**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

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

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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: hiroteruk@med.niigata-u.ac.jp

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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Masaaki Takamura, Hirokazu Kawai, Satoshi Yamagiwa and Shuji Terai

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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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[32] Inoue N, Yamazaki Z, Oda T, Sugiura M, Wada T. Treatment of intractable ascites by continuous reinfusion of the sterilized, cell-free and concentrated ascitic fluid. Transactions

[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

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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

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

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. Currently accepted theory supports the fact that brain cells adjust their osmolarity with certain osmolites, like inositol, betaine, and glutamine. 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. Currently accepted theory supports the fact that brain cells adjust their osmolarity with certain osmolites, like inositol, betaine, and glutamine. 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: andrasuceveanu@yahoo.com 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: andrasuceveanu@yahoo.com

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

Management of Ascites Associated with Severe Hyponatremia

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29

[23] Adrogué HJ, Madias NE. Hyponatremia. The New England Journal of Medicine.

[24] Córdoba J, García-Martinez R, Simón-Talero M. Hyponatremic and hepatic encephalopathies: Similarities, differences and coexistence. Metabolic Brain Disease. 2010;**25**:73-80

[25] Häussinger D. Low grade cerebral edema and the pathogenesis of hepatic encephalopa-

[26] Singh TD, Fugate JE, Rabinstein AA. Central pontine and extrapontine myelinolysis: A systematic review. European Journal of Neurology. 2014 Dec;**21**(12):1443-1450

[27] Karp BI, Laureno R. Pontine and extrapontine myelinolysis: A neurologic disorder following rapid correction of hyponatremia. Medicine (Baltimore). 1993 Nov;**72**(6):359-373

[28] Laureno R, Karp BI. Myelinolysis after correction of hyponatremia. Annals of Internal

[29] Odier C, Nguyen DK, Panisset M. Central pontine and extrapontine myelinolysis: From epileptic and other manifestations to cognitive prognosis. Journal of Neurology. July

[30] Crivellin C, Cagnin A, Manara R, Boccagni P, Cillo U, Feltracco P, et al. Risk factors for central pontine and extrapontine myelinolysis after liver transplantation: A single-center

[31] Bose P, Kunnacherry A, Maliakal P. Central pontine myelinolysis without hyponatraemia. The Journal of the Royal College of Physicians of Edinburgh.. 19 September

[32] Graff-Radford J, Fugate JE, Kaufmann TJ, Mandrekar JN, Rabinstein AA. Clinical and radiologic correlations of central pontine myelinolysis syndrome. Mayo Clinic

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[16] Heuman DM, Abou-Assi SG, Habib A, Williams LM, Stravitz RT, Sanyal AJ, Fisher RA, Mihas AA. Persistent ascites and low serum sodium identify patients with cirrosis and low MELD scores who are at high risk for early death. Hepatology. 2004 Oct;

[17] Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, Rimola A, Gassull MA, Arroyo V, Rodés J. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: Incidence, clinical course, predictive factors and prognosis. Hepatology. 1994

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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

[38] Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. The New England

[39] OLeary JG, Favis G. Conivaptan increases serum sodium in hyponatremic patients with

[40] Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG, Ouyang J, Czerwiec FS, SALTWATER investigators. Oral tolvaptan is safe and effective in chronic hyponatremia.

[41] Afdhal N, Cardenas A, Gins P, et al. Randomized, placebo-controlled trial of tolvaptan, a novel V2-receptor antagonist, in hyponatremia: Results of the SALT 2 trial with empha-

[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

[44] Sterns RH, Cappuccio JD, silver SM, Cohen EP. Neurologic sequelae after treatment of severe hyponatremia: A multicenter perspective. Journal of the American Society of

[45] Miller PD, Linas SL, Schrier RW. Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients. JAMA. 1980 Jun 27;**243**(24):2513-2515 [46] Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology.

[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

[48] Solà E, Lens S, Guevara M, Martín-Llahí M, Fagundes C, Pereira G, Pavesi M, Fernández J, González-Abraldes J, Escorsell A, Mas A, Bosch J, Arroyo V, Ginès P. Hyponatremia in patients treated with terlipressin for severe gastrointestinal bleeding due to portal

[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-

tive study with time-dependent analysis [abstract]. Hepatology. 2006;**233A**:44

sis on efficacy and safety in cirrhosis. Hepatology. 2005;**42**:LB19A ([Abstract])

dose-ranging pilot study. Journal of Cardiac Failure. 2008 Oct;**14**(8):641-647

end stage liver disease. Liver Transplantation. 2009;**15**:13251329

[42] Vaprisol [package insert] Deerfield, IL: Astellas Pharma US, Inc; 2006

Journal of the American Society of Nephrology. 2010 Apr;**21**(4):705-712

Nephrology. 2006;**26**:234243

30 Management of Chronic Liver Diseases - Recent Advances

Journal of Medicine. 2006;**355**:20992112

Nephrology. 1994 Feb;**4**(8):1522-1530

Journal of Gastroenterology. 2005;**100**(4):879-885

hypertension. Hepatology. 2010 Nov;**52**(5):1783-1790

shunt (TIPSS). Journal of Hepatology. 1995;**23**:123-128

2008;**48**(6):2064-2077

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

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

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],

In 2010, the International Ascites Club (IAC) and the Acute Dialysis Quality Initiative (ADQI)

In 2015, the International Ascites Club established a new definition and staging of acute renal

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

decided to use the nomenclature of the Acute Kidney Injury (AKI).

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

failure for patients with liver cirrhosis [19].

in the splanchnic arteries is last due to

20% of patients with advanced stage cirrhosis who are hospitalized [4, 5].

these patients and represents an important predictor for short-term mortality [11].

rhosis and entails a bad prognosis [2, 3].

32 Management of Chronic Liver Diseases - Recent Advances

and KDIGO [18].

necrosis (ATN), a type of intrinsic renal damage.

**b.** vasodilation by pro-inflammatory cytokines such as tumor necrosis factor and interleukin 6, derived from bacterial translocation of the intestine [22].

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 renal perfusion [23].

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 arginine-vasopressin.

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 [24, 25].

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


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 reduced systemic vascular resistance. The elevated cardiac output and low systemic vascular resistance are characteristics of the portal hypertension and hyperdynamic circulation in cirrhosis. Arterial vasodilation in the splanchnic circulation and the resulting decrease in systemic vascular resistance are associated with portal hypertension in cirrhosis. Compensatory mechanisms following the reduction of systemic vascular resistance lead to hyperdynamic circulation. Nevertheless, hyperdynamic circulation is insufficient to correct the effective arterial hypovolemia when the disease progresses and arterial vasodilation increases, resulting in arterial hypotension and consequent activation of the circulating renin-angiotensin-aldosterone system and the sympathetic nervous system and secretion of antidiuretic hormone [27].

In the early stages of disease, the circulating RAS is not activated at early stages of the disease. The patients at the advanced stages of cirrhosis presented an activation of peripheral and splanchnic renin-aldosterone system, and a metabolic deviation toward the RAS vasodilator axis in the splanchnic circulation (**Figure 1**).

#### **2.1. Causes of acute kidney injury in cirrhosis**

The acute kidney injury has prerenal, intrarenal, or postrenal causes (**Figure 2**). The most common causes of acute kidney injury between patients with cirrhosis are the prerenal etiologies, followed by acute tubular necrosis, and the postrenal etiology is extremely rare. The prerenal and acute tubular necrosis are the etiology of 80% of cases (49% prerenal and 35% acute tubular

necrosis). Postrenal injury accounted for only 0.2%. In a prospective study, among patients with cirrhosis listed for liver transplantation who had acute kidney injury, prerenal injury was the most common cause in 76% followed by intrarenal etiology in 33%, while postrenal etiology did

**Figure 2.** Management approach and algorithm for acute kidney injury in patients with cirrhosis. AKI, acute kidney injury; ESLD, end-stage liver disease; HRS, hepatorenal syndrome; LVP, large-volume paracentesis; RRT, renal replacement therapy; LTA, liver transplant alone; SLK, simultaneous liver kidney; TIPS, transjugular intrahepatic

Acute Kidney Injury in Cirrhosis

35

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

The hemodynamic state in cirrhosis with vascular dilatation and reduced vascular resistance in cirrhosis is quite similar to hemodynamic state in sepsis, especially spontaneous bacterial peritonitis. Prerenal injury occurs commonly due to gastrointestinal bleeding, infections, use of diuretics, diarrhea often related to lactulose use for hepatic encephalopathy, and from large-volume paracentesis without albumin infusion. Large-volume paracentesis may be associated with intravascular volume depletion and acute kidney failure. This condition occurs in up to 70% of patients undergoing paracentesis when more

not occur in any patient [66, 67].

portosystemic shunt; USG, ultrasonogram.

**3.1. Volume responsive prerenal AKI**

**3. Prerenal injury**

**Figure 1.** Hemodynamic alterations in the early and advanced stages of cirrhosis. In the early stages of cirrhosis, there is an increased cardiac output and a diminished systemic vascular resistance without changes in the circulating levels of the renin-angiotensin system components and antidiuretic hormone. In later phases of the cirrhosis, the components of the renin-angiotensin-aldosterone system are elevated, with activation of the sympathetic nervous system and secretion of the antidiuretic hormone, like a response to persistent arterial hypotension. Ang II: angiotensin II; Ang-(1–7): angiotensin (1–7); SNS: sympathetic nervous system; SVR: systemic vascular resistance.

**Figure 2.** Management approach and algorithm for acute kidney injury in patients with cirrhosis. AKI, acute kidney injury; ESLD, end-stage liver disease; HRS, hepatorenal syndrome; LVP, large-volume paracentesis; RRT, renal replacement therapy; LTA, liver transplant alone; SLK, simultaneous liver kidney; TIPS, transjugular intrahepatic portosystemic shunt; USG, ultrasonogram.

necrosis). Postrenal injury accounted for only 0.2%. In a prospective study, among patients with cirrhosis listed for liver transplantation who had acute kidney injury, prerenal injury was the most common cause in 76% followed by intrarenal etiology in 33%, while postrenal etiology did not occur in any patient [66, 67].

## **3. Prerenal injury**

reduced systemic vascular resistance. The elevated cardiac output and low systemic vascular resistance are characteristics of the portal hypertension and hyperdynamic circulation in cirrhosis. Arterial vasodilation in the splanchnic circulation and the resulting decrease in systemic vascular resistance are associated with portal hypertension in cirrhosis. Compensatory mechanisms following the reduction of systemic vascular resistance lead to hyperdynamic circulation. Nevertheless, hyperdynamic circulation is insufficient to correct the effective arterial hypovolemia when the disease progresses and arterial vasodilation increases, resulting in arterial hypotension and consequent activation of the circulating renin-angiotensin-aldosterone system and the sympathetic nervous system and secretion of antidiuretic hormone [27].

In the early stages of disease, the circulating RAS is not activated at early stages of the disease. The patients at the advanced stages of cirrhosis presented an activation of peripheral and splanchnic renin-aldosterone system, and a metabolic deviation toward the RAS vasodilator

The acute kidney injury has prerenal, intrarenal, or postrenal causes (**Figure 2**). The most common causes of acute kidney injury between patients with cirrhosis are the prerenal etiologies, followed by acute tubular necrosis, and the postrenal etiology is extremely rare. The prerenal and acute tubular necrosis are the etiology of 80% of cases (49% prerenal and 35% acute tubular

**Figure 1.** Hemodynamic alterations in the early and advanced stages of cirrhosis. In the early stages of cirrhosis, there is an increased cardiac output and a diminished systemic vascular resistance without changes in the circulating levels of the renin-angiotensin system components and antidiuretic hormone. In later phases of the cirrhosis, the components of the renin-angiotensin-aldosterone system are elevated, with activation of the sympathetic nervous system and secretion of the antidiuretic hormone, like a response to persistent arterial hypotension. Ang II: angiotensin II; Ang-(1–7):

angiotensin (1–7); SNS: sympathetic nervous system; SVR: systemic vascular resistance.

axis in the splanchnic circulation (**Figure 1**).

34 Management of Chronic Liver Diseases - Recent Advances

**2.1. Causes of acute kidney injury in cirrhosis**

#### **3.1. Volume responsive prerenal AKI**

The hemodynamic state in cirrhosis with vascular dilatation and reduced vascular resistance in cirrhosis is quite similar to hemodynamic state in sepsis, especially spontaneous bacterial peritonitis. Prerenal injury occurs commonly due to gastrointestinal bleeding, infections, use of diuretics, diarrhea often related to lactulose use for hepatic encephalopathy, and from large-volume paracentesis without albumin infusion. Large-volume paracentesis may be associated with intravascular volume depletion and acute kidney failure. This condition occurs in up to 70% of patients undergoing paracentesis when more than 5 L are removed and albumin is not infused. The use of any drugs like NSAIDs can precipitate acute kidney failure by decreasing renal prostaglandins and accentuating the intrarenal vasoconstriction and further decrease renal blood flow. The advice to the patients should be provided to avoid these drugs for the management of pain. The use of intravenous contrast agents in patients with cirrhosis is another potential risk factor for acute kidney failure. The infections have common occurrence in patients with cirrhosis. Hence, superimposed infections/sepsis in cirrhosis patients worsen this physiology, causing a reduction of circulating blood volume and leading to the development of AKI. Before the widespread use of antibiotic prophylaxis for acute gastrointestinal bleeding in cirrhosis, more than 20% of patients with cirrhosis hospitalized for acute gastrointestinal bleeding had a bacterial infection present on admission, with up to 50% developing an infection while hospitalized.

**4. Postrenal injury**

set to 1.73 m2

widely used [32].

severity of cirrhosis.

easily be excluded using renal ultrasound or CT scan.

clearance of a marker occurs only through glomerular filtration [28].

**4.1. Evaluation of the renal function**

As stated earlier, postrenal injury is a rare cause of AKI in cirrhosis [66, 68]. This etiology can

Acute Kidney Injury in Cirrhosis

37

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

The glomerular filtration rate (GFR) is the universally used index to quantify kidney function. The principle of GFR determination is to determine the body clearance of a substance with the supposed exclusive renal clearance. The substance used for determinate GFR must be freely filtered and neither reabsorbed or secreted along the renal tubule. Also, no extrarenal excretion of the substance occurs, and it cannot be stored or be bound to plasma proteins: then it can be assumed that the plasmatic clearance is only due to renal clearance. Thus, the GFR can be inferred from the plasma disappearance of the substance. It is considered that the renal

Calculation of the eGFR requires normalization to BSA. Studies that tested the performance of this method showed a clear trend to overestimate mGFR by 4–80%. A normalization based on the assumption that the GFR is positively correlated with the basal metabolism rate of individuals which is proportional to their stature on arbitrarily fixed body surface area (BSA)

dardization on other criteria has been proposed [31]. The formula most commonly used to determine the BSA is the Dubois formula, and the adjustment on the body surface remains

Historically, the Cockcroft and Gault formula was the most popular before the MDRD formula was published in the early 2000s. This formula is not adjusted to the patient BSA, and the adjustment has, theoretically, to be done afterwards (even if the relevance of this adjustment remains to be assessed in cirrhotic patients). The relationship between GFR level and overestimation could be explained by the secretion of creatinine by the tubule in patients with CKD. However, the importance of this overestimation does not seem to be related to the

Creatinine clearance is a simple method to estimate GFR, based on the assumption that creatinine has the characteristics of a perfect renal marker. It requests the accurate recollection of urine from a 24-h period. It has several limitations: mainly, the possible inadequate urine collection by the patients, the occurrence of tubular secretion of creatinine, which leads to

The definition of acute kidney injury in cirrhosis consists in an acute increase in serum creatinine of >0.3 mg/dL in a time lapse of 48 h or by <50% from a stable baseline serum creatinine, in the last 3 months (presumed to have developed within the past 7 days when no prior readings are available) [19, 33]. In addition, the use of urine output as part of the diagnostic criteria was eliminated, since many patients with cirrhosis and ascites maintain a preserved renal function despite being oliguric due to sodium and water retention. The main modifications over the previous,

overestimation of the GFR, and that is on a longer or a shorter than 24-h time period.

**4.2. Definition of acute kidney injury in cirrhosis**

is commonly done [29]. This normalization has been questioned [30] and stan-

## **3.2. Volume nonresponsive prerenal AKI: hepatorenal syndrome**

The volume expansion is the first treatment after acute kidney failure is diagnosed, using crystalloids or intravenous albumin and discontinuation of precipitating medications. If renal function does not normalize or improve with this intervention, it is important to consider hepatorenal syndrome (HRS) in the differential diagnosis to consider as the cause for AKI. HRS is a functional form of renal failure without any major structural or histological changes in the kidneys that is characterized by intense renal vasoconstriction. It is important to differentiate it from another intrarenal cause, because management and prognosis differ. In the absence of renal biopsy, the diagnosis of HRS remains difficult and is essentially a diagnosis of exclusion. In patients with cirrhosis, HRS develops in about 18% at 1 year and 39% at 5 years.

Approximately, 66% of all HRS cases are type 2, or HRS-AKI which are rapidly occurring with an increase in serum creatinine to over 2.5 mg/dL over 1 or 2 weeks. Type 1 HRS has high mortality with a median survival of around 50% at 2 weeks and is usually precipitated by infections. The type 2 HRS has a better outcome with a median survival of about 6 months and a slower course in the setting of refractory ascites, with slowly increasing serum creatinine to over 1.5 mg/dL. The definition of type I HRS has been recently revised and changed the value of 2.5 mg/dL serum creatinine for diagnosis, thus avoid delaying the initiation of therapy.

#### **3.3. Volume nonresponsive intrinsic AKI: acute tubular necrosis**

The most common cause for intrarenal AKI in cirrhosis is ATN. This occurs commonly either as a complication of sepsis or due to unrecognized and untreated prerenal injury. The main cause of ATN has been attributed to sepsis, followed by hypovolemia and rarely nephrotoxic drugs.

Other less common causes of intrarenal injury include tubular damage due to bile cast nephropathy from high-conjugated bilirubin excreted through the glomeruli, membranoproliferative glomerulonephritis with or without cryoglobulinemia associated with hepatitis C, and acute interstitial nephritis due to medications, such as antibiotics, NSAIDS, and proton pump inhibitors.

## **4. Postrenal injury**

than 5 L are removed and albumin is not infused. The use of any drugs like NSAIDs can precipitate acute kidney failure by decreasing renal prostaglandins and accentuating the intrarenal vasoconstriction and further decrease renal blood flow. The advice to the patients should be provided to avoid these drugs for the management of pain. The use of intravenous contrast agents in patients with cirrhosis is another potential risk factor for acute kidney failure. The infections have common occurrence in patients with cirrhosis. Hence, superimposed infections/sepsis in cirrhosis patients worsen this physiology, causing a reduction of circulating blood volume and leading to the development of AKI. Before the widespread use of antibiotic prophylaxis for acute gastrointestinal bleeding in cirrhosis, more than 20% of patients with cirrhosis hospitalized for acute gastrointestinal bleeding had a bacterial infection present on admission, with up to 50% developing an

The volume expansion is the first treatment after acute kidney failure is diagnosed, using crystalloids or intravenous albumin and discontinuation of precipitating medications. If renal function does not normalize or improve with this intervention, it is important to consider hepatorenal syndrome (HRS) in the differential diagnosis to consider as the cause for AKI. HRS is a functional form of renal failure without any major structural or histological changes in the kidneys that is characterized by intense renal vasoconstriction. It is important to differentiate it from another intrarenal cause, because management and prognosis differ. In the absence of renal biopsy, the diagnosis of HRS remains difficult and is essentially a diagnosis of exclusion. In patients with cirrhosis, HRS develops in about 18% at 1 year and

Approximately, 66% of all HRS cases are type 2, or HRS-AKI which are rapidly occurring with an increase in serum creatinine to over 2.5 mg/dL over 1 or 2 weeks. Type 1 HRS has high mortality with a median survival of around 50% at 2 weeks and is usually precipitated by infections. The type 2 HRS has a better outcome with a median survival of about 6 months and a slower course in the setting of refractory ascites, with slowly increasing serum creatinine to over 1.5 mg/dL. The definition of type I HRS has been recently revised and changed the value of 2.5 mg/dL serum creatinine for diagnosis, thus avoid delaying the initiation of

The most common cause for intrarenal AKI in cirrhosis is ATN. This occurs commonly either as a complication of sepsis or due to unrecognized and untreated prerenal injury. The main cause of ATN has been attributed to sepsis, followed by hypovolemia and rarely nephrotoxic

Other less common causes of intrarenal injury include tubular damage due to bile cast nephropathy from high-conjugated bilirubin excreted through the glomeruli, membranoproliferative glomerulonephritis with or without cryoglobulinemia associated with hepatitis C, and acute interstitial nephritis due to medications, such as antibiotics, NSAIDS, and proton

infection while hospitalized.

36 Management of Chronic Liver Diseases - Recent Advances

39% at 5 years.

therapy.

drugs.

pump inhibitors.

**3.2. Volume nonresponsive prerenal AKI: hepatorenal syndrome**

**3.3. Volume nonresponsive intrinsic AKI: acute tubular necrosis**

As stated earlier, postrenal injury is a rare cause of AKI in cirrhosis [66, 68]. This etiology can easily be excluded using renal ultrasound or CT scan.

## **4.1. Evaluation of the renal function**

The glomerular filtration rate (GFR) is the universally used index to quantify kidney function. The principle of GFR determination is to determine the body clearance of a substance with the supposed exclusive renal clearance. The substance used for determinate GFR must be freely filtered and neither reabsorbed or secreted along the renal tubule. Also, no extrarenal excretion of the substance occurs, and it cannot be stored or be bound to plasma proteins: then it can be assumed that the plasmatic clearance is only due to renal clearance. Thus, the GFR can be inferred from the plasma disappearance of the substance. It is considered that the renal clearance of a marker occurs only through glomerular filtration [28].

Calculation of the eGFR requires normalization to BSA. Studies that tested the performance of this method showed a clear trend to overestimate mGFR by 4–80%. A normalization based on the assumption that the GFR is positively correlated with the basal metabolism rate of individuals which is proportional to their stature on arbitrarily fixed body surface area (BSA) set to 1.73 m2 is commonly done [29]. This normalization has been questioned [30] and standardization on other criteria has been proposed [31]. The formula most commonly used to determine the BSA is the Dubois formula, and the adjustment on the body surface remains widely used [32].

Historically, the Cockcroft and Gault formula was the most popular before the MDRD formula was published in the early 2000s. This formula is not adjusted to the patient BSA, and the adjustment has, theoretically, to be done afterwards (even if the relevance of this adjustment remains to be assessed in cirrhotic patients). The relationship between GFR level and overestimation could be explained by the secretion of creatinine by the tubule in patients with CKD. However, the importance of this overestimation does not seem to be related to the severity of cirrhosis.

Creatinine clearance is a simple method to estimate GFR, based on the assumption that creatinine has the characteristics of a perfect renal marker. It requests the accurate recollection of urine from a 24-h period. It has several limitations: mainly, the possible inadequate urine collection by the patients, the occurrence of tubular secretion of creatinine, which leads to overestimation of the GFR, and that is on a longer or a shorter than 24-h time period.

### **4.2. Definition of acute kidney injury in cirrhosis**

The definition of acute kidney injury in cirrhosis consists in an acute increase in serum creatinine of >0.3 mg/dL in a time lapse of 48 h or by <50% from a stable baseline serum creatinine, in the last 3 months (presumed to have developed within the past 7 days when no prior readings are available) [19, 33]. In addition, the use of urine output as part of the diagnostic criteria was eliminated, since many patients with cirrhosis and ascites maintain a preserved renal function despite being oliguric due to sodium and water retention. The main modifications over the previous, rather stringent, criteria that were based on absolute serum creatinine level, were abandoning the threshold of serum creatinine >1.5 mg/dL to diagnose acute kidney injury, because milder degrees of renal failure in cirrhotic patients had often remained underdiagnosed [34, 35].

Similar to the ICA-AKI criteria, most of these studies diagnosed AKI solely on serum creatinine. In 2013, a modified, AKIN-derived score for cirrhosis was developed, by division of AKI stage 1 into two groups depending on whether or not serum creatinine surpassed the threshold of 1.5 mg/dL and by merging AKI stages 2 and 3 into stage "C" [40]; this reclassification did not gain wide acceptance. Several clinical studies have evaluated the prognostic value of the AKIN/KDIGO criteria that constitute the basis for the International Club of Ascites (ICA)- AKI criteria in patients with cirrhosis [37–39]. The acute kidney injury can be classified into three stages according to severity. Stage 1 AKI is defined by rather small changes in serum creatinine, while stages 2 and 3 AKI are defined by a twofold and threefold increase in serum creatinine, respectively (**Table 1**) [36]. Since their publication in 2015, the newer and cirrhosis-specific ICA criteria have been assessed within one retrospective study in hospitalized patients with cirrhosis [41]. Within this study, approximately 40% of patients experienced AKI during their hospitalization with the majority of cases having been diagnosed at stage 1. Also, in patients with AKI stage 1 and a serum creatinine of <1.5 mg/dL, already a 3.5-fold increase in 30-day mortality as compared to patients without AKI was reported [41], again underlining the prognostic importance of even small increases in serum creatinine levels.

The Guidelines of the European Association for the Study of Liver Diseases (EASL) and the American Association for the Study of the Liver (AASLD) Clinical Practice Guidelines for ascites and hepatorenal syndrome still proclaim the threshold of 2.5 mg/dL for diagnosing HRS-AKI [42, 43]. The use of this threshold in clinical practice would mean that proper diagnosis and treatment of HRS would be withheld as long as serum creatinine does not reach this threshold. In order to prevent misclassification or even treatment delay, the newer International Club of Ascites criteria focus on the relative increase in creatinine rather than absolute values, since also smaller rises in serum creatinine have been shown to have a nega-

Acute Kidney Injury in Cirrhosis

39

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

The hepatorenal syndrome is classified in two types. HRS type 1 is a quickly progressive acute renal failure. It commonly occurs in patients with end-stage cirrhosis following a septic insult such as spontaneous bacterial peritonitis or severe alcoholic hepatitis; this kind of hepatorenal syndrome frequently is developed in temporal relationship with a precipitating factor for a deterioration of liver function together with a deterioration of other organ function, although it may occur in the absence of any identifiable triggering event. Type 1 HRS is only diagnosed when the serum creatinine increases more than 100% from baseline to a final level of greater

Patients with type 2 HRS may eventually develop type 1 HRS; this can be spontaneously or

HRS should be diagnosed and excludes other known causes of renal failure and by demonstrating a significant increase in serum creatinine. For practical purposes, HRS is usually diagnosed only when serum creatinine increases to >133 mol/L (1.5 mg/dL). Repeated measurement of serum creatinine over time, particularly in hospitalized patients, is helpful in the

The diverse etiologies of renal failure in cirrhosis should be excluded before to conclude the diagnosis of HRS. Parenchymal renal diseases should be suspected if there is significant

tive prognostic impact in patients with cirrhosis [44].

**Table 2.** Diagnostic criteria for hepatorenal syndrome [12].

following a precipitating event such as an infection [12].

than 2.5 mg/dL.

early identification of HRS.

## **4.3. Hepatorenal syndrome type of acute kidney injury or type 1 hepatorenal syndrome**

Hepatorenal syndrome (HRS) is defined as the occurrence of renal failure in a patient with advanced liver disease in the absence of an identifiable cause of renal failure [12].

The hepatorenal syndrome type I requires the fulfillment of several specific diagnostic criteria that are summarized in **Table 2**. This Acute Kidney Injury (HRS-AKI) is defined as >stage 2 ICA-AKI that is diagnosed after other causes of renal failure have been ruled out [35].


**Table 1.** Criteria of AKI of the International Club of Ascites [36].

**Table 2.** Diagnostic criteria for hepatorenal syndrome [12].

rather stringent, criteria that were based on absolute serum creatinine level, were abandoning the threshold of serum creatinine >1.5 mg/dL to diagnose acute kidney injury, because milder degrees of renal failure in cirrhotic patients had often remained underdiagnosed [34, 35].

38 Management of Chronic Liver Diseases - Recent Advances

Similar to the ICA-AKI criteria, most of these studies diagnosed AKI solely on serum creatinine. In 2013, a modified, AKIN-derived score for cirrhosis was developed, by division of AKI stage 1 into two groups depending on whether or not serum creatinine surpassed the threshold of 1.5 mg/dL and by merging AKI stages 2 and 3 into stage "C" [40]; this reclassification did not gain wide acceptance. Several clinical studies have evaluated the prognostic value of the AKIN/KDIGO criteria that constitute the basis for the International Club of Ascites (ICA)- AKI criteria in patients with cirrhosis [37–39]. The acute kidney injury can be classified into three stages according to severity. Stage 1 AKI is defined by rather small changes in serum creatinine, while stages 2 and 3 AKI are defined by a twofold and threefold increase in serum creatinine, respectively (**Table 1**) [36]. Since their publication in 2015, the newer and cirrhosis-specific ICA criteria have been assessed within one retrospective study in hospitalized patients with cirrhosis [41]. Within this study, approximately 40% of patients experienced AKI during their hospitalization with the majority of cases having been diagnosed at stage 1. Also, in patients with AKI stage 1 and a serum creatinine of <1.5 mg/dL, already a 3.5-fold increase in 30-day mortality as compared to patients without AKI was reported [41], again underlining the prognostic importance of even small increases in serum creatinine levels.

**4.3. Hepatorenal syndrome type of acute kidney injury or type 1 hepatorenal** 

advanced liver disease in the absence of an identifiable cause of renal failure [12].

**Table 1.** Criteria of AKI of the International Club of Ascites [36].

ICA-AKI that is diagnosed after other causes of renal failure have been ruled out [35].

Hepatorenal syndrome (HRS) is defined as the occurrence of renal failure in a patient with

The hepatorenal syndrome type I requires the fulfillment of several specific diagnostic criteria that are summarized in **Table 2**. This Acute Kidney Injury (HRS-AKI) is defined as >stage 2

**syndrome**

The Guidelines of the European Association for the Study of Liver Diseases (EASL) and the American Association for the Study of the Liver (AASLD) Clinical Practice Guidelines for ascites and hepatorenal syndrome still proclaim the threshold of 2.5 mg/dL for diagnosing HRS-AKI [42, 43]. The use of this threshold in clinical practice would mean that proper diagnosis and treatment of HRS would be withheld as long as serum creatinine does not reach this threshold. In order to prevent misclassification or even treatment delay, the newer International Club of Ascites criteria focus on the relative increase in creatinine rather than absolute values, since also smaller rises in serum creatinine have been shown to have a negative prognostic impact in patients with cirrhosis [44].

The hepatorenal syndrome is classified in two types. HRS type 1 is a quickly progressive acute renal failure. It commonly occurs in patients with end-stage cirrhosis following a septic insult such as spontaneous bacterial peritonitis or severe alcoholic hepatitis; this kind of hepatorenal syndrome frequently is developed in temporal relationship with a precipitating factor for a deterioration of liver function together with a deterioration of other organ function, although it may occur in the absence of any identifiable triggering event. Type 1 HRS is only diagnosed when the serum creatinine increases more than 100% from baseline to a final level of greater than 2.5 mg/dL.

Patients with type 2 HRS may eventually develop type 1 HRS; this can be spontaneously or following a precipitating event such as an infection [12].

HRS should be diagnosed and excludes other known causes of renal failure and by demonstrating a significant increase in serum creatinine. For practical purposes, HRS is usually diagnosed only when serum creatinine increases to >133 mol/L (1.5 mg/dL). Repeated measurement of serum creatinine over time, particularly in hospitalized patients, is helpful in the early identification of HRS.

The diverse etiologies of renal failure in cirrhosis should be excluded before to conclude the diagnosis of HRS. Parenchymal renal diseases should be suspected if there is significant proteinuria or micro-hematuria, or if renal ultrasonography demonstrates abnormalities in kidney size. The hypovolemia, shock, parenchymal renal diseases, and concomitant use of nephrotoxic drugs are common causes of acute kidney injury and must be excluded before to diagnose HRS. Renal biopsy is important in these patients to help plan the further management, including the potential need for combined liver and kidney transplantation [42].

The terlipressin is the most intensively studied vasoconstrictor for the treatment of HRS-AKI. A bolus of terlipressin induces a significant reduction in the portal pressure for over a 3- to 4-h period and also increases the mean arterial pressure [55]. Hyponatremia must be considered, and this commonly occurs in less advanced liver disease and normal baseline serum sodium levels [56, 57]. Considering the pharmacodynamic profile and the costs of terlipressin, continuous infusion might be preferred over bolus administration. Although terlipressin has been consistently shown to improve renal function, its impact on survival is less clear [58]. Terlipressin is particularly beneficial in patients with sepsis and might also prevent variceal bleeding during the period of discontinuation of nonselective beta

Acute Kidney Injury in Cirrhosis

41

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

Norepinephrine is an alternative to the use of terlipressin with an initial dose: 0.5 mg/h, and a max. Dose studied in randomized controlled trials of 3 mg/h, norepinephrine is equally effective and inexpensive. A meta-analysis of four randomized-controlled trials demonstrated similar efficacy for HRS, when compared to terlipressin [60]. The therapy recommended for type 2 hepatorenal syndrome is similar [61, 62]; however, HRS type 2 commonly recurs after

Complete response is defined by a decrease in serum creatinine to a value within 0.3 mg/dL of baseline, while a regression of at least one AKI stage is considered as partial response [35]. If there is no response after 3 days of treatment, the vasoconstrictor dose should be increased. In nonresponders, treatment should be discontinued after 14 days. In responders, longer treat-

Potential alternative therapies to terlipressin include norepinephrine or midodrine plus octreotide, both in association with albumin, but there is very limited information with respect to the use of these drugs in patients with type 1 HRS. Treatment with terlipressin should be repeated and is frequently successful. The recurrence of type 1 HRS after discontinuation of

Cardiovascular ischemic disease is a contraindication to terlipressin therapy. Patients on terlipressin should be carefully monitored for signs of splanchnic or digital ischemia, the development of cardiac arrhythmias and fluid overload, and treatment modified or stopped

The use of TIPS may improve renal function in some patients; there are insufficient data in patients with type 1 HRS to support the use of TIPS as a treatment. The renal replacement therapy may be useful when the patients do not respond to vasoconstrictor therapy. There are limited data on the use of artificial liver support systems, and further studies are required

Hepatitis C (HCV) infection can induce kidney injury, mainly due to the formation of immune complexes and cryoglobulins, and possibly to a direct cytopathic effect. HCV is responsible for membranous glomerulonephritis or mesangiocapillary and accelerates the progression of chronic kidney disease due to other causes. It may cause acute kidney injury as a part of systemic vasculitis and augments the risk of AKI due to other etiologies. HCV-infected patients are at an

ment durations can be used as a bridging therapy to liver transplantation.

blockers [59].

accordingly.

for its use [43].

termination of treatment with vasoconstrictors [63].

terlipressin therapy is relatively uncommon.

**4.4. Hepatitis C and acute kidney injury**

#### *4.3.1. Treatment*

The initial management of acute kidney injury should focus on the early recognition and correction of potential trigger events and on preventing further hemodynamic deterioration [25, 33, 45]. In volume-depleted patients, diuretic therapy and/or lactulose should be withdrawn and plasma volume should be expanded with albumin, or blood transfusions in anemic patients due to gastrointestinal blood loss, is important the careful review of all medications, and consider the withdrawn of nephrotoxic agents. The use of medications that may induce or aggravate arterial should be carefully evaluated [46, 47].

Bacterial infections are a common precipitant of acute kidney injury, including the hepatorenal syndrome; in cirrhosis, these patients should be thoroughly screened for. The early initiation of empiric antibiotic treatment based on clinical suspicion and the local epidemiology and resistance patterns must be considered [48, 49].

The therapeutic response is defined as a decrease of creatinine in serum to a value within 0.3 mg/dL of baseline; in this case, the patients should be followed up closely for the early detection of recurrent episodes kidney failure. It is necessary to consider the possibility of hepatorenal syndrome In case of stage 2 or 3 or progression to a higher acute kidney injury stage, diuretics should be withdrawn immediately. The patients should receive plasma volume expansion with albumin for 2 consecutive days (1 g per kg of body weight, maximum 100 g/day). Albumin is particularly beneficial in patients with sepsis because in addition to its volume-expanding effect, it has antioxidant, scavenging, and endothelial-stabilizing functions [50]. A follow-up assessment of creatinine every 2–4 days during hospitalization and every 2–4 weeks during the first 6 months after discharge is advised [35].

In stages 2 and 3, the patients who meet diagnostic criteria of HRS-AKI should be treated with vasoconstrictors in combination with albumin [35]. The albumin initial dose is 1 g/kg body weight up to 100 g on the first day, then ongoing with 20–40 g/day, as it has been shown that the effects of intravenous albumin in the prevention and treatment of HRS are dosedependent, with better results when higher cumulative doses were administered [51, 52]. In all large-volume paracentesis (>5 L, with 8 g/L of ascites removed), albumin should be administered since it prevents post-paracentesis circulatory dysfunction, which reduces the risk of renal dysfunction and improve survival [53, 54].

The first-line drug therapy of type 1 hepatorenal syndrome is the use of terlipressin (1 mg/4–6 h intravenous bolus) in combination with albumin. The therapeutic target improves renal function enough to decrease serum creatinine to less than 133 mol/L (1.5 mg/dL); this is considered a complete response. If serum creatinine does not decrease at least 25% after 3 days, the dose of terlipressin should be increased in a stepwise manner up to a maximum of 2 mg/4 h. For patients with partial response (serum creatinine does not decrease <133 mol/L) or in those patients without reduction of serum creatinine, treatment should be discontinued within 14 days.

The terlipressin is the most intensively studied vasoconstrictor for the treatment of HRS-AKI. A bolus of terlipressin induces a significant reduction in the portal pressure for over a 3- to 4-h period and also increases the mean arterial pressure [55]. Hyponatremia must be considered, and this commonly occurs in less advanced liver disease and normal baseline serum sodium levels [56, 57]. Considering the pharmacodynamic profile and the costs of terlipressin, continuous infusion might be preferred over bolus administration. Although terlipressin has been consistently shown to improve renal function, its impact on survival is less clear [58]. Terlipressin is particularly beneficial in patients with sepsis and might also prevent variceal bleeding during the period of discontinuation of nonselective beta blockers [59].

Norepinephrine is an alternative to the use of terlipressin with an initial dose: 0.5 mg/h, and a max. Dose studied in randomized controlled trials of 3 mg/h, norepinephrine is equally effective and inexpensive. A meta-analysis of four randomized-controlled trials demonstrated similar efficacy for HRS, when compared to terlipressin [60]. The therapy recommended for type 2 hepatorenal syndrome is similar [61, 62]; however, HRS type 2 commonly recurs after termination of treatment with vasoconstrictors [63].

Complete response is defined by a decrease in serum creatinine to a value within 0.3 mg/dL of baseline, while a regression of at least one AKI stage is considered as partial response [35]. If there is no response after 3 days of treatment, the vasoconstrictor dose should be increased. In nonresponders, treatment should be discontinued after 14 days. In responders, longer treatment durations can be used as a bridging therapy to liver transplantation.

Potential alternative therapies to terlipressin include norepinephrine or midodrine plus octreotide, both in association with albumin, but there is very limited information with respect to the use of these drugs in patients with type 1 HRS. Treatment with terlipressin should be repeated and is frequently successful. The recurrence of type 1 HRS after discontinuation of terlipressin therapy is relatively uncommon.

Cardiovascular ischemic disease is a contraindication to terlipressin therapy. Patients on terlipressin should be carefully monitored for signs of splanchnic or digital ischemia, the development of cardiac arrhythmias and fluid overload, and treatment modified or stopped accordingly.

The use of TIPS may improve renal function in some patients; there are insufficient data in patients with type 1 HRS to support the use of TIPS as a treatment. The renal replacement therapy may be useful when the patients do not respond to vasoconstrictor therapy. There are limited data on the use of artificial liver support systems, and further studies are required for its use [43].

### **4.4. Hepatitis C and acute kidney injury**

proteinuria or micro-hematuria, or if renal ultrasonography demonstrates abnormalities in kidney size. The hypovolemia, shock, parenchymal renal diseases, and concomitant use of nephrotoxic drugs are common causes of acute kidney injury and must be excluded before to diagnose HRS. Renal biopsy is important in these patients to help plan the further management, including the potential need for combined liver and kidney transplantation [42].

The initial management of acute kidney injury should focus on the early recognition and correction of potential trigger events and on preventing further hemodynamic deterioration [25, 33, 45]. In volume-depleted patients, diuretic therapy and/or lactulose should be withdrawn and plasma volume should be expanded with albumin, or blood transfusions in anemic patients due to gastrointestinal blood loss, is important the careful review of all medications, and consider the withdrawn of nephrotoxic agents. The use of medications that may induce

Bacterial infections are a common precipitant of acute kidney injury, including the hepatorenal syndrome; in cirrhosis, these patients should be thoroughly screened for. The early initiation of empiric antibiotic treatment based on clinical suspicion and the local epidemiology

The therapeutic response is defined as a decrease of creatinine in serum to a value within 0.3 mg/dL of baseline; in this case, the patients should be followed up closely for the early detection of recurrent episodes kidney failure. It is necessary to consider the possibility of hepatorenal syndrome In case of stage 2 or 3 or progression to a higher acute kidney injury stage, diuretics should be withdrawn immediately. The patients should receive plasma volume expansion with albumin for 2 consecutive days (1 g per kg of body weight, maximum 100 g/day). Albumin is particularly beneficial in patients with sepsis because in addition to its volume-expanding effect, it has antioxidant, scavenging, and endothelial-stabilizing functions [50]. A follow-up assessment of creatinine every 2–4 days during hospitalization and

In stages 2 and 3, the patients who meet diagnostic criteria of HRS-AKI should be treated with vasoconstrictors in combination with albumin [35]. The albumin initial dose is 1 g/kg body weight up to 100 g on the first day, then ongoing with 20–40 g/day, as it has been shown that the effects of intravenous albumin in the prevention and treatment of HRS are dosedependent, with better results when higher cumulative doses were administered [51, 52]. In all large-volume paracentesis (>5 L, with 8 g/L of ascites removed), albumin should be administered since it prevents post-paracentesis circulatory dysfunction, which reduces the risk of

The first-line drug therapy of type 1 hepatorenal syndrome is the use of terlipressin (1 mg/4–6 h intravenous bolus) in combination with albumin. The therapeutic target improves renal function enough to decrease serum creatinine to less than 133 mol/L (1.5 mg/dL); this is considered a complete response. If serum creatinine does not decrease at least 25% after 3 days, the dose of terlipressin should be increased in a stepwise manner up to a maximum of 2 mg/4 h. For patients with partial response (serum creatinine does not decrease <133 mol/L) or in those patients with-

out reduction of serum creatinine, treatment should be discontinued within 14 days.

every 2–4 weeks during the first 6 months after discharge is advised [35].

or aggravate arterial should be carefully evaluated [46, 47].

and resistance patterns must be considered [48, 49].

40 Management of Chronic Liver Diseases - Recent Advances

renal dysfunction and improve survival [53, 54].

*4.3.1. Treatment*

Hepatitis C (HCV) infection can induce kidney injury, mainly due to the formation of immune complexes and cryoglobulins, and possibly to a direct cytopathic effect. HCV is responsible for membranous glomerulonephritis or mesangiocapillary and accelerates the progression of chronic kidney disease due to other causes. It may cause acute kidney injury as a part of systemic vasculitis and augments the risk of AKI due to other etiologies. HCV-infected patients are at an increased risk of acute posttransplant complications. HCV infection increases cardiovascular and liver-related mortality in patients on regular dialysis. Long-term graft survival is compromised by chronic transplant glomerulopathy or recurrent or de novo glomerulonephritis. The increased incidence of diabetes, sepsis, posttransplant lymphoproliferative disease, and liver failure compromises the patient survival. Directly acting antiviral agents (DAAs) are currently available for treatment at different stages of kidney disease. It is concluded that the thoughtful use of DAAs will result in a significant change in the epidemiology and clinical profiles of kidney disease, as well as improvement of dialysis and transplant outcomes, in endemic areas [64].

The acute kidney failure induced by HCV is a systemic disease reported in <5% of HCVinfected (HCV+ve) patients. It is characterized by multiorgan involvement, mainly affecting the lungs and kidneys, skin, musculoskeletal system, and peripheral nerves. The fundamental lesion is endothelial injury, perivascular inflammation with lymphocytic and neutrophilic infiltration, small vessel necrosis, and luminal occlusion by cryoglobulins and fibrin thrombi.

## **4.5. Cryoglobulinemic vasculitis**

In the kidneys, this leads to focal fibrinoid necrosis of the glomerular tufts, often with crescent formation (**Figure 3**). The renal tubules are affected by ischemic and inflammatory lesions and contain hyaline and blood casts. The ureteric and bladder mucosa may display vasculitic purpuric lesions. The interstitium is infiltrated with inflammatory cells and found edematous.

prognosis becomes bad for the renal function, as well as patient survival. The successful treatment may lead to complete or partial recovery, unless the damage has already been extensive,

**Figure 4.** Blood smear in a patient with cryoglobulinemic vasculitis and thrombotic microangiopathy. Note the red cell

Acute Kidney Injury in Cirrhosis

43

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

HCV-infected patient, compared to the general population are at many-fold risk of developing acute kidney injury of diverse etiology. The most frequent cause of kidney injury is hypovolemia associated with excessive vomiting or diarrhea. The second common cause was bacterial infection in the lungs, urinary, or gastrointestinal tract; 7.3% of patients had advanced cirrhosis and developed AKI following an episode of hematemesis, presumably due to ischemic acute tubular necrosis, and 6.5% were associated with hepatic encephalopathy including the hepatorenal syndrome. Decompensated liver disease, diabetes mellitus, history of intravenous drug abuse, and high baseline serum creatinine were independent predictors of developing AKI. End-stage kidney disease eventually developed in 17.5% of patients who developed AKI, compared to 1% of those who did not. Risk factors for end-stage renal kidney disease were preexisting hypertension, diabetes, or chronic kidney

Patients with cirrhosis are prone to developing acute kidney failure. The acute decrease of the kidney function contributes to the mortality of patients with cirrhosis. The criteria of the International Club of Ascites for acute kidney injury provide a simple and relevant staging system for acute kidney injury in patients with liver cirrhosis based on relative increases in serum creatinine. It is very important to consider the potential triggers of renal failure, and this should be recognized early and removed; this includes discontinuation of nephrotoxic drugs and diuretics, treatment of infections and gastrointestinal bleeding, and plasma expan-

leading to healing with focal or global sclerosis.

**4.6. Non-cryoglobulinemic AKI**

fragmentation with microcytes and schistocytes.

disease [65].

**5. Summary**

sion in case of hypovolemia.

The mechanism of vascular injury is typically attributed to component C1q of the complement, complement activation generates chemotactic factors, C3a and C5a, which recruit and activate pro-inflammatory leucocytes. It also leads to the formation of C5–9, the membrane attack complex that may have an important role in endothelial damage, the active complement component incorporated within the cryoglobulin complex. This leads to endothelial injury by dual effects, namely the activation of the complement cascade via the classical pathway and binding to endothelial complement receptors, thereby localizing the injury in target capillary beds.

The clinical presentation has a wide range from isolated hematuria to acute kidney injury, sometimes associated with thrombotic microangiopathy (**Figure 4**). If left untreated, the

**Figure 3.** Cryoglobulinemic renal vasculitis. Renal arteriole showing endothelialitis and cryoglobulin deposits in a patient with AKI due to HCV-associated cryoglobulinemia. Hematoxylin and eosin stain. Reproduced with permission from Ref. [64].

**Figure 4.** Blood smear in a patient with cryoglobulinemic vasculitis and thrombotic microangiopathy. Note the red cell fragmentation with microcytes and schistocytes.

prognosis becomes bad for the renal function, as well as patient survival. The successful treatment may lead to complete or partial recovery, unless the damage has already been extensive, leading to healing with focal or global sclerosis.

### **4.6. Non-cryoglobulinemic AKI**

increased risk of acute posttransplant complications. HCV infection increases cardiovascular and liver-related mortality in patients on regular dialysis. Long-term graft survival is compromised by chronic transplant glomerulopathy or recurrent or de novo glomerulonephritis. The increased incidence of diabetes, sepsis, posttransplant lymphoproliferative disease, and liver failure compromises the patient survival. Directly acting antiviral agents (DAAs) are currently available for treatment at different stages of kidney disease. It is concluded that the thoughtful use of DAAs will result in a significant change in the epidemiology and clinical profiles of kidney disease, as well as improvement of dialysis and transplant outcomes, in endemic areas [64]. The acute kidney failure induced by HCV is a systemic disease reported in <5% of HCVinfected (HCV+ve) patients. It is characterized by multiorgan involvement, mainly affecting the lungs and kidneys, skin, musculoskeletal system, and peripheral nerves. The fundamental lesion is endothelial injury, perivascular inflammation with lymphocytic and neutrophilic infiltration, small vessel necrosis, and luminal occlusion by cryoglobulins and fibrin thrombi.

In the kidneys, this leads to focal fibrinoid necrosis of the glomerular tufts, often with crescent formation (**Figure 3**). The renal tubules are affected by ischemic and inflammatory lesions and contain hyaline and blood casts. The ureteric and bladder mucosa may display vasculitic purpuric lesions. The interstitium is infiltrated with inflammatory cells and found edematous. The mechanism of vascular injury is typically attributed to component C1q of the complement, complement activation generates chemotactic factors, C3a and C5a, which recruit and activate pro-inflammatory leucocytes. It also leads to the formation of C5–9, the membrane attack complex that may have an important role in endothelial damage, the active complement component incorporated within the cryoglobulin complex. This leads to endothelial injury by dual effects, namely the activation of the complement cascade via the classical pathway and binding to endothelial complement receptors, thereby localizing the injury in target capillary beds.

The clinical presentation has a wide range from isolated hematuria to acute kidney injury, sometimes associated with thrombotic microangiopathy (**Figure 4**). If left untreated, the

**Figure 3.** Cryoglobulinemic renal vasculitis. Renal arteriole showing endothelialitis and cryoglobulin deposits in a patient with AKI due to HCV-associated cryoglobulinemia. Hematoxylin and eosin stain. Reproduced with permission

**4.5. Cryoglobulinemic vasculitis**

42 Management of Chronic Liver Diseases - Recent Advances

from Ref. [64].

HCV-infected patient, compared to the general population are at many-fold risk of developing acute kidney injury of diverse etiology. The most frequent cause of kidney injury is hypovolemia associated with excessive vomiting or diarrhea. The second common cause was bacterial infection in the lungs, urinary, or gastrointestinal tract; 7.3% of patients had advanced cirrhosis and developed AKI following an episode of hematemesis, presumably due to ischemic acute tubular necrosis, and 6.5% were associated with hepatic encephalopathy including the hepatorenal syndrome. Decompensated liver disease, diabetes mellitus, history of intravenous drug abuse, and high baseline serum creatinine were independent predictors of developing AKI. End-stage kidney disease eventually developed in 17.5% of patients who developed AKI, compared to 1% of those who did not. Risk factors for end-stage renal kidney disease were preexisting hypertension, diabetes, or chronic kidney disease [65].

## **5. Summary**

Patients with cirrhosis are prone to developing acute kidney failure. The acute decrease of the kidney function contributes to the mortality of patients with cirrhosis. The criteria of the International Club of Ascites for acute kidney injury provide a simple and relevant staging system for acute kidney injury in patients with liver cirrhosis based on relative increases in serum creatinine. It is very important to consider the potential triggers of renal failure, and this should be recognized early and removed; this includes discontinuation of nephrotoxic drugs and diuretics, treatment of infections and gastrointestinal bleeding, and plasma expansion in case of hypovolemia.

Cardiovascular ischemic disease is a contraindication to terlipressin therapy. Patients on terlipressin should be carefully monitored for signs of splanchnic or digital ischemia, the development of cardiac arrhythmias and fluid overload, and treatment modified or stopped accordingly.

[10] Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology. 2008;

Acute Kidney Injury in Cirrhosis

45

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## **Author details**

Marco Antonio López Hernández

Address all correspondence to: niklaus2003@yahoo.com.mx

Internal Medicine Department, Tacuba General Hospital, Mexico City, Mexico

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**Chapter 4**

**Provisional chapter**

**Portal Vein Thrombosis in Liver Cirrhosis**

**Portal Vein Thrombosis in Liver Cirrhosis**

DOI: 10.5772/intechopen.76295

In liver cirrhosis, portal vein thrombosis (PVT), which is defined as thrombosis that occurs within the main portal vein and intrahepatic portal branches, is one of the most common complications. High incidence of PVT in the setting of liver cirrhosis is mainly due to hypercoagulable state and altered dynamic of blood flow in the portal vein. The clinical manifestations of PVT are variable among different patients, so the diagnosis of PVT is mainly dependent on the imaging examinations, like ultrasound, computed tomography and magnetic resonance imaging. The overall goal of treatment for PVT can be summarized as reducing risk factors of PVT, thus to prevent further expansion of thrombus and maintain portal patency and prevent and treat the symptoms of PVT by anticoagulants, local thrombolysis, transjugular intrahepatic portosystemic shunt and/ or surgery. In future, due to the progress in vascular imaging and innovation in clinical

Portal vein thrombosis (PVT) is diagnosed when a venous thrombosis occurs within the main portal vein and intrahepatic portal branches [1, 2]. In liver cirrhosis, especially in advanced stages, PVT is one of the most common complications [3–5]. High incidence of PVT in the setting of liver cirrhosis is mainly due to hypercoagulable state and altered dynamics of blood flow in the portal vein [6–8]. Moreover, PVT will deteriorate liver cirrhosis by increasing portal vein pressure and decreasing blood flow into liver. Under severe circumstances, it will worsen symptoms of cirrhosis such as ascites, upper gastrointestinal bleeding, intestinal avascular necrosis and so on [3, 4, 9–11]. However, 30–50% patients with PVT will spontaneously

anti-thrombotic drug, PVT could be prevented and cured effectively.

**Keywords:** portal vein thrombosis, cirrhosis, management, anticoagulant

© 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.

Shuai Xue, Peisong Wang, Hui Han and

Shuai Xue, Peisong Wang, Hui Han and

http://dx.doi.org/10.5772/intechopen.76295

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Guang Chen

Guang Chen

**Abstract**

**1. Introduction**

#### **Portal Vein Thrombosis in Liver Cirrhosis Portal Vein Thrombosis in Liver Cirrhosis**

DOI: 10.5772/intechopen.76295

Shuai Xue, Peisong Wang, Hui Han and Guang Chen Shuai Xue, Peisong Wang, Hui Han and Guang Chen

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.76295

#### **Abstract**

In liver cirrhosis, portal vein thrombosis (PVT), which is defined as thrombosis that occurs within the main portal vein and intrahepatic portal branches, is one of the most common complications. High incidence of PVT in the setting of liver cirrhosis is mainly due to hypercoagulable state and altered dynamic of blood flow in the portal vein. The clinical manifestations of PVT are variable among different patients, so the diagnosis of PVT is mainly dependent on the imaging examinations, like ultrasound, computed tomography and magnetic resonance imaging. The overall goal of treatment for PVT can be summarized as reducing risk factors of PVT, thus to prevent further expansion of thrombus and maintain portal patency and prevent and treat the symptoms of PVT by anticoagulants, local thrombolysis, transjugular intrahepatic portosystemic shunt and/ or surgery. In future, due to the progress in vascular imaging and innovation in clinical anti-thrombotic drug, PVT could be prevented and cured effectively.

**Keywords:** portal vein thrombosis, cirrhosis, management, anticoagulant

#### **1. Introduction**

Portal vein thrombosis (PVT) is diagnosed when a venous thrombosis occurs within the main portal vein and intrahepatic portal branches [1, 2]. In liver cirrhosis, especially in advanced stages, PVT is one of the most common complications [3–5]. High incidence of PVT in the setting of liver cirrhosis is mainly due to hypercoagulable state and altered dynamics of blood flow in the portal vein [6–8]. Moreover, PVT will deteriorate liver cirrhosis by increasing portal vein pressure and decreasing blood flow into liver. Under severe circumstances, it will worsen symptoms of cirrhosis such as ascites, upper gastrointestinal bleeding, intestinal avascular necrosis and so on [3, 4, 9–11]. However, 30–50% patients with PVT will spontaneously

© 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.

alleviate or recover without any treatment [4, 10, 12, 13]. This highlights the over-diagnosis of PVT in cirrhosis and questions whether PVT treatment will benefit cirrhotic patients, especially when they are diagnosed incidentally on imaging. Right now, there is no guideline or expert consensus on how to manage cirrhotic patients with PVT. A meta-analysis which includes 3735 cirrhotic patients demonstrated that PVT negatively influenced both mortality and hepatic decompensation, despite its limitation of including heterogeneous populations [14]. However, another prospective multicenter study which includes 863 Child-Pugh class A and 380 class B cirrhotic patients found PVT was not a prognostic factor for either mortality or hepatic decompensation [15]. A study that only investigated 42 cirrhotic patients with extrahepatic nonmalignant partial PVT reported that no association was found between progression or regression of partial PVT and clinical outcomes. The model for end-stage liver disease **(**MELD) score, rather than PVT, was the predictor of worse prognosis in cirrhotic patients [16]. So, at present, the issue of whether PVT does or does not have influence on the natural history of cirrhosis is still controversial [17–19].

diagnostic biomarker of PVT [9, 35, 36]. Toshiki Matsui also reported that soluble form of glycoprotein VI, as a platelet activation marker, was associated with PVT formation after hepatectomy and splenectomy in patients with liver cirrhosis [37]. Another study from Poland found platelet aggregability was decreased in PVT patients [31]. In another logistic regression model, incidence of PVT was highly related with D-dimer and bilirubin [38, 39]. Additionally, increased whole blood viscosity due to increased number of erythrocytes and ability of aggregation as well as decreased deformability may be reasons for increased PVT formation [34, 40]. Both procoagulant and anticoagulant proteins decreased in liver cirrhosis patients at the same time, owing to decreased synthesis function of the liver, which often largely maintained in a dynamic balance [7, 8, 34, 41]. Therefore, the body is neither to bleed nor to form thrombosis. However, after liver transplantation surgery, venous injury would reduce the flow rate of portal vein; thus, anticoagulant-associated protein S and C decreased as well as anti-thrombin III [21]. Meanwhile, surgery consumes numerous coagulation factors. Factor VIII, VII factorrelated antigens and anti-cardiolipin antibody increased, which both resulted in PVT formation. Factor VIII concentration and the ratio of the most powerful procoagulant (factor VIII) and anticoagulant (protein C) were considered as markers to indicate hypercoagulability [25, 38, 42–44]. Studies showed factor VIII was related to PVT in cirrhotic patients independently. Patients with factor VIII level above 129 IU/dl had six times the probability to PVT [45]. Some researchers reported in the literature that procoagulant gene mutations, including coagulation factor V Leiden G1691A, methylenetetrahydrofolate reductase C677T and prothrombin G20210A, may be associated with PVT [46, 47]. Recent studies showed that increased hemagglutinin activated fibrinolysin inhibition gene mutation and blood coagulation factor VII,

Portal Vein Thrombosis in Liver Cirrhosis http://dx.doi.org/10.5772/intechopen.76295 53

PVT formation is associated with intrahepatic resistance and poor portal blood flow. Moreover, portal blood flow decreases more if cirrhosis progresses. That's why the incidence of PVT is much higher in advanced-stage cirrhotic patients compared with well-compensated ones [48]. Cirrhotic patients with PVT had low portal flow volumes and high collateral vessel flow velocity. Intraoperative clamp and squeeze will cause vein intimal injury, collagen exposure and activation of the coagulation system. After liver transplantation, blood flow in portal vein is relatively slow, which is easy to form turbulence and thrombosis [9, 25, 49, 50]. Portal vein blood flow velocity and PVT have an important relationship. Studies demonstrated that patients with portal vein blood flow <15 cm/s had higher incidence of PVT [17, 27, 50–52]. So, some researchers often regarded portal vein diameter as an independent risk factor for the formation of PVT. In short, because there are various changes in portal hemodynamics, the

Cirrhosis is more likely to damage intestinal mucosal barrier which facilitates bacterial translocation and endotoxinemia [53]. Endotoxinemia not only can increase portal vein pressure but also can activate coagulation cascade. That explains why it can increase the PVT incidence

which were closely related to the occurrence of PVT [1, 2].

incidence of PVT is quite high after liver transplantation.

**3.3. Endotoxinemia**

in the portal system [54].

**3.2. Hemodynamic changes in the portal vein**

## **2. Prevalence**

The prevalence and incidence of PVT in cirrhosis often varies from 1 to 28% among different studies depending on heterogeneity in diagnosis methods, different populations and variable followup time [16–22]. In a retrospective study of 150 patients with viral cirrhosis, the cumulative overall incidences of PVT were 12.8% at 1 year, 18.6% at 3 years, 20% at 5 years and 38.7% at 8–10 years, respectively [23]. In another study, which includes 701 cirrhosis patients without hepatocellular carcinoma, the incidence of PVT was 11.2% since they used ultrasound for diagnosis routinely [24]. PVT is more common in advanced cirrhosis and the incidence is positively related with the stage of cirrhosis, which is only 1% in compensated patients but 8.4% in severe cirrhosis waiting for liver transplantation [21, 25–28]. However, there are some limitations in these studies which weaken the magnitude and reliability of these conclusions like different subgroup patients and follow-up times as we previously mentioned. Violi et al. reported a study aimed at evaluating the prevalence of PVT in a broad spectrum of patients with cirrhosis and found 17% of 753 cirrhotic patients had PVT [29]. A multicenter randomized trial that includes 898 well-compensated cirrhosis patients reported that the 5-year cumulative incidence of PVT was 11.9% [30].

## **3. Pathophysiology**

#### **3.1. Hypercoagulable state of blood flow**

After liver transplantation, the number of platelets will increase temporarily for a short time, which contributes to the hypercoagulable state of blood [31, 32]. That would be one of the significant reasons for PVT formation in liver transplantation patients. The study showed that surgery not only increased blood platelets but also activated their surface glycoprotein CD62P, reflecting the degree of platelet activation and causing a hypercoagulable state [33, 34]. Postoperative-elevated CD62P is closely related with PVT, which can be used as a sensitive diagnostic biomarker of PVT [9, 35, 36]. Toshiki Matsui also reported that soluble form of glycoprotein VI, as a platelet activation marker, was associated with PVT formation after hepatectomy and splenectomy in patients with liver cirrhosis [37]. Another study from Poland found platelet aggregability was decreased in PVT patients [31]. In another logistic regression model, incidence of PVT was highly related with D-dimer and bilirubin [38, 39]. Additionally, increased whole blood viscosity due to increased number of erythrocytes and ability of aggregation as well as decreased deformability may be reasons for increased PVT formation [34, 40]. Both procoagulant and anticoagulant proteins decreased in liver cirrhosis patients at the same time, owing to decreased synthesis function of the liver, which often largely maintained in a dynamic balance [7, 8, 34, 41]. Therefore, the body is neither to bleed nor to form thrombosis. However, after liver transplantation surgery, venous injury would reduce the flow rate of portal vein; thus, anticoagulant-associated protein S and C decreased as well as anti-thrombin III [21]. Meanwhile, surgery consumes numerous coagulation factors. Factor VIII, VII factorrelated antigens and anti-cardiolipin antibody increased, which both resulted in PVT formation. Factor VIII concentration and the ratio of the most powerful procoagulant (factor VIII) and anticoagulant (protein C) were considered as markers to indicate hypercoagulability [25, 38, 42–44]. Studies showed factor VIII was related to PVT in cirrhotic patients independently. Patients with factor VIII level above 129 IU/dl had six times the probability to PVT [45]. Some researchers reported in the literature that procoagulant gene mutations, including coagulation factor V Leiden G1691A, methylenetetrahydrofolate reductase C677T and prothrombin G20210A, may be associated with PVT [46, 47]. Recent studies showed that increased hemagglutinin activated fibrinolysin inhibition gene mutation and blood coagulation factor VII, which were closely related to the occurrence of PVT [1, 2].

#### **3.2. Hemodynamic changes in the portal vein**

PVT formation is associated with intrahepatic resistance and poor portal blood flow. Moreover, portal blood flow decreases more if cirrhosis progresses. That's why the incidence of PVT is much higher in advanced-stage cirrhotic patients compared with well-compensated ones [48]. Cirrhotic patients with PVT had low portal flow volumes and high collateral vessel flow velocity. Intraoperative clamp and squeeze will cause vein intimal injury, collagen exposure and activation of the coagulation system. After liver transplantation, blood flow in portal vein is relatively slow, which is easy to form turbulence and thrombosis [9, 25, 49, 50]. Portal vein blood flow velocity and PVT have an important relationship. Studies demonstrated that patients with portal vein blood flow <15 cm/s had higher incidence of PVT [17, 27, 50–52]. So, some researchers often regarded portal vein diameter as an independent risk factor for the formation of PVT. In short, because there are various changes in portal hemodynamics, the incidence of PVT is quite high after liver transplantation.

#### **3.3. Endotoxinemia**

alleviate or recover without any treatment [4, 10, 12, 13]. This highlights the over-diagnosis of PVT in cirrhosis and questions whether PVT treatment will benefit cirrhotic patients, especially when they are diagnosed incidentally on imaging. Right now, there is no guideline or expert consensus on how to manage cirrhotic patients with PVT. A meta-analysis which includes 3735 cirrhotic patients demonstrated that PVT negatively influenced both mortality and hepatic decompensation, despite its limitation of including heterogeneous populations [14]. However, another prospective multicenter study which includes 863 Child-Pugh class A and 380 class B cirrhotic patients found PVT was not a prognostic factor for either mortality or hepatic decompensation [15]. A study that only investigated 42 cirrhotic patients with extrahepatic nonmalignant partial PVT reported that no association was found between progression or regression of partial PVT and clinical outcomes. The model for end-stage liver disease **(**MELD) score, rather than PVT, was the predictor of worse prognosis in cirrhotic patients [16]. So, at present, the issue of whether PVT does or does not have influence on the natural history

The prevalence and incidence of PVT in cirrhosis often varies from 1 to 28% among different studies depending on heterogeneity in diagnosis methods, different populations and variable followup time [16–22]. In a retrospective study of 150 patients with viral cirrhosis, the cumulative overall incidences of PVT were 12.8% at 1 year, 18.6% at 3 years, 20% at 5 years and 38.7% at 8–10 years, respectively [23]. In another study, which includes 701 cirrhosis patients without hepatocellular carcinoma, the incidence of PVT was 11.2% since they used ultrasound for diagnosis routinely [24]. PVT is more common in advanced cirrhosis and the incidence is positively related with the stage of cirrhosis, which is only 1% in compensated patients but 8.4% in severe cirrhosis waiting for liver transplantation [21, 25–28]. However, there are some limitations in these studies which weaken the magnitude and reliability of these conclusions like different subgroup patients and follow-up times as we previously mentioned. Violi et al. reported a study aimed at evaluating the prevalence of PVT in a broad spectrum of patients with cirrhosis and found 17% of 753 cirrhotic patients had PVT [29]. A multicenter randomized trial that includes 898 well-compensated cir-

rhosis patients reported that the 5-year cumulative incidence of PVT was 11.9% [30].

After liver transplantation, the number of platelets will increase temporarily for a short time, which contributes to the hypercoagulable state of blood [31, 32]. That would be one of the significant reasons for PVT formation in liver transplantation patients. The study showed that surgery not only increased blood platelets but also activated their surface glycoprotein CD62P, reflecting the degree of platelet activation and causing a hypercoagulable state [33, 34]. Postoperative-elevated CD62P is closely related with PVT, which can be used as a sensitive

of cirrhosis is still controversial [17–19].

52 Management of Chronic Liver Diseases - Recent Advances

**2. Prevalence**

**3. Pathophysiology**

**3.1. Hypercoagulable state of blood flow**

Cirrhosis is more likely to damage intestinal mucosal barrier which facilitates bacterial translocation and endotoxinemia [53]. Endotoxinemia not only can increase portal vein pressure but also can activate coagulation cascade. That explains why it can increase the PVT incidence in the portal system [54].

## **4. Diagnosis**

## **4.1. Clinical manifestations**

A study which includes 79 cirrhotic patients has shown that 57% of PVT were symptomatic and among them 39% had gastrointestinal bleeding and 70% had intestinal infarction [24]. Abdominal pain is generally the earliest clinical symptom after the acute formation of PVT. Usually, abdominal pain is limited within a specific region while few are diffuse pain and intermittent colic pain with longer durations. Nausea and vomiting occur in 50% of PVT patients [3, 4, 51, 55–57]. A few patients will have diarrhea or bloody stool. If complete intestinal obstruction occurs suddenly, abdominal pain is paroxysmal accompanied by significant nausea, vomiting without fart and defecation. Under this circumstance, there are no obvious physical examination signs, that the degree of pain is not consistent with the signs of the abdomen [19, 58, 59]. Increased anterior hepatic obstructive factors will cause decreased portal vein blood flow which aggravates liver damage, increases portal pressure, causes repeated upper gastrointestinal bleeding and refractory ascites and so on. In some severe cases, clinical manifestations of intestinal necrosis such as persistent abdominal pain, bloating, hemafecia, hematemesis, shock and peritoneal irritation will occur [18, 24, 26]. Abdominal puncture can be bloody ascites. In the event of intestinal necrosis, disease mortality rate can rise to 20–60%. Patients often suffer from persistent abdominal pain, hemafecia, abdominal cramps, ascites, multiple organ failure and so on. For chronic PVT, patients will have refractory bloating, diarrhea, upper abdominal pain and ascites due to gastrointestinal congestion and insufficient perfusion of liver portal vein [24]. The clinical manifestations of PVT are variable among different patients, so the clinical diagnosis of PVT is mainly dependent on the imaging examination.

Enhanced computer tomography (CT) or enhanced magnetic resonance imaging (MRI) examination by intravenous injection contrast can effectively solve the above deficiencies. By comparison with contrast, we can discover intraluminal filling defects and perfusion conditions for nearby organs at different times of the imaging process. CT angiography (CTA) and magnetic resonance angiography (MRA) greatly increase the accuracy of diagnosis. Some studies have showed that the sensitivity and the specificity for CTA were 86 and 95%. For MRA, the sensitivity was 100% and specificity was 98% [60, 65–67]. Typical CT signs of PVT are very intuitive: no-enhanced low-density intraluminal stripe or massive lesions within portal static. Occasionally, CT can also find an enhanced ring around thrombus due to nourishing small blood vessels. Moreover, CT can also help to diagnose primary liver cancer, cirrhosis and evaluate intestinal ischemia and necrosis. CTA has several advantages including short scan time, fast imaging speed and reduced motion artifact [67]. However, its main drawbacks can be related to some complications like contrast agent allergy, contrast agent nephropathy and other adverse reactions. The safety of MRA contract is significantly better than that of CTA. But MRA has the same disadvantages like motion artifacts, long-signal acquisition time and limited imaging range [66]. Therefore, patients with suspicious PVT should be enrolled in

Portal Vein Thrombosis in Liver Cirrhosis http://dx.doi.org/10.5772/intechopen.76295 55

contract CT or MRI imaging, which can be more accurate for clinical diagnosis.

**4.3. Laboratory tests**

Angiography is the traditional method for diagnosis of PVT. It is not the routine examination of PVT because of its invasive feature. Angiography includes two categories: indirect and direct. Indirect angiography is through splenic artery and superior mesenteric artery to image [2, 65]. In this way, we can see the portal vein filling defect as well as the collateral circulation. The most important thing is we can put the catheter into the superior mesenteric artery and/or splenic artery branch to infuse thrombolytic drugs after indirect angiography. It means we can finish diagnosis and follow treatment after invasive process at one time. Direct angiography is divided into: percutaneous transhepatic portal angiography, which can display directly portal vein system and evaluate portal hemodynamics, and umbilical portal vein angiography, which is indicated for splenic vein thrombosis, spleen resection and failure of arterial portal angiography [50].

Usually, prothrombin time (PT) and activated partial thromboplastin time (APTT) were used as predictors for the coagulation state with cirrhosis, and even the predictive ability was poor [7, 34, 68]. Because they could not explain and represent natural anticoagulants such as antithrombin and protein C in vivo, the thrombin generation test, which used tissue factor as trigger and phospholipids as platelet substitutes, was considered more appropriate for evaluating thrombin generation. The test was regarded as representation of the balance between the pro- and anticoagulant proteins in plasma [33, 44]. Another test named thromboelastography (TEG) can monitor all kinds of hemostatic functions (coagulation, anticoagulation, fibrinolysis) continuously to predict thrombosis formation and dissolution dynamically. This test also emphasized the dynamic assessment of balanced status in blood coagulation and anticoagulation process [17, 18]. This is a new laboratory test to evaluate whether the blood is hypercoagulable, whether there is the formation of thrombus and whether the thrombus is stable. The effectiveness of clinical application needs to be further studied. Additionally, we

#### **4.2. Imaging**

Ultrasound, the most common imaging way, is simple and easy to accurately evaluate PVT [60]. Thus, it is the preferred imaging method for diagnosis. Ultrasound diagnosis of PVT is characterized by abnormal echo in the portal vein, unclear boundary with the wall, CDFI: no blood flow signal, portal venous cavernous hemangioma; portal vein expansion before thrombosis site; and no display of portal vein if PVT is formed within a wide range [11, 17, 18, 60, 61]. The sensitivity and specificity of ultrasonography to diagnose PVT are up to 60 and 100% [60, 62]. Ultrasound can clearly demonstrate the blood flow, vascular diameter and the changes and the presence of thrombi. Ultrasound can also determine the formation of collateral circulation simultaneously through CDFI. But the ultrasound cannot reflect directly the situation of the portal vein and its branches, and the experience of the operator affects the accuracy of the diagnosis. Ultrasound angiography or ultrasound endoscopy can diagnose PVT more accurately that even raises the diagnostic sensitivity to 81% [24]. Some authors recommended contrasting enhanced ultrasound as the first-line imaging and "gold standard method" for the diagnosis of PVT [63, 64]. But ultrasound angiography and endoscopy also have some limitations. Firstly, they cannot evaluate the portal vein within the part of the liver and superior mesenteric vein end accurately. Moreover, they cannot assess the surrounding organs which may be affected by PVT [50, 63, 64].

Enhanced computer tomography (CT) or enhanced magnetic resonance imaging (MRI) examination by intravenous injection contrast can effectively solve the above deficiencies. By comparison with contrast, we can discover intraluminal filling defects and perfusion conditions for nearby organs at different times of the imaging process. CT angiography (CTA) and magnetic resonance angiography (MRA) greatly increase the accuracy of diagnosis. Some studies have showed that the sensitivity and the specificity for CTA were 86 and 95%. For MRA, the sensitivity was 100% and specificity was 98% [60, 65–67]. Typical CT signs of PVT are very intuitive: no-enhanced low-density intraluminal stripe or massive lesions within portal static. Occasionally, CT can also find an enhanced ring around thrombus due to nourishing small blood vessels. Moreover, CT can also help to diagnose primary liver cancer, cirrhosis and evaluate intestinal ischemia and necrosis. CTA has several advantages including short scan time, fast imaging speed and reduced motion artifact [67]. However, its main drawbacks can be related to some complications like contrast agent allergy, contrast agent nephropathy and other adverse reactions. The safety of MRA contract is significantly better than that of CTA. But MRA has the same disadvantages like motion artifacts, long-signal acquisition time and limited imaging range [66]. Therefore, patients with suspicious PVT should be enrolled in contract CT or MRI imaging, which can be more accurate for clinical diagnosis.

Angiography is the traditional method for diagnosis of PVT. It is not the routine examination of PVT because of its invasive feature. Angiography includes two categories: indirect and direct. Indirect angiography is through splenic artery and superior mesenteric artery to image [2, 65]. In this way, we can see the portal vein filling defect as well as the collateral circulation. The most important thing is we can put the catheter into the superior mesenteric artery and/or splenic artery branch to infuse thrombolytic drugs after indirect angiography. It means we can finish diagnosis and follow treatment after invasive process at one time. Direct angiography is divided into: percutaneous transhepatic portal angiography, which can display directly portal vein system and evaluate portal hemodynamics, and umbilical portal vein angiography, which is indicated for splenic vein thrombosis, spleen resection and failure of arterial portal angiography [50].

#### **4.3. Laboratory tests**

**4. Diagnosis**

**4.2. Imaging**

**4.1. Clinical manifestations**

54 Management of Chronic Liver Diseases - Recent Advances

A study which includes 79 cirrhotic patients has shown that 57% of PVT were symptomatic and among them 39% had gastrointestinal bleeding and 70% had intestinal infarction [24]. Abdominal pain is generally the earliest clinical symptom after the acute formation of PVT. Usually, abdominal pain is limited within a specific region while few are diffuse pain and intermittent colic pain with longer durations. Nausea and vomiting occur in 50% of PVT patients [3, 4, 51, 55–57]. A few patients will have diarrhea or bloody stool. If complete intestinal obstruction occurs suddenly, abdominal pain is paroxysmal accompanied by significant nausea, vomiting without fart and defecation. Under this circumstance, there are no obvious physical examination signs, that the degree of pain is not consistent with the signs of the abdomen [19, 58, 59]. Increased anterior hepatic obstructive factors will cause decreased portal vein blood flow which aggravates liver damage, increases portal pressure, causes repeated upper gastrointestinal bleeding and refractory ascites and so on. In some severe cases, clinical manifestations of intestinal necrosis such as persistent abdominal pain, bloating, hemafecia, hematemesis, shock and peritoneal irritation will occur [18, 24, 26]. Abdominal puncture can be bloody ascites. In the event of intestinal necrosis, disease mortality rate can rise to 20–60%. Patients often suffer from persistent abdominal pain, hemafecia, abdominal cramps, ascites, multiple organ failure and so on. For chronic PVT, patients will have refractory bloating, diarrhea, upper abdominal pain and ascites due to gastrointestinal congestion and insufficient perfusion of liver portal vein [24]. The clinical manifestations of PVT are variable among different patients,

so the clinical diagnosis of PVT is mainly dependent on the imaging examination.

organs which may be affected by PVT [50, 63, 64].

Ultrasound, the most common imaging way, is simple and easy to accurately evaluate PVT [60]. Thus, it is the preferred imaging method for diagnosis. Ultrasound diagnosis of PVT is characterized by abnormal echo in the portal vein, unclear boundary with the wall, CDFI: no blood flow signal, portal venous cavernous hemangioma; portal vein expansion before thrombosis site; and no display of portal vein if PVT is formed within a wide range [11, 17, 18, 60, 61]. The sensitivity and specificity of ultrasonography to diagnose PVT are up to 60 and 100% [60, 62]. Ultrasound can clearly demonstrate the blood flow, vascular diameter and the changes and the presence of thrombi. Ultrasound can also determine the formation of collateral circulation simultaneously through CDFI. But the ultrasound cannot reflect directly the situation of the portal vein and its branches, and the experience of the operator affects the accuracy of the diagnosis. Ultrasound angiography or ultrasound endoscopy can diagnose PVT more accurately that even raises the diagnostic sensitivity to 81% [24]. Some authors recommended contrasting enhanced ultrasound as the first-line imaging and "gold standard method" for the diagnosis of PVT [63, 64]. But ultrasound angiography and endoscopy also have some limitations. Firstly, they cannot evaluate the portal vein within the part of the liver and superior mesenteric vein end accurately. Moreover, they cannot assess the surrounding

Usually, prothrombin time (PT) and activated partial thromboplastin time (APTT) were used as predictors for the coagulation state with cirrhosis, and even the predictive ability was poor [7, 34, 68]. Because they could not explain and represent natural anticoagulants such as antithrombin and protein C in vivo, the thrombin generation test, which used tissue factor as trigger and phospholipids as platelet substitutes, was considered more appropriate for evaluating thrombin generation. The test was regarded as representation of the balance between the pro- and anticoagulant proteins in plasma [33, 44]. Another test named thromboelastography (TEG) can monitor all kinds of hemostatic functions (coagulation, anticoagulation, fibrinolysis) continuously to predict thrombosis formation and dissolution dynamically. This test also emphasized the dynamic assessment of balanced status in blood coagulation and anticoagulation process [17, 18]. This is a new laboratory test to evaluate whether the blood is hypercoagulable, whether there is the formation of thrombus and whether the thrombus is stable. The effectiveness of clinical application needs to be further studied. Additionally, we can exclude PVT patients with a 90% negative predictive value when the D-dimer level is less than 1.82 mg/l [38, 39, 69, 70]. Systemic evaluation of coagulation tests, including PT, international standardization ratio, partial thromboplastin time, and so on, could not fully assess the patient's coagulation abnormalities. Dynamic monitoring of vitamin K-related coagulation factors, fibrinogen, platelet function, fibrinolysis status as well as other coagulation factors simultaneously is essential.

effectively [75]. Meanwhile, these anticoagulants will not increase the incidence of any kinds of bleedings [75]. Another study from Italy found the benefits patients got overweighed the potential minor bleeding risk [76]. And they also concluded that portal hypertension, rather than anticoagulants, would be the real reason for the risk of major bleeding among cirrhotic patients with PVT. A prospective study from China which focused on patients with cirrhosis undergoing elective transjugular intrahepatic portosystemic shunt (TIPS) found that warfarin treatment within 12 months achieved a much higher rate of complete recanalization [77]. The commonly used drugs include warfarin, low molecular weight heparin and urokinase [78–81]. Most patients with acute PVT were recommended early anticoagulant therapy at least for 6 months. A systematic review and meta-analysis that summarized different regiments of anticoagulation has been reported [82]. In this study, the overall rate of portal vein recanalization was 37–93% and the anti-coagulation related bleeding was 0–18% [82]. In this way, we can not only reduce the incidence of PVT greatly but also increase PVT recanalization rate up

Portal Vein Thrombosis in Liver Cirrhosis http://dx.doi.org/10.5772/intechopen.76295 57

In recent years, inhibitors of activated factor Xa (e.g., rivaroxaban) have been used in the prevention of clinical PVT. The advantages are convenient oral administration, no effect on the international standardization ratio and no need to monitor blood coagulation indicators. Hyeyoung Yang et al. reported a 63-year-old female who experienced complete resolution of recurrent acute PVT in liver cirrhosis after rivaroxaban treatment [83]. The disadvantage is there is no effective antagonist. When bleeding happens during anticoagulant therapy, the consequence is serious. However, some new oral anticoagulants' antidotes have been under investigation like andexanet alfa, P-glycoprotein substrates and drugs inducing CYP3A4. They all could inhibit the concentration or absorption of new oral anticoagulants and attenu-

In short, clinical non-surgical methods are still mainly treatments of PVT in cirrhotic patients.

Local thrombolysis is divided into indirect way (femoral artery-superior mesenteric artery indwelling catheter thrombolysis) and direct way (percutaneous transhepatic portal vein

The advantages of the femoral artery-superior mesenteric artery catheter thrombolysis are simple and relative small trauma. It is just suitable for mild PVT without vascular occlusion. Because when PVT is found by this method, portal vein branches are usually in the stenosis or occlusion state by obstruction of thrombosis. Most of the drugs we injected for thrombolysis cannot reach the site of thrombus effectively. So, indications of this method are limited.

The advantages of the percutaneous transhepatic portal vein thrombolysis method are simple and show high success rates. However, we must stop this treatment when the patient has: (1) APTT significantly longer; (2) the international standardization ratio > 2; and (3) obvious abdominal pain, bloating, vomiting, hemafecia, increased puncture-point bleeding, more subcutaneous ecchymosis, hemoglobin continuing to decrease, faster heart rate, lower blood

to 39.3–100.0%.

ate their effects remarkably [83, 84].

**6.2. Local thrombolytic treatment**

thrombolysis) [13, 17, 18, 27, 35, 56, 85].

pressure and other signs of active bleeding.

## **5. Classification**

According to PVT imaging findings preoperatively, Yerdel found a classification system as the following: grade I, <50% portal vein obstruction with or without micro-thrombus of the superior mesenteric vein; grade II, >50% portal vein obstruction with or without micro-thrombus of the superior mesenteric vein; grade III, complete portal vein and proximal superior mesenteric vein obstruction; and grade IV, complete portal vein and entire superior mesenteric vein obstruction [71].

## **6. PVT treatment**

The overall goal of treatment for PVT can be summarized as reducing risk factors of PVT, thus to prevent further expansion of thrombus and maintain portal patency, prevent and treat the symptoms of PVT. For acute PVT, the aim is to prevent thrombus extension and intestinal infarction, whereas for chronic PVT, it is to prevent recurrent thrombosis, gastrointestinal bleeding and portal cholangiopathy [20, 35, 51].

### **6.1. Non-surgical treatment**

The incidence of PVT is high in cirrhotic patients, but clinical studies found that 30–50% of patients with PVT could alleviate without any treatment. Longest diameter of portal vein and blood flow of the largest collateral circulation vein were closely related with the incidence of spontaneous alleviation in PVT patients [1, 21]. But another study demonstrated that untreated PVT was associated with increased mortality, especially in patients with low Child-Pugh scores. And there were strong correlations between anticoagulation therapy and lower thrombus progress rate as well as higher recanalization rate [11, 72, 73]. Furthermore, PVT has been reported as an independent risk factor for recurrent and refractory acute variceal bleeding [23, 74]. There is inconsistent guidance on the anticoagulant management of PVT. However, once the PVT is diagnosed, the optimal time of prevention and treatment often has been missed. Serious complications would increase mortality greatly for PVT patients. So, it is recommended for cirrhotic patients that routine color Doppler ultrasound assessment should be performed. Early diagnosis, early anticoagulant and thrombolytic therapy can effectively improve the prognosis of patients. A meta-analysis from Italy, which includes 8 studies comprising 353 patients with cirrhosis and PVT, demonstrated anticoagulant therapy (low-weight heparin or warfarin) could increase recanalization and reduce progression of thrombosis effectively [75]. Meanwhile, these anticoagulants will not increase the incidence of any kinds of bleedings [75]. Another study from Italy found the benefits patients got overweighed the potential minor bleeding risk [76]. And they also concluded that portal hypertension, rather than anticoagulants, would be the real reason for the risk of major bleeding among cirrhotic patients with PVT. A prospective study from China which focused on patients with cirrhosis undergoing elective transjugular intrahepatic portosystemic shunt (TIPS) found that warfarin treatment within 12 months achieved a much higher rate of complete recanalization [77]. The commonly used drugs include warfarin, low molecular weight heparin and urokinase [78–81]. Most patients with acute PVT were recommended early anticoagulant therapy at least for 6 months. A systematic review and meta-analysis that summarized different regiments of anticoagulation has been reported [82]. In this study, the overall rate of portal vein recanalization was 37–93% and the anti-coagulation related bleeding was 0–18% [82]. In this way, we can not only reduce the incidence of PVT greatly but also increase PVT recanalization rate up to 39.3–100.0%.

In recent years, inhibitors of activated factor Xa (e.g., rivaroxaban) have been used in the prevention of clinical PVT. The advantages are convenient oral administration, no effect on the international standardization ratio and no need to monitor blood coagulation indicators. Hyeyoung Yang et al. reported a 63-year-old female who experienced complete resolution of recurrent acute PVT in liver cirrhosis after rivaroxaban treatment [83]. The disadvantage is there is no effective antagonist. When bleeding happens during anticoagulant therapy, the consequence is serious. However, some new oral anticoagulants' antidotes have been under investigation like andexanet alfa, P-glycoprotein substrates and drugs inducing CYP3A4. They all could inhibit the concentration or absorption of new oral anticoagulants and attenuate their effects remarkably [83, 84].

In short, clinical non-surgical methods are still mainly treatments of PVT in cirrhotic patients.

## **6.2. Local thrombolytic treatment**

can exclude PVT patients with a 90% negative predictive value when the D-dimer level is less than 1.82 mg/l [38, 39, 69, 70]. Systemic evaluation of coagulation tests, including PT, international standardization ratio, partial thromboplastin time, and so on, could not fully assess the patient's coagulation abnormalities. Dynamic monitoring of vitamin K-related coagulation factors, fibrinogen, platelet function, fibrinolysis status as well as other coagulation factors

According to PVT imaging findings preoperatively, Yerdel found a classification system as the following: grade I, <50% portal vein obstruction with or without micro-thrombus of the superior mesenteric vein; grade II, >50% portal vein obstruction with or without micro-thrombus of the superior mesenteric vein; grade III, complete portal vein and proximal superior mesenteric vein obstruction; and grade IV, complete portal vein and entire superior mesen-

The overall goal of treatment for PVT can be summarized as reducing risk factors of PVT, thus to prevent further expansion of thrombus and maintain portal patency, prevent and treat the symptoms of PVT. For acute PVT, the aim is to prevent thrombus extension and intestinal infarction, whereas for chronic PVT, it is to prevent recurrent thrombosis, gastrointestinal

The incidence of PVT is high in cirrhotic patients, but clinical studies found that 30–50% of patients with PVT could alleviate without any treatment. Longest diameter of portal vein and blood flow of the largest collateral circulation vein were closely related with the incidence of spontaneous alleviation in PVT patients [1, 21]. But another study demonstrated that untreated PVT was associated with increased mortality, especially in patients with low Child-Pugh scores. And there were strong correlations between anticoagulation therapy and lower thrombus progress rate as well as higher recanalization rate [11, 72, 73]. Furthermore, PVT has been reported as an independent risk factor for recurrent and refractory acute variceal bleeding [23, 74]. There is inconsistent guidance on the anticoagulant management of PVT. However, once the PVT is diagnosed, the optimal time of prevention and treatment often has been missed. Serious complications would increase mortality greatly for PVT patients. So, it is recommended for cirrhotic patients that routine color Doppler ultrasound assessment should be performed. Early diagnosis, early anticoagulant and thrombolytic therapy can effectively improve the prognosis of patients. A meta-analysis from Italy, which includes 8 studies comprising 353 patients with cirrhosis and PVT, demonstrated anticoagulant therapy (low-weight heparin or warfarin) could increase recanalization and reduce progression of thrombosis

simultaneously is essential.

56 Management of Chronic Liver Diseases - Recent Advances

teric vein obstruction [71].

**6.1. Non-surgical treatment**

bleeding and portal cholangiopathy [20, 35, 51].

**6. PVT treatment**

**5. Classification**

Local thrombolysis is divided into indirect way (femoral artery-superior mesenteric artery indwelling catheter thrombolysis) and direct way (percutaneous transhepatic portal vein thrombolysis) [13, 17, 18, 27, 35, 56, 85].

The advantages of the femoral artery-superior mesenteric artery catheter thrombolysis are simple and relative small trauma. It is just suitable for mild PVT without vascular occlusion. Because when PVT is found by this method, portal vein branches are usually in the stenosis or occlusion state by obstruction of thrombosis. Most of the drugs we injected for thrombolysis cannot reach the site of thrombus effectively. So, indications of this method are limited.

The advantages of the percutaneous transhepatic portal vein thrombolysis method are simple and show high success rates. However, we must stop this treatment when the patient has: (1) APTT significantly longer; (2) the international standardization ratio > 2; and (3) obvious abdominal pain, bloating, vomiting, hemafecia, increased puncture-point bleeding, more subcutaneous ecchymosis, hemoglobin continuing to decrease, faster heart rate, lower blood pressure and other signs of active bleeding.

#### **6.3. TIPS**

When severe PVT happened, thrombus blocked more than 50% lumen or completely blocked, anticoagulant therapy was unlikely to recanalization. Under this condition, we can choose TIPS. This method has the advantages as the following: the risk of thrombolysis is relatively small, and punctures can often reach directly to the thrombus site; at the same time intravascular technology (balloon plasty, stent replacement, thrombectomy and thrombolytic therapy surgery) can be applied to achieve the goal of treatment of PVT. A study from China which compared transcatheter selective superior mesenteric artery urokinase infusion and TIPS has found they were safe and effective for acute symptomatic PVT in cirrhosis [86]. But the operation was a relative difficult and lethal event as well as severe complications were still possible, so it is particularly important to assess the risk-benefit ratio of TIPS preoperatively. At present, the TIPS therapy methods for PVT are the following [87–89]:


For cirrhotic patients with refractory variceal bleeding and ascites, TIPS was considered as one of the major treatment strategies if the patient did not have PVT. PVT has changed natural history of liver cirrhosis and affected outcomes. So, in this circumstance, TIPS should be recommended with caution. No convincing evidence has been published to verify the superiority of TIPS over traditional anticoagulants. TIPS should only be recommended for severe PVT patients although technical difficulty rose sharply when severe PVT was diagnosed [89]. That means reliable predictors for PVT progression should be further investigated in future.

> vein diameter ≥10 mm, simple AT III prevention treatment; and high risk: splenic vein diameter ≥15 mm or from the liver collateral circulation vein diameter ≥10 mm, AT III, low molecu-

> **Figure 1.** Algorithm for the treatment of portal vein thrombosis in liver cirrhosis. *Abbreviations*: PVT, portal vein thrombosis; TIPS, transjugular intrahepatic portosystemic shunt; AT III, anti-thrombin III therapy; LWMH, low-weight

Portal Vein Thrombosis in Liver Cirrhosis http://dx.doi.org/10.5772/intechopen.76295 59

Enoxaparin was found to prevent PVT in advanced cirrhotic patients. Daily subcutaneous enoxaparin (4000 IU/day) could significantly reduce incidence of PVT in the short and long term [91, 92]. And enoxaparin can also decrease the liver decompensation rate and improve

Surgery on the portal vein system should be gentle and accurate. We should prevent unnecessary damage to the vascular endothelium and avoid ligation of chunk tissue. If there is no obvious bleeding tendency, surgeons should not use hemostatic after surgery which may

PVT was a clinical rare deep venous thrombosis but highly occurred in liver cirrhotic patients. Local or systemic factors alone or in combination make contribution to the formation of PVT. In clinical, PVT should be given enough attention due to its severe threat to the patient's

lar weight heparin in conjunction with warfarin [90].

result in thrombosis (**Figure 1**).

**8. Conclusion**

survival of patients who received liver transplantation [52, 91, 92].

molecular heparin; \*according to Yerdel's study [68]; # according to Kawanaka's study [90].

#### **6.4. Surgical treatment of PVT**

Surgery is relatively high risk. The commonly used methods are (1) PVT excision; (2) portal vein stent implantation, mainly aimed to relieve portal vein obstruction; (3) liver transplantation. During treatment, if the patient has the sustained abdominal pain, abdominal distension and other signs of peritonitis, laparotomy exploration should be performed early to prevent the occurrence of intestinal necrosis. When intestinal necrosis is diagnosed, intestinal and mesangial resections should be performed. At the same time, the intestinal end-to-end anastomosis should be done. Anticoagulation was continued after surgery to prevent thrombus reformation.

## **7. PVT prevention**

Kawanaka et al. have shown that anti-thrombin III (AT III) activity and splenic vein diameter were the risk factors of PVT after surgery. Moreover, they used those risk factors to formulate risk stratification system [90]. According to the risk stratification, doctors can decide whether to give prevention or not: low risk: AT III activity ≥70% and splenic vein straight diameter <10 mm, no preventive treatment; intermediate risk: AT III activity <70% or splenic

**Figure 1.** Algorithm for the treatment of portal vein thrombosis in liver cirrhosis. *Abbreviations*: PVT, portal vein thrombosis; TIPS, transjugular intrahepatic portosystemic shunt; AT III, anti-thrombin III therapy; LWMH, low-weight molecular heparin; \*according to Yerdel's study [68]; # according to Kawanaka's study [90].

vein diameter ≥10 mm, simple AT III prevention treatment; and high risk: splenic vein diameter ≥15 mm or from the liver collateral circulation vein diameter ≥10 mm, AT III, low molecular weight heparin in conjunction with warfarin [90].

Enoxaparin was found to prevent PVT in advanced cirrhotic patients. Daily subcutaneous enoxaparin (4000 IU/day) could significantly reduce incidence of PVT in the short and long term [91, 92]. And enoxaparin can also decrease the liver decompensation rate and improve survival of patients who received liver transplantation [52, 91, 92].

Surgery on the portal vein system should be gentle and accurate. We should prevent unnecessary damage to the vascular endothelium and avoid ligation of chunk tissue. If there is no obvious bleeding tendency, surgeons should not use hemostatic after surgery which may result in thrombosis (**Figure 1**).

## **8. Conclusion**

**6.3. TIPS**

58 Management of Chronic Liver Diseases - Recent Advances

When severe PVT happened, thrombus blocked more than 50% lumen or completely blocked, anticoagulant therapy was unlikely to recanalization. Under this condition, we can choose TIPS. This method has the advantages as the following: the risk of thrombolysis is relatively small, and punctures can often reach directly to the thrombus site; at the same time intravascular technology (balloon plasty, stent replacement, thrombectomy and thrombolytic therapy surgery) can be applied to achieve the goal of treatment of PVT. A study from China which compared transcatheter selective superior mesenteric artery urokinase infusion and TIPS has found they were safe and effective for acute symptomatic PVT in cirrhosis [86]. But the operation was a relative difficult and lethal event as well as severe complications were still possible, so it is particularly important to assess the risk-benefit ratio of TIPS preoperatively. At pres-

**C.** TIPS placement between hepatic vein and collateral vessel → no portal vein recanalization For cirrhotic patients with refractory variceal bleeding and ascites, TIPS was considered as one of the major treatment strategies if the patient did not have PVT. PVT has changed natural history of liver cirrhosis and affected outcomes. So, in this circumstance, TIPS should be recommended with caution. No convincing evidence has been published to verify the superiority of TIPS over traditional anticoagulants. TIPS should only be recommended for severe PVT patients although technical difficulty rose sharply when severe PVT was diagnosed [89]. That means reliable predictors for PVT progression should be further investigated in future.

Surgery is relatively high risk. The commonly used methods are (1) PVT excision; (2) portal vein stent implantation, mainly aimed to relieve portal vein obstruction; (3) liver transplantation. During treatment, if the patient has the sustained abdominal pain, abdominal distension and other signs of peritonitis, laparotomy exploration should be performed early to prevent the occurrence of intestinal necrosis. When intestinal necrosis is diagnosed, intestinal and mesangial resections should be performed. At the same time, the intestinal end-to-end anastomosis should be done. Anticoagulation was continued after surgery to prevent thrombus

Kawanaka et al. have shown that anti-thrombin III (AT III) activity and splenic vein diameter were the risk factors of PVT after surgery. Moreover, they used those risk factors to formulate risk stratification system [90]. According to the risk stratification, doctors can decide whether to give prevention or not: low risk: AT III activity ≥70% and splenic vein straight diameter <10 mm, no preventive treatment; intermediate risk: AT III activity <70% or splenic

ent, the TIPS therapy methods for PVT are the following [87–89]:

**6.4. Surgical treatment of PVT**

reformation.

**7. PVT prevention**

**A.** TIPS placement → portosystemic shunt → portal vein recanalization; **B.** TIPS placement through percutaneous ways portal vein recanalization;

> PVT was a clinical rare deep venous thrombosis but highly occurred in liver cirrhotic patients. Local or systemic factors alone or in combination make contribution to the formation of PVT. In clinical, PVT should be given enough attention due to its severe threat to the patient's

life and health. The overall treatment principles are early diagnosis, early treatment and prevention combined with treatment. In the future, due to the progress in vascular imaging and innovation in clinical anti-thrombotic drug, PVT could be prevented and cured effectively.

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## **Author details**

Shuai Xue, Peisong Wang, Hui Han and Guang Chen\*

\*Address all correspondence to: cg9293@sina.com

The General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China

## **References**


[11] Borjas-Almaguer OD, Cortez-Hernandez CA, Gonzalez-Moreno EI, Bosques-Padilla FJ, Gonzalez-Gonzalez JA, Garza AA, et al. Portal vein thrombosis in patients with cirrhosis: Just a common finding or a predictor of poor outcome? Annals of Hepatology. 2016;**15**(6):902-906

life and health. The overall treatment principles are early diagnosis, early treatment and prevention combined with treatment. In the future, due to the progress in vascular imaging and innovation in clinical anti-thrombotic drug, PVT could be prevented and cured effectively.

The General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China

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66 Management of Chronic Liver Diseases - Recent Advances

2016;**36**(5):667-676


**Chapter 5**

**Provisional chapter**

**Predictors of 50 Day In-Hospital Mortality in**

**Predictors of 50 Day In-Hospital Mortality in** 

**Bacterial Peritonitis**

**Bacterial Peritonitis**

Vikram Bhatia

Vikram Bhatia

**Abstract**

Chinmaya Kumar Bal, Ripu Daman and

Chinmaya Kumar Bal, Ripu Daman and

http://dx.doi.org/10.5772/intechopen.76795

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

spontaneous bacterial peritonitis (SBP).

end stage liver disease sodium

**Decompensated Cirrhosis Patients with Spontaneous**

**Decompensated Cirrhosis Patients with Spontaneous** 

**Aim**: Predictors of 50 day in-hospital mortality in decompensated cirrhosis patients with

**Methods**: 218 SBP patients admitted to intensive care units in a tertiary care hospital were retrospectively analyzed. Student t test, multivariate logistic regression, Cox proportional hazard ratio, receiver operating characteristics curves and Kaplan-Meier survival analysis were utilized for statistical analysis. Predictive powers of the statistical significant variables were compared using the area under receiver operating characteris-

**Results**: SBP related in-hospital mortality rate was 43%. Multivariate regression analysis showed acute kidney injury, hepatic encephalopathy, positive ascitic culture, leucocyte count, bilirubin, serum glutamic oxaloacetic transaminase (SGOT), Child Pugh score, and Model for End stage Liver Disease Sodium (MELD-Na) were significantly associated with 50 day in-hospital mortality. The prognostic accuracy for acute kidney injury,

**Conclusion**: Acute kidney injury, MELD-Na and septic shock were predictors of 50 day

**Keywords:** spontaneous bacterial peritonitis, cirrhosis, acute kidney injury, model for

tics curve (AUC). p values <0.05 were considered statistical significant.

MELD-Na and septic shock was 77, 74 and 71% respectively.

in-hospital mortality in decompensated cirrhotic patients with SBP.

© 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.

DOI: 10.5772/intechopen.76795

#### **Predictors of 50 Day In-Hospital Mortality in Decompensated Cirrhosis Patients with Spontaneous Bacterial Peritonitis Predictors of 50 Day In-Hospital Mortality in Decompensated Cirrhosis Patients with Spontaneous Bacterial Peritonitis**

DOI: 10.5772/intechopen.76795

Chinmaya Kumar Bal, Ripu Daman and Vikram Bhatia Chinmaya Kumar Bal, Ripu Daman and Vikram Bhatia

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.76795

#### **Abstract**

**Aim**: Predictors of 50 day in-hospital mortality in decompensated cirrhosis patients with spontaneous bacterial peritonitis (SBP).

**Methods**: 218 SBP patients admitted to intensive care units in a tertiary care hospital were retrospectively analyzed. Student t test, multivariate logistic regression, Cox proportional hazard ratio, receiver operating characteristics curves and Kaplan-Meier survival analysis were utilized for statistical analysis. Predictive powers of the statistical significant variables were compared using the area under receiver operating characteristics curve (AUC). p values <0.05 were considered statistical significant.

**Results**: SBP related in-hospital mortality rate was 43%. Multivariate regression analysis showed acute kidney injury, hepatic encephalopathy, positive ascitic culture, leucocyte count, bilirubin, serum glutamic oxaloacetic transaminase (SGOT), Child Pugh score, and Model for End stage Liver Disease Sodium (MELD-Na) were significantly associated with 50 day in-hospital mortality. The prognostic accuracy for acute kidney injury, MELD-Na and septic shock was 77, 74 and 71% respectively.

**Conclusion**: Acute kidney injury, MELD-Na and septic shock were predictors of 50 day in-hospital mortality in decompensated cirrhotic patients with SBP.

**Keywords:** spontaneous bacterial peritonitis, cirrhosis, acute kidney injury, model for end stage liver disease sodium

© 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**

SBP is defined as an ascitic fluid infection without an evident intra-abdominal surgicallytreatable source [1]. SBP is a major complication of decompensated cirrhosis with ascites [2]. The diagnosis of SBP is established based on diagnostic paracentesis with an elevated ascitic fluid absolute polymorphonuclear leucocyte (PMN) count (≥250 cells/mm<sup>3</sup> ) and/ or a positive ascitic fluid bacterial culture. The most common pathogens involved are Gram-negative bacteria (60%), usually *Escherichia coli* or *Klebsiella pneumonia* [3]. In about 25% of the cases, Gram-positive bacteria are involved, mainly Streptococcus species and Enterococci [3]. The prevalence of SBP is up to 30% in hospitalized cirrhotic patients with ascites [4]. Despite intensive management, the in-hospital mortality remains between 20 and 40% [5]. MELD scores have clinical utility in terms of predictive ability in SBP patients [6, 7]. Acute kidney injury (AKI) and septic shock are fairly common in patients with decompensated cirrhosis with ascites [8, 9]. Hence our study aimed to have a collective approach to determine common prognostic factors predicting SBP related in-hospital mortality. We also compared the predictive powers of AKI, MELD-Na and septic shock to predict 50 day in-hospital mortality.

No patient underwent fluid restriction or hypertonic saline for management of dilution

Predictors of 50 Day In-Hospital Mortality in Decompensated Cirrhosis Patients…

AKI was defined by AKIN (acute kidney injury network) criteria [8]. AKI was managed by intravenous vasopressors (terlipressin) and intravenous albumin infusions. The dose was titrated as-per response and tolerance. Intravenous albumin was used in all patients, with a minimal daily dose of 20 g and increased to up to 60 g/d [13], titrated by clinical monitoring and hourly urine output. We did not stratify renal dysfunction into hepatorenal syndrome (HRS) and non-hepatorenal syndrome. Renal replacement therapy (RRT) was used at the bedside to correct fluid overload, ascites, and electrolyte dysfunction. We did not consider

We defined septic shock according to the American college of chest physicians/society of criti-

munity with SBP. Patients presented with ascites unrelated to cirrhosis. Patients with second-

All statistical analyses were conducted using Stata version 14 for windows. The continuous clinical and biochemical variables and prognostic scores were expressed as mean ± standard deviation. All the variables were assumed to be normally distributed with equal variance. The means were compared using student's t test. Categorical variables were expressed as proportions and compared with logistics regression. All significant variables were analyzed using multivariate logistics regression. Cox proportional hazard model was used to analyze the hazard ratio of the predictors adjusted by age and gender. Receiver operating characteristics (ROC) curves were plotted for prognostic variables (MELD-Na, AKI and) to measure the predictive accuracy. The best cut-off point for MELD-Na was created using the ROC analysis to determine 50 day in-hospital mortality risk. The sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), positive and negative likelihood ratio were calculated for each predictor variable so that patients could be correctly classified for each prognostic model. For all analyses, p value < 0.05 was considered statistically significant.

A total of 218 patients with decompensated cirrhosis with ascites and SBP were included in the study. Patients that were diagnosed with SBP for the first time were 97% (n = 211) with only 0.03% (n = 7) had more than one episode previously. The 50 day in-hospital mortality

. Patients admitted from the com-

http://dx.doi.org/10.5772/intechopen.76795

71

advanced liver disease as a contraindication to RRT in our patient cohort.

cal care medicine consensus conference [14].

Patients with cirrhosis and ascites fluid PMN <250 cells/mm<sup>3</sup>

STROBE checklist for retrospective analysis was performed.

ary peritonitis, variceal hemorrhage, advanced malignancy and HIV.

hyponatremia.

**2.2. Exclusion criteria**

**2.3. Statistical analysis**

**3. Results**

## **2. Materials and methods**

#### **2.1. Patients**

Retrospective analysis and review of 218 adult patients admitted to hepatology ICU with a diagnosis of SBP was done. The study was approved by the Institutional review Board and was conducted with the provisions of Declaration of Helsinki [10].

The diagnosis of cirrhosis was based on clinical, laboratory and imaging findings. SBP was diagnosed by diagnostic paracentesis in the presence of PMN ≥250 cells/mm<sup>3</sup> in the peritoneal fluid with positive culture report and the absence of the features suggestive of secondary bacterial peritonitis [11].

Data from patient's medical records were collected and tabulated. It comprises of demographics, etiology of liver disease, severity of liver disease, laboratory parameters, co-existing medical conditions (diabetes mellitus, hepatocellular carcinoma), previous medication use, organ failure, ascitic fluid analysis results, duration of ICU stay, and patient outcome. In culturepositive cases growth of the organisms and antibiotic sensitivity were recorded.

MELD-Na score was based on laboratory parameters (bilirubin, creatinine levels and INR) collected at admission and determined by using the Internet site MELD calculator [12]. Diagnostic ascitic tapping was done upon admission to ICU in all patients with ascites except in those with severe coagulopathy. Ascitic fluid was sent for differential cell count and culture. Blood sample was also sent for culture at admission in all patients. Antibiotics administered in patients based on previous antibiotic exposure and based on culture and sensitivity. No patient underwent fluid restriction or hypertonic saline for management of dilution hyponatremia.

AKI was defined by AKIN (acute kidney injury network) criteria [8]. AKI was managed by intravenous vasopressors (terlipressin) and intravenous albumin infusions. The dose was titrated as-per response and tolerance. Intravenous albumin was used in all patients, with a minimal daily dose of 20 g and increased to up to 60 g/d [13], titrated by clinical monitoring and hourly urine output. We did not stratify renal dysfunction into hepatorenal syndrome (HRS) and non-hepatorenal syndrome. Renal replacement therapy (RRT) was used at the bedside to correct fluid overload, ascites, and electrolyte dysfunction. We did not consider advanced liver disease as a contraindication to RRT in our patient cohort.

We defined septic shock according to the American college of chest physicians/society of critical care medicine consensus conference [14].

### **2.2. Exclusion criteria**

**1. Introduction**

70 Management of Chronic Liver Diseases - Recent Advances

in-hospital mortality.

bacterial peritonitis [11].

**2.1. Patients**

**2. Materials and methods**

SBP is defined as an ascitic fluid infection without an evident intra-abdominal surgicallytreatable source [1]. SBP is a major complication of decompensated cirrhosis with ascites [2]. The diagnosis of SBP is established based on diagnostic paracentesis with an elevated ascitic fluid absolute polymorphonuclear leucocyte (PMN) count (≥250 cells/mm<sup>3</sup>

or a positive ascitic fluid bacterial culture. The most common pathogens involved are Gram-negative bacteria (60%), usually *Escherichia coli* or *Klebsiella pneumonia* [3]. In about 25% of the cases, Gram-positive bacteria are involved, mainly Streptococcus species and Enterococci [3]. The prevalence of SBP is up to 30% in hospitalized cirrhotic patients with ascites [4]. Despite intensive management, the in-hospital mortality remains between 20 and 40% [5]. MELD scores have clinical utility in terms of predictive ability in SBP patients [6, 7]. Acute kidney injury (AKI) and septic shock are fairly common in patients with decompensated cirrhosis with ascites [8, 9]. Hence our study aimed to have a collective approach to determine common prognostic factors predicting SBP related in-hospital mortality. We also compared the predictive powers of AKI, MELD-Na and septic shock to predict 50 day

Retrospective analysis and review of 218 adult patients admitted to hepatology ICU with a diagnosis of SBP was done. The study was approved by the Institutional review Board and

The diagnosis of cirrhosis was based on clinical, laboratory and imaging findings. SBP was

fluid with positive culture report and the absence of the features suggestive of secondary

Data from patient's medical records were collected and tabulated. It comprises of demographics, etiology of liver disease, severity of liver disease, laboratory parameters, co-existing medical conditions (diabetes mellitus, hepatocellular carcinoma), previous medication use, organ failure, ascitic fluid analysis results, duration of ICU stay, and patient outcome. In culture-

MELD-Na score was based on laboratory parameters (bilirubin, creatinine levels and INR) collected at admission and determined by using the Internet site MELD calculator [12]. Diagnostic ascitic tapping was done upon admission to ICU in all patients with ascites except in those with severe coagulopathy. Ascitic fluid was sent for differential cell count and culture. Blood sample was also sent for culture at admission in all patients. Antibiotics administered in patients based on previous antibiotic exposure and based on culture and sensitivity.

was conducted with the provisions of Declaration of Helsinki [10].

diagnosed by diagnostic paracentesis in the presence of PMN ≥250 cells/mm<sup>3</sup>

positive cases growth of the organisms and antibiotic sensitivity were recorded.

) and/

in the peritoneal

Patients with cirrhosis and ascites fluid PMN <250 cells/mm<sup>3</sup> . Patients admitted from the community with SBP. Patients presented with ascites unrelated to cirrhosis. Patients with secondary peritonitis, variceal hemorrhage, advanced malignancy and HIV.

### **2.3. Statistical analysis**

All statistical analyses were conducted using Stata version 14 for windows. The continuous clinical and biochemical variables and prognostic scores were expressed as mean ± standard deviation. All the variables were assumed to be normally distributed with equal variance. The means were compared using student's t test. Categorical variables were expressed as proportions and compared with logistics regression. All significant variables were analyzed using multivariate logistics regression. Cox proportional hazard model was used to analyze the hazard ratio of the predictors adjusted by age and gender. Receiver operating characteristics (ROC) curves were plotted for prognostic variables (MELD-Na, AKI and) to measure the predictive accuracy. The best cut-off point for MELD-Na was created using the ROC analysis to determine 50 day in-hospital mortality risk. The sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), positive and negative likelihood ratio were calculated for each predictor variable so that patients could be correctly classified for each prognostic model. For all analyses, p value < 0.05 was considered statistically significant. STROBE checklist for retrospective analysis was performed.

## **3. Results**

A total of 218 patients with decompensated cirrhosis with ascites and SBP were included in the study. Patients that were diagnosed with SBP for the first time were 97% (n = 211) with only 0.03% (n = 7) had more than one episode previously. The 50 day in-hospital mortality


rate was 43.11% (n = 94). Median survival duration for those who died was 9 days. In univariate analysis AKI, hepatic encephalopathy, total leucocyte count, serum bilirubin, INR, SGOT, and MELD-Na are significantly associated with in hospital mortality in patients with SBP

**Table 1.** Baseline characteristics of the hospitalized patients with spontaneous bacterial peritonitis in decompensated

**Variables Overall (n = 218) Survivors (n = 124) Deaths (n = 94) P-value** MELD 24.79 ± 8.28 22.20 ± 7.59 28.20 ± 7.94 <0.001 MELD-Na 27.53 ± 7.57 25.21 ± 7.44 30.59 ± 6.62 <0.001

Predictors of 50 Day In-Hospital Mortality in Decompensated Cirrhosis Patients…

http://dx.doi.org/10.5772/intechopen.76795

73

The baseline characteristics of the demographics, etiology, clinical and laboratory data shown in **Table 1**. Mean age was 49.90 ± 12.52 years and the male was predominant (83%). Most common etiology of liver cirrhosis was ethanol induced (45.87%) followed by crypto/ NAFLD (28.9%). Liver cirrhosis due to HCV infection constitute only 11% in our study. Total 50.0% patients (n = 109) had hepatic encephalopathy with 62.77% deaths (n = 59, p = 0.001). Overall 45.11% subjects (n = 99) had AKI who were hospitalized, out of which 68.09% (n = 64, p ≤ 0.001) died. Compared with survivors, the non-survivors had a higher proportion of septic shock (25.53 vs. 3.23%), p < 0.001. Mean leucocyte count, bilirubin, INR, AST were significantly higher in the persons who died in comparing to the survivors. Mean MELD-Na score was higher among the non-survivors compared with the survivors (30.59 ± 6.62 vs. 25.21 ± 7.44) (p < 0.001). It is surprising to notice that CTP (B/C) score was not different among the survivors and non-survivors. The mean CTP scores were high

On multivariate regression analysis, AKI (p = 0.001), septic shock (p = 0.029), MELD-Na (p<0.001) were found to be independent predictors of 50 day in-hospital mortality in patients with SBP (**Table 2**). Cox proportional hazard model showed the hazard ratio of AKI was 2.16 (95% CI = 1.36–3.42), septic shock (HR 1.73, 95% CI = 1.05–2.83) and MELD-Na (HR 1.1, 95% CI = 1.02–1.21). ROC curve for AKI, septic shock and MELD-Na had better prognostic

**P value**

(**Table 1**).

\*

cirrhosis.

Results obtained on the day of diagnosis of SBP.

(10.72 ± 1.82).

\*

**Variables Hazard ratio\***

Hazard ratio adjusted for age and gender.

**(95% CI)**

AKI, acute kidney injury; MELD-Na, model for end-stage liver disease sodium.

AKI 2.16 (1.36–3.42) 0.001 Septic shock 1.73 (1.05–2.83) 0.029 MELD-Na 1.06 (1.02–1.09) <0.001

**Table 2.** Cox proportional regression analysis of risk factors for SBP related in-hospital related mortality.


**Variables Overall (n = 218) Survivors (n = 124) Deaths (n = 94) P-value**

Age (yrs) mean ± SD 49.90 ± 12.52 49.86 ± 13.37 49.96 ± 11.37 0.950 Male (%) 177 (81.19%) 99 (79.84%) 78 (82.98%) 0.557

Ethanol 100 (45.87%) 48 (38.71%) 52 (55.32%) 0.689 Crypto/NAFLD 63 (28.90%) 38 (30.65%) 25 (26.60%) 0.104 HCV 23 (10.55%) 16 (12.905) 7 (7.45%) 0.068

Diabetes 47 (21.56%) 27 (21.77%) 20 (21.28%) 0.929 Acute kidney injury 99 (45.41%) 35 (28.23%) 64 (68.09%) <0.001 Respiratory failure 10 (4.59%) 6 (4.84%) 4 (4.26%) 0.978

Septic shock 28 (12.84%) 4 (3.23%) 24 (25.53%) <0.001 Positive culture 48 (22.02%) 21 (16.94%) 27 (28.72%) 0.038

Hemoglobin (g/dl) 9.42 ± 1.88 9.58 ± 1.77 9.21 ± 2.01 0.154

Sodium (mEq/L) 132.14 ± 7.69 132.50 ± 6.54 131.67 ± 9.01 0.454 Bilirubin (mg/dL) 8.17 ± 8.81 5.85 ± 6.27 11.24 ± 10.61 <0.001 Albumin (g/dL) 2.32 ± 0.50 2.35 ± −0.48 2.28 ± 0.52 0.250 INR 2.31 ± 1.11 2.09 ± 1.08 2.59 ± 1.08 0.001 AST (U/L) 59.66 ± 109.81 79.23 ± 98.71 171.3 ± 321.94 0.003 ALT (U/L) 59.66 ± 109.81 46.49 ± 72.93 77.04 ± 143.41 0.041 Urea (mg/dL) 70.31 ± 52.42 62.24 ± 48.23 80.94 ± 55.98 0.008 Creatinine (mg/dL) 1.67 ± 1.29 1.58 ± 1.39 1.80 ± 1.15 0.217

CTP (B/C) 10.72 ± 1.82 10.50 ± 1.95 11.02 ± 1.60 0.034

17 (7.80%) 9 (7.26%) 8 (8.51%) 0.733

109 (50.0%) 50 (40.32%) 59 (62.77%) 0.001

3346.07 ± 4700.60 3899.28 ± 5003.75 2616.30 ± 4182.81 0.040

128.24 ± 102.11 138.43 ± 111.25 115.03 ± 87.69 0.095

13.30 ± 9.35 11.86 ± 8.65 15.17 ± 9.92 0.009

*Demographic data*

72 Management of Chronic Liver Diseases - Recent Advances

*Etiology of cirrhosis* (%)

*Clinical data* (%) Hepatocellular carcinoma

Hepatic encephalopathy

*Laboratory data*\*

Platelet count (mmol/L)

Leucocyte count

*Scores* (*mean* ± *SD*)

(103 /μL)

Ascitic neutrophil count (cells/mm<sup>3</sup>

(*mean* ± *SD*)

)

**Table 1.** Baseline characteristics of the hospitalized patients with spontaneous bacterial peritonitis in decompensated cirrhosis.

rate was 43.11% (n = 94). Median survival duration for those who died was 9 days. In univariate analysis AKI, hepatic encephalopathy, total leucocyte count, serum bilirubin, INR, SGOT, and MELD-Na are significantly associated with in hospital mortality in patients with SBP (**Table 1**).

The baseline characteristics of the demographics, etiology, clinical and laboratory data shown in **Table 1**. Mean age was 49.90 ± 12.52 years and the male was predominant (83%). Most common etiology of liver cirrhosis was ethanol induced (45.87%) followed by crypto/ NAFLD (28.9%). Liver cirrhosis due to HCV infection constitute only 11% in our study. Total 50.0% patients (n = 109) had hepatic encephalopathy with 62.77% deaths (n = 59, p = 0.001). Overall 45.11% subjects (n = 99) had AKI who were hospitalized, out of which 68.09% (n = 64, p ≤ 0.001) died. Compared with survivors, the non-survivors had a higher proportion of septic shock (25.53 vs. 3.23%), p < 0.001. Mean leucocyte count, bilirubin, INR, AST were significantly higher in the persons who died in comparing to the survivors. Mean MELD-Na score was higher among the non-survivors compared with the survivors (30.59 ± 6.62 vs. 25.21 ± 7.44) (p < 0.001). It is surprising to notice that CTP (B/C) score was not different among the survivors and non-survivors. The mean CTP scores were high (10.72 ± 1.82).

On multivariate regression analysis, AKI (p = 0.001), septic shock (p = 0.029), MELD-Na (p<0.001) were found to be independent predictors of 50 day in-hospital mortality in patients with SBP (**Table 2**). Cox proportional hazard model showed the hazard ratio of AKI was 2.16 (95% CI = 1.36–3.42), septic shock (HR 1.73, 95% CI = 1.05–2.83) and MELD-Na (HR 1.1, 95% CI = 1.02–1.21). ROC curve for AKI, septic shock and MELD-Na had better prognostic


**Table 2.** Cox proportional regression analysis of risk factors for SBP related in-hospital related mortality.

**Figure 1.** Receiver operator characteristic (ROC) curve for AKI, septic shock and MELD-Na had better prognostic accuracy for 50 day in-hospital mortality in patients with SBP.


**4. Discussion**

prognostic variables like AKI, MELD-Na, and septic shock.

The prevalence of SBP in outpatients has been reported to be 1.5–3.5% [15]. The prevalence among in-patients is around 10% [16]. Half of the episodes of SBP are nosocomial related. In our retrospective observational study 43% (n = 93) of the decompensated cirrhotic patients with SBP died within 50 day of hospital admission. Our study considered a variety of prognostic factors that can be used to predict mortality in hospitalized patient with SBP. Our findings support previous study results that variables like hepatic encephalopathy, total leucocyte count, serum bilirubin, SGOT, INR, Child Pugh scores are significantly associated with mortality [5, 6]. The MELD score was found to be an independent predictor of death in cirrhotic patients [7] including those waiting for liver transplantation. MELD-Na is a better prognostic model compared with MELD model [17] for predictive accuracy of mortality in liver cirrhosis. Serum creatinine level measurement for renal dysfunction in decompensated liver cirrhosis is erroneous. It can be due to decrease in creatinine production in liver and associated muscle wasting due to malnutrition [18]. We found that AKI, MELD-Na and septic shock are significant in terms of predicting mortality. We overlooked other predictable variables like total leucocyte count, serum bilirubin, INR to avoid confusion and complexity as those were the

**Figure 2.** Kaplan-Meier survival analysis was plotted for the 50 day survival in SBP patients along with individual

Predictors of 50 Day In-Hospital Mortality in Decompensated Cirrhosis Patients…

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75

components in our predictive model like MELD-Na and septic shock.

1 Cut off score for MELD-Na, PPV: positive predictive value, NPV: negative predictive value, +LR: positive likelihood ratio, −LR: negative likelihood ratio, AKI: acute kidney injury, MELD-Na: model for end stage liver disease sodium.

**Table 3.** Diagnostic accuracy of prognostic variables to predict SBP related in-hospital mortality.

accuracy for 50 day in-hospital mortality in patients with SBP (**Figure 1**). AKI had highest Area Under Curve (AUC) 0.77, 95% confidence interval (95% CI = 0.71–0.83), followed by MELD-Na (AUC 0.74, 95% CI=0.69–0.79), septic shock (AUC 0.71, 95% CI=0.65–0.77). **Table 3** reported the sensitivity, specificity, PPV, NPV, positive likelihood ratio (+LR) and negative likelihood ratio (−LR) for these predictors. The cut off for MELD-Na derived from the ROC with the best ability to predict 50 day in-hospital mortality in decompensated cirrhotic patient with SBP was 28, with sensitivity 92.9%, specificity 60.3%, and NPV of 97.9%. The Kaplan-Meier survival analysis was plotted for the 50 day survival in SBP patients along with individual prognostic variables like AKI, MELD-Na, and septic shock (**Figure 2**).

Predictors of 50 Day In-Hospital Mortality in Decompensated Cirrhosis Patients… http://dx.doi.org/10.5772/intechopen.76795 75

**Figure 2.** Kaplan-Meier survival analysis was plotted for the 50 day survival in SBP patients along with individual prognostic variables like AKI, MELD-Na, and septic shock.

## **4. Discussion**

accuracy for 50 day in-hospital mortality in patients with SBP (**Figure 1**). AKI had highest Area Under Curve (AUC) 0.77, 95% confidence interval (95% CI = 0.71–0.83), followed by MELD-Na (AUC 0.74, 95% CI=0.69–0.79), septic shock (AUC 0.71, 95% CI=0.65–0.77). **Table 3** reported the sensitivity, specificity, PPV, NPV, positive likelihood ratio (+LR) and negative likelihood ratio (−LR) for these predictors. The cut off for MELD-Na derived from the ROC with the best ability to predict 50 day in-hospital mortality in decompensated cirrhotic patient with SBP was 28, with sensitivity 92.9%, specificity 60.3%, and NPV of 97.9%. The Kaplan-Meier survival analysis was plotted for the 50 day survival in SBP patients along with individual prognostic variables like AKI, MELD-Na, and septic shock

**Table 3.** Diagnostic accuracy of prognostic variables to predict SBP related in-hospital mortality.

accuracy for 50 day in-hospital mortality in patients with SBP.

74 Management of Chronic Liver Diseases - Recent Advances

Cut off score for MELD-Na, PPV: positive predictive value, NPV: negative predictive value, +LR: positive likelihood ratio, −LR: negative likelihood ratio, AKI: acute kidney injury, MELD-Na: model for end stage liver disease sodium.

**Predictors Sensitivity Specificity PPV NPV +LR −LR** AKI 64.6 74.8 68.1 71.8 2.56 0.47 Septic shock 85.7 63.2 25.5 96.8 2.33 0.23 MELD-Na(28)<sup>1</sup> 92.9 60.3 24.5 97.9 2.34 0.12

**Figure 1.** Receiver operator characteristic (ROC) curve for AKI, septic shock and MELD-Na had better prognostic

(**Figure 2**).

1

The prevalence of SBP in outpatients has been reported to be 1.5–3.5% [15]. The prevalence among in-patients is around 10% [16]. Half of the episodes of SBP are nosocomial related. In our retrospective observational study 43% (n = 93) of the decompensated cirrhotic patients with SBP died within 50 day of hospital admission. Our study considered a variety of prognostic factors that can be used to predict mortality in hospitalized patient with SBP. Our findings support previous study results that variables like hepatic encephalopathy, total leucocyte count, serum bilirubin, SGOT, INR, Child Pugh scores are significantly associated with mortality [5, 6]. The MELD score was found to be an independent predictor of death in cirrhotic patients [7] including those waiting for liver transplantation. MELD-Na is a better prognostic model compared with MELD model [17] for predictive accuracy of mortality in liver cirrhosis. Serum creatinine level measurement for renal dysfunction in decompensated liver cirrhosis is erroneous. It can be due to decrease in creatinine production in liver and associated muscle wasting due to malnutrition [18]. We found that AKI, MELD-Na and septic shock are significant in terms of predicting mortality. We overlooked other predictable variables like total leucocyte count, serum bilirubin, INR to avoid confusion and complexity as those were the components in our predictive model like MELD-Na and septic shock.

Our study demonstrated that AKI has the single best predictive ability (AUC = 0.77) followed by MELD-Na (AUC = 0.74) and septic shock (AUC = 0.71). We set a cut-off value for MELD-Na to be 28. It has sensitivity 92.9% and NPV of 97.9%. AKI has the highest hazards of mortality (HR 2.16, 95% CI 1.36–3.42) followed by septic shock (HR 1.73, 95% CI 1.05–2.83) and MELD-Na (HR 1.06, 95% 1.02–1.09). We plotted graph of Kaplan-Meier survival analysis. The graph illustrated AKI, MELD-Na, and septic shock as predictors for the 50 day in-hospital mortality in decompensated patients with SBP. We hope that these prognostic variables can help in the further improvement of the quality of care of hospitalized SBP patients. The cut-off value 28 for MELD-Na can be utilized to stratify patients diagnosed with SBP into high risk category upon hospital admission.

our patients according to different stages of AKI as per AKIN criteria. We did not take HRS into account in our study. The standard first line antibiotics were not used in the treatment of SBP. The choice of antibiotics coverage based of culture sensitivity and previous exposure. We did not thoroughly evaluate the antibiotic resistance in SBP patients who are culture positive at the baseline. We included only nosocomial acquired SBP. Most of our patients presented with advanced decompensated liver cirrhosis at the time of SBP diagnosis as it is a tertiary care center. The advanced liver cirrhosis was assessed by lower serum albumin, high serum bilirubin and INR values. As an observational study we were unable to assess the impact of volume expansion and SBP specific therapy on patient outcome. Our study is a single center study,

Predictors of 50 Day In-Hospital Mortality in Decompensated Cirrhosis Patients…

http://dx.doi.org/10.5772/intechopen.76795

77

Our study findings can guide in advanced liver cirrhosis patients that would benefit them

these findings needed to be supplemented by multicenter prospective studies.

Department of Hepatology, Institute of Liver and Biliary Science, New Delhi, India

[1] Rimola A, García-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, Inadomi JM. Diagnosis treatment and prophylaxis of spontaneous bacterial peritonitis: A consensus document. International Ascites Club. Journal of Hepatology. 2000;**32**:142-153. DOI:

[2] Such J, Runyon BA. Spontaneous bacterial peritonitis. Clinical Infectious Diseases.

[3] Dever JB, Sheikh MY. Review article: Spontaneous bacterial peritonitis-bacteriology, diagnosis, treatment, risk factors and prevention. Alimentary Pharmacology & Therap-

[4] Gunjaca I, Francetić I. Prevalence and clinical outcome of spontaneous bacterial peritonitis in hospitalized patients with liver cirrhosis: A prospective observational study in

[5] Thuluvath PJ, Morss S, Thompson R. Spontaneous bacterial peritonitis in-hospital mortality, predictors of survival, and health care costs from 1988 to 1998. The American Journal of Gastroenterology. 2001;**96**:1232-1236. DOI: 10.1111/j.1572-0241.2001.03708.x [6] Dănulescu RM, Stanciu C, Trifan A. Evaluation of prognostic factors in decompensated liver cirrhosis with ascites and spontaneous bacterial peritonitis. Revista Medico-

Chirurgicală̆ a Societă̆ţ̜ii de Medici ş̧i Naturaliş̧ti din Iaş̧i. 2015;**119**(4):1018-1024

from intensive management where liver transplant is not feasible.

Chinmaya Kumar Bal\*, Ripu Daman and Vikram Bhatia \*Address all correspondence to: chinmaya.bal@gmail.com

10.1016/S0168-8278(00)80201-9

1998;**27**(4):669-674 quiz 675-6

eutics. 2015;**41**(11):1116-1131. DOI: 10.1111/apt.13172

central part of Croatia. Acta Clinica Croatica. 2010;**49**(1):11-18

**Author details**

**References**

Diagnosis of SBP is based on the demonstration of an absolute number of polymorphonuclear cells in ascitic fluid equal to or greater than 250/mm<sup>3</sup> with culture positivity. There is a controversy regarding antibiotic therapy in culture positivity with normal ascitic fluid PMN count (bacteriascites). Runyon et al. recommend antibiotic treatment only if the patient shows signs of infection [2]. The first-line of choice antibiotics for treatment of SBP include third generation cephalosporins, amoxicillin-clavulanic acid, ciprofloxacin, and ofloxacin [19]. There is increasing evidence of antibiotic resistance [20].

In our study ascitic fluid culture is positive in 40% of all cases. The most common growth include Gram-negative bacteria (GNB), mostly *Escherichia coli* and Gram-positive cocci (mainly streptococcus species and enterococci) [3]. The epidemiology of bacterial infections differs between community-acquired (in which GNB infections predominate) and nosocomial infections (in which Gram-positive infections predominate) [3]. The infections resistant to first lines of antibiotics are usually caused by *Enterococcus faecium* and extended-spectrum β-lactamase (ESBL) organism like Enterobacteriaceae [21]. There are compelling evidence that nosocomial SBP should be treated with carbapenems or with tigecycline [22].

We included only nosocomial SBP patients in our study because most of the ICU admissions includes referred patients from other hospitals, with a variable but inconsistent antibiotic exposure. Only a minority of our patients are admitted directly from the community, and usually to the wards and not to the ICU. Hospital-acquired infections due to a higher incidence of multidrug resistance (third-generation cephalosporins) were an independent predictor of death [23]. These results are in keeping with recent data showing higher rates of drug resistance in patients with nosocomial SBP and increased rates of and death in patients with multidrug resistance [24].

Dr. Garcia-Tsao recently reviewed 18 studies, and reported that the most common predictors of death were renal dysfunction, lack of SBP resolution, immunosuppressive factors, and hospital-acquired SBP [24]. It identified renal dysfunction and levels of blood urea nitrogen and creatinine as the most important variables. The mortality rate among patients with renal dysfunction was 67%, compared with only 11% of patients who maintained normal renal function. Renal dysfunction was defined somewhat variably in the studies, but most defined it as a creatinine level greater than 1.5 mg/dL.

Our study has certain strengths and limitations. The results clearly show that AKI has greater predictive ability than septic shock and MELD-Na as far as 50 day in-hospital mortality in SBP patient is concerned. Our study did not account for the stages of ascites. We did not stratify our patients according to different stages of AKI as per AKIN criteria. We did not take HRS into account in our study. The standard first line antibiotics were not used in the treatment of SBP. The choice of antibiotics coverage based of culture sensitivity and previous exposure. We did not thoroughly evaluate the antibiotic resistance in SBP patients who are culture positive at the baseline. We included only nosocomial acquired SBP. Most of our patients presented with advanced decompensated liver cirrhosis at the time of SBP diagnosis as it is a tertiary care center. The advanced liver cirrhosis was assessed by lower serum albumin, high serum bilirubin and INR values. As an observational study we were unable to assess the impact of volume expansion and SBP specific therapy on patient outcome. Our study is a single center study, these findings needed to be supplemented by multicenter prospective studies.

Our study findings can guide in advanced liver cirrhosis patients that would benefit them from intensive management where liver transplant is not feasible.

## **Author details**

Our study demonstrated that AKI has the single best predictive ability (AUC = 0.77) followed by MELD-Na (AUC = 0.74) and septic shock (AUC = 0.71). We set a cut-off value for MELD-Na to be 28. It has sensitivity 92.9% and NPV of 97.9%. AKI has the highest hazards of mortality (HR 2.16, 95% CI 1.36–3.42) followed by septic shock (HR 1.73, 95% CI 1.05–2.83) and MELD-Na (HR 1.06, 95% 1.02–1.09). We plotted graph of Kaplan-Meier survival analysis. The graph illustrated AKI, MELD-Na, and septic shock as predictors for the 50 day in-hospital mortality in decompensated patients with SBP. We hope that these prognostic variables can help in the further improvement of the quality of care of hospitalized SBP patients. The cut-off value 28 for MELD-Na can be utilized to stratify patients diagnosed with SBP into high risk

Diagnosis of SBP is based on the demonstration of an absolute number of polymorphonuclear

versy regarding antibiotic therapy in culture positivity with normal ascitic fluid PMN count (bacteriascites). Runyon et al. recommend antibiotic treatment only if the patient shows signs of infection [2]. The first-line of choice antibiotics for treatment of SBP include third generation cephalosporins, amoxicillin-clavulanic acid, ciprofloxacin, and ofloxacin [19]. There is

In our study ascitic fluid culture is positive in 40% of all cases. The most common growth include Gram-negative bacteria (GNB), mostly *Escherichia coli* and Gram-positive cocci (mainly streptococcus species and enterococci) [3]. The epidemiology of bacterial infections differs between community-acquired (in which GNB infections predominate) and nosocomial infections (in which Gram-positive infections predominate) [3]. The infections resistant to first lines of antibiotics are usually caused by *Enterococcus faecium* and extended-spectrum β-lactamase (ESBL) organism like Enterobacteriaceae [21]. There are compelling evidence that

We included only nosocomial SBP patients in our study because most of the ICU admissions includes referred patients from other hospitals, with a variable but inconsistent antibiotic exposure. Only a minority of our patients are admitted directly from the community, and usually to the wards and not to the ICU. Hospital-acquired infections due to a higher incidence of multidrug resistance (third-generation cephalosporins) were an independent predictor of death [23]. These results are in keeping with recent data showing higher rates of drug resistance in patients with nosocomial SBP and increased rates of and death in patients with multidrug resistance [24]. Dr. Garcia-Tsao recently reviewed 18 studies, and reported that the most common predictors of death were renal dysfunction, lack of SBP resolution, immunosuppressive factors, and hospital-acquired SBP [24]. It identified renal dysfunction and levels of blood urea nitrogen and creatinine as the most important variables. The mortality rate among patients with renal dysfunction was 67%, compared with only 11% of patients who maintained normal renal function. Renal dysfunction was defined somewhat variably in the studies, but most defined

Our study has certain strengths and limitations. The results clearly show that AKI has greater predictive ability than septic shock and MELD-Na as far as 50 day in-hospital mortality in SBP patient is concerned. Our study did not account for the stages of ascites. We did not stratify

nosocomial SBP should be treated with carbapenems or with tigecycline [22].

with culture positivity. There is a contro-

category upon hospital admission.

76 Management of Chronic Liver Diseases - Recent Advances

cells in ascitic fluid equal to or greater than 250/mm<sup>3</sup>

increasing evidence of antibiotic resistance [20].

it as a creatinine level greater than 1.5 mg/dL.

Chinmaya Kumar Bal\*, Ripu Daman and Vikram Bhatia

\*Address all correspondence to: chinmaya.bal@gmail.com

Department of Hepatology, Institute of Liver and Biliary Science, New Delhi, India

## **References**


[7] Nobre SR, Cabral JE, Gomes JJ, Leitão MC. In-hospital mortality in spontaneous bacterial peritonitis: A new predictive model. European Journal of Gastroenterology & Hepatology. 2008;**20**:1176-1181. DOI: 10.1097/MEG.0b013e32830607a2

[20] Cheong HS, Kang CI, Lee JA, et al. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clinical

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[21] Ariza X, Castellote J, Lora-Tamayo J, Girbau A, Salord S, Rota R, et al. Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous bacterial peritonitis. Journal of Hepatology. 2012;**56**:825-832. DOI:

[22] Fernández J, Acevedo J, Castro M, Garcia O, de Lope CR, Roca D, Pavesi M, Sola E, Moreira L, Silva A, Seva-Pereira T, Corradi F, Mensa J, Ginès P, Arroyo V. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: A prospective study.

[23] Umgelter A, Reindl W, Miedaner M, Schmid RM, Huber W. Failure of current antibiotic first-line regimens and mortality in hospitalized patients with spontaneous bacterial

[24] Tandon P, Garcia-Tsao G. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clinical Gastroenterology and Hepatology. 2011;**9**(**3**):260-265. DOI: 10.1016/j.cgh.2010.11.038

Infectious Diseases. 2009;**48**:1230-1236. DOI: 10.1086/597585

Hepatology. 2012;**55**:1551-1561. DOI: 10.1002/hep.25532

peritonitis. Infection. 2009;**37**:2-8. DOI: 10.1007/s15010-008-8060-9

10.1016/j.jhep.2011.11.010


[20] Cheong HS, Kang CI, Lee JA, et al. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clinical Infectious Diseases. 2009;**48**:1230-1236. DOI: 10.1086/597585

[7] Nobre SR, Cabral JE, Gomes JJ, Leitão MC. In-hospital mortality in spontaneous bacterial peritonitis: A new predictive model. European Journal of Gastroenterology &

[8] de Araujo A, Alvares-da-Silva MR. Akin criteria as a predictor of mortality in cirrhotic patients after spontaneous bacterial peritonitis. Annals of Hepatology. 2014;**13**(3):390-395

[9] Moreau R, Hadengue A, Soupison T, Kirstetter P, Mamzer MF, Vanjak D, et al. Septic shock in patients with cirrhosis: Hemodynamic and metabolic characteristics and inten-

[10] WMA declaration of Helsinki-ethical principles for medical research involving human subjects [internet]. 2013. Available from: https://www.wma.net/what-we-do/education/

[11] Runyon BA. The evolution of ascitic fluid analysis in the diagnosis of spontaneous bacterial peritonitis. The American Journal of Gastroenterology. 2003;**98**(8):1675-1677

[12] MELDNa/MELD-Na Score for Liver Cirrhosis [Internet]. 2016. Available from: https:// www.mdcalc.com/meldna-meld-na-score-liver-cirrhosis [Accessed: 2018-03-19]

[13] de Mattos A. Current indicators for use of albumin in the treatment of cirrhosis. Annals

[14] Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. DOI: 10.1378/

[15] Chu CM, Chang KY, Liaw YF. Prevalence and prognostic significance of bacterascites in

[16] Terg R, Gadano A, Cartier M et al. Serum creatinine and bilirubin predict renal failure and mortality in patients with spontaneous bacterial peritonitis: A retrospective study.

[17] Musskopf MI, Fonseca FP, Gass J, de Mattos AZ, John JA, de Mello Brandão AB.Prognostic factors associated with in-hospital mortality in patients with spontaneous bacterial peri-

[18] MacAulay J, Thompson K, Kiberd BA, Barnes DC, Peltekian KM. Serum creatinine in patients with advanced liver disease is of limited value for identification of moderate renal dysfunction: Are the equations for estimating renal function better? Canadian

[19] European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology. 2010;**53**(3):397-417. DOI: 10.1016/j.jhep.2010.05.004

cirrhosis with ascites. Digestive Diseases and Sciences. 1995;**40**(3):561-565

Hepatology. 2008;**20**:1176-1181. DOI: 10.1097/MEG.0b013e32830607a2

sive care unit outcome. Critical Care Medicine. 1992;**20**(6):746-750

medical-ethics-manual [Accessed: 2018-03-19]

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of Hepatology. 2011;**10**(Suppl. 1):S15-S20

Liver International. 2009;**29**:415-19

tonitis. Annals of Hepatology. 2012;**11**(6):915-920

Journal of Gastroenterology. 2006;**20**(8):521-526

chest.101.6.1644


**Section 3**

**Hepatocellular Carcinoma**

**Hepatocellular Carcinoma**

**Chapter 6**

**Provisional chapter**

**Stereotactic Body Radiation Therapy for Hepatocellular**

**Stereotactic Body Radiation Therapy for Hepatocellular** 

In the medically inoperable patients with solitary hepatocellular carcinoma (HCC), local therapies, such as radiofrequency ablation and transarterial chemoembolization, are used as alternatives. However, several factors, including anatomic and vascular variants, make procedures more challenging. Radiotherapy has historically been used as a palliative option for unresectable HCC. However, recent advances in modern radiotherapy, such as stereotactic body radiation therapy (SBRT), have dramatically increased the use of radiotherapy as a curative modality, particularly in cases ineligible for local ablation therapy or surgical resection. SBRT is a modern approach for delivering ablative high doses of irradiation in small volumes. SBRT in liver tumors, including HCC, provided local control with potential survival benefits in patients with inoperable status. However, the following issues remain to be addressed: the difference between primary and metastatic liver cancers; SBRT-related toxicity and prevention; pathological features of liver cancers; and potential SBRT strategies, including radiobiology-based SBRT and SBRT combined with immunotherapy. We summarized the effectiveness of SBRT and patient tolerance of the therapy. In addition, we present the current status and future perspective of SBRT as a treatment option for HCC.

**Keywords:** radiotherapy, stereotactic body radiation therapy, stereotactic ablative

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver [1]. Liver cancers have the seventh highest age-adjusted incidence rate in the world, with 0.8 million cases diagnosed a year [2]. The development of cirrhosis is associated with a high risk for developing HCC with most common risk factors including alcohol, viral hepatitis such

radiotherapy, hepatocellular carcinoma, cirrhosis, liver

© 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.

DOI: 10.5772/intechopen.76505

**Carcinoma in Cirrhotic Liver**

**Carcinoma in Cirrhotic Liver**

http://dx.doi.org/10.5772/intechopen.76505

**Abstract**

**1. Introduction**

Hiroshi Doi, Hiroya Shiomi and Ryoong-Jin Oh

Hiroshi Doi, Hiroya Shiomi and Ryoong-Jin Oh

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver**

DOI: 10.5772/intechopen.76505

Hiroshi Doi, Hiroya Shiomi and Ryoong-Jin Oh Hiroshi Doi, Hiroya Shiomi and Ryoong-Jin Oh

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.76505

#### **Abstract**

In the medically inoperable patients with solitary hepatocellular carcinoma (HCC), local therapies, such as radiofrequency ablation and transarterial chemoembolization, are used as alternatives. However, several factors, including anatomic and vascular variants, make procedures more challenging. Radiotherapy has historically been used as a palliative option for unresectable HCC. However, recent advances in modern radiotherapy, such as stereotactic body radiation therapy (SBRT), have dramatically increased the use of radiotherapy as a curative modality, particularly in cases ineligible for local ablation therapy or surgical resection. SBRT is a modern approach for delivering ablative high doses of irradiation in small volumes. SBRT in liver tumors, including HCC, provided local control with potential survival benefits in patients with inoperable status. However, the following issues remain to be addressed: the difference between primary and metastatic liver cancers; SBRT-related toxicity and prevention; pathological features of liver cancers; and potential SBRT strategies, including radiobiology-based SBRT and SBRT combined with immunotherapy. We summarized the effectiveness of SBRT and patient tolerance of the therapy. In addition, we present the current status and future perspective of SBRT as a treatment option for HCC.

**Keywords:** radiotherapy, stereotactic body radiation therapy, stereotactic ablative radiotherapy, hepatocellular carcinoma, cirrhosis, liver

## **1. Introduction**

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver [1]. Liver cancers have the seventh highest age-adjusted incidence rate in the world, with 0.8 million cases diagnosed a year [2]. The development of cirrhosis is associated with a high risk for developing HCC with most common risk factors including alcohol, viral hepatitis such

© 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.

as hepatitis C virus (HCV), and nonalcoholic fatty liver disease (NAFLD). Due to the wide prevalence of HCC, it carries a significant economic burden on society at large, especially in the East Asian countries that have hepatitis B virus (HBV). Surveillance programs halve also been implemented to screen for HCC in high-risk individuals, which is more cost-effective than the treatment of HCC. Hepatotropic viruses such as HBV and HCV have a strong association with the development of HCC; thus, the worldwide distribution of HCC mirrors the distributions of such viral infections [3]. Around 80–90% of HCC cases occur in the setting of underlying cirrhosis [4]. In addition, there is an incremental effect of the presence of more than one risk factor responsible for HCC as the presence of HBV/HCV coinfections increases the risk of HCC by two- to sixfolds. Similarly, alcohol abuse further increases this risk [5, 6]. Subsequently, we describe the role of radiotherapy in the treatment of HCC, including conventional to modern techniques, possible beneficial cases of radiotherapy, and future direction of liver stereotactic body radiation therapy (SBRT).

**3. SBRT for HCC**

Advantages

duct

medical cost

Current issues

• High possibility of local control

which are difficult to puncture

• Effects of re-irradiation are unclear

**Table 1.** Features of SBRT for liver tumors.

The use of SBRT for extracranial tumors was developed by Blomgren et al. [17]. The major feature that distinguishes SBRT from conventional radiation treatment is the delivery of large doses of radiation in a few fractions, which results in a high biologically effective dose (BED). In addition, Zheng et al. have reported that a shortened delivery time could significantly increase the cell killing using *in vitro* experimentation [41]. The use of a high precision technique is critical to deliver a high dose of radiation to the target and keep rapid fall-off doses away from the target, thereby achieving a maximum treatment efficacy with minimal toxicity to normal tissues [42]. SBRT is now widely accepted as a treatment option for lung and liver

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver

http://dx.doi.org/10.5772/intechopen.76505

85

Current advantages and challenges of SBRT in the liver are presented in **Table 1**. The clinical outcomes of SBRT for HCC in the previous reports are shown in **Table 2**. SBRT has been reported to provide 1-, 2-, and 3-year local control rates of 56–100, 53–95, and 51–92%, and 1-, 2-, and 3-year survival rates of 32–100, 55–100, and 21–82% for HCC, respectively [19–38]. **Figure 1** indicates the local control and overall survival after SBRT, BED<sup>10</sup> ≥ 75 Gy in ≤10 fractions (e.g., 40 Gy/4 fr), for HCC at our institute. **Figure 2** indicates a typical course of SBRT for HCC in cirrhotic liver. Recent reports indicated that SBRT was as effective as TACE and RFA, although there are only a small number of randomized trials examining the use of SBRT in HCC [34, 35, 38]. However, additional prospective studies involving large sample sizes are

required to consolidate the evidences on SBRT with aim to standardize liver SBRT.

• High possibility to overcome anatomical limitations, including poorly defined tumors on ultrasound and tumors

• No concern regarding the location close to major vessels, including the portal vein, inferior vein cava, and bile

• Short treatment term (usually within 2 weeks), possibility of benefit to the patient's quality of life and reduced

• Challenges involved in the treatment of tumors close to critical organs, such as the gastrointestinal tract

Abbreviations: SBRT = stereotactic body radiation therapy; IMRT = intensity modulated radiation therapy.

• Minimally invasive treatment modality, no requirements for anesthesia or injections

• Possible to treat complicated forms of tumors, particularly using IMRT

• Possibility to enhance the immune reaction to tumors

• Inaccuracy due to respiration and the presence of ascites

• Poor outcomes and high possibility of toxicity with large tumors

tumors characterized by their small size and limited numbers [43].

## **2. General approaches and conventional radiotherapy in the treatment of HCC**

The initial approach in the management of HCC is to determine if either surgical resection or liver transplantation is feasible and best survival. The Barcelona Clinic Liver Cancer staging system is the most accepted staging system in clinical settings [7]. Orthotopic liver transplantation is the most efficient option for the treatment of HCC even though the insufficient number of donors makes challenging [8]. Therefore, local therapy is anticipated to be not only a bridging therapy but also a radical therapy in the treatment of HCC. Surgical resection is the standard local therapy for HCC [7]. Since the majority of HCC cases develop in cirrhotic patients, surgical interventions can become challenging, and the treatment has been directed toward liver transplantation. Other local therapies, such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), are used as alternatives in patients with HCC [7–9]. However, radical treatment for liver tumors can be challenging due to poor liver function, tumor location, and anatomical barriers. Furthermore, the preservation of residual liver function is required, as liver tumors have a high recurrence potential [9].

Radiotherapy is a local treatment modality and has also been used for palliative care in liver tumors. Conventional radiotherapy has been used approximately 50 Gy in a conventional fractionated schedule which could lead to a response rate as approximately 50–70% [10–14]. High doses of radiation, which are required for HCC, would sometimes exceed the levels tolerated by the background liver [15, 16]. However, modern radiotherapies, including stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), have recently attracted increasing attention as a therapeutic modality for various malignancies including HCC and have dramatically increased the use of radiation therapy as a curative modality [17–40]. However, certain issues regarding the current use of SBRT in HCC need to be addressed (e.g., ideal prescription doses, prevention of adverse events, and possible microscopic extension). In this chapter, we document the clinical utility and the present status of SBRT in the management of HCC, including clinical messages and pitfalls in liver cirrhosis and the probable treatment-related toxicities and their prevention, and summarize recent significant updates on biology-based SBRT strategies.

## **3. SBRT for HCC**

as hepatitis C virus (HCV), and nonalcoholic fatty liver disease (NAFLD). Due to the wide prevalence of HCC, it carries a significant economic burden on society at large, especially in the East Asian countries that have hepatitis B virus (HBV). Surveillance programs halve also been implemented to screen for HCC in high-risk individuals, which is more cost-effective than the treatment of HCC. Hepatotropic viruses such as HBV and HCV have a strong association with the development of HCC; thus, the worldwide distribution of HCC mirrors the distributions of such viral infections [3]. Around 80–90% of HCC cases occur in the setting of underlying cirrhosis [4]. In addition, there is an incremental effect of the presence of more than one risk factor responsible for HCC as the presence of HBV/HCV coinfections increases the risk of HCC by two- to sixfolds. Similarly, alcohol abuse further increases this risk [5, 6]. Subsequently, we describe the role of radiotherapy in the treatment of HCC, including conventional to modern techniques, possible beneficial cases of radiotherapy, and future direc-

tion of liver stereotactic body radiation therapy (SBRT).

84 Management of Chronic Liver Diseases - Recent Advances

**treatment of HCC**

**2. General approaches and conventional radiotherapy in the** 

function is required, as liver tumors have a high recurrence potential [9].

recent significant updates on biology-based SBRT strategies.

The initial approach in the management of HCC is to determine if either surgical resection or liver transplantation is feasible and best survival. The Barcelona Clinic Liver Cancer staging system is the most accepted staging system in clinical settings [7]. Orthotopic liver transplantation is the most efficient option for the treatment of HCC even though the insufficient number of donors makes challenging [8]. Therefore, local therapy is anticipated to be not only a bridging therapy but also a radical therapy in the treatment of HCC. Surgical resection is the standard local therapy for HCC [7]. Since the majority of HCC cases develop in cirrhotic patients, surgical interventions can become challenging, and the treatment has been directed toward liver transplantation. Other local therapies, such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), are used as alternatives in patients with HCC [7–9]. However, radical treatment for liver tumors can be challenging due to poor liver function, tumor location, and anatomical barriers. Furthermore, the preservation of residual liver

Radiotherapy is a local treatment modality and has also been used for palliative care in liver tumors. Conventional radiotherapy has been used approximately 50 Gy in a conventional fractionated schedule which could lead to a response rate as approximately 50–70% [10–14]. High doses of radiation, which are required for HCC, would sometimes exceed the levels tolerated by the background liver [15, 16]. However, modern radiotherapies, including stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), have recently attracted increasing attention as a therapeutic modality for various malignancies including HCC and have dramatically increased the use of radiation therapy as a curative modality [17–40]. However, certain issues regarding the current use of SBRT in HCC need to be addressed (e.g., ideal prescription doses, prevention of adverse events, and possible microscopic extension). In this chapter, we document the clinical utility and the present status of SBRT in the management of HCC, including clinical messages and pitfalls in liver cirrhosis and the probable treatment-related toxicities and their prevention, and summarize The use of SBRT for extracranial tumors was developed by Blomgren et al. [17]. The major feature that distinguishes SBRT from conventional radiation treatment is the delivery of large doses of radiation in a few fractions, which results in a high biologically effective dose (BED). In addition, Zheng et al. have reported that a shortened delivery time could significantly increase the cell killing using *in vitro* experimentation [41]. The use of a high precision technique is critical to deliver a high dose of radiation to the target and keep rapid fall-off doses away from the target, thereby achieving a maximum treatment efficacy with minimal toxicity to normal tissues [42]. SBRT is now widely accepted as a treatment option for lung and liver tumors characterized by their small size and limited numbers [43].

Current advantages and challenges of SBRT in the liver are presented in **Table 1**. The clinical outcomes of SBRT for HCC in the previous reports are shown in **Table 2**. SBRT has been reported to provide 1-, 2-, and 3-year local control rates of 56–100, 53–95, and 51–92%, and 1-, 2-, and 3-year survival rates of 32–100, 55–100, and 21–82% for HCC, respectively [19–38]. **Figure 1** indicates the local control and overall survival after SBRT, BED<sup>10</sup> ≥ 75 Gy in ≤10 fractions (e.g., 40 Gy/4 fr), for HCC at our institute. **Figure 2** indicates a typical course of SBRT for HCC in cirrhotic liver. Recent reports indicated that SBRT was as effective as TACE and RFA, although there are only a small number of randomized trials examining the use of SBRT in HCC [34, 35, 38]. However, additional prospective studies involving large sample sizes are required to consolidate the evidences on SBRT with aim to standardize liver SBRT.

#### Advantages


#### Current issues


Abbreviations: SBRT = stereotactic body radiation therapy; IMRT = intensity modulated radiation therapy.

**Table 1.** Features of SBRT for liver tumors.


**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Andolino

2011

Prospective

60

Child-Pugh A

Child-Pugh

27

3-year 90%

3-year

n = 56 (93%)

1.8% G2 chest wall

toxicity

23.2% G1-2 fatigue,

nausea, and/or right

16.1% G3 liver enzymes

elevation and/or

hyperbilirubinemia

16.1% G3

thrombocytopenia

3.6% PT-INR

12.5% G3 albumin

(17 patients of 21

patients with G3

hypoalbuminemia

preexisting Grade 2

dysfunction)

1.8% G4

thrombocytopenia and

hyperbilirubinemia

20.0% Child-Pugh

classification

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver

progression

Kang et al.

2012

Prospective

47

57 (42-60) Gy/3 fr

165.3

17

2-year 94.6%

2-year

4.3% G3 hyperbilirubinemia (pre-existing

Grade 1 or 2 hyperbilirubinemia and/or

thrombocytopenia)

10.6% G3 Thrombocytopenia

http://dx.doi.org/10.5772/intechopen.76505

4.3% G3 Ascites

6.4% G3, 4.3% G4 Gastrointestinal ulcer

(3 of 5 patients had pre-existing ulcer, 2

patients experienced Grade 4 gastric ulcer

perforation at 7 months and 10 months after

87

SBRT)

68.7%

(100.8–180.0)

(70–80% isodose

line covered at

least 97% of the

PTV)

[22]

upper quadrant

discomfort

67%

A: 108.5

(60%): 44 Gy/3 fr

Child-Pugh B

Child-Pugh

B: 85.5

(40%): 40 Gy/5 fr

(80% isodose line,

encompassing

PTV)

et al. [21]


**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Kwon

2010

Retrospective 42

33 (30-39) Gy/3 fr

69.2 (60-89.7) 29

1-year 72%

1-year

35.7% G1

2.4% (1 patient) G4

Liver failure

92.9%

Constitutional

3-year

symptoms

58.6%

31.0% G1-2 Elevated

86 Management of Chronic Liver Diseases - Recent Advances

liver enzyme

19.0% G1–2

Leukopenia

2.4% G1

hyperbilirubinemia

and ALP

Seo et al.

2010

Retrospective 38

33-57 Gy/3 fr

69.3-165.3

15

1-year 78.5%

1-year

(57.9% G1-2 acute

2.6% G3 soft tissue

toxicity (the right

upper quadrate of the

abdomen)

68.4%

toxicities)

2-year

10.5% G1-2

hyperbilirubinemia

2.6% G1 albumin

61.4%

3-year

42.1%

5.3% G1 AST/ALT

2.6% G1 ALP

44.7% G1–2 Nausea,

vomiting

7.9% G1 anorexia

13.2% G1–2

abdominal pain

2.6% G2 Paralytic

ileus

2.6% G2 radiation

dermatitis

2-year 66.4%

or

or

40-44 Gy/4 fr

80-92.4

(89.7–165.3)

(60.5% patients

received 39–57

Gy/3 fr)

[20]

3-year 68%

(70–85% isodose

line covered the

PTV)

et al. [19] Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver http://dx.doi.org/10.5772/intechopen.76505 87


**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Bae et al.

2013

Retrospective 35

45 (30-60) Gy/3-5

101 (58–180) 14

1-year 69%

1-year

(23% of patients

2.9% G4 Myelitis

(18 months after SBRT,

spine Dmax = 31 Gy/4

experienced grade ≥

52%

3-year

3 toxicity)

21%

8.6% G3 AST

fr)

2.9% G3 gastric ulcer

perforation (7 months

after SBRT)

2.9% G5 duodenal ulcer

bleeding (5 months

after SBRT)

2.9% G4 colonic ulcer

(3 months after SBRT)

(1 patient also

had grade 3

hyperbilirubinemia,

all patients had

existing grade 2

elevation of AST or

hyperbilirubinemia

and experienced

progression

of HCC)

2.9% G3 Hepatic

failure (1 month

after SBRT)

2.9% G3 colonic

ulcer (1 month after

SBRT)

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver

http://dx.doi.org/10.5772/intechopen.76505

89

intrahepatic

 pre-

3-year 51%

fr

(56–83% isodose

line of the

maximum dose or

D95 prescription

of 91–100%

prescription doses

for PTV)

[25]


**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Huang

2012

Retrospective 36

37 (25-48) Gy/4-5

NA(31.2–

14

1-year 87.6%

2-year

36.1% G1-2 fatigue

5.6% RILD (2 patients

with Child-Pugh B)

25.0% G1-2 anorexia

13.9% G1-2 nausea/

vomiting

88 Management of Chronic Liver Diseases - Recent Advances

5.6% G1-2

abdominal pain

2.8% G2, 2.8% G3

gastric ulcer

(Both of 2 patients

had gastritis before

SBRT

2.8% G1

musculoskeletal

Honda

2013

Retrospective 30

48 Gy/4 fr (86.7%

105.6

12.3

CR:96.3%

1-year

93.3% G1-2, 6.7% G3

3.3% Child-Pugh class

progression

leukocytopenia

96.7% G1-2, 3.3% G3

thrombocytopenia

100%

2-year

100%

100% G1–2

hemoglobin

G1-2

hyperbilirubinemia

G1 AST/ALT

G1 ALP

of patients) or

or

60 Gy/8 fr (13.3%

105.0

of patients)

(isocenter

prescription)

et al. [24]

64%

2-year 75.1%

105.6)

fr (70–83%

isodose line,

encompassing

PTV)

et al. [23] SBRT)


**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Sanuki

2014

Retrospective 185

Child-Pugh A

Child-Pugh

24

1-year 99%

1-year

4.9% mild fatigue

10.3% Child-Pugh

score progression (by

two points)

1.1% G5 liver failures

(both 2 patients were

classified as Child-Pugh B before SBRT 3, 6 months after SBRT)

3.2% G3 laboratory

abnormalities (prior

95%

2-year 93%

3-year 91%

2-year

83%

to SBRT)

3-year

70%

A: 72.0

(74.1%): 40 Gy/5 fr

Child-Pugh B

Child-Pugh

(25.9%): 35 Gy/5 fr

B: 59.5

(70–80%

isodose line,

encompassing

PTV)

Takeda

2014

Retrospective 63

Child-Pugh A

Child-Pugh

31.1

1-year 100%

1-year

\*n = 63

\*n = 63

76%

7.9% mild fatigue

20.6% G3 liver toxicity

15.8% G3 subacute

liver toxicity (6.3%

2-year 95%

3-year 92%

2-year

87%

3-year

before SBRT)

73%

A: 72.0

(69.8%): 40 Gy/5 fr

Child-Pugh B

Child-Pugh

(30.2%): 35 Gy/5 fr

B: 59.5

(70 or 80%

isodose line,

encompassing

PTV)

Yamashita

2014

Retrospective 79

48 Gy/4 fr (40

96 (75-106)

15.9

2-year

2-year

n = 130 (79 HCC, 51 liver metastases)

2.3% G2 gastrointestinal toxicity (gastric

inflammation in 2 patients 1 month after

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver

SBRT, gastric ulcer in 1 patient; 27 months

3.1% G3 gastrointestinal toxicity (duodenal

ulcer 17 months, intestinal tract bleeding

5, 6 months, transverse colon ulceration 5

http://dx.doi.org/10.5772/intechopen.76505

months, respectively, after SBRT)

0.8% G4 gastro-duodenal artery rupture (5

months after SBRT)

0.8% chest wall pain (combined with TACE)

91

after SBRT)

52.9%

74.1%

Gy/4 fr-60 Gy/10

fr)

et al. [30]

et al. [29]

et al. [28]


**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Bujold

2013

Prospective

102

36 (24-54) Gy/6 fr

57.6

31

1-year 87%

NA

1.0% G3 fatigue

(median

10.9% AST/ALT

17

months)

3.0% G3, 2.0% G4 hyperbilirubinemia

90 Management of Chronic Liver Diseases - Recent Advances

1.0% G3 creatinine

2.0% G3 hemoglobin

1.0% G3 leukocytes

9.0% G3 platelets

29% (3-month), 6% (12-month) Child-Pugh

class progression

46% (3-month), 17% (12-month) Child-Pugh

score progression

1.0% G3, 1.0% G4, 4.9% G5 Liver failure

1.0% G5 cholangitis (HCC invaded the

common bile duct)

1.0% G3, 1.0% G5 gastritis/gastrointestinal

bleeding (G5 occurred 7.7 months after

SBRT)

Jang et al.

2013

Retrospective

82 (95

51 (33-60) Gy/3 fr

137.7

30

2-year 87%

2-year

1.2% G3 hyperbilirubinemia (pre-existing

63%

G1) 2.4% G3 ascites

3-year

7.3% non-classic RILD (worsening of CTP

score by ≥ 2, ≤ 3 months after SBRT, 2 of 6

with disease progression)

1.2% G3 soft tissue toxicity (this patient had

a large tumor near the skin)

6.1% G3–4 GI toxicity (gastroduodenal ulcer

in 2 patients, clonic ulcer in 1 patient, and

gastroduodenal perforation in 2 patients,

gastroduodenal perforation in 2 patients)

39%

5-year 82%

(70–80% isodose

(69.3–180.0)

line covered at

least 97% of the

PTV)

HCC)

[27]

(33.6–102.6)

et al. [26]


**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Takeda

2016

Prospective

90

Child-Pugh A: 40

Child-Pugh

41.7

3-year 96.3%

3-year

2.2% transaminase elevation

5.6% thrombocytopenia

8.9% Child-Pugh score progression (by two

points)

66.7%

A: 72.0

Gy/5 fr

Child-Pugh B: 35

Child-Pugh

B: 59.5

Gy/5 fr

(prescribed

to the 60–80%

isodose line,

encompassing

PTV, D95

prescription for

PTV)

Wahl et al.

2016

Retrospective 63

30 or 50 Gy/3

100 (NA)

13.0

1-year 97.4%

1-year

1.6% G3 RILD

8.3% G3 luminal

gastrointestinal toxicity

(at 2 years after SBRT)

3.3% G3 biliary toxicity

(at 2 years after SBRT)

\*Child-Pugh score

progression by average

1.2 points) (at 12

months after SBRT)

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver

74.1%

1.6% G3

2-year

gastrointestinal

46.3%

bleeding

1.6% G3 worsening

ascites

2-year 83.8%

or 5 fr (D99.5

prescription for

PTV, the 75 to

85% isodose line

encompassing

PTV

Su, et al.

2017

Retrospective 82

42–48 Gy/3–5 fr

NA

33.0

NA (one

1-year

4.9% G1, 3.7% G2, 1.2% G3 nausea

1.2% G1, 1.2% G2, 2.4% G3 weight loss

96.3%

patient

experienced

3-year

3.7%, G1, 1.2% G2 fatigue

3.7% G1 hyperbilirubinemia

http://dx.doi.org/10.5772/intechopen.76505

81.8%

local

progression)

(PFS; 1-year

5-year

70.0%

3.7% G1 ALT

4.9% G1 anemia

6.1%, 3.7% Child-Pugh progression (1, 2

points, respectively)

93

81.4%,

3-year

50.2%,

5-year 40.7%

(67 (57–80) %

(77.3–124.8)

(Calculated

presupposed

with 42 Gy/5

fr–48 Gy/3 fr)

isodose line

encompassing

PTV)

[35]

[34]

et al. [33]


**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Culleton

2014

Prospective

29

34.4 (20.9–48.7)

54.1

NA

6-month

1-year

48.3% G1-2 fatigue

20.7% G1 nausea

32.3%

69.7%

1-year

(median

10.3% G1-2 vomiting

7.9

months)

10.3% G1-2 diarrhea

92 Management of Chronic Liver Diseases - Recent Advances

10.3% G1 abdominal pain

10.3% G1-2 abdominal distension

Child-Pugh score progression (24.1,

24.1, 10.3% by 1 point, 2 points, 3 points,

respectively, at 1 month after SBRT)

17.2% G3 thrombocytopenia (3 months after

6.9% G3, 3.4% G4 transaminase elevation (1

month after SBRT)

3.4% G4 AST (3 months after SBRT)

Huertas

2015

Retrospective

77 (97

45 Gy/3 fr

112.5

12

1-year

1-year

1.3% G1, 1.3% G2

1.3% G2 asthenia

1.3% G1 radiation

dermatitis

2.6% G1 nausea

2.6% G1, 3.9% G2, 3.9%

81.8%

asthenia

99%

2-year 99%

2-year

2.6% G1, 2.6% G2,

56.6%

1.3% G3 ascites

1.3% G1 rib pain

1.3% G1 anorexia

G3 ascites

2.6% G1 nausea

1.3% G2 colic ulcer

1.3% G3, 1.3% G4

gastric ulcer

3.9% G1 epigastric

pain

1.3% Classic RILD

3.9% Non-classic

RILD

1.3% G5

Hematemesis

HCC)

(prescribed to the

80% isodose line,

encompassing

PTV)

et al. [32]

SBRT)

55.5%

(28.2–88.2)

Gy/6 (5-15) fr

(Mean dose to

46.8

(26.2–83.3)

(Calculated

presupposed

with 6

fractions)

PTV ) or

30.9 (197-46.8)

Gy/6 (5-15) fr

(D95 prescription

for PTV)

et al. [31] Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver http://dx.doi.org/10.5772/intechopen.76505 93


**Table 2.** Summary of studies of hepatocellular carcinoma. **Figure 1.** Local control and overall survival of HCC after SBRT. Local control (LC) and overall survival (OS) were described using the Kaplan Meier method in 100 patients with 116 HCCs underwent SBRT of BED10 ≥75 Gy in ≤10 fractions, between July 2007 and August 2016 at Miyakojima IGRT Clinic (Osaka, Japan, approval no. 9). The 1-, 2- and 3-year LC rate was 100.0, 95.4 and 93.5%, respectively. The 1-, 2- and 3-year OS rate was 83.7, 72.6 and 60.5%, respectively.

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver

http://dx.doi.org/10.5772/intechopen.76505

95

**Figure 2.** Typical course of SBRT for HCC in cirrhotic liver. An 86-year-old man developed HCC in S8. HCC with 50 mm in diameter existed (A, contrast-enhanced CT, arrowhead). SBRT of 40 Gy in four fractions (BED10 = 80.0 Gy) (B, treatment plan). The high intensity area that observed before SBRT in diffusion-weighted imaging of MRI (C, left) disappeared three months after SBRT (C, right). Abbreviations: HCC, hepatocellular carcinoma; CT, computed tomography; MRI,

magnetic resonance imaging; SBRT, stereotactic body radiation therapy; BED, biologically effective dose.

Abbreviations: HCC, hepatocellular carcinoma; SBRT, stereotactic body radiation therapy.

**Figure 1.** Local control and overall survival of HCC after SBRT. Local control (LC) and overall survival (OS) were described using the Kaplan Meier method in 100 patients with 116 HCCs underwent SBRT of BED10 ≥75 Gy in ≤10 fractions, between July 2007 and August 2016 at Miyakojima IGRT Clinic (Osaka, Japan, approval no. 9). The 1-, 2- and 3-year LC rate was 100.0, 95.4 and 93.5%, respectively. The 1-, 2- and 3-year OS rate was 83.7, 72.6 and 60.5%, respectively. Abbreviations: HCC, hepatocellular carcinoma; SBRT, stereotactic body radiation therapy.

**Figure 2.** Typical course of SBRT for HCC in cirrhotic liver. An 86-year-old man developed HCC in S8. HCC with 50 mm in diameter existed (A, contrast-enhanced CT, arrowhead). SBRT of 40 Gy in four fractions (BED10 = 80.0 Gy) (B, treatment plan). The high intensity area that observed before SBRT in diffusion-weighted imaging of MRI (C, left) disappeared three months after SBRT (C, right). Abbreviations: HCC, hepatocellular carcinoma; CT, computed tomography; MRI, magnetic resonance imaging; SBRT, stereotactic body radiation therapy; BED, biologically effective dose.

**Year**

**Prospective/**

**Patient** 

**Total dose/**

**BED10 (Gy)**

**Median** 

**Local** 

**Overall** 

**Adverse events**

**survival**

**Acute response**

**Late response**

**follow-up** 

**control**

**(range)** 

**(months)**

**number**

**fraction (median,** 

**range)**

**retrospective**

**[Ref]**

Lo et al.

2017

Retrospective 89

25–60 Gy/4-6 fr

72 (40 Gy/5

NA

3-year 78.1%

1-year

24.7% G1, 4.5% G2 fatigue

13.5% G1, 2.2 G2 anorexia

13.5% G1, 12.4% G2, 1.1% G3 nausea/

94 Management of Chronic Liver Diseases - Recent Advances

45.9%

3-year

24.3%

vomiting

4.5% G1 abdominal distension

19.1 G1, 7.9% G2, 2.2% G3 abdominal pain

3.4% G2, 2.2% G3 gastritis/gastric ulcer

2.2% G1, 4.5% G2 duodenal ulcer

1.1% G1, 2.2% G2 diarrhea

1.1% G1, 2.2% G2 dermatitis

11.2% RILD (1.1% classic RILD, 9.0%

non-classic RILD (including 2 patients

developed fatal non-classic RILD), 1.1%

fulfilled the criteria of both types)

0.7≤G2, 0.7% G3 cholangiectasis

Uemoto,

2018

Retrospective

121 (146

45 (30–64) Gy/5

80 (48–106)

21

2-year

2-year

73.7%,

1.5% G1 pneumonitis

91.5%,

5-year 89.8%

5-year

57.0%

0.7% mucositis

0.7% G1 rib fracture

25.2% ascites

2.2 jaundice

1.5% pleural effusion (no hematological

abnormality changed from the baselines)

Abbreviations: NA = not applicable, HCC = hepatocellular carcinoma, SBRT = stereotactic body radiation therapy, NA = not applicable; BED = biologically effective

dose, G = grade, PTV = planning target volume, AST = aspartate transaminase elevation, ALT = alanine transaminase elevation, ALP = alkaline phosphatase elevation,

PT-INR = prothrombin time-international normalized ratio prolongation, RILD = radiation-induced liver disease, TACE = transcatheter arterial chemoembolization, PFS

= progression-free survival.

**Table 2.**

Summary of studies of hepatocellular carcinoma.

HCCs)

(4-20) fr

et al. [37]

fr), 85.5 (45

Gy/5 fr),

(40 Gy/5 fr (19

patients), 45 Gy/5

fr (18 patients),

100 (50 Gy/5

50 Gy/5 fr (14

fr)

patients))

[36]

## **4. Radiotherapy in the management of HCC with tumor thrombus in vessels**

Although the efficacy of radiotherapy has been reported in patients with tumor thrombus using conventional schedule, the evidence of the survival benefit is insufficiently strong [39–41, 49–51]. In addition, Lin et al. have reported that radiotherapy can recanalize at a rate of 79% in 14 patients with PVTT [51]. However, there are only a few comparison studies among the techniques of radiotherapy [39, 51]. Matsuo et al. have reported, in a retrospective study, that the response rate of PVTT or inferior vena cava tumor thrombosis to radiotherapy was 67 and 46% in SBRT and 3D-CRT groups, respectively (P = 0.04) [39]. Moreover, SBRT has an advantage with regard to the shortened treatment term. Radiotherapy including SBRT may have the potential to be the standard technique of radiotherapy in the treatment of PVTT.

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Radiotherapy can overcome anatomical barriers such as major vessels and achieve a promising local control with minimal invasion. Therefore, a combined multimodal approach including radiotherapy would be needed in the treatment of the HCC with PVTT in order to maximize tumor control and to keep the normal liver damages due to treatment within a safe limit.

A dose-response relationship has been reported for conventional fractionated and stereotactic radiotherapy, although the best prescription dose of radiotherapy for HCC remains undecided

**Figure 4.** Dose-response relationship in SBRT for HCC. Previous reports that clearly indicates 2-year local control and overall survival were plotted in the scatter diagram [20–24, 27–30, 32, 34, 37]. X- and Y-axis indicates total doses radiotherapy in term of BED10 and the rates of 2-year local control and overall survival, respectively. No apparent doseresponse relationship was observed in local control (r = 0.2828 and P = 0.3732) and overall survival (r = -0.1872 and P = 0.5602) at 2 years after SBRT. Abbreviations: SBRT, stereotactic body radiation therapy; HCC, hepatocellular carcinoma;

**Figure 3** indicates a case of SBRT for HCC with PVTT.

**5. Prescription doses of SBRT for HCC**

[12, 27, 52].

BED, biologically effective dose.

Portal vein tumor thrombosis (PVTT), the most common form of macrovascular invasion of HCC, could propagate further, obstruct the whole vein lumen, and lead to poor prognoses ranging from only 2 to 4 months after supportive care [44, 45]. One of the treatment modalities is surgical resection that could lead to median survival time of 8–64 months, 1-, 2-, and 3-year overall survival rates of 31–87, 0–76, and 0–71%, respectively [46]. In addition, there is a potential survival benefit by surgical resection [47]. However, tumor thrombectomy can be associated with high morbidity and mortality rates, up to 23.7% [48]. TACE might be contraindicated for HCC patients with PVTT because of the potential risk of hepatic ischemic damages due to TACE. In addition, PVTT is not an indication for RFA because of the potential cooling effect and challenging status of percutaneous intervention.

**Figure 3.** SBRT for PVTT. A 77-year-old man developed HCC due to hepatitis C with tumor thrombus in right portal vein (A, arrows, contrast-enhanced CT). The patient underwent SBRT of 60 Gy in 15 fractions (BED10 = 84.0 Gy) (B). The tumor thrombus disappeared after three months after SBRT. Contrast-enhanced CT indicates disobliteration of the right portal vein after SBRT (C, arrows). Abbreviations: SBRT, stereotactic body radiation therapy; PVTT, portal vein tumor thrombosis; HCC, hepatocellular carcinoma; CT, computed tomography; BED, biologically effective dose.

Although the efficacy of radiotherapy has been reported in patients with tumor thrombus using conventional schedule, the evidence of the survival benefit is insufficiently strong [39–41, 49–51]. In addition, Lin et al. have reported that radiotherapy can recanalize at a rate of 79% in 14 patients with PVTT [51]. However, there are only a few comparison studies among the techniques of radiotherapy [39, 51]. Matsuo et al. have reported, in a retrospective study, that the response rate of PVTT or inferior vena cava tumor thrombosis to radiotherapy was 67 and 46% in SBRT and 3D-CRT groups, respectively (P = 0.04) [39]. Moreover, SBRT has an advantage with regard to the shortened treatment term. Radiotherapy including SBRT may have the potential to be the standard technique of radiotherapy in the treatment of PVTT. **Figure 3** indicates a case of SBRT for HCC with PVTT.

Radiotherapy can overcome anatomical barriers such as major vessels and achieve a promising local control with minimal invasion. Therefore, a combined multimodal approach including radiotherapy would be needed in the treatment of the HCC with PVTT in order to maximize tumor control and to keep the normal liver damages due to treatment within a safe limit.

## **5. Prescription doses of SBRT for HCC**

**4. Radiotherapy in the management of HCC with tumor thrombus in** 

cooling effect and challenging status of percutaneous intervention.

Portal vein tumor thrombosis (PVTT), the most common form of macrovascular invasion of HCC, could propagate further, obstruct the whole vein lumen, and lead to poor prognoses ranging from only 2 to 4 months after supportive care [44, 45]. One of the treatment modalities is surgical resection that could lead to median survival time of 8–64 months, 1-, 2-, and 3-year overall survival rates of 31–87, 0–76, and 0–71%, respectively [46]. In addition, there is a potential survival benefit by surgical resection [47]. However, tumor thrombectomy can be associated with high morbidity and mortality rates, up to 23.7% [48]. TACE might be contraindicated for HCC patients with PVTT because of the potential risk of hepatic ischemic damages due to TACE. In addition, PVTT is not an indication for RFA because of the potential

**Figure 3.** SBRT for PVTT. A 77-year-old man developed HCC due to hepatitis C with tumor thrombus in right portal vein (A, arrows, contrast-enhanced CT). The patient underwent SBRT of 60 Gy in 15 fractions (BED10 = 84.0 Gy) (B). The tumor thrombus disappeared after three months after SBRT. Contrast-enhanced CT indicates disobliteration of the right portal vein after SBRT (C, arrows). Abbreviations: SBRT, stereotactic body radiation therapy; PVTT, portal vein tumor

thrombosis; HCC, hepatocellular carcinoma; CT, computed tomography; BED, biologically effective dose.

**vessels**

96 Management of Chronic Liver Diseases - Recent Advances

A dose-response relationship has been reported for conventional fractionated and stereotactic radiotherapy, although the best prescription dose of radiotherapy for HCC remains undecided [12, 27, 52].

**Figure 4.** Dose-response relationship in SBRT for HCC. Previous reports that clearly indicates 2-year local control and overall survival were plotted in the scatter diagram [20–24, 27–30, 32, 34, 37]. X- and Y-axis indicates total doses radiotherapy in term of BED10 and the rates of 2-year local control and overall survival, respectively. No apparent doseresponse relationship was observed in local control (r = 0.2828 and P = 0.3732) and overall survival (r = -0.1872 and P = 0.5602) at 2 years after SBRT. Abbreviations: SBRT, stereotactic body radiation therapy; HCC, hepatocellular carcinoma; BED, biologically effective dose.

Bae et al. reported 85% local control rates at 2 years after an SBRT of 50 Gy in 10 fractions, 75 Gy in terms of biologically effective dose (BED) using the linear-quadratic (LQ) model assuming an α/β = 10 Gy for tumors (BED10) [53]. Lausch et al. have reported that the administration of a biologically equivalent total dose in 2-Gy fractions (EQD2) of 84 Gy (BED<sup>10</sup> = 100.8 Gy) could achieve a 90% probability of a 6-month local control [54]. Jang et al. estimated that a 90% probability of a 2-year local control required 51.1 Gy in three fractions (BED<sup>10</sup> = 138.1 Gy) [27]. Sanuki et al. and Takeda et al. reported a more than 90% 3-year local control rate with 40 Gy in five fractions (BED<sup>10</sup> = 72 Gy) that was intended to enclose the planning target volume (PTV) by 80% isodose line of the maximum dose [28, 29]. **Figure 4** shows no dose–response relationship between a 2-year local control and overall survival rates and the total BED of SBRT with the range of prescription doses of ≥72 Gy. Notably, previous reports include various prescription definitions such as the prescription dose for the iso-center (isocentric prescription), a certain percent isodose line of the maximum dose (marginal prescription), and the dose to cover 95% of the PTV (D95 prescription). Based on these data, HCC has been treated with ≥80 Gy of BED10 and achieved a good local control at our institute as we hypothesized [37].

appropriate for liver irradiation in SBRT have not been adequately investigated. Furthermore, radiotherapy has the potential to reactivate hepatitis B virus and differentiating patients may be necessary [62, 63]. There are differences in radiosensitivity between patients with normal and cirrhotic livers; cirrhotic liver may yield a higher radiosensitivity than normal liver [16, 57]. In addition, Child-Pugh B, particularly scores of ≥8, was considered a significant risk factor for severe hepatic toxicity and poor prognosis [21, 31, 64]. Culleton et al. reported that 63% of 29 HCC patients with Child-Pugh B or C, receiving SBRT, declined Child-Pugh score

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As the liver is widely accepted as a parallel organ, a part of it can receive a high dose of irradiation as long as the functions as a whole organ are preserved [65–67]. Indeed, Schefter et al., Olsen et al., and Kang et al. used dose constraint, as the liver volume was >700 mL when the dose administered was less than 15 and 17 Gy in three fractions [22, 68, 69]. However, intrahepatic recurrence often occurs after a radical treatment for liver tumors because of chronic liver diseases, and such tumors have a chance to receive second radical treatment [9, 70]. Thus, the prediction of the volume of liver dysfunction is essential in order to spare the residual liver volume. After SBRT, focal dysfunction was noted in the irradiated background liver. Sanuki et al. have shown that the threshold dose of focal liver dysfunction was 30 and 25 Gy in five fractions in patients with Child-Pugh A and B, respectively, using magnetic resonance imaging (MRI) [71]. Similarly, Doi et al. have reported that focal liver dysfunction can occur at 40

**Figure 5** indicates a focal liver damage 3 months after SBRT. We have presented SBRT strategy with checkpoints to ensure safe treatment modality in SBRT for liver tumor [72]. To prevent RILD-related mortality, we evaluate the mean doses for the liver first and then analyze the

Ionizing radiation exerts an anticancer effect by reacting with molecular oxygen and water to generate reactive oxygen species that can attack deoxyribose in deoxyribonucleic acid (DNA). Sublethal doses of radiation can cause non-repairable DNA damage [73]. Intestine is a radiosensitive tissue because of the rapid turnover rate, and this can be a dose-limiting factor in SBRT. Gastrointestinal injuries including bleeding, ulcers, and perforations have been described, and the incidence of symptomatic gastrointestinal toxicities was less than 10% in majority of the previous reports (**Table 2**). However, severe toxicities, which can be lethal, have also been described in SBRT in the upper abdomen including liver [22, 30, 74–76]. Kang et al. have highlighted the possible association between severe gastrointestinal toxicity and the existence of mucosal ulceration prior to radiotherapy [22]. Barney et al. reported that the combination of SBRT and vascular endothelial growth factor inhibitor increased the risk of grade 3 or greater gastrointestinal toxicities [77]. Careful assessment is therefore required

For the prevention of severe gastrointestinal injury, analyses of dose-volume responses have been reported. Kopek et al. recommended V21Gy ≤1 cc for the duodenum in abdominal SBRT in their analyses in 29 patients with cholangiocellular carcinoma (CCC) underwent SBRT (45 Gy/3 fractions) [78]. Bae et al. concluded that Dmax of 35 and 38 Gy in three fractions was associated with a probability of 5 and 10% severe gastroduodenal toxicity, respectively [79].

prior to the implementation of combined treatments, such as targeted therapy.

potential loss of hepatic function in terms of BED (**Figure 6**).

in the cirrhotic and normal liver, respectively, at a minimum dose [57].

by two points after 3 months [31].

and 70 Gy of BED<sup>2</sup>

**6.2. Gastrointestinal injury**

## **6. Adverse events of SBRT for HCC in cirrhotic liver, risk factors, and prevention**

Manifestations of liver SBRT toxicity have fatigue, damage to the liver, gastrointestinal tract and biliary duct, cytopenia, dermatitis, and rib fractures (**Table 2**) [18–37]. Adverse events of radiotherapy depend on the treatment site, and the irradiated doses and volume and are categorized into either acute (typically within 3 months of radiotherapy) or late (months to years after radiotherapy), based on their time of onset [55]. The acute phase of radiation-induced injury is characterized by inflammation, in response to therapy, while the late phase is characterized by fibrosis and sclerosis of vessels leading to focal ischemia and chronic inflammation. To distinguish acute and late phases of toxicities is often difficult since liver damage with serum abnormalities can be observed weeks or months later after SBRT [16]. We summarize with focusing on the major toxicities in the liver, gastrointestinal tract, and central bile duct.

### **6.1. Liver toxicity**

Liver toxicity, such as classic and non-classic radiation-induced liver disease (RILD), is one of the most common dose-limiting toxicities in liver radiotherapy [15, 16, 56, 57]. Clinical RILD occurs between 2 weeks and 7 months, typically within 4–8 weeks following hepatic radiotherapy. The patient presents with fatigue, weight gain, increased abdominal girth, hepatomegaly, anicteric ascites, and an elevation in alkaline phosphatase (over twice the upper limit of the normal values). Treatment options for RILD are limited, and the condition can become fatal due to liver failure [56, 58–61]. Non-classic RILD occurs in patients with underlying chronic hepatic disease, such as cirrhosis and viral hepatitis, and is characterized by jaundice and/or markedly elevated serum transaminases (over five times the upper limit of the normal values), developing between 1 week and 3 months after the completion of hepatic radiotherapy [19, 61]. The mean dose of less than 30 Gy has been considered as safe but radiation tolerance of the liver in a conventional radiotherapy [19]. However, the actual mean doses appropriate for liver irradiation in SBRT have not been adequately investigated. Furthermore, radiotherapy has the potential to reactivate hepatitis B virus and differentiating patients may be necessary [62, 63]. There are differences in radiosensitivity between patients with normal and cirrhotic livers; cirrhotic liver may yield a higher radiosensitivity than normal liver [16, 57]. In addition, Child-Pugh B, particularly scores of ≥8, was considered a significant risk factor for severe hepatic toxicity and poor prognosis [21, 31, 64]. Culleton et al. reported that 63% of 29 HCC patients with Child-Pugh B or C, receiving SBRT, declined Child-Pugh score by two points after 3 months [31].

As the liver is widely accepted as a parallel organ, a part of it can receive a high dose of irradiation as long as the functions as a whole organ are preserved [65–67]. Indeed, Schefter et al., Olsen et al., and Kang et al. used dose constraint, as the liver volume was >700 mL when the dose administered was less than 15 and 17 Gy in three fractions [22, 68, 69]. However, intrahepatic recurrence often occurs after a radical treatment for liver tumors because of chronic liver diseases, and such tumors have a chance to receive second radical treatment [9, 70]. Thus, the prediction of the volume of liver dysfunction is essential in order to spare the residual liver volume. After SBRT, focal dysfunction was noted in the irradiated background liver. Sanuki et al. have shown that the threshold dose of focal liver dysfunction was 30 and 25 Gy in five fractions in patients with Child-Pugh A and B, respectively, using magnetic resonance imaging (MRI) [71]. Similarly, Doi et al. have reported that focal liver dysfunction can occur at 40 and 70 Gy of BED<sup>2</sup> in the cirrhotic and normal liver, respectively, at a minimum dose [57]. **Figure 5** indicates a focal liver damage 3 months after SBRT. We have presented SBRT strategy with checkpoints to ensure safe treatment modality in SBRT for liver tumor [72]. To prevent RILD-related mortality, we evaluate the mean doses for the liver first and then analyze the potential loss of hepatic function in terms of BED (**Figure 6**).

#### **6.2. Gastrointestinal injury**

Bae et al. reported 85% local control rates at 2 years after an SBRT of 50 Gy in 10 fractions, 75 Gy in terms of biologically effective dose (BED) using the linear-quadratic (LQ) model assuming an α/β = 10 Gy for tumors (BED10) [53]. Lausch et al. have reported that the administration of a biologically equivalent total dose in 2-Gy fractions (EQD2) of 84 Gy (BED<sup>10</sup> = 100.8 Gy) could achieve a 90% probability of a 6-month local control [54]. Jang et al. estimated that a 90% probability of a 2-year local control required 51.1 Gy in three fractions (BED<sup>10</sup> = 138.1 Gy) [27]. Sanuki et al. and Takeda et al. reported a more than 90% 3-year local control rate with 40 Gy in five fractions (BED<sup>10</sup> = 72 Gy) that was intended to enclose the planning target volume (PTV) by 80% isodose line of the maximum dose [28, 29]. **Figure 4** shows no dose–response relationship between a 2-year local control and overall survival rates and the total BED of SBRT with the range of prescription doses of ≥72 Gy. Notably, previous reports include various prescription definitions such as the prescription dose for the iso-center (isocentric prescription), a certain percent isodose line of the maximum dose (marginal prescription), and the dose to cover 95% of the PTV (D95 prescription). Based on these data, HCC has been treated with ≥80 Gy of

BED10 and achieved a good local control at our institute as we hypothesized [37].

**6. Adverse events of SBRT for HCC in cirrhotic liver, risk factors,** 

Manifestations of liver SBRT toxicity have fatigue, damage to the liver, gastrointestinal tract and biliary duct, cytopenia, dermatitis, and rib fractures (**Table 2**) [18–37]. Adverse events of radiotherapy depend on the treatment site, and the irradiated doses and volume and are categorized into either acute (typically within 3 months of radiotherapy) or late (months to years after radiotherapy), based on their time of onset [55]. The acute phase of radiation-induced injury is characterized by inflammation, in response to therapy, while the late phase is characterized by fibrosis and sclerosis of vessels leading to focal ischemia and chronic inflammation. To distinguish acute and late phases of toxicities is often difficult since liver damage with serum abnormalities can be observed weeks or months later after SBRT [16]. We summarize with focusing on the major toxicities in the liver, gastrointestinal tract, and central bile duct.

Liver toxicity, such as classic and non-classic radiation-induced liver disease (RILD), is one of the most common dose-limiting toxicities in liver radiotherapy [15, 16, 56, 57]. Clinical RILD occurs between 2 weeks and 7 months, typically within 4–8 weeks following hepatic radiotherapy. The patient presents with fatigue, weight gain, increased abdominal girth, hepatomegaly, anicteric ascites, and an elevation in alkaline phosphatase (over twice the upper limit of the normal values). Treatment options for RILD are limited, and the condition can become fatal due to liver failure [56, 58–61]. Non-classic RILD occurs in patients with underlying chronic hepatic disease, such as cirrhosis and viral hepatitis, and is characterized by jaundice and/or markedly elevated serum transaminases (over five times the upper limit of the normal values), developing between 1 week and 3 months after the completion of hepatic radiotherapy [19, 61]. The mean dose of less than 30 Gy has been considered as safe but radiation tolerance of the liver in a conventional radiotherapy [19]. However, the actual mean doses

**and prevention**

98 Management of Chronic Liver Diseases - Recent Advances

**6.1. Liver toxicity**

Ionizing radiation exerts an anticancer effect by reacting with molecular oxygen and water to generate reactive oxygen species that can attack deoxyribose in deoxyribonucleic acid (DNA). Sublethal doses of radiation can cause non-repairable DNA damage [73]. Intestine is a radiosensitive tissue because of the rapid turnover rate, and this can be a dose-limiting factor in SBRT. Gastrointestinal injuries including bleeding, ulcers, and perforations have been described, and the incidence of symptomatic gastrointestinal toxicities was less than 10% in majority of the previous reports (**Table 2**). However, severe toxicities, which can be lethal, have also been described in SBRT in the upper abdomen including liver [22, 30, 74–76]. Kang et al. have highlighted the possible association between severe gastrointestinal toxicity and the existence of mucosal ulceration prior to radiotherapy [22]. Barney et al. reported that the combination of SBRT and vascular endothelial growth factor inhibitor increased the risk of grade 3 or greater gastrointestinal toxicities [77]. Careful assessment is therefore required prior to the implementation of combined treatments, such as targeted therapy.

For the prevention of severe gastrointestinal injury, analyses of dose-volume responses have been reported. Kopek et al. recommended V21Gy ≤1 cc for the duodenum in abdominal SBRT in their analyses in 29 patients with cholangiocellular carcinoma (CCC) underwent SBRT (45 Gy/3 fractions) [78]. Bae et al. concluded that Dmax of 35 and 38 Gy in three fractions was associated with a probability of 5 and 10% severe gastroduodenal toxicity, respectively [79].

**Figure 5.** Focal liver dysfunction after SBRT in the follow-up MRI. A 77-year-old woman developed HCC due to hepatitis B. (A) Contrast-enhanced CT images indicate HCC in S7 area. Arterial phase showed patchy high density area (arrow, left) and contrast washed-out was observed later in delayed phase (arrow, right). (B) SBRT of 55 Gy in 10 fractions (BED10 = 85.3 Gy) was performed for the tumor. (C) Low intensity area was found in accordance with the irradiated area of treatment plan in Gd-EOB-DTPA enhanced-MRI three months after SBRT (left, arrows) and focal liver atrophy was observed later (right, arrow). Abbreviations: SBRT, stereotactic body radiation therapy; MRI, magnetic resonance imaging; CT, computed tomography; HCC, hepatocellular carcinoma; BED, biologically effective dose; Gd-EOB-DTPA, gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid.

Osmundson et al. analyzed 96 patients with liver tumors, including 20 CCCs, who received different schedules of SBRT, and reported that the incidence of hepatobiliary toxicity ≥Grade 2 and 3 was 24.0 and 18.8%, respectively [84]. Furthermore, CCC, biliary stent, VBED1072 ≥ 21 cc, VBED1066 ≥ 24 cc, and DmeanBED<sup>10</sup> ≥ 14 Gy to central hepatobiliary tract were associated with hepatobiliary toxicity [81]. The same groups reported radiation-induced pathological changes of the bile duct in resected surgical specimens 25 months after SBRT and concluded that liver toxicity should be considered while treating central liver lesions [85]. The same group has also reported a dose-volume association between ≥Grade 3 hepatobiliary toxicity and doses for central biliary tract and suggested VBED1040 < 37 cc and VBED1030 < 45 cc as dose-volume

**Figure 6.** The current recommended treatment protocol to provide a safe SBRT for HCC in cirrhotic liver. To minimize the risk of radiation-induced liver disease and liver damage, two different checkpoints were included. Herein, we propose a safe treatment protocol for SBRT of liver tumors. First, liver function is evaluated according to the Child–Pugh classification

Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma in Cirrhotic Liver

liver should be maintained to prevent RILD in patients with Child–Pugh A and B liver function, respectively (Step 2). Finally, the volume of hepatic dysfunction is assessed to estimate the residual liver volume (Step 3). Abbreviations: SBRT,

stereotactic body radiation therapy; HCC, hepatocellular carcinoma; BED, biologically effective dose.

of less than 73 and 16 Gy for the whole

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The anatomical structures in the hepatic hilum make radical treatment for liver tumors, such as surgery and RFA, more challenging. In such a scenario, SBRT can be a better option in comparison to other modalities, and to the best of our knowledge, there is no apparent consensus on the use of SBRT with few reports addressing this point. Further studies are required to determine the dose constraints for the bile duct, as there can be potential dose constraints due

Liver SBRT is a well-established and promising treatment for a limited number of small tumors. We have set out the difference between primary and metastatic liver cancers, considering the occurrence and prevention of toxicities. However, further questions regarding the pathological features of liver cancers, and potential SBRT strategies, including radiobiologybased SBRT and SBRT combined with immunotherapy, have not yet been fully addressed.

constraints in SBRT for primary liver tumors [86].

(Step 1). Next, the liver doses are evaluated to prevent RILD. A mean BED<sup>2</sup>

**7. Current issues and future perspective of liver SBRT**

to the central hepatobiliary tract toxicity.

Kavanagh et al. recommended that the volume of stomach receiving >22.5 Gy should be ideally minimized to <5 cc, with Dmax of <30 Gy in three fractions [80]. Sanuki et al. suggested that SBRT could be performed with the avoidance of severe toxicities when the target had a distance of >2 cm from the bowel [81]. An increased number of fractions may reduce BED for normal tissues in SBRT for liver tumors close to the gastrointestinal tract [57]. Since there are no established strategies for the prevention and treatment of radiation-induced gastrointestinal injury, efforts should be required to minimize radiation doses for gastrointestinal tracts [82].

#### **6.3. Central hepatobiliary tract toxicity**

Eriguchi et al. documented asymptomatic bile duct stenosis in 2/50 patients, receiving >20 Gy in five fractions to the central liver [83]. One of these patients received SBRT on two occasions to the central liver tumors and developed abnormalities in liver enzymes. The abnormal region visible on a computed tomography scan corresponded to the site irradiated up to a cumulative maximum dose of 88 Gy in two sessions of SBRT. The authors concluded that SBRT for liver tumors in the hepatic hilum was feasible with minimal biliary toxicity.

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**Figure 6.** The current recommended treatment protocol to provide a safe SBRT for HCC in cirrhotic liver. To minimize the risk of radiation-induced liver disease and liver damage, two different checkpoints were included. Herein, we propose a safe treatment protocol for SBRT of liver tumors. First, liver function is evaluated according to the Child–Pugh classification (Step 1). Next, the liver doses are evaluated to prevent RILD. A mean BED<sup>2</sup> of less than 73 and 16 Gy for the whole liver should be maintained to prevent RILD in patients with Child–Pugh A and B liver function, respectively (Step 2). Finally, the volume of hepatic dysfunction is assessed to estimate the residual liver volume (Step 3). Abbreviations: SBRT, stereotactic body radiation therapy; HCC, hepatocellular carcinoma; BED, biologically effective dose.

Osmundson et al. analyzed 96 patients with liver tumors, including 20 CCCs, who received different schedules of SBRT, and reported that the incidence of hepatobiliary toxicity ≥Grade 2 and 3 was 24.0 and 18.8%, respectively [84]. Furthermore, CCC, biliary stent, VBED1072 ≥ 21 cc, VBED1066 ≥ 24 cc, and DmeanBED<sup>10</sup> ≥ 14 Gy to central hepatobiliary tract were associated with hepatobiliary toxicity [81]. The same groups reported radiation-induced pathological changes of the bile duct in resected surgical specimens 25 months after SBRT and concluded that liver toxicity should be considered while treating central liver lesions [85]. The same group has also reported a dose-volume association between ≥Grade 3 hepatobiliary toxicity and doses for central biliary tract and suggested VBED1040 < 37 cc and VBED1030 < 45 cc as dose-volume constraints in SBRT for primary liver tumors [86].

The anatomical structures in the hepatic hilum make radical treatment for liver tumors, such as surgery and RFA, more challenging. In such a scenario, SBRT can be a better option in comparison to other modalities, and to the best of our knowledge, there is no apparent consensus on the use of SBRT with few reports addressing this point. Further studies are required to determine the dose constraints for the bile duct, as there can be potential dose constraints due to the central hepatobiliary tract toxicity.

## **7. Current issues and future perspective of liver SBRT**

Kavanagh et al. recommended that the volume of stomach receiving >22.5 Gy should be ideally minimized to <5 cc, with Dmax of <30 Gy in three fractions [80]. Sanuki et al. suggested that SBRT could be performed with the avoidance of severe toxicities when the target had a distance of >2 cm from the bowel [81]. An increased number of fractions may reduce BED for normal tissues in SBRT for liver tumors close to the gastrointestinal tract [57]. Since there are no established strategies for the prevention and treatment of radiation-induced gastrointestinal injury, efforts should be required to minimize radiation doses for gastrointestinal tracts [82].

**Figure 5.** Focal liver dysfunction after SBRT in the follow-up MRI. A 77-year-old woman developed HCC due to hepatitis B. (A) Contrast-enhanced CT images indicate HCC in S7 area. Arterial phase showed patchy high density area (arrow, left) and contrast washed-out was observed later in delayed phase (arrow, right). (B) SBRT of 55 Gy in 10 fractions (BED10 = 85.3 Gy) was performed for the tumor. (C) Low intensity area was found in accordance with the irradiated area of treatment plan in Gd-EOB-DTPA enhanced-MRI three months after SBRT (left, arrows) and focal liver atrophy was observed later (right, arrow). Abbreviations: SBRT, stereotactic body radiation therapy; MRI, magnetic resonance imaging; CT, computed tomography; HCC, hepatocellular carcinoma; BED, biologically effective dose; Gd-EOB-DTPA,

Eriguchi et al. documented asymptomatic bile duct stenosis in 2/50 patients, receiving >20 Gy in five fractions to the central liver [83]. One of these patients received SBRT on two occasions to the central liver tumors and developed abnormalities in liver enzymes. The abnormal region visible on a computed tomography scan corresponded to the site irradiated up to a cumulative maximum dose of 88 Gy in two sessions of SBRT. The authors concluded that

SBRT for liver tumors in the hepatic hilum was feasible with minimal biliary toxicity.

**6.3. Central hepatobiliary tract toxicity**

gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid.

100 Management of Chronic Liver Diseases - Recent Advances

Liver SBRT is a well-established and promising treatment for a limited number of small tumors. We have set out the difference between primary and metastatic liver cancers, considering the occurrence and prevention of toxicities. However, further questions regarding the pathological features of liver cancers, and potential SBRT strategies, including radiobiologybased SBRT and SBRT combined with immunotherapy, have not yet been fully addressed.

#### **7.1. Potent strategies of SBRT based on radiation biology**

Brown et al. reported that a greater endothelial cell damage and vascular damage, leading cancer cell apoptosis, can be caused by SBRT, and reoxygenation can increase antitumor effect in fractionated radiotherapy [87]. Shibamoto et al. concluded that reoxygenation could be promoted by a 72-h break period in SBRT [88]. No prospective clinical trials exist in terms of evaluation of the benefit of a break in SBRT. However, a longer overall treatment time (e.g., 1–2 fractions per week: 2-week schedule) may yield better local control outcomes in SBRT [89, 90]. SBRT for larger tumors has still unclear roles and is challenging because they are usually in exclusion criterion. In addition, large tumor size (≥2–4 cm) has been reported to be a predictive factor for poor outcomes after SBRT for HCC [23, 30, 32]. Further biological assessment might yield potential factors that improve treatment outcomes such as escalated doses, treatment schedule with a break, combined therapy with ideal chemotherapy, individualized treatment, and particle therapies.

could minimize the toxic effects on circulating lymphocytes [106]. By expanding its application range from small tumors to metastases, SBRT might have good potential to achieve newer

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The use of particle therapy, such as proton and carbon ion therapy for liver tumors, is a promising strategy to increase the dose of radiation without a concurrent increase in toxicity. Particle therapy exhibits a narrow Bragg peak at a defined depth for a defined energy [73]. Particle therapy can provide high concentrations of radiation doses to the target by positioning individual Bragg peaks to coincide with the areas of the target. In photon radiotherapy, the doses that the liver receives have a strong positive relationship with the irradiated target volume, and unacceptable higher doses might be irradiating to the background liver in the treatment of large live tumors [72]. Particle therapy can reduce the liver volume that receives low to intermediate doses, resulting in the reduction of mean liver doses with an advantage of target conformity [107, 108]. In addition, carbon ion therapy offers the added potential benefit of an increased relative biological effectiveness and a lower oxygen enhancement ratio due to the high linear energy transfer that may improve responses in hypoxic areas of tumors, which are more resistant to photon radiotherapy [73]. A relevant clinical consideration is that particle therapy can benefit relatively large tumors, such as >3 cm (particularly >5 cm) and

For HCC, SBRT is safe and effective, with excellent local control achieved. Tumors that are relatively small and distant from gastrointestinal tissues are strong candidate for SBRT in curative intent. Therefore, novel strategies should be developed based on new knowledge of biological responses to radiation therapy. State-of-the-art liver SBRT remains a pioneering

The authors would like to thank Messrs. Kenji Uemoto, Norihisa Masai, Koichi Yamada, and

This work was supported by Grant-in-Aid for Young Scientists (B) Grant Number 17 K16493.

objectives in systematic disease, although further investigations are required.

patients with poor liver function, which are limiting for SBRT [109].

Daisaku Tatsumi from Miyakojima IGRT Clinic (Osaka, Japan).

**liver**

**9. Conclusions**

strategy in multimodal therapy.

**Acknowledgements**

**Conflict of interest**

None.

**8. Advantages of particle therapy in treatment for HCC in cirrhotic** 

#### **7.2. Potential needs of clinical tumor volume margin in liver SBRT**

Definition of clinical tumor volume (CTV) is the volume that includes both gross and microscopic disease and is created by adding several mm to 1.5 cm to gross tumor volume (GTV), in order to allow for microscopic extension. However, CTV is frequently equal to GTV in SBRT [91]. It is still poorly understood whether CTV margins are necessary, as there are limited reports of microscopic extension of liver tumors as premises for radiotherapy. HCC is characterized by direct invasion and a potential high presence of daughter nodules around the tumor that may lead to locoregional recurrence [92]. Wang et al. reported that the potential maximum margin extending beyond the gross tumor margin was 8.0 mm, although 94.7% of patients with HCC had a microscopic extension of ≤3.5 mm [93]. Wang et al. analyzed 149 resected HCCs with a mean diameter of 5.8 cm (range: 1.0–22.0 cm) and found that microinvasion was not present in 47.0% patients [94]. Microinvasion distances of ≤2 mm were found in 96.1% of patients with tumor dimensions of ≤5 cm. Uemoto et al. have first reported that a larger margin to GTV inclined to improve local control and survival outcomes in clinical data, suggesting the benefit of CTV margins [37]. Further clinical translational studies should be conducted in order to assess the optimal CTV margins.

#### **7.3. Current knowledge of Immuno-SBRT**

Regression of tumors outside the radiation field after local radiotherapy, due to systemic induction of antitumor immunity, is called the abscopal effect [95]. SBRT combined with immune checkpoint inhibitor has recently resulted in unexpected clinical complete responses from distant sites from the irradiated areas, in various malignancies [96–98]. Recently, synergistic effects of radiotherapy combined with immunotherapy have been reported in both preclinical and clinical studies, with the high possibility of the abscopal effect, which may significantly change the treatment strategies for metastatic diseases [96–105]. However, the optimal treatment schedule and doses in the combined setting of radiotherapy and immunotherapy are poorly understood at present. Young et al. reported an enhanced efficacy of immune-radiotherapy administered concurrently with radiotherapy [101]. In a meta-analysis of preclinical data, Marconi et al. reported that the probability of abscopal effects is 50% when a BED of 60 Gy is generated [102]. Moreover, SBRT may provide smaller target volumes, and in a clinical trial involving patients with pancreatic cancer, Wild et al. found that hypofractionation could minimize the toxic effects on circulating lymphocytes [106]. By expanding its application range from small tumors to metastases, SBRT might have good potential to achieve newer objectives in systematic disease, although further investigations are required.

## **8. Advantages of particle therapy in treatment for HCC in cirrhotic liver**

The use of particle therapy, such as proton and carbon ion therapy for liver tumors, is a promising strategy to increase the dose of radiation without a concurrent increase in toxicity. Particle therapy exhibits a narrow Bragg peak at a defined depth for a defined energy [73]. Particle therapy can provide high concentrations of radiation doses to the target by positioning individual Bragg peaks to coincide with the areas of the target. In photon radiotherapy, the doses that the liver receives have a strong positive relationship with the irradiated target volume, and unacceptable higher doses might be irradiating to the background liver in the treatment of large live tumors [72]. Particle therapy can reduce the liver volume that receives low to intermediate doses, resulting in the reduction of mean liver doses with an advantage of target conformity [107, 108]. In addition, carbon ion therapy offers the added potential benefit of an increased relative biological effectiveness and a lower oxygen enhancement ratio due to the high linear energy transfer that may improve responses in hypoxic areas of tumors, which are more resistant to photon radiotherapy [73]. A relevant clinical consideration is that particle therapy can benefit relatively large tumors, such as >3 cm (particularly >5 cm) and patients with poor liver function, which are limiting for SBRT [109].

## **9. Conclusions**

**7.1. Potent strategies of SBRT based on radiation biology**

102 Management of Chronic Liver Diseases - Recent Advances

**7.2. Potential needs of clinical tumor volume margin in liver SBRT**

**7.3. Current knowledge of Immuno-SBRT**

Brown et al. reported that a greater endothelial cell damage and vascular damage, leading cancer cell apoptosis, can be caused by SBRT, and reoxygenation can increase antitumor effect in fractionated radiotherapy [87]. Shibamoto et al. concluded that reoxygenation could be promoted by a 72-h break period in SBRT [88]. No prospective clinical trials exist in terms of evaluation of the benefit of a break in SBRT. However, a longer overall treatment time (e.g., 1–2 fractions per week: 2-week schedule) may yield better local control outcomes in SBRT [89, 90]. SBRT for larger tumors has still unclear roles and is challenging because they are usually in exclusion criterion. In addition, large tumor size (≥2–4 cm) has been reported to be a predictive factor for poor outcomes after SBRT for HCC [23, 30, 32]. Further biological assessment might yield potential factors that improve treatment outcomes such as escalated doses, treatment schedule with a break, combined therapy with ideal chemotherapy, individualized treatment, and particle therapies.

Definition of clinical tumor volume (CTV) is the volume that includes both gross and microscopic disease and is created by adding several mm to 1.5 cm to gross tumor volume (GTV), in order to allow for microscopic extension. However, CTV is frequently equal to GTV in SBRT [91]. It is still poorly understood whether CTV margins are necessary, as there are limited reports of microscopic extension of liver tumors as premises for radiotherapy. HCC is characterized by direct invasion and a potential high presence of daughter nodules around the tumor that may lead to locoregional recurrence [92]. Wang et al. reported that the potential maximum margin extending beyond the gross tumor margin was 8.0 mm, although 94.7% of patients with HCC had a microscopic extension of ≤3.5 mm [93]. Wang et al. analyzed 149 resected HCCs with a mean diameter of 5.8 cm (range: 1.0–22.0 cm) and found that microinvasion was not present in 47.0% patients [94]. Microinvasion distances of ≤2 mm were found in 96.1% of patients with tumor dimensions of ≤5 cm. Uemoto et al. have first reported that a larger margin to GTV inclined to improve local control and survival outcomes in clinical data, suggesting the benefit of CTV margins [37]. Further clinical translational studies should be conducted in order to assess the optimal CTV margins.

Regression of tumors outside the radiation field after local radiotherapy, due to systemic induction of antitumor immunity, is called the abscopal effect [95]. SBRT combined with immune checkpoint inhibitor has recently resulted in unexpected clinical complete responses from distant sites from the irradiated areas, in various malignancies [96–98]. Recently, synergistic effects of radiotherapy combined with immunotherapy have been reported in both preclinical and clinical studies, with the high possibility of the abscopal effect, which may significantly change the treatment strategies for metastatic diseases [96–105]. However, the optimal treatment schedule and doses in the combined setting of radiotherapy and immunotherapy are poorly understood at present. Young et al. reported an enhanced efficacy of immune-radiotherapy administered concurrently with radiotherapy [101]. In a meta-analysis of preclinical data, Marconi et al. reported that the probability of abscopal effects is 50% when a BED of 60 Gy is generated [102]. Moreover, SBRT may provide smaller target volumes, and in a clinical trial involving patients with pancreatic cancer, Wild et al. found that hypofractionation For HCC, SBRT is safe and effective, with excellent local control achieved. Tumors that are relatively small and distant from gastrointestinal tissues are strong candidate for SBRT in curative intent. Therefore, novel strategies should be developed based on new knowledge of biological responses to radiation therapy. State-of-the-art liver SBRT remains a pioneering strategy in multimodal therapy.

## **Acknowledgements**

The authors would like to thank Messrs. Kenji Uemoto, Norihisa Masai, Koichi Yamada, and Daisaku Tatsumi from Miyakojima IGRT Clinic (Osaka, Japan).

This work was supported by Grant-in-Aid for Young Scientists (B) Grant Number 17 K16493.

## **Conflict of interest**

None.

## **Author details**

Hiroshi Doi1,2\*, Hiroya Shiomi1 and Ryoong-Jin Oh1


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112 Management of Chronic Liver Diseases - Recent Advances

## *Edited by Xingshun Qi*

This book is contributed by worldwide experts in the field of liver diseases. It comprises of 3 sections and 6 chapters to introduce 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 investigators who are interested in the management of chronic liver diseases will be acquainted with its merits and usefulness.

Published in London, UK © 2018 IntechOpen © Dr\_Microbe / iStock

Management of Chronic Liver Diseases - Recent Advances

Management of

Chronic Liver Diseases

Recent Advances

*Edited by Xingshun Qi*