Review article: the management of portal hypertensive gastropathy and gastric antral vascular ectasia in cirrhosis

Transcription

1 Alimentary Pharmacology and Therapeutics Review article: the management of portal hypertensive gastropathy and gastric antral vascular ectasia in cirrhosis V. R. Patwardhan* & A. Cardenas *Beth Israel Deaconess Medical Center, Boston, MA, USA. Institute of Digestive Diseases and Metabolism, University of Barcelona, Hospital Clinic, Barcelona, Spain. Correspondence to: Dr A. Cardenas, Institut de Malalties Digestives i Metaboliques, University of Barcelona, Hospital Clinic Villarroel 170, Esc 3-2, Barcelona, Spain. s: acardena@clinic.ub.es; acv69@hotmail.com Publication data Submitted 9 April 2014 First decision 12 May 2014 Resubmitted 14 May 2014 Accepted 14 May 2014 EV Pub Online 2 June 2014 This commissioned review article was subject to full peer-review and the authors received an honorarium from Wiley, on behalf of AP&T. SUMMARY Background Portal hypertensive gastropathy (PHG) and gastric antral vascular ectasia (GAVE) are important causes of both acute and chronic gastrointestinal bleeding in patients with cirrhosis. Aim To review the current management of PHG and GAVE. Methods PubMed was searched for English language articles using the key words GAVE, gastric antral vascular ectasia, cirrhosis, gastrointestinal bleeding, acute, chronic, portal hypertensive gastropathy, watermelon stomach, radiofrequency ablation, band ligation, thermoablation and TIPSS. Results GAVE and PHG are both encountered in patients with cirrhosis. They can be seen in asymptomatic patients and in those with either acute or chronic gastrointestinal bleeding. PHG, by definition, requires the presence of portal hypertension, with or without cirrhosis, whereas GAVE requires neither cirrhosis nor portal hypertension. They can often be diagnosed on endoscopic appearance alone, but may require biopsy in certain cases. The treatment of PHG is aimed at reducing hepatic venous pressure gradients, most often by pharmacologic means, but may require shunt procedures in severe cases. Management of GAVE on the other hand is predominantly endoscopic, focusing on various ablative techniques. Conclusions Gastric antral vascular ectasia and portal hypertensive gastropathy are distinct entities and are both encountered in cirrhotic patients. Management of portal hypertensive gastropathy is centred on reduction in portal pressures, whereas treatment of gastric antral vascular ectasia is predominantly endoscopic. Aliment Pharmacol Ther 2014; 40: doi: /apt.12824

2 Review: management of portal gastropathy and gastric antral vascular ectasia INTRODUCTION Gastrointestinal bleeding accounts for up to 25% of overall mortality in patients with cirrhosis. 1 Although variceal haemorrhage and peptic ulcer disease account for a significant portion of acute GI bleeding in cirrhotics, portal hypertensive gastropathy (PHG) and gastric antral vascular ectasia (GAVE) represent important causes of chronic gastrointestinal bleeding, responsible for chronic blood loss anaemia in 3 26% of patients with cirrhosis. 2 4 They may also cause acute bleeding, but this is less common, with incidence ranging from 0.8% to 12%. 2, 4 6 PHG is defined as macroscopic changes of the stomach associated with mucosal and submucosal vascular dilation seen on upper endoscopy. GAVE is a distinct entity characterised by ectatic vessels in the stomach antrum, also found on endoscopy, where longitudinal red stripes in the antrum resemble the marking of a striped watermelon. Portal hypertensive gastropathy is more commonly encountered than GAVE in patients with cirrhosis, with prevalence between 20% and 80% and observed more frequently in patients with more severe forms of liver disease. 3 By definition, PHG requires the presence of portal hypertension and can be found even in patients with noncirrhotic portal hypertension. 7, 8 GAVE, on the other hand, requires neither portal hypertension nor cirrhosis, but is encountered in both clinical situations. Cirrhosis is found in 30% of patients with GAVE, and GAVE is seen more frequently in those with more advanced liver disease. 9 It is found in 2 5% of patients awaiting liver transplantation and improves following 5, 10 liver transplantation. GAVE can also be found in patients with autoimmune conditions, scleroderma, chronic renal failure, cardiac disease and following bone marrow transplantation. 11 Although PHG and GAVE have overlapping features, they are in fact two distinct entities, with separate endoscopic findings, characteristic histology and different approaches to treatment. Pathophysiology The disease mechanisms underlying both PHG and GAVE are still incompletely understood. However, as its name implies, PHG appears to require the presence of portal hypertension. Studies have shown that a hepatic venous pressure gradient (HVPG) 12 mmhg is associated with the existence of PHG and that HVPG is higher in patients with severe PHG compared to those with mild or absent PHG In addition, other sequelae of liver insufficiency likely contribute. For instance, there is data from Kumar et al. that suggests that cardiac output is higher and systemic vascular resistance lower in patients with PHG. 12 On the other hand, Curvello et al. found no association between HVPG, Child s class, or haemodynamic parameters suggesting that local mucosal 15, 16 factors may also influence the development of PHG. It should be noted, however, that this study included 46 patients, less than other studies of its kind, and may have been underpowered. Nitric oxide synthase and local ischaemia also appear to play a role. 17 Although the exact mechanisms are unclear, PHG is likely a consequence of both congestion and hyperaemia in the gastric mucosa and submucosa. 18 GAVE appears to be less related to systemic alterations in blood flow, and more a consequence of multiple locally acting vasoactive substances, potentially in combination with mechanical stress. In particular, gastrin and prostaglandin have been implicated in the development of GAVE owing to their being found in increased amounts in serum and gastric mucosa in those with GAVE, as well as their local vasodilatory properties, in particular prostaglandin E. 19, 20 However, data surrounding gastrin are mixed suggesting multiple mechanisms. There also appears to be an association between vascular ectatic lesions and their proximity to neuroendocrine cells, particularly those producing vasoactive intestinal peptide and 5-hydroxytryptamine, implicating the role of these locally produced neurotransmitters. 21 These systemic and local hormones, in combination with abnormal antral motility compared to cirrhotics without GAVE are felt to be responsible for the classic watermelon appearance of GAVE as well as its characteristic histological features including fibromuscular dysplasia. 22 Diagnosis and clinical manifestations Both PHG and GAVE may be encountered during endoscopy in asymptomatic patients with cirrhosis or discovered during varices screening or evaluation of abdominal pain. They may also be found during evaluation for chronic occult GI bleeding, or less frequently for acute overt GI bleeding, rarely even in large volumes. However, in most instances, they are distinguished by their endoscopic appearance, location and when needed, biopsy for histology. (Table 1) While PHG classically affects the gastric body and fundus, GAVE almost exclusively inhabits the antrum. PHG has a snakeskin or mosaic background mucosa and when severe, is associated with flat or bulging red or brown spots that may have friability or frank bleeding (Figure 1a c). For ease and consistency in classification, Aliment Pharmacol Ther 2014; 40:

3 V. R. Patwardhan and A. Cardenas Associated with portal hypertension PHG Always GAVE Location Fundus and body Antrum Endoscopic appearance Histology First Line Treatment Salvage Therapy Mosaic/snakeskin mucosa (mild) with red or brown spots (severe) Dilated submucosal and mucosal veins, along with ectatic capillaries without inflammation or thrombi Non-selective betablockers Thermocoagulation or TIPSS In ~30% of cases Tortuous columns of ectatic vessels in watermelon or diffuse pattern which can be erythematous (mild) or haemorrhagic (severe) Dilated mucosal capillaries with fibrin thrombi and fibromuscular hyperplasia of the lamina propia and spindle cell proliferation Thermocoagulation Band ligation, radiofrequency ablation, cryotherapy, surgical antrectomy Table 1 Characteristics of portal hypertensive gastropathy and gastric antral vascular ectasia consensus guidelines suggest classifying PHG into mild, 23, 24 moderate or severe forms (Table 2). However, a 3-category system, in which moderate disease is defined by the presence of red or brown spots without bleeding vs. severe disease with friable or frankly bleeding mucosa, has also been proposed. 25 In addition, similar endoscopic findings can be seen in the small intestine and colon, also as a consequence of portal hypertension, both in asymptomatic patients and those with gastrointestinal bleeding GAVE was initially described as watermelon stomach by Jabbari et al., in one of the first reports of GAVE in three patients with iron deficiency anaemia found to have visible convoluted and tortuous columns of ectatic (a) (b) (c) (d) Figure 1 Endoscopic appearance of PHG and GAVE. (a) The mosaic or snake-skin appearance of gastric body mucosa without red spots, characteristic of mild PHG. (b) Congested mosaic appearing mucosa with red spots, characteristic of moderate PHG. (c) Background snake-skin mucosa in the cardia and fundus with red and brown spots with active oozing characteristic of moderate-to-severe PHG. (d) GAVE with the classic watermelon stomach of the antrum, with columns of tortuous ectactic vessels converging on the pylorus without active bleeding. 356 Aliment Pharmacol Ther 2014; 40:

4 Review: management of portal gastropathy and gastric antral vascular ectasia Table 2 Classification of portal hypertensive gastropathy according to New Italian Endoscopic Club for the Study and Treatment of Oesophageal Varices 24 Mosaic like pattern Mild diffusely pink areola Moderate flat red spot in centre of pink areola Severe diffusely red areola Red marks Red lesions of variable diameter, flat or slightly protruding Discrete or confluent vessels along each longitudinal rugal fold of the antrum, converging on the pylorus, which in aggregate, resembled the stripes of a watermelon (Figure 1d). 29 Similar to portal gastropathy, GAVE has a number of different classifications based on both location and severity. Lesions can appear erythematous in the mild form or haemorrhagic when more severe. Additionally, although initially reported as a linear, watermelon-like appearance confined to the antrum, GAVE can exist as more discrete punctate lesions or present more diffusely with extension to the body, making the distinction between GAVE and PHG less obvious. Interestingly, diffuse punctate lesions are associated more strongly with GAVE in cirrhotics 30, 31 than in GAVE due to other causes. In the rare instance that PHG and GAVE cannot be distinguished on the basis of endoscopic appearance and location alone, biopsy for histology may prove useful. Histology of PHG lesions show dilated submucosal and mucosal veins, along with ectatic capillaries without inflammation or thrombi. 32 Vascular ectasias in GAVE are also associated with dilated mucosal capillaries, but also with fibrin thrombi and fibromuscular hyperplasia of the lamina propia as well as spindle cell proliferation. 33 The presence of fibrin thrombi and fibromuscular hyperplasia in particular can be helpful to distinguish diffuse GAVE from PHG on biopsy. Management Portal hypertensive gastropathy. Management of PHG is centred on reduction in portal pressure, largely through the use of medical rather than endoscopic means. Although different entities, the management of PHG tends to mirror that of oesophageal varices, in which reduction in the HVPG to 12 mmhg or by 20% has been associated with not only reduction in oesophageal variceal rebleeding, but also mortality in some studies To reduce portal pressures, particularly for patients with chronic GI bleeding due to PHG, nonselective betablockers are first line. At the current time, there is not enough data to recommend betablockers for primary prophylaxis of bleeding from PHG in patients with cirrhosis who do not require betablocker for other reasons. 37 However, in patients receiving either propranolol or nadolol for primary prophylaxis of oesophageal variceal bleeding, betablocker therapy may have a reduction on future PHG bleeding. Interestingly, there are data suggesting an increased risk of developing portal gastropathy following oesophageal variceal banding and an attenuated risk in those who receive concomitant betablocker therapy following oesophageal band ligation. 38, 39 Therefore, in asymptomatic patients with both oesophageal varices and PHG, who undergo oesophageal band ligation, co-administration of a nonselective betablocker, titrated to goal heart rate of bpm or 25% reduction from baseline is appropriate. In patients who have previously experienced clinically significant GI blood loss, either acute or chronic, the benefit of betablocker therapy for PHG is clearer. In a study by Perez-Ayuso et al., 54 patients with acute and chronic bleeding due to severe PHG were randomized to receive propranolol vs. placebo at a dose that reduced resting heart rate to 55 beats per min or by 25%. Daily doses of mg were used. At 12 months, 65% of patients receiving propranolol were free of bleeding compared with 38% in the control group. At 30 months, greater than half the patients on betablocker were free of rebleeding compared to less than 10% of controls. 40 Similarly, in a smaller study by Hosking et al. propranolol at a dose of mg/day decreased the incidence of acute bleeding in 16 patients with PHG and also reduced the grade of PHG in 24 asymptomatic patients when given at a dose of 160 mg/day. 41 The incidence of acute bleeding from PHG is low and estimated to be around 2.5%. 2 Although there are obvious drawbacks to betablocker therapy in the acute setting, studies have shown resolution of acute PHG bleeding within 3 days, highlighting their potential role for the management of acute as well as chronic GI bleeding. 41 Current guidelines 42 suggest using betablockers for secondary prophylaxis in patients with chronic gastrointestinal bleeding from PHG and after stabilization to prevent recurrent acute bleeding. On the other hand, in the acute setting of GI bleeding, when patients may be unstable and their course is yet undetermined, faster acting agents that do not blunt heart rate, may be more suitable. Such agents, including somatostatin, octreotide, terlipressin and vasopressin have been studied, with varying efficacy. A small open label study of somatostatin and its analogues showed complete control of Aliment Pharmacol Ther 2014; 40:

5 V. R. Patwardhan and A. Cardenas acute bleeding from PHG with only 11% having re-bleeding after withdrawal of infusion. 43 Similarly, Zhou et al., in a prospective study, found that intravenous octreotide controlled acute PHG bleeding in 100% of patients within 48 h with vasopressin and omeprazole controlling bleeding in 64% and 59% of patients respectively over the same time period. 44 Terlipressin, has also been shown to have efficacy, controlling bleeding in 90% of patients in the first 2 days. 45 Both mild and severe forms of portal gastropathy improve following transjugular intrahepatic portosystemic shunting (TIPSS). 46 In a prospective study of 30 patients with mild and 10 with severe PHG with recurrent GI bleeding, TIPSS placement was associated with a 75% reduction in endoscopic severity as well as transfusion requirement and 89% of patients with mild PHG showed endoscopic improvement. The mean Childs-Pugh Score was 11.5 and there was a mean reduction in portocaval gradient from 20 to 12 mmhg in both groups. Maximal effect of HVPG reduction was seen at 3 months, but some patients received benefit even at 6 weeks after TIPSS. There was no improvement in GAVE following TIPSS. 46 Similarly, surgical shunting has also shown benefit in refractory acute and recurrent bleeding from PHG in lower risk cirrhotics. 47 A retrospective case control study of 40 Childs A/B cirrhotics found improved outcomes from surgical shunting with reduced 30 day mortality, reduced rebleeding, fewer shunt revisions and fewer hospitalizations compared to TIPSS. 48 However, long-term mortality was similar. A subsequent prospective randomized control, on the other hand, found equivalent results between TIPSS and distal splenorenal shunting with regards to rebleeding, encephalopathy, and survival. 49 There were increased rates of stent thrombosis, restenosis and re-intervention in the TIPSS group; however, suggesting that the method of shunting in patients with refractory bleeding from PHG should be tailored to centre expertise. Given the high surgical risk with more severe liver disease, surgical shunting may be an option for those with Child A cirrhosis or PHG due to noncirrhotic portal hypertension. 50 For those patients with refractory bleeding who are not appropriate candidates for porto-systemic shunting, limited data suggests endoscopic thermal therapy may be efficacious. In a study by Herrera et al. argon plasma coagulation was used to treat GAVE and PHG with no episodes of rebleeding in 11 patients with PHG over a mean follow-up of 22 months following treatment. 51 It should be noted, however, that none of the patients in their study were haemodynamically unstable and those with PHG may have had overlap with diffuse GAVE, for which there is a more established role for endoscopic thermal therapy. Emerging data indicate that the use of haemostatic powder (Hemospray â ) may be useful in patients with acute bleeding due to PHG. This haemostatic powder, which acts by forming a barrier over the bleeding site and enhancing the concentration of clotting factors, was successfully used in four patients actively bleeding from PHG. 52 A treatment algorithm for patients with PHG is described in Figure 2. GAVE. While much of the management of PHG is centred on pharmacotherapy and reduction in portal pressure, the mainstay of GAVE management is endoscopic therapy. Many of the drugs that have been studied in GAVE have been borrowed from the treatment of portal hypertensive bleeding and other vascular ectatic diseases such as Osler-Weber-Rendu, also known as hereditary haemorrhagic telangiectasia (HHT), but with little data demonstrating success. Octreotide has been studied in vascular ectasias in the gastrointestinal tract, but few studies have examined GAVE specifically. One study showed improvement in rebleeding and need for iron replacement in 2 of 3 patients. 53 Borrowed from its treatment of HHT, oestrogen and progesterone combination were shown to stop bleeding in six patients with GAVE. 54 Thalidomide and serotonin antagonists have also been used but their data are similarly limited Data on endoscopic treatments for GAVE are most robust for thermal therapy. Although argon plasma coagulation (APC) and Nd:YAG laser coagulation have both been used, more recently APC has been the treatment of choice given its more favourable side effect profile. 58 Multiple studies have shown APC to improve anaemia and reduce transfusion requirements in cirrhotic patients with GAVE. 31, 51, Large case series using APC have reported an efficacy ranging from 90% to 100% with no further need for blood transfusions and a mean increase in haemoglobin levels by 3 g/dl This approach almost always requires multiple sessions and can be repeated if bleeding recurs. Although very effective, patients need repeated sessions every 2 6 weeks. The most common settings make use of W of electricity with L/min of argon gas flow. However, while APC is successful in treating bleeding from GAVE it is frequently associated with recurrence of bleeding in 30 60% of cases in the medium to long term. 60, 61 The rationale for recurrent bleeding following 358 Aliment Pharmacol Ther 2014; 40:

6 Review: management of portal gastropathy and gastric antral vascular ectasia Portal Hypertensive Gastropathy Treatment algorithm Asymptomatic or no history of bleeding Chronic Bleed Acute Bleed No gastroesophageal varices Gastroesophageal varices requiring medical therapy Non-selective betablocker Octreotide or terlipressin followed by non selective betablocker Refractory or No therapy Non-selective betablocker recurrent bleeding Endoscopic therapy* Consider TIPPS or surgical shunt** Figure 2 Proposed algorithm for management of PHG. *Endoscopic thermal therapy with argon plasma coagulation or haemostatic powder (Hemospray â ) if not candidate for shunt procedure. **Decision for TIPSS vs. surgical shunting determined by centre expertise and medical co-morbidities. thermal treatment for GAVE is that GAVE commonly involves deeper structures than the superficial epithelium, including the submucosa, which may not be treated adequately with coagulation. It has been postulated that band ligation, on the other hand, may more reliably obliterate vascular structures in the deep mucosa and submucosa, thus reducing the need for further treatments. Both Sato et al. and Wells et al., in retrospective studies, found that endoscopic band ligation reduced recurrent bleeding more frequently and required less treatment sessions than did 64, 65 APC. Wells et al. also found that band ligation reduced hospital admissions. In their study, endoscopists (a) (b) Figure 3 Examples of endoscopic treatments for GAVE. (a) Antrum with GAVE prior to treatment (b) Stomach antrum with GAVE immediately following a single session of argon plasma coagulation. (c) Antrum with GAVE pre-treatment (d) GAVE immediately post band ligation. (c) (d) Aliment Pharmacol Ther 2014; 40:

7 V. R. Patwardhan and A. Cardenas banded vascular ectasias in the most distal antrum closest to the pylorus and then moved proximally until the entire affected areas were treated (up to 12 bands placed in a single session). Patients required between 2 and 4 sessions of EBL for resolution of GAVE. Other authors have also reported similar results 66, 67 Examples of APC and band ligation to treat GAVE are shown in Figure 3. Newer studies have also examined radiofrequency ablation for the treatment of GAVE. Radiofrequency ablation with the HALO system that delivers a uniform depth of ablation over a 3 cm 2 area, may theoretically allow for more reliable destruction of vascular ectasias and more surface area to be treated in a single session. In a small open label prospective series, radiofrequency ablation using the HALO90 system was used to treat six patients with anaemia due to GAVE. 68 In this population, 83% of patients had cessation of bleeding with improvement in haemoglobin after 1 3 treatments. More recently, in a prospective study of 21 patients with bleeding GAVE refractory to APC, 86% of patients became transfusion independent after radiofrequency ablation (maximum of four treatment sessions). 69 Additional therapy for GAVE includes cryotherapy, which makes use nitrous oxide to freeze the abnormal mucosa causing ablation. 70, 71 Cryotherapy was trialled by Cho et al. in 12 patients, 8 of whom had failed prior APC. Complete response was seen in 6 patients and partial response in the other 6 without complications. 71 Cyanoacrylate spray has also been used for difficult to control bleeding, including GAVE. In a study by Walia et al. cyanoacrylate was used to effectively treat a bleeding GAVE lesion refractory to APC and clipping. In this patient, bleeding did recur 18 days later, but from a different lesion. 72 Endoscopic mucosectomy has also been performed, but this requires further study. 73 Lastly, surgical antrectomy has been used for refractory GAVE and may be considered in otherwise well compensated cirrhotic patients with refractory bleeding who are surgical candidates. 74, 75 A treatment algorithm for patients with GAVE is described in Figure 4. GAVE Treatment Algorithm Chronic anemia or bleeding Iron therapy/transfusions Treatment with Argon plasma coagulation No control after 3-4 Repeat sessions sessions response Follow up response Refractory case Consider banding Consider : RFA, cryotherapy or surgical antrectomy Figure 4 Proposed algorithm for management of GAVE. RFA, radiofrequency ablation. CONCLUSION In summary, PHG and GAVE are important causes of gastrointestinal bleeding in cirrhotic patients. They are distinct entities that most often can be differentiated by endoscopic appearance alone, but when needed, may require biopsy for a conclusive diagnosis. PHG treatment centres on pharmacotherapy to reduce portal pressures, and when needed, porto-systemic shunting. GAVE therapy centres on endoscopic therapies, with newer therapies emerging to reduce the number of treatments required and reduce rates of rebleeding. AUTHORSHIP Guarantor of the article: Dr Andres Cardenas. Author contributions: Vilas Patwardhan, MD and Andres Cardenas, MD reviewed the literature and drafted the manuscript. All authors approved the final version of the manuscript. ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES 1. Schlichting P, Christensen E, Fauerholdt L, Poulsen H, Juhl E, Tygstrup N. Main causes of death in cirrhosis. Scand J Gastroenterol 1983; 18: Primignani M, Carpinelli L, Preatoni P, et al. Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC). Gastroenterology 2000; 119: Merli M, Nicolini G, Angeloni S, Gentili F, Attili AF, Riggio O. The natural history of portal hypertensive gastropathy in patients with liver cirrhosis and mild portal hypertension. Am J Gastroenterol 2004; 99: D Amico G, Montalbano L, Traina M, et al. Natural history of congestive gastropathy in cirrhosis. The Liver 360 Aliment Pharmacol Ther 2014; 40:

8 Review: management of portal gastropathy and gastric antral vascular ectasia Study Group of V. Cervello Hospital. Gastroenterology 1990; 99: Ward EM, Raimondo M, Rosser BG, Wallace MB, Dickson RD. Prevalence and natural history of gastric antral vascular ectasia in patients undergoing orthotopic liver transplantation. J Clin Gastroenterol 2004; 38: Gostout CJ, Viggiano TR, Balm RK. Acute gastrointestinal bleeding from portal hypertensive gastropathy: prevalence and clinical features. Am J Gastroenterol 1993; 88: Sarin SK, Misra SP, Singal A, Thorat V, Broor SL. Evaluation of the incidence and significance of the mosaic pattern in patients with cirrhosis, noncirrhotic portal fibrosis, and extrahepatic obstruction. Am J Gastroenterol 1988; 83: Papazian A, Braillon A, Dupas JL, Sevenet F, Capron JP. Portal hypertensive gastric mucosa: an endoscopic study. Gut 1986; 27: Spahr L, Villeneuve JP, Dufresne MP, et al. Gastric antral vascular ectasia in cirrhotic patients: absence of relation with portal hypertension. Gut 1999; 44: Vincent C, Pomier-Layrargues G, Dagenais M, et al. Cure of gastric antral vascular ectasia by liver transplantation despite persistent portal hypertension: a clue for pathogenesis. Liver Transpl 2002; 8: Ripoll C, Garcia-Tsao G. The management of portal hypertensive gastropathy and gastric antral vascular ectasia. Dig Liver Dis. Editrice Gastroenterologica Italiana 2011; 43: Kumar A, Mishra SR, Sharma P, Sharma BC, Sarin SK. Clinical, laboratory, and hemodynamic parameters in portal hypertensive gastropathy: a study of 254 cirrhotics. J Clin Gastroenterol 2010; 44: Kim MY, Choi H, Baik SK, et al. Portal hypertensive gastropathy: correlation with portal hypertension and prognosis in cirrhosis. Dig Dis Sci 2010; 55: Merkel C, Schipilliti M, Bighin R, et al. Portal hypertension and portal hypertensive gastropathy in patients with liver cirrhosis: a haemodynamic study. Dig Liver Dis 2003; 35: Curv^elo LA, Brabosa W, Rhor R, et al. Underlying mechanism of portal hypertensive gastropathy in cirrhosis: a hemodynamic and morphological approach. J Gastroenterol Hepatol 2009; 24: Hashizume M, Tanaka K, Inokuchi K. Morphology of gastric microcirculation in cirrhosis. Hepatology 1983; 3: Kaviani A, Ohta M, Itani R, Sander F, Tarnawski AS, Sarfeh IJ. Tumor necrosis factor-alpha regulates inducible nitric oxide synthase gene expression in the portal hypertensive gastric mucosa of the rat. J Gastrointest Surg 1997; 1: Ohta M, Hashizume M, Higashi H, et al. Portal and gastric mucosal hemodynamics in cirrhotic patients with portal-hypertensive gastropathy. Hepatology 1994; 20: Quintero E, Pique JM, Bombi JA, et al. Gastric mucosal vascular ectasias causing bleeding in cirrhosis. A distinct entity associated with hypergastrinemia and low serum levels of pepsinogen I. Gastroenterology 1987; 93: Saperas E, Perez-Ayuso RM, Poca E, Bordas JM, Gaya J, Pique JM. Increased gastric PGE2 biosynthesis in cirrhotic patients with gastric vascular ectasia. Am J Gastroenterol 1990; 85: Lowes JR, Rode J. Neuroendocrine cell proliferations in gastric antral vascular ectasia. Gastroenterology 1989; 97: Charneau J, Petit R, Cales P, Dauver A, Boyer J. Antral motility in patients with cirrhosis with or without gastric antral vascular ectasia. Gut 1995; 37: De Franchis R. Updating consensus in portal hypertension: report of the Baveno III Consensus Workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000; 33: Spina GP, Arcidiacono R, Bosch J, et al. Gastric endoscopic features in portal hypertension: final report of a consensus conference, Milan, Italy. 19 September 1992; 1994, pp Tanoue K, Hashizume M, Wada H, Ohta M, Kitano S, Sugimachi K. Effects of endoscopic injection sclerotherapy on portal hypertensive gastropathy: a prospective study. Gastrointest Endosc 1992; 38: Jeon SR, Kim JO, Kim JB, et al. Portal hypertensive enteropathy diagnosed by capsule endoscopy in cirrhotic patients: a nationwide multicenter study. Dig Dis Sci 2014; 59: Matsushita Y, Narahara Y, Fujimori S, et al. Effects of transjugular intrahepatic portosystemic shunt on changes in the small bowel mucosa of cirrhotic patients with portal hypertension. J Gastroenterol 2012; 48: Diaz-Sanchez A. Portal hypertensive colopathy is associated with portal hypertension severity in cirrhotic patients. World J Gastroenterol 2009; 15: Jabbari M, Cherry R, Lough JO, Daly DS, Kinnear DG, Goresky CA. Gastric antral vascular ectasia: the watermelon stomach. Gastroenterology 1984; 87: Ito M, Uchida Y, Kamano S, Kawabata H, Nishioka M. Clinical comparisons between two subsets of gastric antral vascular ectasia. Gastrointest Endosc 2001; 53: Dulai GS, Jensen DM, Kovacs TOG, Gralnek IM, Jutabha R. Endoscopic treatment outcomes in watermelon stomach patients with and without portal hypertension. Endoscopy 2004; 36: McCormack TT, Sims J, Eyre-Brook I, et al. Gastric lesions in portal hypertension: inflammatory gastritis or congestive gastropathy? Gut 1985; 26: Suit PF, Petras RE, Bauer TW, Petrini JL. Gastric antral vascular ectasia. A histologic and morphometric study of the watermelon stomach. Am J Surg Pathol 1987; 11: D Amico G, Garcıa-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology 2006; 131: Albillos A, Ba~nares R, Gonzalez M, et al. Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a meta-analysis. Am J Gastroenterol 2007; 102: Villanueva C, Aracil C, Colomo A, et al. Acute hemodynamic response to beta-blockers and prediction of longterm outcome in primary prophylaxis of variceal bleeding. Gastroenterology 2009; 137: Cubillas R, Rockey DC. Portal hypertensive gastropathy: a review. Liver Int 2010; 30: LoGH,LaiKH,ChengJS,et al. The effects of endoscopic variceal ligation and propranolol on portal hypertensive gastropathy: a prospective, controlled trial. Gastrointest Endosc 2001; 53: Sarin SK, Shahi HM, Jain M, Jain AK, Issar SK, Murthy NS. The natural history of portal hypertensive gastropathy: influence of variceal eradication. Am J Gastroenterol 2000; 95: Perez-Ayuso RM, Pique JM, Bosch J, et al. Propranolol in prevention of recurrent bleeding from severe portal hypertensive gastropathy in cirrhosis. Lancet 1991; 337: Hosking SW, Kennedy HJ, Seddon I, Triger DR. The role of propranolol in congestive gastropathy of portal hypertension. Hepatology 1987; 7: Aliment Pharmacol Ther 2014; 40:

9 V. R. Patwardhan and A. Cardenas 42. de Franchis R. Evolving consensus in portal hypertension. Report of the Baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2005; 43: Kouroumalis EA, Koutroubakis IE, Manousos ON. Somatostatin for acute severe bleeding from portal hypertensive gastropathy. Eur J Gastroenterol Hepatol 1998; 10: Zhou Y, Qiao L, Wu J, Hu H, Xu C. Comparison of the efficacy of octreotide, vasopressin, and omeprazole in the control of acute bleeding in patients with portal hypertensive gastropathy: a controlled study. J Gastroenterol Hepatol 2002; 17: Bruha R, Marecek Z, Spicak J, et al. Double-blind randomized, comparative multicenter study of the effect of terlipressin in the treatment of acute esophageal variceal and/or hypertensive gastropathy bleeding. Hepatogastroenterology 2002; 49: Kamath PS, Lacerda M, Ahlquist DA, McKusick MA, Andrews JC, Nagorney DA. Gastric mucosal responses to intrahepatic portosystemic shunting in patients with cirrhosis. Gastroenterology 2000; 118: Orloff MJ, Orloff MS, Orloff SL, Haynes KS. Treatment of bleeding from portal hypertensive gastropathy by portacaval shunt. Hepatology 1995; 21: Helton WS, Maves R, Wicks K, Johansen K. Transjugular intrahepatic portasystemic shunt vs surgical shunt in good-risk cirrhotic patients: a casecontrol comparison. Arch Surg 2001; 136: Henderson JM, Boyer TD, Kutner MH, et al. Distal splenorenal shunt versus transjugular intrahepatic portal systematic shunt for variceal bleeding: a randomized trial. Gastroenterology 2006; 130: Jacqueline GO, Leary MDM, Patrick S, Yachimski MDM. MD LSF. Surgery in the patient with liver disease. Clin Liver Dis 2009; 13: Herrera S, Bordas JM, Llach J, et al. The beneficial effects of argon plasma coagulation in the management of different types of gastric vascular ectasia lesions in patients admitted for GI hemorrhage. Gastrointest Endosc 2008; 68: Smith LA, Morris AJ, Stanley AJ. The use of Hemospray in portal hypertensive bleeding; a case series. J Hepatol. European Association for the Study of the. Liver 2014; 60: Nardone G, Rocco A, Balzano T, Budillon G. The efficacy of octreotide therapy in chronic bleeding due to vascular abnormalities of the gastrointestinal tract. Aliment Pharmacol Ther 1999; 13: Tran A, Villeneuve JP, Bilodeau M, et al. Treatment of chronic bleeding from gastric antral vascular ectasia (GAVE) with estrogen-progesterone in cirrhotic patients: an open pilot study. Am J Gastroenterol 1999; 94: Dunne KA, Hill J, Dillon JF. Treatment of chronic transfusion-dependent gastric antral vascular ectasia (watermelon stomach) with thalidomide. Eur J Gastroenterol Hepatol 2006; 18: Soykan I, Toruner M, Idilman R, Ozden A. Reversal of iron deficiency anemia in a patient with gastric antral vascular ectasia treated with cyproheptadine. J Clin Gastroenterol 2003; 36: Swanson E, Mahgoub A, Macdonald R, Shaukat A. Medical and Endoscopic Therapies for Angiodysplasia and Gastric Antral Vascular Ectasia: a Systematic Review. Clin Gastroenterol Hepatol 2014; 12: Manner H, May A, Faerber M, Rabenstein T, Ell C. Safety and efficacy of a new high power argon plasma coagulation system (hp-apc) in lesions of the upper gastrointestinal tract. Dig Liver Dis 2006; 38: Fuccio L, Zagari RM, Serrani M, et al. Endoscopic argon plasma coagulation for the treatment of gastric antral vascular ectasia-related bleeding in patients with liver cirrhosis. Digestion 2009; 79: Yusoff I, Brennan F, Ormonde D, Laurence B. Argon plasma coagulation for treatment of watermelon stomach. Endoscopy 2002; 34: Roman S, Saurin JC, Dumortier J, Perreira A, Bernard G, Ponchon T. Tolerance and efficacy of argon plasma coagulation for controlling bleeding in patients with typical and atypical manifestations of watermelon stomach. Endoscopy 2003; 35: Sebastian S, McLoughlin R, Qasim A, O Morain CA, Buckley MJ. Endoscopic argon plasma coagulation for the treatment of gastric antral vascular ectasia (watermelon stomach): long-term results. Dig Liver Dis 2004; 36: Kwan V, Bourke MJ, Williams SJ, et al. Argon Plasma Coagulation in the Management of Symptomatic Gastrointestinal Vascular Lesions: experience in 100 Consecutive Patients with Long-Term Follow-Up. Am J Gastroenterol 2006; 101: Sato T, Yamazaki K, Akaike J. Endoscopic band ligation versus argon plasma coagulation for gastric antral vascular ectasia associated with liver diseases. Dig Endosc 2011; 24: Wells CD, Harrison ME, Gurudu SR, et al. Treatment of gastric antral vascular ectasia (watermelon stomach) with endoscopic band ligation. Gastrointest Endosc 2008; 68: Keohane J, Berro W, Harewood GC, Murray FE, Patchett SE. Band ligation of gastric antral vascular ectasia is a safe and effective endoscopic treatment. Dig Endosc 2012; 25: Prachayakul V, Aswakul P, Leelakusolvong S. Massive gastric antral vascular ectasia successfully treated by endoscopic band ligation as the initial therapy. World J Gastrointest Endosc. 2013; 5: Gross SA, Al-Haddad M, Gill KRS, Schore AN, Wallace MB. Endoscopic mucosal ablation for the treatment of gastric antral vascular ectasia with the HALO90 system: a pilot study. Gastrointest Endosc 2008; 67: McGorisk T, Krishnan K, Keefer L, Komanduri S. Radiofrequency ablation for refractory gastric antral vascular ectasia (with video). Gastrointest Endosc 2013; 78: Kantsevoy SV, Cruz-Correa MR, Vaughn CA, Jagannath SB, Pasricha PJ, Kalloo AN. Endoscopic cryotherapy for the treatment of bleeding mucosal vascular lesions of the GI tract: a pilot study. Gastrointest Endosc 2003; 57: Cho S, Zanati S, Yong E, et al. Endoscopic cryotherapy for the management of gastric antral vascular ectasia. Gastrointest Endosc 2008; 68: Walia SS, Sachdeva A, Kim JJ, Portocarrero DJ, Lewis TD, Zhao YS. Cyanoacrylate spray for treatment of difficult-to-control GI bleeding. Gastrointest Endosc 2013; 78: Katsinelos P, Chatzimavroudis G, Katsinelos T, et al. Endoscopic mucosal resection for recurrent gastric antral vascular ectasia. Vasa 2008; 37: Mann NS, Rachut E. Gastric antral vascular ectasia causing severe hypoalbuminemia and anemia cured by antrectomy. J Clin Gastroenterol 2002; 34: Sherman V, Klassen DR, Feldman LS, Jabbari M, Marcus V, Fried GM. Laparoscopic antrectomy: a novel approach to treating watermelon stomach. J Am Coll Surg 2003; 197: Aliment Pharmacol Ther 2014; 40: