Gastric varices in patients with liver cirrhosis: pathogenesis, classification, and therapeutic management

Portal hypertension

Portal hypertension (PH) is defined as an increase in pressure in the portal vein > 12 mmHg (normal: 5-10 mmHg), with a simultaneous increase in the wedged hepatic venous pressure (WHVP) between portal vein pressure and inferior vena cava pressure by > 2-6 mmHg. WHVP values > 5 mmHg indicate an increase in pressure within the hepatic sinusoids. According to the Baveno VII guidelines [1-3], in patients with alcoholic cirrhosis, hepatitis B (HBV) or hepatitis C (HCV) infection, the hepatic venous pressure gradient (HVPG) measurement is the gold standard, while in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) cirrhosis it is the “imperfect gold standard”, enabling the diagnosis of clinically significant portal hypertension (CSPH), reaching a value of HVPG ≥ 10 mmHg. However, the presence or absence of CSPH does not necessarily determine the progression of liver disease of varying etiologies or the associated risk of mortality.
A significant diagnostic challenge arises in patients with primary biliary cholangitis (formerly known as primary biliary cirrhosis – PBC), in whom the pre-sinusoidal component of portal hypertension cannot be assessed using the WHVP measurement. This is because HVPG measurement reflects sinusoidal pressure, whereas in early stage PBC portal hypertension is often presinusoidal; therefore, WHVP may remain normal despite clinically significant portal hypertension. Additionally, the pathophysiology of portal vein confluence is further complicated by increased vascular capacity and elevated cardiac output – hallmarks of a hyperkinetic circulation [4-8].
In clinical practice, the most common cause of portal hypertension is advanced hepatic fibrosis or cirrhosis, which are currently collectively described as compensated advanced chronic liver disease (cACLD), a designation that appears to be more practical and clinically meaningful than the traditionally used term “established liver cirrhosis.” Nevertheless, the etiologies of portal hypertension are diverse and frequently coexist. These causes are listed in Table 1. Unfortunately, the severity of portal hypertension – and consequently, the risk of hemorrhage – typically increases in parallel with the progression of hepatic dysfunction and the advancement of parenchymal fibrosis. This progression can occur particularly rapidly in patients who experience either simultaneous or sequential exposure to multiple pathogenic factors contributing to liver disease. Moreover, in patients with PBC, varices and an elevated risk of GI bleeding may be observed even before the full remodeling of hepatic architecture due to cirrhosis [1, 9].

Gastric varices: a definition

The term “gastric varices” refers to dilated submucosal veins within the stomach. Along with varices in other segments of the tubular gastrointestinal (GI) tract, these structures function as collateral channels that decompress the portal hypertension within the portal vein confluence, facilitating the diversion of blood flow from the portal to the systemic circulation – unfortunately, bypassing the liver. Regardless of their anatomical location, GI varices pose a substantial risk of hemorrhage, which almost invariably occurs in the GI lumen. Gastric varices are observed less frequently than esophageal varices; they are present in approximately 15-20% of patients with cirrhosis, typically in more advanced stages of the disease, and in about 5-33% of patients with portal hypertension, regardless of its etiology. Approximately 34.5% of gastric varices are isolated, although their presence does not exclude the simultaneous occurrence of varices in other regions of the gastrointestinal tract, particularly in the esophagus [9-12].

Classification of gastric varices (according to Sarin classification [9])

It is estimated that approximately 75% of gastric varices are classified as type 1 gastroesophageal varices. These varices, also referred to as GEV or GOV-1, are located just below the gastric cardia along the lesser curvature of the stomach and represent a direct continuation of esophageal varices. In some cases, they are considered secondary varices, representing a complication of esophageal variceal banding, occurring in approximately 10-15% of patients following such intervention.
A second, less common subtype is fundal varices, which likewise represent a continuation of esophageal varices; these are also referred to as type 2 gastroesophageal varices (GOV-2). These varices are typically larger and may, in extreme cases, appear as “bunches of grapes.” GOV-2 varices carry a considerable risk of hemorrhage that may be challenging to manage.
Another distinct category comprises the, relatively rare, isolated gastric varices (IGV), defined by their occurrence in the absence of esophageal varices (see above). These are subdivided into type 1 isolated gastric varices (IGV-1), which are located in the fundus of the stomach, tend to be large, and have a higher propensity to bleed (often related to splenic vein thrombosis), and type 2 isolated gastric varices (IGV2), which are rarely observed and found in the body and antral regions of the stomach [9-13].

Risk of bleeding from gastric varices

Gastrointestinal bleeding constitutes a dramatic and potentially life-threatening clinical event. However, portal hypertension and its complications account for bleeding in only 15-20% of such cases. In practical terms, hemorrhage is generally observed only in patients with clinically significant portal hypertension, with a HVPG of ≥ 10 mmHg. Nonetheless, the risk of bleeding affects as many as 20-50% of patients with portal hypertension, and is even higher in those with cirrhosis. Of all variceal hemorrhages, approximately 60-70% originate from esophageal varices, 20% from portal hypertensive gastropathy, 5% from gastric varices (although this percentage varies across studies and constitutes the problem discussed in this paper), and 1-2% from other sites, including rectal varices. Among patients with grade 3 esophageal varices, regardless of location, 25-35% experience bleeding within two years of observation. Bleeding from esophageal varices ceases spontaneously in 40-50% of cases, and in specialized centers equipped with trained personnel – including endoscopy and interventional radiology services – the six-week mortality rate during the first hemorrhagic episode does not exceed 20% (compared to approximately 50% thirty years ago). In the absence of causative treatment and secondary prophylaxis (which may include pharmacological agents, endoscopic ligation, or obliterative procedures), the risk of rebleeding within six weeks is approximately 20% (most notably in the first week), and approaches 64% within two years. Unfortunately, the mortality rate associated with each successive hemorrhagic episode remains around 20%. Furthermore, esophageal variceal band ligation may contribute to the formation and increased filling of gastric varices, a phenomenon we have also periodically observed in clinical practice. Approximately 20-30% of patients with portal hypertension experience bleeding due to gastric varices, portal hypertensive gastropathy or enteropathy, hemorrhagic gastritis, or gastroduodenal ulcers – collectively referred to as hepatogenic ulcers.
Focusing specifically on variceal bleeding, gastric varices are responsible for approximately 5-10% of such events. These episodes are generally more severe and associated with higher mortality compared to bleeding from esophageal varices. Spontaneous hemostasis occurs less frequently in gastric variceal bleeding – i.e. in less than 40% of cases. Both mortality without endoscopic intervention and the frequency of rebleeding are higher (based on clinical observations). Of those patients who achieve spontaneous hemostasis, 35-90% experience rebleeding within a short period following the initial hemorrhagic event. A particularly high risk of bleeding – responsible for approximately 80% of gastric variceal hemorrhages – is associated with fundal varices (IGV-1 and GOV-2), a finding consistently confirmed across numerous studies over the years. Moreover, gastric varices that develop as a consequence of successful esophageal variceal eradication exhibit a higher bleeding rate than primary gastric varices, regardless of anatomical location [1-4, 10-12]. Researchers in China have developed a bleeding risk stratification model for esophageal and gastric varices in patients infected with hepatitis B virus, utilizing nuclear MRI techniques. This model may support more precise decision-making regarding prophylactic interventions [13].

Risk factors for bleeding from gastric varices

The following are established risk factors for gastrointestinal bleeding, several of which have been partially discussed above. (It is important to emphasize that, in patients with advanced liver disease, these risk factors are equally relevant to bleeding originating from other locations within the gastrointestinal tract.) The risk factors are:
1. Liver cirrhosis classified as Child-Pugh class C;
2. Tense ascites, which emphasizes the significance of resolving ascites prior to conducting endoscopic procedures;
3. HVPG exceeding 12 mmHg (gastric variceal bleeding may occur at lower values);
4. Use of nonsteroidal anti-inflammatory drugs (NSAID);
5. Elevated portal venous pressure resulting from alcohol abuse, decreased hepatic function (e.g., hepatitis A virus [HAV] or hepatitis E virus [HEV] infection in a patient with non-infectious cirrhosis), excessive physical exertion, increased intra-abdominal pressure, or consumption of large quantities of food, particularly fatty or gas-producing meals;
6. Location of varices, with risk increasing in the following order: IGV-1 > GOV-2 > GOV-1;
7. Variceal size, particularly varices > 10 mm in diameter. However, patients with smaller varices who exhibit red signs or who have advanced cirrhosis (Child-Pugh class C) demonstrate a comparable risk of bleeding to those with large varices;
8. Presence of mucosal erosions or red signs markings on varices;
9. Coexistence of primary liver cancer or other malignant hepatic tumors;
10. Progression of thrombosis within the portal venous system [1-4, 9, 10, 12-14].

Diagnosis and treatment of gastric varices

The diagnosis and management of portal hypertension, including gastric varices, require a multifaceted approach that is both etiological and symptomatic; this management paradigm demands substantial clinical expertise. Preventive strategies, promoted in current clinical practice, should begin by addressing the root causes of portal hypertension and treating liver disease at a stage prior to the development of clinically significant portal hypertension. Interventions may include metabolic correction, weight reduction, or abstinence from alcohol. However, in many instances, portal hypertension is not diagnosed until the disease has already progressed to an advanced stage. In such cases, efforts focus on eliminating underlying causes, pharmacologically reducing portal pressure, initiating anticoagulant or surgical interventions in the presence of extrahepatic vascular pathology, and implementing adjunctive therapies with mechanisms that are not always fully elucidated.
1. MASLD – metabolic dysfunction-associated steatotic liver disease – management of metabolic syndrome, weight reduction, dietary modifications, and pharmacotherapies such as: resmetirom, metformin, cenicriviroc (CCR5 co-receptor inhibitor), statins, vitamin A, ursodeoxycholic acid, thiazolidinediones, and bariatric surgery; other agents are currently in clinical trials;
2. ALD – alcohol-associated liver disease – abstinence from alcohol; in ASH/MASH – GSK combined with N-acetylcysteine;
3. HBV infection – antiviral therapy: entecavir, tenofovir disoproxil, or tenofovir alafenamide;
4. HBV/hepatitis D (HDV) coinfection – at least one year of peginterferon alpha-2a therapy and/or the use of new agents: bulevirtide and lonafarnib (drug being tested for HDV infection);
5. HCV infection – direct-acting antiviral (DAA) therapy;
6. Wilson’s disease – copper-restricted diet, treatment with d-penicillamine (Cuprenil), zinc acetate, or trientine;
7. Hemochromatosis or hemosiderosis – iron-restricted diet, therapeutic phlebotomy, and administration of deferoxamine (Desferal);
8. Other rare metabolic diseases – such as α1 antitrypsin deficiency, hereditary tyrosinemia, and glycogenosis (GSD). These often have no definitive treatment or require expensive and scarcely available pharmacotherapies;
9. Autoimmune diseases (AIH, PSC, PBC, and overlap syndromes) – GKS, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, ursodeoxycholic acid (UDCA), budesonide + UDCA, bezafibrate (off-label in PBC) + UDCA, seladelpar ± UDCA, or elafibranor ± UDCA;
10. Biliary tract disorders – cholelithiasis, malignancies, schistosomiasis, and Clonorchis sinensis infection, treated surgically, via endoscopic bile duct stenting, or with antiparasitic agents;
11. Drug-induced liver injury (DILI) and toxic hepatic or vascular damage – managed with GKS, statins, or low-molecular-weight heparins.
12. Diseases affecting hepatic veins and the portal venous confluence – treated with surgical intervention and/or low-molecular-weight heparin in cases of extrahepatic vascular pathology.
It must be acknowledged that elimination of the causative agent of liver disease does not universally halt the progression of liver pathology or prevent the emergence of clinically significant portal hypertension [1, 2, 14, 15]. Spanish investigators followed 230 patients with HCV infection over a period of 36 months. All patients achieved a sustained virologic response (SVR) following treatment with direct-acting antivirals. Among 151 patients who were free of varices at baseline 64 (42.4%) remained under endoscopic surveillance – out of that group, 8 individuals (12.5%) developed new varices. In a subgroup of 50 out of 151 patients with low-risk varices at baseline (LR-GEV), 12 patients (24%) progressed to develop high-risk gastroesophageal varices (HR-GEV) [16].

Symptomatic treatment – primary prophylaxis

The principal objective of symptomatic treatment is to reduce the HVPG to < 12 mmHg or to achieve a reduction of HVPG > 20% from baseline values, both of which are associated with a significant decrease in the risk of gastric variceal hemorrhage. Several approaches are employed to mitigate bleeding risk in patients with large gastric varices; endoscopic injection of N-butyl cyanoacrylate (Histoacryl) into the lumen of gastric varices that are predisposed to bleeding – particularly type 2 gastroesophageal varices and isolated type 1 gastric varices – has proven more effective than prophylactic administration of propranolol. However, this intervention does not appear to impact overall survival rates. The use of non-selective beta-adrenergic antagonists (especially carvedilol) is effective in reducing the risk of hepatic decompensation in this patient population. According to current recommendations (Baveno VII), there is no indication for transvenous obliteration of gastric varices using balloon-assisted techniques (BRTO – balloon-occluded retrograde transvenous obliteration, BATO – balloon-occluded anterograde transvenous obliteration, BARTO – balloon-assisted retrograde transvenous obliteration) as a form of primary prophylaxis against gastric variceal bleeding in patients with compensated cirrhosis [1, 17].
Immediate management: The goal is to stop GI bleeding.
Gastrointestinal variceal hemorrhage, especially from gastric varices, is life-threatening and must be managed in an intensive care setting. According to current standards:
1. The first priority is hemodynamic resuscitation, which includes: correction of circulatory and respiratory disturbances and electrolyte imbalances, as well as blood loss replacement (hemoglobin should not exceed 7-8 g%, as higher levels increase the risk of rebleeding; however, this should be individualized based on the patient’s age, comorbidities, and hemodynamic status); correction of clotting factor deficiencies, although PT/INR is not a reliable indicator of coagulation status in this patient group; evacuation of blood from the gastrointestinal tract and paracentesis in cases of massive ascites should also be performed; intubation is recommended for patients with disturbed consciousness.
2. Pharmacotherapy should be initiated simultaneously and continued for up to 5 days (terlipressin [Glypressin] – synthetic vasopressin analog, somatostatin, or octreotide – synthetic somatostatin analog), which help reduce pressure in the portal venous system. Once hemodynamic stabilization is achieved, urgent esophagogastroduodenoscopy should be performed (within 12 hours of hospital admission). This combined approach has a clear advantage in hemorrhage control over standalone pharmacological or endoscopic treatment. Pharmacological bleeding control is successful in approximately 90% of patients with Child-Pugh class A cirrhosis and about 58% in class C. Pharmacotherapy also assists the endoscopist in identifying the source of bleeding and performing therapeutic procedures. Additionally, it is effective for managing bleeding from the gastric mucosa in portal gastropathy, which is often difficult to treat endoscopically.
3. In the absence of contraindications (e.g., QT interval prolongation on ECG), intravenous erythromycin (250 mg) should be administered 30-120 minutes prior to the procedure.
4. The standard treatment of bleeding from gastric varices (particularly isolated types IGV and GOV-2) is injection of Histoacryl (N-butyl-cyanoacrylate) directly into the lumen of the bleeding varix, aiming to fill both the active bleeding site and adjacent varices. This procedure should be repeated every 2-3 days. Effectiveness is confirmed by achieving hemostasis and through endoscopic assessment of the “firmness” of the filled varix. GOV-1 varices may be treated using combined or mixed techniques, although loop ligation or banding and superficial injection of 1% polidocanol are less effective, often associated with rebleeding, and therefore rarely used. Endoscopic band ligation is not recommended for IGV-1 and GOV-2, as efficacy is lower and rebleeding risk higher compared to tissue adhesives. All these procedures require high technical skills and experience to avoid damage to the endoscope, particularly when using Histoacryl.
5. EUS-guided variceal obliteration using either Histoacryl (glue) or thrombin in combination with coiled fibers (coils) shows promising results, as the coils expand within the varix and promote more complete filling [18]. Some studies suggest that EUS-guided varices obliteration may be superior to direct endoscopic injection [19];
6. Intravenous antibiotics (quinolones such as norfloxacin or ciprofloxacin, or cephalosporins such as ceftriaxone) should always be administered and continued for 5-7 days;
7. In cases of acute GI variceal hemorrhage, intravenous fresh frozen plasma, recombinant factor VIIa, or tranexamic acid have not demonstrated clinical efficacy;
8. Anticoagulation – in patients taking anticoagulants (e.g. PVT), treatment should be suspended until bleeding is controlled. The timing of resumption of treatment should be individualized based on the bleeding control, indication for anticoagulation, and the risk of rebleeding. It requires careful balancing of bleeding and thrombosis risks.
In the event of failure of pharmacological and endoscopic treatment in controlling bleeding from gastric varices, the following steps should be considered:
– early percutaneous transjugular intrahepatic portosystemic shunt (PTFE-TIPS) – limited availability in some medical centers. It is recommended to conduct early TIPS insertion in patients with high risk of rebleeding, after endoscopic intervention [20];
– in some countries (mainly Japan), transvenous obliteration of gastric varices using special balloon systems is also employed (BRTO, BATO, and BARTO techniques) [18];
– in selected cases with good liver function, within 12 hours of diagnosing bleeding from esophageal or gastric varices, creating a portosystemic shunt via a surgical procedure may be considered (this approach is currently used very rarely);
– hemostatic powders – not recommended as first-line treatment;
– splenectomy/splenic artery embolization – may be considered in variceal bleeding associated with left-side portal hypertension [21, 22].
The therapeutic effectiveness and safety of the above methods depend largely on the experience of the treating team and the availability of the techniques [14-17, 23-27].
Indian authors identified 34 publications in the Cochrane database involving 2,783 patients with gastric varices who were treated or received prophylactic invasive procedures using all currently known methods: Histoacryl or thrombin injections into the variceal lumen, rubber band ligation, endo-EUS-guided administration of Histoacryl, coils, and transvenous obliteration of gastric varices with balloon systems (BRTO techniques). They concluded that BRTO techniques and obliterative agent administration under ultrasound guidance demonstrated higher therapeutic efficacy and lower mortality compared to Histoacryl injections. However, the scientific strength of these findings is limited [23].

Secondary prophylaxis of GI variceal bleeding, including gastric varices

Recognized risk factors for recurrence of gastric variceal bleeding – many of which clinicians have limited control over – include: portal vein thrombosis, ascites, active inflammatory process and fever (regardless of cause), history of recurrent variceal bleeding, red signs on the varices, and perigastric varices. Simultaneously, the use of proton pump inhibitors (PPIs) may reduce the risk of hemorrhage [28, 29], although according to Baveno VII guidelines, PPIs should be discontinued after acute variceal bleeding unless there is another strict indication. Therefore, their role in secondary prophylaxis is not supported.
In all patients who have survived an initial episode of GI variceal bleeding, preventive measures should be implemented to minimize the risk of recurrence. These include β-blockers and repeated Histoacryl injections into the variceal lumen, regardless of the prophylactic method used prior to the episode.
The therapeutic effectiveness of TIPS in preventing recurrent GI variceal bleeding is comparable to that of surgical procedures such as devascularization or portosystemic shunt creation.
Failure of standard therapy is an indication for PTFE-covered TIPS in patients who are not candidates for surgery [30].
In patients who have survived variceal bleeding and have advanced liver disease (Child-Pugh score > 8 points or MELD score > 16 points), liver transplantation should be considered [1-4].

Conclusions

Portal hypertension is one of the most significant complications of chronic liver disease, leading to the development of collateral circulation and varices within the gastrointestinal tract. Gastric varices, although less common than esophageal varices, represent a distinct and potentially life-threatening complication, and requires careful differentiation from esophageal varices, which justify their separate consideration.
Diagnosis and treatment require a comprehensive approach that combines etiological and symptomatic interventions. Primary prevention is crucial and focuses on managing underlying liver disease and reducing portal pressure before high-risk varices develop. In the event of acute bleeding, initial management includes hemodynamic resuscitation, vasoactive pharmacotherapy, antibiotic prophylaxis, and urgent endoscopy with N-butyl cyanoacrylate injection, which remains the gold standard for gastric variceal hemostasis. In cases where pharmacological and endoscopic therapy fail, early transjugular intrahepatic portosystemic shunt (TIPS) placement is recommended, while BRTO/BATO techniques or surgical interventions may be considered in selected settings.
In patients with advanced liver failure, liver transplantation should be considered as the definitive therapeutic option.

Disclosures

This research received no external funding.
Institutional review board statement: Not applicable.
The authors declare no conflict of interest.

References