Ultrasound in Med. & Biol., Vol. 40, No. 9, pp. 2058–2063, 2014 Copyright Ó 2014 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2014.03.017
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Original Contribution ESOPHAGEAL VARIX PREDICTIVE PERFORMANCE OF LOWER ESOPHAGEAL DOPPLER SIGNALS DURING THE SWALLOWING PROCESS CHAO-XUE ZHANG,* XIAO-YONG XU,y LING WANG,* MENG HUANG,* and LIANG LI* * Department of Ultrasound, First Affiliated Hospital, Anhui Medical University, Anhui, China; and y Department of Gastroenterology, First Affiliated Hospital, Anhui Medical University, Anhui, China (Received 26 November 2013; revised 9 March 2014; in final form 12 March 2014)
Abstract—The objective of this study was to assess whether the swallowing action can improve the display of lower esophageal Doppler signals (LEDS) during transabdominal ultrasound (TUS). Eighty-four patients with cirrhosis underwent both TUS and endoscopic examination for esophageal varices (EVs). LEDS were assessed under the esophageal resting state and during the swallowing process. Univariate analysis indicated that spleen diameter, spleen vein diameter, portal vein diameter, LEDS and left gastric vein hepatofugal flow were significantly associated with the presence of EVs. No LEDS were detected in patients without EVs at rest or during swallowing. Of the 69 patients with EVs, LEDS could be detected in 21 cases (30.4%) in the esophageal resting state and in 58 cases (84.1%) during the swallowing process. Compared with the esophageal resting state, the swallowing action can significantly improve display of LEDS during TUS (p 5 0.000), which may be beneficial for TUS detection of EVs. (E-mail: [email protected]) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Esophageal varices, Doppler ultrasound, Cirrhosis.
et al. 2012; Yu et al. 2011), but their clinical value remains controversial. Transabdominal ultrasound (TUS), a non-invasive technique, provides a simple method of evaluating the abdominal esophagus (Chen et al. 1997). The diameter of medium or large EVs is greater than 5 mm, which can be easily detected by TUS in theory. However, to date, the diagnostic value of TUS in detecting EVs is still considered unsatisfactory. The resting pressure of the lower esophageal sphincter (LES) in most individuals varies from 10 to 40 mm Hg (Mittal et al. 1988). In addition, the EV pressure is similar: 15.5 to 25.6 mm Hg (Bosch et al. 1986; Kong et al. 2009; Pontes et al. 2002). Therefore, LES pressure may cause varices to be flattened or closed in the esophageal resting state (Schiano et al. 1998). Such a mechanism may be the reason for the low rate of display of EVs during TUS. During swallowing, the LES relaxes, and LES pressure decreases significantly, even to 0 mm Hg (Fornari et al. 2009; Goyal and Chaudhury 2008; Mittal et al. 1995). One study reported that the varices initially increased in size, subsequently decreased in size and later flattened, closed and opened sequentially during swallowing, with a mean variceal cross-sectional area increase of 41% above baseline (Miller et al. 2004). TUS may be beneficial for the detection of EVs.
INTRODUCTION Esophageal varices (EVs) are the most important portosystemic collaterals, because their rupture results in esophageal varix bleeding, which is the most common lethal complication of cirrhosis. EVs are present in approximately 50% of patients with cirrhosis, and the incidence of EVs is increasing by approximately 5% to 8% per year (Groszmann et al. 2005; Merli et al. 2003; Murachima et al. 2001). The gold standard in the diagnosis of EVs is endoscopy. A number of practice guidelines recommend periodic endoscopic examination of patients with cirrhosis for varices (Garcia-Tsao et al. 2007; Jalan and Hayes 2000). These recommendations imply a considerable burden for endoscopy units and an increased number of unpleasant procedures for patients. To reduce the frequency of endoscopies in patients with cirrhosis, many researchers have evaluated possible non-invasive markers of EVs (Adithan et al. 2010; Chen et al. 2012; Joseph et al. 2011; Lipp et al. 2011; Sporea et al. 2011; Stefanescu et al. 2011; Tamano et al. 2004; Ying
Address correspondence to: Chao-Xue Zhang, Department of Ultrasound, First Affiliated Hospital, Anhui Medical University, 218 Jixi Road, Hefei, Anhui 230022, China. E-mail: [email protected] 2058
Lower esophageal Doppler signals during swallowing d C.-X. ZHANG et al.
In this study, we attempted to identify the ultrasonographic parameters associated with the presence of EVs and to assess whether the swallowing action can improve the TUS display of lower esophageal Doppler signals (LEDS). METHODS Patients This study population consisted of 84 patients with cirrhosis (57 men and 27 women, median age 5 52 y, range: 30–74 y). The patients were diagnosed on the basis of standard clinical, imaging, endoscopic examination and biochemical parameters. In addition, the patients were classified according to Child-Pugh criteria. The patients were recruited consecutively at the Gastroenterology, Infectious Diseases and General Surgery departments of our hospital between August 3, 2012 and July 31, 2013. The exclusion criteria included previous operative treatment for portal hypertension and previous endoscopic sclerosis or band ligation of EVs. The study was approved by the institutional ethics committee of our hospital and was conducted according to the principles of the Declaration of Helsinki. The nature of the study was explained to the patients, each of whom provided written informed consent before beginning of the study. Gastroesophageal endoscopy Gastroesophageal endoscopy was performed by X. Y. Xu in a single endoscopy unit using an Olympus GIF-XQ 260 video endoscope (Olympus, Beijing, China), and EVs were classified as present or absent according to the same criteria: EVs were classified as present when there were elevated veins above the esophageal mucosal surface irrespective of size or shape. Large varices were defined as those occupying more than one-third of the esophageal lumen. Ultrasound Ultrasound examination was performed using a GE Logiq 7 system (General Electric Healthcare Medical Systems, Milwaukee, WI, USA) and a 4C convex-arrayed transducer with a frequency of 3–6 MHz. All patients were given a TUS examination within one wk after gastroesophageal endoscopy. Ultrasound examinations were performed by C. X. Zhang or M. Huang, who have more than 10 y of ultrasound experience and were blinded to the endoscopy findings. All patients fasted overnight before TUS examination. First, spleen diameter, spleen vein diameter, portal vein diameter, portal vein velocity and left gastric vein hepatofugal flow were evaluated via TUS. (i) Portal vein velocity was measured in the midportion, where the hepatic artery crosses the portal vein. The angle be-
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tween the long axis of the portal vein and the Doppler beam was less than 60 . (ii) Portal vein diameter was measured in the longitudinal section, at the exact site in the portal vein midportion. (iii) Spleen diameter was the maximum length of the poles on oblique subcostal scans. (iv) Spleen vein diameter was measured in the longitudinal section at the hilum of the spleen. (v) The left gastric vein was identified as a vessel communicating with the superior aspect of the portal or splenic vein in the region of the confluence. Hepatofugal flow was defined as the blood flow away from the portal vein. The LEDS of the patients were then evaluated. After visualization of the lower esophagus under normal Bmode scanning, color Doppler flow imaging was used to detect LEDS in the esophageal resting state (defined as LEDS—resting). Next, patients were asked to swallow a bolus of water. The LEDS were detected again immediately before the water reached the lower esophagus (defined as LEDS—swallowing). To visualize the lower esophagus clearly, all patients were examined in the supine position and right anterior oblique. A few patients were given 500 mL of water to distend the stomach. The Doppler ultrasound settings had to be optimized for slow blood flow detection. Optimization included the lowest wall filter and the highest Doppler gain possible without flash artifacts and the lowest possible pulse repetition frequency without aliasing. These technical approaches were kept constant for all examinations. Moreover, ultrasound settings remained unchanged for the same patient when LEDS were detected in the resting state or during swallowing. Spectral analysis was performed on a few patients to identify the continuous venous flow or noise signal. The platelet count/spleen bipolar diameter ratio was also calculated for all patients. Statistical analysis Statistical analysis was performed with SPSS 15.0 software (SPSS, Chicago, IL, USA). Comparisons between groups were performed using the c2 test for qualitative data and Student’s t-test for quantitative data. A p-value , 0.05 was considered to indicate a significant difference. All variables found to be of significance by univariate analysis were included as candidate variables in a logistic regression analysis to identify independent predictors of the presence of EVs. RESULTS The intra-abdominal esophagus appeared longitudinally as a curving tubular structure with inner hyper-echoic and outer hypo-echoic layers. LEDS were expressed as short cordlike or continuous color signals in the esophageal wall and lumen (Fig. 1). The left gastric vein exhibits hepatopetal blood flow normally
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Fig. 1. Ultrasonographic images of lower esophagus and lower esophageal Doppler signals. (a) The lower esophagus appears longitudinally as a curving tubular structure with inner hyper-echoic and outer hypo-echoic layers. (b) There are no lower esophageal Doppler signals in the esophageal wall and lumen. (c) There are continuous lower esophageal Doppler signals in the esophageal wall and lumen during swallowing.
and usually exhibits hepatofugal flow in cirrhosis patients with EVs (Fig. 2). Esophageal varices were detected in 69 of 84 patients (82.1%) by endoscopy, and 57 patients had large EVs (67.9%). Among these 84 patients, 40 were ChildPugh class A (47.6%), 38 class B (45.2%) and 6 class C (7.1%). Forty-three patients had ascites (51.2%). Table 1 summarizes the clinical, biochemical and ultrasonographic characteristics of the patients stratified by the presence of EVs. According to the univariate analysis, spleen diameter, spleen vein diameter, portal vein diameter, LEDS, left gastric vein hepatofugal flow and platelet count/ spleen diameter ratio were significantly associated with the presence of EVs (see Table 1). Spleen diameter, spleen vein diameter and portal vein diameter were significantly larger in the EV group than in the non-EV group. The platelet count/spleen diameter ratio was significantly lower in the EV group than in the non-EV group. The frequencies of detection of left gastric vein hepatofugal flow and LEDS were significantly higher in patients with EVs than in those without EVs. There were no significant differences between the two groups with respect to platelet count, portal vein velocity, Child-Pugh score and other biochemical parameters. Multivariate analysis was performed using logistic regression analysis for all variables that differed signifi-
cantly between the EV and non-EV groups. The presence of EVs was significantly associated with a spleen diameter .160 mm (odds ratio [OR] 5 4.5, 95% CI: 1.8–10.4, p 5 0.012); spleen vein diameter .9.5 mm (OR 5 4.2, 95% CI: 1.3–12.1, p 5 0.004); platelet count/spleen diameter ratio ,680 (OR 5 2.2, 95% CI: 1.1–6.7, p 5 0.000); and portal vein diameter .13.8 mm (OR 5 4.1, 95% CI: 1.7–8.4, p 5 0.024). Lower esophageal Doppler signals were not detected in the patients without EVs at rest or during swallowing. Compared with the resting state, swallowing significantly improved the display of LEDS on TUS in patients with EVs (p 5 0.000). Of the 69 patients with EVs, LEDS were observed in 21 cases (30.4%) during esophageal resting and in 58 cases (84.1%) during swallowing. Among these 84 patients, there were 52 (75.4%) patients with left gastric vein hepatofugal flow. On the contrary, there were no patients with left gastric vein hepatofugal flow in the non-EV group. These results indicate that LEDS and left gastric vein hepatofugal flow have high specificity in the diagnosis of EV. DISCUSSION To reduce the frequency of endoscopies in patients with cirrhosis, many studies have evaluated possible
Lower esophageal Doppler signals during swallowing d C.-X. ZHANG et al.
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Fig. 2. Ultrasonographic images of left gastric vein. (a) A dilated left gastric vein (white arrow) connects with the portal vein (black arrow) in this gray-scale image. (b) The hepatofugal blood flow in the left gastric vein (white arrow) appears red in patients with esophageal varices.
non-invasive markers of EVs, even though the clinical value of these markers is controversial. As a non-invasive technique, TUS has played an important role in the estimation of cirrhosis and portal hypertension. Although detection of the abdominal esophagus by TUS is limited by the lungs, sternum and gas in the stomach, gastroesophageal reflux disease, esophageal achalasia and esophageal carcinoma have been detected by TUS (Eckardt et al. 2004; Koumanidou et al. 2004; Sezgin et al. 2001). The lower esophageal display can be improved by changing the TUS inspection methods (Chen et al. 1997). Many studies have reported that TUS can provide useful information in detecting EVs by evaluating aspects of the abdominal esophageal wall,
such as its thickness and pattern (Baek and Lee 2001; Kishimoto et al. 1998; Saverymuttu et al. 1988; Tamano et al. 2004). Baek and Lee (2001) reported that the display rate of the Doppler signal flow in the distal esophageal wall was very low, and the presence of Doppler signal flow was observed in only eight (20%) patients in their research. This finding may be related to the high pressure caused by LES and the low flow velocity of EVs. In our study, there were 69 cases with EVs diagnosed by endoscopy among the 84 patients with cirrhosis. LEDS were displayed in only 21 cases (30.4%) in the esophageal resting state and in 58 cases (84.1%) during swallowing. Compared with the esophageal resting state,
Table 1. Characteristics of patients stratified by the presence of esophageal varices Variable
No EVs (n 5 15)
With EVs (n 5 69)
p-Value
Gender (male) Age (y) Etiology (HBV/alcohol/other) Child-Pugh score Platelet count ( 3 103/mm3) Spleen diameter (mm) Spleen vein diameter (mm) Platelet count/spleen diameter Portal vein diameter (mm) Portal vein velocity (cm/s) Lower esophageal Doppler signals Resting state During swallowing Left gastric vein hepatofugal flow
73% 54 (39–74) 13/0/2 6.7 (5–11) 90 (26–229) 136 (77–220) 8.1 (5–15) 774 (170–2160) 12.6 (9–16) 18.5 (8.8–26.6)
67% 51 (30–74) 41/7/21 7.0 (5–12) 62 (23–260) 173 (104–260) 11.7 (5–22) 398 (105–2281) 14.7 (11–24) 16.3 (8.7–31)
0.616 0.305 0.119 0.644 0.080 0.001 0.001 0.032 0.003 0.130
21 (30.4%) 58 (84.1%) 52 (75.4%)
0.014 ,0.0001 ,0.0001
0 (0%) 0 (0%) 0 (0%)
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swallowing can significantly improve the display of LEDS during TUS (p 5 0.000). The swallowing action triggers LES relaxation, which results in varicose vein dilation and blood flow acceleration. The dilated varicose veins and accelerated blood flow are more easily detected by TUS. Thus, swallowing may be beneficial for detection of EVs with TUS. Furthermore, spleen diameter, spleen vein diameter, portal vein diameter, left gastric vein hepatofugal flow and platelet count/spleen diameter ratio were significantly associated with the presence of EVs in our study. However, the cutoff values of these parameters remain controversial. Indeed, previous findings indicate that different machines and their software settings will affect the sensitivity of Doppler US, and this variability may also affect the resolution of Doppler signals in the distal esophagus. Therefore, to improve resolution, we optimized Doppler US settings to detect slow blood flow. Moreover, training programs and experience can partially avoid inter-equipment and inter-observer variability (Sabba et al. 1995; Sacerdoti et al. 1997). This report describes a pilot study, and there are several limitations, including patient selection bias and higher prevalence of varices and ascites. The present study is only a retrospective analysis. A larger, multicenter study is warranted to validate the results and to assess the clinical value of the study results. CONCLUSIONS Upper gastrointestinal endoscopy remains the gold standard for diagnosis of EVs. Our study indicates that the swallowing action can significantly improve the display of LEDS during TUS compared with the esophageal resting state. This method may be a supplement or screening tool for the detection of EVs, especially medium or large EVs, which may reduce the frequency of endoscopy in patients without a significant risk for EVs. Acknowledgments—We acknowledge financial support from the Provincial Natural Science Research Program of Higher Education Institutions of Anhui Province (KJ2013A151).—We are very grateful to the staff of the Departments of Gastroenterology, Infectious Diseases and General Surgery at the First Affiliated Hospital of Anhui Medical University for their support and help. We thank all the patients and volunteers who participated in this study.
SUPPLEMENTARY DATA Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.ultrasmedbio.2014.03.017.
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Volume 40, Number 9, 2014 with portal hypertension and its correlation with esophageal varices and variceal bleed. Indian J Radiol Imaging 2010;20:289–293. Baek SY, Lee SW. Transabdominal US evaluation of esophageal varices: As a prospective screening test. J Korean Soc Med Ultrasound 2001; 20:29–35. Bosch J, Bordas JM, Rigau J, Viola C, Mastai R, Kravetz D, Navasa M, Rodes J. Noninvasive measurement of the pressure of esophageal varices using an endoscopic gauge: Comparison with measurements by variceal puncture in patients undergoing endoscopic sclerotherapy. Hepatology 1986;6:667–672. Chen MH, Kikuchi Y, Chu BC, Kishimoto R, Choji K, Miyasaka K. Demonstration of the distal end of the oesophagus by transabdominal ultrasound. Br J Radiol 1997;70:1215–1221. Chen YP, Zhang Q, Dai L, Liang XE, Peng J, Hou JL. Is transient elastography valuable for high-risk esophageal varices prediction in patients with hepatitis-B-related cirrhosis? J Gastroenterol Hepatol 2012;27:533–539. Eckardt VF, Schmitt T, Kanzler G. Transabdominal ultrasonography in achalasia. Scand J Gastroenterol 2004;39:634–637. Fornari F, Bravi I, Penagini R, Tack J, Sifrim D. Multiple rapid swallowing: A complementary test during standard oesophageal manometry. Neurogastroenterol Motil 2009;21:718-e41. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922–938. Goyal RK, Chaudhury A. Physiology of normal esophageal motility. J Clin Gastroenterol 2008;42:610–619. Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS, Gao H, Makuch R. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;353:2254–2261. Jalan R, Hayes PC. UK guidelines on the management of variceal haemorrhage in cirrhotic patients. British Society of Gastroenterology. Gut 2000;46(Suppl 3–4):III1–III15. Joseph T, Madhavan M, Devadas K, Ramakrishnannair VK. Doppler assessment of hepatic venous waves for predicting large varices in cirrhotic patients. Saudi J Gastroenterol 2011;17:36–39. Kishimoto R, Chen M, Ogawa H, Wakabayashi MN, Kogutt MS. Esophageal varices: Evaluation with transabdominal US. Radiology 1998; 206:647–650. Kong DR, Xu JM, Zhang L, Zhang C, Fu ZQ, He BB, Sun B, Xie Y. Computerized endoscopic balloon manometry to detect esophageal variceal pressure. Endoscopy 2009;41:415–420. Koumanidou C, Vakaki M, Pitsoulakis G, Anagnostara A, Mirilas P. Sonographic measurement of the abdominal esophagus length in infancy: A diagnostic tool for gastroesophageal reflux. AJR Am J Roentgenol 2004;183:801–807. Lipp MJ, Broder A, Hudesman D, Suwandhi P, Okon SA, Horowitz M, Clain DJ, Friedmann P, Min AD. Detection of esophageal varices using CT and MRI. Dig Dis Sci 2011;56:2696–2700. Merli M, Nicolini G, Angeloni S, Rinaldi V, De Santis A, Merkel C, Attili AF, Riggio O. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003;38:266–272. Miller LS, Kim JK, Dai Q, Mekapati J, Izanec J, Chung C, Liu JB, Sanderson A, Bohning M, Desipio J, Gandegok J, Harberson JJ, Schneck C, Nicosia MA, Thangada V, Thomas B, Copeland B, Miller E, Miller A, Ahmed N, Brasseur JG. Mechanics and hemodynamics of esophageal varices during peristaltic contraction. Am J Physiol Gastrointest Liver Physiol 2004;287:G830–G835. Mittal RK, Holloway RH, Penagini R, Blackshaw LA, Dent J. Transient lower esophageal sphincter relaxation. Gastroenterology 1995;109: 601–610. Mittal RK, Rochester DF, McCallum RW. Electrical and mechanical activity in the human lower esophageal sphincter during diaphragmatic contraction. J Clin Invest 1988;81:1182–1189. Murachima N, Ikeda K, Kobayashi M, Saitoh S, Chayama K, Tsubota A, Suzuki Y, Suzuki F, Arase Y, Kumada H. Incidence of the appearance of the red color sign on esophageal varices and its predictive factors: Long-term observations of 359 patients with cirrhosis. J Gastroenterol 2001;36:368–374.
Lower esophageal Doppler signals during swallowing d C.-X. ZHANG et al. Pontes JM, Leitao MC, Portela F, Nunes A, Freitas D. Endosonographic Doppler-guided manometry of esophageal varices: Experimental validation and clinical feasibility. Endoscopy 2002;34:966–972. Sabba C, Merkel C, Zoli M, Ferraioli G, Gaiani S, Sacerdoti D, Bolondi L. Interobserver and interequipment variability of echoDoppler examination of the portal vein: Effect of a cooperative training program. Hepatology 1995;21:428–433. Sacerdoti D, Gaiani S, Buonamico P, Merkel C, Zoli M, Bolondi L, Sabba C. Interobserver and interequipment variability of hepatic, splenic, and renal arterial Doppler resistance indices in normal patients and patients with cirrhosis. J Hepatol 1997;27:986–992. Saverymuttu SH, Wright J, Maxwell JD, Joseph AE. Ultrasound detection of oesophageal varices: Comparison with endoscopy. Clin Radiol 1988;39:513–515. Schiano TD, McCray WH, Liu JB, Baranowski RJ, Bellary SV, Black M, Miller LS. In vivo comparison of esophageal varices at and above the diaphragmatic high pressure zone using high resolution endoluminal sonography. J Clin Gastroenterol 1998;26:249–252. Sezgin O, Ulker A, Temucin G. Sonographic findings in achalasia. J Clin Ultrasound 2001;29:31–40.
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Sporea I, Ratiu I, Sirli R, Popescu A, Bota S. Value of transient elastography for the prediction of variceal bleeding. World J Gastroenterol 2011;17:2206–2210. Stefanescu H, Grigorescu M, Lupsor M, Maniu A, Crisan D, Procopet B, Feier D, Badea R. A new and simple algorithm for the non-invasive assessment of esophageal varices in cirrhotic patients using serum fibrosis markers and transient elastography. J Gastrointestin Liver Dis 2011;20:57–64. Tamano M, Yoneda M, Kojima K, Hashimoto T, Murohisa T, Majima Y, Kusano K, Nakamura T, Sugaya H, Terano A. Evaluation of esophageal varices using contrast-enhanced coded harmonic ultrasonography. J Gastroenterol Hepatol 2004;19:572–575. Ying L, Lin X, Xie ZL, Hu YP, Shi KQ. Performance of platelet count/ spleen diameter ratio for diagnosis of esophageal varices in cirrhosis: A meta-analysis. Dig Dis Sci 2012;57:1672–1681. Yu NC, Margolis D, Hsu M, Raman SS, Lu DS. Detection and grading of esophageal varices on liver CT: Comparison of standard and thinsection multiplanar reconstructions in diagnostic accuracy. AJR Am J Roentgenol 2011;197:643–649.
http://dx.doi.org/10.1016/j.ultrasmedbio.2014.03.017
d
Original Contribution ESOPHAGEAL VARIX PREDICTIVE PERFORMANCE OF LOWER ESOPHAGEAL DOPPLER SIGNALS DURING THE SWALLOWING PROCESS CHAO-XUE ZHANG,* XIAO-YONG XU,y LING WANG,* MENG HUANG,* and LIANG LI* * Department of Ultrasound, First Affiliated Hospital, Anhui Medical University, Anhui, China; and y Department of Gastroenterology, First Affiliated Hospital, Anhui Medical University, Anhui, China (Received 26 November 2013; revised 9 March 2014; in final form 12 March 2014)
Abstract—The objective of this study was to assess whether the swallowing action can improve the display of lower esophageal Doppler signals (LEDS) during transabdominal ultrasound (TUS). Eighty-four patients with cirrhosis underwent both TUS and endoscopic examination for esophageal varices (EVs). LEDS were assessed under the esophageal resting state and during the swallowing process. Univariate analysis indicated that spleen diameter, spleen vein diameter, portal vein diameter, LEDS and left gastric vein hepatofugal flow were significantly associated with the presence of EVs. No LEDS were detected in patients without EVs at rest or during swallowing. Of the 69 patients with EVs, LEDS could be detected in 21 cases (30.4%) in the esophageal resting state and in 58 cases (84.1%) during the swallowing process. Compared with the esophageal resting state, the swallowing action can significantly improve display of LEDS during TUS (p 5 0.000), which may be beneficial for TUS detection of EVs. (E-mail: [email protected]) Ó 2014 World Federation for Ultrasound in Medicine & Biology. Key Words: Esophageal varices, Doppler ultrasound, Cirrhosis.
et al. 2012; Yu et al. 2011), but their clinical value remains controversial. Transabdominal ultrasound (TUS), a non-invasive technique, provides a simple method of evaluating the abdominal esophagus (Chen et al. 1997). The diameter of medium or large EVs is greater than 5 mm, which can be easily detected by TUS in theory. However, to date, the diagnostic value of TUS in detecting EVs is still considered unsatisfactory. The resting pressure of the lower esophageal sphincter (LES) in most individuals varies from 10 to 40 mm Hg (Mittal et al. 1988). In addition, the EV pressure is similar: 15.5 to 25.6 mm Hg (Bosch et al. 1986; Kong et al. 2009; Pontes et al. 2002). Therefore, LES pressure may cause varices to be flattened or closed in the esophageal resting state (Schiano et al. 1998). Such a mechanism may be the reason for the low rate of display of EVs during TUS. During swallowing, the LES relaxes, and LES pressure decreases significantly, even to 0 mm Hg (Fornari et al. 2009; Goyal and Chaudhury 2008; Mittal et al. 1995). One study reported that the varices initially increased in size, subsequently decreased in size and later flattened, closed and opened sequentially during swallowing, with a mean variceal cross-sectional area increase of 41% above baseline (Miller et al. 2004). TUS may be beneficial for the detection of EVs.
INTRODUCTION Esophageal varices (EVs) are the most important portosystemic collaterals, because their rupture results in esophageal varix bleeding, which is the most common lethal complication of cirrhosis. EVs are present in approximately 50% of patients with cirrhosis, and the incidence of EVs is increasing by approximately 5% to 8% per year (Groszmann et al. 2005; Merli et al. 2003; Murachima et al. 2001). The gold standard in the diagnosis of EVs is endoscopy. A number of practice guidelines recommend periodic endoscopic examination of patients with cirrhosis for varices (Garcia-Tsao et al. 2007; Jalan and Hayes 2000). These recommendations imply a considerable burden for endoscopy units and an increased number of unpleasant procedures for patients. To reduce the frequency of endoscopies in patients with cirrhosis, many researchers have evaluated possible non-invasive markers of EVs (Adithan et al. 2010; Chen et al. 2012; Joseph et al. 2011; Lipp et al. 2011; Sporea et al. 2011; Stefanescu et al. 2011; Tamano et al. 2004; Ying
Address correspondence to: Chao-Xue Zhang, Department of Ultrasound, First Affiliated Hospital, Anhui Medical University, 218 Jixi Road, Hefei, Anhui 230022, China. E-mail: [email protected] 2058
Lower esophageal Doppler signals during swallowing d C.-X. ZHANG et al.
In this study, we attempted to identify the ultrasonographic parameters associated with the presence of EVs and to assess whether the swallowing action can improve the TUS display of lower esophageal Doppler signals (LEDS). METHODS Patients This study population consisted of 84 patients with cirrhosis (57 men and 27 women, median age 5 52 y, range: 30–74 y). The patients were diagnosed on the basis of standard clinical, imaging, endoscopic examination and biochemical parameters. In addition, the patients were classified according to Child-Pugh criteria. The patients were recruited consecutively at the Gastroenterology, Infectious Diseases and General Surgery departments of our hospital between August 3, 2012 and July 31, 2013. The exclusion criteria included previous operative treatment for portal hypertension and previous endoscopic sclerosis or band ligation of EVs. The study was approved by the institutional ethics committee of our hospital and was conducted according to the principles of the Declaration of Helsinki. The nature of the study was explained to the patients, each of whom provided written informed consent before beginning of the study. Gastroesophageal endoscopy Gastroesophageal endoscopy was performed by X. Y. Xu in a single endoscopy unit using an Olympus GIF-XQ 260 video endoscope (Olympus, Beijing, China), and EVs were classified as present or absent according to the same criteria: EVs were classified as present when there were elevated veins above the esophageal mucosal surface irrespective of size or shape. Large varices were defined as those occupying more than one-third of the esophageal lumen. Ultrasound Ultrasound examination was performed using a GE Logiq 7 system (General Electric Healthcare Medical Systems, Milwaukee, WI, USA) and a 4C convex-arrayed transducer with a frequency of 3–6 MHz. All patients were given a TUS examination within one wk after gastroesophageal endoscopy. Ultrasound examinations were performed by C. X. Zhang or M. Huang, who have more than 10 y of ultrasound experience and were blinded to the endoscopy findings. All patients fasted overnight before TUS examination. First, spleen diameter, spleen vein diameter, portal vein diameter, portal vein velocity and left gastric vein hepatofugal flow were evaluated via TUS. (i) Portal vein velocity was measured in the midportion, where the hepatic artery crosses the portal vein. The angle be-
2059
tween the long axis of the portal vein and the Doppler beam was less than 60 . (ii) Portal vein diameter was measured in the longitudinal section, at the exact site in the portal vein midportion. (iii) Spleen diameter was the maximum length of the poles on oblique subcostal scans. (iv) Spleen vein diameter was measured in the longitudinal section at the hilum of the spleen. (v) The left gastric vein was identified as a vessel communicating with the superior aspect of the portal or splenic vein in the region of the confluence. Hepatofugal flow was defined as the blood flow away from the portal vein. The LEDS of the patients were then evaluated. After visualization of the lower esophagus under normal Bmode scanning, color Doppler flow imaging was used to detect LEDS in the esophageal resting state (defined as LEDS—resting). Next, patients were asked to swallow a bolus of water. The LEDS were detected again immediately before the water reached the lower esophagus (defined as LEDS—swallowing). To visualize the lower esophagus clearly, all patients were examined in the supine position and right anterior oblique. A few patients were given 500 mL of water to distend the stomach. The Doppler ultrasound settings had to be optimized for slow blood flow detection. Optimization included the lowest wall filter and the highest Doppler gain possible without flash artifacts and the lowest possible pulse repetition frequency without aliasing. These technical approaches were kept constant for all examinations. Moreover, ultrasound settings remained unchanged for the same patient when LEDS were detected in the resting state or during swallowing. Spectral analysis was performed on a few patients to identify the continuous venous flow or noise signal. The platelet count/spleen bipolar diameter ratio was also calculated for all patients. Statistical analysis Statistical analysis was performed with SPSS 15.0 software (SPSS, Chicago, IL, USA). Comparisons between groups were performed using the c2 test for qualitative data and Student’s t-test for quantitative data. A p-value , 0.05 was considered to indicate a significant difference. All variables found to be of significance by univariate analysis were included as candidate variables in a logistic regression analysis to identify independent predictors of the presence of EVs. RESULTS The intra-abdominal esophagus appeared longitudinally as a curving tubular structure with inner hyper-echoic and outer hypo-echoic layers. LEDS were expressed as short cordlike or continuous color signals in the esophageal wall and lumen (Fig. 1). The left gastric vein exhibits hepatopetal blood flow normally
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Fig. 1. Ultrasonographic images of lower esophagus and lower esophageal Doppler signals. (a) The lower esophagus appears longitudinally as a curving tubular structure with inner hyper-echoic and outer hypo-echoic layers. (b) There are no lower esophageal Doppler signals in the esophageal wall and lumen. (c) There are continuous lower esophageal Doppler signals in the esophageal wall and lumen during swallowing.
and usually exhibits hepatofugal flow in cirrhosis patients with EVs (Fig. 2). Esophageal varices were detected in 69 of 84 patients (82.1%) by endoscopy, and 57 patients had large EVs (67.9%). Among these 84 patients, 40 were ChildPugh class A (47.6%), 38 class B (45.2%) and 6 class C (7.1%). Forty-three patients had ascites (51.2%). Table 1 summarizes the clinical, biochemical and ultrasonographic characteristics of the patients stratified by the presence of EVs. According to the univariate analysis, spleen diameter, spleen vein diameter, portal vein diameter, LEDS, left gastric vein hepatofugal flow and platelet count/ spleen diameter ratio were significantly associated with the presence of EVs (see Table 1). Spleen diameter, spleen vein diameter and portal vein diameter were significantly larger in the EV group than in the non-EV group. The platelet count/spleen diameter ratio was significantly lower in the EV group than in the non-EV group. The frequencies of detection of left gastric vein hepatofugal flow and LEDS were significantly higher in patients with EVs than in those without EVs. There were no significant differences between the two groups with respect to platelet count, portal vein velocity, Child-Pugh score and other biochemical parameters. Multivariate analysis was performed using logistic regression analysis for all variables that differed signifi-
cantly between the EV and non-EV groups. The presence of EVs was significantly associated with a spleen diameter .160 mm (odds ratio [OR] 5 4.5, 95% CI: 1.8–10.4, p 5 0.012); spleen vein diameter .9.5 mm (OR 5 4.2, 95% CI: 1.3–12.1, p 5 0.004); platelet count/spleen diameter ratio ,680 (OR 5 2.2, 95% CI: 1.1–6.7, p 5 0.000); and portal vein diameter .13.8 mm (OR 5 4.1, 95% CI: 1.7–8.4, p 5 0.024). Lower esophageal Doppler signals were not detected in the patients without EVs at rest or during swallowing. Compared with the resting state, swallowing significantly improved the display of LEDS on TUS in patients with EVs (p 5 0.000). Of the 69 patients with EVs, LEDS were observed in 21 cases (30.4%) during esophageal resting and in 58 cases (84.1%) during swallowing. Among these 84 patients, there were 52 (75.4%) patients with left gastric vein hepatofugal flow. On the contrary, there were no patients with left gastric vein hepatofugal flow in the non-EV group. These results indicate that LEDS and left gastric vein hepatofugal flow have high specificity in the diagnosis of EV. DISCUSSION To reduce the frequency of endoscopies in patients with cirrhosis, many studies have evaluated possible
Lower esophageal Doppler signals during swallowing d C.-X. ZHANG et al.
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Fig. 2. Ultrasonographic images of left gastric vein. (a) A dilated left gastric vein (white arrow) connects with the portal vein (black arrow) in this gray-scale image. (b) The hepatofugal blood flow in the left gastric vein (white arrow) appears red in patients with esophageal varices.
non-invasive markers of EVs, even though the clinical value of these markers is controversial. As a non-invasive technique, TUS has played an important role in the estimation of cirrhosis and portal hypertension. Although detection of the abdominal esophagus by TUS is limited by the lungs, sternum and gas in the stomach, gastroesophageal reflux disease, esophageal achalasia and esophageal carcinoma have been detected by TUS (Eckardt et al. 2004; Koumanidou et al. 2004; Sezgin et al. 2001). The lower esophageal display can be improved by changing the TUS inspection methods (Chen et al. 1997). Many studies have reported that TUS can provide useful information in detecting EVs by evaluating aspects of the abdominal esophageal wall,
such as its thickness and pattern (Baek and Lee 2001; Kishimoto et al. 1998; Saverymuttu et al. 1988; Tamano et al. 2004). Baek and Lee (2001) reported that the display rate of the Doppler signal flow in the distal esophageal wall was very low, and the presence of Doppler signal flow was observed in only eight (20%) patients in their research. This finding may be related to the high pressure caused by LES and the low flow velocity of EVs. In our study, there were 69 cases with EVs diagnosed by endoscopy among the 84 patients with cirrhosis. LEDS were displayed in only 21 cases (30.4%) in the esophageal resting state and in 58 cases (84.1%) during swallowing. Compared with the esophageal resting state,
Table 1. Characteristics of patients stratified by the presence of esophageal varices Variable
No EVs (n 5 15)
With EVs (n 5 69)
p-Value
Gender (male) Age (y) Etiology (HBV/alcohol/other) Child-Pugh score Platelet count ( 3 103/mm3) Spleen diameter (mm) Spleen vein diameter (mm) Platelet count/spleen diameter Portal vein diameter (mm) Portal vein velocity (cm/s) Lower esophageal Doppler signals Resting state During swallowing Left gastric vein hepatofugal flow
73% 54 (39–74) 13/0/2 6.7 (5–11) 90 (26–229) 136 (77–220) 8.1 (5–15) 774 (170–2160) 12.6 (9–16) 18.5 (8.8–26.6)
67% 51 (30–74) 41/7/21 7.0 (5–12) 62 (23–260) 173 (104–260) 11.7 (5–22) 398 (105–2281) 14.7 (11–24) 16.3 (8.7–31)
0.616 0.305 0.119 0.644 0.080 0.001 0.001 0.032 0.003 0.130
21 (30.4%) 58 (84.1%) 52 (75.4%)
0.014 ,0.0001 ,0.0001
0 (0%) 0 (0%) 0 (0%)
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Ultrasound in Medicine and Biology
swallowing can significantly improve the display of LEDS during TUS (p 5 0.000). The swallowing action triggers LES relaxation, which results in varicose vein dilation and blood flow acceleration. The dilated varicose veins and accelerated blood flow are more easily detected by TUS. Thus, swallowing may be beneficial for detection of EVs with TUS. Furthermore, spleen diameter, spleen vein diameter, portal vein diameter, left gastric vein hepatofugal flow and platelet count/spleen diameter ratio were significantly associated with the presence of EVs in our study. However, the cutoff values of these parameters remain controversial. Indeed, previous findings indicate that different machines and their software settings will affect the sensitivity of Doppler US, and this variability may also affect the resolution of Doppler signals in the distal esophagus. Therefore, to improve resolution, we optimized Doppler US settings to detect slow blood flow. Moreover, training programs and experience can partially avoid inter-equipment and inter-observer variability (Sabba et al. 1995; Sacerdoti et al. 1997). This report describes a pilot study, and there are several limitations, including patient selection bias and higher prevalence of varices and ascites. The present study is only a retrospective analysis. A larger, multicenter study is warranted to validate the results and to assess the clinical value of the study results. CONCLUSIONS Upper gastrointestinal endoscopy remains the gold standard for diagnosis of EVs. Our study indicates that the swallowing action can significantly improve the display of LEDS during TUS compared with the esophageal resting state. This method may be a supplement or screening tool for the detection of EVs, especially medium or large EVs, which may reduce the frequency of endoscopy in patients without a significant risk for EVs. Acknowledgments—We acknowledge financial support from the Provincial Natural Science Research Program of Higher Education Institutions of Anhui Province (KJ2013A151).—We are very grateful to the staff of the Departments of Gastroenterology, Infectious Diseases and General Surgery at the First Affiliated Hospital of Anhui Medical University for their support and help. We thank all the patients and volunteers who participated in this study.
SUPPLEMENTARY DATA Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.ultrasmedbio.2014.03.017.
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