**Alternative Diagnostic Tests of Gastroesophageal Varices in Liver Cirrhosis: Recent Advance**

Xingshun Qi, Qiang Zhu and Ye Tian

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68418

#### **Abstract**

Routine screening for gastroesophageal varices in liver cirrhosis is necessary. At present, upper gastrointestinal endoscopy is the golden diagnostic test of gastroesophageal varices. However, the use of upper gastrointestinal endoscopy is restricted because of its poor compliance and adverse events. In this chapter, we reviewed the recent evidence regarding the value of noninvasive or less invasive tests for the diagnosis of gastroesophageal varices in liver cirrhosis.

**Keywords:** varices, liver cirrhosis, endoscopy, meta-analysis, noninvasive

## **1. Introduction**

Gastroesophageal varices and their related bleeding are one of the most common and lethal complications of liver cirrhosis [1, 2]. The prevalence of gastroesophageal varices is approximately 50% at the diagnosis of liver cirrhosis [2]. In the absence of any interventions, Groszmann et al. reported that the incidence of confirmed small varices, large varices, and variceal bleeding in patients without any previous history of varices was 28.6, 3.8, and 2.9% during a median duration of follow-up of 54.9 months, respectively [3]. Merli et al. reported that the 1-, 2-, and 3-year incidence of varices in cirrhotic patients without varices was 5, 17, and 28%, respectively [4]. In this chapter, we mainly review the following contents: the practice guideline and consensus recommendations regarding screening for gastroesophageal varices in liver cirrhosis, current understanding regarding alternative diagnostic tests of gastroesophageal varices in liver cirrhosis, and diagnostic accuracy of different alternative diagnostic tests.

© 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.

## **2. Screening for gastroesophageal varices in liver cirrhosis**

Upper gastrointestinal endoscopy is the golden diagnostic test of gastroesophageal varices. There are some recommendations from practice guideline and consensus regarding endoscopic screening for gastroesophageal varices in liver cirrhosis.

According to the UK practice guideline on the management of variceal hemorrhage in cirrhotic patients, there are high levels of evidence regarding the surveillance of gastroesophageal varices in liver cirrhosis [5]. First, all patients with cirrhosis should undergo endoscopy at the time of diagnosis. Second, in the absence of varices, patients with cirrhosis should undergo endoscopy every 2–3 years. Third, in the cases of grade I varices, patients with cirrhosis should undergo endoscopy every year. Fourth, in the cases of disease progression, the intervals of endoscopy can be modified by the clinicians.

According to the Baveno VI consensus workshop, there are low levels of evidence and weak grade of recommendation regarding the surveillance of esophageal varices in liver cirrhosis [6]. First, compensated cirrhosis without ongoing liver injury or varices should undergo endoscopy every 3 years. Second, compensated cirrhosis with ongoing liver injury without varices should undergo endoscopy every 2 years. Third, compensated patients with small varices without ongoing liver injury should undergo endoscopy every 2 years. Fourth, compensated patients with ongoing liver injury and small varices should undergo endoscopy every year.

The recommendations of the 2016 Practice Guidance by the American Association for the Study of Liver Diseases are similar to those of the Baveno VI consensus [7]. First, in the absence of varices, compensated cirrhosis with and without ongoing liver injury should undergo endoscopy every 2 and 3 years, respectively. Second, in the presence of small varices, compensated cirrhosis with and without ongoing liver injury should undergo endoscopy every 1 and 2 years, respectively. Third, compensated cirrhosis should undergo endoscopy at the time when decompensation events develop.

Although the recommendations regarding the interval of endoscopy and target population are heterogeneous among practice guidelines, repeated endoscopy is necessary for cirrhotic patients. However, endoscopic examinations have several limitations. First, nearly all patients are reluctant for endoscopy. Patients may have poor complaint regarding endoscopy. Second, not all endoscopic examinations are safe. The endoscopy-related adverse events are more frequent and severe in patients with cardiovascular and cerebrovascular diseases.

## **3. Current knowledge about alternative diagnostic tests of gastroesophageal varices in liver cirrhosis**

A questionnaire survey assessed the knowledge about alternative diagnostic tests of gastroesophageal varices in 42 members from the Gastroenterology Branch of the Liaoning Medical Association, China [8]. Indeed, alternative diagnostic tests are rarely or never employed in clinical practice. In the following text, several major alternative diagnostic tests, such as serum liver fibrosis parameters, platelet count to spleen diameter ratio (PSR), liver and spleen stiffness, capsule endoscopy, and computed tomography, are reviewed on the basis of major evidence, especially the results of meta-analyses. The data regarding sensitivity and specificity are primarily presented.

## **4. Serum liver fibrosis parameters for diagnosis of gastroesophageal varices**

**2. Screening for gastroesophageal varices in liver cirrhosis**

scopic screening for gastroesophageal varices in liver cirrhosis.

78 Liver Cirrhosis - Update and Current Challenges

intervals of endoscopy can be modified by the clinicians.

the time when decompensation events develop.

**gastroesophageal varices in liver cirrhosis**

every year.

Upper gastrointestinal endoscopy is the golden diagnostic test of gastroesophageal varices. There are some recommendations from practice guideline and consensus regarding endo-

According to the UK practice guideline on the management of variceal hemorrhage in cirrhotic patients, there are high levels of evidence regarding the surveillance of gastroesophageal varices in liver cirrhosis [5]. First, all patients with cirrhosis should undergo endoscopy at the time of diagnosis. Second, in the absence of varices, patients with cirrhosis should undergo endoscopy every 2–3 years. Third, in the cases of grade I varices, patients with cirrhosis should undergo endoscopy every year. Fourth, in the cases of disease progression, the

According to the Baveno VI consensus workshop, there are low levels of evidence and weak grade of recommendation regarding the surveillance of esophageal varices in liver cirrhosis [6]. First, compensated cirrhosis without ongoing liver injury or varices should undergo endoscopy every 3 years. Second, compensated cirrhosis with ongoing liver injury without varices should undergo endoscopy every 2 years. Third, compensated patients with small varices without ongoing liver injury should undergo endoscopy every 2 years. Fourth, compensated patients with ongoing liver injury and small varices should undergo endoscopy

The recommendations of the 2016 Practice Guidance by the American Association for the Study of Liver Diseases are similar to those of the Baveno VI consensus [7]. First, in the absence of varices, compensated cirrhosis with and without ongoing liver injury should undergo endoscopy every 2 and 3 years, respectively. Second, in the presence of small varices, compensated cirrhosis with and without ongoing liver injury should undergo endoscopy every 1 and 2 years, respectively. Third, compensated cirrhosis should undergo endoscopy at

Although the recommendations regarding the interval of endoscopy and target population are heterogeneous among practice guidelines, repeated endoscopy is necessary for cirrhotic patients. However, endoscopic examinations have several limitations. First, nearly all patients are reluctant for endoscopy. Patients may have poor complaint regarding endoscopy. Second, not all endoscopic examinations are safe. The endoscopy-related adverse events are more

A questionnaire survey assessed the knowledge about alternative diagnostic tests of gastroesophageal varices in 42 members from the Gastroenterology Branch of the Liaoning Medical Association, China [8]. Indeed, alternative diagnostic tests are rarely or never employed in

frequent and severe in patients with cardiovascular and cerebrovascular diseases.

**3. Current knowledge about alternative diagnostic tests of** 

Hyaluronic acid (HA), laminin (LN), amino-terminal propeptide of type III procollagen (PIIINP), and collagen IV (CIV) are major serum parameters for the assessment of liver fibrosis. A retrospective study evaluated their value of diagnosis of gastroesophageal varices [9]. Unfortunately, all of them could not accurately predict the presence of gastroesophageal varices.

APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex are the major scores for the assessment of liver fibrosis. Deng et al. systematically reviewed their diagnostic accuracy of gastroesophageal varices [10]. The authors found that APRI, AAR, FIB-4, Lok, Forns, and FibroIndex scores had been evaluated, but not FI or King score. As for the diagnosis of gastroesophageal varices, the sensitivity and specificity of APRI were 0.60 and 0.67, respectively; those of AAR were 0.64 and 0.63, respectively; those of Lok were 0.74 and 0.68, respectively; and the area under the summary receiver operating characteristic curve of these scores ranged from 0.6774 to 0.7885. As for the diagnosis of large varices, the sensitivity and specificity of APRI were 0.65 and 0.66, respectively; those of AAR were 0.68 and 0.58, respectively; those of FIB-4 were 0.62 and 0.64, respectively; those of Lok were 0.78 and 0.63, respectively; those of Forns were 0.65 and 0.61, respectively; and the area under the summary receiver operating characteristic curve of these scores ranged from 0.6530 to 0.7448. More recently, a retrospective study further confirmed these findings [11]. More importantly, their diagnostic accuracy should be improved after the exclusion of previous gastrointestinal bleeding and splenectomy.

## **5. PSR for diagnosis of gastroesophageal varices**

PSR is a ratio of the platelet count (/mm<sup>3</sup> ) to the spleen diameter (mm). Multiple meta-analyses evaluated the diagnostic accuracy of PSR for varices. Chawla et al. conducted a meta-analysis of eight studies to explore the diagnostic accuracy of PSR with a cut-off value of 909 for the presence of esophageal varices in cirrhosis [12]. They found a sensitivity of 0.89 and a specificity of 0.74, but the evidence was of low quality according to the GRADE rule. Ying et al. performed another meta-analysis of 20 studies to assess the value of PSR with a cut-off value of 909 for esophageal varices in cirrhosis [13]. By comparison, they showed a relatively higher sensitivity of 0.92 and a specificity of 0.87, and the quality of studies was moderate according to the quality assessment of diagnostic accuracy studies (QUADAS) questionnaires. More recently, Chen et al. reported the results from an updated meta-analysis of 49 studies that the summary sensitivity and specificity of PSR for any varices were 0.84 and 0.78, respectively, and that the summary sensitivity and specificity of PSR for high-risk varices were 0.78 and 0.67, respectively [14]. Similarly, the authors considered that the quality of included studies was moderate. Taken together, the evidence supported the use of PSR for identifying the presence of varices. However, its diagnostic accuracy is not high.

## **6. Liver and spleen stiffness measurement for diagnosis of gastroesophageal varices**

Major evidence can be obtained from the results of several large meta-analyses. Pu et al. identified a total of 15 papers regarding liver stiffness measurement by FibroScan transient elastography for esophageal varices [15]. The pooled sensitivity and specificity of liver stiffness for any varices were 0.84 and 0.62, respectively; the pooled sensitivity and specificity of liver stiffness for large varices were 0.78 and 0.76, respectively. Similarly, Qu et al. also performed a meta-analysis of 20 studies to evaluate the performance of liver stiffness by transient elastography for esophageal varices [16]. As for any varices, the pooled sensitivity and specificity were 0.84 and 0.68, respectively. As for large varices, the pooled sensitivity and specificity were 0.84 and 0.72, respectively. Singh et al. synthesized the data from 12 studies regarding spleen stiffness for the diagnosis of esophageal varices [17]. As for any varices, the pooled sensitivity and specificity were 0.78 and 0.67, respectively. As for clinically significant esophageal varices, the pooled sensitivity and specificity were 0.81 and 0.66, respectively. More recently, Ma et al. conducted a meta-analysis of 16 studies to compare the diagnostic accuracy of liver vs. spleen stiffness for the diagnosis of gastroesophageal varices [18]. The authors found that the sensitivity and specificity of liver stiffness for the diagnosis of gastroesophageal varices were 0.83 (95% confidence interval: 0.78–0.87) and 0.66 (95% confidence interval: 0.60–0.72), respectively; those of spleen stiffness were 0.88 (95% confidence interval: 0.83–0.92) and 0.78 (95% confidence interval: 0.73–0.83), respectively. Importantly, the spleen stiffness had a significantly higher diagnostic accuracy than the liver stiffness (summary receiver operating characteristic curve value: 0.88 vs. 0.81, *p* < 0.01; diagnostic odds ratio: 25.73 vs. 9.54, *p* < 0.01).

## **7. Capsule endoscopy for diagnosis of gastroesophageal varices**

Until now, two meta-analyses were published regarding this topic. In 2014, a Cochrane review of 15 studies including 936 patients with liver cirrhosis analyzed the diagnostic performance of capsule endoscopy for the diagnosis of esophageal varices [19]. As for any varices, the pooled sensitivity and specificity were 0.848 and 0.843, respectively. As for large varices, the pooled sensitivity and specificity were 0.737 and 0.905, respectively. More recently, McCarty et al. systematically reviewed the data from 17 studies regarding wireless capsule endoscopy for the diagnosis of esophageal varices [20]. As for any varices, the pooled sensitivity and specificity were 0.83 and 0.85, respectively. As for medium to large varices, the pooled sensitivity and specificity were 0.72 and 0.91, respectively.

## **8. Computed tomography scans for diagnosis of gastroesophageal varices**

There are at least two meta-analyses regarding the value of computed tomography scans for the diagnosis of gastroesophageal varices. The first meta-analysis included 11 studies [21]. As for esophageal varices, the sensitivity and specificity were 0.896 and 0.723, respectively; as for gastric varices, the sensitivity and specificity were 0.955 and 0.658, respectively. The second meta-analysis included 17 studies [22]. As for any varices, the sensitivity and specificity were 0.87 and 0.80, respectively; as for any esophageal varices, the sensitivity and specificity were 0.87 and 0.81, respectively; as for any gastric varices, the sensitivity and specificity were 0.86 and 0.79, respectively. As for high-risk varices, the sensitivity and specificity were 0.87 and 0.88, respectively; as for high-risk esophageal varices, the sensitivity and specificity were 0.87 and 0.88, respectively; as for high-risk gastric varices, the sensitivity and specificity were 0.83 and 0.97, respectively. More recently, a retrospective study found that a diameter of esophageal varices of 3.9 mm on computed tomography scans might be the optimal cut-off value for the diagnosis of high-risk varices [23].

## **9. Endoscopic ultrasound**

summary sensitivity and specificity of PSR for any varices were 0.84 and 0.78, respectively, and that the summary sensitivity and specificity of PSR for high-risk varices were 0.78 and 0.67, respectively [14]. Similarly, the authors considered that the quality of included studies was moderate. Taken together, the evidence supported the use of PSR for identifying the pres-

Major evidence can be obtained from the results of several large meta-analyses. Pu et al. identified a total of 15 papers regarding liver stiffness measurement by FibroScan transient elastography for esophageal varices [15]. The pooled sensitivity and specificity of liver stiffness for any varices were 0.84 and 0.62, respectively; the pooled sensitivity and specificity of liver stiffness for large varices were 0.78 and 0.76, respectively. Similarly, Qu et al. also performed a meta-analysis of 20 studies to evaluate the performance of liver stiffness by transient elastography for esophageal varices [16]. As for any varices, the pooled sensitivity and specificity were 0.84 and 0.68, respectively. As for large varices, the pooled sensitivity and specificity were 0.84 and 0.72, respectively. Singh et al. synthesized the data from 12 studies regarding spleen stiffness for the diagnosis of esophageal varices [17]. As for any varices, the pooled sensitivity and specificity were 0.78 and 0.67, respectively. As for clinically significant esophageal varices, the pooled sensitivity and specificity were 0.81 and 0.66, respectively. More recently, Ma et al. conducted a meta-analysis of 16 studies to compare the diagnostic accuracy of liver vs. spleen stiffness for the diagnosis of gastroesophageal varices [18]. The authors found that the sensitivity and specificity of liver stiffness for the diagnosis of gastroesophageal varices were 0.83 (95% confidence interval: 0.78–0.87) and 0.66 (95% confidence interval: 0.60–0.72), respectively; those of spleen stiffness were 0.88 (95% confidence interval: 0.83–0.92) and 0.78 (95% confidence interval: 0.73–0.83), respectively. Importantly, the spleen stiffness had a significantly higher diagnostic accuracy than the liver stiffness (summary receiver operating characteristic curve value: 0.88 vs. 0.81, *p* < 0.01; diagnostic odds ratio:

ence of varices. However, its diagnostic accuracy is not high.

**gastroesophageal varices**

80 Liver Cirrhosis - Update and Current Challenges

25.73 vs. 9.54, *p* < 0.01).

**6. Liver and spleen stiffness measurement for diagnosis of** 

**7. Capsule endoscopy for diagnosis of gastroesophageal varices**

Until now, two meta-analyses were published regarding this topic. In 2014, a Cochrane review of 15 studies including 936 patients with liver cirrhosis analyzed the diagnostic performance of capsule endoscopy for the diagnosis of esophageal varices [19]. As for any varices, the pooled sensitivity and specificity were 0.848 and 0.843, respectively. As for large varices, the pooled sensitivity and specificity were 0.737 and 0.905, respectively. More recently, McCarty et al. systematically reviewed the data from 17 studies regarding wireless capsule endoscopy Researchers also explored the value of endoscopic ultrasound in the diagnostic evaluation of gastroesophageal varices [24]. Endoscopic ultrasound was inferior to conventional endoscopy in the diagnosis and grading of esophageal varices, but superior in the evaluation of para- or peri-esophageal veins and gastric varices. More importantly, the detection of para- or periesophageal veins by endoscopic ultrasound predicted the risk of bleeding and outcomes.

## **10. Conclusions**

Alternative diagnostic tests of varices in liver cirrhosis have been widely explored in numerous studies. Several scores for the assessment of liver fibrosis are readily available, but have relatively low diagnostic accuracy. PSR and liver and spleen stiffness are noninvasive and have moderate diagnostic accuracy. By comparison, contrast-enhanced computed tomography and capsule endoscopy have relatively high diagnostic accuracy, but are expensive and potentially invasive (exposure to radiation). Thus, a diagnostic algorithm according to the cost and diagnostic performance of various diagnostic tests and clinical necessity should be considered. In detail, PSR and liver and spleen stiffness should be the first step for the noninvasive diagnosis of varices; if a thorough evaluation of severity of liver diseases is simultaneously needed, contrast-enhanced computed tomography scans should be preferred and arranged earlier; if available, an endoscopic ultrasound can be performed to more accurately detect the para- or peri-esophageal veins.

#### **Author details**

Xingshun Qi<sup>1</sup> \*, Qiang Zhu2,3 and Ye Tian<sup>1</sup>

\*Address all correspondence to: xingshunqi@126.com

1 Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang, Liaoning, China

2 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China

3 Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, Shandong, China

### **References**


[7] Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017;**65**:310-335.

considered. In detail, PSR and liver and spleen stiffness should be the first step for the noninvasive diagnosis of varices; if a thorough evaluation of severity of liver diseases is simultaneously needed, contrast-enhanced computed tomography scans should be preferred and arranged earlier; if available, an endoscopic ultrasound can be performed to more accurately

1 Department of Gastroenterology, General Hospital of Shenyang Military Area, Shenyang,

2 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong

3 Shandong Provincial Engineering and Technological Research Center for Liver Diseases

[1] Ge PS, Runyon BA. Treatment of patients with cirrhosis. New England Journal of

[2] Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis.

[3] Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Betablockers to prevent gastroesophageal varices in patients with cirrhosis. New England

[4] Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, et al. Incidence and natural history of small esophageal varices in cirrhotic patients. Journal of Hepatology.

[5] Tripathi D, Stanley AJ, Hayes PC, Patch D, Millson C, Mehrzad H, et al. UK guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015;**64**:1680-1704.

[6] de Franchis R. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension.

detect the para- or peri-esophageal veins.

82 Liver Cirrhosis - Update and Current Challenges

University, Jinan, Shandong, China

Medicine. 2016;**375**:767-777.

2003;**38**:266-272.

Prevention and Control, Jinan, Shandong, China

New England Journal of Medicine. 2010;**362**:823-832.

Journal of Medicine. 2005;**353**:2254-2261.

Journal of Hepatology. 2015;**63**:743-752.

\*, Qiang Zhu2,3 and Ye Tian<sup>1</sup> \*Address all correspondence to: xingshunqi@126.com

**Author details**

Xingshun Qi<sup>1</sup>

Liaoning, China

**References**


## **Correlation Between Transthoracic Contrast-Enhanced Ultrasound and Pulse Oximetry in Hepatopulmonary Syndrome Diagnosis**

Andra‐Iulia Suceveanu, Adrian‐Paul Suceveanu, Irinel‐Raluca Parepa, Felix Voinea and Laura Mazilu

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68550

#### **Abstract**

[19] Colli A, Gana JC, Turner D, Yap J, Adams-Webber T, Ling SC, et al. Capsule endoscopy for the diagnosis of oesophageal varices in people with chronic liver disease or portal

[20] McCarty TR, Afinogenova Y, Njei B. Use of wireless capsule endoscopy for the diagnosis and grading of esophageal varices in patients with portal hypertension: A systematic

review and meta-analysis. Journal of Clinical Gastroenterology. 2017;**51**:174-182. [21] Tseng YJ, Zeng XQ, Chen J, Li N, Xu PJ, Chen SY. Computed tomography in evaluating gastroesophageal varices in patients with portal hypertension: A meta-analysis.

[22] Deng H, Qi X, Guo X. Computed tomography for the diagnosis of varices in liver cirrhosis: A systematic review and meta-analysis of observational studies. Postgraduate

[23] Deng H, Qi X, Zhang Y, Peng Y, Li J, Guo X. Diagnostic accuracy of contrast-enhanced computed tomography for esophageal varices in liver cirrhosis: A retrospective observa-

[24] Wang AJ, Li BM, Zheng XL, Shu X, Zhu X. Utility of endoscopic ultrasound in the diagnosis and management of esophagogastric varices. Endoscopic Ultrasound. 2016;**5**:218-224.

tional study. Journal of Evidence Based Medicine. 2017;**10**:46-52.

Digestive and Liver Disease. 2016;**48**:695-702.

Medicine. 2017;**129**:318-328.

84 Liver Cirrhosis - Update and Current Challenges

vein thrombosis. The Cochrane Database of Systemic Reviews. 2014:CD008760.

The prevalence of hepatopulmonary syndrome (HPS) in the setting of cirrhosis ranges between 4 and 47% and its presence increases the mortality rate, especially when hypox‐ emia is present. Our study aim was to fix whether there is a correlation of results between two simple and non‐invasive procedures such as transthoracic contrast‐enhanced ultra‐ sound (CEUS) and pulse oximetry, used for early detection of HPS in patients with liver cirrhosis, having as endpoint the improvement in their outcome. The rapid lung enhance‐ ment and delayed left ventricle enhancement of the saline solution, after at least three systolic beats during CEUS and pulse oximetry showing a SaO<sup>2</sup> < 95%, were correlated and considered positive for the diagnosis of HPS. One hundred and sixty‐five (44%) of the total of 375 patients diagnosed with liver cirrhosis enrolled in the current study, with or without respiratory symptoms (dyspnea, clubbing, distal cyanosis, cough and/or spi‐ der angioma), showed positive criteria for HPS diagnosis during CEUS. SaO<sup>2</sup> < 95% and PaO2 < 70 mmHg were found in 123 patients (33%) during pulse oximetry investigation. Pearson correlation index showed a good correlation between lung and heart CEUS find‐ ings and pulse oximetry (*r* = 0.97) for HPS diagnosis. CEUS and pulse oximetry results correlate and rapidly diagnose HPS, a highly fatal complication of liver cirrhosis (LC), guiding the future treatment by speeding up orthotopic liver transplant OLT recommen‐ dations to improve the survival rates.

**Keywords:** transthoracic contrast‐enhanced ultrasonography, pulse oximetry, liver cirrhosis, hepatopulmonary syndrome, hypoxemia

© 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.

## **1. Introduction**

The hepatopulmonary syndrome (HPS) represents a complication of liver cirrhosis character‐ ized by a gross dilatation of the pulmonary precapillary and capillary vessels, an increase in the number of dilated vessels, portopulmonary anastomoses, pleural and pulmonary arterio‐ venous shunts. It can be diagnosed when the triad represented by liver disease, impaired oxy‐ genation and intrapulmonary vascular abnormalities, referred to as intrapulmonary vascular dilatations (IPVDs) coexist [1]. The prevalence of pulmonary complications associated with liver cirrhosis ranges between 4 and 47%, worsening the evolution and prognosis, especially when hypoxemia is present [2, 3]. According to the medical literature focused on the current topic, 23% of patients with HPS have an average survival rate around 24 months, compared to 63% of patients without HPS. Survival can be further worsened in case of comorbidities or advanced age [4]. Respiratory signs and symptoms are common in patients with liver cir‐ rhosis, no matter the stage of the disease. Intrapulmonary vascular complications of liver cir‐ rhosis consist of hepatopulmonary syndrome (HPS) and portopulmonary hypertension. HPS appears when intrapulmonary blood shunting impairs arterial gas exchange [5], and por‐ topulmonary hypertension occurs when pulmonary arterial constriction leads to increased pulmonary arterial pressure [6]. The latter, although rare, can cause pulmonary complication, which worsens the morbidity and mortality in patients with liver dysfunction. The outcome of patients with advanced liver disease, complicated with pulmonary involvement, can be influ‐ enced even in the setting of orthotopic liver transplant, due to chronic hypoxemia installed during the evolution of cirrhosis influencing the prognosis. A key factor in the diagnosis of HPS is the exclusion of causes other than HPS that may be involved in cirrhosis and charac‐ terized by hypoxemia (cardiopulmonary abnormalities, pulmonary atelectasis, pneumonia, ascites, pulmonary edema or hepatic hydrothorax) [7]. The challenge for physicians working in the field of hepatology is to raise the idea of establishing new methods for a conventional, rapid and simple diagnosis of pulmonary involvement during the evolution of liver cirrhosis, in order to improve as much as possible the outcome of possible curative treatment.

HPS is defined by a widened alveolar‐arterial oxygen gradient (age corrected) in room air, with or without hypoxemia. It results from intrapulmonary vascular dilatations in the pres‐ ence of hepatic dysfunction and/or portal hypertension [8, 9].

The development of pulmonary vascular dilatation has as pathogenic mechanism a pulmo‐ nary overproduction of endogenous nitric oxide (NO) [10]. According to studies focused on the topic in the last two decades, a theory can be formulated according to which endothelin‐1 and tumor necrosis factor‐α may play a role in pulmonary microvascular tone modulation [11, 12]. The contributing factors to the process of pulmonary microvascular dilatation in HPS include angiogenesis, vascular remodeling, pulmonary arteriovenous shunts and portopul‐ monary venous anastomoses [13, 14].

Trough this pathogenic mechanism, the rapid or direct passage of mixed venous blood into the pulmonary veins is responsible for the pulmonary vascular dilatation. The mismatch of ventilation‐perfusion sequence produces a deficit in the blood oxygenation. The inhibition of hypoxic vasoconstriction produces an increased blood flow and preserved alveolar ventilation. The alveolar‐arterial oxygen tension difference—≥15, or ≥20 mmHg for patients aged >64 is considered as a very sensitive index of early arterial deoxygenation in HPS, and this difference being overload before arterial oxygen tension becomes abnormally low [8]. On the other hand, the alveolar‐capillary interface is too wide to allow for complete equilibration of carbon mon‐ oxide with hemoglobin, thus being translated in reducing the diffusing capacity of the lungs for carbon monoxide.

**1. Introduction**

86 Liver Cirrhosis - Update and Current Challenges

The hepatopulmonary syndrome (HPS) represents a complication of liver cirrhosis character‐ ized by a gross dilatation of the pulmonary precapillary and capillary vessels, an increase in the number of dilated vessels, portopulmonary anastomoses, pleural and pulmonary arterio‐ venous shunts. It can be diagnosed when the triad represented by liver disease, impaired oxy‐ genation and intrapulmonary vascular abnormalities, referred to as intrapulmonary vascular dilatations (IPVDs) coexist [1]. The prevalence of pulmonary complications associated with liver cirrhosis ranges between 4 and 47%, worsening the evolution and prognosis, especially when hypoxemia is present [2, 3]. According to the medical literature focused on the current topic, 23% of patients with HPS have an average survival rate around 24 months, compared to 63% of patients without HPS. Survival can be further worsened in case of comorbidities or advanced age [4]. Respiratory signs and symptoms are common in patients with liver cir‐ rhosis, no matter the stage of the disease. Intrapulmonary vascular complications of liver cir‐ rhosis consist of hepatopulmonary syndrome (HPS) and portopulmonary hypertension. HPS appears when intrapulmonary blood shunting impairs arterial gas exchange [5], and por‐ topulmonary hypertension occurs when pulmonary arterial constriction leads to increased pulmonary arterial pressure [6]. The latter, although rare, can cause pulmonary complication, which worsens the morbidity and mortality in patients with liver dysfunction. The outcome of patients with advanced liver disease, complicated with pulmonary involvement, can be influ‐ enced even in the setting of orthotopic liver transplant, due to chronic hypoxemia installed during the evolution of cirrhosis influencing the prognosis. A key factor in the diagnosis of HPS is the exclusion of causes other than HPS that may be involved in cirrhosis and charac‐ terized by hypoxemia (cardiopulmonary abnormalities, pulmonary atelectasis, pneumonia, ascites, pulmonary edema or hepatic hydrothorax) [7]. The challenge for physicians working in the field of hepatology is to raise the idea of establishing new methods for a conventional, rapid and simple diagnosis of pulmonary involvement during the evolution of liver cirrhosis,

in order to improve as much as possible the outcome of possible curative treatment.

ence of hepatic dysfunction and/or portal hypertension [8, 9].

monary venous anastomoses [13, 14].

HPS is defined by a widened alveolar‐arterial oxygen gradient (age corrected) in room air, with or without hypoxemia. It results from intrapulmonary vascular dilatations in the pres‐

The development of pulmonary vascular dilatation has as pathogenic mechanism a pulmo‐ nary overproduction of endogenous nitric oxide (NO) [10]. According to studies focused on the topic in the last two decades, a theory can be formulated according to which endothelin‐1 and tumor necrosis factor‐α may play a role in pulmonary microvascular tone modulation [11, 12]. The contributing factors to the process of pulmonary microvascular dilatation in HPS include angiogenesis, vascular remodeling, pulmonary arteriovenous shunts and portopul‐

Trough this pathogenic mechanism, the rapid or direct passage of mixed venous blood into the pulmonary veins is responsible for the pulmonary vascular dilatation. The mismatch of ventilation‐perfusion sequence produces a deficit in the blood oxygenation. The inhibition of hypoxic vasoconstriction produces an increased blood flow and preserved alveolar ventilation. Patients complain of symptoms correlated not only with the subsequent liver disease, but also with the respiratory signs and symptoms, usually revealing dyspnea and cyanosis. The man‐ agement of these patients requires the exclusion of other causes for such respiratory symptoms, because chronic obstructive pulmonary disease and pulmonary fibrosis can coexist in approxi‐ mately 30% of patients with HPS [15]. Dyspnea ("platypnea") and hypoxemia ("orthodeoxia") are characteristically worsened in the upright position and improved by lying supine, result‐ ing from a gravitational increase in blood flow through dilated vessels in the lung bases [16].

According to the pathogenic definition, the diagnosis of HPS requires evidence of pulmo‐ nary vascular dilatation and hypoxemia, with no cardiopulmonary disease history. To stage the severity of the disease, it is required to investigate the arterial blood gas tension at rest, while breathing room air and in the sitting position. A sensitive and non‐invasive tool for the detection of pulmonary vascular dilatation is the contrast‐enhanced transthoracic echocar‐ diography after injection of hand‐agitated normal saline. During the first pass, microbubbles are physiologically trapped and absorbed by alveoli, and they should not be seen in the left atrium. The passage of saline microbubbles through abnormally dilated lung vessels requires more than three cardiac cycles to reach left heart chambers [17]. In contrast, the immediate enhancement of saline microbubbles in the left atrium raises the suspicion of an intracar‐ diac right‐to‐left shunt [18]. The alternative to CEUS investigation is scintigraphic perfusion scanning, which uses the technetium‐99‐labeled albumin macroaggregates >20 μm in diam‐ eter. The uptake of tc‐99‐labeled albumin macroaggregated in other organs occurs in case of right‐to‐left shunt, while the trapping of albumin macroaggregates in pulmonary circulation is characteristic for HPS [19].

The present management of HPS lacks of efficient therapy solutions, until the OLT is avail‐ able. Starting from the pathogenic mechanism, physicians investigated several classes of drugs such as β‐blockers, cyclo‐oxygenase inhibitors, systemic corticosteroids, cyclophospha‐ mide, inhaled NO, and NO inhibitors, but without a real benefit in oxygenation improve‐ ment or pulmonary vascular dilatation. The only efficient treatment in case of severe and refractory hypoxemia is the oxygen supplementation, with complete resolution in more than 80%, according to study results [8, 20]. The presence of HPS offers exception points in MELD scoring and an advantage for patients to occupy better places on waiting lists for OLT [21]. Without OLT, the prognosis for HPS is poor, with mortality around 41% of patients over a mean period of 2.5 years [22]. The literature data do not provide reliable clinical predictors or diagnosis guidelines for the outcome of HPS [23].

A retrospective cohort analysis of data submitted to the United Network for Organ Sharing studied the effects of room‐air oxygenation of patients with HPS and the pre‐ and post‐trans‐ plantation outcomes. Patients with HPS were given MELD exception points and prioritized for liver transplantation due to their high pre‐ and post‐transplantation mortality. Comparing the overall survival rates of patients with and without HPS, transplant recipients with more severe hypoxemia had increased risk of death after liver transplantation. The overall mortality was significantly lower among waitlist candidates with HPS (hazard ratio = 0.82; 95% CI: 0.70– 0.96), having the OLT before the deterioration of tissue oxygenation and liver dysfunction, due to exception MELD points given, which provided an advantage for a rapid transplant [24].

The aim of our study was a possible correlation between contrast‐enhanced ultrasound (CEUS) findings on heart and pulse oximetry, in order to early detect HPS, as a prognostic factor for orthotopic liver transplant (OLT) success [25].

## **2. Methods**

Demographic data, etiology and severity scores were recorded. For the diagnosis of HPS, we used the classical triad: presence of chronic liver disease, an increased alveolar‐arterial oxygen gradient, and evidence of right‐to‐left intrapulmonary shunt (IPS) [26]. In order to determine the HPS diagnosis, we used the classical charts provided by the guidelines for transplant candidates (**Table 1**). The diagnosis of liver cirrhosis was based on clini‐ cal, biochemical, ultrasound, and upper endoscopy criteria. The patients with liver cir‐ rhosis were classified according to MELD scores, considering exception points according to international recommendations. The contrast‐enhanced echocardiography (CEUS) [27], technetium‐99m‐labeled macroaggregated albumin (Tc‐99m MAA) scanning [28], and pulmonary arteriography are the current imagistic tools to diagnose the IPS. We corre‐ lated transthoracic CEUS findings with pulse oxymetry as a screening test for detecting IPS in 375 patients diagnosed with liver cirrhosis between December 2009 and June 2016 in Gastroenterology Department of Clinical Emergency Hospital "St Apostle Andrew" of Constanta County.


**Table 1.** Inclusion criteria defining OLT waitlist candidates with HPS based on exception narrative data [28].

All patients were examined by chest X‐ray and pulmonary function tests (to rule out common intrinsic pulmonary disorders such as chronic obstructive pulmonary disease). We used as a contrast agent of hand‐agitated saline solution, in order to produce microbubbles with a mean diameter of up to 10 μm injected through a peripheral vein. Unlike blood, microbubbles reso‐ nate at a frequency similar to clinical transducer frequencies, which make ultrasounds to be reflected. Under normal circumstances, only the right heart chambers are opacified, and the microbubbles are trapped in the pulmonary capillaries (mean diameter, 8 μm). The presence of contrast in the left chamber suggests an arteriovenous connection. In patients with intra‐ cardiac shunts, a small amount of contrast is usually recorded in the left chambers within 1 or 2 cardiac cycles after its appearance in the right‐side chambers (early shunt). On the contrary, late arrival of contrast in the left atrium after a time delay of 4–8 cardiac cycles is diagnostic for HPS (delayed shunt) and is done by the time required for passage through the pulmonary circulation [27]. Measurement of SaO<sup>2</sup> was performed with a portable pulse oximeter. In all patients, the measurements were performed at ambient O2 partial pressure in supine position. We have chosen a SaO2 value of <95% in order to detect all HPS patients with a PaO2 < 70. The correlation of rapid lung enhancement and delayed left ventricle enhancement of the saline solution, after at least three systolic beats in the left ventricle during CEUS and pulse oximetry showing a SaO<sup>2</sup> < 95% was considered positive for the diagnosis of HPS [29].

## **3. Results**

for liver transplantation due to their high pre‐ and post‐transplantation mortality. Comparing the overall survival rates of patients with and without HPS, transplant recipients with more severe hypoxemia had increased risk of death after liver transplantation. The overall mortality was significantly lower among waitlist candidates with HPS (hazard ratio = 0.82; 95% CI: 0.70– 0.96), having the OLT before the deterioration of tissue oxygenation and liver dysfunction, due to exception MELD points given, which provided an advantage for a rapid transplant [24].

The aim of our study was a possible correlation between contrast‐enhanced ultrasound (CEUS) findings on heart and pulse oximetry, in order to early detect HPS, as a prognostic

Demographic data, etiology and severity scores were recorded. For the diagnosis of HPS, we used the classical triad: presence of chronic liver disease, an increased alveolar‐arterial oxygen gradient, and evidence of right‐to‐left intrapulmonary shunt (IPS) [26]. In order to determine the HPS diagnosis, we used the classical charts provided by the guidelines for transplant candidates (**Table 1**). The diagnosis of liver cirrhosis was based on clini‐ cal, biochemical, ultrasound, and upper endoscopy criteria. The patients with liver cir‐ rhosis were classified according to MELD scores, considering exception points according to international recommendations. The contrast‐enhanced echocardiography (CEUS) [27], technetium‐99m‐labeled macroaggregated albumin (Tc‐99m MAA) scanning [28], and pulmonary arteriography are the current imagistic tools to diagnose the IPS. We corre‐ lated transthoracic CEUS findings with pulse oxymetry as a screening test for detecting IPS in 375 patients diagnosed with liver cirrhosis between December 2009 and June 2016 in Gastroenterology Department of Clinical Emergency Hospital "St Apostle Andrew" of

Strict HPS criteria Alveolar‐arterial gradient ≥15 mmHg, or ≥20 mmHg if age older than

fraction on macroaggregated albumin scan

<70 mmHg on room air or

• Pulse oximetry ≤96% (room air or supplemental O<sup>2</sup>

No evidence of concurrent cardiopulmonary disease

Intrapulmonary shunting on transthoracic echocardiogram or >6% shunt

Intrapulmonary shunting (right → left bubbles on echocardiogram after three cardiac cycles and/or free text stating "intrapulmonary shunting")

)

No evidence of severe restrictive or obstructive pulmonary disease

60 years

• PaO2

**Table 1.** Inclusion criteria defining OLT waitlist candidates with HPS based on exception narrative data [28].

factor for orthotopic liver transplant (OLT) success [25].

**Criteria Data requirements**

Hypoxia/hypoxemia+ IP shunts Hypoxemia defined as:

**2. Methods**

88 Liver Cirrhosis - Update and Current Challenges

Constanta County.

A total of 375 patients diagnosed with liver cirrhosis were enrolled in our study. The majority of patients were male (251/375). The average age was 66.04 years (SD 8.81). The etiology of liver cirrhosis was alcohol abuse in 39% (146/375) of patients, viral hepatitis B (VHB) in 28% (105/375) of patients, viral hepatitis C (VHC) in 21% (79/375) of patients, and the rest of 12% (45/375) hav‐ ing uncommon etiologies. Severity in MELD score divided our patients in three groups accord‐ ing to which we could fix the prognosis and the need of transplantation (**Table 2**).

According to present international recommendations, we decided upon exception points for those patients meeting the criteria for MELD exception: patients with PaO<sup>2</sup> < 60 mmHg on room air at rest in the sitting position, arterial blood gas result provided, patients with pulmonary vascular dilatation documented by a positive transthoracic contrast echocardiog‐ raphy, patients with absence of significant alternative pulmonary disease to explain severe hypoxemia (chest X‐ray, pulmonary function tests, and chest computed tomography reports), patients with moderate or severe pulmonary function tests changes or significant chest X‐ray abnormalities or MAA scan positive for intrapulmonary shunting) (**Table 3**). From the total of 375 patients studied, 165 (44%) presented respiratory symptoms. Pulse oximetry showed alterations, such as SaO2 < 95% and PaO2 < 70 mmHg in 123 patients (33%). From 375 patients diagnosed with LC, with or without present respiratory signs and/or symptoms (dyspnea, clubbing, distal cyanosis, cough and/or spider angioma) referred to CEUS examination, 105 (28%) had rapid lung enhancement and delayed left ventricle enhancement of the contrast agent (**Figures 1**–**3**). PaO2 was less than 70 mmHg in all 105 HPS patients (100%) versus 12 (14.76%) of non‐HPS patients (*P* < 0.0001). Pearson correlation index showed a good correla‐ tion between lung and heart CEUS findings and pulse oximetry (*r* = 0.97) in HPS diagnosis.


**Table 2.** Baseline clinical and demographic characteristics of HPS and non‐HPS patients.

Correlation Between Transthoracic Contrast-Enhanced Ultrasound and Pulse Oximetry... http://dx.doi.org/10.5772/intechopen.68550 91


**Table 3.** Allocation of exception points for HPS in MELD scoring system [28].

**Variable HPS (no, %) Non‐HPS (no, %)**

Males 128 (50.99) 123 (49.00) Females 59 (47.58) 65 (52.41)

Caucasians 92 (87.61) 243 (90) Blacks 2 (1.90) 1 (0.37) Asians 11 (10.47) 26 (09.62)

Romanian 51 (48.57) 173 (64.07) Turcs/tatars 8 (7.61) 19 (7.03) Moldavians 4 (3.80) 9 (3.33) Macedonians 31 (29.52) 42 (15.55) Other 11 (10.47) 27 (10)

HCV 27 (25.71) 52 (19.25) HBV 31 (29.52) 74 (27.40) Alcohol 39 (37.14) 106 (39.25) HVD 5 (4.76) 18 (6.66) Autoimmune 2 (1.90) 4 (1.48) NASH/criptogenetic 1 (0.95) 9 (3.33) Other rare causes – 5 (1.85) **MELD score, median (IQR)** 14 (11–22) 16 (11–24)

<15 47 (44.76) 156 (57.77) 15–20 34 (32.38) 76 (28.14) >20 14 (13.33) 38 (14.07)

< 60 mmHG (22 pts) 5 (4.76) –

= 51–55 mmHG (24 pts) 4 (3.80) –

 < 50 mmHG (26 pts) 1 (00.95 – **History of ascites** 84 (80.00) 229 (84.81) **History of liver decompensations** 74 (70.47) 172 (63.70)

**Table 2.** Baseline clinical and demographic characteristics of HPS and non‐HPS patients.

**Gender**

90 Liver Cirrhosis - Update and Current Challenges

**Race**

**Ethnicity**

**Primary diagnosis**

**MELD score categories**

**MELD exceptions**

PaO2

PaO2

PaO2

Mean age (IQR) 66.04 ± 8.81 (95% CI, 58.44–74.85) 63.10 ± 10.71 (95% CI, 61.55–64.65)

**Figure 1.** Contrast‐enhanced echocardiogram. Apical four‐chamber view before contrast injection.

**Figure 2.** Contrast‐enhanced echocardiogram. Apical four‐chamber view after contrast injection (agitated saline) showing the presence of bubbles in the right chambers and no bubbles in the left chambers after the first sistola.

**Figure 3.** Contrast‐enhanced echocardiogram. Apical four‐chamber view after contrast injection (agitated saline) showing the presence of bubbles in the right heart chambers and the appearance of bubbles in the left heart chambers, late, after the forth sistola.

#### **4. Discussion**

HPS was defined as a triad of portal hypertension with or without hepatic dysfunction, intra‐ pulmonary vascular dilatation or shunting, and hypoxemia [30]. Hypoxemia was defined by PaO2 cutoff level of less than 70 mmHg in an arterial blood sample to pick up these patients for further evaluation by CEUS. This arterial PO2 cutoff level was suggested by previous researchers [31], who found that patients with PaO2 of more than 70 mmHg were unlikely to have HPS.

In the current study, among 375 patients diagnosed with liver cirrhosis, 105 patients (28%) met the clinical, laboratory and imagistic criteria of HPS. HPS shows a wide variability in prevalence in different studies, ranging from 4 to 47% among cirrhotic patients [1, 4, 32], depending on the diagnostic criteria and the cutoff levels used for hypoxia. In our study, PaO2 was less than 70 mmHg in 100% of HPS patients versus 12% of non‐HPS patients, in which pulmonary function tests were used to diagnose chronic intrinsic pulmonary disease. All patients with positive CEUS findings had arterial PaO<sup>2</sup> <70 mmHg and were qualified for the diagnosis of HPS. CEUS was proved by previous investigators to be a useful sensitive and specific screening test for HPS even in early stages of liver dysfunction and even in whom the lung scintigraphy was still negative [33]. Some authors suggested transesophageal CEUS as a gold standard [34, 35]. However, others argued that transthoracic CEUS has the same accuracy as transesophageal CEUS in determining the presence of right to left shunt. Proper timing of left atrial opacification by microbubbles during the cardiac cycle was considered a distinguishing step in the transthoracic CEUS between intracardiac and intrapulmonary shunting [36]. Transesophageal CEUS might have higher sensitivity than transthoracic CEUS because it allows the contrast to be seen when entering from the pulmonary veins [37, 38]. However, transthoracic CEUS is diagnostic in the majority of cases. In addition, esophageal varices are relatively common in these patients, and this can be considered as a relative con‐ traindication in transesophageal CEUS performing [29, 39].

According to their correlated results, the transthoracic CEUS and pulse oximetry could be inserted in the algorithm of liver cirrhosis staging, in order to select those patients in need for a more rapid indication of OLT. Both methods provide data regarding the pulmonary dysfunction during liver cirrhosis evolution, improving the outcome after OLT, especially in HPS patients with moderate or severe hypoxemia. The presymptomatic stage of HPS can be correctly diagnosed using the combination of these two methods, making the algorithm of liver cirrhosis staging more accurate.

## **5. Conclusion**

**4. Discussion**

late, after the forth sistola.

92 Liver Cirrhosis - Update and Current Challenges

for further evaluation by CEUS. This arterial PO2

researchers [31], who found that patients with PaO2

All patients with positive CEUS findings had arterial PaO<sup>2</sup>

PaO2

PaO2

have HPS.

HPS was defined as a triad of portal hypertension with or without hepatic dysfunction, intra‐ pulmonary vascular dilatation or shunting, and hypoxemia [30]. Hypoxemia was defined by

**Figure 3.** Contrast‐enhanced echocardiogram. Apical four‐chamber view after contrast injection (agitated saline) showing the presence of bubbles in the right heart chambers and the appearance of bubbles in the left heart chambers,

In the current study, among 375 patients diagnosed with liver cirrhosis, 105 patients (28%) met the clinical, laboratory and imagistic criteria of HPS. HPS shows a wide variability in prevalence in different studies, ranging from 4 to 47% among cirrhotic patients [1, 4, 32], depending on the diagnostic criteria and the cutoff levels used for hypoxia. In our study,

 was less than 70 mmHg in 100% of HPS patients versus 12% of non‐HPS patients, in which pulmonary function tests were used to diagnose chronic intrinsic pulmonary disease.

the diagnosis of HPS. CEUS was proved by previous investigators to be a useful sensitive and specific screening test for HPS even in early stages of liver dysfunction and even in whom the lung scintigraphy was still negative [33]. Some authors suggested transesophageal CEUS as a gold standard [34, 35]. However, others argued that transthoracic CEUS has the same accuracy as transesophageal CEUS in determining the presence of right to left shunt. Proper timing of left atrial opacification by microbubbles during the cardiac cycle was considered a distinguishing step in the transthoracic CEUS between intracardiac and intrapulmonary shunting [36]. Transesophageal CEUS might have higher sensitivity than transthoracic CEUS

cutoff level of less than 70 mmHg in an arterial blood sample to pick up these patients

cutoff level was suggested by previous

of more than 70 mmHg were unlikely to

<70 mmHg and were qualified for

Our study showed a good correlation between lung and heart CEUS findings and pulse oxim‐ etry in HPS diagnosis. When correlated, these two simple, non‐invasive, low‐cost and rapid methods can easily diagnose HPS, a highly fatal complication of liver cirrhosis, which can worsen the outcome of patients even after OLT.

## **Acknowledgements**

This work was accomplished with the support of Dr. Razvan Maxim, for transthoracic enhanced ultrasonography images caption, and Dr. Phillipos Manousos Goniotakis, for the English linguistic assistance.

## **Author details**

Andra‐Iulia Suceveanu<sup>1</sup> \*, Adrian‐Paul Suceveanu<sup>1</sup> , Irinel‐Raluca Parepa3 , Felix Voinea<sup>4</sup> and Laura Mazilu<sup>2</sup>

\*Address all correspondence to: andrasuceveanu@yahoo.com

1 Faculty of Medicine, Department of Gastroenterology, Emergency Hospital of Constanta, Ovidius University, Constanta, Romania

2 Faculty of Medicine, Department of Internal Medicine, Emergency Hospital of Constanta, Ovidius University, Constanta, Romania

3 Faculty of Medicine, Department of Cardiology, Emergency Hospital of Constanta, Ovidius University, Constanta, Romania

4 Faculty of Medicine, Department of Surgery, Emergency Hospital of Constanta, Ovidius University, Constanta, Romania

## **References**


[16] Gómez FP, Martínez‐Pallí G, Barberà JA, Roca J, Navasa M, Rodríguez‐Roisin R. Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology. 2004;**40**:660‐666

**References**

2000;**32**:859‐865

94 Liver Cirrhosis - Update and Current Challenges

2000;**32**:859‐865

Chest. 2003;**123**:562‐576

Gastroenterology. 2009;**136**:1070‐1080

Critical Care Medicine. 2002;**166**:514‐517

Journal of Physiology. 1999;**277**:944‐952

Hepatology. 2006;**43**:1084‐1091

monary syndrome. Lancet. 2004;**363**:1461

Journal of Hepatology. 2001;**34**:756‐758

[1] Hoeper MM, Krowka MJ, Strassburg CP. Portopulmonary hypertension and hepatopul‐

[2] Martinez G, et al. Hepatopulmonary Syndrome in candidates for liver transplantation.

[3] Schenk P, et al. Hepatopulmonary syndrome: Prevalence and predictive value of various cut Fallon M, Abrams G. Pulmonary dysfunction in chronic liver disease. Hepatology.

[4] Rodríguez‐Roisin R, Krowka MJ. Hepatopulmonary syndrome—a liver‐induced lung

[5] Fallon M, Abrams G. Pulmonary dysfunction in chronic liver disease. Hepatology.

[6] Budhiraja R, Hassoun PM. Portopulmonary hypertension: A tale of two circulations.

[7] Varghese J, Ilian H, Dhanasekaran R, Singh S, Venkataraman J. Hepatopulmonary syn‐

[8] Rodríguez‐Roisin R, Krowka MJ, Hervé P, Fallon MB; ERS Task Force Pulmonary‐ Hepatic Vascular Disorders (PHD) Scientific Committee. Pulmonary‐hepatic vascular

[9] Zhang J, et al. Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome.

[10] Cremona G, Higenbottam TW, Mayoral V, et al. Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome. European Respiratory Society. 1995;**8**:1883‐1885 [11] Rabiller A, Nunes H, Lebrec D, et al. Prevention of gramnegative translocation reduces the severity of hepatopulmonary syndrome. American Journal of Respiratory and

[12] Zhang M, Luo B, Chen SJ, Abrams GA, Fallon MB. Endothelin‐1 stimulation of endothe‐ lial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome. American

[13] Berthelot P, Walker JG, Sherlock S, Reid L. Arterial changes in the lungs in cirrhosis of the liver‐lung spider nevi. The New England Journal of Medicine. 1966;**274**:291‐298 [14] Gómez FP, Barberà JA, Roca J, Burgos F, Gistau C, Rodríguez‐Roisin R. Effects of neb‐ ulized NG‐nitro‐l‐arginine methyl ester in patients with hepatopulmonary syndrome.

[15] Martínez GP, Barberà JA, Visa J, Rodriguez‐Roisin R. Hepatopulmonary syndrome asso‐ ciated with cardiorespiratory disease. Journal of Hepatology. 1999;**30**:882‐889

vascular disorder. The New England Journal of Medicine. 2008;**358**:2378

drome—Past to present. Annals of Hepatology. 2007;**6**(3):135‐142

disorders (PHD). European Respiratory Society. 2004;**24**:861‐880

