Epidemiology

The exact prevalence of GAVE is unknown because of its relatively silent presentation and its association with a wide variety of systemic diseases. In addition, GAVE was not described reliably in the past, and it was not until 1995 that the distinction was made between GAVE and PHG in patients with cirrhosis. During the evaluation of chronic anemia, GAVE is typically found to be the cause in elderly women and is also is associated with several chronic systemic diseases (chronic renal failure, autoimmune diseases, systemic sclerosis, cardiac diseases, and bone marrow transplantation). On routine upper endoscopy, GAVE is seen in 3% and 2% of patients with advanced liver disease and those undergoing liver transplantation, respectively. GAVE is considered to be responsible for 4% of nonvariceal upper GIB in patients with and without portal hypertension.

Diagnosis

GAVE is described as a vascular lesion consisting of abnormally dilated and tortuous gastric mucosal capillaries (ectasia) with mural spindle cell proliferation (smooth muscle cells and myofibroblasts), focal thrombosis, and fibrohyalonosis. These histologic findings are incorporated into the “GAVE score” ( Table 1 ), which can be used to make a diagnosis of GAVE with high accuracy (70%–85%) on a gastric biopsy to differentiate it from PHG. Biopsy, however, is often not needed to diagnose GAVE because of its characteristic morphologic appearance. Conventionally, upper endoscopy has been used to diagnose GAVE based on the finding of reddish spots either organized in stripes radially projecting proximally from the pylorus (watermelon stomach) or arranged in a diffuse (honeycomb stomach) or nodular pattern (nodular antral gastropathy) ( Fig. 1 ). These lesions are seen in the form of erythematous and at times raised mucosa with visible underlying ectatic vessels, which are located mainly in the antrum of the stomach. In cirrhotics, a clear distinction from PHG, especially in a diffuse or nodular type pattern, is difficult to make on endoscopic inspection and a biopsy is often needed. Among other endoscopic modalities, capsule endoscopy has been recently used to evaluate GAVE. In addition, endoscopic ultrasound (EUS) is also used, and the EUS appearance of GAVE is described as spongiform mucosa and submucosa with well-preserved muscularis propria and hypertrophied gastric antrum. Red blood cell scan and CT scan findings of GAVE have also been described in a few case reports. Platelet marker CD61 immunostain identifies microthrombi within the vessels and increases the diagnostic accuracy of biopsy specimen evaluation.

Mild GAVE with stripes ( A ); moderate GAVE with mild active GIB ( B ); mild/small nodular GAVE or nodular antral gastropathy (NAG) ( C ); large NAG ( D ).

Pathogenesis

GAVE is considered to be an acquired abnormality, resulting in ectasia of mucosal microvasculature, which results from mechanical stress or neuroendocrine abnormalities. Hemodynamic and autoimmune factors have also been implicated in the pathogenesis of GAVE and its exact cause remains to be further elucidated. The finding of antropyloric dysfunction and abnormal antral motor response to meals in some patients with GAVE relate to the hypothesis that repeated forceful peristalsis induces prolapse and trauma to the antral mucosa, which leads to microvascular abnormalities found in GAVE. Several neuroendocrine hormones (gastrin, vasoactive intestinal polypeptide [VIP], 5-hydroxytryptamine, prostaglandin E2, nitric oxide, and/or glucagon) have also been suggested to play a role in the development of GAVE. Their levels are found to be elevated in some cirrhotics with GAVE. It is postulated that the accumulation of vasoactive substances that are poorly metabolized by the cirrhotic liver results in mucosal microvascular damage and ectasia. It is actually the loss of hepatic function rather than the portal hypertension in liver cirrhosis that is associated with GAVE, in contrast to PHG. GAVE has been reported to have completely resolved after liver transplantation, and portal decompressive techniques have been reported to not improve GAVE and its associated GIB. Up to 60% of GAVE patients have concurrent autoimmune disease (eg, Raynaud disease, systemic sclerosis, Sjogren syndrome) and several auto-antibodies have been detected in patients with GAVE. The association of several other chronic diseases (eg, renal, cardiac, and/or hematologic) with GAVE also needs further investigation.

Management

Similar to any patient with GIB, initial management of these patients consists of adequate resuscitation and hemodynamic stabilization. In patients with GAVE, GIB is most often chronic, with patients presenting with symptoms of anemia, occult blood in their stool, with or without iron deficiency anemia. GAVE is mostly identified as a part of the workup of GIB on upper endoscopy or during screening endoscopies. It is reasonable not to treat GAVE lesions, which are found incidentally or are not the source of bleeding (primary prophylaxis). For symptomatic/bleeding lesions, endoscopic ablative techniques are usually first-line treatment. Thermoablative procedures are used more commonly in clinical practice, while the use of cryotherapy, radiofrequency, or mechanical ablation is less frequent because, generally, they require more expertise.

Major thermoablative techniques include argon plasma coagulation (APC) and neodymium:yettrium-aluminum garnet (YAG) laser therapies, which have been investigated extensively to control GAVE-related GIB. Both techniques are equally effective with up to 80% to 100% eradication of lesions and abolishment of need of blood transfusion in up to 50% to 80% of patients after 2 to 3 sessions on average. There are no head-to-head trials comparing these techniques; they do differ in their safety profile. APC is a reasonably newer ( Fig. 2 ), noncontact technique with lesser depth of coagulation and thus carries a lesser risk of gastric perforation as compared with YAG. YAG therapy is often complicated with gastric ulceration. In addition, cases of pyloric stenosis with gastric outflow obstruction, and hyperplastic gastric polyps forming after repeated sessions of YAG procedure, have been reported. A case of multifocal gastric cancer 5 years after multiple sessions of YAG laser therapy has also been reported. The technical details of these endoscopic procedures are not the focus of this article. The choice of procedure is mainly determined by the availability of expertise and technologies in any center. APC ablation is being used more prevalently these days because of better availability, lower cost, and good safety profile.

Moderate GAVE with significant active GIB ( A ); APC probe introduced via endoscope ( B ); APC deploying argon gas for coagulation to control bleeding ( C ); post-APC hemostasis ( D ).

Endoscopic band ligation (EBL) for GAVE showed a significantly higher rate of bleeding cessation with fewer treatments sessions and reduced need for blood transfusions because of a greater increase in hemoglobin levels after treatment, as compared with endoscopic thermal therapy in a study by Wells and colleagues. This mechanical ablative procedure (EBL) has been reported in a few case reports ; however, its utility requires expertise, has not yet become popular in many centers, and requires further controlled trials before it can be recommended. In addition, several other endoscopic techniques including cryoablation (needs specialized equipment), bipolar coagulation probe (greater depth of energy delivery), endoscopic mucosectomy, and radiofrequency ablation have been attempted with encouraging results for refractory GAVE cases. These techniques also need larger, prospective studies before their general use, to establish their efficacy and safety.

Several classes of drugs have been used to control GAVE-related GIB in case reports and clinical studies. Generally, if endoscopic therapy is not effective or not feasible, medical options are possible. Hormonal therapy with estrogen-progesterone combination pills demonstrated cessation of GIB from GAVE. The GAVE lesions were not eradicated and patients required higher doses, as bleeding recurred with dose reduction during the follow-up period. Maintenance with higher-dose estrogen-progesterone might contribute to untoward side effects of hormonal therapy, including increased risk of endometrial and breast cancer. Octreotide is a somatostatin analogue and has multiple local neuroendocrine effects, including decreasing gastrin levels (growth factor for gastric mucosa), suppression of serotonin, VIP, secretin, motilin, and pancreatic polypeptide. These factors have all been implicated in the pathogenesis of GAVE. In addition, octreotide has been shown to decrease splanchnic circulation and has local anti-angiogenic effects. In addition, it has been shown clinically to effectively reduce the chronic bleeding from gastric vascular abnormalities. Its utility in GAVE still remains of unclear benefit. Other agents, like thalidomide, serotonin antagonists, tranexamic acid, and corticosteroids, have shown some clinical efficacy in separate case reports. Immunosuppressive therapies, methyl prednisone, and cyclophosphamide were used in a patient with systemic sclerosis and resulted in complete resolution of GAVE-related GIB, suggesting the importance of control of the underlying disease as definitive therapy for GAVE.

Surgical resection of the gastric antrum with Billroth-I anastomosis provides definitive cure and has been used in difficult-to-treat cases after endoscopic and medical failures. The analysis of several case reports revealed that a surgical approach (mainly antrectomy) carries up to a 6.6% 30-day mortality.

Gastric Antral Vascular Ectasia in the Presence of Liver Cirrhosis

Liver cirrhosis is found in up to 30% of cases of GAVE. It often presents with chronic, persistent GIB leading to iron deficiency anemia. Overall, cirrhotic patients with GAVE-related GIB carry a higher mortality risk. It is often present with underlying portal hypertension and PHG. Diffuse/nodular pattern is more frequently seen along with PHG in cirrhotics, and clear distinction is sometimes difficult on endoscopic evaluation and, in such cases, careful biopsy and histologic evaluation are preferred. As mentioned above, the use of the GAVE score on histology has high diagnostic accuracy in distinguishing GAVE from PHG. This distinction is of clinical importance because management options are uniquely different for the definitive treatment of GIB from either of these gastric lesions. Treatment of portal hypertension (eg, β-blockers, or portosystemic shunts including transjugular intrahepatic portosystemic shunt [TIPS]) does not have a significant effect on GAVE-related GIB. Endoscopic treatment is mostly the preferred option, APC therapy was found to be effective in 88% of patients with cirrhosis and it required fewer treatment sessions to completely control the GIB related to GAVE, as compared with those without cirrhosis. However, high mortality (53%) was observed in a study among cirrhotics during a 20-month follow-up period and was mostly related to hepatic decompensation. EBL has not been well studied in patients with liver cirrhosis and safety and efficacy of medical therapy has been well defined in this population. Abdominal surgery (antrectomy) carries a high risk of morbidity and mortality in cirrhotics, especially in patients with portal hypertension. Careful selection of patients, accurate diagnosis, and prompt treatment are prudent in cirrhotic patients with GIB related to GAVE. Liver transplantation resulted in complete resolution of GAVE in a patient despite persistent portal hypertension, possibly because of the cure of their underlying liver failure.

In summary, asymptomatic, nonbleeding GAVE lesions do not require any therapy. GIB should be managed with transfusions as needed with a hemoglobin target of 7 to 8 g/dL (cirrhotics) and iron replacements for iron deficiency anemia. Endoscopic therapy (APC) should be attempted first, followed by medical management if endotherapy fails. Surgery can be used in refractory cases of GIB, as a rescue therapy.