Influence of paraesophageal venous collaterals on efficacy of endoscopic sclerotherapy for esophageal varices

Influence of Paraesophageal Venous Collaterals on Efficacy of Endoscopic Sclerotherapy for Esophageal Varices CHING-YIH L I N , PIN-WEN ~ L I N , HONG-MING ~ TSAI,3 XI-ZHANG LIN,' TING-TSUNG CHANG' AND JENG-SHIANN SHIN' 'Diuision of Gastroenterology, Department of Internal Medicine, Department of 2Surgery and 3Radiology, Medical College, National Cheng-Kung University, Tainan 704, Taiwan

To determine the diagnostic accuracy of computer tomography in the detection of venous collaterals surrounding the esophagus in patients with portal hypertension, preoperative computer tomography i n terpretations of these veins in 15 patients who were candidates for the Sugiura procedure for treatment of esophageal varices were correlated with those of the intraoperative assessment. Laparotomy revealed severe paraesophageal varices in five patients; four of them were found to have paraesophageal varices in computer tomography films. The sensitivity and specificity of computer tomography in diagnosing severe paraesophageal varices were 80% and loo%, respectively. A second assessment was performed in 59 additional patients with esophageal variceal hemorrhage to investigate the infiuence of paraesophageal varices on the efficacy of endoscopic sclerotherapy in the treatment of varices. The patients were divided into two groups: Group A included 17 patients with and group B 42 patients without paraesophageal varices on presclerotherapy computer tomography. All patients underwent elective sclerotherapy after being deemed hemodynamically stable. Patients in group A required more treatment sessions, more sclerosant and longer periods to obliterate varices completely than did group B patients. Eight patients in group A and six in group B (57% vs. 16%, p. < 0.06) had variceal recurrence after obliteration d m n g mean follow-ups of 20.8 and 19.9 mo, respectively. The mean time elapsed before variced reappearance was shorter for group A than for group B (4.1 2 3.3 vs. 11.8 2 2.7 mo, p < 0.05). Among patients who developed new varices, five patients in group A and one in group B experienced repeat bleeding. The repeat bleeding rate was higher for group A than for group B (29% vs. 3%. p < 0.05). In conclusion, computer tomography proved a reliable diagnostic procedure in detecting severe paraesophageal varices in patients with portal hypertension. Endoscopic injection sclerotherapy is less effective in treating patients with esophageal variceal hemor

Received April 22,1993;accepted September 24, 1993. Address reprint requests to: Ching-Yih Lin, M.D., Division of Gastroenterology, Department of Internal Medicine, National Cheng-Kung University Hospital, 138,Shing Li Road, Tainan 704,Taiwan. Copyright Q 1994 by the American Association for the Study of Liver Diseases. 0270-9139/94 $1.00 + .I0 31/1/52395

rhage who have severe paraesophageal collaterals. (HEPATOLOGY 1994;19:602-608.)

Endoscopic injection sclerotherapy (EIS) has become the treatment of first choice for controlling and preventing hemorrhage from esophageal varices (1-4). For efficient protection against repeat variceal bleeding, EIS, regularly repeated, is needed for complete variceal eradication (1,5,6). However, the number of treatment sessions required for variceal eradication has varied widely in different published studies and from patient to patient in individual studies (1,7-10). Furthermore, the development of new varices after variceal eradication with EIS has been reported with remarkably different recurrence rates of from 0% to more than 60% (9, 11, 12). Factors affecting these variables have been studied but are still unclear (13-19). PeriesophageaVparaesophageal venous collaterals located at the adventitial aspect of the esophagus in patients with portal hypertension were noted recently (20,211. Studies on these collaterals are scarce, probably because of the difficulty of studying these veins in clinical practice. Percutaneous transhepatic or transsplenic portography is a standard method used to visualize these veins, but its invasiveness and technique limit its usefulness. Computed tomography (CT)has been used to identify these veins (22-24),but its diagnostic value is still uncertain. McCormack et al. (25) proposed that the periesophageal collaterals caused esophageal varices to dilate and rupture by way of the turbulent flow produced by perforating veins between the periesophageal and esophageal varices. Perforating veins are a group of specific vessels situated in the lower esophageal wall that connect intrinsic esophageal varices and extrinsic periesophageal varices. Using resin-casting or a silicon rubber compound injection technique, we easily identified these vessels in the esophageal specimens from fresh human cadavers (28, 29). On direct injection of contrast medium into esophageal varices, the perforating veins could be identified on the venography in some patients with portal hypertension (25). It therefore seems rational to consider that the efficacy of EIS may be influenced by the periesophageal and perforating veins. Thus this two-part study was conducted. The first part determined the diagnostic accuracy of CT in detecting the periesophageaUpara-

602

1,IN ET AI,.

603

FIG. 1. Esophageal varices with large paraesophageal venous collaterals. ( A ! Precontrast and ( B )postcontrast CT scans at the level of lower esophagus near esophagogastric junction demonstrate a lobulated mass (large arrows in IA]) around the esophagus that is vascular in nature, as evidenced by the degree of enhancement rlargc arrows in IBli compared with the adjacent aorta (small ~ ~ ~ O in L UA Sand B).

esophageal veins, a n d the second investigated t h e influence of periesophageallparaesophageal veins on the efficacy of EIS. It i s hoped that the findings of this s t u d y will provide insights on defining t r e a t m e n t strategies for esophageal varices.

PATIENTS AND METHODS Part I : Verification of Collateral Veins Surrounding the E80phqu8 on CT. Fifteen patients with endoscopy-proven

esophageal variceal bleeding admitted to the National Cheng-Kung University Hospital between January and December 1989 were selected. All were candidates for elective esophageal transection with paraesophagogastric devascularization and splenectomy (the Sugiura procedure) in the treatment of varices. There were 13 men and 2 women; their ages ranged from 28 to 65 yr (mean age = 51.3 yr). The severity of the underlying liver diseases !€‘ugh grading 1261 i showed nine patients with grade A and six with grade B. AU patients were scanned on a General Electric model 9800 total body scanner tGE Co.. Medical System Group, Milwaukee, WI)with a scanning time of 2.0 sec!slice after the variceal hemorrhage had been stopped by conservative means including fluid replacement, intravenous vasopressin infusion and esophageal balloon tamponade if necessary, and the patients had been hemodynamically stable for at least 2 days. Scans were obtained with contiguous 1-cm slices beginning at the carina and extending inferiorly 5 cm into the abdomen to include the lower esophagus, esophagogastric junction and proximal stomach before and after intravenous administration of 100 ml iodinated contrast material (‘I’elebrix, 380 nig iodine/ml; Laboratoire Guerbet, Aulnay-Sous-Bois Cedex, France) to enhance the vessels i n the paraesophageal area. Serial CT films were reviewed twice for each patient by two of the authors (C.Y.L. and H.M.T.) for the presence or absence of paraesophageal collateral veins and the evidence of portal hypertension. Unenhanced images of paraesophageal vessels showed nonspecific mass lesions with lobulated contours that, after contrast administration, were enhanced to the same degree as the circulating blood (Figs. 1 and 2 1. Elective surgical interventions for esophageal varices were performed within 2 wk of the origmal hemorrhage by the same

surgcal team (P.W.L.J experienced with the Sugiura procedure. Before ligation and devascularization of paraesophagogastric vessels, the gross appearance, including the size and ext.ent of vessels overlying the esophagus above and the stomach below the esophagogastric junction was inspected and recorded. The procedure was facilitated by mobilization of the left lobe of the liver, freeing of the phrenoesophageal ligament and exertion of gentle downward traction on the esophagus. The severity of paraesophageal varices was assessed objectively by surgeons who were not informed of the details of CT before surgery, using on a classification system comprising four categories: normal (no evidence of varices), mild (minimalsized varices), moderate (large varices without coalescence bet.ween them) and severe (large varices of a polypoid nature with coalescence between them). The preoperative CT evaluation of paraesophageal vessels was correlated with that of the intraoperative assessment. The sensitivity, specificity and clinical diagnostic accuracy of CT to detect the paraesophageal varices were calculated. Part 2: Influence of Paraesophageal Collaterala on Eflcacy ofScleroth4rapy. From January 1990 to December 1991, all patients admitted to the hospital with hematemesis or melena

were included in this prospective study if they met the following eligibility criteria: esophageal variceal hemorrhage documented by emergency endoscopy, no previous EIS or surgical interventions for varices, achievement of hemostasis by conservative means, suitability for elective EIS after full evaluation, completion of CT as described in part 1 before the first, session of EIS and willingness to return for repeated EIS and follow-up. Patients were not included if hemorrhage was thought to originate from gastric varices or if a concomitant hepatoma existed with cirrhosis. Patients were withdrawn from the study if they could not adhere to the protocol during the course of EIS. The purpose of the study was explained to the patients and their relatives, and written informed consent was obtained from each patient. During the study period, 59 patients, comprising 50 men and 9 women, 37 to 74 yr old, were enrolled, all drawn from a total of 271 patients treated at the hospital for esophageal variceal hemorrhage. Two hundred twelve patients were excluded from the study. Reasons for exclusion are listed in Table 1. According to the presence or absence of lower paraesoph-

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604 LINETAL.

FIG.2. Esophageal varices without paraesophageal venous collaterals. (A) Precontrast and (B) postcontrast CT scans at the level of the lower esophagus near esophagogastricjunction demonstrate a thick esophageal wall, a scalloped inner contour and a slightly lobulated outer contour (large arrow in IAl). Varices are confined to the wall of the esophams (large arrow in [B]), marked enhancement to inferior vena cava (WC) and-aorta (small arrows in [A] and [Bl). .

I

TABLE 1. Causes for exclusion

Cirrhosis with concomitant hepatoma Without portal vein thrombosis With portal vein thrombosis Emergency EIS required before completion of CT scan Previous EIS Refusal of EIS Early mortality Esophageal varices combined with prominent cardiac

49 19

45 31 27 19 18

varices

Previous surgical treatment for varices TOTAL

4 2 12

ageal collateral veins demonstrated on CT, the 59 patients were divided into two groups: Group A had 17 patients with and group B 42 patients without prominent paraesophageal collaterals. Relevant clinical data of patients in both groups at the time of entry into the study are shown in Table 2. Underlying liver disease was confined mostly to nonalcoholic cirrhosis, especially viral hepatitis-related cirrhosis diagnosed on the basis of historical, clinical or histological evaluation. Comparison of the two groups with respect to age, sex ratio, extent and size of varices, pathogenesis of portal hypertension and severity of underlying liver diseases showed no statistically significant differences. EIS was carried out with the unmodified Olympus XK-10 endoscope (Olympus Optical Co., Ltd., Tokyo, Japan) and disposable injection needle by means of injection of 1.592 sodium tetradecyl sulfate intravariceally as close to the esophagogastric junction as possible. Two to five milliliters of sclerosant was injected per varix; the total did not exceed 25 ml per treatment session. All of these procedures were performed by three experienced endoscopists (C.Y.L.,X.Z.L., T.T.C.) who were unaware of which groups the patients belonged to. The first two sessions were performed on a weekly basis; sessions were performed every 2 to 3 wk afterward until varices were obliterated. Obliteration of varices was defined either as the absence of varices or the presence of minimal-sized thrombotic veins that did not bleed after puncture with an EIS needle.

Hemorrhage due to EIS-induced esophageal ulceration was managed conservatively. When variceal rebleeding occurred before variceal obliteration, hemostasis was attempted by conservative means and emergency EIS within 12 hr of bleeding. If there was continued bleeding or a further episode of bleeding within 3 days of EIS, the patient underwent another endoscopic examination. If this confirmed further variceal bleeding, one more session of EIS was performed. If bleeding did not stop or if it recurred within 3 days of the second injection, EIS was classified as having failed and an alternative therapy - endoscopic variceal ligation or surgical treatment, depending on the patient’s clinical situation - was considered. After variceal obliteration, endoscopic surveillance was carried out at 3- to 4-mo intervals or when hemorrhage recurred. Patients were considered for new sclerosis if new varices were detected. All patients were monitored until September 1992. For statistical analysis, the number of EIS sessions, the volume of sclerosant and the time duration required to achieve variceal obliteration and the time fi om variceal obliteration to recurrence or repeat bleeding in both groups were analyzed with unpaired Student’s t tests. Differences between the two groups with respect to variceal recurrence and repeat bleeding were compared by means of x2 test, with Yates’ correction when needed. Differences were regarded as significant if p was less than 0.05.

RESULTS Part I : Verificationof Collateral Veins Surrounding the Esophagus on CT. CT abnormalities specific to

esophageal and/or paraesophageal varices were shown in all 15 patients who underwent the Sugiura procedure. In 11of these patients, varices involved only the wall of the esophagus, producing circumferential or localized wall thickening with a lobulated contour and changing the shape of the esophageal lumen from a round or oval to a scalloped contour. The CT diagnosis of paraesophageal varices could not be confidently made in these patients. Of the remaining four patients, CT showed, in addition to the esophageal wall abnormalities, paraesophageal

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HEPATOLOGY Vol. 19. NO. 3, 1994 TABLE 2. Characteristics of the two study groups before EIS Group A (n = 17)

Characteristics ______

~

~

_

_

_

_

_

_

_

_

_

_

~

~

Group B (n = 42)

p Value

59.0 I9.4 36/6 15/27 35f7 32

NS NS NS NS NS NS NS

~

Age (yr)" Sex (M/F) Size of esophageal varices (F2/F3l h Pugh grade (A + B/C) HBsAg Alcoholism Extrahepatic portal venous obstruction

57 4 5 6.8 1413 6/11 14'3

12 2 0

6 1

"Data expressed as mean 2 S D "Size of esophageal varices. an endoscopic feature, was classified according to the criteria of Beppu et al. (27t

TABLE 3. Comparison of EIS treatment characteristics resulting in variceal obliteration in patients of both groups Treatment characteristics to achieve obliteration ~

~

Group B (n = 37)

GroupA (n = 14) ~

No. of EIS sessions Cumulative volume of sclerosant ( m l I Time needed to achieve obliteration wk)

~

8.8 124.3 18.1

2.7 15-14)" 36.8 (78-1801 5 . 5 (12-28)

I

2

~~

p Value ~~

5.5 2 1.6 (3-111 85.2 2 19.1 (60-155) 10.9 z 3.2 (5-21)

~

< 0.001

< 0.001 < 0.001

"Data expressed as mean z S.D. {ranget

needed to obliterate the varices completely were significantly different for the two groups (Table 3). Follow-up was similar for groups A and B, with means of 20.8 and 19.9 mo and ranges of 11 to 28 and 9 to 29 mo, respectively. Eight of the 14 patients in group A had variceal recurrence, compared with 6 of the 37 patients in group B (57% vs. 16%,p < 0.05). The mean time of variceal reappearance after complete obliteration was shorter for group A than for group B (4.1 5 3.3 mo vs. 11.8 5 2.7 mo, p < 0.05). Among the patients in whom new varices developed, five of eight in group A had repeat bleeding associated with recurrence, whereas only one of six in group B had repeat bleeding. All repeat bleeding was from esophageal variceal sources, as confirmed on Part 2: Influence of Paraesophageal Collaterals on endoscopy. The rate of repeat bleeding was 29% for E f i ~ a c of y Sclerotherapy. Two patients in group B did group A, compared with 3%for group B. This difference not comply with repeated EIS and were lost to follow-up. was statistically significant (p < 0.05). Most of the Six (35%)of the 17 patients in group A experienced repeat bleeding episodes were mild. Those patients in repeat bleeding with a total of eight episodes, compared whom variceal recurrence developed with or without with 5 (13%)of the 40 patients in group B with six bleeding continued in the EIS program. Six of them episodes during the course of EIS; this difference was underwent only one additional injection session; four not statistically significant (p = 0.1). All episodes of underwent two, two underwent three and one unbleeding (except one in group A considered to have arisen derwent four sessions to achieve variceal obliteration from esophageal mucosal ulceration) were esophageal again. During follow-up, there were three deaths in variceal sources confirmed by endoscopy. Bleeding in group A, compared with 10 in group B (p > 0.05). Only two patients in each group was not controlled by one death in group B was a direct result of recurrent repeated EIS; one patient in group A was treated with an variceal bleeding; the rest were attributed to progression emergency Sugiura procedure and survived, whereas the of liver failure or severe infection. Causes of death are remaining three died of uncontrolled bleeding. One given in Table 4. No fatal complications of EIS were patient in each group died of progressive liver failure observed in this study. unrelated to variceal bleeding. DISCUSSION After successive sessions of EIS, variceal obliteration Recent developments have greatly enhanced our in the remaining 51 patients (14 in group A, 37 in group B) was achieved in a mean of six EIS sessions (range = 3 understanding of how varices develop and why they to 14 sessions) over a mean period of 13 wk (range = 5 bleed (25, 28-30). The normal venous anatomy of the to 28 wk). The number of EIS sessions required, the lower esophagus comprises four layers: intraepithelial cumulative volume of sclerosant used and the time channels, subepithelial superficial venous plexus, deep vascular structures a t the level of lower esophagus near esophagogastric junction. When larger, they extended up to the lower mediastinum, adjacent to the esophagus. Intraoperative assessment of the size and extent of collateral veins over the paraesophageal area at the level of lower esophagus revealed that 5 of the 15 patients had severe, 4 had moderate and 6 had mild paraesophageal varices. One patient with severe varices and all 10 patients with mild-to-moderate paraesophageal varices could not be identified to have these collateral veins in preoperative CT films. The sensitivity, specificity and clinical diagnostic accuracy of CT in diagnosing severe paraesophageal varices were 80%, 100%- and 93%, respectively.

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TABLE 4. Causes of death in the two study groups

and 39% by Clark et al. (23) but only 7% according to Ishikawa et al. (24). In this study, 28% of the patients (parts 1and 2) were identified as having paraesophageal Cause of Death Group A Group B collaterals in the CT films. It was assumed that Liver failure 2 4 periesophageal/paraesophageal varices existed in all 1 4 Sepsis patients with portal hypertension and esophageal varHepatic encephalopathy 0 1 ices; however, their sizes and extents varied individually. Esophageal variceal repeat bleeding 0 1 Observations in patients who underwent laparotomy TOTAL 3 10 confirmed this point. However, it was not easy to identify mild and moderate degrees of involvement of these vascular structures on the CT films. Mild paraesophsubmucosal veins and adventitial veins situated ordi- aged varices may be in close contact with the esophageal nally from inner esophageal mucosa to outer serosa (28, wall, making it difficult to differentiate the former from 29). In addition, perforating veins through the muscu- the latter and its inner, “true” esophageal varices in the laris propria connect the adventitial and deep submu- CT films. Another explanation may be the insufficient cosal veins. In patients with portal hypertension, all flow of contrast medium through the small paraesophthese venous channels are significantly grossly enlarged aged collaterals. (28-30). Although the deep submucosal veins are the In clinical practice, there appeared to be a number of “true” varices seen at endoscopy in the esophageal patients with considerably more difficult obliteration of lumen, they are not always the main pathway from the varices with EIS (7, 10). Generally, fewer than 10 portal to the systemic circulation, and most shunting sessions of EIS were required to obliterate all varices, as occurs at the adventitial aspect of the esophagus (28). suggested by most of the investigators (1,8, 11).In this There still remains some confusion on terminology of study, seven (13%)patients underwent at least 10 EIS collateral veins around the esophagus in patients with sessions, compared with an average of six sessions in this portal hypertension. Using percutaneous transhepatic and other studies (6, 9, 12). Factors affecting the EIS portography, Soderlund et al. delineated two parts of treatment characteristics had been studied by many collaterals - namely, periesophageal and paraesophageal investigators, but not much is known up to now. Rose et varices - around the lower esophagus (20). Periesoph- al. (18)reported that patients with large varices required ageal varices are situated in the connective tissue more sessions to achieve variceal obliteration than did surrounding the esophagus, whereas paraesophageal those with small varices. Lo et al. (16) suggested that varices are mediastinal veins running longitudinally EIS always failed in patients with bleeding varices and distant to or overlying the esophagus. Percutaneous concomitant unresectable hepatoma as a result of the transhepatic or transsplenic portography is an estab- lethal nature of the underlying malignancy and portal lished method in visualizing the portal-systemic col- vein thrombosis. lateral circulation (31)but it is invasive and technically The efficacy of EIS has been established, but variceal demanding and is not recommended as a standard reappearance after obliteration by EIS is still a problem. clinical routine procedure. CT identification of collateral How the new varices develop and why the recurrence veins in patients with portal hypertension has been rates vary widely in the different studies are not yet fully reported recently (22-24). Most of the described collat- understood (9, 11, 12). Several investigators have erals were large retroperitoneal and intraperitoneal suggested that variceal recurrence after EIS is deterperivisceral veins and mediastinal veins, including the mined by the pathogenesis of portal hypertension (15, collaterals around the esophagus. In these reports, the 18, 19). Dilawari et al. (17) reported that variceal terms periesophageal varices and paraesophageal obliteration by EIS followed by the development of varices were used by different investigators (22-24) to splenorenal shunts protects patients from variceal redescribe the collateral veins around the esophagus. currence. Twenty-seven percent of the patients in this However, none defined both terms clearly. According to study experienced variceal recurrence during follow-up. the results of their studies, periesophageal and para- This figure is similar to those in several studies-21%, esophageal varices seemed to be of the same group of 22% and 31%,as reported by Low et al. (12), Planas et collateral veins. We supposed that periesophageal and al. (8) and Takase et al. (141, respectively-but lower paraesophageal might have indicated the various de- than that of the King’s College study (91, in which as grees in size and extent of collaterals around the many as 60% of patients had new varices. These esophagus; both corresponded to the dilated adventitial investigators supposed that many of the recurrences veins described by Hashizume et al. (28). When these represented failure to obliterate the varices completely vascular structures become massively enlarged and rather than true recurrence. Others considered that display the tortuous polypoid nature, they occupy the high variceal recurrence rate might be due to the mediastinal space and give the impression of being presence of residual esophageal mucosa after EIS, where new varices can form (11). Theoretically and concepdistant from the esophagus. The incidence of CT identification of periesopha- tually, the esophageal varices will probably recur from geal/paraesophageal varices was 45% in patients with the residual small superficial veins and connections with portal hypertension as reported by Balthazar et al. (22) the main blood flow supplies to the esophageal varices, during follow-up

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such as branches of the left gastric vein or paraesophageal veins. In this study, patients with large paraesophageal collaterals had higher risk of variceal recurrence and repeat bleeding than did those without paraesophageal varices. We also observed that possible influencing factors such as severity of esophageal varices, pathogenesis of portal hypertension and hepatic functional reserve (as indicated by Pugh grading) were similar for both groups. Hence the importance of the large paraesophageal collaterals in the efficacy of EIS was emphasized. It is unclear how extrinsic paraesophageal collaterals affect intrinsic esophageal varices. From an anatomical view, the inner esophageal varices are much smaller than the collaterals on the outer esophageal surface formed by the periesophageallparaesophageal veins ( 28 1. Esophageal varices may be considered a “backwater” that developed as a result of high pressure in the collaterals around the esophagus. McCormack et al. (25) demonstrated bidirectional flow in the lower esophageal varices, attributed this to perforating veins between the submucosal intrinsic and adventitial extrinsic vessels and suggested that the turbulent flow into the varix through these perforators may be involved in esophageal dilation and rupture. From this point of view, extrinsic enlarged adventitial veins seemed to play the role of “feeders” of intrinsic esophageal varices. Therefore it is logical to consider that the paraesophageal collaterals and perforating veins affect the efficacy of EIS if persisting high pressure and blood flow in the paraesophageal collaterals continue to feed intrinsic esophageal varices during the course of EIS. Takase et al. ( 14 I suggested that embolization of both the esophageal varices and their feeders, mainly the left gastric vein, is essential in lowering the recurrence rate of varices after EIS. Some differences in the location of feeders exist between Takase’s study and this one. However, the concept of the efficacy of EIS influenced by the feeders of varices is the same. It has also been reported that the recurrence rate is lower among patients whose treatment includes esophageal transection and devascularization than those without devascularization (32) . Conversely, Soderlund et al. (20) suggested that the selective eradication of submucosal varices, leaving the periesophagdparaesophageal collaterals unaffected, were the mechanism counteracting variceal recurrence after EIS. In summary, CT scanning proved to be a reliable diagnostic procedure in the detection of large paraesophageal veins in this study. Patients with bleeding esophageal varices who have large paraesophageal collaterals need more sessions of EIS, more sclerosant and longer periods to achieve variceal obliteration and have higher recurrence and repeat bleeding rates after EIS. The presence and sighting of large paraesophageal varices may account for the difficulty experienced in eradicating esophageal varices in some patients. Recognition of these patients may provide guidelines and define strategies in the management of variceal hemorrhage.

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