gastric antral vascular ectasia ( gave ) is an uncommon cause of occult gastrointestinal ( gi ) bleeding and iron - deficiency anemia , accounting for 4% of nonvariceal upper gi hemorrhage.1 the clinical presentation of gave varies from a more indolent , chronic occult gi blood loss requiring serial transfusions to acute gi hemorrhage.1 first described by jabbari et al . in 1984,2 gave is also named watermelon stomach due to the gross endoscopic appearance of red stripes radiating from the antrum converging on the pylorus . gave is commonly associated with cirrhosis of the liver and , in particular , portal hypertension;3 however , it has also been associated with such underlying chronic diseases as autoimmune connective tissue disorders , chronic renal failure , systemic lupus erythematosus , and diabetes mellitus ( table 1).47 in patients with cirrhosis , gave is found more commonly in patients with the most advanced liver disease.8 gave has two distinct endoscopic forms , diffused or punctate , which is more commonly associated with cirrhosis910 and striped ( linear ) , which typically occurs in the absence of cirrhosis.10 despite the difference in endoscopic appearance , the histopathologic parameters of gave in patients with cirrhosis are identical to patients without cirrhosis11 and is characterized by a combination of four findings : vascular ectasia of mucosal capillaries , focal thrombosis , spindle cell proliferation , and fibrohyalinosis.12 the diagnosis of gave can be difficult , as it can be confused with portal hypertensive gastropathy . however , the pathophysiology of these two diseases is entirely different , as gave is more likely to be driven by the neurohumoral factors prostaglandin e and possibly gastrin , vasoactive intestinal peptide ( vip ) , and/or 5-hydroxytryptamine ( 5-ht),1316 leading to vasodilation and impaired motility.17 in general , there is a lack of epidemiologic evidence supporting differences in clinical outcomes in gave patients with and without cirrhosis . one series of 30 patients by ito et al . observed lower hemoglobin levels at baseline and a greater need for transfusion when comparing patients with gave who did not have cirrhosis to those with cirrhosis.6 here , we examined whether there is a difference in clinically significant gi bleeding secondary to gave in a cohort of patients with and without cirrhosis . we conducted a retrospective case - control study of patients who were found to have gave at the university of virginia between 1 january 2000 and 30 june 2014 using international classification of diseases , ninth revision , clinical modification ( icd-9 ) codes . patients were queried from the clinical data repository , and a primary cohort of patients with gave was constructed . if a disagreement on the diagnosis of gave occurred , a third independent gastroenterologist / hepatologist reviewed the report for final decision on inclusion . the diagnosis of cirrhosis was based initially by screening icd-9 codes and confirmed by available histologic sampling by liver biopsy or by imaging studies ( both cross - sectional and ultrasound ) . patients who had an additional gi bleeding source ( e.g. gastroesophageal varices , gastric ulcer , etc . ) were excluded . baseline covariate characteristics were reviewed , including age , gender , race , etiology of liver disease , severity of liver disease based on model for end - stage liver disease ( meld ) , and child - pugh scores , laboratory values [ platelet counts , creatinine , blood urea nitrogen , sodium , albumin , international normalized ratio ( inr ) , and total bilirubin ] , gave risk factors [ hypothyroidism , bone marrow transplant , chronic kidney disease ( ckd ) , end - stage renal disease ( esrd ) , diabetes , proton pump inhibitor ( ppi ) use , connective tissue disease ] , and gi bleeding risk factors [ active smoking , active alcohol use , anticoagulant or antiplatelet agent use , and non - steroidal anti - inflammatory drug ( nsaid ) use ] . primary outcomes were objective evidence of active gi bleeding , which was defined as symptoms of melena , hematochezia , hematemesis , change in hemodynamics , or gross bleeding on esophagogastroduodenoscopy ( egd ) . secondary outcomes included number of transfusions , baseline hemoglobin , need for endoscopic intervention [ including argon plasma coagulation ( apc ) ] , rebleeding rates , need for surgery , and death . patients with gave and cirrhosis were compared statistically to those without cirrhosis in multiple factors , including demographics , laboratory values , gave risk factors , and gi bleeding risk factors . univariate comparisons were performed using the student - t test , wilcoxon sign rank test , chi - square test , and fisher exact test , as appropriate . when the normality of continuous variables was not assumed or when the equality of variances was not observed , logarithmic transformation was done . multivariable models were constructed to assess statistical associations and risk factors for the development of bleeding from gave using logistic regression and analysis of the maximum likelihood estimates . odds ratios ( or ) were calculated and were used as an estimation of risk under the rare disease assumption . individual factors were included in the multivariable model if they were statistically significant ( p<0.20 ) in the univariate analysis , were clinically important , or have been shown in the literature to be important.18,19 multiple iterations of the model were performed . variables included in the final iteration of the model included presence or absence of cirrhosis , platelet count , hypothyroidism , diabetes , ppi use , nsaid use , hemoglobin , type of gave , egd indication , and ckd . all data set manipulation and statistical analyses were carried out using sas ( version 9.4 , cary , usa ) . all statistical tests for significance were two sided and a significance level of p0.05 was considered statistically significant . patients with gave and cirrhosis were compared statistically to those without cirrhosis in multiple factors , including demographics , laboratory values , gave risk factors , and gi bleeding risk factors . univariate comparisons were performed using the student - t test , wilcoxon sign rank test , chi - square test , and fisher exact test , as appropriate . when the normality of continuous variables was not assumed or when the equality of variances was not observed , logarithmic transformation was done . multivariable models were constructed to assess statistical associations and risk factors for the development of bleeding from gave using logistic regression and analysis of the maximum likelihood estimates . odds ratios ( or ) were calculated and were used as an estimation of risk under the rare disease assumption . individual factors were included in the multivariable model if they were statistically significant ( p<0.20 ) in the univariate analysis , were clinically important , or have been shown in the literature to be important.18,19 multiple iterations of the model were performed . variables included in the final iteration of the model included presence or absence of cirrhosis , platelet count , hypothyroidism , diabetes , ppi use , nsaid use , hemoglobin , type of gave , egd indication , and ckd . all data set manipulation and statistical analyses were carried out using sas ( version 9.4 , cary , usa ) . no data involving prisoners were included in this analysis . all statistical tests for significance were two sided and a significance level of p0.05 was considered statistically significant . a total of 478 patients underwent egd and were diagnosed with gave between january 2000 and june 2014 . eighty - four patients were in the cirrhosis group ( 76.4% ) and 26 were in the noncirrhosis group ( 23.6% ) . in the cirrhosis group , alcohol was the most common etiology of cirrhosis ( 34.5% ) , and the mean meld score was 13.3 . in the noncirrhosis group , the most common concomitant disorder was diabetes mellitus ( n=12 ) , followed by ckd ( n=8 ) . the less commonly associated conditions were bone marrow transplantation recipients , hypothyroidism , and connective tissue disease . baseline characteristics amongst patients with and without cirrhosis were in general similar with several exceptions ( table 2 ) . of the covariates analyzed , the platelet count and albumin level in patients without cirrhosis were higher than patients with cirrhosis ( p<0.05 ) . the indication for initial egd was also similar between the two groups when dichotomized to those performed for suspected gi blood loss versus other indications . use of anticoagulant or antiplatelet agents was rare amongst our patients , and only one patient in the noncirrhosis group was on an anticoagulant . aih , autoimmune hepatitis ; dili , drug induced liver injury ; hcv , hepatitis c virus ; nash , nonalcoholic steatohepatitis ; ns , not significant ; nsaid , nonsteroidal anti - inflammatory inhibitor ; pbc , primary biliary sclerosis ; ppi , proton pump inhibitor ; psc , primary sclerosis cholangitis . in univariate analysis , active gi bleeding was more common in the noncirrhosis group than the cirrhosis group ( 63.4% vs. 32.1% , p=0.003 ) ( table 3 ) . there was no statistically significant difference in the baseline levels of hemoglobin or hematocrit between the two groups . the proportion of patients with cirrhosis who had the striped ( linear ) form of vascular ectasia was 68.0% compared to 46.2% in the noncirrhosis group ( p=0.048 ) . endoscopic treatment with apc was required more often in patients without cirrhosis than patients with cirrhosis and approached statistical significance ( 27.0% vs. 10.7% , p=0.056 ) . however , there was no difference between the two groups in bleeding severity , as evidenced by similar rates of rebleeding , need to escalate therapy to surgery , and death . apc , argon plasma coagulation ; bicap , bipolar circumactive probe ; gave , gastric antral vascular ectasia ; ns , not significant . after adjusting for the presence confounders , our multivariable regression analysis ( table 5 ) showed that absence of cirrhosis was the strongest predictor of active bleeding from gave with or : 5.151 ( 95% ci : 1.084 - 24.480 , p=0.039 ) . no other variable included in our model , except for inr , was significantly associated with an increased risk of active gi bleeding from gave . the model was deemed significant ( p=0.041 for likelihood ratio test statistic ) and had good predictability , as the c - statistic of the model was 0.85 . gave , gastric antral vascular ectasia ; inr , international normalized ratio ; ns , not significant ; nsaid , non - steroidal anti - inflammatory drug ; ppi , proton pump inhibitor . gave is an uncommon cause of acute upper gi bleeding and is traditionally thought to be associated largely with cirrhosis . in our retrospective case - control study , we have found the opposite . patients with gave in the absence of cirrhosis had a higher risk of developing active gi bleeding and required endoscopic treatment more frequently than those with cirrhosis . in fact , after adjusting for the presence of comorbidities associated with gave , risk factors for gi bleeding and coagulopathy , the only significant predictor for clinically evident gi bleeding in the setting of gave was the absence of cirrhosis . however , there was no difference in the severity of gi bleeding measured by levels of hemoglobin and hematocrit or the total number of transfusions prior to presentation . electrocoagulation was the mainstay therapy used in most cases , and the outcome of the therapy was similar between the two groups . irrespective of cirrhosis , patients had a similar response to treatment in terms of rebleeding events , escalation of treatment to surgery , and mortality . our findings confirmed those of ito et al6 and expanded them on a much larger scale . in a retrospective study of 30 patients , of which 25 had cirrhosis , they observed that patients with gave in the absence of cirrhosis had lower hemoglobin levels . however , they failed to control for the presence of confounders in their analysis , and the indication for endoscopy in their patient population included variceal screening , which could introduce lead - time bias in the cirrhosis group in which endoscopies were routinely performed to screen for esophageal varices and could recognize gave in asymptomatic patients . in our study , we reviewed each patient s indication for initial egd , which included esophageal varices screening , chronic anemia , and overt gi bleeding . after excluding esophageal varices screening in asymptomatic patients and only comparing symptomatic patients , we found that egd was done more frequently in the cirrhosis group in the setting of anemia or overt gi bleeding than that of the noncirrhosis group . the small sample size of symptomatic patients is certainly a limitation ; however , it reflects the fact that gave associated nonvariceal gi bleeding is a rare event . regardless , ito et al.6 argued that there was an inherent difference in either the pattern of gave ( punctate vs. linear ) or the presence or absence of cirrhosis , but they could not distinguish the independent contribution of these factors with their analysis . our multivariable analysis argues against this , as the pattern of gave did not reach statistical significance in predicting a patient s likelihood of having active gi bleeding . in addition , the two patterns of gave were indistinguishable histologically , suggesting that the two entities may be more similar than was previously realized . yet , there is a difference in circulating neurohumoral factors ( prostaglandin e , vip , and 5-ht ) between patients with cirrhosis and those without.1316 further study is needed to define the clinical importance of these biomarkers and to investigate any clinical utility . our study had several limitations . while it contained a larger sample size than previous studies and was well powered , it was nonetheless retrospective . missing data was also problematic as roughly  of patients who underwent egd and were coded as having gave were excluded for this reason . another limitation of our study was a lack of follow - up , as our rebleeding rates were calculated at 72 h due to limitations in our retrospective dataset . this is problematic with gave , in particular , as these patients often required multiple treatment sessions ( 3060% ) , sometimes months after their first treatment.2022 based on our findings and the work of others , we argue that the dogma of gave as largely associated with cirrhosis and/or portal hypertension may in fact be incorrect and that gave should be considered on the differential diagnosis for any patient with objective evidence of acute upper gi bleeding . if gave is diagnosed endoscopically , a thorough investigation for not only cirrhosis of the liver but also other noncirrhosis disease processes associated with gave should ensue . future studies should focus on the mechanistic differences between gave patients with and without cirrhosis in order to determine if neurohumoral factors differ as a potential explanation for the differences observed clinically .