GASTRIC VARICES AND PORTAL HYPERTENSIVE GASTROPATHY

PORTAL HYPERTENSION

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GASTRIC VARICES AND PORTAL HYPERTENSIVE GASTROPATHY Shiv K. Sarin, MD, DM, and Shri Ram Agarwal, MD, DM

GASTRIC VARICES

One of the first descriptions of gastric varices and its association with portal hypertension was published in the German literature in 1913."' The prevalence of gastric varices in patients with portal hypertension has been reported to vary from 2% to 70%.20,35,37, 'O0, lZ4 Watanabe et al,132in their study of portal hemodynamics observed gastric varices to be as common as esophageal varices. This substantial variability in the prevalence of gastric varices is probably related to the differences in the patient populations (poorly matched in terms of origin of portal hypertension, stage of cirrhosis, and bleeding status), the techniques used for the diagnosis, and the classifications used for gastric varices. Gastric varices are significantly more common in bleeders than in nonbleeders (27% versus 4%), perhaps indicating that gastric varices develop at a more advanced stage of portal hypertension.'O' Earlier studies depended primarily on contrast radiography, splenoportography, and percutaneous transhepatic portovenography for detecting gastric varices. Today, upper gastrointestinal endoscopy remains the mainstay of diagnosis of gastric varices. Newer diagnostic tools such 43 MR angiography, and multislice CT scanning are as endo~onography,~, likely to improve the accuracy in diagnosing gastric varices. It remains to be seen whether the collaterals identified by these imaging modalities correlate with endoscopically detected gastric varices in the stomach.

From the Department of Gastroenterology, G. 8.Pant Hospital, New Delhi, India

CLINICS IN LIVER DISEASE VOLUME 5 * NUMBER 3 AUGUST 2001

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SARIN 81 AGARWAL

Classification of Gastric Varices

Several classifications of gastric varices have been proposed, based on the location, size, and endoscopic features of the v a r i c e ~ .37, ~ ~Iol, Because of the overlap among different subtypes and the complexity of the grading systems, these classifications have not been found to be very useful. Moreover, these classifications have not been evaluated prospectively. The authors have proposed a simple classification, the Sarin classification, (Fig. 1) based on the anatomic location of varices, their relationship with esophageal varices, and their origin as primary (present at the time of initial presentation) or secondary (presenting after the obliteration of esophageal varices).'O0 This classification was evaluated prospectively in a series of 568 patients and was found to be useful in defining the natural history and outlining the management of gastric varices.lo1This classification was also prospectively evaluated by Kind et a1 in a large study of 657 Italian patients with portal hypertenion.^^ They reaffirmed the usefulness of this classification in determining the natural history and choice of therapy for different types of gastric varices. The recently held Baveno I11 Consensus Conference on Portal Hypertension accepted the Sarin classification of gastric varices.'* According to this classification, gastric varices are divided into two types, gastroesophageal varices (GOV) and isolated gastric varices (IGV).

Gastro Oesophageal Varices (GOV)

GOVI Based on presentation

GOV2

Isolated Gastric Varices (IGV)

IGVl

IGV2

Figure 1. Sarin's classification: Gastric varices (GV) are broadly classified based on location into gastroesophageal varices (GOV) and isolated gastric varices (IGV). They could be primary (at initial presentation) or secondary (post-obliterationof esophageal varices).

i

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Gastroesophageal Varices

Gastroesophageal varices extend beyond the gastroesophageal junction and are always associated with esophageal varices. They are further subdivided into 1. Type 1 (GOV 1):These varices appear as continuation of esophageal varices and extend for 2 to 5 cm below the gastroesophageal junction along the lesser curvature of the stomach. These varices are more-or-less straight (Fig. 2A). 2. Type 2 (GOV 2): These varices extend beyond the gastroesophageal junction towards the fundus of the stomach (Fig. 2B). They appear as long, tortuous, or nodular elevations at the cardia.

Figure 2. Endoscopic view of the different types of GV. A Gastroesophageal varices type I (GOV1) along the lesser curvature. 6 Gastroesophageal varices type II (GOV2) along the greater curvature. C Isolated gastric varices Type I (IGV1) in the fundus of the stomach (Courtesy of Georgio Battaglia, MD, Italy.) (See also Color Plate 1, Fig. 3.)

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Isolated Gastric Varices

Gastric varices in the absence of esophageal varices are termed isolated gastric varices. Depending on their location, they are subdivided into 1. Type 1 (IGV 1):These varices are located in the fundus of the stomach and fall short of the cardia by a few centimeters (Fig. 2C). 2. Type 2 (IGV 2): These varices include isolated ectopic varices present anywhere in the stomach, such as in the antrum, pylorus, or body, or in the first part of the duodenum. Pathogenesis and Hemodynamics of Gastric Varices

To understand the origin of gastric varices, it is necessary to understand the venous drainage of the stomach, lower esophagus, and spleen. The fundus of the stomach has a rich venous plexus in its submucosa. This plexus drains into the splenic vein through the short gastric veins and into the portal vein through the coronary vein (Fig. 3). Gastric varices can develop in patients with either generalized (e.g., in cirrhosis) or segmental (e.g., in splenic vein thrombosis) portal hypertension. In generalized portal hypertension, the raised portal pressure is transmitted by the left gastric vein to esophageal varices and by the short and posterior gastric veins to the fundic plexus and cardiac veins. Gastroesophageal varices type 1 or lesser-curve varices are formed by the dilatation of the left gastric vein at the cardia.l14Hashizume et a134have shown that GOV 1 develop because one of the branches of the left gastric vein perforates the gastric wall perpendicularly (Fig. 4) and joins the deep submucosal veins about 2 cm below the gastroesophageal junction near the cardia. These submucosal veins pierce the muscularis mucosae in the palisade zone and again at the proximal border of the palisade zone to run within the submucosa.128Thus, a high-pressure zone develops below the palisade zone, this high-pressure zone explains the occurrance of both GOV 1 and GOV 2. In segmental portal hypertension, gastric varices develop in the absence of esophageal varices, mainly caused by splenic vein obstruction. The splenic blood flows retrogradely through the short and posterior gastric veins into the submucosal space, and varices subsequently develop in the fundus and cardiac region from which the blood flows hepatopetally through the coronary vein into the portal vein. The lower esophageal veins are thus bypassed, so that esophageal varices do not develop.61Retrograde flow that occurs through the left-to-right gastroepiploic vein and also to the superior mesenteric vein can explain the development of ectopic varices in the stomach. Development of isolated gastric varices in the presence of patent splenic vein is difficult to explain but could possibly occur because of direct anastomosis between the gastric and retroperitoneal veins which open up

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f

I

Figure 3. Normal venous anatomy of the stomach. Splenic vein (SV) thrombosis leads to reversed flow distribution. Left-sided portal hypertension leads to gastric varices and dilatation of short gastric veins, gastroepiploic vein (GEV), and coronary vein (CV). The portal vein (PV) is patent. IMV and SMV, inferior mesenteric vein and superior mesenteric vein. (From Little AG, Moosa AR: Gastrointestinal hemorrhage from leftsided portal hypertension: an unappreciated complication of pancreatitis. American Journal of Surgery 141:153-158, 1981; with permission.)

Figure 4. Gastric varices form in the submucosa where branches of the left gastric vein (LGV) penetrate the gastric wall perpendicularly. M = mucosa; SM = submucosa; MP = muscularis propria; EG = oesophagogastricjunction; dv = deep submucosal vein. (From Hashizume M, Kitano S, Sugimachi K, et al: Three-dimensional view of the vascular structure of the lower esophagus in clinical portal hypertension. Hepatology 8:1482-1487, 1988; with permission.)

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because of raised portal pressure.21How the route is determined by which major portosystemic collaterals develop when portal pressure increases is not known. The size and length of the potential collateral vein probably determines whether a patient develops esophageal or gastric varices, and in the latter case, which type of gastric v a r i c e ~ . ' ~ ~ in their study of the hemodynamics of gastric Watanabe et varices observed a significantly lower portal venous pressure and a higher frequency of large gastrorenal shunts in patients with gastric varices as compared with patients with esophageal varices. Stanley et a170,112 also reported a lower portacaval pressure gradient in patients with gastric varices compared with patients with esophageal varices. Other investigators, however, have reported no difference in portosystemic pressure gradient in patients presenting with esophageal or gastric variceal bleeding.", 93 Frequency of Different Types of Gastric Varices

The frequency of different types of primary gastric varices is shown in Figures 5 and 6. Nearly similar frequency has been observed by other investigator^.^^ In some patients, GOV 1 and GOV 2 coexist.lO' Natural History of Gastric Varices

Patients with gastric varices can be asymptomatic, with the gastric varices detected incidentally, or may present with upper gastrointestinal tract bleeding or, rarely, with hepatic encephalopathy. In nearly three

Total 41 511 424

Bleeders 3511930

Non-bleeders 681493

(29%)

(37%)

(13.7%)

Figure 5. Frequency of different types of GV in patients with different etiologies of portal hypertension.

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Figure 6. Frequency of different types of primary GV,

fourths of the patients, gastric varices are detected during treatment of bleeding esophageal varices or at routine upper gastro-intestinal endoscopy performed in a patient with portal hypertension. Less than one fourth of the patients present with gastric variceal bleeding. Gastric Variceal Bleeding Definition

Bleeding should be considered to have arisen from gastric varices if (1) active bleeding or oozing is seen from the gastric varices; (2) a clot is seen over the varix; or (3) in the presence of distinct, large gastric varices and the absence of esophageal varices, no other source of bleeding is detectable. Incidence

There are conflicting reports on how often and how severely gastric varices bleed. The incidence of bleeding from gastric varices has been reported between 3% and 43%.51-53, lol, lZ4 It is generally believed that gastric varices bleed less frequently than esophageal varices. This belief may not be entirely true, because GOV 1, which constitute a large proportion of gastric varices, have a low incidence of bleeding (11%).52, *01 The incidence of bleeding is higher in IGV 1 (78%) and GOV 2 (55%). Kind et a1,5z in a recent study, found the frequency of bleeding from GOV 2 and IGV 1 to be 60.3%. Korula et a153also observed that the number of bleeding episodes in patients with fundal varices (4.8 f 2.9) was higher than in patients with junctional varices (2.2 2 2.2). They found gastric varices to bleed much more frequently than esophageal varices. In the authors' series, the bleeding risk factor per year (total number of bleeding episodes / time interval between the first and the last episode) was higher for esophageal varices than for gastric varices (4.3 f 0.4 versus 2.0 k 0.6, P < O.O1).lol Moreover, the mean number of

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bleeding episodes in patients with gastric and esophageal varices was comparable (2.14 k 1.03 versus 2.3 k 1.8).lo1 Kind et a1 observed an overall tendencyof bleeding from gastric varices to be lower (43.3%) than from esophageal varices (79.8%):’ Kim et a1,5I in a prospective study of 117 patients with fundal varices, documented cumulative bleeding rates at 1, 3, and 5 years of l6%, 36%, and 44%, respectively. The incidence of hemorrhage from high-risk esophagealvarices has been shown to be 19% to 40% during a similar follow-upperiod. In arecent study, Tomikawa et a1 observed bleeding in 87 (29%)of the 300 patients with gastric varices.IZ1Thus, the incidence of hemorrhage from fundal varices seems tobe similar tothat from moderate to large esophageal varices. Risk Factors for Bleeding There are limited data on thefactors that could predict the risk of bleeding in patients with gastric varices. Kim et al5Ihave identified three risk factors for bleeding gastric varices: the size of varices, presenceof red spots on fundal varices, and theChild’s status of the patient (Table 1). Hashizume et aP5 have also emphasized the significance of size and presence of red spots. These risk factors, however, must be objectively validated. Accurate determination of the size of gastric varices is not easy, because quite often these veins form bunches. A simple approach used by the authors to is use the shaftof the retroflexed endoscope as a measuring scale. Varices larger than the endoscope shaft (approximately 10 mm in diameter) are considered large gastric ~ a r i c e s . ’ ~ ~ There are also difficulties with the interpretationof red-color signs on gastric varices. In esophageal varices, .the red-color signs correspond to the dilated, blood-filledchannels lying within and beneath the mucosal epithelium. The vascular structures of stomach are not the same as those of the esophagus,however, and gastric varices usually lie in the

Table 1. RISK FACTORS FOR PREDICTING HEMORRHAGE FROM GASTRIC VARICES Factor

Size of fundal varices Child’s status Red spot present *Small versus medium tSmall versuslarge $Class Aversus class B §Class A versus class C 1)Absentversus present From Kim T, Shijo H, Kokawa H,et al: Risk factors Hepatology 25:307-312, 1997; with permission.

Risk Ratio

2.18 (1.2-3.93)* 4.75 (1.45-15.5)t 1.70 (1.11-2.59)$ 2.88 (1.213.93)s 2.06 (1.014.19)~~

forhemorrhage

from gastric fundal varices.

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gastric submucosa. Thus, a red-color sign is uncommon and is also difficult to detect in patients with gastric varices. Influence of Esophageal Variceal Sclerotherapy and Endoscopic Variceal Ligation on Gastric Varices It is now well known that endoscopic intervention for esophageal varices can alter the natural history of gastric varices. The possible variables are Influence on coexisting gastric varices Development of new gastric varices following obliteration of esophageal varices (secondary gastric varices) Induction of bleeding from gastric varices while performing sclerotherapy or ligation for esophageal varices Influence on coexisting gastric varices. Logically, only GOVs are likely to be influenced by the treatment of esophageal varices. It is now well accepted that successful eradication of esophageal varices quite often results in obliteration of GOV l.139 Recently, the authors have analyzed 123 patients with GOV 1 who had presented with esophageal variceal bleeding and had undergone endoscopic sclerotherapy. The GOV 1 disappeared after sclerotherapy in 58% of the patients, concurrently in nearly three fourths of these patients and within 6 months of obliteration of the esophageal varices in the remaining patients.l Similarly, GOV 1 disappeared in 35 (70%) of the 50 patients who underwent endoscopic variceal ligation. Thus both methods were found effective in treating GOV 1.1,98 The reason for regression of GOV 1 could be the flow of the sclerosant towards stomach or the formation of a thrombus at the gastroesophageal junction which could propagate 64 Before the obliteration procedure, bleeding was more com~audally.4~, mon in patients in whom GOV 1persisted for more than 6 months after obliteration of esophageal varices than in patients whom gastric varices disappeared (28% versus 2%, P
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2.6%)after esophageal variceal eradication.lo1The frequency of bleeding from secondary gastric varices has been reported to be higher than with primary gastric varices. Over follow-up periods of 16.1 and 12.6 months, the bleeding incidence in secondary GOV 1 and GOV 2 was 37% and 100°/~,respecti~ely.~~ A high incidence of bleeding from secondary GOV 2 and IGV 1 has also been reported by Kind et al.52These observations raise the important issue of whether secondary gastric varices should be treated prophylactically. There is a need to evaluate both pharmacotherapy and endoscopic therapy in this regard. It has been determined that sclerotherapy blocks the shunting veins that are present in the palisade zone. This blockage leads to increased blood flow in the gastric veins74and a rise in portal pressure, possibly leading to dilatation and rupture of these veins.54Bleeding from gastric varices as the result of esophageal variceal sclerotherapy is quite rare,139 although an isolated study has reported bleeding in 10% of patients.lo6 Hepatic Encephalopathy

Cirrhotics with gastric varices develop encephalopathy more often than cirrhotic patients with only esophageal varices (25% versus 3%),132 because nitrogenous substances from the gut enter directly into the systemic circulation through the shunts which form the gastric varices. The stage of underlying liver disease to a large extent determines the development of encephalopathy. Patients with noncirrhotic portal hypertension, however, despite their higher reported incidence of gastric varices,’O’ do not have an increased incidence of hepatic en~ephalopathy.9~ Management of Gastric Variceal Bleeding

Current protocols for bleeding gastric varices have been adopted from the treatment of bleeding esophageal varices. Hemostatic methods that use standard therapy for esophageal varices have not been found effective for gastric varices. Most reports of endoscopic treatment of bleeding gastric varices are small series, case reports, or retrospective reviews.52,53, 58, Iol, Only a few studies have prospectively compared the effectiveness and safety of different treatment modalities. Hence, despite nearly 2 decades of active interest, the management of gastric varices remains controversial and largely empiric. Primary Prophylaxis

Whether nonbleeding gastric varices that accompany bleeding esophageal varices or nonbleeding IGVs should be prophylactically treated can be determined only if more data on the natural history of gastric variceal bleeding becomes available in relation to the location, size, presence of red signs, and Child’s status of the patient. There are

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few long-term data on the effect of any treatment modality on survival in such patients. Thus, prophylactic treatment of gastric varices is not warranted, in general, at the present time. As mentioned previously, however, because patients in whom GOV 1 persist after obliteration of esophageal varices bleed significantly more often, they form a group which requires prophylactic treatment. It is known that fundal varices (GOV 2 and IGV 1) are at a higher ~ ~Large , fundal risk of bleeding than junctional (GOV 1) ~ a r i c e s .lol varices with red signs are even more likely to bleed.51Therefore, large fundal varices constitute a subset which could be treated prophylactically. Kim et a151in their prospective study documented a bleeding rate of 53% from fundal varices larger than 2 cm in size in a median followup period of 15.2 months. According to the available data, the rebleeding rate after glue injection or transjugular intrahepatic portosystemic shunt (TIPS) placement is less than 30% over a similar follow-up period. Therefore, it seems logical to undertake clinical studies to assess the utility of prophylactically treating large fundal varices. Acute Gastric Variceal Bleeding The treatment goals for acute gastric variceal bleeding are the same as for esophageal varices: to control bleeding and to prevent rebleeding. Indications of treatment are Active bleeding are from gastric varices (Fig. 7) Stigmata of a recent bleeding episode on gastric varices History of a previous bleeding episode and presence of gastric varices as the only source of bleeding These patients need to be treated according to the type of gastric varices and the expertise available. Sometimes, however, it is not possible to determine whether a patient with esophagogastric varices is bleeding from esophageal or gastric varices. In such a situation, opinions differ as to whether the esophageal or gastric varix should be injected first. An active hemorrhage from GOV 1 could be controlled by sclerotherapy, variceal ligation, or glue injection of esophageal varices. For bleeding GOV 2, however, there is no clear information. The authors recommend ligating the esophageal varices and injecting the GOV 2 with glue at the same session. The endpoint of treatment in patients who have bled from gastric varices should be eradication of varices, because the rebleeding rate is significantly lower in those in whom eradication is achieved than in those in whom varices do not disappear?8A number of interventional strategies can be employed for the management of gastric varices bleeding. Balloon Tamponade Two types of balloons are available for the control of active bleeding from gastric varices: the Sengstaken-Blakemore tube and the Linton-

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Figure 7. Active bleed from GV. (Courtesy of Georgio Battaglia, Italy.) (See also Color Plate 1, Fig. 4.)

Nachlas tube. The latter has a single, large gastric balloon with a capacity of 600 mL and is preferred for controlling acute gastric varices bleeding.118 Vasoactive agents

Because the primary pathologic condition in patients with gastric varices is raised pressure and splanchnic vasodilation, it is reasonable to assume that vasoactive drugs may be as effective in controlling gastric varices bleeding as in esophageal variceal bleeding. There are, however, limited published data on the role of vasoactive drugs in the control of acute bleeding from gastric varices. Gastric Variceal Sclerotherapy

Gastric variceal sclerotherapy (GVS) could be performed intravariceally or by a combination of intravariceal and paravariceal injections. Initial control of active bleeding has been reported with GVS in 40% to 100% of cases (Table 2).6,9, 13, 24, 72, 75,Io3, 124 Two studies have shown equal efficacy of emergency GVS for GOV 1 and GOV 2,9. Io3 whereas studies by Oho et a1 and Gimson et a1 show a higher success rate for GOV 1 than for GOV 2.24,75 Chiu et a1 performed emergency GVS in 27 patients with isolated gastric varices with a success rate of 67% and a rebleeding rate of 18%at 48 h 0 ~ r s . I ~ The major problem with GVS is a high rebleeding rate. This rebleeding could be caused by rapid blood flow in gastric varices, making

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Table 2. GASTRIC VARICEAL SCLEROTHERAPY IN ACTIVE GASTRIC VARICEAL BLEEDING Author (year)

Agent

T r u d e a ~ ’ ~ ~ STD (1986) Bretagne6(1986) Polidocanol 1.5% Gimsonz4(1991) EO/glue EO 5% Chang9 (1996) Chang9 (1996) ChiuI3 (1997) SarinIo3(1997) Ogawa” (1999)

STD 1.5% GW 50%

STD 1.5% AA 100% EO 5%

Number in Study

Success

Rebleeding

(”/.I

(“4

Complications

100

90

Ulcer 89%

10

60

63

NA

41

40 GOVl GOV2 67 GOVl GOV2 80 GOVl GOV2 92 GOVl GOV2 67 67 GOVl GOV2 81

16

Ulcers 29%

25 20 33 70

Ulcers 25%

30

Ulcers 30%

19 34

NA Ulcers 100%

35

Fever 19%

9

24 25 26 27 18 21

=

54 26

= =

85 50

= =

80 80

=

92 92

=

=

= =

Ulcers 30%

67 60

STD = sodium tetradecyl sulfate; EO = ethanolamine oleate; GW = glucose water; AA = absolute alcohol; NA = data not available; GOV = gastroesophageal varices

formation of a thrombus difficult. The early appearance of ulceration in .incompletely obliterated varices predisposes to recurrent bleeding which usually occurs after the first or second GVS session. Moreover, unlike esophageal variceal ulcers which are generally mucosal, ulcers following GVS are deep and submucosal. Approximately 50% of the post-GVS hemorrhages are from ulcers.9, lz4 Chang et a1 have shown a higher rebleeding rate (70% versus 30%) with sodium tetradecyl sulfate (STD) than with 50% glucose water and also delayed ulcer healing (13 ? 5 days versus 6 ? 2 days).9Once rebleeding occurs, it is difficult to control with repeat GVS, the success rate being only 9% to 44%.9f103,124 Using repeated GVS, variceal eradication can be achieved in 17% to 81% of patients with a bleeding rate of 16% to 70% (Table 3).9,24,103,136 Variceal obliteration is achieved in a higher proportion of patients with GOV 1 (94%) than in patients with GOV 2 (70%) and IGV 1 (41%). Rebleeding is seen in 5.5%, 1970, and 53% of patients, respectively, in the three types of gastric varices.lo3The recurrence rate of gastric varices has been variably reported from 0% to 25Y0.~. lo3, 136 If an agent which produces less mucosal ulceration and achieves complete and rapid obliteration of gastric varices is developed, it will significantly reduce the early rebleeding rate following GVS. The characteristics of an ideal sclerosant for gastric varices are outlined in the box. lo37

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Requisites for an Ideal Sclerosant for Gastric Variceal Sclerotherapy

Instantaneous and local action in the gastric varices Requires single session for obliteration of gastric varices Lack of ulceration Technically easy to inject rapidly Causes no damage to the injector or endoscope No adverse splanchnic, pulmonary, or systemic effects Low in cost Readily available

Poly-N acetyl glucosamine, a polysaccharide polymer originating from marine microalgae, has been shown to produce rapid and effective hemostasis by stimulating erythrocyte aggregation and variceal eradication by inducing an inflammatory reaction in a rabbit Clinical studies with this agent are awaited. Tissue Adhesives Two tissues adhesive agents, N-butyl-2-cyanoacrylate (Histoacryl) and isobutyl-2-cyanoacrylate (Bucrylate) have been used, although the latter agent has been withdrawn from the European market because of concerns about carcinogenicity. Native cyanoacrylate is a liquid with a consistency similar to water and therefore lends itself to intravariceal injection. When added to a physiologic medium such as blood, the cyanoacrylate rapidly polymerizes, forming a hard substance. Thus, after injection into a varix, the cyanoacrylate plugs the lumen and results in rapid hemostasis. Several weeks (2 weeks to 3 months) after the injection,

Table 3. GASTRIC VARICEAL SCLEROTHERAPY IN SECONDARY PROPHYLAXIS OF GASTRIC VARICEAL BLEEDING Agent

Ya~sin’~~ (1985) Girn~on*~EO/glue (1991) STD Chang9 1.5% (1996) Changq GW 50% (1996) AA 100% Sarinlo3 (1997)

No. in

Obliteration

Rebleeding

(“A)

(“G

Recurrence

Study

(“/I

Follow-up (months)

35

17.1

37

NA

-

31

32.3

16

NA

-

25

32

70

25

26

81

30

4.8

57 2 32

60

72 GOVl94 GOV2 70

23

0

24 ? 23

AA = absolute alcohol; EO = ethanolamine oleate; GW tetradecyl sulfate; GOV = gastroesophageal varices

=

glucose water; STD

52 f 37

=

sodium

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the mucosa overlying the injected area sloughs off, and a glue cast is extruded into the stomach (Fig. 8). Because ulceration over the varix occurs much later than with GVS, it does not hinder repeat glue injections and also reduces the risk of ulcer bleeding. Tissue adhesives, therefore, come close to meeting the requirements of a good sclerosing agent for gastric varices. Cyanoacrylate injection has been shown to achieve hemostasis in more than 90% of patients with acute gastric variceal bleeding, with an early rebleeding rate of 0% to 28%.19,27, 29, 39, 52, 58, 72, 75, 89-91, Io9 Glue injection in 1 or 2 sessions can achieve variceal obliteration in 87% to 100% patients (Table 4).19,29, 39, 52, 58, 90, 91, Io9 The term obliteration more accurately describes the desired immediate endpoint for glue injection of gastric varices than eradication, because a varix occluded with cyanoacrylate may remain endoscopically visible for many weeks. The methods used to assess the success of variceal obliteration include palpating the varix with a blunt instrument (soft rather than hard), radiographic visualization of varices filled with lipiodol and cyanoacrylate mixture, and endoscopic ultrasound58(absence of hypoechoic vascular channels in fundus and cardia) (Fig. 9). The clinical significance of using endoscopic ultrasound to define eradication remains to be assessed in terms of rebleeding rate and survival. Although the glue is injected like a sclerosant, its unique adhesive properties require some modifications in the technique. It is important to ensure the intravariceal position of the needle. To prevent damage to the endoscope by the adhesive, lipiodol, an oily contrast agent, or silicone oil can be smeared at the tip of the endoscope and in the working channel. The glue is mixed with lipodol (in a ratio of 0.5:O.g mL)

Figure 8. Extrusion of glue cast after 3 weeks of injection of cyanoacrylate in the GV. (Courtesy of Georgio Battaglia, Italy) (See also Color Plate 1, Fig. 5.)

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Table 4. GLUE INJECTION IN THE MANAGEMENT OF GASTRIC VARICES ~~~

Total No. of Patients

Active Bleeding (“3)

GotlibZ7(1984)

96

22

95

-

RamondS9(1986)

49

31

93

-

138 27 39 23 29

22 26 69 100

54

41

17 174

100

Author (year)

SohendraIo9(1987) Ramondgo(1989) Rauws91(1991) GrimmZ9(1991) oh075 (1995) DImperio19 (1996) O g a ~ a (1999) ’~ Kinds2(2000)

H ~ a n (2000) g~~ Lee58(2000) GOV

=

-

-

90 54

gastroesophageal varices; IGB

5.5 48

=

Immediate Success

(“w

100 86 100 100 93 GOVl 100 GOV2 88 91

100 97

94.4 96.3%

Rebleeding Eradication

(“w

100 100 100 100 -

87

70 GOVl 75 GOV2 73 IGVl 32 36 80

(W (follow-up) 36 (9 months) 42 (1 year) 10 37 41 0 30 25 33 3.7 5.9 30.4 (36 months) GOVl 19.6 GOV2 18.9 IGVl 66.5 23 26 (14.8 months)

isolated gastric varices

to prevent premature solidification within or at the tip of the catheter during injection and to help in radiologic evaluation of the injected material. Unnecessary suction should be avoided during the procedure. The total amount of N-butyl-2-cyanoacrylate injected per aliquot should not exceed 2 mL to decrease the risk of thrombotic complicat i o n ~ Cerebral .~ stroke, presumably caused by anomalous right-to-left

Figure 9. Injection of cyanoacrylate glue into the GV under guidance of endoscopic ultrasound (Courtesy of Georgio Battaglia, Italy) (See also Color Plate 1, Fig. 6.)

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shunt has been reported in two cases,lo7fatal pulmonary embolization has been reported in one and bacteremia has been reported in a patient with portal vein embolizafi~n."~ Splenic infarctionloand formation of retrogastric abscess127have also been reported after injection of cyanoacrylate in patients with bleeding gastric varices. These complications caution against the indiscriminate use of glue in all patients with variceal bleeding. For patients with gastric varices, however, the benefits of glue injection outweigh the potential risks. The concern about the potential carcinogenicity of cyanoacrylate observed in rats are probably ill founded.92So far, there are no reports of carcinogenicity in more than 2000 patients treated for variceal bleeding with cyanoacrylate. Comparison of gastric variceal sclerotherapy and glue injection. Three studies have compared sclerotherapy using ethanolamine oleate (5%) or absolute alcohol and cyanoacrylate injection in acute gastric variceal bleeding (Table 5).", 75, lo5Ogawa et al" in a retrospective study, reported a significantly higher hemostasis rate with cyanoacrylate than with ethanolamine oleate (100% versus 81%). Although 6 (35%) of 17 patients in the ethanolamine oleate group rebled at 2 weeks, none in the histoacryl group rebled. Whereas 5 (23.8%) of 21 patients in ethanolamine group died, none died of bleeding in the group receiving cyanoacrylate glue. Oh0 et a175in their prospective, nonrandomized study of 53 patients with acute gastric varices bleeding reported cyanoacrylate to be significantly more efficacious in achieving hemostasis than ethanolamine oleate (93% versus 67%). Three patients in each group rebled at 1 month. Three other -patients in the cyanoacrylate group rebled 6 months after treatment from the site of polymer elimination. A randomized, controlled trial at the G. B. Pant Hospital in 37 patients with fundal varices showed that cyanoacrylate is more effective than alcohol injection in achieving initial hemostasis and in achieving faster variceal obliteration. The need for emergency surgical rescue was also much less in the glue-injected group.1o5 The results of these three comparative studies indicate that cyanoacTable 5. GASTRIC VARICEAL SCLEROTHERAPY VERSUS GLUE INJECTION IN GASTRIC VARICEAL BLEEDING

Author (year) oh075

(1995)

Ogawan (1999)

Sarir~'"~ (2001)

Agent

EO glue EO glue AA glue

No. in Study

24 29 21 17 8 9

Control of Acute Bleeding

Rebleeding

Mortality

Ulcer

("/I

("/I

("/.I

("/I

67 93 81 100 62 89

12.5 10 35 0 25 22

67 38 23.8 0 25 11

25 30 -

EO = ethanolamine oleate; AA = absolute alcohol

-

82 65

744

SARIN & AGARWAL

rylate is more effective than sclerosants such as ethanolamine oleate or absolute alcohol. The difference in the hemostasis rates between sclerosants and the glue results from their different mechanisms of action. Ethanolamine and absolute alcohol induce hemostasis by formation of a thrombus. Whereas thrombus formation is often possible in esophageal varices, it is difficult to achieve in gastric varices because of rapid blood flow. Cyanoacrylate, on the other hand, induces venous thrombosis instantaneously by polymerization, regardless of the rate of blood flow. Thrombin Human and bovine thrombin have been safely used in esophageal and gastric variceal sclerotherapywithout any report of distant thrombosis. Williams et using bovine thrombin, reconstituted to 1000 U/mL intravariceally, achieved initial hemostasis and obliteration in all 11 patients with two injection sessions. Rebleeding was observed in only one patient over a median follow-up of 9 months. Similar results have been reported in another study.ssThe most important advantage of this approach is the absence of any mucosal damage or postsclerotherapy ulceration that is characteristics of sclerosants and tissue adhesives. The widespread evaluation of this technique is limited by cost and lack of availability of the product, which is yet to be approved by the Food and Drug Administration. Endoscopic Variceal Ligation Endoscopic variceal band ligation is an effective and safe method for managing bleeding esophageal varices. The development of multiband ligating devices has made EVL technically easier even with the endoscope retroflexed in the stomach. Gastric variceal ligation (GVL)has been evaluated for the treatment of bleeding gastric varices in a prospective, uncontrolled study by Shiha et a1 (Fig. These investigators were able to achieve hemostasis in 89% of patients, with rebleeding in 18.5%. Obliteration of gastric varices could be achieved in all patients with a median of three sessions. Ulcers were seen at the ligation site in all patients 1 week later. One study has compared cyanoacrylate injection with GVL in 16 patients. The methods were found to be equally effective in achieving hemostasis with a similar rebleeding rate.5oMore randomized studies would be needed before variceal band ligation can be recommended as a safe and effective modality for the treatment of gastric varices. Endoscopic-snare Ligation The major concern with GVL is incomplete inclusion of large gastric 130 Many investigavarices during ligation and subsequent bleeding.115, tors have therefore used a snare for ligation of gastric varices that are more than 1 cm in size.

GASTRIC VANCES AND PORTAL HYPERTENSIVE GASTROPATHY

745

Figure 10. Gastric variceal ligation. (Courtesy of Garnal Shiha, MD, ECMansoura, Egypt)

Yoshida et used a detachable snare with an inner diameter of 4 cm to tighten around the varix base, grasping the periphery of varix with a forceps through the second channel of the double-channel endoscope. High success rates (83%-100%) in the control of acute gastric varices bleeding and variceal eradication with low recurrence rates have been reported by them and by others (Table 6).15,32, 115, 137, 138 Although no significant ulcer-related complications were seen, gastric perforation was reported in two patients in one There are no randomized, controlled studies in humans comparing various modalities for the treatment of gastric varices. Jutabha et a146 have compared sclerotherapy, cyanoacrylate injection, and rubber-band ligation in a randomized, nonblinded study in canine gastric varices. They reported that intravariceal sclerotherapy was the fastest and easiest to perform. Rubber-band ligation was intermediate in technical ease, but it caused the largest and deepest ulcers and had the highest rate of stigmata of ulcer hemorrhage and secondary bleeding. Cyanoacrylate injection was the most cumbersome endoscopic method. All the three treatments were effective for controlling bleeding. Balloon-occluded Retrograde Transvenous Obliteration of Gastric Varices

A gastrorenal shunt is often present between gastric varices and the catheter can left renal vein in patients with fundal v a r i c e ~A. ~balloon ~~

GVL-S GVL & GVL-S GVL-S GVL-S GVL-S + EIS GVL

Y ~ s h i d a (1994) ’~~ Takeuchi115(1996) Harada32(1997) Cip~lletla’~ (1998) Y ~ s h i d a (1999) ’~~ ShihaIo8(1999)

10 45 5 7 35 27

No. in Study 10 13 100 100 23 7

Active Bleeding (%)

GVL = gastric variceal ligation; GVL-S = gastric variceal snare ligation; EIS varices; IGV = isolated gastric varices

Modality

Author (year)

=

10 2 20 0 3 18.5

Rebleeding (%)

=

=

-

0 5 NA NA 6 NA

gastroesophageal

0 0 11

-

4.4

Mortality (%)

(%I

Recurrence

data not available; GOV

94 NA NA 97 100

100

(“a

Obliteration

endoscopic injection sclerotherapy; NA

100 83 100 100 100 89 GOVl 100 GOV2 80 IGVl 100

(%I

Success

Table 6. GASTRIC VARICEAL LIGATION IN THE MANAGEMENT OF GASTRIC VARICEAL BLEEDING

GASTRIC VARICES A N D PORTAL HYPERTENSIVE GASTROPATHY

747

be introduced in the gastrorenal shunt through the left renal vein, and the shunt can be occluded by inflating the balloon. A sclerosant (usually a mixture of ethanolamine oleate and a noniodinated contrast medium) is then injected into the gastric varices and left to remain for a few hours till injection of the contrast medium shows that clots have formed in the varices (Fig. 11). Balloon-occluded retrograde transvenous obliteration (BRTO) has been reported to have a high success rate (100%) in obliteration of gastric varices and a low recurrence rate.36* 49, 63 The same technique has been used to treat chronic portosystemic encephalopathy.12,73 Therefore, BRTO could serve as a feasible alternative to TIPS for patients with large gastrorenal shunts or hepatic encephalopathy, for whom TIPS is contraindicated. The major problem with BRTO is aggravation of esophageal varices because of a rise in portal pressure subsequent to 49, 63 Another problem is hemolysis occlusion of gastrorenal caused by ethanolamine oleate which requires haptoglobin administration and subsequent renal damage. Transjugular lntrahepatic Portosystemic Shunt

Transjugular intrahepatic portosystemic shunt is considered to be the current standard therapy for bleeding esophagogastric varices that are unresponsive to endoscopic and pharmacologic treatment, and especially for gastric va~ices.~, 9, 55 Placement of TIPS abruptly reduces the outflow hepatic resistance, lowers portal pressure, and diverts portal flow from gastroesophageal collaterals through the stent. The procedure has been shown to achieve initial control of bleeding in more than 90% of patients (Table 7): 11, 93, 112 The rebleeding rate is 16% to 30%, often because of stenosis or obstruction of the stent. Shunt dysfunction occurs

Figure 11. Balloon occluded retrograde transvenous obliteration (BRTO) for obliteration of

GV.(From Hirota S, Matsurnoto S, Tomita M, et al: Retrograde transvenous obliteration of gastric varices. Radiology 211:349-356,1999; with permission.)

Unresponsive to endoscopic treatment in 18 Unresponsive to vasoconstrictors Unresponsive to vasoconstrictors, sclerotherapy, tamponade Naive patients

Stanley” (1997) Chad1 (1998) Barange3(1999)

NA

=

data not available

R e e (2000) ~ ~ ~

Patient Characteristics

Author (year)

12

32 28 32

No. of Patients ~~

NA

34.4 100 62.5

Active Bleeding (%)

Table 7. TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT IN GASTRIC VARICES

NA

NA 96.4 90

Hemostasis (%)

16

15.9 29 31

Rebleeding (“7’0)

17

14.2 7 12

FOllOW-up (months)

GASTRIC VARICES AND PORTAL HYPERTENSIVE GASTROPATHY

749

in approximately 50% to 60% of patients at 6 months, requiring close monitoring and repeated interventions to keep it patent. Because most patients with large IGV 1 have well-developed gastrorenal there is a risk of causing intractable hepatic encephalopathy by TIPS. Surgery

Several studies have reported good results with surgical intervention in gastric varices.28,37, 67 The recommended operations include portosystemic shunt, distal splenorenal shunt, and esophageal transection. The role of surgery in the treatment of gastric varices has, however, changed with the emergence of new treatment modalities, such as glue injection, TIPS, and BRTO. The application of surgical techniques in the management of gastric varices can be divided those used in patients with segmental portal hypertension without any liver disease and those used in patients with generalized portal hypertension. Surgery in patients with segmental portal hypertension. Splenectomy effectively cures most patients with left-sided, segmental portal hypertension without liver disease. Madsen et a160reviewed the literature and described the course of 72 patients, up to 24 years after splenectomy for segmental portal hypertension. Only two patients rebled after splenectomy. The mortality rate after splenectomy has been reported to be Endoscopic interventions are not quite effective in patients around ~YO.'~O with segmental portal hypertension. The success rate of both GVS and glue injection was gastric variceal reported to be around 30% in the Italian failure to control gastric variceal bleeding resulted in a reduced long-term survival rate of 16.6%. Surgery in patients with generalized portal hypertension. Abundant information is available on the surgical management of gastroesophageal varices. Little, however, is mentioned specifically about the management of gastric varices. No clear guidelines are available on the selection of patients for a given surgical procedure. For patients with generalized portal hypertension and isolated gastric varices, a definitive treatment is ,advisable. Hosking and Johnson37advocate surgical ligation of varices with gastric devascularization for the control of active bleeding from such varices but suggest a shunt procedure if lesser-curve varices are present. Alternatively, for patients with acute gastric variceal bleeding, an emergency shunt might be equally effective. According to Wood et al,134the shunt of choice is a large-bore H-graft mesocavall or mesorenal shunt. This shunt effectively controls the acute bleeding, is relatively simple to perform, does not influence the subsequent transplantation, and can be ligated after transplantation is completed. For an elective procedure, a distal splenorenal shunt is preferred by many surgeons because it maintains hepatic portal perfusion and does not require dissection of the porta hepatis.131At the G. B. Pant Hospital, devascularization for uncontrolled bleeding and portosystemic shunting has been used for elective control of recurrent bleeding from gastric varices with

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good long-term contr01.’~Recently, Tomikawa et have used gastric devascularization and splenectomy in 42 patients with IGV, with eradication of gastric varices in 100% of patients and no recurrence in a followup of 46 months. Orthotopic Liver Transplantation

The survival rates in patients who have received transplantation indicate that orthotopic liver transplantation (OLT) is a useful alternative to other modalities of treating gastric varices. The differences become more prominent when the survival rates of Child’s class C patients who received liver transplantation (79% at 1 year and 71% at 5 years) are compared with those of Child’s class C patients who were treated with shunts (30% to 70% at 1 year and 15% to 35% at 5 years).‘,13 These results of OLT bring a ray of hope for the large number of patients with cirrhosis and portal hypertension, including those with gastric varices. At present, however, for a significant proportion of patients, transplantation remains an expensive and difficult option. Long-Term Follow-Up of Gastric Varices

Although a number of trials have reported the long-term outcome of endoscopic management of esophageal varices, data on long-term follow-up after gastric variceal obliteration are scanty.lo3The available data indicate that the recurrence rates after obliteration with sclerotherapy are much lower in patients with gastric varices than in patients with esophageal varices.’03 Summary of Endoscopic Interventions for Gastric Varices

Patients with active gastric varices bleed or those who have bled in the past from gastric varices are candidates for endoscopic intervention. A rational approach to control acute bleeding from gastric varices and subsequent management is shown in Figures 12 and 13. The definitions of success and failure of control of bleeding, however, have been specifically developed only for esophageal varices,’8 and not for gastric varices. If it is not clear whether the active bleeding is from esophageal or gastric varices, it is recommended that the esophageal varices be ligated and the gastric varices be injected. The agent of choice for injection of gastric varices is cyanoacrylate glue because it achieves more rapid and effective hemostasis with high obliteration rates. Gastric variceal sclerotherapy using absolute alcohol or ethanolamine oleate is an effective alternative treatment. With both techniques, but particularly with sclerotherapy, care must be taken to decrease the frequency of ulcers developing following injection, which cause recurrent bleeding. Transjugular intrahepatic portosystemic shunt and surgery remain good options for patients with uncontrolled gastric variceal bleeding or in patients with

GASTRIC VARICES AND PORTAL HYPERTENSIW GASTROPATHY

751

Figure 12. Algorithm for the management of acute bleeding from gastric varices. GVS Gastric variceal sclerotherapy.

=

IGV 1 where endoscopic therapies have limited efficacy. Further advances in the management and outcome of gastric variceal bleeding can come only when the natural history, risk factors for bleeding, and the mechanism of gastric variceal rupture are better defined.

Figure 13. Algorithm for the elective management of gastric varices. EST = Endoscopic sclerotherapy; EVL = Endoscopic variceal ligation; ESO.Vx = Esophageal varix; GVS = Gastric variceal sclerotherapy.

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PORTAL HYPERTENSIVE GASTROPATHY Definition

The coexistence of gastric mucosal lesions and portal hypertension has long been known, but the vascular nature of these lesions was appreciated rather recently.65Portal hypertensive gastropathy (PHG) is generally diagnosed on the basis of endoscopic features. Portal hypertensive gastropathy involves macroscopic changes of gastric mucosa associated with mucosal and submucosal vascular ectasia and dilation without significant inflammatory changes. Histologic comfirmation is needed when the lesions are not characteristic or when other conditions such as gastric antral vascular ectasia (GAVE), Helicobacter pylori infection, or drug-induced mucosal lesions need to be excluded. Description and Classification of Portal Hypertensive Gastropathy Lesions

The elementary lesions of PHG have been classified according to the North Italian Endoscopic Club (NIEC) classification7as follows: 1. Mosaic like pattern (MLP) is defined as the presence of small, polygonal areas surrounded by a whitish-yellow depressed border. The mosaic is defined as mild when the areola is uniformly pink, moderate if the center is red, and severe if the areola is uniformly red. 2. Red-point lesions (RPLs) are small, flat, red, pointlike lesions less than 1 mm in diameter. 3. Cherry-red spots (CRSs)are red-colored, round lesions more than 2 mm in diameter and protrude slightly into the lumen of the stomach. 4. Black-brown spots (BBSs) are irregularly shaped, flat spots, black or brown, persistently present after washing, and caused by intramucosal hemorrhage.

In the recent consensus statement of the Baveno I11 meeting on portal hypertension,ls the following classification was proposed: 1. Mild: when MLP of mild degree (without redness of areola) is present. 2. Severe: when the MLP is superimposed by red signs or if any other red sign is present. Several investigators have examined the sensitivity and specificity of PHG lesions in the diagnosis of portal hypertension.4l.59, 68, 99* lZ3, lz9 They have consistently reported that a snake-skin (mosaic) pattern is of high specificity (93%to loo%), but controversy exists as to the sensitivity of this sign. Papazian et alS1found the mosaic pattern in 94% patients with cirrhosis and in 87% of patients with noncirrhotic portal hyperten-

753

GASTRIC VARICES AND PORTAL HYPERTENSIVE GASTROPATHY

Table 8. SENSITIVITY, SPECIFICITY, AND DIAGNOSTIC ACCURACY OF SNAKE-SKIN (MOSAIC) PATERN FOR DIAGNOSING PORTAL HYPERTENSION Snake-skin Pattern for Diagnosing Portal Hypertension

Sensitivity

(%I

Specificity

Author

(%I

Diagnostic Accuracy (%)

Viggiano & Gostout'2y Papazian et aP1 Sarin et aPY* Misra et a P * Lin et a159 Iwao et a14' Total

40 94 7 14 41 30 38

93 100 99 99 100 95 98

67 98 74 96 71 63 78

*Includespatients with noncirrhotic portal hypertension From Toyonaga A, Iwao T Portal hypertensive gastropathy J Gastroenterol Hepatol 13:865-877, 1998; with permission.

sion. The authors, however, found this sign in only 7% of patients with cirrhosis and in none of the patients with noncirrhotic portal hyperten~ion.~~ Several authors41,59, lZ9have described the prevalence of this sign to be around 30% to 40%. These differences may be explained by differences in the study populations or by poor interobserver agreement (Table 8). The prevalence of PHG in patients with portal hypertension ranges from 4% to 98% (mean prevalence 53%).lZ4 Mild PHG is more common, occurring in 20% to 57% of patients (mean prevalence 49%); severe PHG is found in 7% to 41% of patients (mean 14%) (Table 9). Mucosal abnormalities encountered in PHG are typically found proximal to antrum, most often in the fundus and corpus.123 Table 9. THE PREVALENCE OF PORTAL HYPERTENSIVE GASTROPATHY (PHG) No. of Patients with PHG

Author

Number of Patients Studied

Mild (%)

Severe (%)

Overall (%)

McCormack et a1 McCormick et a1 Sacchetti et a1 Sarin et a1 D'Amico et a1 Cales et a1 Rabinowitz et a1 DeWeert et a1 Gupta et a1 Iwao et a1 Total (%)

93 127 142 107 212 100 510 81 230 476 2078

67 (72) 37 (29) 28 (20) NR 110 (52) 57 (57) NR NR 121 (53) 208 (44) 628/1380 (46)

18 (19) 28 (22) 10 (7) NR 20 (9) 41 (41) NR NR 21 (9) 46 (10) 184/1380 (13)

85 (91) 65 (51) 38 (27) 4 (4) 130 (61) 98 (98) 218 (43) 75 (93) 142 (62) 254 (53) 1109/2078 (53)

NR = not reported From Toyonaga A, Iwao T. Portal hypetensive gastropathy J Gastroenterol Hepatol 1998; 13:865-77; with permission.

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Gastric Antral Vascular Ectasia

Another important endoscopic lesion seen in portal hypertension patients is GAVE. This entity was recognized more than a decade ago as having distinct clinical, endoscopic, and histopathologic features.45It has been reported in association with scleroderma, atrophic gastritis, and cirrhosis.25The lesion is characterized by aggregates of red spots, arranged in a linear pattern in the antrum of the stomach (hence the term watermelon stomach). The ectatic red spots may be more diffuse and involve the proximal antrum as well. The condition is then termed di@se GAVE or gastric vascular ectasia (GVE).The typical watermelon appearance has been described in patients without portal hypertension and is localized in the antral area.23,113 In patients with cirrhosis, the diffuse form is more common. It is therefore not surprising that some investigators may diagnose diffuse GAVE as the severe form (red spots) of PHG. Such disagreement and confusion concerning PHG and GAVE can explain the differences in the reported prevalence of GAVE in cirrhotics. Nevertheless, the histological features of diffuse GAVE are different from those of severe PHG. Gilliam’s (which takes into account the presence of fibrin thrombi and ectasia in mucosal vessels and spindle cell proliferation in the superficial mucosa) is higher in GAVE than in severe PHG. Furthermore, fibrohyalinosis is more frequently observed in GAVE than in severe PHG.MIf this feature is added to Gilliam’s score, it provides increased diagnostic accuracy in differentiating GAVE from severe PHG.8 Portal hypertensive gastropathy should be diagnosed only if the MLP lesion is the underlying lesion. If there is no mosaic appearance, GVE is the likely diagnosis.87In the recently held Baveno I11 meetingla GAVE was described as a distinct entity characterized endoscopically by aggregates of red spots arranged in linear pattern or as a diffuse lesion in the antrum of stomach, if confirmed by biopsy. The pathogenetic role of portal hypertension for the development of GAVE is controversial, because these lesions can occur in the absence of portal hypertensi~n:~and in portal hypertensive patients these lesions do not seem to respond to measures adopted to decrease portal pressure.48, Therefore, although further studies are needed to clarify the pathophysiology of GAVE and PHG, it is important to identify criteria to differentiate between GAVE and severe PHG, because PHG, but not GAVE, seems to respond favourably to a decrease in portal pressure. Histological Findings

Cirrhotic stomachs have a significantly greater number of submucosal arteriovenous communications beneath the muscularis mucosae, dilated precapillaries, capillaries, and veins, thickening of submucosal arteriolar walls and extensive submucosal edema.33An ultrastructure

GASTRIC VARICES AND PORTAL HYPERTENSIVE GASTROPATHY

755

study has shown the extravasation of red blood cells through a defective part of the endothelium and interposition of red blood cells in interepithelial spaces in patients with PHG.4O These findings are quite different from the histologic features of gastritis. Pathogenesis Portal Pressure

Although little correlation has been found between the severity of portal hypertension and PHG, it is agreed that a chronic increase in the portal pressure is a prerequisite for the development of this disorder. First, PHG is not seen in patients who have undergone portal decompressive Second, portosystemic shunt is effective in the management of PHG Portal hypertensive gastropathy tends to develop in patients with esophageal varices rather than in those without varices.16,117 In addition, several authors have found that the size of the esophageal varices is correlated with the severity of PHG.16,117 The frequency of PHG is higher in patients with large esophageal varices and esophagogastric varices. Portal hypertensive gastropathy is uncommon in patients with isolated fundal varices4, and splenogastrorenal Furthermore, there is some evidence that PHG occurs more often in cirrhotic than in noncirrhotic portal hypertension.68,99 In patients with cirrhosis, the degree of liver dysfunction correlates with the severity of PHG.31,lo2Thus, factors other than portal pressure may also be involved in the pathogenesis of PHG. Humoral Factors

Gastrin, glucagon, and prostaglandin E, have been implicated in the pathogenesis of PHG. The systemic and the splanchnic vasodilatation in portal hypertension may be caused, at least in part, by an excess formation of endothelium-derived nitric oxide (NO). In animal models of portal hypertension, Casadevall et a18 have demonstrated that a NO inhibitor attenuates gastric mucosal hyperemia, suggesting that increased gastric NO biosynthesis may be involved in the pathogenesis of PHG. In addition, the levels of endothelin-1 mRNA have been found to be decreased, resulting in the imbalance of endothelin and NO.30The mechanism of angiogenesis in the portal hypertensive gastric mucosa has been recently studied. Vascular endothelial growth factor (VEGF) and hexosamine concentration have been found to be elevated and associated with angiogenesis in PHG.lZ5 Helicobacter Pylori infection

The relationship between PHG and the prevalence of H. pylori infection has been investigated. Colonization with H. pylori was not

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found to be related to the presence of PHG.83Thus, a pathogenic role of H. pylori in PHG seems unlikely. Gastric Mucosal Hemodynamics

An understanding of the gastric mucosal hemodynamics in PHG patients has been elusive because of technical difficulties and lack of reproducibility of the data. Nishiwaki et a171reported a decreased gastric mucosal blood flow in cirrhotics with portal hypertension the reduction was more pronounced in patients who had gastric mucosal lesions. In contrast, increased gastric mucosal blood flow in cirrhotics has been observed using radionuclide angiography, reflectance spectrophotometry, and laser Doppler flowmetry.n, 12* It is important to understand whether congestive gastric mucosal circulation is caused by overflow or stasis. In a recent study, rheologic analysis of gastric mucosal hemodynamics was performed using endoscopic laser Doppler flowmetry. This study revealed significantly higher hemokinetic stress in severe PHG cases than in mild cases or controls.62 These studies suggest an overflow or active congestion rather than passive congestion in PHG. This possibility is further supported by a study by Gupta et al3I in which gastric mucosal blood flow was found to be inversely correlated with the hepatic perfusion index (ratio of arteria1:portalvenous perfusion). It was shown that the hepatic perfusion index decreased according to the Child-Pugh score, confirming that the severity of PHG correlates with the severity of liver disease. Better methods for measurement of gastric mucosal hemodynamics are needed, however. Natural History of Portal Hypertensive Gastropathy

Portal hypertensive gastropathy is a dynamic condition. On endoscopic evaluation, lesions can appear de novo, progress from mild to severe with time, and also revert from severe to mild, and even disappear completelys6,lo4 Primignani et alS6found that PHG remained unchanged in only 29% of patients; worsening or improvement were each observed in about 25% of patients. Spontaneous resolution of PHG lesions, often within 3 to 6 months, was also observed by Hou et a1 in nearly 55% of patients.38In a large study from the G. B. Pant Hospital,lo4 967 patients with variceal bleeding who had achieved variceal obliteration were carefully followed. In all, 88 patients (9.1%) had distinct mucosal lesions of PHG, 22 (26%)had PHG before eradication (Group A), and 64 (74%)had developed PHG after variceal eradication (Group B). During a mean follow-up of 25.1 2 14.2 months, PHG lesions persisted or progressed more often in Group A than in Group B ( P < 0.05) (Table 10). Furthermore, in patients who had preexisting PHG, endoscopic therapy for varices worsen the PHG, with a likelihood of bleeding (Table 11).

757

GASTRIC VARICES AND PORTAL HYPERTENSIVE GASTROPATHY

-

Table 10. CLINICAL COURSE OF PORTAL HYPERTENSIVE GASTROPATHY (PHG) IN PATIENTS WITH PREEXISTING AND POSTSCLEROTHERAPY PHG Clinical Course of PHG

Progressive

No.

Transient (%)

Persistent

Onset of PHG

Preexisting Developing after sclerotherapy Total

22 64 86

2 (9) 28 (44)* 30 (34.9)

17 (77) 31 (48) 48 (55.8)

5 (8) 8 (9.3)

(W

(W

*P < 0.05, compared with group A From Sarin SK, Shahi HM, Jain M, et al: The natural history of portal hypertensive gastropathy: Influence of variceal eradication. Am J Gastroenterol 952888-2893, 2000; with permission.

Several groups have shown that PHG is aggravated after sclerotherspy", Io2, Io4 and banding therapy38for esophageal varices. This aggravation occurs irrespective of the origin of portal hypertension.lo2The aggravation of PHG is probably caused by enhancement of gastric mucosal congestion by acute blockage of gastric mucosal blood flow. The gastric mucosal laser Doppler signal and gastric mucosal oxygen saturation are significantly decreased, and gastric mucosal haemoglobin concentration is significantly increased in patients with aggravation of PHG after banding therapy.lI6 Injection sclerotherapy for esophageal varices has been shown to enhance gastric emptying that may contribute to the pathogenesis of PHG.2Obliteration-induced PHG develops less often in patients with fundal varices. Future studies are needed to investigate whether obliteration of fundal varices aggravates PHG. Relation of Portal Hypertensive Gastropathy with Gastric Varices

Patients with preexisting gastroesophageal varices tend to develop PHG more often than those without them. In the authors’ experience, PHG was present in 42% of patients when gastric varices were present and in only 11%when gastric varices were not present.lMThese findings Table 11. FREQUENCY OF ACUTE AND CHRONIC BLEEDING CAUSED BY PORTAL HYPERTENSIVE GASTROPATHY (PHG)

Onset of PHG

Preexisting Developing after sclerotherapy

No. of Patients 22 64

Frequency of Bleeding Transient 0/2*

2/28

Persistent

Progressive

4/17 0/31

3/3 1/5

Total (YO) 7 (32) 3 (4.7)t

*Deontes number of patients presenting with bleeding out of the total number who had transient PHG t P < 0.02 From Sarin SK, Shahi HM, Jain M The natural history of portal hypertensive gastropathy: influence of variceal eradication. Am J Gastroenterol95:2888-2893,2000; with permission

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have been reaffirmed by Primignani et alS6who found a higher prevalence of PHG in patients with gastric varices (98.6% of 69) than in those without gastric varices (76% of 304, P < 0.001). Some Japanese groups, however, have reported a lower incidence of PHG in patients who have gastrorenal shunts or preexisting fundal v a r i c e ~ .135 ~~, Bleeding from Portal Hypertensive Gastropathy

The Baveno I1 criteria for defining acute and chronic bleeding from PHG are well accepted.17 Acute bleeding from PHG is defined as the presence of hemetemesis or melena associated with endoscopic evidence of an actively bleeding lesion. Chronic bleeding is considered to have occurred if hemoglobin decreases by 2 g/dL or more between two consecutive control visits 6 months apart, provided the patient has not acutely bled in the meantime and is not taking nonsteroidal antiinflammatory drugs. Bleeding is not a consequence of mild PHG but occurs in a significant proportion of patients with severe PHG. Severe PHG probably accounts for most nonvariceal bleeding episodes in patients with cirrhosis and PHT. Bleeding from PHG is a serious complication, which is usually chronic and insidiousE5but occasionally may be massive and life-threatening. D'Amico et all6 found that overt hemorrhage from the gastric mucosa occurred in 12 (60%)of 20 patients with severe PHG and calculated that these patients had a cumulative risk of bleeding of 75% over a 5year follow-up period. The same investigators have also documented a significant risk of minor or chronic bleeding in severe PHG (goo/, of patients) and a considerable need for blood transfusion for severe irondeficiency anemia.I6 These observations have not been supported by other investigators.26, The discrepancy probably arises from methods of detecting blood loss that are insensitive or have not been used carefully enough to assess blood loss as a result of PHG. It is difficult to assess correctly the source of active bleeding in a patient with PHG who also has esophageal or gastric varices. A repeat endoscopy should always be performed a few hours or a day later to detect any oozing from PHG lesions.1o2 Reduction of hemoglobin by more than 2 g/dL, in the absence of a variceal bleeding episode, has been considered significant in the diagnosis of chronic mucosal bleeding from PHG. It is not easy, however, to assess whether the bleeding is from PHG, intestinal vasculopathy, or colopathyZ2Until these issues are resolved, different clinical presentations of PHG will continue to be reported. Using strict definitions of PHG-related acute and chronic bleeding, the overall incidence of bleeding has been shown to be 11?'oS6 to 22%.lo4 Thus, PHG seems to carry a lower risk of bleeding than do esophagogastric varices. Once bleeding occurs, the rebleeding rate from severe PHG is high (62% at 12 months after the first h e m ~ r r h a g e )This . ~ ~ frequency is similar to that of rebleeding from gastroesophageal varices.

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Treatment

While the concept of primary prophylaxis for PHG has not been studied, the approach to secondary prophylaxis is well accepted. Reduction in portal pressure is the mainstay of treatment of PHG. The lack of response of bleeding of PHG to sucralfate, H,-receptor n aproton-pump inhibitors indicates that the genesis of PHG is unrelated to acid peptic activity or gastric inflammation. Propranolol

The nonselective P-blockers are the most thoroughly investigated drugs for sustained reduction in portal pressure. Lebrec et a157showed that none of the 30 patients with gastric mucosal lesions treated with propranolol bled from gastric lesions, whereas such bleeding occurred in 4 of 36 patients receiving placebo. In a multicenter trial, patients with severe PHG who received long-term propranolol treatment had fewer episodes of acute bleeding or chronic bleeding than the control As assessed by laser Doppler flowmetry and reflectance spectrophotometry studies the therapeutic efficacy of propranolol in patients with bleeding from PHG seems to result from the reduction in portal pressure and decreased gastric mucosal blood Treatment usually must be continued on a long-term basis, because discontinuing the drug frequently leads to renewed bleeding. Mild PHG requires no treatment, and as yet not enough is known about the natural history of severe, nonbleeding gastropathy to recommend prophylactic therapy with propranolol. Other Pharmacological Agents

The P-blockers have associated side effects. The administration of propranolol to patients with massive bleeding from PHG may hamper the basic physiologic mechanism to compensate hypovolemia. Thus, the use of other drugs that potentially decrease portal pressure and gastric mucosal hyperemia is warranted. Vasopressin and glypressin reduce splanchnic blood flow and portal pressure79and cause a reduction in laser Doppler signal and hemoglobin concentration with only a mild decrease in gastric mucosal oxygen saturation. Similary, somatostatin also causes a decrease in gastric mucosal perfusion without a change in oxygen saturation (Table 12).80 Administration of octreotide has also been shown to reduce gastric mucosal blood flow by decreasing glucagon and mucosal NO. Both somatostatin and octreotide given as infusion were found to be effective in 23 (88%) of 26 patients presenting with active bleeding from portal hypertensive ga~tropathy.~~ These results support the use of glypressin and somatostatin in future clinical trials in the treatment of patients with bleeding from PHG.

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Table 12. EFFECT OF VASOACTIVE AGENTS ON GASTRIC MUCOSAL HEMODYNAMICS IN PATIENTS WITH CIRRHOSIS AND PORTAL HYPERTENSIVE GASTROPATHY Change in Gastric Mucosal Hernodynamics (“YO)

Author

Drug (dose)

Panes eta178 propranolol (0.15 mg/kg, N) Iwao et a14” vasopressin (0.3 U/min) vasopressin (0.3 U/min) + 0, (4 L/min) Panes et a179 vasopressin (0.4 U/min) glypressin (2 mg) Panes et also somatostatin (250 pg bolus) somatostatin (250 pg/h infusion following 50 pg bolus)

LaserDoppler Signal

Hemoglobin

Oxygen Saturation

23 23 - 22

- 10 - 26 - 21

- 1 - 21 - 7

-

36 34 - 32 - 17

-

-

-

25 11 - 16 -8

- 17 - 6

-

-

- 7 + 2

IV = intravenously From Toyonaga A, Iwao T Portal hypertensive gastropathy. J Gastroenterol Hepatol 13865-877, 1998; with permission.

Combinations of estrogen and progesterone and tranexamic acid have also been used in patients with PHG and GAVE, respectively.66 Portosystemic Shunt

In a restrospective study, before the entity of PHG was well characterized, Safreh et a196found portosystemic shunt to be effective in patients with hemorrhagic gastritis. In a recent prospective study, Orloff et a176performed portosystemic shunt in 12 patients with cirrhosis and bleeding. Of these, eight patients had failed to respond to propranolol therapy for PHG bleeding. During follow-up periods ranging from 1 to 6.75 years, no gastrointestinal bleeding occurred, and no operative deaths occurred. In addition, the gastric mucosa was found to revert to normal in all patients. These results suggest that, portosystemic shunt is useful in the treatment of bleeding from PHG. This evidence is not surprising, because both spontaneous and variceal obliteration-induced PHG develop less commonly in patients with spontaneous, large portosystemic shunt.’, 78, lo*,135 Transjugular lntrahepatic Portosystemic Shunt

A transjugular intrahepatic portosystemic shunt functions like a portosystemic shunt but avoids the risks of general anesthesia and major surgery. Urata et allz6have recently described the improvement in 9 of 10 cirrhotic patients after TIPS. Furthermore, hemostasis was achieved in one patient with cirrhosis who bled from PHG. Similar efficacy has been reported in a more recent

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As with a surgical portosystemic shunt, portosystemic encephalopathy is a major complication after TIPS. In Urata’s series,lZ6encephalopathy developed after TIPS in 5 of 12 PHG patients. Shunt dysfunction is another complication of the procedure but can be successfully treated with balloon angioplasty or by replacement with new stents.

Prognosis of Portal Hypertensive Gastropathy

Limited data are available for bleeding-related mortality rates in patients with PHG. In a recent study, only 1 of 8 (12.5%) patients bleeding from PHG died of uncontrolled bleeding, compared with 9 of 20 (39.1%) patients who had bleeding from v a r i ~ e s Similar .~~ observations in the authors’ studylMsuggest that bleeding from PHG is far less severe than variceal bleeding. Moreover, it is now well established that in a proportion of patients, the lesions of PHG regress, especially if the liver functions improve and the PHG had developed following endoscopic intervention for esophageal varices. Such patients do not require any therapy.lM Only a small proportion of patients ultimately have significant bleeding from PHG requiring intervention. References 1. Aganval SR, Chaudhary A, Sarin SK Influence of endoscopic sclerotherapy and endoscopic variceal ligation on the natural history of gastrooesophageal varices [abstract]. Hepatology 32(part 2):519A, 2000 2. Balan KK, Grime JS, Sutton R, et al: Do alterations in the rate of gastric emptying after injection sclerotherapy for oesophageal varices play any role in the development of portal hypertensive gastropathy? HPB Surg 11:141-148, 1999 3. Barange K, Peron JM, Imani K, et al: Transjugular intrahepatic portosystemic shunt in the treatment of refractory bleeding from ruptured gastric varices. Hepatology 301139-1143, 1999 4. Binmoller KF, Sohendra N Nonsurgical treatment of variceal bleeding: New modalities. Am J Gastroenterol90:1923-1931, 1995 5. Boustiere C, Dumas 0, Jouffre C, et al: Endoscopic ultrasonography classification of gastric varices in patients with cirrhosis. Comparison with endoscopic findings. J Hepatol 19:268-278, 1993 6. Bretagne JF, Dudicourt JC, Morisot D, et al: Is endoscopic variceal sclerotherapy effective for the treatment of gastric varices? Dig Dis Sci 31:A505S, 1986 7. Carpinelli L, Primignani M, Preatoni P, et al: Portal hypertensive gastropathy: Reproducibility of a classification, prevalence of elementary lesions, sensitivity and specificity in the diagnosis of cirrhosis of the liver. A NIEC multicenter study. Ital J Gastroenterol Hepatol 29:53>540, 1997 8. Casadevall M, Panes J, Pique JM, et al: Involvement of nitric oxide and prostaglandins in gastric mucosal hyperemia of portal hypertensive anesthetized rats. Hepatology 18:628-634, 1993 9. Chang KY, Wu CS, Chen PC: Prospective randomized trial of hypertonic glucose water and sodium tetradecyl sulfate for gastric variceal bleeding in patients with advanced liver cirrhosis. Endoscopy 28:481-486, 1996 10. Chang PN, Sheu BS, Chen CY, et al: Splenic infarction after histoacryl injection for bleeding gastric varices. Gastrointest Endosc 48:426-427, 1998 11. Chau TN, Patch D, Chan YW, et al: Salvage transjugular intrahepatic portosystemic

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Address reprint requests to Shiv K. Sarin, MD, DM Professor and Head Department of Gastroenterology G. B. Pant Hospital, New Delhi e-mail: sksarin8nda.vsnl. net.in