**Figures 2** and **3**) [25].

compression of renal vein is suggested to be vital in the development renal dysfunction. IAH is the significant pathological mechanism and independent risk factor in the occurrence and development of HRS [29]. Further, attempts should be made to decrease IAP following surgi-

**Figure 3.** Kidney: microscopic findings showed swelling in the renal tubules. There was no change in the glomerulus and

Intra-Abdominal Hypertension and Abdominal Compartment Syndrome in Liver Diseases

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9

Several methods are reported to control refractory abdominal ascites in end-stage liver cirrhosis, such as avoidance of non-steroidal anti-inflammatory drugs [30], dietary sodium restriction [31], diuretic, LVP, cell-free and concentrated ascites reinfusion therapy [32], transjugular

IAH is defined as an IAP above 12 mmHg. Hence, abdominal ascites in early stage of liver cirrhosis should be treated and early stage of ascites in outpatient should be managed immediately. Outpatients with clinically apparent ascites will require diuretic therapy in addition to dietary sodium restriction. Diuretic therapy typically consists of treatment regimen for cirrhotic ascites such as combination of oral spironolactone and furosemide. Recently, aquaporin-2 is a vasopressin-regulated water channel expressed in the renal collecting duct. Urine aquaporin-2 is considered a marker of collecting duct responsiveness to tolvaptan. In Japan, on September 2013, tolvaptan was approved (in doses up to 7.5 mg/day) for treating patients

Massive ascites also influences IAP and causes oliguria and acute kidney injury (AKI). Commonly, we recognize this symptom at the stage of end stage of liver cirrhosis. This symptom has the possible involvement with HRS. In such patients, we should take into account the

cal decompression, large-volume paracentesis (LVP), and appropriate diuretic drug.

collecting tubule and no renal fibrosis. CT the right renal vein was compressed by massive ascites (arrow).

intrahepatic portosystemic shunt [33], and peritoneovenous shunt [34].

with ascites who showed an inadequate response to conventional diuretics [35].

**8. Drug strategy for ACS**

**9. Conclusion**

HRS was originally described in 1863 by Flint as an association between liver disease and oliguric renal failure in the absence of significant renal histological change [26]. HRS is recognized by intense intrarenal vasospasm caused by the imbalance between vasodilatory and vasoconstrictive mediators seen in end stage of liver disease [27].

Although the precise role of IAH in HRS remains incompletely understood, it can be argued that diminished glomerular perfusion due to venous congestion results in further decline of GFR.

Cade et al. reported significant increases in urine flow rate and creatinine clearance after reduction in IAP from 22 to 10 mmHg with paracentesis in patients with cirrhosis [28]. Moreover,

**Figure 2.** Liver: end-stage liver cirrhosis. Microscopic findings showed hepatic sinusoidal dilation due to portal hypertension and severe jaundice.

Intra-Abdominal Hypertension and Abdominal Compartment Syndrome in Liver Diseases http://dx.doi.org/10.5772/intechopen.77061 9

**Figure 3.** Kidney: microscopic findings showed swelling in the renal tubules. There was no change in the glomerulus and collecting tubule and no renal fibrosis. CT the right renal vein was compressed by massive ascites (arrow).

compression of renal vein is suggested to be vital in the development renal dysfunction. IAH is the significant pathological mechanism and independent risk factor in the occurrence and development of HRS [29]. Further, attempts should be made to decrease IAP following surgical decompression, large-volume paracentesis (LVP), and appropriate diuretic drug.

## **8. Drug strategy for ACS**

An early indication of the open abdomen technique has been shown to reduce mortality [21]. Chen et al. reported that laparoscopy can be used as a safe alternative for ACS decompression [22]. The World Society of the Abdominal Compartment Syndrome has noted that correct fluid therapy and perfusion support during resuscitation form the cornerstone of medical manage-

Pharmacologic therapy is less effective than drainage procedures. Agustí et al. reported that dobutamine restores intestinal mucosal blood flow in a porcine model of intra-abdominal

If a patient experiences decompensation, ACS should be re-examined as a potential cause.

We reported an autopsy case with HRS and ACS diagnosed with a clinical and histopathological consideration of liver and kidney diseases. Further clinical studies are needed to improve the management of renal failure in patients with acute liver failure and advanced liver cir-

HRS was originally described in 1863 by Flint as an association between liver disease and oliguric renal failure in the absence of significant renal histological change [26]. HRS is recognized by intense intrarenal vasospasm caused by the imbalance between vasodilatory and

Although the precise role of IAH in HRS remains incompletely understood, it can be argued that diminished glomerular perfusion due to venous congestion results in further decline of GFR. Cade et al. reported significant increases in urine flow rate and creatinine clearance after reduction in IAP from 22 to 10 mmHg with paracentesis in patients with cirrhosis [28]. Moreover,

**Figure 2.** Liver: end-stage liver cirrhosis. Microscopic findings showed hepatic sinusoidal dilation due to portal hyper-

ment in patients with abdominal hypertension [23].

8 Management of Chronic Liver Diseases - Recent Advances

**7. Possible involvement of IAH/ACS and HRS**

vasoconstrictive mediators seen in end stage of liver disease [27].

hyperpressure [24].

rhosis (**Figures 2** and **3**) [25].

tension and severe jaundice.

Several methods are reported to control refractory abdominal ascites in end-stage liver cirrhosis, such as avoidance of non-steroidal anti-inflammatory drugs [30], dietary sodium restriction [31], diuretic, LVP, cell-free and concentrated ascites reinfusion therapy [32], transjugular intrahepatic portosystemic shunt [33], and peritoneovenous shunt [34].

IAH is defined as an IAP above 12 mmHg. Hence, abdominal ascites in early stage of liver cirrhosis should be treated and early stage of ascites in outpatient should be managed immediately. Outpatients with clinically apparent ascites will require diuretic therapy in addition to dietary sodium restriction. Diuretic therapy typically consists of treatment regimen for cirrhotic ascites such as combination of oral spironolactone and furosemide. Recently, aquaporin-2 is a vasopressin-regulated water channel expressed in the renal collecting duct. Urine aquaporin-2 is considered a marker of collecting duct responsiveness to tolvaptan. In Japan, on September 2013, tolvaptan was approved (in doses up to 7.5 mg/day) for treating patients with ascites who showed an inadequate response to conventional diuretics [35].

## **9. Conclusion**

Massive ascites also influences IAP and causes oliguria and acute kidney injury (AKI). Commonly, we recognize this symptom at the stage of end stage of liver cirrhosis. This symptom has the possible involvement with HRS. In such patients, we should take into account the elevation of renal parenchymal and renal vein pressures, as they are likely the mechanisms of renal impairment. Note that IAH/ACS and HRS are occurring simultaneously. Hepatologists should consider IAH and ACS in end-stage liver cirrhosis.

[6] Malbrain ML, Cheatham ML, Kirkpatrick A, Sugrue M, Parr M, De Waele J, Balogh Z, Leppäniemi A, Olvera C, Ivatury R, D'Amours S, Wendon J, Hillman K, Johansson K, Kolkman K, Wilmer A. Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome. I. Definitions.

Intra-Abdominal Hypertension and Abdominal Compartment Syndrome in Liver Diseases

http://dx.doi.org/10.5772/intechopen.77061

11

[7] Cosgriff N, Moore EE, Sauaia A, Kenny-Moynihan M, Burch JM, Galloway B. Predicting life-threatening coagulopathy in the massively transfused trauma patient: Hypothermia

[8] Aspesi M, Gamberoni C, Severgnini P, Colombo G, Chiumello D, Minoja G, Tulli G, Malacrida R, Pelosi P, Chiaranda M. The abdominal compartment syndrome. Clinical

[9] Malbrain ML, Deeren D, De Potter TJ. Intra-abdominal hypertension in the critically ill:

[10] Burch JM, Moore EE, Moore FA, Franciose R. The abdominal compartment syndrome.

[11] Ridings PC, Bloomfield GL, Blocher CR, Sugerman HJ. Cardiopulmonary effects of raised intra-abdominal pressure before and after intravascular volume expansion. The

[12] Cullen DJ, Coyle JP, Teplick R, Long MC. Cardiovascular, pulmonary, and renal effects of massively increased intra-abdominal pressure in critically ill patients. Critical Care

[13] Constantini S, Cotev S, Rappaport ZH, Pomeranz S, Shalit MN. Intracranial pressure monitoring after elective intracranial surgery. A retrospective study of 514 consecutive

[14] Mohmand H, Goldfarb S. Renal dysfunction associated with intra-abdominal hypertension and the abdominal compartment syndrome. Journal of the American Society of

[15] Mikami O, Fujise K, Matsumoto S, Shingu K, Ashida M, Matsuda T. High intra-abdominal pressure increases plasma catecholamine concentrations during pneumoperitoneum

[16] Diebel LN, Dulchavsky SA, Brown WJ. Splanchnic ischemia and bacterial translocation in the abdominal compartment syndrome. The Journal of Trauma. 1997;**43**:852-855

[17] Mogilner J, Sukhotnik I, Brod V, Hayari L, Coran AG, Shiloni E, Eldar S, Bitterman H. Effect of elevated intra-abdominal pressure on portal vein and superior mesenteric artery blood flow in a rat. Journal of Laparoendoscopic & Advanced Surgical Techniques. Part

[18] Rasmussen IB, Berggren U, Arvidsson D, Ljungdahl M, Haglund U. Effects of pneumoperitoneum on splanchnic hemodynamics: An experimental study in pigs. The European

It is time to pay attention. Current Opinion in Critical Care; 2005;**11**:156-171

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## **Acknowledgements**

The authors would like to thank Takao Tsuchida in the Division of Gastroenterology and Hepatology at the Niigata University for his excellent assistance in histological analyses.

## **Funding**

This work was supported by a Grant-in-Aid for Research Activity Start-up 17H06691 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to Hiroteru Kamimura.

## **Author details**

Hiroteru Kamimura\*, Tomoyuki Sugano, Ryoko Horigome, Naruhiro Kimura, Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa and Shuji Terai

\*Address all correspondence to<EMAIL_ADDRESS>
Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

## **References**

[6] Malbrain ML, Cheatham ML, Kirkpatrick A, Sugrue M, Parr M, De Waele J, Balogh Z, Leppäniemi A, Olvera C, Ivatury R, D'Amours S, Wendon J, Hillman K, Johansson K, Kolkman K, Wilmer A. Results from the international conference of experts on intra-abdominal hypertension and abdominal compartment syndrome. I. Definitions. Intensive Care Medicine. 2006;**32**:1722-1732

elevation of renal parenchymal and renal vein pressures, as they are likely the mechanisms of renal impairment. Note that IAH/ACS and HRS are occurring simultaneously. Hepatologists

The authors would like to thank Takao Tsuchida in the Division of Gastroenterology and Hepatology at the Niigata University for his excellent assistance in histological analyses.

This work was supported by a Grant-in-Aid for Research Activity Start-up 17H06691 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to Hiroteru Kamimura.

Hiroteru Kamimura\*, Tomoyuki Sugano, Ryoko Horigome, Naruhiro Kimura,

Division of Gastroenterology and Hepatology, Niigata University Graduate School of

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[2] Bradley SE, Bradley GP. The effect of increased intra-abdominal pressure on renal func-

[3] Matsumoto N, Ogawa M, Kumagawa M, Watanabe Y, Hirayama M, Miura T, Nakagawara H, Matsuoka S, Moriyama M, Fujikawa H. Renal vein dilation predicts poor outcome in patients with refractory cirrhotic ascites. Hepatology Research. 2018;**48**:E117-E125

[4] Cheatham ML, White MW, Sagraves SG, Johnson JL, Block EF. Abdominal perfusion pressure: A superior parameter in the assessment of intra-abdominal hypertension. The

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Medical and Dental Sciences, Niigata, Japan

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10 Management of Chronic Liver Diseases - Recent Advances

**Acknowledgements**

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[31] Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Annals of Internal Medicine. 1992;**117**:215-220

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[33] Ginès P, Arroyo V, Vargas V, Planas R, Casafont F, Panés J, Hoyos M, Viladomiu L, Rimola A, Morillas R, et al. Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites. The New

[34] Park JS, Won JY, Park SI, Park SJ, Lee DY. Percutaneous peritoneovenous shunt creation for the treatment of benign and malignant refractory ascites. Journal of Vascular and

[35] Sakaida I, Terai S, Kurosaki M, Yasuda M, Okada M, Bando K, Fukuta Y. Effectiveness and safety of tolvaptan in liver cirrhosis patients with edema:Interim results of postmarketing surveillance of tolvaptan in liver cirrhosis (START study). Hepatology

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[19] Desie N, Willems W, De laet I, Dits H, Van Regenmorte N, Schoonheydt K, Van De Vyvere M, Malbrain M. Intra-abdominal pressure measurement using the Foley manometer does not increase the risk for urinary tract infection in critically ill patients. Annals

[20] Kirkpatrick AW, Roberts DJ, De Waele J, Jaeschke R, Malbrain ML, De Keulenaer B, Duchesne J, Bjorck M, Leppaniemi A, Ejike JC, Sugrue M, Cheatham M, Ivatury R, Ball CG, Reintam Blaser A, Regli A, Balogh ZJ, D'Amours S, Debergh D, Kaplan M, Kimball E, Olvera C. Pediatric guidelines sub-Committee for the World Society of the abdominal compartment syndrome. Intra-abdominal hypertension and the abdominal compartment syndrome: Updated consensus definitions and clinical practice guidelines from the world Society of the Abdominal Compartment Syndrome. Intensive Care Medicine.

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**Section 2**

**Liver Cirrhosis**

**Section 2**

## **Liver Cirrhosis**

**Chapter 2**

**Provisional chapter**

**Management of Ascites Associated with Severe**

**Management of Ascites Associated with Severe**

DOI: 10.5772/intechopen.76376

Advanced liver cirrhosis requiring hospitalization is frequently associated with electrolytic disturbances, the most common finding being serum hyponatremia. The goal of treatment in patients with decompensated liver cirrhosis complicated with severe hyponatremia is to normalize the increased amount of water in the body and to improve the sodium concentration. Fluid restriction is recommended at 1.5 L/day to prevent sodium depletion in the serum, but the lack of efficacy is probably due to a poor patient compliance. Discontinuation or adjustments of diuretic dosages are sometimes required. Albumin associated with vasoconstrictors as midodrine can increase the effective arterial blood volume and seems to improve the serum sodium concentration. A promising therapeutic option targeting the pathophysiological mechanism of hyponatremia consists of improving solute-free water excretion, which is markedly impaired in these patients. The use of agents such as k opioid agonists has been attempted, but has been dropped due to the severe side effects. Recently, a new therapeutic class called vaptans has taken an important place in the treatment of hypervolemic hyponatremia. The main side effects during the administration of these drugs in patients with liver cirrhosis are reversible after discontinuing therapy. Therefore, it is recommended to use vaptans for

**Keywords:** hypervolemia, hyponatremia, liver cirrhosis, fluid restriction, vasopressin

© 2016 The Author(s). Licensee InTech. 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.

© 2018 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.

**Hyponatremia**

**Abstract**

short periods of time.

receptor antagonists, vaptans

**Hyponatremia**

Andra Iulia Suceveanu, Roxana Popoiag,

Andra Iulia Suceveanu, Roxana Popoiag,

Andreea Gheorghe, Anca Stoian, Felix Voinea, Claudia Voinea and Adrian Paul Suceveanu

Andreea Gheorghe, Anca Stoian, Felix Voinea, Claudia Voinea and Adrian Paul Suceveanu

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Laura Mazilu, Irinel Raluca Parepa,

Laura Mazilu, Irinel Raluca Parepa,

http://dx.doi.org/10.5772/intechopen.76376

#### **Management of Ascites Associated with Severe Hyponatremia Management of Ascites Associated with Severe Hyponatremia**

DOI: 10.5772/intechopen.76376

Andra Iulia Suceveanu, Roxana Popoiag, Laura Mazilu, Irinel Raluca Parepa, Andreea Gheorghe, Anca Stoian, Felix Voinea, Claudia Voinea and Adrian Paul Suceveanu Andra Iulia Suceveanu, Roxana Popoiag, Laura Mazilu, Irinel Raluca Parepa, Andreea Gheorghe, Anca Stoian, Felix Voinea, Claudia Voinea and Adrian Paul Suceveanu

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76376

#### **Abstract**

Advanced liver cirrhosis requiring hospitalization is frequently associated with electrolytic disturbances, the most common finding being serum hyponatremia. The goal of treatment in patients with decompensated liver cirrhosis complicated with severe hyponatremia is to normalize the increased amount of water in the body and to improve the sodium concentration. Fluid restriction is recommended at 1.5 L/day to prevent sodium depletion in the serum, but the lack of efficacy is probably due to a poor patient compliance. Discontinuation or adjustments of diuretic dosages are sometimes required. Albumin associated with vasoconstrictors as midodrine can increase the effective arterial blood volume and seems to improve the serum sodium concentration. A promising therapeutic option targeting the pathophysiological mechanism of hyponatremia consists of improving solute-free water excretion, which is markedly impaired in these patients. The use of agents such as k opioid agonists has been attempted, but has been dropped due to the severe side effects. Recently, a new therapeutic class called vaptans has taken an important place in the treatment of hypervolemic hyponatremia. The main side effects during the administration of these drugs in patients with liver cirrhosis are reversible after discontinuing therapy. Therefore, it is recommended to use vaptans for short periods of time.

**Keywords:** hypervolemia, hyponatremia, liver cirrhosis, fluid restriction, vasopressin receptor antagonists, vaptans

© 2016 The Author(s). Licensee InTech. 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. © 2018 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.

## **1. Introduction**

Ascites is the most common complication of cirrhosis, approximately 60% of patients develop ascites within 10 years of disease progression. The mechanism of production is the development of portal hypertension and renal retention of sodium. This inability to excrete an adequate amount of sodium in the urine occurs due to arterial splanchnic vasodilatation. Therefore, arterial and pulmonary cardio vascular receptor activation occurs with homeostatic activation of vasoconstrictor and sodium retention systems, resulting in a decrease in the required arterial blood volume. Renal sodium retention increases the volume of extracellular fluid leading to ascites and edema [1–5].

**4. Pathophysiology**

ADH.

elevated levels of epinephrine and norepinephrine.

dilution and hypo-osmolality [6].

the release of free water.

hypovolemia [9].

The mechanism by which ascites fluid is formed is the excess water and sodium retention in the body. Several theories have been developed to understand pathophysiology, and in turn, it has been shown that much of it would arise as a result of portal hypertension. The three proposed theories are three distinct mechanisms named: filling, oversaturation, and peripheral arterial vasodilatation. The first theory of filling is determined by portal hypertension and decreased circulating volume that produces vascular fluid retention. Since cirrhotic patients have a higher percentage of hypervolemia than hypovolemia, the second overload theory is determined by the retention of water and sodium in the absence of volume exhaustion. And the third theory uses the first two theories. This indicates that vasodilation occurs as a result of portal hypertension and favors the increase in arterial blood volume. Also, several factors are involved in ascites fluid formation: hypoalbuminemia and oncotic low plasma pressure,

Management of Ascites Associated with Severe Hyponatremia

http://dx.doi.org/10.5772/intechopen.76376

19

The main mechanism of hyponatremia is represented by arterial vasodilation. By reducing effective blood volume, several neurohumoral systems such as the renin-angiotensin-aldosterone system and the sympathetic nervous system are stimulated and lead to the release of

Activation of those trigger systems causes sodium retention and may lead to renal vasoconstriction. Vasopressin 2 receptors affected by the ADH play an important role in rate of excretion of solute-free water. In the end, water excretion occurs with the appearance of serum

Under normal circumstances, there is a synchronous increase in serum osmolarity and ADH secretion, and reabsorption of water occurs when activating the aquaporin channels in the renal collection tubes. In opposite, the inactivation of aquaporin channels occurs when a decrease in osmolarity appears, resulting in urine dilution as a mechanism in maintaining serum osmolarity. Thus, the good functioning of osmoreceptors in the anterior hypothalamus, the release of ADH and the mutual action between ADH and AQP-2 compete to adapt

ADH is secreted into the supraoptic and paraventricular nuclei of the hypothalamus and maintained in the posterior pituitary gland. Vasopressin secretion is stimulated by increased plasma osmolarity and hypovolemia. The release of ADH is conditioned by osmotic and nonosmotic stimulation. The osmoreceptors in the anterior hypothalamus, near the supraoptic nuclei mediate the osmotic pathway. These receptors detect intracellular water content in neurons and respond to changes in plasma osmolarity. The main nonosmotic pathway delivers an ADH release through the autonomic nervous system mediated by baroreceptors located in the atrium, ventricle, aortic arch, and carotid sinus. Through the parasympathetic pathway, these baroreceptors stimulate the hypothalamus to release ADH in response to

At approximately 75% of patients from Western Europe and USA, the main cause of ascites is represented by cirrhosis. Other causes of ascites may be malignancy, heart failure, tuberculosis, pancreatic disease, or other causes.

Hyponatremia is one of the complications that occurs in end stage cirrhosis due to the impossibility of renal clearance of free water, which leads to a higher water retention than sodium with the occurrence of hyposomolarity, with an increase in mortality and morbidity. In the pathogenesis of hyponatremia, the main factor involved is hypersecretion of antidiuretic hormone (ADH). Hyponatremia is a risk factor for both hepatic encephalopathy and liver transplantation because it is associated with an increased frequency of complications and a short-term survival [6].

## **2. Definition**

Patients with liver cirrhosis show two types of hyponatremia: hypovolemic and hypervolemic.

Hypervolemic hyponatremia is the most common form and is characterized by low levels of serum sodium and increased volume of extracellular fluid, ascites, and edema. It may appear secondary to bacterial infections, excessive hypotonic fluids or may occur spontaneously. Hypovolemic hyponatremia is less common, with low levels of sodium, without ascites and edema as a consequence of excessive diuretic administration.

Hyponatremia is defined when serum sodium levels fall below 130 mmol/L but according to the recent guidelines, reductions below 135 mmol/L should also be considered as hyponatremia [7].

## **3. Prevalence**

A study made over an Asian population following 997 patients with cirrhosis and ascites over 28 days in 28 centers showed that hyponatremia is present in more than half of the patients [8].

## **4. Pathophysiology**

**1. Introduction**

lular fluid leading to ascites and edema [1–5].

18 Management of Chronic Liver Diseases - Recent Advances

sis, pancreatic disease, or other causes.

short-term survival [6].

**2. Definition**

mia [7].

**3. Prevalence**

Ascites is the most common complication of cirrhosis, approximately 60% of patients develop ascites within 10 years of disease progression. The mechanism of production is the development of portal hypertension and renal retention of sodium. This inability to excrete an adequate amount of sodium in the urine occurs due to arterial splanchnic vasodilatation. Therefore, arterial and pulmonary cardio vascular receptor activation occurs with homeostatic activation of vasoconstrictor and sodium retention systems, resulting in a decrease in the required arterial blood volume. Renal sodium retention increases the volume of extracel-

At approximately 75% of patients from Western Europe and USA, the main cause of ascites is represented by cirrhosis. Other causes of ascites may be malignancy, heart failure, tuberculo-

Hyponatremia is one of the complications that occurs in end stage cirrhosis due to the impossibility of renal clearance of free water, which leads to a higher water retention than sodium with the occurrence of hyposomolarity, with an increase in mortality and morbidity. In the pathogenesis of hyponatremia, the main factor involved is hypersecretion of antidiuretic hormone (ADH). Hyponatremia is a risk factor for both hepatic encephalopathy and liver transplantation because it is associated with an increased frequency of complications and a

Patients with liver cirrhosis show two types of hyponatremia: hypovolemic and hypervolemic. Hypervolemic hyponatremia is the most common form and is characterized by low levels of serum sodium and increased volume of extracellular fluid, ascites, and edema. It may appear secondary to bacterial infections, excessive hypotonic fluids or may occur spontaneously. Hypovolemic hyponatremia is less common, with low levels of sodium, without ascites and

Hyponatremia is defined when serum sodium levels fall below 130 mmol/L but according to the recent guidelines, reductions below 135 mmol/L should also be considered as hyponatre-

A study made over an Asian population following 997 patients with cirrhosis and ascites over 28 days in 28 centers showed that hyponatremia is present in more than half of the patients [8].

edema as a consequence of excessive diuretic administration.

The mechanism by which ascites fluid is formed is the excess water and sodium retention in the body. Several theories have been developed to understand pathophysiology, and in turn, it has been shown that much of it would arise as a result of portal hypertension. The three proposed theories are three distinct mechanisms named: filling, oversaturation, and peripheral arterial vasodilatation. The first theory of filling is determined by portal hypertension and decreased circulating volume that produces vascular fluid retention. Since cirrhotic patients have a higher percentage of hypervolemia than hypovolemia, the second overload theory is determined by the retention of water and sodium in the absence of volume exhaustion. And the third theory uses the first two theories. This indicates that vasodilation occurs as a result of portal hypertension and favors the increase in arterial blood volume. Also, several factors are involved in ascites fluid formation: hypoalbuminemia and oncotic low plasma pressure, elevated levels of epinephrine and norepinephrine.

The main mechanism of hyponatremia is represented by arterial vasodilation. By reducing effective blood volume, several neurohumoral systems such as the renin-angiotensin-aldosterone system and the sympathetic nervous system are stimulated and lead to the release of ADH.

Activation of those trigger systems causes sodium retention and may lead to renal vasoconstriction. Vasopressin 2 receptors affected by the ADH play an important role in rate of excretion of solute-free water. In the end, water excretion occurs with the appearance of serum dilution and hypo-osmolality [6].

Under normal circumstances, there is a synchronous increase in serum osmolarity and ADH secretion, and reabsorption of water occurs when activating the aquaporin channels in the renal collection tubes. In opposite, the inactivation of aquaporin channels occurs when a decrease in osmolarity appears, resulting in urine dilution as a mechanism in maintaining serum osmolarity. Thus, the good functioning of osmoreceptors in the anterior hypothalamus, the release of ADH and the mutual action between ADH and AQP-2 compete to adapt the release of free water.

ADH is secreted into the supraoptic and paraventricular nuclei of the hypothalamus and maintained in the posterior pituitary gland. Vasopressin secretion is stimulated by increased plasma osmolarity and hypovolemia. The release of ADH is conditioned by osmotic and nonosmotic stimulation. The osmoreceptors in the anterior hypothalamus, near the supraoptic nuclei mediate the osmotic pathway. These receptors detect intracellular water content in neurons and respond to changes in plasma osmolarity. The main nonosmotic pathway delivers an ADH release through the autonomic nervous system mediated by baroreceptors located in the atrium, ventricle, aortic arch, and carotid sinus. Through the parasympathetic pathway, these baroreceptors stimulate the hypothalamus to release ADH in response to hypovolemia [9].

Most patients with cirrhosis present low serum osmolarity and sodium levels, and it is expected to produce inhibition of ADH release if stimulation was achieved by osmoreceptors [10]. Because of the activation of the neurohumoral mechanisms that retain sodium, the levels of ADH, aldosterone, norepinephrine, and renin activity were significantly higher in patients with cirrhosis and ascites after the water loading test. Effective arterial uptake would result from a decrease in systemic vascular resistance and would result in nonosmotic stimulation due to baroreceptors of ADH and other vasoconstriction systems. These cause the activation of the neurohumoral mechanisms that produce sodium retention in order to restore the perfusion pressure [11].

Sodium concentration was included in the MELD model to indicate the need for liver transplantation and patient priority on waiting lists in order to improve prognosis [19]. It was found that the MELD-Na score indicated an anticipation of short-term mortality of transplant

Management of Ascites Associated with Severe Hyponatremia

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21

Symptoms of hyponatremia are caused by the damage to the nervous system, with cerebral edema due to the migration of water from the intravascular space in the brain [21]. As a rapid adaptive mechanism, there is an increase in electrolytes in brain cells. As a slow adaptation mechanism, organic osmoliths are extruded. Finally, these mechanisms help return the water

patient candidates much better than the initial MELD score [20].

to the intravascular space and prevent brain edema [22].

**Figure 1.** Clinical manifestations of hyponatremia.

**6. Clinical presentation**

It is suggested that hypoosmotic stimuli are suppressed by nonosmotic stimuli to suppress ADH release. That is why the body sacrifices osmolar homeostasis and releases ADH following nonosmotic stimulation of endogenous vasoconstrictors, and thus impairs vascular collapse by exhausting effective circulatory volume. It results in an inability to release sodium and water to replenish the circulation volume. All of these things happen despite the increase in cardiac output, plasma volume, and total body volume. To eliminate the extra amount of water, it is necessary to suppress adherence and the ability of the kidneys to remove water. The presence of nonosmotic adherence leads to the occurrence of a hyponatremia of dilution or hypervolemic hyponatremia. Therefore, in this category of patients, hyponatremia is only dilute and does not represent a sodium deficiency [12].

In a prospective cohort study of patients with ascites, it was demonstrated that the occurrence of hyponatremia is preceded by refractory ascites and subsequently by hepatorenal syndrome. Each of these steps was associated with a progressive Child Pugh score and Model for End Stage Liver Disease (MELD) indicating a worsening of liver function. Therefore, hyponatremia is an intermediate stage between ascites progression and hepatorenal syndrome [13].

## **5. Prognostic value**

Hyponatremia in patients with cirrhosis is chronic, therefore, allows the brain to adapt to the hypo extracellular fluid osmolality. In conclusion, patients are less likely to have severe neurological symptoms. However, hyponatremia can aggravate cerebral edema and swollen astrocytes by adding to their dysfunction created by increased intracellular glutamine concentration, speeding up the appearance of hepatic encephalopathy [6].

Due to the severe restriction of fluid consumption, the quality of life of patients with cirrhosis and hyponatremia is poor [14]. Several studies have shown that the severity of hyponatremia and ascites is a prognostic factor of the disease [15, 16]. In one study, it was demonstrated that the serum sodium level prior to the occurrence of spontaneous bacterial peritonitis (SBP) was an independent predictor of renal insufficiency produced by SBP [17]. It is also a predictive marker with a higher sensitivity than serum creatinine to predict the occurrence of circulatory dysfunction resulting in renal insufficiency or death. Although patients with hyponatremia are susceptible to the hepatorenal syndrome, there is not only an increased level of ADH involved, but there is a decrease in glomerular filtration rate (GFR) and proximal sodium reabsorption [18].

Sodium concentration was included in the MELD model to indicate the need for liver transplantation and patient priority on waiting lists in order to improve prognosis [19]. It was found that the MELD-Na score indicated an anticipation of short-term mortality of transplant patient candidates much better than the initial MELD score [20].

## **6. Clinical presentation**

Most patients with cirrhosis present low serum osmolarity and sodium levels, and it is expected to produce inhibition of ADH release if stimulation was achieved by osmoreceptors [10]. Because of the activation of the neurohumoral mechanisms that retain sodium, the levels of ADH, aldosterone, norepinephrine, and renin activity were significantly higher in patients with cirrhosis and ascites after the water loading test. Effective arterial uptake would result from a decrease in systemic vascular resistance and would result in nonosmotic stimulation due to baroreceptors of ADH and other vasoconstriction systems. These cause the activation of the neurohumoral mechanisms that produce sodium retention in order to restore the perfu-

It is suggested that hypoosmotic stimuli are suppressed by nonosmotic stimuli to suppress ADH release. That is why the body sacrifices osmolar homeostasis and releases ADH following nonosmotic stimulation of endogenous vasoconstrictors, and thus impairs vascular collapse by exhausting effective circulatory volume. It results in an inability to release sodium and water to replenish the circulation volume. All of these things happen despite the increase in cardiac output, plasma volume, and total body volume. To eliminate the extra amount of water, it is necessary to suppress adherence and the ability of the kidneys to remove water. The presence of nonosmotic adherence leads to the occurrence of a hyponatremia of dilution or hypervolemic hyponatremia. Therefore, in this category of patients, hyponatremia is only

In a prospective cohort study of patients with ascites, it was demonstrated that the occurrence of hyponatremia is preceded by refractory ascites and subsequently by hepatorenal syndrome. Each of these steps was associated with a progressive Child Pugh score and Model for End Stage Liver Disease (MELD) indicating a worsening of liver function. Therefore, hyponatremia is an intermediate stage between ascites progression and hepatorenal syndrome [13].

Hyponatremia in patients with cirrhosis is chronic, therefore, allows the brain to adapt to the hypo extracellular fluid osmolality. In conclusion, patients are less likely to have severe neurological symptoms. However, hyponatremia can aggravate cerebral edema and swollen astrocytes by adding to their dysfunction created by increased intracellular glutamine con-

Due to the severe restriction of fluid consumption, the quality of life of patients with cirrhosis and hyponatremia is poor [14]. Several studies have shown that the severity of hyponatremia and ascites is a prognostic factor of the disease [15, 16]. In one study, it was demonstrated that the serum sodium level prior to the occurrence of spontaneous bacterial peritonitis (SBP) was an independent predictor of renal insufficiency produced by SBP [17]. It is also a predictive marker with a higher sensitivity than serum creatinine to predict the occurrence of circulatory dysfunction resulting in renal insufficiency or death. Although patients with hyponatremia are susceptible to the hepatorenal syndrome, there is not only an increased level of ADH involved, but there is a decrease in glomerular filtration rate (GFR) and proximal sodium

centration, speeding up the appearance of hepatic encephalopathy [6].

dilute and does not represent a sodium deficiency [12].

sion pressure [11].

20 Management of Chronic Liver Diseases - Recent Advances

**5. Prognostic value**

reabsorption [18].

Symptoms of hyponatremia are caused by the damage to the nervous system, with cerebral edema due to the migration of water from the intravascular space in the brain [21]. As a rapid adaptive mechanism, there is an increase in electrolytes in brain cells. As a slow adaptation mechanism, organic osmoliths are extruded. Finally, these mechanisms help return the water to the intravascular space and prevent brain edema [22].

**Figure 1.** Clinical manifestations of hyponatremia.

In patients without hepatic impairment, hyponatremia manifests with: headache, disorientation, confusion, and neurological deficits. In contrast, in cirrhotic patients, hyponatremia develops slowly and at a value of 125 mEq/L is asymptomatic due to adaptive mechanisms. However, a rapid drop in sodium concentration may overcome adaptive mechanisms and serious symptoms may occur such as coma, seizures, brain-stern herniation, respiratory failure, and death [23] (**Figure 1**).

**8. Management of hyponatremia**

ally recommended at a value of 130 mmol/L.

improve the sodium concentration.

most patients cannot be compliant.

studied [34].

There are no data to recommend optimal serum sodium to initiate the treatment, but is gener-

Management of Ascites Associated with Severe Hyponatremia

http://dx.doi.org/10.5772/intechopen.76376

23

The identification and adjustment of excessive diuretic dosages and the addition of sodium are the main treatment requirements in the setting of hypovolemic hyponatremia. In case of hypervolemic hyponatremia, the most important issue is to decrease the amount of water to

When patients experience neurological symptoms due to hyponatremia or have a sodium concentration of less than 120 mEq/L, fluid restriction is indicated. In the case of mild and asymptomatic hyponatremia, fluid restriction is not indicated. Increasing sodium concentration in the first 24–48 hours is an important parameter that suggests an adequate fluid restriction. If this increase does not occur, either the restriction has to be more severe or the patient is not compliant. Fluid restriction is useful, but ineffective. Because the fluid restriction is severe,

If patients have severe hyponatremia, there have been no responses to fluid restriction; it is indicated to administer the hypertonic saline. However, caution should be exercised in order not to cause a rapid increase in sodium concentration, which predisposes to the occurrence of numerous complications such as: central myelinolysis, quadriplegia, coma, or death [6].

The efficacy of using hypertonic sodium chloride in severe hypervolemic hyponatremia is partial, short-lived and aggravates ascites and edema. Instead, administration of albumin appears to have benefits, helps to increase the sodium concentration, but is not fully

An important issue in patients with cirrhosis and hyponatremia is the correction of hypokalemia. Hypokalemia favors the appearance of hepatic encephalopathy because it increases the kidney synthesis of ammonium. By correcting it, there is also an increase in sodium concen-

In the past, the use of k-opiod agonist therapy has been attempted due to side effects [36]. According to recent studies, a new class of therapy, called vaptans, has been discovered in the treatment of hypervolemic hyponatremia. Vaptans selectively block the V2-receptors of AVP. They can be used in diseases like syndrome of inappropriate antidiuretic hormone secretion (SIADH), heart failure and cirrhosis, having the role of improving sodium concentration. The benefits of their administration over a short period of time are the increasing of urine volume and solute-free water excretion, and also, the improvement of the low serum

Hypernatremia, dehydration, renal impairment, and osmotic demyelination syndrome owing to a very rapid increase in serum sodium concentration could be the side effects of the administration of vaptans in patients with liver cirrhosis. Therefore, treatment should be initiated in

the hospital and patients should be closely monitored to avoid hypernatremia.

tration because both sodium and potassium are osmotically active [35].

sodium levels in 45–82% of patients [37] (**Figure 2**).

Hyponatremia usually occurs in the final stage of liver disease and is difficult to differentiate if the symptoms are within it or are part of liver encephalopathy occurrence. Both hyponatremia and hyperammonemia cause an alteration in brain metabolism of myoinositol [24].

Some theories show that hyponatremia can cause the appearance of a minimal cerebral edema that occurs by swelling of astrocytes and may cause the appearance of hepatic encephalopathy. This minimal brain edema occurs by increasing the concentration of glutamine resulting from the metabolism of ammonia and leads to a series of neurological changes to the appearance of hepatic encephalopathy [25].

## **7. Complications**

Central pontine myelinolysis (CPM) is a complication of severe hyponatremia and occurs when its correction has been achieved very quickly. It is a neurological disorder that consists of a demyelination that occurs in a region called pons [26].

The mechanism by which this affection occurs is not fully known. One theory claims that this demyelination occurs by compressing fibrous structures as a result of cerebral edema arising from an osmotic fluctuation.  In case of chronic hyponatremia, there is a decrease in these osmoliths in the brain, preventing fluid absorption [27, 28]. Clinical manifestations depend on the affected brain region, initially manifested by symptoms of hyponatremic encephalopathy such as nausea, vomiting, headache, confusion, and seizures. These symptoms can be reversed when adjusting the sodium concentration. Later signs of myelinolysis such as walking disturbances and respiratory dysfunction can occur [29]. Among the risk factors for this condition are: sodium concentration < 120 mEq/L for 48 hours, aggressive correction with saline solution and the occurrence of hypernatremia during treatment. If post liver transplant patients develop symptoms as confusion or weakness, CPM should be suspected because it may complicate a liver transplant [30].

Although the prognosis is poor with the occurrence of numerous neurological complications such as spastic quadriparesis and blocked syndrome, recovery is possible although it has a long duration [31].

Diagnosis can be done clinically and imagistically. The preferred imaging method is MRI, although lesions appear late and often initially may be normal [32]. The most common images are T2 weighted with hyperintense areas where demyelination was performed [33].

## **8. Management of hyponatremia**

In patients without hepatic impairment, hyponatremia manifests with: headache, disorientation, confusion, and neurological deficits. In contrast, in cirrhotic patients, hyponatremia develops slowly and at a value of 125 mEq/L is asymptomatic due to adaptive mechanisms. However, a rapid drop in sodium concentration may overcome adaptive mechanisms and serious symptoms may occur such as coma, seizures, brain-stern herniation, respiratory fail-

Hyponatremia usually occurs in the final stage of liver disease and is difficult to differentiate if the symptoms are within it or are part of liver encephalopathy occurrence. Both hyponatremia and hyperammonemia cause an alteration in brain metabolism of myoinositol [24].

Some theories show that hyponatremia can cause the appearance of a minimal cerebral edema that occurs by swelling of astrocytes and may cause the appearance of hepatic encephalopathy. This minimal brain edema occurs by increasing the concentration of glutamine resulting from the metabolism of ammonia and leads to a series of neurological changes to the appear-

Central pontine myelinolysis (CPM) is a complication of severe hyponatremia and occurs when its correction has been achieved very quickly. It is a neurological disorder that consists

The mechanism by which this affection occurs is not fully known. One theory claims that this demyelination occurs by compressing fibrous structures as a result of cerebral edema arising from an osmotic fluctuation.  In case of chronic hyponatremia, there is a decrease in these osmoliths in the brain, preventing fluid absorption [27, 28]. Clinical manifestations depend on the affected brain region, initially manifested by symptoms of hyponatremic encephalopathy such as nausea, vomiting, headache, confusion, and seizures. These symptoms can be reversed when adjusting the sodium concentration. Later signs of myelinolysis such as walking disturbances and respiratory dysfunction can occur [29]. Among the risk factors for this condition are: sodium concentration < 120 mEq/L for 48 hours, aggressive correction with saline solution and the occurrence of hypernatremia during treatment. If post liver transplant patients develop symptoms as confusion or weakness, CPM should be suspected because it may complicate a liver transplant [30]. Although the prognosis is poor with the occurrence of numerous neurological complications such as spastic quadriparesis and blocked syndrome, recovery is possible although it has a

Diagnosis can be done clinically and imagistically. The preferred imaging method is MRI, although lesions appear late and often initially may be normal [32]. The most common images

are T2 weighted with hyperintense areas where demyelination was performed [33].

ure, and death [23] (**Figure 1**).

22 Management of Chronic Liver Diseases - Recent Advances

ance of hepatic encephalopathy [25].

of a demyelination that occurs in a region called pons [26].

**7. Complications**

long duration [31].

There are no data to recommend optimal serum sodium to initiate the treatment, but is generally recommended at a value of 130 mmol/L.

The identification and adjustment of excessive diuretic dosages and the addition of sodium are the main treatment requirements in the setting of hypovolemic hyponatremia. In case of hypervolemic hyponatremia, the most important issue is to decrease the amount of water to improve the sodium concentration.

When patients experience neurological symptoms due to hyponatremia or have a sodium concentration of less than 120 mEq/L, fluid restriction is indicated. In the case of mild and asymptomatic hyponatremia, fluid restriction is not indicated. Increasing sodium concentration in the first 24–48 hours is an important parameter that suggests an adequate fluid restriction. If this increase does not occur, either the restriction has to be more severe or the patient is not compliant. Fluid restriction is useful, but ineffective. Because the fluid restriction is severe, most patients cannot be compliant.

If patients have severe hyponatremia, there have been no responses to fluid restriction; it is indicated to administer the hypertonic saline. However, caution should be exercised in order not to cause a rapid increase in sodium concentration, which predisposes to the occurrence of numerous complications such as: central myelinolysis, quadriplegia, coma, or death [6].

The efficacy of using hypertonic sodium chloride in severe hypervolemic hyponatremia is partial, short-lived and aggravates ascites and edema. Instead, administration of albumin appears to have benefits, helps to increase the sodium concentration, but is not fully studied [34].

An important issue in patients with cirrhosis and hyponatremia is the correction of hypokalemia. Hypokalemia favors the appearance of hepatic encephalopathy because it increases the kidney synthesis of ammonium. By correcting it, there is also an increase in sodium concentration because both sodium and potassium are osmotically active [35].

In the past, the use of k-opiod agonist therapy has been attempted due to side effects [36]. According to recent studies, a new class of therapy, called vaptans, has been discovered in the treatment of hypervolemic hyponatremia. Vaptans selectively block the V2-receptors of AVP. They can be used in diseases like syndrome of inappropriate antidiuretic hormone secretion (SIADH), heart failure and cirrhosis, having the role of improving sodium concentration. The benefits of their administration over a short period of time are the increasing of urine volume and solute-free water excretion, and also, the improvement of the low serum sodium levels in 45–82% of patients [37] (**Figure 2**).

Hypernatremia, dehydration, renal impairment, and osmotic demyelination syndrome owing to a very rapid increase in serum sodium concentration could be the side effects of the administration of vaptans in patients with liver cirrhosis. Therefore, treatment should be initiated in the hospital and patients should be closely monitored to avoid hypernatremia.

Tolvaptan and conivaptan are recently approved in the USA for the treatment of severe hypervolemic hyponatremia from diseases such as cirrhosis, heart failure and SIADH. Treatment is started at a dose of 15 mg/day and can be increased progressively depending on the sodium concentration. In Europe, tolvaptan is authorized only for the treatment of SIADH. As an alternative option, conivaptan can be used to treat hypervolemic hyponatremia for short periods of time, especially when cirrhosis is associated with various

Management of Ascites Associated with Severe Hyponatremia

http://dx.doi.org/10.5772/intechopen.76376

25

Tolvaptan should be initiated without taking into account the period of meals, but initially it is advisable not to suppress the consumption of fluids to avoid rapid correction of sodium concentration. If, on completion of tolvaptan therapy, hyponatremia recurs, it should be corrected in a hospital unit. There may be no need for hospitalization, if treatment can be moni-

In randomized trials, the only side effects of tolvaptan treatment were gastrointestinal bleeding, but slightly increased incidence compared to placebo. It should be taken into account that the treatment was administered over a short period of time and new studies of the safety of

Treatment with conivaptan is contraindicated in patients who are allergic to constituents, in hyponatremia or hypovolaemia because it can induce from renal failure to shock. CYP3a4 inhibitors should not be administered concomitantly [42]. In general, the treatment was tolerated and adverse reactions were reported: local reactions (pain and erythema at the administration level), orthostatic hypotension, peripheral edema, headache, nausea, vomiting, urinary tract infections, and insomnia [43]. Effective treatment of hyponatremia should be initiated promptly to prevent irreversible neurological damage, but rapid correction may

Domecycline favors the increase in free water excretion as an ADH antagonist, but cannot be

The use of vasoconstrictors in hyponatremia is not tested, but studies of the hepatorenal syn-

The use of vasoconstrictors in hepatorenal syndrome has the following benefits: it improves the effective blood volume, vascular or systemic vasodilation, and renal perfusion. They are usually used in concomitant albumin administration. The most commonly used are: terlipres-

This combination can be used without supervision in a medical unit and is safe. Octreotide produces decreased splanchnic vasodilatation and midodrine improves renal perfusion and in combination with albumin improves kidney function, but there are still insufficient studies

The octreotide is administered subcutaneously at the dose of 100 micrograms, 3 times per day, and the dose can be increased to 200 μg, 3 times per day. Midodrine is given orally 7.5 mg, 3 times per day and the dose can also be increased up to 12.5 mg, 3 times per day [47].

sin, norepinephrine, vasopressin, and octeotrid, in combination with midodrine.

conditions [38, 39].

tored to prevent excessive sodium concentration [40].

cause osmotic demyelination syndrome that can lead to death [44].

drome have shown an improvement in sodium concentration [46].

long-term treatment are needed [41].

used in cirrhosis due to nephrotoxicity [45].

in this regard.

**Figure 2.** Management of hyponatremia.

Due to the risk of dehydration and hypernatremia, vaptans are also contraindicated in patients with an inappropriate consciousness state, unable to measure the volumes of fluid consumed.

The metabolism of vaptans is achieved in the liver by CYP3A enzymes. Therefore, CYP3A inhibitory drugs should be avoided because they increase the concentration of vaptans and may lead to the increase of serum sodium concentration. Also, drugs that are inducers of the CYP3A should be avoided because those drugs can reduce the concentration of vaptans.

Tolvaptan and conivaptan are recently approved in the USA for the treatment of severe hypervolemic hyponatremia from diseases such as cirrhosis, heart failure and SIADH. Treatment is started at a dose of 15 mg/day and can be increased progressively depending on the sodium concentration. In Europe, tolvaptan is authorized only for the treatment of SIADH. As an alternative option, conivaptan can be used to treat hypervolemic hyponatremia for short periods of time, especially when cirrhosis is associated with various conditions [38, 39].

Tolvaptan should be initiated without taking into account the period of meals, but initially it is advisable not to suppress the consumption of fluids to avoid rapid correction of sodium concentration. If, on completion of tolvaptan therapy, hyponatremia recurs, it should be corrected in a hospital unit. There may be no need for hospitalization, if treatment can be monitored to prevent excessive sodium concentration [40].

In randomized trials, the only side effects of tolvaptan treatment were gastrointestinal bleeding, but slightly increased incidence compared to placebo. It should be taken into account that the treatment was administered over a short period of time and new studies of the safety of long-term treatment are needed [41].

Treatment with conivaptan is contraindicated in patients who are allergic to constituents, in hyponatremia or hypovolaemia because it can induce from renal failure to shock. CYP3a4 inhibitors should not be administered concomitantly [42]. In general, the treatment was tolerated and adverse reactions were reported: local reactions (pain and erythema at the administration level), orthostatic hypotension, peripheral edema, headache, nausea, vomiting, urinary tract infections, and insomnia [43]. Effective treatment of hyponatremia should be initiated promptly to prevent irreversible neurological damage, but rapid correction may cause osmotic demyelination syndrome that can lead to death [44].

Domecycline favors the increase in free water excretion as an ADH antagonist, but cannot be used in cirrhosis due to nephrotoxicity [45].

The use of vasoconstrictors in hyponatremia is not tested, but studies of the hepatorenal syndrome have shown an improvement in sodium concentration [46].

The use of vasoconstrictors in hepatorenal syndrome has the following benefits: it improves the effective blood volume, vascular or systemic vasodilation, and renal perfusion. They are usually used in concomitant albumin administration. The most commonly used are: terlipressin, norepinephrine, vasopressin, and octeotrid, in combination with midodrine.

This combination can be used without supervision in a medical unit and is safe. Octreotide produces decreased splanchnic vasodilatation and midodrine improves renal perfusion and in combination with albumin improves kidney function, but there are still insufficient studies in this regard.

Due to the risk of dehydration and hypernatremia, vaptans are also contraindicated in patients with an inappropriate consciousness state, unable to measure the volumes of fluid consumed. The metabolism of vaptans is achieved in the liver by CYP3A enzymes. Therefore, CYP3A inhibitory drugs should be avoided because they increase the concentration of vaptans and may lead to the increase of serum sodium concentration. Also, drugs that are inducers of the CYP3A should be avoided because those drugs can reduce the concentration of vaptans.

**Figure 2.** Management of hyponatremia.

24 Management of Chronic Liver Diseases - Recent Advances

The octreotide is administered subcutaneously at the dose of 100 micrograms, 3 times per day, and the dose can be increased to 200 μg, 3 times per day. Midodrine is given orally 7.5 mg, 3 times per day and the dose can also be increased up to 12.5 mg, 3 times per day [47].

Treatment with terlipressin should be avoided in patients with cirrhosis, as it may cause severe hyponatremia, reversible upon discontinuation of treatment. Terlipresin acts on the vasopressin V1 receptor, but is also a partial vasopressin V2 receptor agonist. This is beneficial in the treatment of bleeding caused by portal hypertension, but also in hepatorenal syndrome [48].

conivaptan and tolvaptan can be administered for a short period of time, and hyponatremia may reappear when the treatment is stopped. Although treatment with vaptans is effective in

, Laura Mazilu1

[1] Gins P, Quintero E, Arroyo V, et al. Compensated cirrhosis: Natural history and prog-

[2] Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology. 2007;**133**:

[3] Schrier RW, Arroyo V, Bernardi M, et al. Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology.

[4] Mller S, Henriksen JH. The systemic circulation in cirrhosis. in: Gins P, Arroyo V, Rods J, Schrier RW, editors. Ascites and renal dysfunction in liver disease. Malden: Blackwell;

[5] Henriksen JH, Mller S. Alterations of hepatic and splanchnic microvascular exchange in cirrhosis: Local factors in the formation of ascites. In: Gins P, Arroyo V, Rods J, Schrier RW, editors. Ascites and Renal Dysfunction in Liver Disease. Malden: Blackwell;

[6] Ginès P, Guevara M. Hyponatremia in cirrhosis: Pathogenesis, clinical significance, and

[7] Gins P, Berl T, Bernardi M, et al. Hyponatremia in cirrhosis: From pathogenesis to treat-

[8] Angeli P, Wong F, Watson H, Ginès P, CAPPS Investigators. Hyponatremia in cirrhosis: Results of a patient population survey. Hepatology. 2006 Dec;**44**(6):1535-1542

, Claudia Voinea1

, Irinel Raluca Parepa<sup>1</sup>

Management of Ascites Associated with Severe Hyponatremia

http://dx.doi.org/10.5772/intechopen.76376

27

and

,

relieving hyponatremia, their use requires additional data.

, Anca Stoian<sup>2</sup>

2 Carol Davila University, Bucharest, Romania

nostic factors. Hepatology. 1987;**7**:122128

management. Hepatology. 2008;**48**:1002

ment. Hepatology. 1998;**28**:851864

\*, Roxana Popoiag1

\*Address all correspondence to<EMAIL_ADDRESS>1 Ovidius University, Faculty of Medicine, Constanta, Romania

, Felix Voinea1

**Author details**

Andra Iulia Suceveanu1

Adrian Paul Suceveanu1

Andreea Gheorghe1

**References**

481488

1988;**8**:11511157

2005:139155

2005:174185

By correcting hyponatremia in patients with cirrhosis, there are number of advantages: avoiding fluid restriction, administering effective doses of diuretics, especially in the treatment of refractory ascites, reducing the risk by developing hepatic encephalopathy, and improving the quality of life. It can also help reduce neurological complications after transplantation [49, 50].

## **9. Conclusions**

Hyponatremia is a complication of cirrhosis, associated with an increased risk of mortality and morbidity in patients on the waiting list for a liver transplant. It also increases the risk of complications, such as hepatic encephalopathy, renal failure, and spontaneous bacterial peritonitis.

Hyponatremia occurred during cirrhosis evolution has as a pathophysiological mechanism arterial vasodilation that produces inadequate AVP secretion and a reduction in glomerular filtration rate with impairment of free water clearance. Clinical presentation does not differ from that of patients without hepatic impairment, but the symptoms of hyponatremia in cirrhosis are sometimes associated and difficult to differentiate from those in hepatic encephalopathy. As a dilutional hyponatremia, its treatment is not indicated if it is asymptomatic. Conversely, at a concentration of Na <120 mEq/L and on the occurrence of neurological symptoms, treatment can be initiated. An exception is the situation where patients are about to receive a liver transplant in a short time and the Na concentration is <130 mEq/L. In this case, its treatment is indicated to prevent the occurrence of serious neurological complications such as osmotic demyelination syndrome as a result of a rapid correction in the operating room. An important role is the differentiation of hypovolemic hyponatremia from the hypervolemic hyponatremia to initiate a suitable therapeutic scheme. In hypovolemic hyponatremia, it is necessary to identify the trigger factor and its treatment, usually discontinuation of diuretic treatment and administration of salt solution represents optimal methods in the correction of this. In hypervolemic hyponatremia, therapeutic methods are limited. Fluid restriction to about 1 L/day is important in improving Na concentration, but a small number of patients may be compliant with this therapy. Administration of saline solution in this case is only recommended if hyponatremia is severe because it usually favors the growth of ascites fluid and edema. Administration of albumin appears to be beneficial, but there is not enough data to confirm this.

A novelty in hyponatremic therapy is the treatment with vaptans. Treatment with tolvaptan should be given in the hospital to avoid a sudden increase in Na concentration, in oral administration, and with the possibility to increase the dose progressively to achieve the desired effects. Concomitant administration with vaptans of saline solution or fluid restriction is contraindicated to prevent osmotic demyelination syndrome. Medications that are inhibitors or inducers of CYP3A are also contraindicated. Conivaptan is given intravenously. Both conivaptan and tolvaptan can be administered for a short period of time, and hyponatremia may reappear when the treatment is stopped. Although treatment with vaptans is effective in relieving hyponatremia, their use requires additional data.

## **Author details**

Treatment with terlipressin should be avoided in patients with cirrhosis, as it may cause severe hyponatremia, reversible upon discontinuation of treatment. Terlipresin acts on the vasopressin V1 receptor, but is also a partial vasopressin V2 receptor agonist. This is beneficial in the treatment of bleeding caused by portal hypertension, but also in hepatorenal syndrome [48]. By correcting hyponatremia in patients with cirrhosis, there are number of advantages: avoiding fluid restriction, administering effective doses of diuretics, especially in the treatment of refractory ascites, reducing the risk by developing hepatic encephalopathy, and improving the quality of life. It can also help reduce neurological complications after transplantation [49, 50].

Hyponatremia is a complication of cirrhosis, associated with an increased risk of mortality and morbidity in patients on the waiting list for a liver transplant. It also increases the risk of complications, such as hepatic encephalopathy, renal failure, and spontaneous bacterial

Hyponatremia occurred during cirrhosis evolution has as a pathophysiological mechanism arterial vasodilation that produces inadequate AVP secretion and a reduction in glomerular filtration rate with impairment of free water clearance. Clinical presentation does not differ from that of patients without hepatic impairment, but the symptoms of hyponatremia in cirrhosis are sometimes associated and difficult to differentiate from those in hepatic encephalopathy. As a dilutional hyponatremia, its treatment is not indicated if it is asymptomatic. Conversely, at a concentration of Na <120 mEq/L and on the occurrence of neurological symptoms, treatment can be initiated. An exception is the situation where patients are about to receive a liver transplant in a short time and the Na concentration is <130 mEq/L. In this case, its treatment is indicated to prevent the occurrence of serious neurological complications such as osmotic demyelination syndrome as a result of a rapid correction in the operating room. An important role is the differentiation of hypovolemic hyponatremia from the hypervolemic hyponatremia to initiate a suitable therapeutic scheme. In hypovolemic hyponatremia, it is necessary to identify the trigger factor and its treatment, usually discontinuation of diuretic treatment and administration of salt solution represents optimal methods in the correction of this. In hypervolemic hyponatremia, therapeutic methods are limited. Fluid restriction to about 1 L/day is important in improving Na concentration, but a small number of patients may be compliant with this therapy. Administration of saline solution in this case is only recommended if hyponatremia is severe because it usually favors the growth of ascites fluid and edema. Administration

of albumin appears to be beneficial, but there is not enough data to confirm this.

A novelty in hyponatremic therapy is the treatment with vaptans. Treatment with tolvaptan should be given in the hospital to avoid a sudden increase in Na concentration, in oral administration, and with the possibility to increase the dose progressively to achieve the desired effects. Concomitant administration with vaptans of saline solution or fluid restriction is contraindicated to prevent osmotic demyelination syndrome. Medications that are inhibitors or inducers of CYP3A are also contraindicated. Conivaptan is given intravenously. Both

**9. Conclusions**

26 Management of Chronic Liver Diseases - Recent Advances

peritonitis.

Andra Iulia Suceveanu1 \*, Roxana Popoiag1 , Laura Mazilu1 , Irinel Raluca Parepa<sup>1</sup> , Andreea Gheorghe1 , Anca Stoian<sup>2</sup> , Felix Voinea1 , Claudia Voinea1 and Adrian Paul Suceveanu1

\*Address all correspondence to<EMAIL_ADDRESS>
1 Ovidius University, Faculty of Medicine, Constanta, Romania

2 Carol Davila University, Bucharest, Romania

## **References**

[9] Oliet SH, Bourque CW. Mechanosensitive channels transduce osmosensitivity in supraoptic neurons. Nature. 1993 Jul 22;**364**(6435):341-343

[22] Hyponatremia Treatment Guidelines 2007. Expert Panel Recommendations. American

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29

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**Chapter 3**

**Provisional chapter**

**Acute Kidney Injury in Cirrhosis**

**Acute Kidney Injury in Cirrhosis**

DOI: 10.5772/intechopen.78571

Acute kidney injury is a very relevant feature in the liver cirrhosis. Acute renal failure is due to prerenal factors, intrinsic factors of the kidney, or postrenal. Prerenal damage is the result of renal hypoperfusion without damage to the glomeruli or renal tubules. Without treatment, prerenal acute renal failure can progress to acute tubular necrosis, a type of intrinsic renal damage. Patients with cirrhosis are prone to developing acute kidney injury. The acute decrease of the kidney function contributes to the mortality of patients with cirrhosis. The potential triggers of acute kidney injury should be recognized and removed; this includes the discontinuation of diuretics and nephrotoxic drugs, the treatment of infections and gastrointestinal bleeding, and plasma expansion in case of hypovolemia. The new International Club of Ascites-Acute Kidney Injury in cirrhosis criteria provide a simple and relevant staging system for acute kidney injury in patients with liver cirrhosis based on relative increases in serum creatinine. Vasopressors such as terlipressin and norepinephrine in combination with intravenous albumin represent the

The association of acute kidney injury (AKI) in patients with liver cirrhosis has been established in the context of the hepatorenal syndrome, but there are several etiologies besides

Acute renal failure is a therapeutic challenge in patients with liver cirrhosis. This may be related to abnormal hemodynamics with systemic arterial vasodilatation and the splanchnic bed, in addition to the vasoconstriction of extrahepatic vessels, characteristic of advanced

> © 2016 The Author(s). Licensee InTech. 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.

© 2018 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.

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

first-line therapy for hepatorenal syndrome.

**Keywords:** acute kidney injury, hepatorenal syndrome, cirrhosis

Marco Antonio López Hernández

Marco Antonio López Hernández

http://dx.doi.org/10.5772/intechopen.78571

**Abstract**

**1. Introduction**

this cause.

#### **Chapter 3 Provisional chapter**

#### **Acute Kidney Injury in Cirrhosis Acute Kidney Injury in Cirrhosis**

Marco Antonio López Hernández Marco Antonio López Hernández

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.78571

#### **Abstract**

[37] Quittnat F, Gross P. Vaptans and the treatment of water-retaining disorders. Seminars in

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[43] Goldsmith SR, Elkayam U, Haught WH, Barve A, He W. Efficacy and safety of the vasopressin V1A/V2-receptor antagonist conivaptan in acute decompensated heart failure: A

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[47] Kalambokis G, Economou M, Fotopoulos A, et al. The effects of chronic treatment with octreotide versus octreotide plus midodrine on systemic hemodynamics and renal hemodynamics and function in nonazotemic cirrhotic patients with ascites. The American

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[49] Jalan R, Elton RA, Redhead DN, Simpson KJ, Finlayson NDC, Hayes PC, et al. Analysis of prognostic variables in the prediction of shunt failure, variceal rebleeding, early mortality and encephalopathy following the transjugular intrahepatic portosystemic stent-

[50] Baccaro ME, Guevara M, Torre A, Arcos E. Martı'n-Llahı'M, Terra C, et al. Hyponatremia predisposes to hepatic encephalopathy in patients with cirrhosis. Results of a prospec-

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Acute kidney injury is a very relevant feature in the liver cirrhosis. Acute renal failure is due to prerenal factors, intrinsic factors of the kidney, or postrenal. Prerenal damage is the result of renal hypoperfusion without damage to the glomeruli or renal tubules. Without treatment, prerenal acute renal failure can progress to acute tubular necrosis, a type of intrinsic renal damage. Patients with cirrhosis are prone to developing acute kidney injury. The acute decrease of the kidney function contributes to the mortality of patients with cirrhosis. The potential triggers of acute kidney injury should be recognized and removed; this includes the discontinuation of diuretics and nephrotoxic drugs, the treatment of infections and gastrointestinal bleeding, and plasma expansion in case of hypovolemia. The new International Club of Ascites-Acute Kidney Injury in cirrhosis criteria provide a simple and relevant staging system for acute kidney injury in patients with liver cirrhosis based on relative increases in serum creatinine. Vasopressors such as terlipressin and norepinephrine in combination with intravenous albumin represent the first-line therapy for hepatorenal syndrome.

DOI: 10.5772/intechopen.78571

**Keywords:** acute kidney injury, hepatorenal syndrome, cirrhosis

### **1. Introduction**

The association of acute kidney injury (AKI) in patients with liver cirrhosis has been established in the context of the hepatorenal syndrome, but there are several etiologies besides this cause.

Acute renal failure is a therapeutic challenge in patients with liver cirrhosis. This may be related to abnormal hemodynamics with systemic arterial vasodilatation and the splanchnic bed, in addition to the vasoconstriction of extrahepatic vessels, characteristic of advanced

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. © 2018 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.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

liver cirrhosis [1]. Acute renal failure frequently occurs in the advanced stages of liver cirrhosis and entails a bad prognosis [2, 3].

**a.** vasodilators such as nitric oxide, carbon monoxide, and endogenous cannabinoids

Acute Kidney Injury in Cirrhosis

33

http://dx.doi.org/10.5772/intechopen.78571

**b.** vasodilation by pro-inflammatory cytokines such as tumor necrosis factor and interleukin

The accumulation of blood in the splanchnic bed leads to a reduction in the effective circulating volume, which leads to a compensatory increase in cardiac output through the activation of the sympathetic nervous system by the carotid baroreceptors in order to maintain adequate

In advanced stages of cirrhosis, systemic vascular resistance is significantly reduced, and the additional increase in cardiac output cannot compensate. Thus, it is evident that cardiac output decreases as cirrhosis progresses. In advanced stages of cirrhosis, cardiac output is maintained through the activation of vasoconstrictor systems, including the sympathetic nervous system and the renin-angiotensin system, and by a non-osmotic hypersecretion of

These compensatory mechanisms can help to maintain effective arterial volume and of this way a relatively normal blood pressure, but this has important effects on kidney function, primarily a retention of water and sodium, which can eventually lead to the formation of ascites and edema, and renal failure conditioned by renal vasoconstriction and hypoperfusion

There are four factors involved in the pathogenesis of hepatorenal syndrome. These are the

**1.** Activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system which causes renal vasoconstriction and a shift in the renal autoregulatory curve, which results in a renal blood flow more sensitive to changes in the arterial pressure.

**2.** Splanchnic vasodilatation, which causes a fall in the effective arterial blood volume and

**3.** Increased synthesis of vasoactive mediators which affect renal blood flow or glomerular microcirculatory hemodynamics, such as leukotrienes, thromboxane A2, isoprostanes, and

**4.** Impairment of cardiac function due to the development of cirrhotic cardiomyopathy, which leads to a relative impairment of the compensatory increase in cardiac output sec-

Hemodynamic disorders can have widespread impact on the body according to the severity of the cirrhosis [26]. The hemodynamic changes in cirrhosis include portal hypertension and hyperdynamic circulation which are the main cause of morbidity and mortality in patients with cirrhosis. The effective arterial blood volume and the circulating levels of RAS components and antidiuretic hormone remain normal at early stages of the disease, even with a

this way a decrease of the mean arterial pressure.

6, derived from bacterial translocation of the intestine [22].

[20, 21];

renal perfusion [23].

arginine-vasopressin.

[24, 25].

following:

endothelin-1.

ondary to vasodilatation.

Acute renal failure is due to prerenal factors, intrinsic factors of the kidney, or postrenal. Prerenal damage is the result of renal hypoperfusion without damage to the glomeruli or renal tubules. Without treatment, prerenal acute renal failure can progress to acute tubular necrosis (ATN), a type of intrinsic renal damage.

The prevalence of acute renal failure in cirrhosis has been reported from 14 to 50% in patients with cirrhosis. Its prevalence is approximately 50% in patients with cirrhosis and ascites and 20% of patients with advanced stage cirrhosis who are hospitalized [4, 5].

The definition of acute kidney injury is a reduction in the glomerular filtration rate (GFR) over a short time of period, and this is a common and severe complication in the patients with liver cirrhosis. Acute kidney failure can be triggered by a precipitating event, for example, overdose of diuretics, gastrointestinal bleeding, large-volume paracentesis without albumin replacement, bacterial infections, and so on [6]. The prevalence of acute kidney injury is approximately 20–50% among hospitalized patients with cirrhosis [6–9] and the renal failure development is more common in patients with cirrhosis compared to individuals without liver disease [10]. The presence of acute kidney failure is associated with poor prognosis in these patients and represents an important predictor for short-term mortality [11].

The criteria for acute renal failure in cirrhosis were initially proposed in 1996 [12] and redefined in subsequent years [13]. Traditionally, renal failure in cirrhosis was defined as a 50% increase in serum creatinine, with an increase greater than 1.5 mg/dL (133 μm/L) of it. The cutoff value of serum creatinine to define acute renal failure in patients with decompensated cirrhosis has changed [14, 15]. Several nephrology academic societies have proposed the use of the concept of acute renal injury to represent acute changes in kidney function. The diagnostic criteria constitute a combination of changes in the glomerular filtration rate as well as a reduction in urine output. In the past decade, the definition of acute kidney injury evolved to the classifications and diagnostic criteria known as RIFLE [16], AKIN [17], and KDIGO [18].

In 2010, the International Ascites Club (IAC) and the Acute Dialysis Quality Initiative (ADQI) decided to use the nomenclature of the Acute Kidney Injury (AKI).

In 2015, the International Ascites Club established a new definition and staging of acute renal failure for patients with liver cirrhosis [19].

## **2. Physiopathology of renal failure in cirrhosis**

Patients with liver cirrhosis develop portal hypertension, which results in the vasodilatation of the splanchnic vascular bed, resulting in blood accumulation due to resistance in the portal venous flow. This is due to an increase in the fixed resistance of liver fibrosis, and dynamics in the splanchnic arteries is last due to

**a.** vasodilators such as nitric oxide, carbon monoxide, and endogenous cannabinoids [20, 21];

liver cirrhosis [1]. Acute renal failure frequently occurs in the advanced stages of liver cir-

Acute renal failure is due to prerenal factors, intrinsic factors of the kidney, or postrenal. Prerenal damage is the result of renal hypoperfusion without damage to the glomeruli or renal tubules. Without treatment, prerenal acute renal failure can progress to acute tubular

The prevalence of acute renal failure in cirrhosis has been reported from 14 to 50% in patients with cirrhosis. Its prevalence is approximately 50% in patients with cirrhosis and ascites and