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## **Meet the editor**

Prof. Luis Rodrigo is actually emeritus full professor of Medicine at the University of Oviedo (Spain). He has been the chief of Gastroenterology Service at the HUCA Hospital in Oviedo, for more than 40 years. He achieved his doctoral degree in 1975 and has developed a long teaching and research career during this time period. He has published a total of 565 scientific papers, of which

284 are written in English. He has directed 40 doctoral thesis, and he was the main investigator in a total of 45 clinical trials. He has contributed actively to the formation of around 100 specialists in gastroenterology. He has written around 35 chapters in books of several subjects and has been the Editor of 15 books.

## Contents

**Preface XI**

	- Chapter 2 **Cirrhotic Ascites: Pathophysiological Changes and Clinical Implications 17** Abdulrahman Bendahmash, Hussien Elsiesy and Waleed K. Alhamoudi
	- Chapter 3 **Modern Tools for Diagnosis in Tuberculous Ascites 33** Andra-Iulia Suceveanu, Despina Todescu, Laura Mazilu, Filippos Goniotakis Manousos, Roxana Hulea, Felix Voinea, Eugen Dumitru and Adrian Paul Suceveanu
	- Chapter 4 **Ascitic Fluid in Ovarian Carcinoma From Pathophysiology to the Treatment 47** Radomir Živadinović, Aleksandra Petrić, Dane Krtinić, Sonja Pop-Trajković Dinić and Biljana Živadinović
	- **Section 2 Treatment, Complications and Prognosis 77**
	- Chapter 5 **Ascites: Treatment, Complications, and Prognosis 79** Patricia Huelin, Jose Ignacio Fortea, Javier Crespo and Emilio Fábrega
	- Chapter 6 **Pharmacological Therapy of Ascites 109** Aziza Ajlan, Waleed K. Al-hamoudi and Hussein Elsiesy

Chapter 7 **Predictors of the Response to Tolvaptan Therapy and Its Effect on Prognosis in Cirrhotic Patients with Ascites 125** Tomomi Kogiso, Kuniko Yamamoto, Mutsuki Kobayashi, Yuichi Ikarashi, Kazuhisa Kodama, Makiko Taniai, Nobuyuki Torii, Etsuko Hashimoto and Katsutoshi Tokushige Chapter 8 **Non-pharmacological Treatment of Ascites 137** Asma Alnajjar, Faisal Abaalkhail, Tala Beidas, Mohamed R. Abdelfattah and Hussien Elsiesy

### Chapter 9 **Ascites in Ovarian Cancer Progression: Opportunities for Biomarker Discovery and New Avenues for Targeted Therapies 145**

Isabelle Matte, Paul Bessette and Alain Piché

## Preface

Chapter 7 **Predictors of the Response to Tolvaptan Therapy and Its Effect on Prognosis in Cirrhotic Patients with Ascites 125**

Hashimoto and Katsutoshi Tokushige

Chapter 8 **Non-pharmacological Treatment of Ascites 137**

Chapter 9 **Ascites in Ovarian Cancer Progression: Opportunities for**

Isabelle Matte, Paul Bessette and Alain Piché

Abdelfattah and Hussien Elsiesy

**Therapies 145**

**VI** Contents

Tomomi Kogiso, Kuniko Yamamoto, Mutsuki Kobayashi, Yuichi Ikarashi, Kazuhisa Kodama, Makiko Taniai, Nobuyuki Torii, Etsuko

Asma Alnajjar, Faisal Abaalkhail, Tala Beidas, Mohamed R.

**Biomarker Discovery and New Avenues for Targeted**

Several pathogenic processes have been implicated in the development of the abdominal ascites. Portal hypertension, most usually in the context of liver cirrhosis, can explain about 75% of the cases, whereas infective, inflammatory and infiltrative etiologies can account for the rest.

The use of ascitic amylase and mycobacterial cultures/PCR when there is strong suspicion for tuber‐ culosis and pancreatitis, respectively, helps to achieve a correct diagnosis. Ascitic cytology can be useful when cancer is suspected and has a good diagnostic yield, if it is performed correctly.

Effective treatment of the cirrhotic ascites is based on the use of a salt-free diet together with the rational use of diuretics. The most commonly used are the antagonists of aldosterone acting on the distal tubule and associated in some situations with furosemide that acts on the proximal tub‐ ular part of the kidney inhibiting the sodium reabsorption at this level. When the situation is un‐ responsive to diuretics, other techniques including the performance of a TIPS (Transjugular Intrahepatic Portosystemic Shunt) can be used. The correct management of ascites permits to ach‐ ieve a great improvement on the quality of life and also on the survival rate.

Common complications of decompensated liver cirrhosis are esophageal varices, hepatic encephal‐ opathy, and ascites. After the onset of complications, the prognosis notably worsens. In patients with ascites, the 5-year mortality rate is 44%. Furthermore, the presence of hyponatremia, the spon‐ taneous bacterial peritonitis presentation, and the onset of a hepatorenal syndrome, together with an increase in the liver insufficiency degree, also greatly worsen the prognosis of the patient.

There is a general agreement about the recommendation to use cefotaxime as the first antibiotic of choice for SBP and large-volume paracentesis for the management of ascites greater than 5L in vol‐ ume. For hepatorenal syndrome, cautious diuresis, volume expansion with albumin, and the use of vasoactive drugs are usually recommended. Finally, in the refractory ascites associated with ad‐ vanced cirrhosis, the liver transplant performance is the best option to apply in these patients.

The great advances achieved in the last years will help to get an early and clear diagnosis of tu‐ berculous peritonitis, due to a quick response immunological-based analysis that has permitted to get a better and early treatment for the affected patients.

In carcinomatous peritoneal ascites, there is an increasing evidence supporting an active role of the own ascites in the progression of ovarian cancer. Although much work is still needed, to fully understand the contribution of ascites to ovarian cancer aggressiveness, this tumor environment potentially provides a wealth of opportunities for translational research including biomarker dis‐ covery and novel therapeutic target identification.

I want to thank all the authors for their excellent contributions, InTechOpen editorial team and especially to Ms. Maja Bozicevic, for her continuous collaboration and kind support in the book preparation and for maintaining help all the time when needed during the editorial process.

> **Prof. Luis Rodrigo, MD** Emeritus Full Professor of Medicine, University of Oviedo Oviedo, Spain

**Diagnosis and Physiopathology**

**Provisional chapter**

## **Introductory Chapter: Treatment of Ascites Associated with Cirrhosis and Its Complications with Cirrhosis and Its Complications**

**Introductory Chapter: Treatment of Ascites Associated**

DOI: 10.5772/intechopen.70232

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

Luis Rodrigo

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70232

## **1. Introduction**

The presence of ascites is the commonest complication in patients with cirrhosis. Approximately 60% of cirrhotics end up exhibiting it during the course of their disease. The development of ascites indicates a clear decompensation of the disease and is generally associated with a bad prognosis, with an approximately 40% of 1-year mortality [1, 2].

## **2. Pathophysiology**

In patients with cirrhosis of the liver, a circulatory dysfunction is common, characterized by a decrease in systemic vascular resistance secondary to splanchnic arterial vasodilatation, which occurs as a consequence of portal hypertension.

In the early stages, when cirrhosis is compensated for and patients remain asymptomatic, systemic vascular resistance is low and effective blood volume and blood pressure remain normal, due to an increased cardiac output.

In more advanced phases of cirrhosis, there is progressive splanchnic vasodilatation, accompanied by a marked reduction in the effective arterial volume that can no longer be compensated for by an increase in cardiac output.

In this situation, to maintain an effective blood volume and to maintain blood pressure within normal limits, the systemic baroreceptor systems are activated, leading to the activation of the vasoconstrictor systems, including the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system (SNS) and, in later stages, the non-osmotic hypersecretion of vasopressin.

Despite these positive effects, these vasoconstricting factors also have negative effects, especially because they facilitate the retention of sodium and water by the kidneys, influencing the appearance and maintenance of ascites, oedemas and dilutional hyponatraemia.

In the later stages of the disease, intense renal vasoconstriction occurs, leading to a significant decrease in glomerular filtration and the development of hepatorenal syndrome (HRS).

At this stage, there is also a notable drop in the cardiac output, probably arising from cirrhosis-associated cardiomyopathy, which further worsens the decrease in effective arterial volume (**Table 1**).

**Table 1.** Pathophysiology of ascites and its complications in cirrhosis.

#### **3. Diagnosis**

For every patient who attends a consultation with suspected ascites, it is essential to confirm, using exploratory paracentesis, that they have a clinical decompensation. This is irrespective of whether it is their first occasion or if they have previously had ascites. The analysis of the ascitic fluid makes it possible to rule out other causes of ascites, such as the presence of associated spontaneous bacterial peritonitis (SBP).

The diagnosis of cirrhosis is usually based on clinical, analytical and ultrasound criteria. In case of doubt, the serum albumin/ascites gradient (SAAG) should be determined. When this is greater than 1.1 g/dl, it suggests the existence of portal hypertension. Furthermore, patients with low concentrations of proteins in the ascitic fluid (<1.5 g/dl) have a worse prognosis. Likewise, the polymorphonuclear (PMN) leukocyte count is very useful for ruling out the presence of SBP; in these cases, ascitic fluid cultures must be grown in blood culture bottles.

## **4. Classification**

Despite these positive effects, these vasoconstricting factors also have negative effects, especially because they facilitate the retention of sodium and water by the kidneys, influencing the

In the later stages of the disease, intense renal vasoconstriction occurs, leading to a significant decrease in glomerular filtration and the development of hepatorenal syndrome (HRS).

At this stage, there is also a notable drop in the cardiac output, probably arising from cirrhosis-associated cardiomyopathy, which further worsens the decrease in effective arterial

Cirrhosis

Portal hypertension

Splanchnic arterial vasodilation

Reduction in effective arterial volume

Activation of Vasoconstrictor Systems (Renin-Angiotensin, Sympathetic Nervous, Arginine-Vasopressin Systems)

Normalisation of Persistent activation of vasoconstrictor systems vasoconstrictor systems

Normal excretion Retention Retention Renal of sodium and water of sodium of water vasoconstriction

No ascites Ascites Hyponatremia Hepato-renal

syndrome

For every patient who attends a consultation with suspected ascites, it is essential to confirm, using exploratory paracentesis, that they have a clinical decompensation. This is irrespective

appearance and maintenance of ascites, oedemas and dilutional hyponatraemia.

4 Ascites - Physiopathology, Treatment, Complications and Prognosis

volume (**Table 1**).

**3. Diagnosis**

**Table 1.** Pathophysiology of ascites and its complications in cirrhosis.

The International Club of Ascites has a three-grade classification:

Grade 1: Ascites can only be detected by abdominal ultrasound, since it comprises only a small quantity or is of slight degree and is not accompanied by any clinically evident abdominal distension.

Grade 2: Ascites is usually detected by physical exploration and the patient exhibits moderate abdominal distension.

Grade 3: A voluminous ascites is present, giving rise to pronounced abdominal distension.

## **5. Treatment**

In the absence of other, associated complications, patients with uncomplicated ascites can be treated on an outpatient basis.

#### **5.1. Grade 1 ascites**

In principle, neither dietary nor pharmacological treatments are required.

At present, there is insufficient information about its natural history and possibilities of progression.

#### **5.2. Grade 2 ascites**

This is the most common form of presentation. There is generally a moderate retention of sodium (urinary Na >20 mEq/day), without upsetting the excretion of the solute-free water and with normal glomerular filtration.

The main aim of the treatment is to achieve a negative sodium balance, to which end its oral intake must be reduced and its elimination increased by using diuretics. There is increased sodium reabsorption at the level of the distal tubule due to the presence of secondary-associated hyperaldosteronism.

Therefore, aldosterone-antagonist diuretics, such as spironolactone, are the drugs of choice and are more effective than loop diuretics.

Patients with primary ascitic decompensation should be treated with spironolactone at a dose of 50–100 mg/day and, in the event of the failure to respond, the dose should be progressively increased week by week until a maximum dose of 400 mg/day is reached.

In patients with recurrent ascites, it is recommended to combine furosemide with aldosterone antagonists. The dose of diuretics should be adjusted in order to yield a weight loss of around 500 g/day in patients who only present ascites and of up to 1 kg/day in those with associated oedemas.

As a maintenance treatment, the minimum dose of diuretics necessary to avoid the development of complications related to the treatment, such as hyponatraemia, hepatic encephalopathy or renal failure, should be recommended (**Table 2**).

#### **5.3. Grade 3 ascites**

The first-line treatment for patients with voluminous ascites consists of performing periodic evacuation paracentesis combined with administering intravenous infusions of albumin at a dose of 8 g/l of ascites removed, which is usually carried out under a regime of a short-stay admission in the day hospital.

The evacuation of a large quantity of ascitic fluid may be associated with the well-known post-paracentesis circulatory dysfunction syndrome. To prevent this, appearing infusions of albumin are administered, which reduce the incidence of complications during the following month.

After performing evacuation paracentesis with the subsequent replacement of albumin, patients must continue with a diuretic treatment of the minimum dose necessary to prevent reaccumulation of the ascites. It has been confirmed that intravenous albumin is the most effective plasma expander when more than 5 l of ascites is removed [3–5] (**Table 3**).

**Table 2.** Treatment of moderate (Grade 2) ascites.

- Adhere to a low-sodium diet, with an average content of 80–120 mEq/day

- Initiate diuretic treatment with spironolactone (50–100 mg/day) in a single dose

- Control weight on a daily basis, maintaining a loss of approximately 500 g/day without oedema and 500–1000 g/day when there is ascites with oedema

- If there is no response, progressively increase the dose of spironolactone week by week, up to a maximum of 400 mg/day

- In non-responders, add furosemide at an initial dose of 40 mg/day, possibly increasing this up to a maximum of 160 mg/day

**Table 3.** Treatment of severe (Grade 3) ascites.

#### **6. Refractory ascites**

sodium reabsorption at the level of the distal tubule due to the presence of secondary-associated

Therefore, aldosterone-antagonist diuretics, such as spironolactone, are the drugs of choice

Patients with primary ascitic decompensation should be treated with spironolactone at a dose of 50–100 mg/day and, in the event of the failure to respond, the dose should be progressively

In patients with recurrent ascites, it is recommended to combine furosemide with aldosterone antagonists. The dose of diuretics should be adjusted in order to yield a weight loss of around 500 g/day in patients who only present ascites and of up to 1 kg/day in those with associated

As a maintenance treatment, the minimum dose of diuretics necessary to avoid the development of complications related to the treatment, such as hyponatraemia, hepatic encephalopa-

The first-line treatment for patients with voluminous ascites consists of performing periodic evacuation paracentesis combined with administering intravenous infusions of albumin at a dose of 8 g/l of ascites removed, which is usually carried out under a regime of a short-stay

The evacuation of a large quantity of ascitic fluid may be associated with the well-known post-paracentesis circulatory dysfunction syndrome. To prevent this, appearing infusions of albumin are administered, which reduce the incidence of complications during the following

After performing evacuation paracentesis with the subsequent replacement of albumin, patients must continue with a diuretic treatment of the minimum dose necessary to prevent reaccumulation of the ascites. It has been confirmed that intravenous albumin is the most

effective plasma expander when more than 5 l of ascites is removed [3–5] (**Table 3**).

increased week by week until a maximum dose of 400 mg/day is reached.

hyperaldosteronism.

oedemas.

month.

mg/day

160 mg/day

reaccumulation of ascites

**5.3. Grade 3 ascites**

admission in the day hospital.

g/day when there is ascites with oedema

**Table 2.** Treatment of moderate (Grade 2) ascites.

and are more effective than loop diuretics.

6 Ascites - Physiopathology, Treatment, Complications and Prognosis

thy or renal failure, should be recommended (**Table 2**).

The development of refractory ascites is associated with a poorer short-term prognosis, the median survival being about 6 months. For this reason, all these patients, except the very elderly or those who have serious associated illnesses that contraindicate it, must be considered potential candidates for a liver transplant and should be evaluated to determine their degree of priority in the waiting list.

#### **6.1. Periodic evacuation paracentesis**

The commonest treatment indicated for patients with refractory ascites is to perform periodic evacuation paracentesis simultaneously with the administration of intravenous albumin infusions. In most cases, diuretics are not effective under these circumstances, and they must permanently cease to be used in patients who develop complications related to a diuretic treatment.

In the other patients, who maintain a level of urinary excretion of sodium greater than 30 mEq/day, the diuretic treatment may be maintained in order to delay the reaccumulation of the ascites and thereby also the need for periodic evacuation paracentesis to be performed so often [6, 7].

#### **6.2. Portosystemic venous shunts (TIPS)**

These consist of an anastomosis and an intravascular prosthesis that is introduced percutaneously by a medical expert in haemodynamic techniques. This establishes a new route of communication, at the intrahepatic level, between the portal system and the general circulation. The insertion is generally achieved by entering through the external jugular vein. This gives rise to the term for the prosthesis, the transjugular intrahepatic portosystemic shunt, and its acronym, TIPS.

After the placement, there is an increase in renal blood flow, accompanied by an increase in renal excretion of sodium, consequently giving rise to an improvement in the control of the ascites. The method is more effective than performing evacuation paracentesis for controlling ascites.

However, the placement of TIPS is associated with a higher incidence of complications, among which the most common is the occurrence of episodes of hepatic encephalopathy, as occurs in 30–50% of cases. The use of TIPS is out of the question for patients with advanced cirrhosis [8].

There are no data concerning improved survival rates, for which reason a second-line treatment is considered. It is considered to be indicated only in patients with preserved hepatic function, or when paracentesis is ineffective or has to be performed frequently (**Table 4**).

**Table 4.** Treatment of refractory ascites.

## **7. Hyponatraemia**

This is a frequent complication in patients with advanced cirrhosis and is associated with a poor prognosis. It is an important factor related to the deterioration in the quality of life of these patients.

#### **7.1. Definition and differential diagnosis**

Hyponatraemia is defined in an arbitrary manner, by the presence of a serum sodium concentration of less than 130 mEq/l. It has a mean prevalence of 22% in patients with cirrhosis and ascites. There are two varieties of hyponatraemia: hypovolaemic and hypervolaemic (or dilutional). The differential diagnosis between the two types is fundamental, since their treatment and prognosis are completely different.

#### *7.1.1. Hypovolaemic hyponatraemia*

In general, its origin is related to the loss of extracellular fluid. Patients show signs of dehydration, frequently associated with hepatic encephalopathy. Its most frequent causes are very copious diuresis, secondary to the prolonged or intense administration of diuretics, or the presence

- Adhere to a low-salt diet, with a sodium content less than 80 mEq/day

- Perform evacuation paracentesis repeatedly, in conjunction with intravenous administration of albumin at a dose of 8 g/l of removed ascites

- Avoid diuretic treatment, except when no complications arise and when the patient maintains a level of renal excretion of sodium of >30 mEq/day

of digestive losses of fluids, in the form of vomiting or diarrhoea. Its treatment is based on controlling the cause, suspending diuretics and administering saline solutions to solve the problem.

#### *7.1.2. Hypervolaemic hyponatraemia*

After the placement, there is an increase in renal blood flow, accompanied by an increase in renal excretion of sodium, consequently giving rise to an improvement in the control of the ascites. The method is more effective than performing evacuation paracentesis for controlling

However, the placement of TIPS is associated with a higher incidence of complications, among which the most common is the occurrence of episodes of hepatic encephalopathy, as occurs in 30–50% of cases. The use of TIPS is out of the question for patients with advanced cirrhosis [8]. There are no data concerning improved survival rates, for which reason a second-line treatment is considered. It is considered to be indicated only in patients with preserved hepatic function, or when paracentesis is ineffective or has to be performed frequently (**Table 4**).

This is a frequent complication in patients with advanced cirrhosis and is associated with a poor prognosis. It is an important factor related to the deterioration in the quality of life of

Hyponatraemia is defined in an arbitrary manner, by the presence of a serum sodium concentration of less than 130 mEq/l. It has a mean prevalence of 22% in patients with cirrhosis and ascites. There are two varieties of hyponatraemia: hypovolaemic and hypervolaemic (or dilutional). The differential diagnosis between the two types is fundamental, since their treat-

In general, its origin is related to the loss of extracellular fluid. Patients show signs of dehydration, frequently associated with hepatic encephalopathy. Its most frequent causes are very copious diuresis, secondary to the prolonged or intense administration of diuretics, or the presence

ascites.

**7. Hyponatraemia**

8 g/l of removed ascites

excretion of sodium of >30 mEq/day

to evacuate the ascites by loculation

**Table 4.** Treatment of refractory ascites.

**7.1. Definition and differential diagnosis**

8 Ascites - Physiopathology, Treatment, Complications and Prognosis

ment and prognosis are completely different.

*7.1.1. Hypovolaemic hyponatraemia*

these patients.

This is predominant in patients with advanced cirrhosis and is characterized by the marked expansion of the extracellular volume. It arises as a direct consequence of the reduction in the capacity of the kidneys to eliminate solute-free water and is secondary to the existing circulatory dysfunction.

Its origin is probably multifactorial, although the most important factor is the presence of a non-osmotic hypersecretion of vasopressin, which acts at the level of the renal collecting tubules, causing a significant increase in the retention of free water [9–11].

#### **7.2. Treatment of hypervolaemic or dilutional hyponatraemia**

Treatment is based on increasing the excretion of retained free water, for which several options are available.

#### *7.2.1. Fluid restriction*

This remains the first-line treatment in these patients. Clinical experience indicates that such restriction prevents the progressive drop in plasma sodium levels but is not sufficient to reverse hyponatraemia.

#### *7.2.2. Administration of saline solutions*

Hypertonic saline infusion has been used, but has proved to be of little value. In addition, it is associated with two types of problem. First, their effect is of short duration and, second, sodium levels fall shortly after the treatment is discontinued. Furthermore, they increase ascites and oedema, so their administration was discontinued rapidly.

#### *7.2.3. Albumin*

Infusion of intravenous albumin is usually effective, since, being a good plasma expander, it alleviates circulatory dysfunction. However, because there have been few cases, experience of this recently established method has been very limited so far. Therefore, more studies, with a greater number of patients, are needed to demonstrate its true efficacy [12, 13].

#### *7.2.4. Vaptanes*

These are active, orally administered drugs and are selective antagonists of V2 receptors of vasopressin. They have the effect of increasing renal excretion of solute-free water. They are therefore used in different situations, such as in the treatment of patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in cases of heart failure and in liver cirrhosis, being effective in 45–80% of cirrhosis cases.

Its most frequent side effect is thirst. Significant increases in plasma sodium levels should be avoided, in order to prevent the appearance of neurological complications, such as central pontine myelinolysis, among others.

Tolvaptan was approved in the United States for the treatment of severe hypervolaemic hyponatraemia (Na <125 mEq/l), whereas in Europe it was only approved for the treatment of SIADH. It is mainly indicated only for cirrhotic patients who are on the waiting list for a liver transplant.

However, the US Food and Drug Administration has drawn attention to the potential risk of liver injury from tolvaptan and recommends this drug not be used in patients with liver disease [14, 15].

## **8. Spontaneous bacterial peritonitis**

This is the most frequent and characteristic bacterial infection of patients with liver cirrhosis and associated ascites.

It is defined as the infection of ascitic fluid in the absence of an intra-abdominal focus. The most frequently associated bacteria are the enterobacteriaceae (*Escherichia coli*, *Klebsiella pneumoniae*, etc.) and non-enterococcal streptococci (*Streptococcus pneumoniae*, *S. viridans*, etc.).

In its initial stages, the patient may be asymptomatic, but characteristic symptoms, such as abdominal pain, fever, nausea, vomiting and diarrhoea, soon appear. Patients may also suffer from paralytic ileus, hepatic encephalopathy, digestive haemorrhage or renal failure.

To confirm its diagnosis, it is necessary to perform diagnostic paracentesis and undertake a cell count of the ascitic fluid.

The finding of more than 250 polymorphonuclear leukocytes/cm3 of ascitic fluid is considered diagnostic of SBP, irrespective of the results obtained from bacterial cultures.

Once the diagnosis has been made, an antibiotic treatment should be instituted as soon as possible. Third-generation cephalosporins continue to be the empirical treatment of choice for community-acquired SBPs. In nosocomial episodes and potentially in those related to the health system, antibiotic coverage should be broader and adapted to the local pattern of resistance. The duration of the treatment is adjusted with respect to the results obtained from the paracentesis control diagnostics, continuing for up to 24–48 h after confirmation of the resolution of the infection (<250 PMN/cm3 ).

It should also be remembered that patients presenting with renal and/or hepatic dysfunction at the time of diagnosis should receive intravenous albumin in order to prevent the development of renal failure and to improve short-term survival [16–18].

#### **8.1. Primary SBP prophylaxis**

Patients with a low protein concentration in the ascitic fluid (>10–15 g/dl) have a higher risk of developing a first episode of SBP, in comparison with those in whom the protein concentration remains high. In the absence of additional risk factors, the probability of developing it during the course of 1 year is less than 20%.

Evidence of advanced hepatic impairment (Child-Pugh >9 points), with bilirubin >3 mg/dl, or circulatory dysfunction (creatinine >1.2 mg/dl or a plasma sodium level of <130 mEq/l) in patients with low levels of proteins in the ascites increases the risk of developing an SBP by up to 60%.

Administration of norfloxacin at a dose of 400 mg/day in these patients reduces the probability of infection to 7%, prevents the development of hepatorenal syndrome and improves short-term survival. For this reason, it is appropriate for this subgroup of patients to make long-term use of norfloxacin, especially if they are on the waiting list for a liver transplant [19].

## **9. Hepatorenal syndrome**

Hepatorenal syndrome is a frequent cause of renal failure in patients with advanced liver cirrhosis and is associated with poor short-term prognosis. It is a functional renal failure that develops as a consequence of intense renal vasoconstriction.

#### **9.1. Diagnosis**

Its most frequent side effect is thirst. Significant increases in plasma sodium levels should be avoided, in order to prevent the appearance of neurological complications, such as central

Tolvaptan was approved in the United States for the treatment of severe hypervolaemic hyponatraemia (Na <125 mEq/l), whereas in Europe it was only approved for the treatment of SIADH. It is mainly indicated only for cirrhotic patients who are on the waiting list for a liver transplant. However, the US Food and Drug Administration has drawn attention to the potential risk of liver injury from tolvaptan and recommends this drug not be used in patients with liver

This is the most frequent and characteristic bacterial infection of patients with liver cirrhosis

It is defined as the infection of ascitic fluid in the absence of an intra-abdominal focus. The most frequently associated bacteria are the enterobacteriaceae (*Escherichia coli*, *Klebsiella pneumoniae*, etc.) and non-enterococcal streptococci (*Streptococcus pneumoniae*, *S. viridans*, etc.).

In its initial stages, the patient may be asymptomatic, but characteristic symptoms, such as abdominal pain, fever, nausea, vomiting and diarrhoea, soon appear. Patients may also suffer

To confirm its diagnosis, it is necessary to perform diagnostic paracentesis and undertake a

Once the diagnosis has been made, an antibiotic treatment should be instituted as soon as possible. Third-generation cephalosporins continue to be the empirical treatment of choice for community-acquired SBPs. In nosocomial episodes and potentially in those related to the health system, antibiotic coverage should be broader and adapted to the local pattern of resistance. The duration of the treatment is adjusted with respect to the results obtained from the paracentesis control diagnostics, continuing for up to 24–48 h after confirmation of the resolu-

It should also be remembered that patients presenting with renal and/or hepatic dysfunction at the time of diagnosis should receive intravenous albumin in order to prevent the develop-

Patients with a low protein concentration in the ascitic fluid (>10–15 g/dl) have a higher risk of developing a first episode of SBP, in comparison with those in whom the protein concentration

of ascitic fluid is considered

from paralytic ileus, hepatic encephalopathy, digestive haemorrhage or renal failure.

The finding of more than 250 polymorphonuclear leukocytes/cm3

diagnostic of SBP, irrespective of the results obtained from bacterial cultures.

).

ment of renal failure and to improve short-term survival [16–18].

pontine myelinolysis, among others.

10 Ascites - Physiopathology, Treatment, Complications and Prognosis

**8. Spontaneous bacterial peritonitis**

disease [14, 15].

and associated ascites.

cell count of the ascitic fluid.

tion of the infection (<250 PMN/cm3

**8.1. Primary SBP prophylaxis**

There are two types of HRS: 1 and 2.

Type 1 HRS presents as rapidly progressing acute renal failure, with blood creatinine values increasing sharply to a level greater than 2.5 mg/dl. It is associated with very poor short-term prognosis, with a median survival without treatment of only 2 weeks.

Type 2 HRS is characterized by more moderate and stable renal failure, with plasma creatinine values generally ranging from 1.5 to 2.5 mg/dl. It typically occurs in patients with refractory ascites; their median survival is 6 months.

During follow-up, patients with type 2 HRS may develop type 1 HRS, either spontaneously or due to the presence of a precipitating factor, usually an associated bacterial infection [20–22].

#### *9.1.1. Differential diagnosis*

The diagnosis of HRS involves excluding other causes for the development of renal failure in a cirrhotic patient, since they can present different causes, such as hypovolaemia, bacterial infections, acute tubular necrosis, administration of nephrotoxic drugs (nonsteroidal anti-inflammatory drugs, antibiotics such as gentamicin, etc.) and parenchymal nephropathy.

There are no objective variables by which these causes of renal failure can be distinguished, which sometimes make differential diagnosis complicated, especially when trying to discriminate between HRS and acute tubular necrosis. Their diagnostic criteria are described subsequently [23, 24] (**Table 5**).

**Table 5.** Diagnostic criteria for hepatorenal syndrome.

#### **9.2. Treatment**

HRS treatment depends on the severity of renal failure and its associated complications. Patients with type 1 HRS who are on a liver transplant waiting list should be treated in an intensive or intermediate care unit, with close monitoring to detect any intercurrent complications at an early stage.

By contrast, patients with type 2 HRS without associated complications can be controlled on an outpatient basis. Therefore, we describe the therapeutic options available to patients with type 1 HRS.

#### *9.2.1. Vasoconstrictors*

The use of vasoconstrictors in conjunction with the intravenous administration of albumin is considered the first-line treatment in the management of patients with type 1 HRS.

Vasoconstrictors used include vasopressin analogues, especially terlipressin and alpha-adrenergic agonists, such as noradrenaline and midodrine.

Treatment with terlipressin and albumin produces a significant improvement in renal function in 40–50% of patients and is accompanied by improved survival.

Treatment usually starts at a dose of 1 mg/4 h in the form of intravenous boluses, increasing to 2 mg/4 h after 3 days if there is no response (defined as a decrease in creatinine by more than 25% of the baseline level).

Relapse after treatment is infrequent; if it occurs, it is advisable to repeat the same treatment [25–27].

Patients being treated with vasoconstrictors and albumin should be monitored closely in order to detect the presence of possible side effects. These are mainly of an ischaemic and cardiovascular nature and can appear in 10–15% of cases. The treatment is also effective and safe in patients with associated bacterial infections.

#### *9.2.2. Other vasoconstrictors*

The wider availability and lower cost of noradrenaline and midodrine, both in combination with albumin, make them an attractive alternative to treatment with terlipressin. The efficacy and safety of noradrenaline are similar to those of terlipressin in the treatment of patients with type 1 HRS. The same is true of midodrine, although clinical experience of its use is more limited.

Norepinephrine is given at a dose of 0.5–3.0 mg/h in continuous intravenous infusion, with the aim of increasing the mean blood pressure to 10 mm Hg. Treatment is continued until the level of blood creatinine drops below 1.5 mg/dl.

#### *9.2.3. TIPS*

**9.2. Treatment**

type 1 HRS.

tions at an early stage.

12 Ascites - Physiopathology, Treatment, Complications and Prognosis

**Table 5.** Diagnostic criteria for hepatorenal syndrome.

(>50 red cells/high-magnification field) and/or an abnormal renal ultrasound result.

*9.2.1. Vasoconstrictors*

25% of the baseline level).

[25–27].

agonists, such as noradrenaline and midodrine.

safe in patients with associated bacterial infections.

HRS treatment depends on the severity of renal failure and its associated complications. Patients with type 1 HRS who are on a liver transplant waiting list should be treated in an intensive or intermediate care unit, with close monitoring to detect any intercurrent complica-

By contrast, patients with type 2 HRS without associated complications can be controlled on an outpatient basis. Therefore, we describe the therapeutic options available to patients with

The use of vasoconstrictors in conjunction with the intravenous administration of albumin is

Vasoconstrictors used include vasopressin analogues, especially terlipressin and alpha-adrenergic

Treatment with terlipressin and albumin produces a significant improvement in renal func-

Treatment usually starts at a dose of 1 mg/4 h in the form of intravenous boluses, increasing to 2 mg/4 h after 3 days if there is no response (defined as a decrease in creatinine by more than

Relapse after treatment is infrequent; if it occurs, it is advisable to repeat the same treatment

Patients being treated with vasoconstrictors and albumin should be monitored closely in order to detect the presence of possible side effects. These are mainly of an ischaemic and cardiovascular nature and can appear in 10–15% of cases. The treatment is also effective and

considered the first-line treatment in the management of patients with type 1 HRS.

tion in 40–50% of patients and is accompanied by improved survival.

TIPS may be considered an alternative treatment to that with vasoconstrictors, since it also improves renal function in this type of patient. Its clinical application under these circumstances is rather limited, since many patients with type 1 HRS present contraindications for its implementation, of which the most frequent and serious is advanced liver failure.

#### *9.2.4. Renal substitution therapy (hepatic dialysis)*

This treatment modality is only indicated in patients with type 1 HRS who do not respond to treatment with vasoconstrictors and albumin, and who develop criteria requiring urgent dialysis, such as hypervolaemia, hyperkalaemia, metabolic acidosis, and so on. Fortunately, however, these situations are rare in this group of patients.

Other dialysis methods include the use of the molecular adsorbent recirculation system (MARS) and Prometheus, a dialysis machine to which a module is added for fractional plasma separation and adsorption. However, their usefulness is very limited in these patients.

#### *9.2.5. Liver transplant*

Liver transplant is the definitive treatment and therefore the first choice for patients with types 1 and 2 HRS. Therefore, every patient who presents an HRS should be referred to a reference centre where the operation can be performed.

Its functional nature makes HRS potentially reversible after orthotopic liver transplantation (OLT) without associated renal transplantation. Double transplantation (liver and kidney) should only be considered in patients who have required prolonged renal support for 6–8 weeks, because the probability of their HRS reverting is very low.

Patients with type 1 HRS should be prioritized on the transplant waiting list, since they are at a high risk of early mortality. The use of the model for end-stage liver disease (MELD) scoring method as an organ distribution system has made it possible to prioritize these patients, since it includes serum creatinine in the scoring.

It should be noted that although the renal function of patients with type 1 HRS improves after treatment with vasoconstrictors, the creatinine used to calculate the MELD score in these patients should be that obtained beforehand, at the beginning of treatment, so that they remain as priorities in the waiting list [28].

Treatment with vasoconstrictors and albumin before the liver transplant is recommended, since prior improvement of renal function may improve the prognosis during the post-transplant period.

## **Author details**

Luis Rodrigo

Address all correspondence to<EMAIL_ADDRESS>
University of Oviedo, Spain

## **References**

[10] John S, Thuluvath PJ. Hyponatremia in cirrhosis: Pathophysiology and management. World Journal of Gastroenterology. 2015;**21**:3197-3205

these patients should be that obtained beforehand, at the beginning of treatment, so that they

Treatment with vasoconstrictors and albumin before the liver transplant is recommended, since prior improvement of renal function may improve the prognosis during the post-transplant

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[2] Fukui H, Saito H, Ueno Y, Uto H, Obara K, Sakaida I, et al. Evidence-based clinical practice guidelines for liver cirrhosis 2015. Journal of Gastroenterology. 2016;**51**:629-650

[3] James J, Liou IW. Comprehensive care of patients with chronic liver disease. Medical

[4] Pedersen JS, Bendtsen F, Møller S. Management of cirrhotic ascites. Therapeutic

[5] Solá E, Solé C, Ginés P. Management of uninfected and infected ascites in cirrhosis. Liver

[6] Annamalai A, Wisdom L, Herada M, Nourredin M, Ayoub W, Sundaram V, et al. Management of refractory ascites in cirrhosis: Are we out of date? World Journal of

[7] Sen Sarma M, Yachha SK, Bhatia V, Srivastava A, Poddar U. Safety, complications and outcome of large volume paracentesis with or without albumin therapy in children with

[8] Sankar K, Moore CM. Transjugular intrahepatic portosystemic shunts. Journal of

[9] Sinha VK, Ko B. Hyponatremia in cirrhosis, pathogenesis, treatment and prognostic

severe ascites due to liver disease. Journal of Hepatology. 2015;**63**:1126-1132

significance. Advances in Chronic Kidney Disease. 2015;**22**:361-367

remain as priorities in the waiting list [28].

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Address all correspondence to<EMAIL_ADDRESS>
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Luis Rodrigo

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**Provisional chapter**

## **Cirrhotic Ascites: Pathophysiological Changes and Clinical Implications Clinical Implications**

**Cirrhotic Ascites: Pathophysiological Changes and**

DOI: 10.5772/intechopen.70537

Abdulrahman Bendahmash, Hussien Elsiesy and Waleed K. Al-hamoudi and Waleed K. Al-hamoudi Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Abdulrahman Bendahmash, Hussien Elsiesy

http://dx.doi.org/10.5772/intechopen.70537

#### **Abstract**

[24] Acevedo JG, Cramp ME. Hepatorenal syndrome: Update on diagnosis and therapy.

[25] Sanyal A, Boyer T, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt B, et al. A prospective, randomized, double-blind, placebo-controlled trial of terlipressin for type 1

[26] Martin-Llahi M, Pepin MN, Guevara G, Díaz F, Torre A, Monescillo A, et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: A ran-

[27] Boyer TD, Sanyal AJ, Wong F, Frederick RT, Lake JR, O'Leary JG, et al.; Reverse Study Investigators. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1.

[28] Ginés P, Fernández J, Durand F, Saliba F. Management of critically-ill cirrhotic patients.

hepatorenal syndrome (HRS). Gastroenterology. 2008;**134**:1360-1368

World Journal of Hepatology. 2017;**9**:293-299

16 Ascites - Physiopathology, Treatment, Complications and Prognosis

Gastroenterology. 2016;**150**:1579-1589

Journal of Hepatology. 2012;**56**(Suppl 1):S13-S24

domized study. Gastroenterology. 2008;**134**:1352-1359

Liver cirrhosis is associated with a wide range of systemic and pulmonary vascular abnormalities. Cardiac dysfunction also occurs in patients with advanced liver disease (cirrhotic cardiomyopathy). The circulation in cirrhosis is hyperdynamic, which is typically characterized by hypotension resulting from the associated vasodilatation and reflex tachycardia. The circulatory dysfunction in cirrhosis is the proposed pathophysiological mechanism leading to sodium and water retention in patients with liver cirrhosis. Hyperdynamic circulation is triggered by increased intrahepatic resistance due to cirrhosis, leading to a progressive increase in portal venous pressure. As portal hypertension worsens, local production of vasodilators increases due to endothelial activation, leading to splanchnic and systemic arterial vasodilation. Nitric oxide (NO) is considered one of the most important vasodilator molecules in the splanchnic and systemic circulation. The reduction in the effective arterial blood volume results in diminished renal arterial blood flow and subsequently triggers the rennin-angiotensin-aldosterone system (RAAS), antidiuretic hormones (ADHs) and sympathetic nervous system (SNS), leading to renal artery vasoconstriction. All these changes lead to sodium retention and volume expansion, manifested as ascites and peripheral edema. Furthermore, disease progression is associated with various degrees of renal dysfunction.

**Keywords:** cirrhosis, portal hypertension, hyperdynamic circulation, ascites

#### **1. Introduction**

Liver cirrhosis is associated with a wide range of systemic and pulmonary vascular abnormalities. Cardiac dysfunction has also been described in patients with advanced liver disease (cirrhotic cardiomyopathy) [1–4]. The circulation in cirrhosis has been described as being

© 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. © 2017 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.

hyperdynamic, which is typically characterized by hypotension resulting from the associated vasodilatation and reflex tachycardia. These cardiovascular abnormalities play a major role in the pathogenesis of multiple life-threatening complications, including ascites, spontaneous bacterial peritonitis, hepatorenal syndrome (HRS), esophageal varices and pulmonary related complications [5, 6]. The hyperdynamic circulation is triggered by increased intrahepatic resistance due to cirrhosis, leading to a progressive increase in portal venous pressure [7, 8]. As portal hypertension worsens, there is an increased local production of vasodilators due to endothelial activation, leading to splanchnic and systemic arterial vasodilation. Nitric oxide (NO) is thought to be one of the most important vasodilator molecules in the splanchnic and systemic circulation. NO is overproduced in cirrhosis; measured serum levels are significantly elevated in both cirrhotic patients and in animal models [9–11]. The reduction in the effective arterial blood volume results in diminished renal arterial blood flow and subsequently triggers the rennin-angiotensin-aldosterone system (RAAS), antidiuretic hormone (ADH) and sympathetic nervous system (SNS), leading to renal artery vasoconstriction. All these changes lead to sodium retention and volume expansion, manifested as ascites and peripheral edema. Furthermore, advanced liver disease is usually associated with various degrees of renal dysfunction. In cirrhotic patients with hepatorenal syndrome (HRS), renal plasma flow and glomerular filtration rate (GFR) are significantly diminished and may reach levels similar to those seen in patients with advanced renal disease [12, 13]. Sodium retention usually occurs in association with the inability to excrete a normal water load, resulting in increased total body water and dilutional hyponatremia [14, 15]. However, unlike the situation of end-stage renal disease, no significant histological abnormality is present within the kidneys of patients with HRS, and the process is reversible after liver transplantation (LT) [16]. The aim of this chapter is to discuss the impact of portal hypertension on the cardiovascular system in cirrhosis, with special emphasis on the pathogenesis of ascites.

#### **2. Ascites**

The peritoneum is a serous membrane made up of visceral and parietal layers. The parietal peritoneum lines the coelomic cavity, and the visceral layer of the peritoneum lines the surface of organs. The peritoneal cavity is an empty space between the visceral and parietal layers of the peritoneum. The potential space of the peritoneal cavity is normally not visible on imaging as it contains only a small amount of fluid (approximately 100 mL). The fluid is mostly water with electrolytes, antibodies, white blood cells, albumin, glucose and other biochemicals [17]. Its main function is to reduce the friction between the abdominal organs as they move around during digestion. The word ascites is derived from the Greek word "askos," which means a bag or sack and is defined as pathological fluid accumulation within the peritoneal cavity. Ascites is a frequent complication of cirrhosis and portal hypertension because of the increase of the sinusoidal hydrostatic pressure. Cirrhosis accounts for over 75% of episodes of ascites, with all other causes accounting for less than 25% (**Table 1**) [18]. Ascites has been associated with increased morbidity and mortality, with liver transplant-free mortality rates ranging from 15 to 20% at 1 year to nearly 50–60% at 5 years from the time of diagnosis [19, 20].

## **3. The heart (cirrhotic cardiomyopathy)**

**Table 1.** Causes of ascites.

hyperdynamic, which is typically characterized by hypotension resulting from the associated vasodilatation and reflex tachycardia. These cardiovascular abnormalities play a major role in the pathogenesis of multiple life-threatening complications, including ascites, spontaneous bacterial peritonitis, hepatorenal syndrome (HRS), esophageal varices and pulmonary related complications [5, 6]. The hyperdynamic circulation is triggered by increased intrahepatic resistance due to cirrhosis, leading to a progressive increase in portal venous pressure [7, 8]. As portal hypertension worsens, there is an increased local production of vasodilators due to endothelial activation, leading to splanchnic and systemic arterial vasodilation. Nitric oxide (NO) is thought to be one of the most important vasodilator molecules in the splanchnic and systemic circulation. NO is overproduced in cirrhosis; measured serum levels are significantly elevated in both cirrhotic patients and in animal models [9–11]. The reduction in the effective arterial blood volume results in diminished renal arterial blood flow and subsequently triggers the rennin-angiotensin-aldosterone system (RAAS), antidiuretic hormone (ADH) and sympathetic nervous system (SNS), leading to renal artery vasoconstriction. All these changes lead to sodium retention and volume expansion, manifested as ascites and peripheral edema. Furthermore, advanced liver disease is usually associated with various degrees of renal dysfunction. In cirrhotic patients with hepatorenal syndrome (HRS), renal plasma flow and glomerular filtration rate (GFR) are significantly diminished and may reach levels similar to those seen in patients with advanced renal disease [12, 13]. Sodium retention usually occurs in association with the inability to excrete a normal water load, resulting in increased total body water and dilutional hyponatremia [14, 15]. However, unlike the situation of end-stage renal disease, no significant histological abnormality is present within the kidneys of patients with HRS, and the process is reversible after liver transplantation (LT) [16]. The aim of this chapter is to discuss the impact of portal hypertension on the cardiovas-

18 Ascites - Physiopathology, Treatment, Complications and Prognosis

cular system in cirrhosis, with special emphasis on the pathogenesis of ascites.

The peritoneum is a serous membrane made up of visceral and parietal layers. The parietal peritoneum lines the coelomic cavity, and the visceral layer of the peritoneum lines the surface of organs. The peritoneal cavity is an empty space between the visceral and parietal layers of the peritoneum. The potential space of the peritoneal cavity is normally not visible on imaging as it contains only a small amount of fluid (approximately 100 mL). The fluid is mostly water with electrolytes, antibodies, white blood cells, albumin, glucose and other biochemicals [17]. Its main function is to reduce the friction between the abdominal organs as they move around during digestion. The word ascites is derived from the Greek word "askos," which means a bag or sack and is defined as pathological fluid accumulation within the peritoneal cavity. Ascites is a frequent complication of cirrhosis and portal hypertension because of the increase of the sinusoidal hydrostatic pressure. Cirrhosis accounts for over 75% of episodes of ascites, with all other causes accounting for less than 25% (**Table 1**) [18]. Ascites has been associated with increased morbidity and mortality, with liver transplant-free mortality rates ranging from 15 to 20% at 1 year to nearly 50–60% at 5 years from the time of

**2. Ascites**

diagnosis [19, 20].

In 1953, Kowalski and Abelmann described an abnormal circulatory pattern in a group of cirrhotic patients. The examined the circulation in 22 alcoholic cirrhotic patients and concluded that these patients had a large stroke volume, prolonged Q-T interval and reduced peripheral vascular resistance. They were some of the first researchers to question the impact of liver disease on the heart [21]. These findings were then confirmed in multiple experimental models of portal hypertension and in patients with cirrhosis. Initially, it was thought that these circulatory manifestations were secondary to alcoholic-related malnutrition; however, future studies confirmed the same circulatory dysregulation in cirrhotic patients with various underlying etiologies [1–4]. In the absence of known cardiac disease, the diagnostic criteria for cirrhotic cardiomyopathy rest on the presence of an attenuated systolic or diastolic response to stressful stimuli and are supported by the presence of structural or histological changes in cardiac chambers, electrophysiological abnormalities and elevation in serum markers suggestive of cardiac stress [22]. In addition to abnormal systolic dysfunction, cirrhotic patients also clearly demonstrate abnormal diastolic dysfunction, especially in patients with ascites, and it has been shown that paracentesis can improve diastolic dysfunction. Left ventricular (LV) diastolic dysfunction manifests as impaired LV relaxation secondary to LV wall stiffness, which results in the increase in filling pressure. Glenn et al. investigated the role of passive tension regulators—titin and collagen—in the pathogenesis of cirrhotic diastolic dysfunction. They showed that alterations in titin modulation, PKA levels, and collagen configuration contributed to the pathogenesis of this condition [23]. Velocity of blood flow from the left atrium to the left ventricle during early (E wave) and late (A wave) phases of diastole can help in assessing diastolic function. A low E/A ratio indicates a noncompliant ventricle [24]. This finding was also confirmed in other studies [25, 26]. Multiple factors affecting cardiac cell function have been implicated in the pathogenesis of cirrhotic cardiomyopathy, including: (a) Down regulation of β-adrenergic receptors, which negatively impacts cardiac contractility [27]; (b) Reduction in the cardiac cell membrane fluidity, which impairs the function of membrane-bound ion channels, alters control of vascular tone and reduces the β-adrenoceptor function [28, 29]; (c) Reduced muscarinic receptor activity, which has a negative inotropic effect on the heart [30]; (d) Augmented nitric oxide activity, which negatively impacts cardiac contractility [31, 32]; (e) Carbon monoxide (CO) and endocannabinoid activity negatively impacts cardiac contractility in cirrhotic patients [33–35]. Multiple other studies have demonstrated significant structural cardiac abnormalities in all cardiac chambers of cirrhotic patients [36].

#### **4. Systemic and splanchnic circulation**

Portosystemic collaterals are formed secondary to cirrhosis-induced portal hypertension, which allows gut-derived humoral substances to directly enter systemic circulation without detoxification by the liver. Arterial vasodilatation in portal hypertension results from the predominant production of various vasodilators [37]. NO is thought to be the major vasodilator molecule in cirrhotic patients. The intrahepatic microcirculation is altered significantly in liver cirrhosis, secondary to both architectural and vasoactive humoral changes, resulting in an increase in vasoactive molecules associated with a decrease in intrahepatic NO production [38, 39]. On the other hand, multiple studies have documented an elevated serum level of NO in the systemic and splanchnic circulation in both cirrhotic patients and in animal models [40–43]. NO is an endothelial-derived relaxing factor that leads to systemic arterial vasodilatation. Three isoforms of NO synthase (NOS) have been described: endothelial (eNOS), inducible (iNOS), and neuronal (nNOS). However, the leading isoform contributing to these vascular changes remains obscure [44]. Ferguson and colleagues were the first group to use a highly selective iNOS inhibitor to evaluate the role iNOS in the regulation of vascular tone in patients with ascites. Forearm blood flow was measured in eight patients with ascites and was compared with eight matched healthy volunteers, during intrabrachial infusion of 1400 W (0.1–1 μmol/min), NG-monomethyl-L-arginine (L-NMMA, a non-selective NOS inhibitor; 2–8 μmol), and norepinephrine. They showed that iNOS inhibitor causes systemic vasoconstriction in patients with ascites only. This supports the role of iNOS in the circulatory changes associated with cirrhosis [45]. One major factor that plays an important role in promoting NO production is the altered intestinal permeability in patients with advanced liver disease. As a result various endotoxins cross the intestine to the systemic circulation and stimulate the production of NO [46, 47]. TNF-α is also considered to be a NO inducers. Inhibition of TNF-α production resulted in improvement in the hyperdynamic circulation in various animal model studies [48, 49]. Endocannabinoids have also been implicated in the peripheral vasodilatation of cirrhosis. Activation of endothelial cannabinoid receptors by the endogenously produced endocannabinoids causes pronounced vasodilatation in cirrhotic rats [50, 51]. Interestingly, multiple studies have shown a potentially important role of the central nervous system (CNS) in the pathogenesis of the portal hypertension-induced hyperdynamic circulation. The cardiovascular system is controlled by neural influences that include the central nervous system (CNS) and peripheral afferent and efferent nerves. Portal hypertension activates receptors in the mesenteric area; the signals are relayed to central

**Table 2.** Pathogenic mechanisms of cardiovascular disturbance in cirrhotic patients.

cardiovascular-regulatory nuclei via afferent nerves. These nuclei then process the inputs and send out signals to the cardiovascular system through efferent pathways, leading to cardiovascular changes [52]. Li and colleagues demonstrated that neonatal capsaicin denervation in rats prevented the development of hyperdynamic circulation and renal dysfunction as well as ascites formation in cirrhosis. These results indicate that intact primary afferent innervation is necessary for the development of hyperdynamic circulation and ascites formation [53]. A recent study revealed reversal of the cirrhosis associated vascular dysregulation after afferent denervation in an animal model. Portal vein ligation in cirrhotic rats activates a marker protein in the brain stem indicating CNS activation. Furthermore, blocking CNS Fos expression in cirrhotic rats resulted in eliminating the development of the hyperdynamic circulation [54]. The various potential pathogenic mechanisms leading to cardiovascular disturbance and fluid retention are summarized in **Table 2**.

#### **5. The lymphatic system**

impacts cardiac contractility [27]; (b) Reduction in the cardiac cell membrane fluidity, which impairs the function of membrane-bound ion channels, alters control of vascular tone and reduces the β-adrenoceptor function [28, 29]; (c) Reduced muscarinic receptor activity, which has a negative inotropic effect on the heart [30]; (d) Augmented nitric oxide activity, which negatively impacts cardiac contractility [31, 32]; (e) Carbon monoxide (CO) and endocannabinoid activity negatively impacts cardiac contractility in cirrhotic patients [33–35]. Multiple other studies have demonstrated significant structural cardiac abnormalities in all cardiac

Portosystemic collaterals are formed secondary to cirrhosis-induced portal hypertension, which allows gut-derived humoral substances to directly enter systemic circulation without detoxification by the liver. Arterial vasodilatation in portal hypertension results from the predominant production of various vasodilators [37]. NO is thought to be the major vasodilator molecule in cirrhotic patients. The intrahepatic microcirculation is altered significantly in liver cirrhosis, secondary to both architectural and vasoactive humoral changes, resulting in an increase in vasoactive molecules associated with a decrease in intrahepatic NO production [38, 39]. On the other hand, multiple studies have documented an elevated serum level of NO in the systemic and splanchnic circulation in both cirrhotic patients and in animal models [40–43]. NO is an endothelial-derived relaxing factor that leads to systemic arterial vasodilatation. Three isoforms of NO synthase (NOS) have been described: endothelial (eNOS), inducible (iNOS), and neuronal (nNOS). However, the leading isoform contributing to these vascular changes remains obscure [44]. Ferguson and colleagues were the first group to use a highly selective iNOS inhibitor to evaluate the role iNOS in the regulation of vascular tone in patients with ascites. Forearm blood flow was measured in eight patients with ascites and was compared with eight matched healthy volunteers, during intrabrachial infusion of 1400 W (0.1–1 μmol/min), NG-monomethyl-L-arginine (L-NMMA, a non-selective NOS inhibitor; 2–8 μmol), and norepinephrine. They showed that iNOS inhibitor causes systemic vasoconstriction in patients with ascites only. This supports the role of iNOS in the circulatory changes associated with cirrhosis [45]. One major factor that plays an important role in promoting NO production is the altered intestinal permeability in patients with advanced liver disease. As a result various endotoxins cross the intestine to the systemic circulation and stimulate the production of NO [46, 47]. TNF-α is also considered to be a NO inducers. Inhibition of TNF-α production resulted in improvement in the hyperdynamic circulation in various animal model studies [48, 49]. Endocannabinoids have also been implicated in the peripheral vasodilatation of cirrhosis. Activation of endothelial cannabinoid receptors by the endogenously produced endocannabinoids causes pronounced vasodilatation in cirrhotic rats [50, 51]. Interestingly, multiple studies have shown a potentially important role of the central nervous system (CNS) in the pathogenesis of the portal hypertension-induced hyperdynamic circulation. The cardiovascular system is controlled by neural influences that include the central nervous system (CNS) and peripheral afferent and efferent nerves. Portal hypertension activates receptors in the mesenteric area; the signals are relayed to central

chambers of cirrhotic patients [36].

**4. Systemic and splanchnic circulation**

20 Ascites - Physiopathology, Treatment, Complications and Prognosis

The lymphatic vascular system plays a critical role in ascites formation [55]. Lymphatic vessels remove fluid from the interstitial fluid from various parts of the body and drain it into the blood stream. In healthy adult individuals, the lymphatic system returns as much as eight liters of interstitial fluid with 20–30 g of protein per liter to venous circulation every day. Any disturbance to this process leads to fluid accumulation, manifested as edema and ascites [55–58]. As with systemic and splanchnic circulation, the lymphatic system is also influenced by nitric oxide, leading to vasodilatation [59]. The development of portal hypertension in cirrhosis is associated with an increase in portal lymph flow. Normally, the liver produces a large amount of lymph, which is estimated to be over 25% of the lymph flowing through the thoracic duct. Barrowman and colleagues demonstrated an increase in lymph flows from the intestine and liver in cirrhotic animals by threefold and 30-fold, respectively, over values obtained from control animals. They also demonstrated a good correlation between intestinal and liver lymph flows and portal venous pressure [60]. In portal hypertension, compensatory lymphangiogenic response may initially help to reduce the high portal pressure. Oikawa and colleagues used a morphometric analysis to examine portal hypertensive-associated changes in lymph vessels and branches of the portal vein, with use of immunohistochemical staining for alpha smooth muscle actin, and quantitated these changes using an image analysis system. They obtained wedge liver biopsies from 10 patients with advanced portal hypertension and 10 control samples from patients with gastric carcinoma without liver disease. They showed that the proliferation of lymph vessels were higher in portal hypertension samples compared to the control samples. On the other hand, the number of portal vein branches in portal hypertension samples was not different from control samples. They concluded that these alterations in portal hypertension may result in a decrease in portal flow associated with an increase in lymph flow resulting in a reduction of the high portal vein pressure in idiopathic portal hypertension [61]. With worsening liver fibrosis and ongoing portal hypertension, the lymphatic system fails, resulting in buildup of interstitial fluids and ascites formation [55].

### **6. Renal response**

The systemic vasodilation in patients with cirrhosis leads to under filling of arterial vascular space and that leads to systemic hypotension. Consequently, baroreceptor-mediated activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) and nonosmotic release of antidiuretic hormone (ADH) occur to restore normal hemodynamics. This leads to fluid and sodium retention (**Figure 1**). Sodium retention is the most common abnormality of renal function in patients with cirrhosis and ascites [12, 62, 63]. The total amount of sodium retained in patients with cirrhosis is dependent on sodium intake, non-renal sodium losses and sodium excreted in the urine. Minimizing sodium intake in cirrhotic patients may help control ascites. With ongoing hemodynamic disturbance in cirrhosis, the equation tips toward sodium retention. Associated with this is an increase in splanchnic permeability that, aided by the changes in oncotic pressure, combines to lead to ascites formation [63]. In the initial phases of the disease, this is compensated by an increase in lymph return. In fact, the thoracic duct lymph flow, which in normal conditions is lower than 1 liter per day, may increase by several folds. When lymph formation overcomes lymph drainage, this also results in ascites formation. As a result, renal vasoconstriction persists and results in various degrees of renal impairment. The extreme effect would result in severe renal failure with elevation of blood urea nitrogen and serum-creatinine concentration. The associated hyponatremia in portal hypertensive ascites carries a bad prognostic value and has been linked to mortality [64].

Refractory ascites refers to ascites that cannot be resolved by dietary sodium restriction and diuretic treatment. The severity of renal sodium retention increases with the progression of

Renal Vasoconstriction

Baroreceptor-mediated activation of 1- Renin-angiotensin-aldosterone system (RAAS)

2-Sympathetic nervous system 3- Antidiuretic hormone (ADH)

Sodium and water retention

Ascites Formation

**Figure 1.** The cascade of changes leading to ascites formation.

hypertension in cirrhosis is associated with an increase in portal lymph flow. Normally, the liver produces a large amount of lymph, which is estimated to be over 25% of the lymph flowing through the thoracic duct. Barrowman and colleagues demonstrated an increase in lymph flows from the intestine and liver in cirrhotic animals by threefold and 30-fold, respectively, over values obtained from control animals. They also demonstrated a good correlation between intestinal and liver lymph flows and portal venous pressure [60]. In portal hypertension, compensatory lymphangiogenic response may initially help to reduce the high portal pressure. Oikawa and colleagues used a morphometric analysis to examine portal hypertensive-associated changes in lymph vessels and branches of the portal vein, with use of immunohistochemical staining for alpha smooth muscle actin, and quantitated these changes using an image analysis system. They obtained wedge liver biopsies from 10 patients with advanced portal hypertension and 10 control samples from patients with gastric carcinoma without liver disease. They showed that the proliferation of lymph vessels were higher in portal hypertension samples compared to the control samples. On the other hand, the number of portal vein branches in portal hypertension samples was not different from control samples. They concluded that these alterations in portal hypertension may result in a decrease in portal flow associated with an increase in lymph flow resulting in a reduction of the high portal vein pressure in idiopathic portal hypertension [61]. With worsening liver fibrosis and ongoing portal hypertension, the lymphatic system fails, resulting in

The systemic vasodilation in patients with cirrhosis leads to under filling of arterial vascular space and that leads to systemic hypotension. Consequently, baroreceptor-mediated activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) and nonosmotic release of antidiuretic hormone (ADH) occur to restore normal hemodynamics. This leads to fluid and sodium retention (**Figure 1**). Sodium retention is the most common abnormality of renal function in patients with cirrhosis and ascites [12, 62, 63]. The total amount of sodium retained in patients with cirrhosis is dependent on sodium intake, non-renal sodium losses and sodium excreted in the urine. Minimizing sodium intake in cirrhotic patients may help control ascites. With ongoing hemodynamic disturbance in cirrhosis, the equation tips toward sodium retention. Associated with this is an increase in splanchnic permeability that, aided by the changes in oncotic pressure, combines to lead to ascites formation [63]. In the initial phases of the disease, this is compensated by an increase in lymph return. In fact, the thoracic duct lymph flow, which in normal conditions is lower than 1 liter per day, may increase by several folds. When lymph formation overcomes lymph drainage, this also results in ascites formation. As a result, renal vasoconstriction persists and results in various degrees of renal impairment. The extreme effect would result in severe renal failure with elevation of blood urea nitrogen and serum-creatinine concentration. The associated hyponatremia in portal hypertensive ascites carries a bad prognostic value and has been

Refractory ascites refers to ascites that cannot be resolved by dietary sodium restriction and diuretic treatment. The severity of renal sodium retention increases with the progression of

buildup of interstitial fluids and ascites formation [55].

22 Ascites - Physiopathology, Treatment, Complications and Prognosis

**6. Renal response**

linked to mortality [64].

the underlying liver disease and associated portal and systemic hemodynamic disturbance. The ongoing activation of the various neurohumoral pathways leads to aggressive renal reabsorption of sodium and water. Activation of the neurhormonal pathway also leads to a reduction in the glomerular filtration rate (GFR) and subsequently leads to a decline in the renal function. The enhanced sodium reabsorption at the proximal convoluted tubule leads to a significant reduction in the sodium reaching the distal segments of the nephron. This explains the failure of loop diuretics and antimineralocorticoid in treating these patients as they work predominantly at the distal segments of the nephron. Thus, renal sodium retention mainly occurs proximally to the site of action of both antimineralocorticoid and loop diuretics, and this can explain why diuretic treatment becomes unsuccessful in some patients. Furthermore, when cirrhosis progresses and the arterial vasodilation becomes more marked, the heart can no longer keep pace with the marked systemic vasodilatation. This results in an increase in the production of endogenous vasoactive compounds, which further increases sodium and water retention as a result of this physiological response to the relative arterial underfilling [63, 64]. This increased sodium and water retention contributes to increasing ascites, and in many cases, to the development of refractory ascites and type 2 HRS. Kraq and colleagues investigated the relation between cardiac and renal function in patients with cirrhosis and ascites and the impact of cardiac systolic function on survival. Cardiac function was investigated by gated myocardial perfusion imaging for assessment of cardiac index and cardiac volumes. Renal function was assessed by determination of GFR and renal blood flow, and the patients were followed up for 12 months. They demonstrated that patients with a low CI had a lower GFR and a higher creatinine level. The number of patients who developed type 1 HRS within 3 months was significantly higher in the group with low CI than that in the group with high CI. They also showed that patients with the lowest CI had significantly poorer survival at 3, 9, and 12 months than did those with a higher CI [65].

#### **7. Clinical implications**

This circulatory dysfunction in cirrhosis is the proposed pathophysiological mechanism leading to sodium and water retention in patients with liver cirrhosis. Treatment aimed at reversing this pathophysiological process would likely result in improving the outcome. Albumin has been used in clinical trials as a volume expander and, when given with a vasoconstrictor, has been shown to improve renal function in the setting of cirrhotic ascites. Martín-Llahí and colleagues randomized 46 patients with cirrhosis and HRS to receive terlipressin, a vasopressin analog, and albumin (n = 23) or albumin alone (n = 23) for a maximum of 15 days. They monitored renal function closely during the study period. Improvement of renal function occurred in 10 patients (43.5%) treated with terlipressin and albumin compared with that in two patients (8.7%) treated with albumin alone (P = .017) [66]. Similarly, Guevara and colleagues treated 16 patients with HRS with a combination of ornipressin, a potent vasoconstrictor agent, and albumin to improve the cardiovascular dysfunction. The combined treatment was administered for either 3 or 15 days (eight patients each). The shorter treatment duration was associated with normalization of the overactivity of renin-angiotensin and sympathetic nervous systems, a marked increase in atrial-natriuretic peptide levels, and only a slight improvement in renal function. However, when treatment was administered for 15 days outcome was significantly better. Renal function improved dramatically manifested by normalization of serum creatinine associated with an increase in the GFR and a persistent suppression in the activity of vasoconstrictor systems [67]. In another study, Ortega and colleagues showed that terlipressin therapy reverses HRS, and the effect was augmented when coupled with albumin [68]. Patel and colleagues assessed the efficacy of midodrine and octreotide as a therapeutic approach to increasing urinary electrolyte-free water clearance in advanced cirrhosis. Patients were treated with albumin, midodrine and octreotide within the first 24 h. Urinary electrolyte-free water clearance and serum sodium concentration were assessed before and 72 h after treatment. The assessments showed a statistically significant increase in serum sodium concentration and urinary electrolyte-free water clearance with the use of midodrine and octreotide in the treatment of cirrhosis-associated hyponatremia [69]. These studies demonstrate the importance of targeting circulatory dysfunction in endstage liver disease. A more challenging aspect in managing these patients is the associated cirrhotic cardiomyopathy. The development of HRS in the setting of advanced liver disease is associated with a drop in the cardiac output, emphasizing the additional role of cirrhotic cardiomyopathy in the pathogenesis of hepatorenal dysfunction [65]. Other reports suggested a possible role of cirrhotic cardiomyopathy in spontaneous bacterial peritonitis [70].

the underlying liver disease and associated portal and systemic hemodynamic disturbance. The ongoing activation of the various neurohumoral pathways leads to aggressive renal reabsorption of sodium and water. Activation of the neurhormonal pathway also leads to a reduction in the glomerular filtration rate (GFR) and subsequently leads to a decline in the renal function. The enhanced sodium reabsorption at the proximal convoluted tubule leads to a significant reduction in the sodium reaching the distal segments of the nephron. This explains the failure of loop diuretics and antimineralocorticoid in treating these patients as they work predominantly at the distal segments of the nephron. Thus, renal sodium retention mainly occurs proximally to the site of action of both antimineralocorticoid and loop diuretics, and this can explain why diuretic treatment becomes unsuccessful in some patients. Furthermore, when cirrhosis progresses and the arterial vasodilation becomes more marked, the heart can no longer keep pace with the marked systemic vasodilatation. This results in an increase in the production of endogenous vasoactive compounds, which further increases sodium and water retention as a result of this physiological response to the relative arterial underfilling [63, 64]. This increased sodium and water retention contributes to increasing ascites, and in many cases, to the development of refractory ascites and type 2 HRS. Kraq and colleagues investigated the relation between cardiac and renal function in patients with cirrhosis and ascites and the impact of cardiac systolic function on survival. Cardiac function was investigated by gated myocardial perfusion imaging for assessment of cardiac index and cardiac volumes. Renal function was assessed by determination of GFR and renal blood flow, and the patients were followed up for 12 months. They demonstrated that patients with a low CI had a lower GFR and a higher creatinine level. The number of patients who developed type 1 HRS within 3 months was significantly higher in the group with low CI than that in the group with high CI. They also showed that patients with the lowest CI had significantly poorer survival

This circulatory dysfunction in cirrhosis is the proposed pathophysiological mechanism leading to sodium and water retention in patients with liver cirrhosis. Treatment aimed at reversing this pathophysiological process would likely result in improving the outcome. Albumin has been used in clinical trials as a volume expander and, when given with a vasoconstrictor, has been shown to improve renal function in the setting of cirrhotic ascites. Martín-Llahí and colleagues randomized 46 patients with cirrhosis and HRS to receive terlipressin, a vasopressin analog, and albumin (n = 23) or albumin alone (n = 23) for a maximum of 15 days. They monitored renal function closely during the study period. Improvement of renal function occurred in 10 patients (43.5%) treated with terlipressin and albumin compared with that in two patients (8.7%) treated with albumin alone (P = .017) [66]. Similarly, Guevara and colleagues treated 16 patients with HRS with a combination of ornipressin, a potent vasoconstrictor agent, and albumin to improve the cardiovascular dysfunction. The combined treatment was administered for either 3 or 15 days (eight patients each). The shorter treatment duration was associated with normalization of the overactivity of renin-angiotensin and sympathetic nervous systems, a marked increase in atrial-natriuretic peptide levels, and

at 3, 9, and 12 months than did those with a higher CI [65].

24 Ascites - Physiopathology, Treatment, Complications and Prognosis

**7. Clinical implications**

Transjugular intrahepatic portosystemic shunts (TIPS) have been commonly used to treat refractory ascites. Following TIPS insertion, a sudden increase in the preload results in further hemodynamic disturbance, and therefore, careful cardiovascular evaluation prior to the procedure is a necessity [71, 72]. The preexisting subclinical diastolic dysfunction becomes clinically obvious with the sudden increase in the right atrial and pulmonary circulation, leading to heart failure. In a recent study, Ascha and colleagues investigated if echocardiographic and hemodynamic changes at the time of TIPS can provide any prognostic information. After evaluating 418 patients, they showed that a change in the right atrial (RA) pressure after TIPS predicted long-term mortality [73]. Others showed a possible impact of intra-procedural RA pressure on early post-TIPS mortality [74]. Other studies suggested that an E/A ratio of ≤1 was predictive of slow ascites clearance and mortality post-TIPS insertion [75, 76].

Liver transplantation results in correction of portal hypertension and reversal of all the pathophysiological mechanisms that lead to hyperdynamic circulation [77]. We studied the hemodynamics in the immediate post-transplant period and compared patients with alcoholic vs. viral cirrhosis. Within the first 24 h, there was a significant decrease in HR and increase in MAP; the extent of the change was similar in both groups. The central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), and systemic vascular resistance index (SVRI) increased, and changes were more pronounced in the viral group [78]. Navasa and colleagues assessed systemic hemodynamics and plasma levels of aldosterone, glucagon and plasma renin in 12 patients with advanced cirrhosis before and 2 weeks and 2 months after LT. Elevated aldosterone, plasma renin and glucagon levels decreased to near-normal values 2 weeks after transplantation. This decrease was associated with reversal of the associated splanchnic and systemic vasodilation and restoration of normal hemodynamics [79]. Following LT, the rapid reversal of systemic vasodilatation and the associated increase in blood pressure exposes the previously subclinical cirrhotic cardiomyopathy. Cardiovascular complications are a major cause of postoperative morbidity and mortality after liver transplantation [80]. Fouad and colleagues reviewed 197 liver transplant recipients for post-liver transplant-related cardiac complications. Eighty-two patients suffered one or more cardiac complications within 6 months after LT. Pulmonary edema was the most common complication, occurring in 61 patients; other complications included heart failure (7 patients), arrhythmia (13 patients), pulmonary hypertension (7 patients), pericardial effusion (2 patients), and cardiac thrombus formation (1 patient). In their study, cardiac causes were the leading cause of death (23.8% of all mortality) [81].

LT induces significant cardiovascular stress. Predicting the development of postoperative cardiac complications is very difficult. Two-dimensional and dobutamine stress echocardiography were utilized to predict the development of adverse cardiac events following liver transplantation, and both had a low predictive value [82]. More recently, a study utilizing dobutamine stress perfusion, which provides an assessment of both regional systolic and diastolic function as well as microvascular perfusion, revealed a better prediction of posttransplant cardiac outcome [83]. Management at the time of liver transplantation should involve careful fluid management. Immediate postoperative care should include continuous cardiac and hemodynamic monitoring and early detection of any potential arrhythmia or any other cardiac complication.

## **Author details**

Abdulrahman Bendahmash1 , Hussien Elsiesy2,3 and Waleed K. Al-hamoudi2,4\*

\*Address all correspondence to<EMAIL_ADDRESS>
1 Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia

2 Department of Liver Transplantation, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia

3 Department of Medicine, Alfaisal University, Riyadh, Saudi Arabia

4 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia

#### **References**

[4] Al-Hamoudi WK. Cardiovascular changes in cirrhosis: Pathogenesis and clinical implications. Saudi Journal of Gastroenterology. 2010 Jul-Sep;**16**(3):145-153

complications are a major cause of postoperative morbidity and mortality after liver transplantation [80]. Fouad and colleagues reviewed 197 liver transplant recipients for post-liver transplant-related cardiac complications. Eighty-two patients suffered one or more cardiac complications within 6 months after LT. Pulmonary edema was the most common complication, occurring in 61 patients; other complications included heart failure (7 patients), arrhythmia (13 patients), pulmonary hypertension (7 patients), pericardial effusion (2 patients), and cardiac thrombus formation (1 patient). In their study, cardiac causes were the leading cause

LT induces significant cardiovascular stress. Predicting the development of postoperative cardiac complications is very difficult. Two-dimensional and dobutamine stress echocardiography were utilized to predict the development of adverse cardiac events following liver transplantation, and both had a low predictive value [82]. More recently, a study utilizing dobutamine stress perfusion, which provides an assessment of both regional systolic and diastolic function as well as microvascular perfusion, revealed a better prediction of posttransplant cardiac outcome [83]. Management at the time of liver transplantation should involve careful fluid management. Immediate postoperative care should include continuous cardiac and hemodynamic monitoring and early detection of any potential arrhythmia or any

, Hussien Elsiesy2,3 and Waleed K. Al-hamoudi2,4\*

1 Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh,

2 Department of Liver Transplantation, King Faisal Specialist Hospital & Research Center,

4 Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia

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of death (23.8% of all mortality) [81].

26 Ascites - Physiopathology, Treatment, Complications and Prognosis

other cardiac complication.

Abdulrahman Bendahmash1

\*Address all correspondence to<EMAIL_ADDRESS>
3 Department of Medicine, Alfaisal University, Riyadh, Saudi Arabia

culatory dysfunction in liver disease. Heart. 2002;**87**:9-15

**Author details**

Saudi Arabia

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## **Modern Tools for Diagnosis in Tuberculous Ascites**

**Modern Tools for Diagnosis in Tuberculous Ascites**

DOI: 10.5772/intechopen.70417

Andra-Iulia Suceveanu, Despina Todescu, Laura Mazilu, Filippos Goniotakis Manousos, Roxana Hulea, Felix Voinea, Eugen Dumitru and Adrian Paul Suceveanu Laura Mazilu, Filippos Goniotakis Manousos, Roxana Hulea, Felix Voinea, Eugen Dumitru and Adrian Paul Suceveanu Additional information is available at the end of the chapter

Andra-Iulia Suceveanu, Despina Todescu,

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70417

#### **Abstract**

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32 Ascites - Physiopathology, Treatment, Complications and Prognosis

Tuberculosis (TB) is a highly contagious bacterial infection caused by *Mycobacterium tuberculosis* (MTB), affecting about 1/3rd of the world population and being responsible for lot of deaths worldwide, despite the progress achieved in the diagnosis and treatment fields. TB can affect the peritoneum, the TB ascites being a concern for physicians, especially when dealing with immunocompromised patients. The clinical presentation of TB ascites is challenging, due to nonspecific symptoms that make confusion with other diseases and the late results of cultures from ascites. The late diagnosis leads to a delayed treatment and high mortality. This manuscript describes recent tools used for early diagnosis in TB ascites. Molecular methods based on mycobacterial nucleic acid amplification tests (NAATs), polymerase chain reaction (PCR) detecting minimal amounts of bacterial DNA, or interferongamma release assays (IGRA) and biochemical methods such as the serum-ascites albumin gradient (SAAG) <1.1 g/dL, ratio between lactic dehydrogenase (LDH) in ascites fluid/serum total protein (TP) ratio of 0.5 and fluid ascites/serum LDH ratio of 0.6, and adenosine deaminase activity (ADA) > 40 UI/ml were recently considered more accurate diagnostic procedures. These methods allow a rapid and accurate differential diagnosis of ascites fluid, making possible the early treatment with appropriate drugs.

**Keywords:** peritoneal tuberculosis, ascites, diagnosis, molecular tests, biochemical tests

## **1. Introduction**

Tuberculosis (TB) is a dangerous infection affecting about one third of the world population despite the availability of affordable and effective chemotherapy, remaining one of the major

© 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. © 2017 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.

causes of death from a single infectious agent worldwide. The most affected organ is the lung. It is preventable through Bacillus of Calmette and Guérin (BCG) vaccination and curable with antituberculous drugs.

Tuberculosis is a serious and highly contagious bacterial infection which in humans is usually caused by bacteria called *Mycobacterium tuberculosis* (MTB), a member of the *Mycobacteriaceae* family. This complex also includes *M. bovis* and *M. africanum*. *M. bovis* is more frequently found in cattle and other animals, but it's also responsible for some cases in humans. *M. africanum* is more common in West African countries. Mycobacterial infection is spread through the air from one person to another and causes active disease or latent infection [1].

The absolute number of incident cases has been decreasing since the early 2000s. The lowest incidence rate is found in high-income countries including the United States of America, Canada, New Zealand, Western Europe, and Australia. The largest number of incident cases is found in low- and middle-income countries. In 2015, 61% of the new cases occurred in Asia, followed by 26% new cases in Africa (**Figure 1**) [2].

The HIV infection is the prevalent risk factor for the development of TB because HIV alters the pathogenesis of TB by producing a progressive decline in cell-mediated immunity and raises the chances of extrapulmonary involvement [3, 4].

Tuberculosis is a disease which typically involves the respiratory system, being characterized by the growth of tubercles in tissues, but it can affect any other organ, in which case it's called extrapulmonary tuberculosis (EPTB) and usually results from hematogenous dissemination, being particularly present in immunocompromised patients. In some cases the infection directly extends from an adjacent organ. The most common sites of extrapulmonary tuberculosis are the lymph nodes, abdomen, bones and joints, pleura, spinal cord, and brain [5, 6].

**Figure 1.** Worldwide incidence of TB infections.

Abdominal tuberculosis is a common form of extrapulmonary tuberculosis. The infection involving *M. tuberculosis* or *M. bovis* could be the result of a primary infection or the reactivation of a latent focus in immunocompromised patients. The spread of abdominal tuberculosis can be hematogenous or can result from direct contact with primary focus or ingestion of sputum containing bacilli from the active pulmonary focus. This form of EPTB affects the peritoneum, the gut, the abdominal lymph nodes, and sometimes, less frequently, the parenchymatous organs in the abdomen like the spleen, liver, and pancreas leading to severe complications. There are three types of abdominal tuberculosis: ascitic, obstructive, and glandular. Diagnosis can be achieved through different methods: ultrasound of the abdomen, CT/MRI scans, biopsies of the suspected organ, endoscopy, and various function tests.

Peritoneal tuberculosis is an uncommon site of extrapulmonary infection caused by *M. tuberculosis*. Patients susceptible of developing EPTB are those with malignant diseases, HIV infection, diabetes, and cirrhosis or patients treated with antitumor necrosis factor (TNF) agents or peritoneal dialysis. Peritoneal TB is divided into three types: the wet ascitic type, the fixed fibrotic type, and the dry plastic type. The wet ascitic type is more common and is associated with large amounts of free or loculated fluid in the abdomen. The high attenuation of the ascites in abdominal ultrasound is thought to be due to high protein and cellular content. Associated peritoneal enhancement is usually present.

Infection occurs frequently following reactivation of latent tuberculous in the peritoneum from hematogenous spread from a primary lung focus. It can also occur via hematogenous spread from active pulmonary or miliary TB. Not so often, the organisms enter the peritoneal cavity transmurally, from an infected small intestine or contiguously from tuberculous salpingitis. Over time, the visceral and parietal peritoneum becomes studded with tubercles [7–9].

## **2. Definition**

causes of death from a single infectious agent worldwide. The most affected organ is the lung. It is preventable through Bacillus of Calmette and Guérin (BCG) vaccination and curable with

Tuberculosis is a serious and highly contagious bacterial infection which in humans is usually caused by bacteria called *Mycobacterium tuberculosis* (MTB), a member of the *Mycobacteriaceae* family. This complex also includes *M. bovis* and *M. africanum*. *M. bovis* is more frequently found in cattle and other animals, but it's also responsible for some cases in humans. *M. africanum* is more common in West African countries. Mycobacterial infection is spread through the air

The absolute number of incident cases has been decreasing since the early 2000s. The lowest incidence rate is found in high-income countries including the United States of America, Canada, New Zealand, Western Europe, and Australia. The largest number of incident cases is found in low- and middle-income countries. In 2015, 61% of the new cases occurred in Asia,

The HIV infection is the prevalent risk factor for the development of TB because HIV alters the pathogenesis of TB by producing a progressive decline in cell-mediated immunity and raises

Tuberculosis is a disease which typically involves the respiratory system, being characterized by the growth of tubercles in tissues, but it can affect any other organ, in which case it's called extrapulmonary tuberculosis (EPTB) and usually results from hematogenous dissemination, being particularly present in immunocompromised patients. In some cases the infection directly extends from an adjacent organ. The most common sites of extrapulmonary tuberculosis are the

from one person to another and causes active disease or latent infection [1].

lymph nodes, abdomen, bones and joints, pleura, spinal cord, and brain [5, 6].

followed by 26% new cases in Africa (**Figure 1**) [2].

34 Ascites - Physiopathology, Treatment, Complications and Prognosis

the chances of extrapulmonary involvement [3, 4].

**Figure 1.** Worldwide incidence of TB infections.

antituberculous drugs.

Ascites is defined as an abnormal accumulation of fluid in the peritoneal cavity, the presence of serous fluid between the visceral and parietal peritoneum. The word ascites is derived from the ancient Greek word "*askos*" meaning a bag or a sack. Under normal circumstances, the amount of peritoneal fluid depends on a balance between plasma flowing into and out of the blood and lymphatic vessels. This balance, once being disrupted, leads to abnormal accumulation of fluid [10]. Ascites can be a consequence or a complication of infections, malignancy, and many severe diseases: cardiac, endocrine, hepatic, or renal. The prognosis is usually poor, but it depends on the underlying causes. Laboratory tests of ascitic fluid, clinical, paraclinical, and pathological data are required for the differential diagnosis.

Tuberculous ascites, one of the clinical signs of abdominal TB, implies accumulation of fluid in the abdomen, a swollen abdomen, and slightly raised tubercles of 1–2 mm all over the peritoneum. In EPTB, ascites develops secondary to "exudation" of proteinaceous fluid from the tubercles, similar to the mechanism leading to ascites in patients with peritoneal carcinomatosis, and it's often misdiagnosed in elderly patients. Most patients with tuberculous peritonitis have ascites at the time of diagnosis, while the rest present the advanced phase, the dry or fibroadhesive form of the disease [11, 12].

## **3. Clinical manifestations**

Tuberculous peritonitis is a subacute disease, and its symptoms evolve over a period of several weeks or months.

The insidious onset of this condition and the fact that the diagnosis is rarely suspected explains why patients have symptoms for more than 4 months before the diagnosis is established. Tuberculous peritonitis should be considered in any patient presenting with several weeks of abdominal pain, fever, and weight loss. Systemic and constitutional manifestations are common. Symptoms may be mild, with fatigue, abdominal pain, and tenderness, or severe enough to mimic acute abdomen [13]. Other clinical manifestations could be:

The clinical presentation of TB ascites is challenging, since it is nonspecific and can be confused with a plethora of other infectious or noninfectious diseases, leading to a delayed diagnosis and treatment which are major factors that contribute to the high mortality of TB.

Another situation that contributes to a delayed diagnosis is the presence of multiple comorbidities such as HIV/AIDS, cirrhosis, uremia, or other chronic conditions. Additional illness results in atypical presentation of TB ascites which render the symptoms more difficult to identify and distinguish. Moreover, in elderly patients, clinical manifestation is minimal with abdominal discomfort, constipation, or fatigue, symptoms that most people tend to ignore as minor or non-perilous (**Figure 2**) [14, 15].

**Figure 2.** Factors associated with delayed diagnosis.

## **4. Diagnosis**

tubercles, similar to the mechanism leading to ascites in patients with peritoneal carcinomatosis, and it's often misdiagnosed in elderly patients. Most patients with tuberculous peritonitis have ascites at the time of diagnosis, while the rest present the advanced phase, the dry or

Tuberculous peritonitis is a subacute disease, and its symptoms evolve over a period of several

The insidious onset of this condition and the fact that the diagnosis is rarely suspected explains why patients have symptoms for more than 4 months before the diagnosis is established. Tuberculous peritonitis should be considered in any patient presenting with several weeks of abdominal pain, fever, and weight loss. Systemic and constitutional manifestations are common. Symptoms may be mild, with fatigue, abdominal pain, and tenderness, or severe

The clinical presentation of TB ascites is challenging, since it is nonspecific and can be confused with a plethora of other infectious or noninfectious diseases, leading to a delayed diagnosis and treatment which are major factors that contribute to the high mortality of TB.

Another situation that contributes to a delayed diagnosis is the presence of multiple comorbidities such as HIV/AIDS, cirrhosis, uremia, or other chronic conditions. Additional illness results in atypical presentation of TB ascites which render the symptoms more difficult to identify and distinguish. Moreover, in elderly patients, clinical manifestation is minimal with abdominal discomfort, constipation, or fatigue, symptoms that most people tend to ignore as

enough to mimic acute abdomen [13]. Other clinical manifestations could be:

fibroadhesive form of the disease [11, 12].

36 Ascites - Physiopathology, Treatment, Complications and Prognosis

**3. Clinical manifestations**

weeks or months.

• Constipation/diarrhea

• Low-grade fever

• Anorexia • Malaise

• Nocturnal hyperhidrosis

minor or non-perilous (**Figure 2**) [14, 15].

**Figure 2.** Factors associated with delayed diagnosis.

Due to the fact that the nature of this disease is insidious, the diagnosis represents a challenge for clinicians. With the ever-increasing demographic shifts, more cases are now detected in areas where TB was a rarity until present. Unless a high degree of suspicion is maintained, the diagnosis can easily be missed or delayed [12].

Diagnostic techniques and procedures include:

Generally, diagnosis is based on clinical suspicion, imaging of tuberculous infected zone, and detection of *M. tuberculosis* in ascitic fluid using acid-fast bacillus staining or culturing. The sensitivity of standard diagnostic methods such as Ziehl-Neelsen staining of smears and Lowenstein-Jensen culture done from ascitic fluid is very low for the diagnosis of abdominal TB.Ziehl-Neelsen staining of the ascitic fluid for mycobacterial detection is positive in only about 3% of the cases with proven TB peritonitis. Detection of mycobacteria requires the presence of more than 5000 bacilli/mL of specimen. In comparison, for positive culture, the presence of at least 10 organisms is considered to be sufficient. For a successful detection, culture methods based on a combination of liquid or biphasic media, together with solid media, are necessary [16, 17].

Nucleic acid amplification tests (NAATs) are molecular diagnostic methods based on amplification of mycobacterial nucleic acid. These are rapid methods that provide results within a day, and they are more specific and sensitive than Acid-Fast Bacillus Smear (AFB) smear. Albeit NAATs were originally designed for respiratory specimens, they can also be used on specimens from other TB sites like ascitic fluid samples, but this technique is still under evaluation.

Ascites of TB peritonitis obtained through ultrasound-guided paracentesis is an exudative type, and macroscopically its appearance is chylous and cloudy or turbid. Biochemically, the serumascites albumin gradient (SAAG) is now considered a more sensitive and specific measure than the ascitic total protein concentration which has been used for many years, in differentiating the ascites due to portal hypertension from ascites due to other pathophysiological mechanisms, such as tuberculous ascites which has a SAAG <1.1 g/dL and total proteins >3–4 g% [18, 19]. Combining LDH with total protein analysis has been explored for ascitic fluid. The cutoff values for three parameters in the ascitic fluid for differentiation between hepatic and non-hepatic ascites are as follows: LDH of 400 Sigma units, fluid/serum total protein (TP) ratio of 0.5, and fluid/serum LDH ratio of 0.6. The presence of any two of these three findings is usually associated with TB; the absence of all three indicates a hepatic cause [20].

Glucose concentration in the ascitic fluid, under normal conditions, is similar to that in the serum. Ascitic glucose concentration decreases due to consumption by bacteria, white blood cells, or cancer cells in the fluid in TB peritonitis. Ascitic glucose concentration is lower than normal in TB ascites, which makes it an indicator in differentiating tuberculosis from other diseases, such as cirrhosis. The ascitic/blood glucose ratio is a useful test in differentiating TB peritonitis from other causes of ascites [18].

Ascitic fluid adenosine deaminase activity (ADA) is considered a more sensitive and specific method used for early diagnosis of TB ascites. Even if the full physiological role of ADA is not yet completely understood, it is known that ADA values are notably higher (>40 U/L) in patients with TB ascites [21–23].

Non-biochemical tests of ascitic fluid, including cell counts, bacterial culture, and polymerase chain reaction (PCR), have an important role in diagnosing the cause of ascites.

The total cell count in tuberculous ascites is 150–4000/μL, and the cytologic examination shows over 70–80% lymphocytes and more than 250 leucocytes/mm3 (**Table 1**).

The sensitivity of direct microscopic smear detection of acid-fast bacilli in the ascitic fluid (0–6%) and ascitic fluid mycobacterial culture (20–35%) is low, and because of the delay in obtaining the results of mycobacterial cultures of ascitic fluid, the mortality is high, and the value of these tests in the differential diagnosis of ascites is limited.

Recently, a new approach to the fast diagnosis of bacterial infections emerged, including tuberculosis. The advanced molecular techniques provided a new method represented by PCR which can detect minimal amounts of bacterial DNA and improves the rates of bacterial identification from 4 to 6 weeks for microbiological cultures to 24 hours. In diagnosing TB effusions, PCR appears to be an ideal tool, with 94% sensitivity and 88% specificity, becoming a rapid and reliable method for identification of infectious ascites [24].

The tuberculin skin testing (TST or purified protein derivative (PPD) skin test) is controversial, despite the high specificity of this test which is between 95 and 99%. Skin testing is currently used only for detection of latent infection because of its low sensitivity and low positive predictive value. At the moment, there are no recommendations for using this test to diagnose active

**Table 1.** Characteristics of tuberculous ascites.

disease like tuberculous peritonitis. At best, tuberculin skin testing can only offer auxiliary information. Several studies have reported positivity rates ranging between 24 and 100% with no significant difference between high and low endemicity areas. Currently, the recommendations about the cut point for the induration differ depending on the risk scale. For patients at low risk, the cut point is at 15 mm; in cases of moderate risk, the cut point is 10 mm, and for those at high risk, the cut point is 5 mm. Generally, about 50% of the patients would have falsenegative reactions to this test, suggesting the fact that it has many potential sources of error. In conclusion, anergy testing may yield confusing information and is no longer recommended for diagnosis [25].

normal in TB ascites, which makes it an indicator in differentiating tuberculosis from other diseases, such as cirrhosis. The ascitic/blood glucose ratio is a useful test in differentiating TB

Ascitic fluid adenosine deaminase activity (ADA) is considered a more sensitive and specific method used for early diagnosis of TB ascites. Even if the full physiological role of ADA is not yet completely understood, it is known that ADA values are notably higher (>40 U/L) in

Non-biochemical tests of ascitic fluid, including cell counts, bacterial culture, and polymerase

The total cell count in tuberculous ascites is 150–4000/μL, and the cytologic examination

The sensitivity of direct microscopic smear detection of acid-fast bacilli in the ascitic fluid (0–6%) and ascitic fluid mycobacterial culture (20–35%) is low, and because of the delay in obtaining the results of mycobacterial cultures of ascitic fluid, the mortality is high, and the

Recently, a new approach to the fast diagnosis of bacterial infections emerged, including tuberculosis. The advanced molecular techniques provided a new method represented by PCR which can detect minimal amounts of bacterial DNA and improves the rates of bacterial identification from 4 to 6 weeks for microbiological cultures to 24 hours. In diagnosing TB effusions, PCR appears to be an ideal tool, with 94% sensitivity and 88% specificity, becoming

The tuberculin skin testing (TST or purified protein derivative (PPD) skin test) is controversial, despite the high specificity of this test which is between 95 and 99%. Skin testing is currently used only for detection of latent infection because of its low sensitivity and low positive predictive value. At the moment, there are no recommendations for using this test to diagnose active

(**Table 1**).

chain reaction (PCR), have an important role in diagnosing the cause of ascites.

shows over 70–80% lymphocytes and more than 250 leucocytes/mm3

value of these tests in the differential diagnosis of ascites is limited.

a rapid and reliable method for identification of infectious ascites [24].

peritonitis from other causes of ascites [18].

38 Ascites - Physiopathology, Treatment, Complications and Prognosis

**Type Exudative**

Total cell count 150–4000/μL Leucocytes >250/mm3 Lymphocytes >70–80% Total proteins >3–4 g% ADA >40 U/L LDH >400 SU Glucose <6 mg/dL SAAG <1.1 g/dL

**Table 1.** Characteristics of tuberculous ascites.

Appearance Chylous and cloudy/turbid

patients with TB ascites [21–23].

A great scientific advance has been the development of an IFN-c-based test with an 89% sensitivity, which is a quantitative in vitro assay evaluating the cell-mediated immune response to *M. tuberculosis* and has excellent agreement with tuberculin skin testing. The principle of this test is that previously sensitized T lymphocytes release IFN-c in response to stimulation by purified protein derivative (PPD).

In the past few years, the tuberculin skin test has been replaced by T-cell-based interferon-gamma release assay (IGRA) which is more sensitive and more specific. IGRA is an in vitro test used in all circumstances in which the TST is currently used, including evaluation of immigrants, surveillance programs, or contact investigations [26]. There are three commercially available IFN-γ tests: QuantiFERON-TB Gold assay (QFN-Gold), QuantiFERON-TB Gold *In-Tube* assay (QFN-G-IT), and T-SPOT.TB assay. They are rapid immunodiagnostic tests that can detect interferon-γ (IFN-γ) produced by lymphocytes in response to *Mycobacterium tuberculosis* (MTB). T-SPOT.TB test is a blood IFN-γ assay that measures the number of IFN-γ-producing T cells by identifying IFN-γ release when stimulated by MTB-specific antigens, including early secretory antigenic target 6 and culture filtrate protein 10, using enzyme-linked immunospot assay. QuantiFERON-TB Gold test is the predecessor of QuantiFERON-TB Gold In-Tube test, and they both measure production of IFN-γ in culture supernatant using enzyme-linked immunosorbent assay (ELISA). This measurement is possible by circulating T cells in whole blood being challenged with *M. tuberculosis*-specific antigens. The advantage of blood IGRA tests over tuberculin skin tests is the fact that IGRAs do not cross-react with the Bacillus of Calmette and Guérin (BCG) vaccine antigens, but suboptimal results can be possible in diagnosing EPTB because they aren't able to distinguish latent infection from active disease [27]. According to some researches, *M. tuberculosis* antigen-specific T cells may accumulate at infection sites; therefore, investigating body fluid IGRAs may increase the accuracy of EPTB diagnosis [28, 29].

Imaging techniques used for detection of TB ascites are ultrasound and computed tomography. These methods also increase the accuracy of several procedures like paracentesis or peritoneal biopsies, providing a safer and affordable replacement to diagnostic laparoscopy [30].

Ultrasound is the most sensitive and reliable method of detecting ascites, guiding paracentesis and monitoring the effects of therapy. It can detect even small volumes of fluid (as little as 100 ml of fluid could be detected). Ascites is usually seen as an anechoic space. In TB ascites, particulate matter within the ascitic fluid or fine, mobile strands, representing echogenic debris, can be detected. Less commonly, the ultrasound can reveal calcifications in the walls of encysted ascitic fluid [12].

On computed tomography the ascitic fluid has high attenuation values, between 20 and 45 HU, and the peritoneum is symmetrically thickened and nodular. Frequently, an early sign of abdominal TB is a thickened mesentery (>15 mm) with mesenteric lymph nodes.

Many studies concluded that ultrasonography and computed tomography are complementary to each other in detecting TB ascites, as they provide different details. CT focuses on the peritoneum and omental and mesentery involvement, and the ultrasound shows fine, mobile septations (**Figure 3**) [31].

However, the only certain way to diagnose TB ascites is the histological examination. Various methods that include excision, laparoscopy, needle biopsy and ultrasound-guided biopsies, endoscopy, computed tomography (CT), or endoscopic ultrasound are used to establish the

**Figure 3.** Circumferential parietal thickness, with an edematous appearance of the appendix, cecum, ascending colon, and up to the hepatic flexura, associating stripe thickening of adjacent fat. Multiple adenopathies containing calcifications and central necrosis. Fluid accumulation in the peritoneal cavity associating symmetrical, iodophilic thickening of parietal peritoneum. Osteolytic areas with an adjacent osteosclerotic reaction in L2, L3, and L4 vertebrae. Parafluid accumulation in L2–L3 and L3–L4 intervertebral spaces that reaches the anterior epidural space and the roots of L2 and L3 nerves, extending to L3–L4 adjacent smooth tissues, with no visible border toward the right psoas muscle.

diagnosis. The presence of granulomas is typical for TB ascites [32]. The relative sensitivities of different procedures and the potential therapeutic benefits should be considered in making the choice of diagnostic approach. In superficial TB lymphadenitis, fine needle aspiration (FNA) biopsy of affected lymph nodes is the gold-standard diagnostic technique. Excision biopsy has the highest sensitivity, whereas FNA is less invasive and may be useful. If FNA examination results are doubtful, excision biopsy may be needed. Laparoscopy with target peritoneal biopsy is the current first-line investigation in the diagnosis of peritoneal TB [33, 34]. Several studies revealed a diagnostic accuracy of 84–96% for TB peritonitis.

Generally, tissue biopsy is superior to fluid aspiration in providing positive culture results. The diagnosis is more accurate when the biopsy results and polymerase chain reaction assays are combined with culture results [35].

## **5. Differential diagnosis**