Non-Invasive Assessment and Endoscopy in Portal Hypertension

*Portal Hypertension - Recent Advances*

[160] Van Deventer SJH, Butler HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood

Multimer Distribution in Cirrhotic Patients with Stable Disease or Acute Decompensation. Thromb Haemost.

2018;118(8):1397-1408

[161] Federici AB, Berkowitz SD, Zimmerman TS, Mannucci PM. Proteolysis of von Willebrand factor after thrombolytic therapy in patients with acute myocardial infarction. Blood

[162] Atichartarn V, Marder V, Kirby EP, Budzynski AZ. Effects of enzymatic degradation on the subunit composition and biologic properties of human factor

[163] Semeraro N, Biondi A, Lorenzet R, Locati D, Mantovani A, Donati MB. Direct induction of tissue factor synthesis by endotoxin in human macrophages from diverse anatomical sites. Immunology 1983;50:529-535.

[164] Colucci M, Balconi G, Lorenzet R, Pietra A, Locati D. Cultured human endothelial cells generate tissue factor in response to endotoxins. J Ciin Invest

[165] Van der Poll T, Buller HR, ten Cate H, Wortel CH, Bauer KA, Van Deventer SJH, Hack E, Sauerwein HP, Rosemberg RD, ten Cate JW. Activation of coagulation after administration

of tumor necrosis factor to normal subjects. N Engl J Med

[166] Yamamoto K, Shimokawa T, Kojima T, Loskutoff DJ, Saito H. Regulation of murine protein C gene expression in vivo: effects of tumor necrosis factor- alpha, interleukin-1, and transforming growth factor-beta. Thromb Haemost 1999;82:1297-1301.

[167] Palyu E, Harsfalvi J, Tornai T, et al. Major Changes of von Willebrand Factor

1990;322:1622-1627

VIII. Blood 1978;51:281-292

1983; 71:1893-1896.

1990;12:2520-2526.

1992;79:38-44.

**78**

**81**

considered.

**Chapter 5**

**Abstract**

prediction

**1. Introduction**

6-week mortality rate of 12–26% [2, 3].

Non-Invasive Prediction of

Gastroesophageal Varices in

*Ran Wang, Xiaozhong Guo and Xingshun Qi*

Patients with Portal Hypertension

Gastroesophageal varices are the most common complication of portal hypertension and associated with a worse prognosis. Endoscopy is the gold standard method to diagnose gastroesophageal varices. However, endoscopy is an invasive method with potential complications and is not well adhered by patients. Non-invasive methods, including serum markers or scores, computed tomography, ultrasonographic, and elastography-based methods, have been explored for the diagnosis of gastroesophageal varices. In the current chapter, we will briefly review

**Keywords:** portal hypertension, gastroesophageal varices, non-invasive, diagnosis,

Portal hypertension is defined as the pressure of portal vein is 5 mmHg higher

Endoscopy, the gold standard method to diagnose GEVs, is recommended for all patients at the time of diagnosis of cirrhosis. Endoscopy should be periodic for screening GEVs. It is reported that nearly 30% of cirrhotic patients screened by endoscopy found to have moderate-to-large varices [4, 5]. Endoscopy is not only a diagnostic method but also serves as a therapeutic option in the form of sclerotherapy and band ligation. However, endoscopy is an invasive method, which is not well perceived by patients. Complications following diagnostic endoscopy mainly include infection, bleeding, duodenal hematoma, bowel perforation, airway obstruction, arrhythmias, and aspiration. Additionally, in some less developed regions or countries, advanced endoscopy and experienced endoscopists are still in shortage. It is thus important to identify patients who can avoid unnecessary endoscopy or patients with high-risk GEVs that need further treatment should be

than that of inferior vena cava. It is the most important complication of liver cirrhosis. Clinically significant portal hypertension is associated with an increased risk of developing varices, which is defined as hepatic venous pressure gradient over 10 mmHg [1]. Gastroesophageal varices (GEVs) is appeared in approximately 50% of patients with cirrhosis, which is associated with a worse outcome. Despite an improvement of treatment strategy, variceal bleeding is still associated with a

non-invasive methods for the prediction of gastroesophageal varices.

#### **Chapter 5**

## Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension

*Ran Wang, Xiaozhong Guo and Xingshun Qi*

#### **Abstract**

Gastroesophageal varices are the most common complication of portal hypertension and associated with a worse prognosis. Endoscopy is the gold standard method to diagnose gastroesophageal varices. However, endoscopy is an invasive method with potential complications and is not well adhered by patients. Non-invasive methods, including serum markers or scores, computed tomography, ultrasonographic, and elastography-based methods, have been explored for the diagnosis of gastroesophageal varices. In the current chapter, we will briefly review non-invasive methods for the prediction of gastroesophageal varices.

**Keywords:** portal hypertension, gastroesophageal varices, non-invasive, diagnosis, prediction

#### **1. Introduction**

Portal hypertension is defined as the pressure of portal vein is 5 mmHg higher than that of inferior vena cava. It is the most important complication of liver cirrhosis. Clinically significant portal hypertension is associated with an increased risk of developing varices, which is defined as hepatic venous pressure gradient over 10 mmHg [1]. Gastroesophageal varices (GEVs) is appeared in approximately 50% of patients with cirrhosis, which is associated with a worse outcome. Despite an improvement of treatment strategy, variceal bleeding is still associated with a 6-week mortality rate of 12–26% [2, 3].

Endoscopy, the gold standard method to diagnose GEVs, is recommended for all patients at the time of diagnosis of cirrhosis. Endoscopy should be periodic for screening GEVs. It is reported that nearly 30% of cirrhotic patients screened by endoscopy found to have moderate-to-large varices [4, 5]. Endoscopy is not only a diagnostic method but also serves as a therapeutic option in the form of sclerotherapy and band ligation. However, endoscopy is an invasive method, which is not well perceived by patients. Complications following diagnostic endoscopy mainly include infection, bleeding, duodenal hematoma, bowel perforation, airway obstruction, arrhythmias, and aspiration. Additionally, in some less developed regions or countries, advanced endoscopy and experienced endoscopists are still in shortage. It is thus important to identify patients who can avoid unnecessary endoscopy or patients with high-risk GEVs that need further treatment should be considered.

Non-invasive prediction of GEVs could relieve medical, social, and economic costs. Numerous efforts have been made to predict GEVs non-invasively, and some progress has been achieved. In the Baveno VI consensus conference, it was underlined that non-invasive methods should be used to rule out patients with varices or high-risk varices [6]. In this chapter, we focus on non-invasive methods in the prediction of GEVs.

#### **2. Serum markers or scores**

#### **2.1 Serum ammonia**

Serum ammonia is well recognized as a serum marker for hepatic encephalopathy in cirrhotic patients. Studies have demonstrated serum ammonia has a positive correlation with the presence of portosystemic collateral veins including GEVs [7]. In a newly published study by **Darweesh et al.** serum ammonia was found significantly higher in patients with esophageal varices (EVs) than those without [8]. A total of 204 hepatitis C virus (HCV) relate cirrhotic patients were enrolled. Serum ammonia with a cutoff value of 82 μmol/L had a sensitivity of 92.3% and specificity of 92% in detecting EVs and that with a cutoff value of 95.5 μmol/L had a sensitivity of 92.7% and specificity of 92.3% in detecting large EVs. Conversely, a study by **Hafez et al.** found that serum ammonia alone cannot predict the presence or grade of EVs [9]. The predictive value of serum ammonia for GEVs still needs further evaluation.

#### **2.2 Platelet count/spleen diameter ratio**

Platelet count/spleen diameter ratio (PSR) was first proposed by **Giannini et al.** [10] to explore the non-invasive method for predicting GEVs. In the first part of Giannini's study, 145 patients were included. The results found that PSR was the only parameter independently associated with the EVs with a cutoff value of 909. The PSR with cutoff value of 909 had a sensitivity of 100%, a specificity of 93%, a positive predictive value (PPV) of 96%, and an negative predictive value (NPV) of 100%. In the second part of this study, 103 patients were included, the results validated that the reproducibility of the predictive value of PSR for EVs. Additionally, in all 266 patients, PSR was the only parameter significantly different between patients with and without EVs at baseline.

Since then, extensive studies have focused on the PSR for the non-invasive prediction of GEVs. However, a study by **Schwarzenberger et al.** found PSR maybe not sufficient for the diagnosis of GEVs [11]. In this study, a total of 137 patients were enrolled. The diameter of spleen was measured using computed tomography (CT), magnetic resonance imaging, and ultrasonography. Ascites, splenomegaly, Child-Pugh score were found to have a positive correlation with EVs. The PSR with a cutoff of 909 had a sensitivity of 80%, specificity of 66%, and PPV of 74%.

In a recent meta-analysis by **Chen et al.** where 49 studies were enrolled, found that the area under curves (AUC) of PSR for GEVs was 0.8719, the summary sensitivity and specificity were 0.84 and 0.78, respectively [12]. The results suggest that PSR can be used for predicting EVs, especially in patients with viral hepatitis.

#### **2.3 Liaoning score**

The Liaoning score was proposed by **Qi et al.** from a prospective cohort of cirrhotic patients who underwent the first-time endoscopy at 11 hospitals in Liaoning

**83**

*Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension*

Province, China [13]. In this study, a total of 363 cirrhotic patients were enrolled. The incidence of EVs was 71.63% (260/363). The results suggest that acute upper gastrointestinal bleeding (AUGIB), platelet count, and ascites were independently associated with the presence of EVs. In the whole cirrhotic patients, the Liaoning score, whose equation was 0.466 + 1.088 × AUGIB (1 = yes; 0 = no) + 1.147 × ascites (1 = yes; 0 = no) - 0.012 × platelet count, had an AUC of 0.807 (p < 0.0001). The cutoff value was 0.474 with a sensitivity of 70%, a specificity of 77.67%, a PPV of 88.8%, and an NPV of 50.6%. In patients with AUGIB, the equation was 1.205 + 1.557 × ascites (1 = yes; 0 = no) - 0.008 × platelet count, with an AUC of 0.782 (p < 0.0001). The results of this study suggested that Liaoning score was a newly developed scoring system which can be employed to predict EVs in cirrhotic

For external validation of Liaoning score, **Li et al.** performed a nationwide multicenter cross-sectional study to evaluate the predictive ability of Liaoning score for EVs and high-risk EVs [14]. In this study, 612 cirrhotic patients with AUGIB were enrolled. The incidence of EVs and high-risk EVs was 96.2% and 95.6%, respectively. The results showed that the AUC of Liaoning score for predicting EVs

Other than the non-invasive methods we have discussed above, many scores have been developed for the evaluation of liver fibrosis, including aspartate aminotransferase-to-platelet ratio index (APRI), aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), FIB-4, and Lok scores. Some studies explore the predictive ability of these non-invasive scores for GEVs. In a meta-analysis by **Deng et al.** several non-invasive scores had been systematically reviewed for the predictive ability of EVs [15]. In the overall analysis, a total of 650 patients were included, 81.4% of them had moderate–severe EVs. Only Child-Pugh and FI scores were significantly higher in patients with EVs than those without. The AUC of FI was 0.612, FIB-4 was 0.567, AAR was 0.56, and APRI was 0.539. However, the AUC among these scores was not significantly different. For further validation, **Deng et al**. also performed a retrospective study, the results were in agreement with their previous meta-analysis [16]. A total of 650 cirrhotic patients were included, and 81.4% of them had high-risk EVs. The results of this study concluded that APRI, AAR, and FIB-4 scores had only modest diagnostic accuracy of EVs in cirrhotic patients.

CT scanning is one of the most important image tools in clinical practice, is recommended for the surveillance of hepatocellular carcinoma in all cirrhotic patients. GEVs characteristics as round, tubular, or serpentine structures in the esophagus and/ or gastric lumen in CT images. It provides a possibility that an experienced physician can diagnosis GEVs using CT images, especially in contrast-enhanced CT images. **Perri et al.** designed a prospective study that explores the ability of CT for the prediction of GEVs [5]. A total of 102 patients who had a CT and endoscopy within 5 days were enrolled. Two radiologists read the CT independently. The sensitivity of EVs was 93% in both radiologists, the specificity was 55% and 45%, respectively. The sensitivity of gastric varices was 87% in both radiologists. The results suggest

that CT should be used as initial surveillance for GEVs.

was 0.708 (p = 0.0016), and that of high-risk EVs was 0.702 (p = 0.0147).

*DOI: http://dx.doi.org/10.5772/intechopen.98879*

patients.

**2.4 Other scores**

**3. Image tools**

**3.1 CT**

*Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.98879*

Province, China [13]. In this study, a total of 363 cirrhotic patients were enrolled. The incidence of EVs was 71.63% (260/363). The results suggest that acute upper gastrointestinal bleeding (AUGIB), platelet count, and ascites were independently associated with the presence of EVs. In the whole cirrhotic patients, the Liaoning score, whose equation was 0.466 + 1.088 × AUGIB (1 = yes; 0 = no) + 1.147 × ascites (1 = yes; 0 = no) - 0.012 × platelet count, had an AUC of 0.807 (p < 0.0001). The cutoff value was 0.474 with a sensitivity of 70%, a specificity of 77.67%, a PPV of 88.8%, and an NPV of 50.6%. In patients with AUGIB, the equation was 1.205 + 1.557 × ascites (1 = yes; 0 = no) - 0.008 × platelet count, with an AUC of 0.782 (p < 0.0001). The results of this study suggested that Liaoning score was a newly developed scoring system which can be employed to predict EVs in cirrhotic patients.

For external validation of Liaoning score, **Li et al.** performed a nationwide multicenter cross-sectional study to evaluate the predictive ability of Liaoning score for EVs and high-risk EVs [14]. In this study, 612 cirrhotic patients with AUGIB were enrolled. The incidence of EVs and high-risk EVs was 96.2% and 95.6%, respectively. The results showed that the AUC of Liaoning score for predicting EVs was 0.708 (p = 0.0016), and that of high-risk EVs was 0.702 (p = 0.0147).

#### **2.4 Other scores**

*Portal Hypertension - Recent Advances*

**2. Serum markers or scores**

**2.2 Platelet count/spleen diameter ratio**

patients with and without EVs at baseline.

prediction of GEVs.

**2.1 Serum ammonia**

evaluation.

Non-invasive prediction of GEVs could relieve medical, social, and economic costs. Numerous efforts have been made to predict GEVs non-invasively, and some progress has been achieved. In the Baveno VI consensus conference, it was underlined that non-invasive methods should be used to rule out patients with varices or high-risk varices [6]. In this chapter, we focus on non-invasive methods in the

Serum ammonia is well recognized as a serum marker for hepatic encephalopathy in cirrhotic patients. Studies have demonstrated serum ammonia has a positive correlation with the presence of portosystemic collateral veins including GEVs [7]. In a newly published study by **Darweesh et al.** serum ammonia was found significantly higher in patients with esophageal varices (EVs) than those without [8]. A total of 204 hepatitis C virus (HCV) relate cirrhotic patients were enrolled. Serum ammonia with a cutoff value of 82 μmol/L had a sensitivity of 92.3% and specificity of 92% in detecting EVs and that with a cutoff value of 95.5 μmol/L had a sensitivity of 92.7% and specificity of 92.3% in detecting large EVs. Conversely, a study by **Hafez et al.** found that serum ammonia alone cannot predict the presence or grade of EVs [9]. The predictive value of serum ammonia for GEVs still needs further

Platelet count/spleen diameter ratio (PSR) was first proposed by **Giannini et al.** [10] to explore the non-invasive method for predicting GEVs. In the first part of Giannini's study, 145 patients were included. The results found that PSR was the only parameter independently associated with the EVs with a cutoff value of 909. The PSR with cutoff value of 909 had a sensitivity of 100%, a specificity of 93%, a positive predictive value (PPV) of 96%, and an negative predictive value (NPV) of 100%. In the second part of this study, 103 patients were included, the results validated that the reproducibility of the predictive value of PSR for EVs. Additionally, in all 266 patients, PSR was the only parameter significantly different between

Since then, extensive studies have focused on the PSR for the non-invasive prediction of GEVs. However, a study by **Schwarzenberger et al.** found PSR maybe not sufficient for the diagnosis of GEVs [11]. In this study, a total of 137 patients were enrolled. The diameter of spleen was measured using computed tomography (CT), magnetic resonance imaging, and ultrasonography. Ascites, splenomegaly, Child-Pugh score were found to have a positive correlation with EVs. The PSR with a

cutoff of 909 had a sensitivity of 80%, specificity of 66%, and PPV of 74%.

In a recent meta-analysis by **Chen et al.** where 49 studies were enrolled, found that the area under curves (AUC) of PSR for GEVs was 0.8719, the summary sensitivity and specificity were 0.84 and 0.78, respectively [12]. The results suggest that PSR can be used for predicting EVs, especially in patients with viral hepatitis.

The Liaoning score was proposed by **Qi et al.** from a prospective cohort of cirrhotic patients who underwent the first-time endoscopy at 11 hospitals in Liaoning

**82**

**2.3 Liaoning score**

Other than the non-invasive methods we have discussed above, many scores have been developed for the evaluation of liver fibrosis, including aspartate aminotransferase-to-platelet ratio index (APRI), aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), FIB-4, and Lok scores. Some studies explore the predictive ability of these non-invasive scores for GEVs. In a meta-analysis by **Deng et al.** several non-invasive scores had been systematically reviewed for the predictive ability of EVs [15]. In the overall analysis, a total of 650 patients were included, 81.4% of them had moderate–severe EVs. Only Child-Pugh and FI scores were significantly higher in patients with EVs than those without. The AUC of FI was 0.612, FIB-4 was 0.567, AAR was 0.56, and APRI was 0.539. However, the AUC among these scores was not significantly different. For further validation, **Deng et al**. also performed a retrospective study, the results were in agreement with their previous meta-analysis [16]. A total of 650 cirrhotic patients were included, and 81.4% of them had high-risk EVs. The results of this study concluded that APRI, AAR, and FIB-4 scores had only modest diagnostic accuracy of EVs in cirrhotic patients.

#### **3. Image tools**

#### **3.1 CT**

CT scanning is one of the most important image tools in clinical practice, is recommended for the surveillance of hepatocellular carcinoma in all cirrhotic patients. GEVs characteristics as round, tubular, or serpentine structures in the esophagus and/ or gastric lumen in CT images. It provides a possibility that an experienced physician can diagnosis GEVs using CT images, especially in contrast-enhanced CT images.

**Perri et al.** designed a prospective study that explores the ability of CT for the prediction of GEVs [5]. A total of 102 patients who had a CT and endoscopy within 5 days were enrolled. Two radiologists read the CT independently. The sensitivity of EVs was 93% in both radiologists, the specificity was 55% and 45%, respectively. The sensitivity of gastric varices was 87% in both radiologists. The results suggest that CT should be used as initial surveillance for GEVs.

In a study by **Li et al.** contrast-enhanced CT was used for the non-invasive prediction of GEVs [17]. In this retrospectively study, a total of 279 patients were included. High-risk varices including EVs and gastric varices was defined as varices that need treatment. All patients were divided into four groups according to the history of bleeding events, endoscopic surveillance, and drug prophylaxis (primary or secondary prophylaxis). In the overall population, only contrast-enhanced CT was significantly associated with EVs, high-risk EVs, and gastric varices. In primary prophylaxis, acute bleeding, previous bleeding, and secondary prophylaxis population, a diameter < 0.5 cm, <0.38 cm <0.46 cm and < 0.33 cm was considered as the cut-off value of high-risk EVs, respectively. Which can spare 47.8%, 10.5%, 12.1%, and 7.8% of endoscopic surveillance with no high-risk EVs was missed, respectively. This study showed a good diagnostic performance for contrast-enhanced CT for patients with GEVs.

#### **3.2 Ultrasonography**

Ultrasonography is the most common, cost-effective, and convenient imaging tool in clinical practice, which can be used for screening of hepatocellular carcinoma, measure the width of the portal vein, inferior vena cava, and diameter of the spleen.

Splenoportal index was calculated as the splenic index divided by mean portal vein velocity. In a study by **Mansoor et al.** 200 HCV-induced cirrhotic patients were included [18]. All patients underwent ultrasonography first to calculate splenoportal index and then underwent endoscopy. The incidence of EVs was 60.5% (121/200) in ultrasonography and 63.5% (127/200) in endoscopy. The sensitivity, specificity, PPV, NPV of ultrasonography for predicting EVs was 88.98%, 89.04%, 93.00%, 82.28%, and 89.00%, respectively. This study showed a good diagnostic performance for splenoportal index by ultrasonography for patients with EVs.

#### **3.3 Elastography-based methods**

Elastography-based methods, Including transient elastography (TE), point shear wave elastography, two-dimensional shear wave elastography, and magnetic resonance elastography have been used to non-invasively detected liver fibrosis and GEVs. There is substantial evidence suggesting that TE had a good correlation with portal hypertension and varices in cirrhotic patients [19, 20]. In 2015, TE was recommended for the surveillance of GEVs by Baveno VI consensus [6]. According to the Baveno VI consensus, in patients with compensated advanced chronic liver disease, who had a liver stiffness <20 kPa measured by TE and platelet count >150,000/mm3 , had a low risk of developed GEVs that may spear endoscopy. **Augustin et al.** performed a prospective study that taking the Baveno VI recommendation a step forward [21]. This study suggests that platelet count >110,000/ mm3 and liver stiffness <25 kPa can spare more endoscopies than the Baveno VI consensus recommendation (41% vs. 21%). Only minority (0.6%) of overall patients were missed varices needing treatment. The negative predictive value for varices of the Baveno VI consensus and expanded Baveno VI consensus criteria is confirmed by further studies [22, 23].

In a study by **Kim et al.** a new model was generate based on the liver elasticity and the spleen diameter/platelet count (LSPS) [24]. A total of 280 hepatitis B virus relate cirrhotic patients were enrolled into the training cohort, and 121 patients were enrolled into the validation cohort. Liver stiffness was measured by TE. LSPS was calculated by the equation: Liver Stiffness Measurement × spleen diameter/ platelet count. In the training cohort, the cutoff value of LSPS was 3.5. In patients

**85**

*Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension*

with LSPS <3.5, the absence of high-risk EVs had a sensitivity of 87.7%, a specificity of 91.1%, an NPV of 94%, and a PPV of 82.3%. When applying the cutoff value of LSPS <3.5, the AUC in the validation cohorts was 0.953. The results of this study showed that in patients with LSPS <3.5, endoscopy may avoid safely in cirrhotic

In a study by **Sharma et al.** spleen stiffness was used for the non-invasive prediction of GEVs [25]. A total of 174 cirrhotic patients were prospectively enrolled. Liver stiffness and spleen stiffness were measured by the TE. Median liver stiffness, median spleen stiffness, LSPS, and PSR were significantly different between patients with and without EVs. On multivariate analysis, only liver stiffness and spleen stiffness showed predictive ability of EVs. Liver stiffness with a cutoff value of 27.3 kPa had a higher AUC than spleen stiffness with a cutoff value of 40.8 kPa (0.908 vs. 0.898). The liver stiffness with a cutoff value of ≥27.3 kPa had a sensitivity of 91%, a specificity of 72%, a PPV of 89%, an NPV of 76%, and a diagnostic accuracy of 86% in predicting EVs; the spleen stiffness with a cutoff of ≥40.8 kPa had a sensitivity of 94%, a specificity of 76%, a PPV of 91%, an NPV of 84%, and a diagnostic accuracy of 86% in predicting EVs. In patients who had performed hepatic venous pressure gradient, spleen stiffness showed a correlation with hepatic venous pressure gradient (r = 0.335, P = 0.01). The results of this study suggest that

GEVs exists in almost 30–60% of cirrhotic patients, depending on the severity of portal hypertension [24]. The occurrence of GEVs and varices-related AUGIB significantly worsened the prognosis of patients with portal hypertension, emphasizes the importance of diagnosis and management of GEVs. There are numerous studies have focused on developing non-invasive methods to predict the presence of GEVs, including serum markers, CT scanning, and ultrasonographic parameters. However, endoscopy is still difficult to replace, especially considering cost-effectiveness and diagnostic accuracy [26]. From other perspectives, in regular physical examination or surveillance of hepatocellular carcinoma, non-invasive methods can be employed to predict the severity of portal hypertension and GEVs. In this situation, if the patients have a high-risk of variceal bleeding in a short time, then the patient must perform endoscopy; if the patient has a low-risk of bleeding in a certain period,

Liver stiffness and spleen stiffness measured by the TE were the most promising non-invasive methods available, as they have proven having a good correlation with liver fibrosis, portal hypertension, and the presence with varices [27, 28]. The limitations of TE is that the results of TE should interpreted by a specialist in liver disease which may not available in less development hospital and TE should inap-

Approximately 10% of the whole portal hypertension patients were non-cirrhotic portal hypertension [29]. In general, patients with non-cirrhotic portal hypertension have higher prevalence and larger size of varices than those in cirrhotic patients [30, 31]. Until now, few studies focus on the non-invasive prediction of GEVs in patients with non-cirrhotic portal hypertension. In a retrospective observational study by **Cunningham et al.** [32] a total of 44 non-cirrhotic portal hypertension patients were enrolled, and 15 of them had high-risk varices. The results of this study found that spleen diameter > 17.2 cm had a sensitivity of 78.6% and specificity of 64.3% for prediction of high-risk varices. In patients with non-cirrhotic portal

spleen stiffness can be used for the non-invasive assessment of EVs.

then the patient can waive an unnecessary endoscopy.

propriate be performed in patients with ascites and/or obesity [26].

hypertension, the LSM and PSR may not as useful as cirrhotic patients.

*DOI: http://dx.doi.org/10.5772/intechopen.98879*

patients.

**4. Discussion**

*Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.98879*

with LSPS <3.5, the absence of high-risk EVs had a sensitivity of 87.7%, a specificity of 91.1%, an NPV of 94%, and a PPV of 82.3%. When applying the cutoff value of LSPS <3.5, the AUC in the validation cohorts was 0.953. The results of this study showed that in patients with LSPS <3.5, endoscopy may avoid safely in cirrhotic patients.

In a study by **Sharma et al.** spleen stiffness was used for the non-invasive prediction of GEVs [25]. A total of 174 cirrhotic patients were prospectively enrolled. Liver stiffness and spleen stiffness were measured by the TE. Median liver stiffness, median spleen stiffness, LSPS, and PSR were significantly different between patients with and without EVs. On multivariate analysis, only liver stiffness and spleen stiffness showed predictive ability of EVs. Liver stiffness with a cutoff value of 27.3 kPa had a higher AUC than spleen stiffness with a cutoff value of 40.8 kPa (0.908 vs. 0.898). The liver stiffness with a cutoff value of ≥27.3 kPa had a sensitivity of 91%, a specificity of 72%, a PPV of 89%, an NPV of 76%, and a diagnostic accuracy of 86% in predicting EVs; the spleen stiffness with a cutoff of ≥40.8 kPa had a sensitivity of 94%, a specificity of 76%, a PPV of 91%, an NPV of 84%, and a diagnostic accuracy of 86% in predicting EVs. In patients who had performed hepatic venous pressure gradient, spleen stiffness showed a correlation with hepatic venous pressure gradient (r = 0.335, P = 0.01). The results of this study suggest that spleen stiffness can be used for the non-invasive assessment of EVs.

#### **4. Discussion**

*Portal Hypertension - Recent Advances*

patients with GEVs.

**3.2 Ultrasonography**

**3.3 Elastography-based methods**

confirmed by further studies [22, 23].

count >150,000/mm3

the spleen.

In a study by **Li et al.** contrast-enhanced CT was used for the non-invasive prediction of GEVs [17]. In this retrospectively study, a total of 279 patients were included. High-risk varices including EVs and gastric varices was defined as varices that need treatment. All patients were divided into four groups according to the history of bleeding events, endoscopic surveillance, and drug prophylaxis (primary or secondary prophylaxis). In the overall population, only contrast-enhanced CT was significantly associated with EVs, high-risk EVs, and gastric varices. In primary prophylaxis, acute bleeding, previous bleeding, and secondary prophylaxis population, a diameter < 0.5 cm, <0.38 cm <0.46 cm and < 0.33 cm was considered as the cut-off value of high-risk EVs, respectively. Which can spare 47.8%, 10.5%, 12.1%, and 7.8% of endoscopic surveillance with no high-risk EVs was missed, respectively. This study showed a good diagnostic performance for contrast-enhanced CT for

Ultrasonography is the most common, cost-effective, and convenient imaging tool in clinical practice, which can be used for screening of hepatocellular carcinoma, measure the width of the portal vein, inferior vena cava, and diameter of

Splenoportal index was calculated as the splenic index divided by mean portal vein velocity. In a study by **Mansoor et al.** 200 HCV-induced cirrhotic patients were included [18]. All patients underwent ultrasonography first to calculate splenoportal index and then underwent endoscopy. The incidence of EVs was 60.5% (121/200) in ultrasonography and 63.5% (127/200) in endoscopy. The sensitivity, specificity, PPV, NPV of ultrasonography for predicting EVs was 88.98%, 89.04%, 93.00%, 82.28%, and 89.00%, respectively. This study showed a good diagnostic performance for splenoportal index by ultrasonography for patients with EVs.

Elastography-based methods, Including transient elastography (TE), point shear wave elastography, two-dimensional shear wave elastography, and magnetic resonance elastography have been used to non-invasively detected liver fibrosis and GEVs. There is substantial evidence suggesting that TE had a good correlation with portal hypertension and varices in cirrhotic patients [19, 20]. In 2015, TE was recommended for the surveillance of GEVs by Baveno VI consensus [6]. According to the Baveno VI consensus, in patients with compensated advanced chronic liver disease, who had a liver stiffness <20 kPa measured by TE and platelet

**Augustin et al.** performed a prospective study that taking the Baveno VI recommendation a step forward [21]. This study suggests that platelet count >110,000/

 and liver stiffness <25 kPa can spare more endoscopies than the Baveno VI consensus recommendation (41% vs. 21%). Only minority (0.6%) of overall patients were missed varices needing treatment. The negative predictive value for varices of the Baveno VI consensus and expanded Baveno VI consensus criteria is

In a study by **Kim et al.** a new model was generate based on the liver elasticity and the spleen diameter/platelet count (LSPS) [24]. A total of 280 hepatitis B virus relate cirrhotic patients were enrolled into the training cohort, and 121 patients were enrolled into the validation cohort. Liver stiffness was measured by TE. LSPS was calculated by the equation: Liver Stiffness Measurement × spleen diameter/ platelet count. In the training cohort, the cutoff value of LSPS was 3.5. In patients

, had a low risk of developed GEVs that may spear endoscopy.

**84**

mm3

GEVs exists in almost 30–60% of cirrhotic patients, depending on the severity of portal hypertension [24]. The occurrence of GEVs and varices-related AUGIB significantly worsened the prognosis of patients with portal hypertension, emphasizes the importance of diagnosis and management of GEVs. There are numerous studies have focused on developing non-invasive methods to predict the presence of GEVs, including serum markers, CT scanning, and ultrasonographic parameters. However, endoscopy is still difficult to replace, especially considering cost-effectiveness and diagnostic accuracy [26]. From other perspectives, in regular physical examination or surveillance of hepatocellular carcinoma, non-invasive methods can be employed to predict the severity of portal hypertension and GEVs. In this situation, if the patients have a high-risk of variceal bleeding in a short time, then the patient must perform endoscopy; if the patient has a low-risk of bleeding in a certain period, then the patient can waive an unnecessary endoscopy.

Liver stiffness and spleen stiffness measured by the TE were the most promising non-invasive methods available, as they have proven having a good correlation with liver fibrosis, portal hypertension, and the presence with varices [27, 28]. The limitations of TE is that the results of TE should interpreted by a specialist in liver disease which may not available in less development hospital and TE should inappropriate be performed in patients with ascites and/or obesity [26].

Approximately 10% of the whole portal hypertension patients were non-cirrhotic portal hypertension [29]. In general, patients with non-cirrhotic portal hypertension have higher prevalence and larger size of varices than those in cirrhotic patients [30, 31]. Until now, few studies focus on the non-invasive prediction of GEVs in patients with non-cirrhotic portal hypertension. In a retrospective observational study by **Cunningham et al.** [32] a total of 44 non-cirrhotic portal hypertension patients were enrolled, and 15 of them had high-risk varices. The results of this study found that spleen diameter > 17.2 cm had a sensitivity of 78.6% and specificity of 64.3% for prediction of high-risk varices. In patients with non-cirrhotic portal hypertension, the LSM and PSR may not as useful as cirrhotic patients.

There are heterogeneities among these studies and methods. Several reasons for the heterogeneities, including: 1) different target populations were enrolled among studies, including different races, etiology of liver cirrhosis; 2) different severity of underlying liver disease among patients; 3) different definitions for the risk of GEVs: in some studies, such as the study by **Li et al**. the severity of EVs was defined using the shape of varices and the red color sign [17]; in some other studies, the severity of varices was defined using the size of varices [5]. Therefore, the heterogeneities make it difficult to compare different studies or methods systematically.

#### **5. Conclusion**

Endoscopy is still the first choice for the diagnosis of GEVs in patients with portal hypertension. Liver stiffness and spleen stiffness measured by TE are the most studied methods. With the development of non-invasive prediction of GEVs, it is promising to exempt some patients from endoscopy.

#### **Author details**

Ran Wang\*, Xiaozhong Guo and Xingshun Qi Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China

\*Address all correspondence to: wangran891017@163.com

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

**87**

230-236.

*Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension*

*presence of oesophageal varices in Egyptian patients with liver cirrhosis.* Journal of Gastroenterology, 2015. **4**(5):

[10] Giannini, E., et al., *Platelet count/ spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.* Gut, 2003.

[11] Schwarzenberger, E., et al., *Utilization of platelet count spleen* 

*esophageal varices in patients with cirrhosis.* J Clin Gastroenterol, 2010.

[12] Chen, R., et al., *Platelet Count to Spleen Diameter Ratio for the Diagnosis of* 

*Gastroesophageal Varices in Liver Cirrhosis: A Systematic Review and Meta-Analysis.* Gastroenterol Res Pract,

[13] Qi, X., et al., *Liaoning Score for Prediction of Esophageal Varices in Cirrhotic Patients Who Had Never Undergone Endoscopy: A Multicenter Cross-Sectional Study in Liaoning Province, China.* Adv Ther, 2019. **36**(8):

[14] Li, Q., et al., *External validation of Liaoning score for predicting esophageal varices in liver cirrhosis: a Chinese multicenter cross-sectional study.* Ann Transl Med, 2019. **7**(23): p. 755.

[15] Deng, H., X. Qi, and X. Guo, *Diagnostic Accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex Scores in Predicting the Presence of Esophageal Varices in Liver Cirrhosis: A Systematic Review and Meta-Analysis.* Medicine (Baltimore),

[16] Deng, H., et al., *Diagnostic Accuracy of APRI, AAR, FIB-4, FI, and King Scores* 

2015. **94**(42): p. e1795.

*diameter ratio in predicting the presence of* 

p. 1613-1617.

**52**(8): p. 1200-1205.

**44**(2): p. 146-150.

2017. **2017**: p. 7407506.

p. 2167-2178.

*DOI: http://dx.doi.org/10.5772/intechopen.98879*

[1] Garcia-Tsao, G., et al., *Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.* Hepatology, 2017. **65**(1): p. 310-335.

[2] Fortune, B.E., et al., *Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study.* J Clin Gastroenterol, 2017. **51**(5): p. 446-453.

[3] Lee, H.H., et al., *A simplified prognostic model to predict mortality in patients with acute variceal bleeding.* Dig Liver Dis, 2018. **50**(3): p. 247-253.

[4] Zaman, A., et al., *Prevalence of upper and lower gastrointestinal tract findings in liver transplant candidates undergoing screening endoscopic evaluation.* Am J Gastroenterol, 1999. **94**(4): p. 895-899.

[5] Perri, R.E., et al., *A prospective evaluation of computerized tomographic (CT) scanning as a screening modality for esophageal varices.* Hepatology, 2008.

[6] de Franchis, R. and V.I.F. Baveno, *Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and* 

*hypertension.* J Hepatol, 2015. **63**(3): p.

[7] Tarantino, G., et al., *Blood ammonia levels in liver cirrhosis: a clue for the presence of portosystemic collateral veins.* BMC Gastroenterol, 2009. **9**: p. 21.

[8] Darweesh, S.K., et al., *Serum ammonia as a non-invasive marker for early prediction of esophageal varices.* Eur J Gastroenterol Hepatol, 2021. **32**(2): p.

[9] Hafez, H.A., *Predictive value of non-invasive blood ammonia level for the* 

*individualizing care for portal* 

**47**(5): p. 1587-1594.

743-752.

**References**

*Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.98879*

#### **References**

*Portal Hypertension - Recent Advances*

**5. Conclusion**

**86**

**Author details**

Shenyang, China

Ran Wang\*, Xiaozhong Guo and Xingshun Qi

provided the original work is properly cited.

\*Address all correspondence to: wangran891017@163.com

Department of Gastroenterology, General Hospital of Northern Theater Command,

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

There are heterogeneities among these studies and methods. Several reasons for the heterogeneities, including: 1) different target populations were enrolled among studies, including different races, etiology of liver cirrhosis; 2) different severity of underlying liver disease among patients; 3) different definitions for the risk of GEVs: in some studies, such as the study by **Li et al**. the severity of EVs was defined using the shape of varices and the red color sign [17]; in some other studies, the severity of varices was defined using the size of varices [5]. Therefore, the heterogeneities make it difficult to compare different studies or methods systematically.

Endoscopy is still the first choice for the diagnosis of GEVs in patients with portal hypertension. Liver stiffness and spleen stiffness measured by TE are the most studied methods. With the development of non-invasive prediction of GEVs,

it is promising to exempt some patients from endoscopy.

[1] Garcia-Tsao, G., et al., *Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.* Hepatology, 2017. **65**(1): p. 310-335.

[2] Fortune, B.E., et al., *Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study.* J Clin Gastroenterol, 2017. **51**(5): p. 446-453.

[3] Lee, H.H., et al., *A simplified prognostic model to predict mortality in patients with acute variceal bleeding.* Dig Liver Dis, 2018. **50**(3): p. 247-253.

[4] Zaman, A., et al., *Prevalence of upper and lower gastrointestinal tract findings in liver transplant candidates undergoing screening endoscopic evaluation.* Am J Gastroenterol, 1999. **94**(4): p. 895-899.

[5] Perri, R.E., et al., *A prospective evaluation of computerized tomographic (CT) scanning as a screening modality for esophageal varices.* Hepatology, 2008. **47**(5): p. 1587-1594.

[6] de Franchis, R. and V.I.F. Baveno, *Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension.* J Hepatol, 2015. **63**(3): p. 743-752.

[7] Tarantino, G., et al., *Blood ammonia levels in liver cirrhosis: a clue for the presence of portosystemic collateral veins.* BMC Gastroenterol, 2009. **9**: p. 21.

[8] Darweesh, S.K., et al., *Serum ammonia as a non-invasive marker for early prediction of esophageal varices.* Eur J Gastroenterol Hepatol, 2021. **32**(2): p. 230-236.

[9] Hafez, H.A., *Predictive value of non-invasive blood ammonia level for the*  *presence of oesophageal varices in Egyptian patients with liver cirrhosis.* Journal of Gastroenterology, 2015. **4**(5): p. 1613-1617.

[10] Giannini, E., et al., *Platelet count/ spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.* Gut, 2003. **52**(8): p. 1200-1205.

[11] Schwarzenberger, E., et al., *Utilization of platelet count spleen diameter ratio in predicting the presence of esophageal varices in patients with cirrhosis.* J Clin Gastroenterol, 2010. **44**(2): p. 146-150.

[12] Chen, R., et al., *Platelet Count to Spleen Diameter Ratio for the Diagnosis of Gastroesophageal Varices in Liver Cirrhosis: A Systematic Review and Meta-Analysis.* Gastroenterol Res Pract, 2017. **2017**: p. 7407506.

[13] Qi, X., et al., *Liaoning Score for Prediction of Esophageal Varices in Cirrhotic Patients Who Had Never Undergone Endoscopy: A Multicenter Cross-Sectional Study in Liaoning Province, China.* Adv Ther, 2019. **36**(8): p. 2167-2178.

[14] Li, Q., et al., *External validation of Liaoning score for predicting esophageal varices in liver cirrhosis: a Chinese multicenter cross-sectional study.* Ann Transl Med, 2019. **7**(23): p. 755.

[15] Deng, H., X. Qi, and X. Guo, *Diagnostic Accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex Scores in Predicting the Presence of Esophageal Varices in Liver Cirrhosis: A Systematic Review and Meta-Analysis.* Medicine (Baltimore), 2015. **94**(42): p. e1795.

[16] Deng, H., et al., *Diagnostic Accuracy of APRI, AAR, FIB-4, FI, and King Scores*  *for Diagnosis of Esophageal Varices in Liver Cirrhosis: A Retrospective Study.* Med Sci Monit, 2015. **21**: p. 3961-3977.

[17] Li, Q., et al., *Contrast-Enhanced CT May Be a Diagnostic Alternative for Gastroesophageal Varices in Cirrhosis with and without Previous Endoscopic Variceal Therapy.* Gastroenterol Res Pract, 2019. **2019**: p. 6704673.

[18] Mansoor, A., et al., *Diagnostic Accuracy of Doppler Ultrasonography in Predicting Presence of Esophageal Varices in Patients with Hepatitis-C Induced Cirrhosis.* J Coll Physicians Surg Pak, 2019. **29**(7): p. 612-615.

[19] Jangouk, P., et al., *Validating, deconstructing and refining Baveno criteria for ruling out high-risk varices in patients with compensated cirrhosis.* Liver Int, 2017. **37**(8): p. 1177-1183.

[20] Maurice, J.B., et al., *Validation of the Baveno VI criteria to identify low risk cirrhotic patients not requiring endoscopic surveillance for varices.* J Hepatol, 2016. **65**(5): p. 899-905.

[21] Augustin, S., et al., *Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease.* Hepatology, 2017. **66**(6): p. 1980-1988.

[22] Giannini, E.G., et al., *Course of oesophageal varices and performance of noninvasive predictors following Hepatitis C Virus clearance in compensated advanced chronic liver disease.* Eur J Clin Invest, 2020. **50**(5): p. e13231.

[23] Gaete, M.I., et al., *Baveno VI and Expanded Baveno VI criteria successfully predicts the absence of highrisk gastro-oesophageal varices in a Chilean cohort.* Liver Int, 2020. **40**(6): p. 1427-1434.

[24] Kim, B.K., et al., *A liver stiffness measurement-based, noninvasive* 

*prediction model for high-risk esophageal varices in B-viral liver cirrhosis.* Am J Gastroenterol, 2010. **105**(6): p. 1382-1390.

[25] Sharma, P., et al., *Spleen stiffness in patients with cirrhosis in predicting esophageal varices.* Am J Gastroenterol, 2013. **108**(7): p. 1101-7.

[26] European Association for Study of, L. and H. Asociacion Latinoamericana para el Estudio del, *EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis.* J Hepatol, 2015. **63**(1): p. 237-264.

[27] Carrion, J.A., et al., *Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation.* Liver Transpl, 2006. **12**(12): p. 1791-1798.

[28] Lemoine, M., et al., *Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or alcohol-related cirrhosis.* Aliment Pharmacol Ther, 2008. **28**(9): p. 1102-1110.

[29] Simonetto, D.A., M. Liu, and P.S. Kamath, *Portal Hypertension and Related Complications: Diagnosis and Management.* Mayo Clin Proc, 2019. **94**(4): p. 714-726.

[30] Madhu, K., et al., *Idiopathic noncirrhotic intrahepatic portal hypertension: common cause of cryptogenic intrahepatic portal hypertension in a Southern Indian tertiary hospital.* Indian J Gastroenterol, 2009. **28**(3): p. 83-87.

[31] Dhiman, R.K., et al., *Non-cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature.* J Gastroenterol Hepatol, 2002. **17**(1): p. 6-16.

**89**

*Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension*

*DOI: http://dx.doi.org/10.5772/intechopen.98879*

[32] Cunningham, M.E., et al., *Noninvasive Predictors of High-Risk Varices in Patients with Non-Cirrhotic Portal Hypertension.* Can J Gastroenterol

Hepatol, 2019. **2019**: p. 1808797.

*Non-Invasive Prediction of Gastroesophageal Varices in Patients with Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.98879*

[32] Cunningham, M.E., et al., *Noninvasive Predictors of High-Risk Varices in Patients with Non-Cirrhotic Portal Hypertension.* Can J Gastroenterol Hepatol, 2019. **2019**: p. 1808797.

*Portal Hypertension - Recent Advances*

*for Diagnosis of Esophageal Varices in Liver Cirrhosis: A Retrospective Study.* Med Sci Monit, 2015. **21**: p. 3961-3977. *prediction model for high-risk esophageal varices in B-viral liver cirrhosis.* Am J Gastroenterol, 2010. **105**(6): p.

[25] Sharma, P., et al., *Spleen stiffness in patients with cirrhosis in predicting esophageal varices.* Am J Gastroenterol,

[26] European Association for Study of, L. and H. Asociacion Latinoamericana para el Estudio del, *EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis.* J Hepatol, 2015. **63**(1): p.

[27] Carrion, J.A., et al., *Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation.* Liver Transpl,

[28] Lemoine, M., et al., *Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or alcohol-related cirrhosis.* Aliment

Pharmacol Ther, 2008. **28**(9): p.

*Complications: Diagnosis and Management.* Mayo Clin Proc, 2019.

**94**(4): p. 714-726.

2009. **28**(3): p. 83-87.

p. 6-16.

[29] Simonetto, D.A., M. Liu, and P.S. Kamath, *Portal Hypertension and Related* 

[30] Madhu, K., et al., *Idiopathic noncirrhotic intrahepatic portal hypertension: common cause of cryptogenic intrahepatic portal hypertension in a Southern Indian tertiary hospital.* Indian J Gastroenterol,

[31] Dhiman, R.K., et al., *Non-cirrhotic portal fibrosis (idiopathic portal hypertension): experience with 151 patients and a review of the literature.* J Gastroenterol Hepatol, 2002. **17**(1):

2006. **12**(12): p. 1791-1798.

1382-1390.

237-264.

1102-1110.

2013. **108**(7): p. 1101-7.

[17] Li, Q., et al., *Contrast-Enhanced CT May Be a Diagnostic Alternative for Gastroesophageal Varices in Cirrhosis with and without Previous Endoscopic Variceal Therapy.* Gastroenterol Res Pract, 2019.

[18] Mansoor, A., et al., *Diagnostic Accuracy of Doppler Ultrasonography in Predicting Presence of Esophageal Varices in Patients with Hepatitis-C Induced Cirrhosis.* J Coll Physicians Surg Pak,

[19] Jangouk, P., et al., *Validating, deconstructing and refining Baveno criteria for ruling out high-risk varices in patients with compensated cirrhosis.* Liver

[20] Maurice, J.B., et al., *Validation of the Baveno VI criteria to identify low risk cirrhotic patients not requiring endoscopic surveillance for varices.* J Hepatol, 2016.

[21] Augustin, S., et al., *Expanding the Baveno VI criteria for the screening of varices in patients with compensated advanced chronic liver disease.*

Hepatology, 2017. **66**(6): p. 1980-1988.

[22] Giannini, E.G., et al., *Course of oesophageal varices and performance of noninvasive predictors following Hepatitis* 

*C Virus clearance in compensated advanced chronic liver disease.* Eur J Clin

[23] Gaete, M.I., et al., *Baveno VI and Expanded Baveno VI criteria successfully predicts the absence of highrisk gastro-oesophageal varices in a Chilean cohort.* Liver Int, 2020. **40**(6):

[24] Kim, B.K., et al., *A liver stiffness measurement-based, noninvasive* 

Invest, 2020. **50**(5): p. e13231.

Int, 2017. **37**(8): p. 1177-1183.

**65**(5): p. 899-905.

**2019**: p. 6704673.

2019. **29**(7): p. 612-615.

**88**

p. 1427-1434.

**91**

**Chapter 6**

**Abstract**

**1. Introduction**

ply, whereby varices may form.

Endoscopy in Management of

Portal hypertension (PH) is a serious consequence of several disease states affecting prehepatic, intrahepatic, or posthepatic portal circulation. Backpressure caused by PH transmits through the collaterals to form varices at various sites. PH also leads to hyperdynamic congestion and altered gastrointestinal mucosal immune response, resulting in portal hypertensive gastropathy (PHG), portal hypertensive enteropathy (PHE), and portal colopathy (PC). These PH associated phenomena may lead to torrential life-threatening bleed or chronic blood loss leading to debilitating chronic anemia. Endoscopy plays a pivotal role in the management of these patients both for diagnostic and therapeutic purpose. The choice of therapeutic strategy depends on many factors: severity of the disease, patient's clinical performance, and whether it is done as an emergency or as a prophylactic approach. In this chapter, we evaluate the endoscopic management of patients with

Portal Hypertension

*Bhavik Bharat Shah, Usha Goenka* 

*and Mahesh Kumar Goenka*

the gastrointestinal complications of PH.

portal hypertensive enteropathy, portal colopathy

**Keywords:** portal hypertension, esophageal varices, gastric varices, portal hypertensive gastropathy, gastric antral vascular ectasia,

Portal hypertension (PH) is a serious consequence of disease states affecting prehepatic, intrahepatic, or posthepatic portal circulation. Liver cirrhosis, which leads to sinusoidal hypertension, is the most frequent etiology of PH. Cirrhosis causes structural distortion in the liver architecture accompanied by the rise in local intrahepatic vasoconstrictors. Cirrhosis also causes an increase in systemic vasodilation and increased cardiac output leading to increased portal blood flow. When portal pressure, measured as hepatic vein portal gradient (HPVG), is >10 mm of Hg, it leads to development of portosystemic collaterals (**Figure 1**). These collaterals arise due to recanalization of fetal vascular channels, reversal of flow within adult veins, and/or because of neoangiogenesis [1]. Backpressure caused by PH transmits through these collaterals to perforating veins and the submucosal vessels they sup-

A PH related increase in the portal vein pressure leads to hyperdynamic congestion in the gastric, small intestinal, and colonic mucosa. The mucosa undergoes microcirculatory changes, such as submucosal angiogenesis and vascular ectasia, that impair its integrity and promote its susceptibility to damage. Moreover, local

#### **Chapter 6**

## Endoscopy in Management of Portal Hypertension

*Bhavik Bharat Shah, Usha Goenka and Mahesh Kumar Goenka*

#### **Abstract**

Portal hypertension (PH) is a serious consequence of several disease states affecting prehepatic, intrahepatic, or posthepatic portal circulation. Backpressure caused by PH transmits through the collaterals to form varices at various sites. PH also leads to hyperdynamic congestion and altered gastrointestinal mucosal immune response, resulting in portal hypertensive gastropathy (PHG), portal hypertensive enteropathy (PHE), and portal colopathy (PC). These PH associated phenomena may lead to torrential life-threatening bleed or chronic blood loss leading to debilitating chronic anemia. Endoscopy plays a pivotal role in the management of these patients both for diagnostic and therapeutic purpose. The choice of therapeutic strategy depends on many factors: severity of the disease, patient's clinical performance, and whether it is done as an emergency or as a prophylactic approach. In this chapter, we evaluate the endoscopic management of patients with the gastrointestinal complications of PH.

**Keywords:** portal hypertension, esophageal varices, gastric varices, portal hypertensive gastropathy, gastric antral vascular ectasia, portal hypertensive enteropathy, portal colopathy

#### **1. Introduction**

Portal hypertension (PH) is a serious consequence of disease states affecting prehepatic, intrahepatic, or posthepatic portal circulation. Liver cirrhosis, which leads to sinusoidal hypertension, is the most frequent etiology of PH. Cirrhosis causes structural distortion in the liver architecture accompanied by the rise in local intrahepatic vasoconstrictors. Cirrhosis also causes an increase in systemic vasodilation and increased cardiac output leading to increased portal blood flow. When portal pressure, measured as hepatic vein portal gradient (HPVG), is >10 mm of Hg, it leads to development of portosystemic collaterals (**Figure 1**). These collaterals arise due to recanalization of fetal vascular channels, reversal of flow within adult veins, and/or because of neoangiogenesis [1]. Backpressure caused by PH transmits through these collaterals to perforating veins and the submucosal vessels they supply, whereby varices may form.

A PH related increase in the portal vein pressure leads to hyperdynamic congestion in the gastric, small intestinal, and colonic mucosa. The mucosa undergoes microcirculatory changes, such as submucosal angiogenesis and vascular ectasia, that impair its integrity and promote its susceptibility to damage. Moreover, local

**Figure 1.** *Pathophysiology of formation of varices in cirrhosis.*

immune mucosal defense mechanisms are impaired in PH. All these lead to portal hypertensive gastropathy (PHG), portal hypertensive enteropathy (PHE), and portal colopathy (PC) [2, 3]. This chapter focuses on the endoscopic management of varices, PHG, Gastric antral vascular ectasia (GAVE), PHE, and PC.

#### **2. Esophageal varices**

Esophageal varices are present in 30–40% of patients with Child A cirrhosis and approximately 85% of those with Child B/C cirrhosis [4]. Despite improved surveillance and treatment, the rate of variceal hemorrhage (VH) continues to be 10–15% per year, with an 6-week mortality of 15–25% [5]. Mortality risk is particularly high when VH is associated with acute kidney injury (AKI) and/or concomitant bacterial infections [6]. Recurrent VH occurs in 60% of patients without treatment [7].

Considering the high-risk of death when VH occurs, implementing surveillance strategies to prevent bleeding and death should be pursued actively in patients with cirrhosis. Once the patient is diagnosed with cirrhosis, a periodic surveillance endoscopy is warranted to look for esophageal varices. Other modalities such as video capsule endoscopy (VCE), computed tomography (CT) scan, or Fibroscan have been assessed for their role in detecting esophageal varices [8, 9]. However, endoscopy is still regarded as the investigation of choice.

#### **2.1 Primary prophylaxis**

The risk factors of VH are the large size of varices, red signs, and the severity of liver disease [10]. Primary prophylaxis must be initiated in "high-risk varices" **(Figure 2a)**. This includes small varices (<5 mm) with red color signs, any varix in Child-C patients or large varices (>5 mm) irrespective of Child-Pugh

**93**

**Figure 3.**

*Algorithm for surveillance and primary prophylaxis of esophageal varix.*

**Figure 2.**

*varix after endoscopic band ligation.*

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

classification [11]. In patients with "low-risk varices" or no varices, surveillance endoscopy should be undertaken at interval of 2–3 years, depending on the severity of the liver disease and whether the liver injury is ongoing or not (**Figure 3**). The patients with active alcoholism, non-alcoholic steatohepatitis (NASH), hepatitis B

*Endoscopic appearance of esophageal varix. (a) Large esophageal varix with red color signs, (b) esophageal* 

The primary prophylaxis of "high-risk varices" involves pharmacological prophylaxis using a nonselective beta-adrenergic blockers (NSBB) or endoscopic band ligation (EVL). NSBBs such as propranolol and nadolol reduce cardiac output and splanchnic blood flow through nonselective beta-blockade, and the unopposed effect of alpha-1 adrenergic receptors leads to splanchnic vasoconstriction. This reduces the portal pressure and its consequential complications. Carvedilol, an NSBB with

and C with detectable viral load are some examples of ongoing liver injury.

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

#### **Figure 2.**

*Portal Hypertension - Recent Advances*

**2. Esophageal varices**

*Pathophysiology of formation of varices in cirrhosis.*

**Figure 1.**

**2.1 Primary prophylaxis**

immune mucosal defense mechanisms are impaired in PH. All these lead to portal hypertensive gastropathy (PHG), portal hypertensive enteropathy (PHE), and portal colopathy (PC) [2, 3]. This chapter focuses on the endoscopic management

Esophageal varices are present in 30–40% of patients with Child A cirrhosis and approximately 85% of those with Child B/C cirrhosis [4]. Despite improved surveillance and treatment, the rate of variceal hemorrhage (VH) continues to be 10–15% per year, with an 6-week mortality of 15–25% [5]. Mortality risk is particularly high when VH is associated with acute kidney injury (AKI) and/or concomitant bacterial infections [6]. Recurrent VH occurs in 60% of patients without treatment [7].

Considering the high-risk of death when VH occurs, implementing surveillance

The risk factors of VH are the large size of varices, red signs, and the severity of liver disease [10]. Primary prophylaxis must be initiated in "high-risk varices" **(Figure 2a)**. This includes small varices (<5 mm) with red color signs, any varix in Child-C patients or large varices (>5 mm) irrespective of Child-Pugh

strategies to prevent bleeding and death should be pursued actively in patients with cirrhosis. Once the patient is diagnosed with cirrhosis, a periodic surveillance endoscopy is warranted to look for esophageal varices. Other modalities such as video capsule endoscopy (VCE), computed tomography (CT) scan, or Fibroscan have been assessed for their role in detecting esophageal varices [8, 9]. However,

endoscopy is still regarded as the investigation of choice.

of varices, PHG, Gastric antral vascular ectasia (GAVE), PHE, and PC.

**92**

*Endoscopic appearance of esophageal varix. (a) Large esophageal varix with red color signs, (b) esophageal varix after endoscopic band ligation.*

classification [11]. In patients with "low-risk varices" or no varices, surveillance endoscopy should be undertaken at interval of 2–3 years, depending on the severity of the liver disease and whether the liver injury is ongoing or not (**Figure 3**). The patients with active alcoholism, non-alcoholic steatohepatitis (NASH), hepatitis B and C with detectable viral load are some examples of ongoing liver injury.

The primary prophylaxis of "high-risk varices" involves pharmacological prophylaxis using a nonselective beta-adrenergic blockers (NSBB) or endoscopic band ligation (EVL). NSBBs such as propranolol and nadolol reduce cardiac output and splanchnic blood flow through nonselective beta-blockade, and the unopposed effect of alpha-1 adrenergic receptors leads to splanchnic vasoconstriction. This reduces the portal pressure and its consequential complications. Carvedilol, an NSBB with

**Figure 3.**

*Algorithm for surveillance and primary prophylaxis of esophageal varix.*

intrinsic anti-alpha-1 receptor activity, reduces both porto-collateral and intrahepatic resistance. However, this is at the cost of more profound effects on the systemic arterial pressure, particularly in decompensated patients. Carvedilol is therefore, preferred in patients where NSSB are contraindicated or produce side effect.

EVL (**Figure 2b**) involves the placement of rubber rings on variceal columns, which are sucked into a plastic hollow cylinder attached to the endoscope tip. Ligation causes occlusion of the varix and subsequent thrombosis with ischemic necrosis of the mucosa. Band placement should be limited to the distal 8 cm segment of the esophagus in order to target the palisade drainage and perforating zones. Bands should be placed helically, moving distal to proximal to allow the maximum number of bands to be applied while avoiding overlapping circumferential placement. More proximal placement has less efficacy and may cause post ligation retrosternal discomfort. Complications after EBL occur in approximately 2–20% of the patients and include transient dysphagia, retrosternal pain, esophageal stricture, ulceration, perforation, and infection [12]. Occasionally, massive bleeding can occur, either from recurrent variceal rupture or from post-ligation ulceration.

It is generally recommended that small varices with red signs should be treated with NSBBs. Large varices can be treated with either NSBBs or EBL. The treatment choice is based on local resource and expertise, patient preference, contraindications, and adverse events [11, 13, 14].

#### **2.2 Acute esophageal variceal hemorrhage (AVH)**

Ruptured esophageal varices contributes to 70% of all the upper gastrointestinal (GI) bleeding episodes in patients with portal hypertension [15]. Initial treatment should always target restoring the euvolemic status. Restrictive blood transfusion strategy is adequate in most patients with GI bleed [16]. Vasoactive drug therapy and antibiotic prophylaxis should be initiated as soon as AVH is suspected [11]. After adequate resuscitation, an endoscopic evaluation should be carried out in patients with acute variceal bleed, in the first 12 hours after admission [13]. **Table 1** shows various modalities which can be used to treat esophageal variceal bleed.

#### **2.3 Endoscopic variceal band ligation (EVL)**

EVL is the preferred endoscopic therapy for active bleeding, as it allows greater bleeding control, with lower adverse events, and improves survival compared to endoscopic sclerotherapy (ES) which was practiced earlier [17]. In AVH, EVL should be preferentially targeted toward the culprit variceal column evidenced by the ongoing ooze or presence of stigmata of hemorrhage. However, during active


**95**

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

should also be optimized.

and in young children.

visualization and appropriate targeting of subsequent bands.

**2.4 Endoscopic sclerotherapy and glue injection**

bleeding, banding at the gastroesophageal junction may reduce bleeding, allowing

Despite adequate therapy with vasoactive drugs combined with EVL, up to 10–15% of patients with variceal hemorrhage have persistent bleeding or early rebleeding [18]. Transjugular intrahepatic portosystemic shunts (TIPS) should be considered as a rescue therapy of choice in this group of patients [13]. When TIPS is not feasible or in case of modest rebleeding, a second endoscopic therapy with repeat EVL or alternate methods may be attempted, and vasoactive drugs doses

The sclerosant injection acts by precipitating inflammation and thrombosis of the varix. ES involves intravariceal injection of sclerosant at and just distal to the site of the bleeding, or perivariceal injection performed adjacent to a varix. Injection should be first performed at the bleeding site, followed by perivariceal or intravariceal injection starting from the GE junction, with proximal injections at 2-cm intervals, extending up to 5 cm to 6 cm from the GE junction. Sclerosants used include sodium tetradecyl sulfate (Food and Drug Administration approved),

A meta-analysis of 14 studies found that EVL is better than ES in terms of lower rates of rebleeding and complications and a higher rate of variceal eradication [19]. The complications related to ES occur in up to 40% of patients, and include esophageal ulceration, stricture, perforation, pleural effusion, hemothorax, pulmonary thromboembolism, pericarditis, mediastinitis, pneumothorax, renal dysfunction, and even death [20]. Though EVL is the therapy of choice for the management of bleeding varices, there are a few indications where EVL is technically demanding, and ES can be utilized. This includes massive ongoing bleed when visualization is impaired, when adequate tissue suctioning into the cap is not possible due to scar,

Glue injection have also been performed for active variceal bleeding. Overall, there is no definitive evidence supporting the use of cyanoacrylate injection for the management of bleeding varices or for VH prophylaxis. Tissue adhesive injection may be considered in conjunction with sclerotherapy. However, a RCT did show that using n-butyl cyanoacrylate and sclerosant injection in conjunction, resulted in

lower rebleeding and mortality compared to using sclerotherapy alone [21].

For persistent VH, where EVL has failed, as well as for EVL-related ulcer bleeding, balloon tamponade (BT) using Sengstaken-Blakemore (SB) tube and emergency TIPS have been advocated [13]. SB tube is associated with many complications and rebound bleeding. Performing TIPS in emergencies may not be feasible in many centres. Besides, there are cost issues and a definite risk of encephalopathy in the presence of advanced liver dysfunction [22]. Covered self-expanding metal stents (SEMS) with distinctive designs are used to produce an effective tamponade, controlling persistent variceal bleeding and ulcer bleeding following VBL [23, 24]. Initially, the Choo stent (diameter 18 mm, length 140 mm, NES − 18 − 080 − 070, MI Tech Co., Ltd) and the EllaBoubella-Danis stent (diameter 20 mm, length 95 mm,

Ella-CS, Hradec Kralove, Czech Republic) were used. Despite demonstrating efficacy, these stent designs were not ideal for deployment and use in variceal

bleeding; hence the SX-ELLA Danis Stent (Ella-CS, Hradec Kralove, Czech Republic) was designed [23]. SX\_ELLA Danis Stent (**Figure 4**) is the most commonly used

**2.5 Tamponade using balloons or metal stents**

sodium morrhuate, ethanolamine oleate, polidocanol, or absolute alcohol.

#### **Table 1.**

*Therapeutic options for control of acute esophageal variceal bleed.*

#### *Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

*Portal Hypertension - Recent Advances*

tions, and adverse events [11, 13, 14].

**2.2 Acute esophageal variceal hemorrhage (AVH)**

**2.3 Endoscopic variceal band ligation (EVL)**

*Therapeutic options for control of acute esophageal variceal bleed.*

Endoscopic Therapy

• Tamponade using ○ SB tube ○ Metal stents

• Variceal band ligation (EVL) • Sclero therapy/ Glue injection

• Argon plasma coagulation

intrinsic anti-alpha-1 receptor activity, reduces both porto-collateral and intrahepatic resistance. However, this is at the cost of more profound effects on the systemic arterial pressure, particularly in decompensated patients. Carvedilol is therefore, preferred in patients where NSSB are contraindicated or produce side effect.

EVL (**Figure 2b**) involves the placement of rubber rings on variceal columns, which are sucked into a plastic hollow cylinder attached to the endoscope tip. Ligation causes occlusion of the varix and subsequent thrombosis with ischemic necrosis of the mucosa. Band placement should be limited to the distal 8 cm segment of the esophagus in order to target the palisade drainage and perforating zones. Bands should be placed helically, moving distal to proximal to allow the maximum number of bands to be applied while avoiding overlapping circumferential placement. More proximal placement has less efficacy and may cause post ligation retrosternal discomfort. Complications after EBL occur in approximately 2–20% of the patients and include transient dysphagia, retrosternal pain, esophageal stricture, ulceration, perforation, and infection [12]. Occasionally, massive bleeding can occur, either from recurrent variceal rupture or from post-ligation ulceration.

It is generally recommended that small varices with red signs should be treated with NSBBs. Large varices can be treated with either NSBBs or EBL. The treatment choice is based on local resource and expertise, patient preference, contraindica-

Ruptured esophageal varices contributes to 70% of all the upper gastrointestinal (GI) bleeding episodes in patients with portal hypertension [15]. Initial treatment should always target restoring the euvolemic status. Restrictive blood transfusion strategy is adequate in most patients with GI bleed [16]. Vasoactive drug therapy and antibiotic prophylaxis should be initiated as soon as AVH is suspected [11]. After adequate resuscitation, an endoscopic evaluation should be carried out in patients with acute variceal bleed, in the first 12 hours after admission [13]. **Table 1** shows various modalities which can be used to treat esophageal variceal bleed.

EVL is the preferred endoscopic therapy for active bleeding, as it allows greater

bleeding control, with lower adverse events, and improves survival compared to endoscopic sclerotherapy (ES) which was practiced earlier [17]. In AVH, EVL should be preferentially targeted toward the culprit variceal column evidenced by the ongoing ooze or presence of stigmata of hemorrhage. However, during active

**94**

TIPS

**Table 1.**

bleeding, banding at the gastroesophageal junction may reduce bleeding, allowing visualization and appropriate targeting of subsequent bands.

Despite adequate therapy with vasoactive drugs combined with EVL, up to 10–15% of patients with variceal hemorrhage have persistent bleeding or early rebleeding [18]. Transjugular intrahepatic portosystemic shunts (TIPS) should be considered as a rescue therapy of choice in this group of patients [13]. When TIPS is not feasible or in case of modest rebleeding, a second endoscopic therapy with repeat EVL or alternate methods may be attempted, and vasoactive drugs doses should also be optimized.

#### **2.4 Endoscopic sclerotherapy and glue injection**

The sclerosant injection acts by precipitating inflammation and thrombosis of the varix. ES involves intravariceal injection of sclerosant at and just distal to the site of the bleeding, or perivariceal injection performed adjacent to a varix. Injection should be first performed at the bleeding site, followed by perivariceal or intravariceal injection starting from the GE junction, with proximal injections at 2-cm intervals, extending up to 5 cm to 6 cm from the GE junction. Sclerosants used include sodium tetradecyl sulfate (Food and Drug Administration approved), sodium morrhuate, ethanolamine oleate, polidocanol, or absolute alcohol.

A meta-analysis of 14 studies found that EVL is better than ES in terms of lower rates of rebleeding and complications and a higher rate of variceal eradication [19]. The complications related to ES occur in up to 40% of patients, and include esophageal ulceration, stricture, perforation, pleural effusion, hemothorax, pulmonary thromboembolism, pericarditis, mediastinitis, pneumothorax, renal dysfunction, and even death [20]. Though EVL is the therapy of choice for the management of bleeding varices, there are a few indications where EVL is technically demanding, and ES can be utilized. This includes massive ongoing bleed when visualization is impaired, when adequate tissue suctioning into the cap is not possible due to scar, and in young children.

Glue injection have also been performed for active variceal bleeding. Overall, there is no definitive evidence supporting the use of cyanoacrylate injection for the management of bleeding varices or for VH prophylaxis. Tissue adhesive injection may be considered in conjunction with sclerotherapy. However, a RCT did show that using n-butyl cyanoacrylate and sclerosant injection in conjunction, resulted in lower rebleeding and mortality compared to using sclerotherapy alone [21].

#### **2.5 Tamponade using balloons or metal stents**

For persistent VH, where EVL has failed, as well as for EVL-related ulcer bleeding, balloon tamponade (BT) using Sengstaken-Blakemore (SB) tube and emergency TIPS have been advocated [13]. SB tube is associated with many complications and rebound bleeding. Performing TIPS in emergencies may not be feasible in many centres. Besides, there are cost issues and a definite risk of encephalopathy in the presence of advanced liver dysfunction [22]. Covered self-expanding metal stents (SEMS) with distinctive designs are used to produce an effective tamponade, controlling persistent variceal bleeding and ulcer bleeding following VBL [23, 24].

Initially, the Choo stent (diameter 18 mm, length 140 mm, NES − 18 − 080 − 070, MI Tech Co., Ltd) and the EllaBoubella-Danis stent (diameter 20 mm, length 95 mm, Ella-CS, Hradec Kralove, Czech Republic) were used. Despite demonstrating efficacy, these stent designs were not ideal for deployment and use in variceal bleeding; hence the SX-ELLA Danis Stent (Ella-CS, Hradec Kralove, Czech Republic) was designed [23]. SX\_ELLA Danis Stent (**Figure 4**) is the most commonly used

**Figure 4.** *Ela stent: SX ELLA STENT. A) Stent design, B) stent in esophagus.*

stent for the treatment of persistent VH. It differs from the Choo stent and the EllaBoubela-Danis stent in having a balloon-style delivery system. These stents are made of nitinol, measuring 13.5 cm in length with a diameter of 25 mm in the shaft and 30 mm at the ends. The stents are placed usually over an endoscopically placed guidewire but can also be inserted at bedside without the need of an endoscope. The stent's unique delivery system uses a gastric positioning balloon placed just distal to caudal end of the stent. The correct positioning of the stent in the distal half of the esophagus is established by inflating the gastric balloon and retracting the catheter assembly until the gastric balloon hits against the cardia. The stent is then released, and the gastric balloon is deflated, and the assembly catheter is removed [24]. These stents act by causing a steady mechanical compression causing an immediate tamponade at the variceal bleed site. Compared to SB tube, these stents allow oral feeding and endoscopic assessment of rebleed.

In a meta-analysis of 12 studies, which evaluated SEMS placement for refractory esophageal variceal hemorrhage, the reported clinical success (absence of bleeding within 24 hours of SEMS placement) rate was 96% (95% CI, 0.90–1.00) and technical success (guidewire-assisted endoscopic SEMS deployment) rate was 97% (95% CI, 0.91–1.00). Adverse events associated with the placement of SEMS include stent migration (28%), rebleeding (16%), and ulcer. However, there was no significant difference in mortality compared to balloon tamponade [25]. Removal of SX-ELLA Danis stent is advised within 2 weeks following stent insertion, under endoscopic guidance using the custom PEXElla extractor (Ella-CS) or usual foreign body forceps [26].

#### **2.6 Argon plasma coagulation (APC)**

APC is an electrosurgery-based, non-contact, multi-directional coagulation method. A high-frequency current is applied to the target tissue through an argon plasma jet with a constant depth of energy penetration (maximum 4 mm). APC has been used to coagulate the distal esophageal mucosa after eradicating esophageal varices by endoscopic variceal ligation to reduce the rate of variceal recurrence and need for rebanding. This technique is generally recommended as secondary prophylaxis for esophageal variceal bleeding in those who have contraindications, are intolerant, or are non-compliant to NSSB [27]. A meta-analysis of four randomized controlled trials (RCT) compared the safety and efficacy of EVL alone, with EVL along with APC, for secondary prophylaxis of esophageal variceal bleeding. Across the 4 RCTs, combination therapy showed significantly lower variceal recurrence

**97**

**Figure 5.**

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

gastric veins and originate in the submucosa.

*Sarin Classifiaction of gastric varix. GOV- gastroesophageal varix, IGV- isolated gastric varix.*

coagulated tissue.

**3. Gastric varices**

occurred more often after combination therapy [28].

rates (relative risk 0.19). There was no difference in re-bleeding or mortality. Fever

After ensuring the complete eradication of varices, APC is initiated 2 to 3 weeks after the last EVL session. APC is generally performed at a gas flow rate of 1.2–2 L/ min. The power setting of the APC current generator is adjusted at 50 to 70 W. The entire esophageal mucosa proximal to the esophageal junction is coagulated with APC in 2 sessions at 2-week intervals. In each session, one half of the mucosa is ablated thermally starting at the esophagogastric junction by retracting the probe proximally, while delivering thermal energy creating longitudinal parallel stripes of

Gastric varices (GV) are the source of bleeding in 5–10% of patients with PH, second only to the esophageal variceal bleed [15]. GV is, however, relatively more common in non-cirrhotic portal hypertension (NCPH) and extrahepatic portal vein obstruction (EHPVO) occurring in 1/4th and 1/3rd of patients, respectively [20]. The GV classification system aligns with the therapeutic distinction and categorizes GV based on whether they are contiguous with esophageal varices or not, and as per their location in the stomach (**Figure 5**) [29]. Gastroesophageal varices (GOV) are contiguous with the esophageal varices extending either into the lesser curvature (GOV1) or the fundus along the greater curvature (GOV2). These varices share the pathophysiology of esophageal varices, arising from the left gastric vein and originate in the lamina propria. Isolated Gastric Varices (IGV) are distinct from GOV and can be located either in the cardia (IGV1) or outside of the cardia and fundus, usually the antrum or pylorus (IGV2). These arise from the short and posterior

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

rates (relative risk 0.19). There was no difference in re-bleeding or mortality. Fever occurred more often after combination therapy [28].

After ensuring the complete eradication of varices, APC is initiated 2 to 3 weeks after the last EVL session. APC is generally performed at a gas flow rate of 1.2–2 L/ min. The power setting of the APC current generator is adjusted at 50 to 70 W. The entire esophageal mucosa proximal to the esophageal junction is coagulated with APC in 2 sessions at 2-week intervals. In each session, one half of the mucosa is ablated thermally starting at the esophagogastric junction by retracting the probe proximally, while delivering thermal energy creating longitudinal parallel stripes of coagulated tissue.

#### **3. Gastric varices**

*Portal Hypertension - Recent Advances*

and endoscopic assessment of rebleed.

**2.6 Argon plasma coagulation (APC)**

body forceps [26].

**Figure 4.**

stent for the treatment of persistent VH. It differs from the Choo stent and the EllaBoubela-Danis stent in having a balloon-style delivery system. These stents are made of nitinol, measuring 13.5 cm in length with a diameter of 25 mm in the shaft and 30 mm at the ends. The stents are placed usually over an endoscopically placed guidewire but can also be inserted at bedside without the need of an endoscope. The stent's unique delivery system uses a gastric positioning balloon placed just distal to caudal end of the stent. The correct positioning of the stent in the distal half of the esophagus is established by inflating the gastric balloon and retracting the catheter assembly until the gastric balloon hits against the cardia. The stent is then released, and the gastric balloon is deflated, and the assembly catheter is removed [24]. These stents act by causing a steady mechanical compression causing an immediate tamponade at the variceal bleed site. Compared to SB tube, these stents allow oral feeding

*Ela stent: SX ELLA STENT. A) Stent design, B) stent in esophagus.*

In a meta-analysis of 12 studies, which evaluated SEMS placement for refractory esophageal variceal hemorrhage, the reported clinical success (absence of bleeding within 24 hours of SEMS placement) rate was 96% (95% CI, 0.90–1.00) and technical success (guidewire-assisted endoscopic SEMS deployment) rate was 97% (95% CI, 0.91–1.00). Adverse events associated with the placement of SEMS include stent migration (28%), rebleeding (16%), and ulcer. However, there was no significant difference in mortality compared to balloon tamponade [25]. Removal of SX-ELLA Danis stent is advised within 2 weeks following stent insertion, under endoscopic guidance using the custom PEXElla extractor (Ella-CS) or usual foreign

APC is an electrosurgery-based, non-contact, multi-directional coagulation method. A high-frequency current is applied to the target tissue through an argon plasma jet with a constant depth of energy penetration (maximum 4 mm). APC has been used to coagulate the distal esophageal mucosa after eradicating esophageal varices by endoscopic variceal ligation to reduce the rate of variceal recurrence and need for rebanding. This technique is generally recommended as secondary prophylaxis for esophageal variceal bleeding in those who have contraindications, are intolerant, or are non-compliant to NSSB [27]. A meta-analysis of four randomized controlled trials (RCT) compared the safety and efficacy of EVL alone, with EVL along with APC, for secondary prophylaxis of esophageal variceal bleeding. Across the 4 RCTs, combination therapy showed significantly lower variceal recurrence

**96**

Gastric varices (GV) are the source of bleeding in 5–10% of patients with PH, second only to the esophageal variceal bleed [15]. GV is, however, relatively more common in non-cirrhotic portal hypertension (NCPH) and extrahepatic portal vein obstruction (EHPVO) occurring in 1/4th and 1/3rd of patients, respectively [20].

The GV classification system aligns with the therapeutic distinction and categorizes GV based on whether they are contiguous with esophageal varices or not, and as per their location in the stomach (**Figure 5**) [29]. Gastroesophageal varices (GOV) are contiguous with the esophageal varices extending either into the lesser curvature (GOV1) or the fundus along the greater curvature (GOV2). These varices share the pathophysiology of esophageal varices, arising from the left gastric vein and originate in the lamina propria. Isolated Gastric Varices (IGV) are distinct from GOV and can be located either in the cardia (IGV1) or outside of the cardia and fundus, usually the antrum or pylorus (IGV2). These arise from the short and posterior gastric veins and originate in the submucosa.

**Figure 5.** *Sarin Classifiaction of gastric varix. GOV- gastroesophageal varix, IGV- isolated gastric varix.*

Gastric variceal bleeding **(Figure 6**), although less common, has the predisposition to be more severe, associated with higher blood transfusion requirement, and increased morbidity, and mortality compared with esophageal variceal bleeding [30]. The probable cause for this is a large submucosal component of GV, the vascular structures feeding and draining the gastric varix, and, also, the lack of widespread expertise. Bleeding risk is significantly higher for the IGV1 (77%) and GOV2 (55%), than for GOV1 or ectopic varices (10%) [29]. EHPVO more commonly results in IGV1 varices, whereas cirrhosis related portal hypertension more commonly results in GOV2 varices.

#### **3.1 Primary prophylaxis**

There is limited data on the primary prophylaxis of GV bleeding. In a RCT with a sample size of 89 patients, endoscopic glue was found to be more effective than the beta-blocker therapy in preventing the first GV bleeding, the risk of not having bleed, being 87% vs. 62% respectively. There was a survival advantage also in the patients with GOV2 and IGV1. High-risk factors for first bleeding from GVs are variceal size >20 mm, MELD score > 16, and the presence of severe portal hypertensive gastropathy (PHG) [31] and these may be suitable for glue injection. The algorithm for the management of gastric varix, including role of primary prophylaxis is depicted in **Figure 7**.

#### **3.2 Acute gastric variceal hemorrhage (AGVH)**

Medical management of suspected gastric variceal bleeding includes airway protection, restrictive blood transfusion, vasoactive agents, antibiotics, and admission to the intensive care unit. **Table 2** shows various modalities which can be used to treat GV. Endoscopic therapy is the initial treatment of choice. The methods utilized often depend on the local availability and experience. An algorithm for management of GV is shown in **Figure 7**.

#### **3.3 Glue injection**

N-butyl-2-cyanoacrylate, is a monomer that rapidly undergoes exothermic polymerization upon contact with living tissues, getting transformed from liquid to a hard, brittle acrylic plastic. This tissue adhesive is used to treat bleeding GV.

#### **Figure 6.**

*Endoscopic appearance of gastric varix. (a) Spurting bleeding from the gastric varix, (b) hemostasis after glue injection.*

**99**

**Figure 7.**

*Antegrade Transvenous obliteration.*

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

*Therapeutic options for control of acute gastric variceal bleed.*

**Endoscopic therapy**

**Interventional Radiology**

Glue Coil Thrombin Sclerotherapy

TIPS BRTO/BATO **Surgery**

**Table 2.**

For the glue injection, a therapeutic endoscope with a 3.7 mm working channel may be preferred for the accurate control of the injector catheter. The injection catheter should be primed with distilled water (DW) or normal saline (NS) (0.8–1 ml) to fill up the dead space. The gastroscope is placed in a retroflexed position close to the target varix. The suction is turned off, and the injection catheter with the needle still withdrawn, is advanced without variceal contact juxtaposed to the target varix. The needle is then pushed out directly into the varix, and glue is injected in 1 ml aliquots by using NS or DW solution to flush the glue into the varix. The needle should be immediately withdrawn after the glue injection to prevent entrapment into the varix. While withdrawing the needle, the flushing of a steady stream of the solution is aimed at the varix's puncture site. The varix's blunt palpation is done by catheter or biopsy forceps, and additional glue is injected until the varix is 'hard' to palpate. Overall success in term of hemostasis is noted in 84–100% of GV treated with glue. Technical complications related to glue injection include needle entrapment in a varix, exposure to the eyes of endoscopists or the assistants, or endoscope damage. Clinical complications from cyanoacrylate injection occur in up to 7% of cases and involve systemic embolization, sepsis, gastric ulcer, rebleeding due to cast extrusion, and mesenteric hematoma. Embolisation can be fatal and can involve

*Algorithm for management of gastric varix. Depending the expertise available. TIPS Transjugular intrahepatic portosystemic shunt. BRTO balloon-occluded retrograde transvenous obliteration. BATO balloon-occluded* 


#### **Table 2.**

*Portal Hypertension - Recent Advances*

commonly results in GOV2 varices.

prophylaxis is depicted in **Figure 7**.

ment of GV is shown in **Figure 7**.

**3.3 Glue injection**

**3.2 Acute gastric variceal hemorrhage (AGVH)**

**3.1 Primary prophylaxis**

Gastric variceal bleeding **(Figure 6**), although less common, has the predisposition to be more severe, associated with higher blood transfusion requirement, and increased morbidity, and mortality compared with esophageal variceal bleeding [30]. The probable cause for this is a large submucosal component of GV, the vascular structures feeding and draining the gastric varix, and, also, the lack of widespread expertise. Bleeding risk is significantly higher for the IGV1 (77%) and GOV2 (55%), than for GOV1 or ectopic varices (10%) [29]. EHPVO more commonly results in IGV1 varices, whereas cirrhosis related portal hypertension more

There is limited data on the primary prophylaxis of GV bleeding. In a RCT with a sample size of 89 patients, endoscopic glue was found to be more effective than the beta-blocker therapy in preventing the first GV bleeding, the risk of not having bleed, being 87% vs. 62% respectively. There was a survival advantage also in the patients with GOV2 and IGV1. High-risk factors for first bleeding from GVs are variceal size >20 mm, MELD score > 16, and the presence of severe portal hypertensive gastropathy (PHG) [31] and these may be suitable for glue injection. The algorithm for the management of gastric varix, including role of primary

Medical management of suspected gastric variceal bleeding includes airway protection, restrictive blood transfusion, vasoactive agents, antibiotics, and admission to the intensive care unit. **Table 2** shows various modalities which can be used to treat GV. Endoscopic therapy is the initial treatment of choice. The methods utilized often depend on the local availability and experience. An algorithm for manage-

N-butyl-2-cyanoacrylate, is a monomer that rapidly undergoes exothermic polymerization upon contact with living tissues, getting transformed from liquid to a hard, brittle acrylic plastic. This tissue adhesive is used to treat bleeding GV.

*Endoscopic appearance of gastric varix. (a) Spurting bleeding from the gastric varix, (b) hemostasis after glue* 

**98**

**Figure 6.**

*injection.*

*Therapeutic options for control of acute gastric variceal bleed.*

#### **Figure 7.**

*Algorithm for management of gastric varix. Depending the expertise available. TIPS Transjugular intrahepatic portosystemic shunt. BRTO balloon-occluded retrograde transvenous obliteration. BATO balloon-occluded Antegrade Transvenous obliteration.*

For the glue injection, a therapeutic endoscope with a 3.7 mm working channel may be preferred for the accurate control of the injector catheter. The injection catheter should be primed with distilled water (DW) or normal saline (NS) (0.8–1 ml) to fill up the dead space. The gastroscope is placed in a retroflexed position close to the target varix. The suction is turned off, and the injection catheter with the needle still withdrawn, is advanced without variceal contact juxtaposed to the target varix. The needle is then pushed out directly into the varix, and glue is injected in 1 ml aliquots by using NS or DW solution to flush the glue into the varix. The needle should be immediately withdrawn after the glue injection to prevent entrapment into the varix. While withdrawing the needle, the flushing of a steady stream of the solution is aimed at the varix's puncture site. The varix's blunt palpation is done by catheter or biopsy forceps, and additional glue is injected until the varix is 'hard' to palpate.

Overall success in term of hemostasis is noted in 84–100% of GV treated with glue. Technical complications related to glue injection include needle entrapment in a varix, exposure to the eyes of endoscopists or the assistants, or endoscope damage. Clinical complications from cyanoacrylate injection occur in up to 7% of cases and involve systemic embolization, sepsis, gastric ulcer, rebleeding due to cast extrusion, and mesenteric hematoma. Embolisation can be fatal and can involve

lung, portal vein, coronary arteries, spleen, or even brain with risk increasing more with excessive and forceful glue injection. Visceral fistulization from the stomach into the pleura or mediastinum also may occur after unintentional paravariceal glue injection [32].

#### **3.4 Sclerosant injection**

Injection of sclerosants like tetradecyl sulphate and alcohol is one of the oldest techniques endoscopists used, in order to control acute gastric variceal bleeding. Sclerotherapy involves injection of a combination of para- and intra-variceal injections, or 5–10 ml of intravariceal sclerosant injection into the actively bleeding GV. Rebleeding rate is reported to be between 10 and 20%.

On comparing glue injection versus sclerotherapy in a RCT of 37 patients with IGV-1, glue was more efficacious than alcohol sclerotherapy in immediate hemostasis (89% vs. 62%), variceal obliteration (100% vs. 44%), and achieving quicker variceal obliteration (2 weeks vs. 4.7 weeks) [33]. Sclerosant injection is associated with high rates of complications, including gastric ulceration, perforation, and rebleeding (37–53%), and hence, it is not a good option in the management of GV [34, 35].

#### **3.5 Thrombin injection**

Thrombin tissue adhesives include thrombin, a human or bovine protein that affects hemostasis by converting fibrinogen to a fibrin clot. Thrombin also achieves hemostasis by altering the platelet aggregation. Human thrombin injection generally consists of 5 ml of reconstituted solution in calcium-chloride containing thrombin 500 IU/ml (Floseal; Baxter Healthcare Corporation, CA, Hayward, USA). During each session, usually 5 mL of thrombin solution is injected in a varix.

In an only RCT available which compares thrombin to cyanoacrylate injection in the control of AGVH, thrombin injection and glue injection had similar success rate (90% vs. 90.9%). However, a higher incidence of complications (51% vs. 12%) and ulcers (37% vs. 0%) were noted with glue injection as compared to thrombin [36]. Results of this study cannot be generalized as the sample size used in this study was small.

#### **3.6 Endoscopic ultrasound (EUS) -guided therapies**

EUS can improve the endoscopic management of gastric varices in many regards. These include – a) Increased detection rate of gastric varices overlooked as gastric folds. b) Ability to use doppler to confirm variceal obliteration and predicting the rebleeding risk. c) Adequate visualization of culprit gastric varix even in presence of torrential hemorrhage or blood clots and d) EUS-guided glue injection can be done precisely into a perforating vessel with preceding contrast injection to identify the feeding vessel as efferent or afferent, and thereby reducing embolization risk by enabling the use of a smaller volume of glue. e) EUS provides additional information regarding portal vein and splenic vein patency, helping to assess need and feasibility candidacy for TIPS/Balloon-occluded retrograde transvenous obliteration (BRTO) in failed cases [37].

The technique of EUS guided glue therapy involves filling the gastric fundus with water to improve acoustic coupling and visualization. The EUS is then positioned either in the distal esophagus (transesophageal-transcrural approach) or in the cardia/fundus (transgastric approach) to visualize the intramural varices and feeder vessels. EUS-directed intravascular puncture of the GV is performed using a standard FNA needle.

**101**

**3.7 Hemospray**

**Figure 8.**

**4. Ectopic varices**

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

Reports have suggested that the initial deployment of intravascular coils in the GV provides a scaffold for glue polymerization and fixation, reducing the glue requirement and inadvertent glue embolization [38] (**Figure 8**). Various commercially available coils include 0.035-inch MReye coils (extended embolus length 5 to 10 cm, coiled embolus diameter 10 mm; IMWCE 35, Cook Medical) or Hilal micro coils (extended embolus length 2 cm, coiled embolus diameter 2 mm; Embolization micro coil, MWCE, William Cook Europe, Bjeeverskov, DK). Generally, a 5-cm MReye coil are used if the vessel diameter is less than 10 mm, and a 10-cm MReye coil is used if the vessel diameter was more than 10 mm. Once the needle is inside the gastric varix, stylet is withdrawn, and the coil is deployed by advancing the stiffer part of a 0.035-inch guidewire. After coil is deployed, 1 ml aliquots of glue is injected, followed by NS flush, using the same needle. Color Doppler after treat-

*Endosonographic coil embolization of the gastric varix. (a)Endosonography view of gastric varix (blue arrow)* 

EUS-guided coil and cyanoacrylate injection was found to yield a 100% hemostatic success rate in a single-center pilot study [39]. Additionally, there were no procedurerelated complications reported [39]. A recently published meta-analysis that compared treatment efficacy of EUS guided glue and coil injection with the endoscopic glue injection alone reported a statistically significant benefit of variceal obliteration in the EUS group (86.2% vs. 62.6%). The results were however, comparable in both the groups in terms of treatment efficacy, recurrence of gastric varix, early and late rebleeding [40].

TC-325 (Hemospray, Cook Medical, Winstom-Salem, North Carolina, United States) is a hemostatic powder which, when in contact with blood or tissue in the GI tract, becomes cohesive and adhesive, and forms a physical barrier, coating the bleeding site. Its effect lasts approximately 24 hours because the hemostatic layer sloughs off. Currently, it is only licensed for the treatment of non-variceal upper GI bleed. However, two recent studies demonstrated that Hemospray could be used as

Ectopic varices (EcV) have a very complex anatomy. Understanding anastomosis

with the splanchnic venous system is essential in managing EcV. These are rare

a bridge to a definitive treatment in active variceal bleeding [41, 42].

ment can confirm the absence of flow in the treated varix.

*(b) Endosonography view of gastric varix after coil embolization(blue arrow).*

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

**Figure 8.**

*Portal Hypertension - Recent Advances*

injection [32].

**3.4 Sclerosant injection**

management of GV [34, 35].

**3.5 Thrombin injection**

lung, portal vein, coronary arteries, spleen, or even brain with risk increasing more with excessive and forceful glue injection. Visceral fistulization from the stomach into the pleura or mediastinum also may occur after unintentional paravariceal glue

Injection of sclerosants like tetradecyl sulphate and alcohol is one of the oldest techniques endoscopists used, in order to control acute gastric variceal bleeding. Sclerotherapy involves injection of a combination of para- and intra-variceal injections, or 5–10 ml of intravariceal sclerosant injection into the actively bleeding GV.

On comparing glue injection versus sclerotherapy in a RCT of 37 patients with IGV-1, glue was more efficacious than alcohol sclerotherapy in immediate hemostasis (89% vs. 62%), variceal obliteration (100% vs. 44%), and achieving quicker variceal obliteration (2 weeks vs. 4.7 weeks) [33]. Sclerosant injection is associated with high rates of complications, including gastric ulceration, perforation, and rebleeding (37–53%), and hence, it is not a good option in the

Thrombin tissue adhesives include thrombin, a human or bovine protein that affects hemostasis by converting fibrinogen to a fibrin clot. Thrombin also achieves hemostasis by altering the platelet aggregation. Human thrombin injection generally consists of 5 ml of reconstituted solution in calcium-chloride containing thrombin 500 IU/ml (Floseal; Baxter Healthcare Corporation, CA, Hayward, USA).

In an only RCT available which compares thrombin to cyanoacrylate injection in the control of AGVH, thrombin injection and glue injection had similar success rate (90% vs. 90.9%). However, a higher incidence of complications (51% vs. 12%) and ulcers (37% vs. 0%) were noted with glue injection as compared to thrombin [36]. Results of this study cannot be generalized as the sample size used in this study was small.

During each session, usually 5 mL of thrombin solution is injected in a varix.

EUS can improve the endoscopic management of gastric varices in many regards. These include – a) Increased detection rate of gastric varices overlooked as gastric folds. b) Ability to use doppler to confirm variceal obliteration and predicting the rebleeding risk. c) Adequate visualization of culprit gastric varix even in presence of torrential hemorrhage or blood clots and d) EUS-guided glue injection can be done precisely into a perforating vessel with preceding contrast injection to identify the feeding vessel as efferent or afferent, and thereby reducing embolization risk by enabling the use of a smaller volume of glue. e) EUS provides additional information regarding portal vein and splenic vein patency, helping to assess need and feasibility candidacy for TIPS/Balloon-occluded retrograde transvenous

The technique of EUS guided glue therapy involves filling the gastric fundus with water to improve acoustic coupling and visualization. The EUS is then positioned either in the distal esophagus (transesophageal-transcrural approach) or in the cardia/fundus (transgastric approach) to visualize the intramural varices and feeder vessels. EUS-directed intravascular puncture of the GV is performed using a

Rebleeding rate is reported to be between 10 and 20%.

**3.6 Endoscopic ultrasound (EUS) -guided therapies**

obliteration (BRTO) in failed cases [37].

**100**

standard FNA needle.

*Endosonographic coil embolization of the gastric varix. (a)Endosonography view of gastric varix (blue arrow) (b) Endosonography view of gastric varix after coil embolization(blue arrow).*

Reports have suggested that the initial deployment of intravascular coils in the GV provides a scaffold for glue polymerization and fixation, reducing the glue requirement and inadvertent glue embolization [38] (**Figure 8**). Various commercially available coils include 0.035-inch MReye coils (extended embolus length 5 to 10 cm, coiled embolus diameter 10 mm; IMWCE 35, Cook Medical) or Hilal micro coils (extended embolus length 2 cm, coiled embolus diameter 2 mm; Embolization micro coil, MWCE, William Cook Europe, Bjeeverskov, DK). Generally, a 5-cm MReye coil are used if the vessel diameter is less than 10 mm, and a 10-cm MReye coil is used if the vessel diameter was more than 10 mm. Once the needle is inside the gastric varix, stylet is withdrawn, and the coil is deployed by advancing the stiffer part of a 0.035-inch guidewire. After coil is deployed, 1 ml aliquots of glue is injected, followed by NS flush, using the same needle. Color Doppler after treatment can confirm the absence of flow in the treated varix.

EUS-guided coil and cyanoacrylate injection was found to yield a 100% hemostatic success rate in a single-center pilot study [39]. Additionally, there were no procedurerelated complications reported [39]. A recently published meta-analysis that compared treatment efficacy of EUS guided glue and coil injection with the endoscopic glue injection alone reported a statistically significant benefit of variceal obliteration in the EUS group (86.2% vs. 62.6%). The results were however, comparable in both the groups in terms of treatment efficacy, recurrence of gastric varix, early and late rebleeding [40].

#### **3.7 Hemospray**

TC-325 (Hemospray, Cook Medical, Winstom-Salem, North Carolina, United States) is a hemostatic powder which, when in contact with blood or tissue in the GI tract, becomes cohesive and adhesive, and forms a physical barrier, coating the bleeding site. Its effect lasts approximately 24 hours because the hemostatic layer sloughs off. Currently, it is only licensed for the treatment of non-variceal upper GI bleed. However, two recent studies demonstrated that Hemospray could be used as a bridge to a definitive treatment in active variceal bleeding [41, 42].

#### **4. Ectopic varices**

Ectopic varices (EcV) have a very complex anatomy. Understanding anastomosis with the splanchnic venous system is essential in managing EcV. These are rare

#### **Figure 9.**

*Hemobilia due to choledochal varix and its treatment with metal stent. (a) Endoscopic appearance at side viewing examination showing spurting from papilla due to choledochal varix, (b) after deployment of covered self-expanding metal stent.*

cause of bleeding in patients with cirrhosis and PH, accounting for only 2–5% cases [43]. They are more common in patients with prehepatic PH, occurring in 27–40% of patients with splanchnic vein thrombosis [44]. However, EcV bleed is more severe than esophageal variceal bleeding, with mortality rates up to 37.5% [45]. Ectopic varix can develop in the duodenum, small bowel, rectum, colon, gallbladder, and biliary tract, periumbilical, peristomal, and the retroperitoneal areas. Endoscopy is used for both diagnosis and therapy. Most of the EcV are within reach of standard EGD and colonoscopy. A bleeding small intestinal varix may occasionally require the use of capsule endoscopy and device-assisted enteroscopy.

The treatment of bleeding of EcV is extrapolated from the esophageal and gastric varices literature. Successful outcomes depend on local expertise, location of varices, and the technical feasibility. ES and glue injection are commonly used modalities. EVL can be used to manage the rectal and duodenal varix. Caution however, must be exercised if the varix size is bigger, as the chances of hemostasis are less and the risk of rebleeding is high. Use of APC with EBL may be considered for the prevention of variceal occurrence, as has been reported in the treatment of ileocolonic anastomotic varices [45]. Hemostatic clip placement has been reported for ectopic variceal therapy [46]. Hemobilia, due to choledochal varices, can be lifethreatening. Placement of a covered biliary metal stent (**Figure 9a**, **b**) is a promising approach to achieve immediate hemostasis for bleeding from portal biliopathy and associated choledochal varix. Biliary stenting serves as salvage therapy and a bridge to elective devascularization and shunt surgery [47].

#### **5. Portal hypertensive gastropathy (PHG)**

PHG, typically seen in patients with PH, is a condition of gastric mucosal ectasia and impaired mucosal defense. The incidence of PHG in patients with PH, varies greatly, ranging between 20 and 75%. Of those approximately 65–90%

**103**

**Figure 10**

*Severe portal hypertensive gastropathy.*

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

have mild PHG (mosaic pattern of the gastric mucosa without red spots), whereas 10–25% have severe PHG (mosaic pattern of the gastric mucosa with red spots; **Figure 10**) [48]. The ectatic mucosal capillaries and venules of PHG may cause recurrent bleeding, presenting as acute or chronic occult blood loss. The annual incidence of overt bleeding from mild PHG is about 5%, while it is 15% for severe

APC has been evaluated for the treatment of PHG, in combination with adequate

GAVE is characterized by erythematous or raised mucosa with underlying tortuous ectatic vessels as red spots. Patterns of GAVE include honeycombing, diffuse or speckled patchy erythema, and nodular antral GAVE. These appear as diffuse or linear array in the gastric antrum **(Figure 11a**). Both PHG and GAVE may be found during endoscopy in patients with PH or discovered during variceal screening. However, in most instances, they are distinguished by their endoscopic appearance, location and when needed, biopsy for histological examination. (**Table 3**). On histology, GAVE shows presence of fibromuscular hyperplasia, fibrin microthrombi, and increased neuroendocrine cells in the lamina propria [54]. GAVE can be isolated or can be associated with cirrhosis and with systemic illnesses like scleroderma, chronic renal failure, and can occur after bone marrow transplantation. PH does not play a direct role in development of GAVE, as it is not present in up to 70% of patients, and the reduction of portal hypertension does not affect the course of the disease [55]. The endoscopic treatment includes laser photoablation, APC, radio-frequency

NSBB. This does reduce rates of blood transfusion, ICU admission, and improve hemoglobin levels in 80–90% of patients [51, 52]. Hemospray is also an option for the treatment of active PHG bleeding. However, these endoscopic methods may be

an effective bridging therapy till TIPS or liver transplant is performed [53].

ablation [56], EVL, and cryotherapy. APC is the most common, efficacious, and feasible therapeutic option for the treatment of GAVE **(Figure 11b),** with a reported efficacy of 90%- 100% causing a significant reduction in blood

PHG [49]. The frequency of rebleeding of PHG is 11–30% [50].

**6. Gastric antral vascular ectasia (GAVE)**

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

*Portal Hypertension - Recent Advances*

*Hemobilia due to choledochal varix and its treatment with metal stent. (a) Endoscopic appearance at side viewing examination showing spurting from papilla due to choledochal varix, (b) after deployment of covered* 

cause of bleeding in patients with cirrhosis and PH, accounting for only 2–5% cases [43]. They are more common in patients with prehepatic PH, occurring in 27–40% of patients with splanchnic vein thrombosis [44]. However, EcV bleed is more severe than esophageal variceal bleeding, with mortality rates up to 37.5% [45]. Ectopic varix can develop in the duodenum, small bowel, rectum, colon, gallbladder, and biliary tract, periumbilical, peristomal, and the retroperitoneal areas. Endoscopy is used for both diagnosis and therapy. Most of the EcV are within reach of standard EGD and colonoscopy. A bleeding small intestinal varix may occasion-

ally require the use of capsule endoscopy and device-assisted enteroscopy. The treatment of bleeding of EcV is extrapolated from the esophageal and gastric varices literature. Successful outcomes depend on local expertise, location of varices, and the technical feasibility. ES and glue injection are commonly used modalities. EVL can be used to manage the rectal and duodenal varix. Caution however, must be exercised if the varix size is bigger, as the chances of hemostasis are less and the risk of rebleeding is high. Use of APC with EBL may be considered for the prevention of variceal occurrence, as has been reported in the treatment of ileocolonic anastomotic varices [45]. Hemostatic clip placement has been reported for ectopic variceal therapy [46]. Hemobilia, due to choledochal varices, can be lifethreatening. Placement of a covered biliary metal stent (**Figure 9a**, **b**) is a promising approach to achieve immediate hemostasis for bleeding from portal biliopathy and associated choledochal varix. Biliary stenting serves as salvage therapy and a

bridge to elective devascularization and shunt surgery [47].

PHG, typically seen in patients with PH, is a condition of gastric mucosal ectasia and impaired mucosal defense. The incidence of PHG in patients with PH, varies greatly, ranging between 20 and 75%. Of those approximately 65–90%

**5. Portal hypertensive gastropathy (PHG)**

**102**

**Figure 9.**

*self-expanding metal stent.*

**Figure 10** *Severe portal hypertensive gastropathy.*

have mild PHG (mosaic pattern of the gastric mucosa without red spots), whereas 10–25% have severe PHG (mosaic pattern of the gastric mucosa with red spots; **Figure 10**) [48]. The ectatic mucosal capillaries and venules of PHG may cause recurrent bleeding, presenting as acute or chronic occult blood loss. The annual incidence of overt bleeding from mild PHG is about 5%, while it is 15% for severe PHG [49]. The frequency of rebleeding of PHG is 11–30% [50].

APC has been evaluated for the treatment of PHG, in combination with adequate NSBB. This does reduce rates of blood transfusion, ICU admission, and improve hemoglobin levels in 80–90% of patients [51, 52]. Hemospray is also an option for the treatment of active PHG bleeding. However, these endoscopic methods may be an effective bridging therapy till TIPS or liver transplant is performed [53].

#### **6. Gastric antral vascular ectasia (GAVE)**

GAVE is characterized by erythematous or raised mucosa with underlying tortuous ectatic vessels as red spots. Patterns of GAVE include honeycombing, diffuse or speckled patchy erythema, and nodular antral GAVE. These appear as diffuse or linear array in the gastric antrum **(Figure 11a**). Both PHG and GAVE may be found during endoscopy in patients with PH or discovered during variceal screening. However, in most instances, they are distinguished by their endoscopic appearance, location and when needed, biopsy for histological examination. (**Table 3**). On histology, GAVE shows presence of fibromuscular hyperplasia, fibrin microthrombi, and increased neuroendocrine cells in the lamina propria [54]. GAVE can be isolated or can be associated with cirrhosis and with systemic illnesses like scleroderma, chronic renal failure, and can occur after bone marrow transplantation. PH does not play a direct role in development of GAVE, as it is not present in up to 70% of patients, and the reduction of portal hypertension does not affect the course of the disease [55].

The endoscopic treatment includes laser photoablation, APC, radio-frequency ablation [56], EVL, and cryotherapy. APC is the most common, efficacious, and feasible therapeutic option for the treatment of GAVE **(Figure 11b),** with a reported efficacy of 90%- 100% causing a significant reduction in blood

#### **Figure 11.**

*Endoscopic appearance of gastric antral vascular ectasia. (a) Endoscopic appearance of gastric antral vascular ectasia, (b) appearance after argon plasma coagulation.*


#### **Table 3.**

*Difference between portal hypertensive Gastropathy and gastric antral vascular ectasia.*

transfusion requirement [57, 58]. The setting of argon gas flow usually ranges between 0.8–2.0 L/min, the electrical power from 40 to 60 W, and, generally, a mean of 2.5 sessions are needed to achieve complete eradication [59]. Few studies have compared EVL with APC for GAVE treatment, where band ligation showed a

**105**

**Figure 12.**

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

of the abnormal vasculature in the mucosa and submucosa.

(villous edema, erythema, or polyps) changes [64] (**Figure 12a-f)**.

bility, radiological coil embolization is an option [64].

**8. Portal hypertensive COLOPATHY (PHC)**

Colonic abnormalities in patients with PH are referred to as PHC, and these are vascular ectasias, mosaic pattern mucosa, mucosal hemorrhages, anorectal or colonic varices, hemorrhoids, and nonspecific inflammatory changes. Its prevalence in patients with cirrhosis varies from 25 to 70%, with an estimated bleeding

*Capsule endoscopy appearance of portal hypertensive enteropathy. a-c: Vascular: (a) red spot, (b) telangiectasia, (c) small intestinal varix. d-e: Inflammatory: (d) villous edema, (e) erythema, (f) polyp.*

**7. Portal hypertensive enteropathy (PHE)**

significantly higher rate of hemostasis, required fewer treatment sessions, a higher increase in hemoglobin values, and reduced need for blood transfusions [60, 61]. The higher efficacy EVL is attributed to a more controlled and reliable eradication

PHE is a condition associated with pathologic changes and mucosal abnormalities in the small intestine of patients with PH. It is being increasingly diagnosed, due to the advent of video capsule endoscopy and deep enteroscopy. In recent studies, the prevalence of PHE varies around 93–97%, with 8–12% of patients showing evidence of ongoing bleeding [62–64]. The findings of PHE are characterized as vascular (red spots, telangiectasia, or varices) and non-vascular or inflammatory

Treatment options for PHE related bleed include glue or sclerosant for variceal bleeding and APC for non-variceal bleeding. In patients with hemodynamic insta*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

*Portal Hypertension - Recent Advances*

**Portal Hypertensive Gastropathy**

*Endoscopic appearance of gastric antral vascular ectasia. (a) Endoscopic appearance of gastric antral vascular* 

patients with PH, is a condition of gastric mucosal ectasia and impaired mucosal defense

submucosal veins along with ectatic capillaries without microthrombi or

inflammation

6. Incidence of bleed Low Higher than PHG related

red spots (severe)

Thermocoagulation Liver transplantation

2. Location Gastric fundus and body Gastric antrum

1. Definition PHG, typically seen in

4. Histology Dliated mucosal and

5. Endoscopy Mosaic pattern (mild) with

Second line

*Difference between portal hypertensive Gastropathy and gastric antral vascular ectasia.*

transfusion requirement [57, 58]. The setting of argon gas flow usually ranges between 0.8–2.0 L/min, the electrical power from 40 to 60 W, and, generally, a mean of 2.5 sessions are needed to achieve complete eradication [59]. Few studies have compared EVL with APC for GAVE treatment, where band ligation showed a

7. Treatment First line NSBB EBL

3. Association with Portal HTN

*ectasia, (b) appearance after argon plasma coagulation.*

**Gastric Antral Vascular** 

It is characterized by erythematous or raised mucosa with underlying tortuous ectatic vessels as red spots in either a diffuse or linear array

**Ectasia**

case

bleed

Fibromuscular hyperplasia, fibrin microthrombi, and increased neuroendocrine cells in the lamina propria

Honeycombing, Diffuse or speckled patchy erythema, and nodular antral lesions

Thermocoagulation

Radiofrequency ablation

Cryotherapy

Anterectomy

Always In approximately 30%

**104**

**Table 3.**

**Figure 11.**

significantly higher rate of hemostasis, required fewer treatment sessions, a higher increase in hemoglobin values, and reduced need for blood transfusions [60, 61]. The higher efficacy EVL is attributed to a more controlled and reliable eradication of the abnormal vasculature in the mucosa and submucosa.

#### **7. Portal hypertensive enteropathy (PHE)**

PHE is a condition associated with pathologic changes and mucosal abnormalities in the small intestine of patients with PH. It is being increasingly diagnosed, due to the advent of video capsule endoscopy and deep enteroscopy. In recent studies, the prevalence of PHE varies around 93–97%, with 8–12% of patients showing evidence of ongoing bleeding [62–64]. The findings of PHE are characterized as vascular (red spots, telangiectasia, or varices) and non-vascular or inflammatory (villous edema, erythema, or polyps) changes [64] (**Figure 12a-f)**.

Treatment options for PHE related bleed include glue or sclerosant for variceal bleeding and APC for non-variceal bleeding. In patients with hemodynamic instability, radiological coil embolization is an option [64].

**Figure 12.**

*Capsule endoscopy appearance of portal hypertensive enteropathy. a-c: Vascular: (a) red spot, (b) telangiectasia, (c) small intestinal varix. d-e: Inflammatory: (d) villous edema, (e) erythema, (f) polyp.*

#### **8. Portal hypertensive COLOPATHY (PHC)**

Colonic abnormalities in patients with PH are referred to as PHC, and these are vascular ectasias, mosaic pattern mucosa, mucosal hemorrhages, anorectal or colonic varices, hemorrhoids, and nonspecific inflammatory changes. Its prevalence in patients with cirrhosis varies from 25 to 70%, with an estimated bleeding rate of 0–9% [65–68]. Treatment options are ES or glue injection for variceal bleed, EVL for hemorrhoidal bleed, and APC for the non-variceal bleed and are similar to those in PHE.

#### **9. Summary**

PH can result in formation of varices at various sites with mucosal changes anywhere in the gastrointestinal tract. These can lead to acute gastrointestinal bleed or anemia. Endoscopy plays an important role in diagnosis and treatment of these complications. EVL and glue are the usual first line treatment for esophageal and GV respectively. Other therapies include sclerosant or thrombin injection, EUS-guided therapies, esophageal stent placement, APC or hemospray.

#### **Author details**

Bhavik Bharat Shah, Usha Goenka and Mahesh Kumar Goenka\* Apollo Gleneagles Hospitals, Kolkata, India

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

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**107**

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

> [10] North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J

> [11] European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J. Hepatol. 2018 Aug 1;69(2):406-60.

[12] Kapoor A, Dharel N, Sanyal AJ. Endoscopic diagnosis and therapy in gastroesophageal variceal bleeding. Gastrointest Endosc Clin N Am

[13] De Franchis R Baveno VI faculty. Expanding consensus in portal hypertension: report of the BAVENO VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743-752.

[14] Garcia-Tsao G, Sanyal AJ,

Grace ND, Carey W. Practice Guidelines Committee of the American Association for the Study of Liver Diseases Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922-938.

[15] D'Amico G, De Franchis R. Upper digestive bleeding in cirrhosis. Posttherapeutic outcome and prognostic indicators. Hepatology 2003; 38: 599-612.

[16] Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl

Stefanidis G, et al. Sustained rise of portal pressure after sclerotherapy, but not band ligation, in acute variceal bleeding in cirrhosis. Hepatology 2004; 39:1623-1630.

J Med 2013;368:11 21.

[17] Avgerinos A, Armonis A,

Med 1988; 319: 983-989

2015;25(3):491-507.

[1] Sharma M, Rameshbabu CS. Collateral pathways in portal hypertension. J Clin Exp Hepatol

[2] Thuluvath PJ, Yoo HY. Portal hypertensive gastropathy. Am J

[4] Garcia-Tsao G, Abraldes JG,

Gastroenterol 2002 Dec 1;97(12):2973-8.

[3] D'Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995;

Berzigotti A, et al. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 2017;65(1):310-35.

[5] D'Amico G, Pasta L, Morabito A, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther 2014;39:1180-1193.

Altamirano JT, et al. Predicting early

[7] Bosch J, García-Pagán JC. Prevention of variceal rebleeding. Lancet. 2003 Mar

[8] de Franchis R, Eisen GM, Laine L, et al. Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension. Hepatology.

[9] Wang HM, Lo GH, Chen WC, et al. Efficacy of transient elastography in screening for large esophageal varices in patients with suspicious or proven liver cirrhosis. J Dig Dis. 2012;13:430-438.

[6] Augustin S, Muntaner L,

mortality after acute variceal hemorrhage based on classification and regression tree analysis. Clin Gastroenterol Hepatol 2009;7:1347-1354.

15;361(9361):952-4.

2008;47:1595-1603.

2012;2(4): 338-52.

**References**

22: 332-354.

### **References**

*Portal Hypertension - Recent Advances*

those in PHE.

**9. Summary**

rate of 0–9% [65–68]. Treatment options are ES or glue injection for variceal bleed, EVL for hemorrhoidal bleed, and APC for the non-variceal bleed and are similar to

PH can result in formation of varices at various sites with mucosal changes anywhere in the gastrointestinal tract. These can lead to acute gastrointestinal bleed or anemia. Endoscopy plays an important role in diagnosis and treatment of these complications. EVL and glue are the usual first line treatment for esophageal and GV respectively. Other therapies include sclerosant or thrombin injection,

EUS-guided therapies, esophageal stent placement, APC or hemospray.

**106**

**Author details**

Bhavik Bharat Shah, Usha Goenka and Mahesh Kumar Goenka\*

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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

Apollo Gleneagles Hospitals, Kolkata, India

provided the original work is properly cited.

[1] Sharma M, Rameshbabu CS. Collateral pathways in portal hypertension. J Clin Exp Hepatol 2012;2(4): 338-52.

[2] Thuluvath PJ, Yoo HY. Portal hypertensive gastropathy. Am J Gastroenterol 2002 Dec 1;97(12):2973-8.

[3] D'Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. Hepatology 1995; 22: 332-354.

[4] Garcia-Tsao G, Abraldes JG, Berzigotti A, et al. Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 2017;65(1):310-35.

[5] D'Amico G, Pasta L, Morabito A, et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther 2014;39:1180-1193.

[6] Augustin S, Muntaner L, Altamirano JT, et al. Predicting early mortality after acute variceal hemorrhage based on classification and regression tree analysis. Clin Gastroenterol Hepatol 2009;7:1347-1354.

[7] Bosch J, García-Pagán JC. Prevention of variceal rebleeding. Lancet. 2003 Mar 15;361(9361):952-4.

[8] de Franchis R, Eisen GM, Laine L, et al. Esophageal capsule endoscopy for screening and surveillance of esophageal varices in patients with portal hypertension. Hepatology. 2008;47:1595-1603.

[9] Wang HM, Lo GH, Chen WC, et al. Efficacy of transient elastography in screening for large esophageal varices in patients with suspicious or proven liver cirrhosis. J Dig Dis. 2012;13:430-438.

[10] North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988; 319: 983-989

[11] European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J. Hepatol. 2018 Aug 1;69(2):406-60.

[12] Kapoor A, Dharel N, Sanyal AJ. Endoscopic diagnosis and therapy in gastroesophageal variceal bleeding. Gastrointest Endosc Clin N Am 2015;25(3):491-507.

[13] De Franchis R Baveno VI faculty. Expanding consensus in portal hypertension: report of the BAVENO VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743-752.

[14] Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Practice Guidelines Committee of the American Association for the Study of Liver Diseases Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922-938.

[15] D'Amico G, De Franchis R. Upper digestive bleeding in cirrhosis. Posttherapeutic outcome and prognostic indicators. Hepatology 2003; 38: 599-612.

[16] Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013;368:11 21.

[17] Avgerinos A, Armonis A, Stefanidis G, et al. Sustained rise of portal pressure after sclerotherapy, but not band ligation, in acute variceal bleeding in cirrhosis. Hepatology 2004; 39:1623-1630.

[18] 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.

[19] Dai C, Liu WX, Jiang M, et al. Endoscopic variceal ligation compared with endoscopic injection sclerotherapy for treatment of esophageal variceal hemorrhage: a meta-analysis. World J Gastroenterol 2015;21(8):2534-41.

[20] Kapoor A, Dharel N, Sanyal AJ. Endoscopic diagnosis and therapy in gastroesophageal variceal bleeding. Gastrointest Endosc Clin N Am 2015;25(3): 491-507.

[21] Maluf-Filho F, Sakai P, Ishioka S, et al. Endoscopic sclerosis versus cyanoacrylate endoscopic injection for the first episode of variceal bleeding: a prospective, controlled, and randomized study in Child-Pugh class C patients. Endoscopy 2001;33(5):421-7.

[22] Azoulay D, Castaing D, Majno P, et al. Salvage transjugular intrahepatic portosystemic shunt for uncontrolled variceal bleeding in patients with decompensated cirrhosis. J Hepatol. 2001;35:590-7.

[23] Chesta FN, Rizvi ZH, Oberoi M, Buttar N. The role of stenting in patients with variceal bleeding. Techniques and Innovations in Gastrointestinal Endoscopy. 2020 Jul 23 (In press).

[24] Goenka MK, Goenka U, Tiwary IK, Rai V. Use of self-expanding metal stents for difficult variceal bleed. Indian J Gastroenterol. 2017 Nov 1;36(6):468-73.

[25] McCarty TR, Njei B: Self-expanding metal stents for acute refractory esophageal variceal bleeding: A systematic review and meta-analysis. Dig Endosc 2016, 28(5):539-547.

[26] Maufa F, Al-Kawas FH: Role of self-expandable metal stents in acute variceal bleeding. Int J Hepatol 2012, 2012:418369-418369.

[27] Kamal A, Abd Elmoety AA, Hamza Y, Zeid A. Endoscopic variceal ligation followed by argon plasma coagulation against endoscopic variceal ligation alone. J Clin Gastroenterol. 2017 Jan 1;51(1):49-55.

[28] Li X, Jiang T, Gao J. Endoscopic variceal ligation combined with argon plasma coagulation versus ligation alone for the secondary prophylaxis of variceal bleeding: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017;29(6):621-8.

[29] Sarin SK, Lahoti D, Saxena SP, et al. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 1992;16:1343-1349.

[30] de Franchis R, Primignani M. Natural history of portal hypertension in patients with cirrhosis. Clin Liver Dis 2001; 5: 645-63.

[31] Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and betablockers: a randomized controlled trial. J Hepatol 2011; 54: 1161-1167.

[32] Tripathi D, Ferguson JW, Therapondos G, Plevris JN, Hayes PC. Recent advances in the management of bleeding gastric varices Aliment. Pharmacol. Ther. 2006 Jul;24(1):1-7.

[33] Sarin SK, Jain AK, Jain M, Gupta R. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol. 2002;97(4):1010-5.

[34] Sarin SK. Long-term follow-up of gastric variceal sclerotherapy: an eleven year experience. Gastrointest Endosc 1997; 46: 8-14.

**109**

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

thrombosis: evaluation and

Hepatol 2007;5(1):80-6.

2017;96(1):e5860.

determinants of survival during longterm follow-up. Clin Gastroenterol

[45] Helmy A, Al Kahtani K, Al Fadda M. Updates in the pathogenesis, diagnosis and management of ectopic varices. Hepatol Int 2008;2(3):322-34.

[46] Park SW, Cho E, Jun CH, et al. Upper gastrointestinal ectopic

[47] Goenka MK, Harwani Y, Rai V, Goenka U. Fully covered self-expandable metal biliary stent for hemobilia caused by portal biliopathy. Gastrointest Endosc. 2014 Dec 1;80(6):1175.

[48] Merli M, Nicolini G, Angeloni S, Gentili F, Attili AF, Riggio O. The natural

history of portal hypertensive gastropathy in patients with liver cirrhosis and mild portal hypertension. Am J Gastroenterol. 2004;**99**:1959-654.

[49] D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44: 217-231.

[50] Primignani M, Carpinelli L, Preatoni P et al. Portal hypertensive gastropathy (PHG) in liver cirrhosis: natural history. A multicenter study by the New Italian Endoscopic Club (NIEC). J Gastroenterol 1996; 110: 1299.

[51] Herrera S, Bordas JM, Liach J et al. The beneficial effects of argon plasma coagulation in the management of different types of gastric vascular ectasia lesions in patients admitted for GI hemorrhage. Gastrointest Endosc

[52] Hanafy AS, El Hawary AT. Efficacy of argon plasma coagulation in the management of portal hypertensive

2008; 68: 440-446.

variceal bleeding treated with various endoscopic modalities: case reports and literature review. Medicine (Baltimore)

[35] Trudeau W, Prindiville T. Endoscopic injection sclerosis in bleeding gastric varices. Gastrointest

[36] Lo GH, Lin CW, Tai CM, et al. A prospective, randomized trial of thrombin versus cyanoacrylate injection in the control of acute gastric variceal hemorrhage. Endoscopy. 2020.

[37] Nett A, Binmoeller KF. Endoscopic Management of Portal Hypertension– related Bleeding Gastrointest Endoscopy

[39] Binmoeller KF, Weilert F, Shah JN, Kim J. EUS-guided transesophageal treatment of gastric fundal varices with combined coiling and cyanoacrylate

Gastrointest Endosc. 2011;74:1019-25.

[40] Mohan BP, Chandan S, Khan SR, et al. Efficacy and safety of endoscopic ultrasound-guided therapy versus direct endoscopic glue injection therapy for gastric varices: systematic review and meta-analysis. Endoscopy.

[41] HolIbrahim M, El-Mikkawy A, Hamid MA, et al. Early application of haemostatic powder added to standard management for oesophagogastric variceal bleeding: a randomised trial.

[42] Holster IL, Poley JW, Kuipers EJ, Tjwa ET. Controlling gastric variceal bleeding with endoscopically applied hemostatic powder (Hemospray™). J

[43] Henry Z, Uppal D, Saad W, et al. Gastric and ectopic varices. Clin Liver

[44] Orr DW, Harrison PM, Devlin J, et al. Chronic mesenteric venous

Clin N Am 29 (2019) 321-337.

[38] Weilert F, Binmoeller KF. Endoscopic management of gastric variceal bleeding. Gastroenterol Clin

North Am 2014;43(4):807-18.

glue injection (with videos).

2020;52(4):259-67.

Gut. 2019 1;68(5):844-53.

Hepatol 2012; 57: 1397-1398.

Dis 2014;18:371-88.

Endosc 1986;32(4):264-8.

*Endoscopy in Management of Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.94716*

[35] Trudeau W, Prindiville T. Endoscopic injection sclerosis in bleeding gastric varices. Gastrointest Endosc 1986;32(4):264-8.

*Portal Hypertension - Recent Advances*

[18] Garcia-Tsao G, Abraldes JG,

[19] Dai C, Liu WX, Jiang M, et al. Endoscopic variceal ligation compared with endoscopic injection sclerotherapy for treatment of esophageal variceal hemorrhage: a meta-analysis. World J Gastroenterol 2015;21(8):2534-41.

[20] Kapoor A, Dharel N, Sanyal AJ. Endoscopic diagnosis and therapy in gastroesophageal variceal bleeding. Gastrointest Endosc Clin N Am

[21] Maluf-Filho F, Sakai P, Ishioka S, et al. Endoscopic sclerosis versus cyanoacrylate endoscopic injection for the first episode of variceal

bleeding: a prospective, controlled, and randomized study in Child-Pugh class C patients. Endoscopy 2001;33(5):421-7.

[22] Azoulay D, Castaing D, Majno P, et al. Salvage transjugular intrahepatic portosystemic shunt for uncontrolled variceal bleeding in patients with decompensated cirrhosis. J Hepatol.

[23] Chesta FN, Rizvi ZH, Oberoi M, Buttar N. The role of stenting in patients with variceal bleeding. Techniques and Innovations in Gastrointestinal Endoscopy. 2020 Jul 23 (In press).

[24] Goenka MK, Goenka U, Tiwary IK, Rai V. Use of self-expanding metal stents for difficult variceal bleed. Indian J Gastroenterol. 2017 Nov 1;36(6):468-73.

[25] McCarty TR, Njei B: Self-expanding

metal stents for acute refractory esophageal variceal bleeding: A systematic review and meta-analysis. Dig Endosc 2016, 28(5):539-547.

[26] Maufa F, Al-Kawas FH: Role of self-expandable metal stents in acute

2015;25(3): 491-507.

2001;35:590-7.

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.

variceal bleeding. Int J Hepatol 2012,

[27] Kamal A, Abd Elmoety AA, Hamza Y, Zeid A. Endoscopic variceal ligation followed by argon plasma coagulation against endoscopic variceal ligation alone. J Clin Gastroenterol. 2017

[28] Li X, Jiang T, Gao J. Endoscopic variceal ligation combined with argon plasma coagulation versus ligation alone for the secondary prophylaxis of variceal bleeding: a systematic review and meta-analysis. Eur J Gastroenterol

[29] Sarin SK, Lahoti D, Saxena SP, et al. Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology

[30] de Franchis R, Primignani M. Natural history of portal hypertension in patients with cirrhosis. Clin Liver Dis

[31] Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and betablockers: a randomized controlled trial.

Therapondos G, Plevris JN, Hayes PC. Recent advances in the management of bleeding gastric varices Aliment. Pharmacol. Ther. 2006 Jul;24(1):1-7.

Gupta R. A randomized controlled trial of cyanoacrylate versus alcohol injection in patients with isolated fundic varices. Am J Gastroenterol. 2002;97(4):1010-5.

[34] Sarin SK. Long-term follow-up of gastric variceal sclerotherapy: an eleven year experience. Gastrointest Endosc

J Hepatol 2011; 54: 1161-1167.

[32] Tripathi D, Ferguson JW,

[33] Sarin SK, Jain AK, Jain M,

1997; 46: 8-14.

Hepatol 2017;29(6):621-8.

1992;16:1343-1349.

2001; 5: 645-63.

2012:418369-418369.

Jan 1;51(1):49-55.

**108**

[36] Lo GH, Lin CW, Tai CM, et al. A prospective, randomized trial of thrombin versus cyanoacrylate injection in the control of acute gastric variceal hemorrhage. Endoscopy. 2020.

[37] Nett A, Binmoeller KF. Endoscopic Management of Portal Hypertension– related Bleeding Gastrointest Endoscopy Clin N Am 29 (2019) 321-337.

[38] Weilert F, Binmoeller KF. Endoscopic management of gastric variceal bleeding. Gastroenterol Clin North Am 2014;43(4):807-18.

[39] Binmoeller KF, Weilert F, Shah JN, Kim J. EUS-guided transesophageal treatment of gastric fundal varices with combined coiling and cyanoacrylate glue injection (with videos). Gastrointest Endosc. 2011;74:1019-25.

[40] Mohan BP, Chandan S, Khan SR, et al. Efficacy and safety of endoscopic ultrasound-guided therapy versus direct endoscopic glue injection therapy for gastric varices: systematic review and meta-analysis. Endoscopy. 2020;52(4):259-67.

[41] HolIbrahim M, El-Mikkawy A, Hamid MA, et al. Early application of haemostatic powder added to standard management for oesophagogastric variceal bleeding: a randomised trial. Gut. 2019 1;68(5):844-53.

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

[43] Henry Z, Uppal D, Saad W, et al. Gastric and ectopic varices. Clin Liver Dis 2014;18:371-88.

[44] Orr DW, Harrison PM, Devlin J, et al. Chronic mesenteric venous

thrombosis: evaluation and determinants of survival during longterm follow-up. Clin Gastroenterol Hepatol 2007;5(1):80-6.

[45] Helmy A, Al Kahtani K, Al Fadda M. Updates in the pathogenesis, diagnosis and management of ectopic varices. Hepatol Int 2008;2(3):322-34.

[46] Park SW, Cho E, Jun CH, et al. Upper gastrointestinal ectopic variceal bleeding treated with various endoscopic modalities: case reports and literature review. Medicine (Baltimore) 2017;96(1):e5860.

[47] Goenka MK, Harwani Y, Rai V, Goenka U. Fully covered self-expandable metal biliary stent for hemobilia caused by portal biliopathy. Gastrointest Endosc. 2014 Dec 1;80(6):1175.

[48] Merli M, Nicolini G, Angeloni S, Gentili F, Attili AF, Riggio O. The natural history of portal hypertensive gastropathy in patients with liver cirrhosis and mild portal hypertension. Am J Gastroenterol. 2004;**99**:1959-654.

[49] D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44: 217-231.

[50] Primignani M, Carpinelli L, Preatoni P et al. Portal hypertensive gastropathy (PHG) in liver cirrhosis: natural history. A multicenter study by the New Italian Endoscopic Club (NIEC). J Gastroenterol 1996; 110: 1299.

[51] Herrera S, Bordas JM, Liach J et al. The beneficial effects of argon plasma coagulation in the management of different types of gastric vascular ectasia lesions in patients admitted for GI hemorrhage. Gastrointest Endosc 2008; 68: 440-446.

[52] Hanafy AS, El Hawary AT. Efficacy of argon plasma coagulation in the management of portal hypertensive

gastropathy. Endosc Int Open 2016;4(10):E1057-62.

[53] Smith LA, Morris AJ, Stanley AJ. The use of hemospray in portal hypertensive bleeding; a case series. J Hepatol 2014;60(2):457-60.

[54] Burak KW, Lee SS, Beck PL. Portal hypertensive gastropathy and gastric antral vascular ectasia (GAVE) syndrome. Gut 2001; 49: 866-872.

[55] Spahr L, Villeneuve JP, Dufresne MP, et al. Gastric antral vascular ectasia in cirrhotic patients: absence of relation with portal hypertension. Gut 1999; 44: 739-742.

[56] Thandassery RB, Jha AK, Goenka MK. Gastrointestinal radiofrequency ablation in the management of refractory gastric antral vascular eclasia. J Gastroenterol hepatol 2014; 29: 894

[57] Roman S, Saurin JC, Dumortier J, Perreira A, Bernard G, Ponchon T. Tolerance and efficacy of argon plasma coagulation for controlling bleeding in patients with typical and atypical manifestations of watermelon stomach. Endoscopy 2003; 35: 1024-1028.

[58] Yusoff I, Brennan F, Ormonde D, Laurence B. Argon plasma coagulation for treatment of watermelon stomach. Endoscopy 2002; 34: 407-410.

[59] Sebastian S, McLoughlin R, Qasim A, O'Morain CA, Buckley MJ. Endoscopic argon plasma coagulation for the treatment of gastric antral vascular ectasia (watermelon stomach): long-term results. Dig Liver Dis 2004; 36: 212-217.

[60] Wells CD, Harrison ME, Gurudu SR, Crowell MD, Byrne TJ, Depetris G, Sharma VK. Treatment of gastric antral vascular ectasia (watermelon stomach) with endoscopic band ligation. Gastrointest Endosc 2008; 68: 231-236.

[61] Elhendawy M, Mosaad S, Alkhalawany W, Abo-Ali L, Enaba M, Elsaka A, Elfert AA. Randomized controlled study of endoscopic band ligation and argon plasma coagulation in the treatment of gastric antral and fundal vascular ectasia. United European Gastroenterol. J.. 2016 Jun;4(3):423-8.

[62] Chandrasekar TS, Janakan GB, Chandrasekar VT, Kalamegam RY, Suriyanarayanan S, Sanjeevaraya PM. Spectrum of small-bowel mucosal identified by capsule endoscopy in patients with portal hypertension of varied etiology. Indian J Gastroenterol 2017;36:32-37.

[63] Akyuz F, Pinarbasi B, Ermis F, et al. Is portal hypertensive enteropathy an important additional cause of blood loss in portal hypertensive patients? J Gastroenterol 2010;45:1497-1502.

[64] Goenka MK, Shah BB, Rai VK, Jajodia S, Goenka U. Mucosal changes in the small intestines in portal hypertension: first study using the Pillcam SB3 capsule endoscopy system. Clin Endosc. 2018 Nov;51(6):563.

[65] Bresci G, Parisi G, Capria A. Clinical relevance of colonic lesions in cirrhotic patients with portal hypertension. Endoscopy. 2006; 38:830-5.

[66] Rabinovitz M, Schade RR, Dindzans VJ, et al. Colonic disease in cirrhosis. An endoscopic evaluation in 412 patients. Gastroenterology. 1990; 99:195-9.

[67] Chen LS, Lin HC, Lee FY, et al. Portal hypertensive colopathy in patients with cirrhosis. Scand J Gastroenterol. 1996; 31:490-4.

[68] Goenka M K, Kochhar R, Nagi B, Mehta S K. Rectosigmoid varices and other mucosal changes in patients with portal hypertension. Am J Gastroenterol 1991; 86 : 1185-9.

*Portal Hypertension - Recent Advances*

gastropathy. Endosc Int Open

bleeding; a case series. J Hepatol

[54] Burak KW, Lee SS, Beck PL. Portal hypertensive gastropathy and gastric antral vascular ectasia (GAVE) syndrome. Gut 2001; 49: 866-872.

[53] Smith LA, Morris AJ, Stanley AJ. The use of hemospray in portal hypertensive

[61] Elhendawy M, Mosaad S,

Alkhalawany W, Abo-Ali L, Enaba M, Elsaka A, Elfert AA. Randomized controlled study of endoscopic band ligation and argon plasma coagulation in the treatment of gastric antral and fundal vascular ectasia. United European Gastroenterol. J.. 2016 Jun;4(3):423-8.

[62] Chandrasekar TS, Janakan GB, Chandrasekar VT, Kalamegam RY, Suriyanarayanan S, Sanjeevaraya PM. Spectrum of small-bowel mucosal identified by capsule endoscopy in patients with portal hypertension of varied etiology. Indian J Gastroenterol

[63] Akyuz F, Pinarbasi B, Ermis F, et al. Is portal hypertensive enteropathy an important additional cause of blood loss in portal hypertensive patients? J Gastroenterol 2010;45:1497-1502.

[64] Goenka MK, Shah BB, Rai VK, Jajodia S, Goenka U. Mucosal changes in the small intestines in portal hypertension: first study using the Pillcam SB3 capsule endoscopy system. Clin Endosc. 2018 Nov;51(6):563.

[65] Bresci G, Parisi G, Capria A. Clinical relevance of colonic lesions in cirrhotic patients with portal hypertension. Endoscopy. 2006; 38:830-5.

[66] Rabinovitz M, Schade RR, Dindzans VJ, et al. Colonic disease in cirrhosis. An endoscopic evaluation in 412 patients. Gastroenterology. 1990;

[67] Chen LS, Lin HC, Lee FY, et al. Portal hypertensive colopathy in patients with cirrhosis. Scand J Gastroenterol. 1996; 31:490-4.

[68] Goenka M K, Kochhar R, Nagi B, Mehta S K. Rectosigmoid varices and other mucosal changes in patients with portal hypertension. Am J Gastroenterol

99:195-9.

1991; 86 : 1185-9.

2017;36:32-37.

[55] Spahr L, Villeneuve JP, Dufresne MP, et al. Gastric antral vascular ectasia in cirrhotic patients: absence of relation with portal hypertension. Gut 1999; 44:

[56] Thandassery RB, Jha AK, Goenka MK. Gastrointestinal radiofrequency ablation in the management of

refractory gastric antral vascular eclasia. J Gastroenterol hepatol 2014; 29: 894

[57] Roman S, Saurin JC, Dumortier J, Perreira A, Bernard G, Ponchon T. Tolerance and efficacy of argon plasma coagulation for controlling bleeding in patients with typical and atypical manifestations of watermelon stomach.

Endoscopy 2003; 35: 1024-1028.

Endoscopy 2002; 34: 407-410.

[60] Wells CD, Harrison ME, Gurudu SR, Crowell MD, Byrne TJ, Depetris G, Sharma VK. Treatment of gastric antral vascular ectasia

2008; 68: 231-236.

[58] Yusoff I, Brennan F, Ormonde D, Laurence B. Argon plasma coagulation for treatment of watermelon stomach.

[59] Sebastian S, McLoughlin R, Qasim A, O'Morain CA, Buckley MJ. Endoscopic argon plasma coagulation for the treatment of gastric antral vascular ectasia (watermelon stomach): long-term results. Dig Liver Dis 2004; 36: 212-217.

(watermelon stomach) with endoscopic band ligation. Gastrointest Endosc

2016;4(10):E1057-62.

2014;60(2):457-60.

739-742.

**110**

### *Edited by Xingshun Qi*

*Portal Hypertension - Recent Advances* discusses several important topics related to portal hypertension, such as pediatric portal hypertension, sinusoidal obstructions syndrome, endoscopy in the management of portal hypertension, and non-invasive assessment of esophageal varices, along with recent advances in the field.

Published in London, UK © 2021 IntechOpen © ISpiyaphong / iStock

Portal Hypertension - Recent Advances

Portal Hypertension

Recent Advances

*Edited by Xingshun Qi*