- Email: [email protected]
The epidemiology and pathogenesis of gastrointestinal varices
Author’s Accepted Manuscript The Epidemiology and Gastrointestinal Varices
Pathogenesis
of
Aliya F. Gulamhusein, Patrick S. Kamath
www.elsevier.com/locate/tgie
PII: DOI: Reference:
S1096-2883(17)30032-3 http://dx.doi.org/10.1016/j.tgie.2017.03.005 YTGIE50527
To appear in: Techniques in Gastrointestinal Endoscopy Cite this article as: Aliya F. Gulamhusein and Patrick S. Kamath, The Epidemiology and Pathogenesis of Gastrointestinal Varices, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2017.03.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Epidemiology and Pathogenesis of Gastrointestinal Varices
Dr. Aliya F Gulamhusein, MD Toronto Center for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, ON, Canada
Dr. Patrick S Kamath, MD Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Corresponding Author:
Dr. Patrick S. Kamath, MD Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine 200 First Street SW, Rochester, Minnesota 55905 email: [email protected] phone: (507) 284-2511 fax: (507) 284-0538
Abstract
Gastrointestinal varices are a consequence of portal hypertension that can occur in the setting of cirrhosis or extrahepatic portal vein obstruction. Increased intrahepatic vascular resistance, a hyperdynamic circulation, and increased flow through the portal and collateral venous system lead to persistently elevated portal pressures that result in angiogenesis and formation of collaterals between the portal and systemic circulation. Despite this physiologic attempt at decompression, portal hypertension persists as collateral vessels have higher resistance than the normal liver. Variceal wall tension is the main factor that determines vessel rupture and bleeding occurs when tension in the wall exceeds the limit of elasticity of the vessel. Progressive distension leads to increasing resistance to flow and hemorrhage ensues when the limits of resistance to further dilation are surpassed. Gastroesophageal varices are present in 50% of patients with cirrhosis and progress in size at a rate of 8-10% per year. Hemorrhage occurs at a rate of approximately 12% per year and large esophageal varices carry a higher risk of rupture. Gastric varices occur in 20% of patients with portal hypertension and bleed less frequently, but more severely. Cardiofundal varices have a complex vascular anatomy that is important to consider as it pertains to the effectiveness of strategies used for management. Ectopic varices make up 2-5% of all variceal bleeding, occur more frequently in patients with extrahepatic portal hypertension, and their identification should prompt assessment of the intraabdominal vasculature. Varices in the setting of splenic vein thrombosis should be considered a distinct entity due to their disparate etiologic basis and treatment approach.
Keywords Portal hypertension Esophageal varices Gastric varices Ectopic varices
Abbreviations CTP = Child-Turcotte-Pugh CSPH = clinically significant portal hypertension eNOS = endothelial nitric oxide synthase EV = esophageal varices GV = gastric varices GOV = gastroesophageal varices HVPG = hepatic venous pressure gradient IGV = isolated gastric varices LSM = liver stiffness measurement MELD = model for end-stage liver disease PSC = Primary sclerosing cholangitis PVT = portal vein thrombosis SVT = splenic vein thrombosis TE = transient elastography VEGF = vascular endothelial growth factor WHVP = wedged hepatic vein pressure
Introduction Cirrhosis has traditionally been conceptualized as a discrete rather than dynamic disease associated with advanced degrees of histologic fibrosis. Liver injury from a variety of causes, including viral, autoimmune, metabolic, or cholestatic, lead to progressive fibrosis on liver biopsies which are often staged using semi-quantitative systems such as METAVIR or Ishak. These staging systems report degree of fibrosis ranging from none to the pathologic “end-stage” of cirrhosis (1-3). While a clinical distinction between compensated and decompensated cirrhosis is often made, there is increasing evidence that cirrhosis, both histologically and clinically, is a much more dynamic phenotype, and that classification systems ought to be more granular to better reflect the natural history and prognosis of patients with advanced liver disease (1, 4). Characterizing cirrhosis as it relates to degree of underlying portal hypertension and associated circulatory dynamics likely more accurately reflects risk of progression to clinically relevant endpoints.
Portal hypertension is a critical consequence of cirrhosis and causes many of the clinical manifestations of advanced liver disease. Though indirect, the wedged hepatic venous pressure (WHVP) is the preferred method for assessing portal pressure (5). It is obtained by wedging a catheter into a small branch of the hepatic vein and has been shown to closely correlate with portal pressures (6). The free hepatic vein pressure is then subtracted from the WHVP (to correct for increases in intra-abdominal pressure) resulting in the hepatic venous pressure gradient (HVPG). Importantly, this value is a measure of sinusoidal pressure and as such will be elevated in intrahepatic causes of portal hypertension but will be notably normal in pre-hepatic causes, such as portal vein thrombosis (PVT) (5). The HVPG is an important predictor of varices and clinical decompensation, including ascites, variceal hemorrhage and hepatic encephalopathy (7-9). A normal HVPG is 3-5 mmHg whereas an HVPG >10 mmHg has been
termed “clinically significant portal hypertension (CSPH),” that is, the threshold that defines risk of developing varices and/or clinical complications (1, 10). Patients without CSPH by definition do not have varices and are at a low five-year risk of developing them (10). Recurrent variceal hemorrhage and ascites do not occur when the HVPG is <12 mmHg, making this an important threshold to consider in understanding a patient’s risk for decompensating events (11-13). On the other hand, an HVPG >20 mmHg is an important negative prognostic indicator of poor outcome in the setting of acute variceal hemorrhage (14).
Considering cirrhosis in terms of degree of portal hypertension allows for a more granular classification system that more closely reflects a patient’s risk of liver related outcomes. One such proposed system breaks down compensated cirrhosis into that: a) without portal hypertension (i.e., HVPG < 6 mmHg); b) portal hypertension that is not clinically significant (i.e., HVPG between 6 and 10 mmHg); and c) CSPH (i.e., HVPG 10mmHg or with the presence of collaterals) (1). While such a system is physiologically rational, several inherent limitations to the use of HVPG exist, including its invasive nature, lack of local expertise, variable adherence to guidelines ensuring reliability and reproducibility of measurements, and cost (5, 15). Noninvasive approaches, such as liver stiffness measurement (LSM) using transient elastography (TE), are important advancements in monitoring for fibrosis progression and worsening of portal hypertension in patients with chronic liver disease, and their increasing use is likely to have implications on the role of endoscopy in screening for gastrointestinal varices (1, 10). While HVPG measurement remains the gold standard to assess for the presence of CSPH, LSM shows excellent correlation with HVPG values below a threshold of 10-12 mmHg (16, 17). In fact, the recent Baveno VI consensus document suggests that in patients with virus-related chronic liver disease, non-invasive methods are sufficient to rule in CSPH, with patients with an LSM measurement by TE of >20-25 kPa being at risk of having endoscopic signs of portal hypertension and thus warranting endoscopic assessment (10). In contrast, a liver stiffness of
<20 kPa and a platelet count of >150,000 in those with virus-related chronic liver disease are at very low risk of having varices and can avoid screening endoscopy (10). Importantly, the diagnostic value of TE for other etiologies of liver disease remains to be clarified.
Diagnosis of Varices Endoscopy is the gold standard in diagnosis of gastrointestinal varices. Varices identified endoscopically should simply be classified as either small or large with the suggested cut-off diameter being 5 mm (5). Recommendations for management of medium sized varices are equivalent to those for large varices making this distinction clinically unnecessary. While a selected subset of patients may possibly be able to avoid screening endoscopy as indicated above (i.e., patients with viral hepatitis, LSM <20 kPa, and platelets >150,000), patients with a diagnosis of cirrhosis should undergo endoscopy to screen for the presence of gastrointestinal varices. In patients with compensated cirrhosis and no varices at baseline, the interval for repeat screening should be 2-3 years. In patients with compensated cirrhosis and small varices at baseline, repeat endoscopy in 1-2 years is appropriate, with the shorter end of the interval being used particularly for patients with ongoing liver injury (e.g., active alcohol use or untreated viral hepatitis). In patients with decompensated liver disease, yearly endoscopy for variceal screening is recommended (10).
Pathogenesis of Gastrointestinal Varices Mechanisms of Portal Hypertension From a pathophysiologic perspective, gastrointestinal varices are a consequence of portal hypertension that develops and persists as a result of increased intrahepatic vascular resistance and increased flow through the portal and collateral venous systems (18, 19). Increased vascular resistance is the inciting factor and occurs primarily due to vascular obliteration with regenerative nodules and scar tissue compressing and occluding the intrahepatic vasculature
(19-21). This is further aggravated by endothelial dysfunction at the level of the sinusoids that occurs due to an imbalance between local vasoconstrictors, which are increased in number, and potent vasodilators, such as nitric oxide, which have been demonstrated to have reduced bioavailability in cirrhosis (18, 20). At the same time, increased blood flow through the splanchnic circulation occurs as a result of overproduction of endogenous vasodilators, such as nitric oxide, and from increased cardiac output (18, 22). Collateral vessels form between the portal and systemic circulation when the HVPG increases beyond a threshold level both through dilation of pre-existing embryonic channels connecting these circulatory systems and via angiogenesis likely driven by angiogenic factors, such as vascular endothelial growth factor (VEGF) and VEGFR-2, which have been observed in splanchnic organs of animal models of portal hypertension (20, 21, 23). Despite the development of these collaterals, portal hypertension persists because of the increased portal venous inflow as well as inadequate decompression by the collaterals, which have higher resistance than that of the normal liver (21, 22). Gastroesophageal varices are the most clinically relevant of these collaterals because of their risk of growth and rupture as a result of increased pressure and flow through them.
Many of these mechanisms have been used as pharmacologic targets for clinical intervention. Splanchnic vasoconstriction can be achieved through use of vasoactive agents, such as vasopressin and somatostatin or its analogs, which decrease portal pressure through a decline in portal venous flow (18, 22). Non selective beta-adrenergic blockade decreases portal flow both through a decline in cardiac output via its beta-1 action and splanchnic vasoconstriction via beta-2 blockade (24). Attempts to target endothelial dysfunction and intrahepatic vascular resistance have included transfection of nitric oxide synthase genes into cirrhotic livers (20). An increase in nitric oxide synthesis and reduced portal pressures have been observed after transfer of endothelial nitric oxide synthase (eNOS) and neuronal NOS in in vivo models (20). Interestingly, simvastatin has been shown to increase eNOS expression and phosphorylation in
liver tissue, which may drive declines in portal pressures observed in patients treated with this agent (20). Finally, inhibition of angiogenesis through action at the VEGF signaling pathway has also been shown to improve portal pressures, the hyperdynamic circulation, and splanchnic neovascularization in experimental models (20).
Mechanisms of Bleeding The most accepted theory explaining the mechanism behind variceal bleeding suggests that the main factor leading to rupture is increased hydrostatic pressure inside the varix causing an increase in variceal size and decrease in wall thickness, ultimately resulting in rupture (25). This fits with Laplace’s law, which suggests that wall tension is directly proportional to transmural pressure and radius and inversely proportional to wall thickness (25). The risk of bleeding from esophageal varices (EV) is directly related to variceal size and it has been shown that the presence of large varices is an important predictor of first hemorrhage (5). That said, variceal wall tension is likely the main factor that determines variceal rupture. Bleeding occurs when the tension exerted over the thin wall of the varix exceeds the limit of elasticity of the vessel (26). Tension within the wall is generated when progressive distention of the vessel leads to increasing resistance. When this limit of resistance to further dilation is reached, the vessel ruptures and hemorrhage ensues (21). All of this is in keeping with clinically reported independent predictors of variceal bleeding, including variceal size and presence of high risk stigmata, such as red wale signs as markers of reduced wall thickness (27-29).
Esophageal Varices Anatomy Under normal conditions, venous drainage of the esophagus is divided into four zones, which from distal to proximal include the gastric zone, the palisade zone, the perforating zone, and the truncal zone (21, 30). The perforating zone, also known as the transitional zone, has been
identified as the most susceptible area for variceal rupture; whereas the palisade zone is a key site of development of varices as this is where spontaneous communication between the portal and systemic circulations occur through the azygos venous system (21, 30). In the absence of portal hypertension, two sets of parallel blood vessels run independently and longitudinally through this zone, one in the lamina propria and one in the submucosa (30). When chronic portal hypertension develops, the increase in pressure and blood flow causes dilation of the submucosal veins, which in turn is transmitted to veins in the lamina propria that subsequently become visible endoscopically (30).
Epidemiology Gastroesophageal varices are present in approximately 50% of patients with cirrhosis and their presence is correlated with severity of liver disease as per the Child-Turcotte-Pugh (CTP) severity index (22, 31). Approximately 40% of patients with CTP A cirrhosis have varices whereas varices are seen in up to 85% of patients with CTP C disease. While in general, varices are thought to develop in the setting of established cirrhotic stage disease, non-cirrhotic portal hypertension also leads to varices in the absence of advanced fibrosis (5, 32). A not infrequent example of this is in the setting of chronic biliary disease such as primary biliary cirrhosis or primary sclerosing cholangitis (PSC) where varices can be seen early in the course of disease (32). Varices develop at a rate of about 7% per year and the strongest predictor of the development of varices in patients with cirrhosis is an HVPG of >10 mmHg (7, 33). Rates of progression in size from small to large varices are variable in the literature but generally reported to be about 10% per year. One study of 93 patients with small EV at study entry reported progression to larger varices in 12% at one year, 25% at 2 years and 31% at 3 years (33). Variceal hemorrhage occurs at a rate of about 12% per year in those with varices, ranging from a low of 5% in patients with small varices to 15% in those with large varices (34). Though esophageal variceal bleeding can cease spontaneously in up to 40% of patients, those with an
HVPG >20 mmHg are at high risk of failure to control bleeding, early re-bleeding within the first week of admission, as well as increased risk of mortality compared to those with lower HVPG pressures (35-37). Late re-bleeding, defined as within 1-2 years of the index bleed, occurs in approximately 60% of patients (12). Despite improvements in pharmacologic and endoscopic therapies, esophageal variceal bleeding continues to carry a high mortality. The model for endstage liver disease (MELD) score has been shown to be useful risk stratification tool to predict mortality in patients with acute esophageal variceal bleeding, with 6-week mortality rates of 5% in patients with admission MELD scores of less than 11 compared to 20% in those with MELD scores of 19 or greater at presentation (38). While patients with esophageal variceal hemorrhage are by definition considered to have decompensated liver disease, longer term mortality rates differ between those presenting with isolated variceal bleeding as their sole decompensation event compared to patients who have additional manifestations of portal hypertension, such as ascites or hepatic encephalopathy. Those with variceal hemorrhage alone have 5-year mortality rates of approximately 20% compared to the latter group, which have a much higher risk of death, estimated at about 80% at 5 years (39).
Gastric Varices Gastric varices (GV) can occur in the setting of portal hypertension of any etiology, both with and without cirrhosis and including with splanchnic thrombosis. As with EV, they develop as a consequence of increased intrahepatic vascular resistance and a hyperdynamic circulation leading to increased blood flow through a collateral vascular system (18, 19). GV arising through this mechanism should be distinguished from those developing in the setting of splenic vein thrombosis (SVT) which have a different etiologic basis, natural history, and management strategy (40). GV bleeding can occur at an HVPG lower than that seen in EV hemorrhage. One study analyzing the efficacy of secondary prophylaxis in patients with GV reported a baseline HVPG of 14-15 mmHg in patients with prior GV bleeding (41). As will be discussed later, GV
occurring in the setting of SVT are often a result of pancreatitis or an underlying pancreatic neoplasm and because of this, identification of isolated GV requires exclusion of underlying SVT (5). This section will mainly focus on GV in the absence of thrombotic disease, and gastrointestinal varices in the setting of vascular thrombosis will be discussed later.
Anatomy and Classification The gastric variceal system is complex anatomically and unique from that of the esophageal variceal system. The detailed architecture of these venous collaterals have been most thoroughly described by investigators from Japan (42). Importantly, not all varices seen in the stomach are anatomically similar and the well-known Sarin classification for GV highlights some but not all of these differences. In this system, GV are seen as either extensions of EV, so called gastroesophageal varices (GOV), or as isolated gastric varices (IGV) (43). Type I GOV are most common and include GV that extend from the esophagus along the lesser curvature of the stomach (44). These are located near the gastroesophageal junction and are often supplied by the same venous source as EV. Type 2 GOV extend from the esophagus along the gastric fundus and are often longer and more tortuous. In contrast, IGV occur in the absence of EV and are also classified into two types: IGV1 which are isolated to the fundus and IGV2 which are found in the body, antrum, or around the pylorus (43).
As mentioned, while GOV1 usually occur in continuity with EV and share a similar vascular anatomy, varices in the cardia and fundus (i.e., those classified as GOV2 and IGV1) have a rather unique supply. These cardiofundal varices are part of the so-called “left-sided circulation,” that is, they arise to the left of the patient’s midline, or more specifically to the left of the confluence of the splenic vein and mesenteric vein as they form the main portal vein (45). Most commonly, the afferent supply of GV comes from the splenic vein via the posterior gastric and left gastric vein (also known as the coronary vein) (45). These vessels then supply GV
themselves and are subsequently drained by the efferent venous system, which is most commonly through a gastrorenal shunt that empties into the left renal vein (45). This anatomic variability is important to consider as it pertains to the effectiveness of interventional strategies used for management.
Epidemiology GV are less common than EV, occurring in about 20% of patients with portal hypertension (46). Pathologic studies have reported rates as high as 40% whereas endoscopic studies report rates varying between 15-35% (21, 47). With the use of endoscopic ultrasound, rates as high as 5578% have been reported; though, it is unclear whether fundal varices seen using this modality carry a bleeding risk (48). GV in the absence of EV (i.e., IGV1 or 2 in the Sarin classification) occur in about 5-10% of patients (46). Gastric variceal bleeding accounts for 3-30% of variceal bleeding episodes, with bleeding risk related to their anatomic location (46). Type 1 GOV are the most common subtype, comprising 70% of GV, yet account for just 11% of GV bleeds. In comparison, type 1 IGV comprise less than 10% of all GV, yet 78% of this subtype bleeds (46). Type 2 IGV are uncommon, making up less than 5% of all GV, and bleeding occurs in just 5.7% of this subgroup (46). While reports on the natural history of GV are variable, in one study of 132 patients, bleeding risk at 1 year, 3 years and 5 years was estimated at 16%, 36% and 44%, respectively (49). In addition to anatomic location, other risk factors for bleeding are similar to those of EV; namely, large size (>5 mm), advanced liver disease, and endoscopic high-risk stigmata (49). Overall, compared to EV, GV bleed less frequently but when bleeding does occur it tends to be more severe (46).
Ectopic Varices Ectopic varices generally refer to dilated portosystemic collaterals occurring in unusual sites other than the gastroesophageal region. They can occur along the length of the luminal GI tract
from the gastric body (IGV2) to the rectum and include peristomal varices seen postoperatively. Several other extra-luminal ectopic sites of varices have been reported, including in the biliary tree, peritoneum, bladder, ovary, vagina, and diaphragm though this discussion will be limited to intraluminal sites (50).
Pathogenesis Similar to gastroesophageal varices, ectopic varices occur as a result of portal hypertension, be it related to intrahepatic disease or extrahepatic obstruction. In an attempt to decompress high portal pressures, these normally collapsed vessels become engorged and are at risk of bleeding. Less commonly, other causative mechanisms exist, including intra-abdominal surgery involving visceral organs and vasculature, venous outflow anomalies, vascular thrombosis, and intra-abdominal malignancy (50, 51). Surgical intervention involving structures drained by the systemic and portal systems may result in the formation of collaterals at unusual sites; the prototypic example being the formation of stomal varices after colectomy in patients with PSC (52). In addition, small bowel varices have also been reported post-pancreaticoduodenectomy with portal vein resection (53). Depending on the site, intra-abdominal thrombosis has been reported to lead to ectopic varices along the length of the gastrointestinal tract from the proximal duodenum to rectum.
Epidemiology Ectopic varices make up 2-5% of all variceal bleeding and occur more frequently in patients with extrahepatic portal hypertension (20-30%) than intrahepatic causes (1-5%) (54, 55). The prevalence of ectopic varices depends on the mode of testing used. Up to 40% of patients with intrahepatic portal hypertension undergoing angiography were found to have duodenal varices, whereas small bowel varices have been reported to occur in 8% of patients with cirrhosis undergoing capsule endoscopy (50, 56). Colonic varices have been reported in 3.4% of patients
with intrahepatic portal hypertension, and anorectal varices have a reported prevalence of 1040% in cirrhotic patients undergoing colonoscopy (57-59).
Small Intestinal Varices Most duodenal varices have their afferent supply via the portal or superior mesenteric vein and efferent drainage is directly into the inferior vena cava (60). They are seen in 0.2-0.4% of patients undergoing upper endoscopy and make up 17% of all ectopic variceal bleeding (54, 61). Patients with duodenal varices on upper endoscopy often have extrahepatic portal hypertension and, in fact, most patients with PVT or SVT identified on angiography also show duodenal varices (54). Varices in the jejunum and ileum are uncommon but when seen are often in the setting of patients with intrahepatic portal hypertension who have undergone prior intra-abdominal surgery (54, 55).
Colorectal Varices Colonic varices are rare but may develop in the absence of portal hypertension due to congenital or acquired anomalies of portosystemic anastomoses or arteriovenous fistulas (50). Rectal varices are most common, with reports suggesting they make up to 77% of prevalent ectopic varices (62). Like small bowel varices, they occur more frequently with extrahepatic portal vein obstruction (63-94%) compared to intrahepatic portal hypertension from cirrhosis (28-56%) (63, 64). While bleeding from rectal varices is rare, it can be massive and lifethreatening. Rebleeding rates of up to 10-20% despite portal decompression with transjugular intrahepatic portosystemic shunt (TIPS) have been reported, likely related to the complex efferent vascular pathways that exist at this location and, thus, multimodal therapy for effective control of bleeding may be necessary (44, 65-68).
Gastrointestinal Varices with Vascular Thrombosis
Varices occurring in the setting of PVT and SVT should be considered distinct from each other due to their disparate underlying etiologies. PVT can occur in patients with and without cirrhosis. PVT occurs in about 10% of patients with cirrhosis and is related to reduced portal flow into the liver as a result of increased intrahepatic vascular resistance (69-71). In fact, low portal flow is the most important risk factor for PVT in cirrhosis and predicts future PVT (72, 73). At presentation, the rates of variceal bleeding in patients with cirrhosis and PVT ranges from 39 to 50%, with most bleeding occurring from EV (74). Patients with cirrhosis-related PVT have a higher risk of bleeding than patients with non-cirrhotic PVT, and the presence of PVT is associated with a longer time to achieve endoscopic eradication of varices (75, 76). Noncirrhotic PVT is the second leading cause of portal hypertension in the Western world and in this group of patients, EV can be seen in up to 90% of patients and GV have a reported prevalence of 15-50% (77-79). Ectopic varices are more common in the setting of thrombosis than in portal hypertension secondary to cirrhosis alone, and have been reported to occur in approximately 30% of patients with splanchnic vein thrombosis, including isolated PVT with or without SVT or mesenteric vein thrombosis (63, 79). Up to 50% of patients with non-cirrhotic splanchnic vein thrombosis can present with portal hypertensive bleeding, with EV being the most common culprit (80). Secondary bleeds have however been reported to be more commonly related to GV (26%) or ectopic varices (33%) (80). Anticoagulation is warranted in the setting of acute PVT, thrombosis of the main portal vein or progressive PVT in liver transplant candidates, or in those with an underlying hypercoagulable state (80, 81). Data regarding the benefit of anticoagulation in chronic or non-occlusive PVT and in non-liver transplant candidates are less clear aside from the setting of a hypercoagulable state in which case treatment should be considered (44). In general, the bleeding risk in patients with cirrhotic PVT treated with vitamin K antagonists or low-molecular weight heparin is low and treatment may prevent extension and slow progression
of liver disease (44, 70). Furthermore, mortality risk is not associated with bleeding and is rather related to the thrombosis itself or underlying liver disease (82, 83). In general, endoscopic screening and variceal obliteration prior to initiation of anticoagulation is recommended. Subsequent endoscopic screening should occur 6 months after diagnosis and then yearly thereafter, with management of varices as per recommendations in patients with cirrhosis (44, 70).
SVT is most commonly caused by pancreatitis, pancreatic pseudocysts or neoplasms, and should be considered distinct from cirrhosis and PVT (84, 85). GV have been reported to occur in 15-57% of patients with SVT and bleeding is the presenting symptom in 45 to 72% of patients with SVT (86-89). Splenectomy, which eliminates collateral venous outflow, is the treatment of choice to stop active bleeding and prevent future bleeding from GV due to SVT (85, 88-90).
Conclusions In summary, gastrointestinal varices are a common consequence of portal hypertension that can occur with and without cirrhosis. Elevated portal pressures, as a result of structural and functional resistance to flow, a hyperdynamic circulation, or extrahepatic venous obstruction, lead to increased blood flow through a collateral venous system. Hemorrhage ensues when tension exerted on the thin wall of the varix exceeds its limit of elasticity. Gastroesophageal varices are the most common subtype occurring in 50% of patients with cirrhosis, and their presence and bleeding risk is correlated with severity of liver disease. Gastric varices are less common but tend to bleed more severely. Cardiofundal varices are complex anatomically and thus may require multimodal therapy for effective management. Isolated gastric varices and ectopic varices should prompt investigation for mesenteric thrombosis, particularly splenic vein thrombosis, which carries a different etiology, prognosis and therapeutic approach than gastrointestinal varices that occur due to portal vein thrombosis.
Conflict of Interest Statement: None
References 1.
Garcia-Tsao G, Friedman S, Iredale J, et al: Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 51:1445-1449, 2010
2.
Desmet VJ. Knodell RG, Ishak KG, et al: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. J Hepatol 38:382-386, 2003
3.
Batts KP, Ludwig J: Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 19:1409-1417, 1995
4.
D'Amico G, Garcia-Tsao G, Pagliaro L: Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 44: 217-231, 2006
5.
Garcia-Tsao G, Sanyal AJ, Grace ND, et al: Practice Guidelines Committee of the American Association for the Study of Liver D, Practice Parameters Committee of the American College of G. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 46: 922-38, 2007
6.
Perello A, Escorsell A, Bru C, et al: Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virus-related cirrhosis. Hepatology 30:1393-1397, 1999
7.
Groszmann RJ, Garcia-Tsao G, Bosch J, et al: Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 353:2254-2261, 2005
8.
Ripoll C, Groszmann R, Garcia-Tsao G, et al: Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 133: 481-488, 2007
9.
Garcia-Tsao G, Groszmann RJ, Fisher RL, et al: Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 5: 419-424, 1985
10.
de Franchis R, Baveno VIF: Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 63: 743-752, 2015
11.
Groszmann RJ, Bosch J, Grace ND, et al: Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 99: 1401-1407, 1990
12.
Bosch J, Garcia-Pagan JC: Prevention of variceal rebleeding. Lancet 361:952-4, 2003.
13.
Casado M, Bosch J, Garcia-Pagan JC, et al: Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology 114: 1296-1303, 1998
14.
Moitinho E, Escorsell A, Bandi JC, et al: Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology 117: 626-631, 1999
15.
Groszmann RJ, Wongcharatrawee S: The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology 39: 280-282, 2004
16.
Carrion JA, Navasa M, Bosch J, et al: Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transpl 12: 1791-1798, 2006
17.
Vizzutti F, Arena U, Romanelli RG, et al: Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 45: 1290-1297, 2007
18.
Vorobioff JD, Groszmann RJ: Prevention of portal hypertension: from variceal development to clinical decompensation. Hepatology 61: 375-381, 2015
19.
Groszmann RJ, Abraldes JG: Portal hypertension: from bedside to bench. J Clin Gastroenterol 39: 125-130, 2005 (suppl)
20.
Bosch J, Abraldes JG, Fernandez M, et al: Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J Hepatol 53: 558-567, 2010
21.
Berzigotti A: Pathophysiology of variceal bleeding in cirrhotics. Ann Gastroenterol 14:150-157, 2001
22.
Garcia-Tsao G, Bosch J: Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 362: 823-382, 2010
23.
Abraldes JG, Iwakiri Y, Loureiro-Silva M, et al. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 290: G980-987, 2006
24.
Bosch J, Berzigotti A, Garcia-Pagan JC, et al: The management of portal hypertension: rational basis, available treatments and future options. J Hepatol 48: 68-92, 2008 (suppl)
25.
Polio J, Groszmann RJ: Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin Liver Dis 6: 318-331, 1986
26.
Polio J, Groszmann RJ, Reuben A, et al: Portal hypertension ameliorates arterial hypertension in spontaneously hypertensive rats. J Hepatol 8: 294-301, 1989
27.
Rigau J, Bosch J, Bordas JM, et al: Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage. Gastroenterology 96: 873-880, 1989
28.
Siringo S, Bolondi L, Gaiani S, et al: Timing of the first variceal hemorrhage in cirrhotic patients: prospective evaluation of Doppler flowmetry, endoscopy and clinical parameters. Hepatology 20: 66-73, 1994
29.
Zoli M, Merkel C, Magalotti D, et al: Evaluation of a new endoscopic index to predict first bleeding from the upper gastrointestinal tract in patients with cirrhosis. Hepatology 24: 1047-1052, 1996
30.
Noda T: Angioarchitectural study of esophageal varices. With special reference to variceal rupture. Virchows Arch A Pathol Anat Histopathol 404: 381-392, 1984
31.
Kovalak M, Lake J, Mattek N, et al: Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database. Gastrointest Endosc 65: 82-88, 2007
32.
Navasa M, Pares A, Bruguera M, et al: Portal hypertension in primary biliary cirrhosis. Relationship with histological features. J Hepatol 5: 292-298, 1987
33.
Merli M, Nicolini G, Angeloni S, et al: Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 38: 266-272, 2003
34.
D'Amico G, Pagliaro L, Bosch J: Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 19: 475-505, 1999
35.
El-Serag HB, Everhart JE. Improved survival after variceal hemorrhage over an 11-year period in the Department of Veterans Affairs. Am J Gastroenterol 95: 3566-3573, 2000
36.
D'Amico G, De Franchis R, Cooperative Study G: Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 38: 599-612, 2003
37.
Carbonell N, Pauwels A, Serfaty L, et al: Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 40: 652-659, 2004
38.
Reverter E, Tandon P, Augustin S, et al: A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. Gastroenterology 146: 412-419, 2014
39.
Garcia-Tsao G, Abraldes JG, Berzigotti A, et al: Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 65: 310-335, 2017
40.
Caldwell S: Gastric varices: is there a role for endoscopic cyanoacrylates, or are we entering the BRTO era? Am J Gastroenterol 107: 1784-1790, 2012
41.
Mishra SR, Chander Sharma B, Kumar A, et al: Endoscopic cyanoacrylate injection versus beta-blocker for secondary prophylaxis of gastric variceal bleed: a randomised controlled trial. Gut 59: 729-735, 2010
42.
Watanabe K, Kimura K, Matsutani S, et al: Portal hemodynamics in patients with gastric varices. A study in 230 patients with esophageal and/or gastric varices using portal vein catheterization. Gastroenterology 95: 434-440, 1988
43.
Sarin SK, Lahoti D, Saxena SP, et al: Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 16:1343-1349, 1992
44.
Henry Z, Uppal D, Saad W, et al: Gastric and ectopic varices. Clin Liver Dis 18: 371-388, 2014
45.
Saad WE: Vascular anatomy and the morphologic and hemodynamic classifications of gastric varices and spontaneous portosystemic shunts relevant to the BRTO procedure. Tech Vasc Interv Radiol 16: 60-100, 2013
46.
Classen M, Tytgat GNJ, Lightdale CJ (eds): Gastroenterological endoscopy (ed 2). New York, NY, Thieme, 2010
47.
Caletti G, Brocchi E, Baraldini M, et al: Assessment of portal hypertension by endoscopic ultrasonography. Gastrointest Endosc 36: 21-27, 1990 (suppl)
48.
Boustiere C, Dumas O, Jouffre C, et al: Endoscopic ultrasonography classification of gastric varices in patients with cirrhosis. Comparison with endoscopic findings. J Hepatol 19: 268-272, 1993
49.
Kim T, Shijo H, Kokawa H et al. Risk factors for hemorrhage from gastric fundal varices. Hepatology 25: 307-312, 1997
50.
Helmy A, Al Kahtani K, Al Fadda M: Updates in the pathogenesis, diagnosis and management of ectopic varices. Hepatol Int 2: 322-334, 2008
51.
Zaman L, Bebb JR, Dunlop SP, et al: Familial colonic varices--a cause of "polyposis" on barium enema. Br J Radiol 81: 17-19, 2008
52.
Wiesner RH, LaRusso NF, Dozois RR, et al: Peristomal varices after proctocolectomy in patients with primary sclerosing cholangitis. Gastroenterology 90(2): 316-322, 1986
53.
Bromfield EB, Altshuler L, Leiderman DB, et al. Cerebral metabolism and depression in patients with complex partial seizures. Arch Neurol 49: 617-623, 1992
54.
Norton ID, Andrews JC, Kamath PS: Management of ectopic varices. Hepatology 28: 1154-1158, 1998
55.
Lebrec D, Benhamou JP: Ectopic varices in portal hypertension. Clin Gastroenterol 14:105-121, 1985
56.
De Palma GD, Rega M, Masone S, et al. Mucosal abnormalities of the small bowel in patients with cirrhosis and portal hypertension: a capsule endoscopy study. Gastrointest Endosc 62: 529-534, 2005
57.
McCormack TT, Bailey HR, Simms JM, et al: Rectal varices are not piles. Br J Surg 71: 163, 1984
58.
Hosking SW, Smart HL, Johnson AG, et al: Anorectal varices, haemorrhoids, and portal hypertension. Lancet 1: 349-352, 1989
59.
Naveau S, Poynard T, Pauphilet C, et al: Rectal and colonic varices in cirrhosis. Lancet 1: 624, 1989
60.
Hashizume M, Tanoue K, Ohta M, et al: Vascular anatomy of duodenal varices: angiographic and histopathological assessments. Am J Gastroenterol 88: 1942-1945, 1993
61.
Al-Mofarreh M, Al-Moagel-Alfarag M, Ashoor T et al: Duodenal varices. Report of 13 cases. Z Gastroenterol 24: 673-680, 1986
62.
Chawla Y, Dilawari JB: Anorectal varices--their frequency in cirrhotic and non-cirrhotic portal hypertension. Gut 32: 309-311, 1991
63.
Ganguly S, Sarin SK, Bhatia V, et al: The prevalence and spectrum of colonic lesions in patients with cirrhotic and noncirrhotic portal hypertension. Hepatology 21: 1226-1231, 1995
64.
Misra SP, Dwivedi M, Misra V, et al: Colonic changes in patients with cirrhosis and in patients with extrahepatic portal vein obstruction. Endoscopy 37: 454-459, 2005
65.
Kochar N, Tripathi D, McAvoy NC, et al: Bleeding ectopic varices in cirrhosis: the role of transjugular intrahepatic portosystemic stent shunts. Aliment Pharmacol Ther 28: 294303, 2008
66.
Vangeli M, Patch D, Terreni N, et al: Bleeding ectopic varices--treatment with transjugular intrahepatic porto-systemic shunt (TIPS) and embolisation. J Hepatol 41: 560-566, 2004
67.
Shibata D, Brophy DP, Gordon FD, et al: Transjugular intrahepatic portosystemic shunt for treatment of bleeding ectopic varices with portal hypertension. Dis Colon Rectum 42: 1581-1585, 1999
68.
Nayar M, Saravanan R, Rowlands PC, et al: TIPSS in the treatment of ectopic variceal bleeding. Hepatogastroenterology 53: 584-587, 2006
69.
Rodriguez-Castro KI, Porte RJ, Nadal E, et al: Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review. Transplantation 94:1145-1153, 2012
70.
Harding DJ, Perera MT, Chen F, et al: Portal vein thrombosis in cirrhosis: Controversies and latest developments. World J Gastroenterol 21: 6769-6784, 2015
71.
Shah V: Molecular mechanisms of increased intrahepatic resistance in portal hypertension. J Clin Gastroenterol 41: 259-261, 2007 (suppl)
72.
Amitrano L, Guardascione MA, Ames PR: Coagulation abnormalities in cirrhotic patients with portal vein thrombosis. Clin Lab 53: 583-589, 2007
73.
Kinjo N, Kawanaka H, Akahoshi T, et al: Risk factors for portal venous thrombosis after splenectomy in patients with cirrhosis and portal hypertension. Br J Surg 97: 910-916, 2010
74.
Amitrano L, Guardascione MA, Brancaccio V, et al: Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 40: 736-741, 2004
75.
Merkel C, Bolognesi M, Bellon S, et al: Long-term follow-up study of adult patients with non-cirrhotic obstruction of the portal system: comparison with cirrhotic patients. J Hepato 15: 299-303, 1992
76.
Dell'Era A, Iannuzzi F, Fabris FM, et al: Impact of portal vein thrombosis on the efficacy of endoscopic variceal band ligation. Dig Liver Dis 46: 152-156, 2014
77.
Valla DC, Condat B, Lebrec D: Spectrum of portal vein thrombosis in the West. J Gastroenterol Hepatol 17: 224-227, 2002 (suppl)
78.
Amitrano L, Guardascione MA, Scaglione M, et al: Prognostic factors in noncirrhotic patients with splanchnic vein thromboses. Am J Gastroenterol 102: 2464-2470, 2007
79.
Sarin SK, Sollano JD, Chawla YK, et al: Consensus on extra-hepatic portal vein obstruction. Liver Int 26: 512-519, 2006
80.
Orr DW, Harrison PM, Devlin J, et al: Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up. Clin Gastroenterol Hepatol 5: 80-86, 2007
81.
DeLeve LD, Valla DC, Garcia-Tsao G: American Association for the Study Liver D. Vascular disorders of the liver. Hepatology 49: 1729-1764, 2009
82.
Janssen HL, Wijnhoud A, Haagsma EB, et al: Extrahepatic portal vein thrombosis: aetiology and determinants of survival. Gut 49: 720-724, 2001
83.
Donadini MP, Dentali F, Ageno W: Splanchnic vein thrombosis: new risk factors and management. Thromb Res 129: 93-96, 2012 (suppl)
84.
Butler JR, Eckert GJ, Zyromski NJ, et al: Natural history of pancreatitis-induced splenic vein thrombosis: a systematic review and meta-analysis of its incidence and rate of gastrointestinal bleeding. HPB 13: 839-845, 2011
85.
Agarwal AK, Raj Kumar K, Agarwal S, et al: Significance of splenic vein thrombosis in chronic pancreatitis. Am J Surg 196: 149-154, 2008
86.
Heider TR, Azeem S, Galanko JA, et al: The natural history of pancreatitis-induced splenic vein thrombosis. Ann Surg 239: 876-880, 2004
87.
Bernades P, Baetz A, Levy P, et al: Splenic and portal venous obstruction in chronic pancreatitis. A prospective longitudinal study of a medical-surgical series of 266 patients. Dig Dis Sci 37: 340-346, 1992
88.
Sakorafas GH, Sarr MG, Farley DR, et al: The significance of sinistral portal hypertension complicating chronic pancreatitis. Am J Surg 179: 129-133, 2000
89.
Weber SM, Rikkers LF: Splenic vein thrombosis and gastrointestinal bleeding in chronic pancreatitis. World J Surg 27: 1271-1274, 2003
90.
Gunther RW, Vorwerk D, Thon HJ, et al: Balloon dilatation and insertion of a selfexpandable flexible metallic stent in a benign stricture of the left hepatic duct: case report. Cardiovasc Intervent Radiol 12: 69-71, 1989
Legend Figure 1.
Gastrointestinal varices are a consequence of portal hypertension and develop as a result of increased intrahepatic vascular resistance and increased flow through a hyperdynamic circulation. In patients with cirrhosis, increased intrahepatic vascular resistance occurs due to vascular obliteration by regenerative nodules and scar tissue compressing intrahepatic small vessels and is further aggravated by an imbalance between local vasoconstrictors and vasodilators. At the same time, increased blood flow through the splanchnic circulation due to overproduction of endogenous vasodilators and a hyperdynamic circulation lead to increased portal flow and contribute to the persistence of portal hypertension and progression of varices. Once portal pressures exceed 10 mmHg, varices develop and are at risk of growth and subsequent hemorrhage.
Pathogenesis
of
Aliya F. Gulamhusein, Patrick S. Kamath
www.elsevier.com/locate/tgie
PII: DOI: Reference:
S1096-2883(17)30032-3 http://dx.doi.org/10.1016/j.tgie.2017.03.005 YTGIE50527
To appear in: Techniques in Gastrointestinal Endoscopy Cite this article as: Aliya F. Gulamhusein and Patrick S. Kamath, The Epidemiology and Pathogenesis of Gastrointestinal Varices, Techniques in Gastrointestinal Endoscopy, http://dx.doi.org/10.1016/j.tgie.2017.03.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Epidemiology and Pathogenesis of Gastrointestinal Varices
Dr. Aliya F Gulamhusein, MD Toronto Center for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto, ON, Canada
Dr. Patrick S Kamath, MD Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
Corresponding Author:
Dr. Patrick S. Kamath, MD Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine 200 First Street SW, Rochester, Minnesota 55905 email: [email protected] phone: (507) 284-2511 fax: (507) 284-0538
Abstract
Gastrointestinal varices are a consequence of portal hypertension that can occur in the setting of cirrhosis or extrahepatic portal vein obstruction. Increased intrahepatic vascular resistance, a hyperdynamic circulation, and increased flow through the portal and collateral venous system lead to persistently elevated portal pressures that result in angiogenesis and formation of collaterals between the portal and systemic circulation. Despite this physiologic attempt at decompression, portal hypertension persists as collateral vessels have higher resistance than the normal liver. Variceal wall tension is the main factor that determines vessel rupture and bleeding occurs when tension in the wall exceeds the limit of elasticity of the vessel. Progressive distension leads to increasing resistance to flow and hemorrhage ensues when the limits of resistance to further dilation are surpassed. Gastroesophageal varices are present in 50% of patients with cirrhosis and progress in size at a rate of 8-10% per year. Hemorrhage occurs at a rate of approximately 12% per year and large esophageal varices carry a higher risk of rupture. Gastric varices occur in 20% of patients with portal hypertension and bleed less frequently, but more severely. Cardiofundal varices have a complex vascular anatomy that is important to consider as it pertains to the effectiveness of strategies used for management. Ectopic varices make up 2-5% of all variceal bleeding, occur more frequently in patients with extrahepatic portal hypertension, and their identification should prompt assessment of the intraabdominal vasculature. Varices in the setting of splenic vein thrombosis should be considered a distinct entity due to their disparate etiologic basis and treatment approach.
Keywords Portal hypertension Esophageal varices Gastric varices Ectopic varices
Abbreviations CTP = Child-Turcotte-Pugh CSPH = clinically significant portal hypertension eNOS = endothelial nitric oxide synthase EV = esophageal varices GV = gastric varices GOV = gastroesophageal varices HVPG = hepatic venous pressure gradient IGV = isolated gastric varices LSM = liver stiffness measurement MELD = model for end-stage liver disease PSC = Primary sclerosing cholangitis PVT = portal vein thrombosis SVT = splenic vein thrombosis TE = transient elastography VEGF = vascular endothelial growth factor WHVP = wedged hepatic vein pressure
Introduction Cirrhosis has traditionally been conceptualized as a discrete rather than dynamic disease associated with advanced degrees of histologic fibrosis. Liver injury from a variety of causes, including viral, autoimmune, metabolic, or cholestatic, lead to progressive fibrosis on liver biopsies which are often staged using semi-quantitative systems such as METAVIR or Ishak. These staging systems report degree of fibrosis ranging from none to the pathologic “end-stage” of cirrhosis (1-3). While a clinical distinction between compensated and decompensated cirrhosis is often made, there is increasing evidence that cirrhosis, both histologically and clinically, is a much more dynamic phenotype, and that classification systems ought to be more granular to better reflect the natural history and prognosis of patients with advanced liver disease (1, 4). Characterizing cirrhosis as it relates to degree of underlying portal hypertension and associated circulatory dynamics likely more accurately reflects risk of progression to clinically relevant endpoints.
Portal hypertension is a critical consequence of cirrhosis and causes many of the clinical manifestations of advanced liver disease. Though indirect, the wedged hepatic venous pressure (WHVP) is the preferred method for assessing portal pressure (5). It is obtained by wedging a catheter into a small branch of the hepatic vein and has been shown to closely correlate with portal pressures (6). The free hepatic vein pressure is then subtracted from the WHVP (to correct for increases in intra-abdominal pressure) resulting in the hepatic venous pressure gradient (HVPG). Importantly, this value is a measure of sinusoidal pressure and as such will be elevated in intrahepatic causes of portal hypertension but will be notably normal in pre-hepatic causes, such as portal vein thrombosis (PVT) (5). The HVPG is an important predictor of varices and clinical decompensation, including ascites, variceal hemorrhage and hepatic encephalopathy (7-9). A normal HVPG is 3-5 mmHg whereas an HVPG >10 mmHg has been
termed “clinically significant portal hypertension (CSPH),” that is, the threshold that defines risk of developing varices and/or clinical complications (1, 10). Patients without CSPH by definition do not have varices and are at a low five-year risk of developing them (10). Recurrent variceal hemorrhage and ascites do not occur when the HVPG is <12 mmHg, making this an important threshold to consider in understanding a patient’s risk for decompensating events (11-13). On the other hand, an HVPG >20 mmHg is an important negative prognostic indicator of poor outcome in the setting of acute variceal hemorrhage (14).
Considering cirrhosis in terms of degree of portal hypertension allows for a more granular classification system that more closely reflects a patient’s risk of liver related outcomes. One such proposed system breaks down compensated cirrhosis into that: a) without portal hypertension (i.e., HVPG < 6 mmHg); b) portal hypertension that is not clinically significant (i.e., HVPG between 6 and 10 mmHg); and c) CSPH (i.e., HVPG 10mmHg or with the presence of collaterals) (1). While such a system is physiologically rational, several inherent limitations to the use of HVPG exist, including its invasive nature, lack of local expertise, variable adherence to guidelines ensuring reliability and reproducibility of measurements, and cost (5, 15). Noninvasive approaches, such as liver stiffness measurement (LSM) using transient elastography (TE), are important advancements in monitoring for fibrosis progression and worsening of portal hypertension in patients with chronic liver disease, and their increasing use is likely to have implications on the role of endoscopy in screening for gastrointestinal varices (1, 10). While HVPG measurement remains the gold standard to assess for the presence of CSPH, LSM shows excellent correlation with HVPG values below a threshold of 10-12 mmHg (16, 17). In fact, the recent Baveno VI consensus document suggests that in patients with virus-related chronic liver disease, non-invasive methods are sufficient to rule in CSPH, with patients with an LSM measurement by TE of >20-25 kPa being at risk of having endoscopic signs of portal hypertension and thus warranting endoscopic assessment (10). In contrast, a liver stiffness of
<20 kPa and a platelet count of >150,000 in those with virus-related chronic liver disease are at very low risk of having varices and can avoid screening endoscopy (10). Importantly, the diagnostic value of TE for other etiologies of liver disease remains to be clarified.
Diagnosis of Varices Endoscopy is the gold standard in diagnosis of gastrointestinal varices. Varices identified endoscopically should simply be classified as either small or large with the suggested cut-off diameter being 5 mm (5). Recommendations for management of medium sized varices are equivalent to those for large varices making this distinction clinically unnecessary. While a selected subset of patients may possibly be able to avoid screening endoscopy as indicated above (i.e., patients with viral hepatitis, LSM <20 kPa, and platelets >150,000), patients with a diagnosis of cirrhosis should undergo endoscopy to screen for the presence of gastrointestinal varices. In patients with compensated cirrhosis and no varices at baseline, the interval for repeat screening should be 2-3 years. In patients with compensated cirrhosis and small varices at baseline, repeat endoscopy in 1-2 years is appropriate, with the shorter end of the interval being used particularly for patients with ongoing liver injury (e.g., active alcohol use or untreated viral hepatitis). In patients with decompensated liver disease, yearly endoscopy for variceal screening is recommended (10).
Pathogenesis of Gastrointestinal Varices Mechanisms of Portal Hypertension From a pathophysiologic perspective, gastrointestinal varices are a consequence of portal hypertension that develops and persists as a result of increased intrahepatic vascular resistance and increased flow through the portal and collateral venous systems (18, 19). Increased vascular resistance is the inciting factor and occurs primarily due to vascular obliteration with regenerative nodules and scar tissue compressing and occluding the intrahepatic vasculature
(19-21). This is further aggravated by endothelial dysfunction at the level of the sinusoids that occurs due to an imbalance between local vasoconstrictors, which are increased in number, and potent vasodilators, such as nitric oxide, which have been demonstrated to have reduced bioavailability in cirrhosis (18, 20). At the same time, increased blood flow through the splanchnic circulation occurs as a result of overproduction of endogenous vasodilators, such as nitric oxide, and from increased cardiac output (18, 22). Collateral vessels form between the portal and systemic circulation when the HVPG increases beyond a threshold level both through dilation of pre-existing embryonic channels connecting these circulatory systems and via angiogenesis likely driven by angiogenic factors, such as vascular endothelial growth factor (VEGF) and VEGFR-2, which have been observed in splanchnic organs of animal models of portal hypertension (20, 21, 23). Despite the development of these collaterals, portal hypertension persists because of the increased portal venous inflow as well as inadequate decompression by the collaterals, which have higher resistance than that of the normal liver (21, 22). Gastroesophageal varices are the most clinically relevant of these collaterals because of their risk of growth and rupture as a result of increased pressure and flow through them.
Many of these mechanisms have been used as pharmacologic targets for clinical intervention. Splanchnic vasoconstriction can be achieved through use of vasoactive agents, such as vasopressin and somatostatin or its analogs, which decrease portal pressure through a decline in portal venous flow (18, 22). Non selective beta-adrenergic blockade decreases portal flow both through a decline in cardiac output via its beta-1 action and splanchnic vasoconstriction via beta-2 blockade (24). Attempts to target endothelial dysfunction and intrahepatic vascular resistance have included transfection of nitric oxide synthase genes into cirrhotic livers (20). An increase in nitric oxide synthesis and reduced portal pressures have been observed after transfer of endothelial nitric oxide synthase (eNOS) and neuronal NOS in in vivo models (20). Interestingly, simvastatin has been shown to increase eNOS expression and phosphorylation in
liver tissue, which may drive declines in portal pressures observed in patients treated with this agent (20). Finally, inhibition of angiogenesis through action at the VEGF signaling pathway has also been shown to improve portal pressures, the hyperdynamic circulation, and splanchnic neovascularization in experimental models (20).
Mechanisms of Bleeding The most accepted theory explaining the mechanism behind variceal bleeding suggests that the main factor leading to rupture is increased hydrostatic pressure inside the varix causing an increase in variceal size and decrease in wall thickness, ultimately resulting in rupture (25). This fits with Laplace’s law, which suggests that wall tension is directly proportional to transmural pressure and radius and inversely proportional to wall thickness (25). The risk of bleeding from esophageal varices (EV) is directly related to variceal size and it has been shown that the presence of large varices is an important predictor of first hemorrhage (5). That said, variceal wall tension is likely the main factor that determines variceal rupture. Bleeding occurs when the tension exerted over the thin wall of the varix exceeds the limit of elasticity of the vessel (26). Tension within the wall is generated when progressive distention of the vessel leads to increasing resistance. When this limit of resistance to further dilation is reached, the vessel ruptures and hemorrhage ensues (21). All of this is in keeping with clinically reported independent predictors of variceal bleeding, including variceal size and presence of high risk stigmata, such as red wale signs as markers of reduced wall thickness (27-29).
Esophageal Varices Anatomy Under normal conditions, venous drainage of the esophagus is divided into four zones, which from distal to proximal include the gastric zone, the palisade zone, the perforating zone, and the truncal zone (21, 30). The perforating zone, also known as the transitional zone, has been
identified as the most susceptible area for variceal rupture; whereas the palisade zone is a key site of development of varices as this is where spontaneous communication between the portal and systemic circulations occur through the azygos venous system (21, 30). In the absence of portal hypertension, two sets of parallel blood vessels run independently and longitudinally through this zone, one in the lamina propria and one in the submucosa (30). When chronic portal hypertension develops, the increase in pressure and blood flow causes dilation of the submucosal veins, which in turn is transmitted to veins in the lamina propria that subsequently become visible endoscopically (30).
Epidemiology Gastroesophageal varices are present in approximately 50% of patients with cirrhosis and their presence is correlated with severity of liver disease as per the Child-Turcotte-Pugh (CTP) severity index (22, 31). Approximately 40% of patients with CTP A cirrhosis have varices whereas varices are seen in up to 85% of patients with CTP C disease. While in general, varices are thought to develop in the setting of established cirrhotic stage disease, non-cirrhotic portal hypertension also leads to varices in the absence of advanced fibrosis (5, 32). A not infrequent example of this is in the setting of chronic biliary disease such as primary biliary cirrhosis or primary sclerosing cholangitis (PSC) where varices can be seen early in the course of disease (32). Varices develop at a rate of about 7% per year and the strongest predictor of the development of varices in patients with cirrhosis is an HVPG of >10 mmHg (7, 33). Rates of progression in size from small to large varices are variable in the literature but generally reported to be about 10% per year. One study of 93 patients with small EV at study entry reported progression to larger varices in 12% at one year, 25% at 2 years and 31% at 3 years (33). Variceal hemorrhage occurs at a rate of about 12% per year in those with varices, ranging from a low of 5% in patients with small varices to 15% in those with large varices (34). Though esophageal variceal bleeding can cease spontaneously in up to 40% of patients, those with an
HVPG >20 mmHg are at high risk of failure to control bleeding, early re-bleeding within the first week of admission, as well as increased risk of mortality compared to those with lower HVPG pressures (35-37). Late re-bleeding, defined as within 1-2 years of the index bleed, occurs in approximately 60% of patients (12). Despite improvements in pharmacologic and endoscopic therapies, esophageal variceal bleeding continues to carry a high mortality. The model for endstage liver disease (MELD) score has been shown to be useful risk stratification tool to predict mortality in patients with acute esophageal variceal bleeding, with 6-week mortality rates of 5% in patients with admission MELD scores of less than 11 compared to 20% in those with MELD scores of 19 or greater at presentation (38). While patients with esophageal variceal hemorrhage are by definition considered to have decompensated liver disease, longer term mortality rates differ between those presenting with isolated variceal bleeding as their sole decompensation event compared to patients who have additional manifestations of portal hypertension, such as ascites or hepatic encephalopathy. Those with variceal hemorrhage alone have 5-year mortality rates of approximately 20% compared to the latter group, which have a much higher risk of death, estimated at about 80% at 5 years (39).
Gastric Varices Gastric varices (GV) can occur in the setting of portal hypertension of any etiology, both with and without cirrhosis and including with splanchnic thrombosis. As with EV, they develop as a consequence of increased intrahepatic vascular resistance and a hyperdynamic circulation leading to increased blood flow through a collateral vascular system (18, 19). GV arising through this mechanism should be distinguished from those developing in the setting of splenic vein thrombosis (SVT) which have a different etiologic basis, natural history, and management strategy (40). GV bleeding can occur at an HVPG lower than that seen in EV hemorrhage. One study analyzing the efficacy of secondary prophylaxis in patients with GV reported a baseline HVPG of 14-15 mmHg in patients with prior GV bleeding (41). As will be discussed later, GV
occurring in the setting of SVT are often a result of pancreatitis or an underlying pancreatic neoplasm and because of this, identification of isolated GV requires exclusion of underlying SVT (5). This section will mainly focus on GV in the absence of thrombotic disease, and gastrointestinal varices in the setting of vascular thrombosis will be discussed later.
Anatomy and Classification The gastric variceal system is complex anatomically and unique from that of the esophageal variceal system. The detailed architecture of these venous collaterals have been most thoroughly described by investigators from Japan (42). Importantly, not all varices seen in the stomach are anatomically similar and the well-known Sarin classification for GV highlights some but not all of these differences. In this system, GV are seen as either extensions of EV, so called gastroesophageal varices (GOV), or as isolated gastric varices (IGV) (43). Type I GOV are most common and include GV that extend from the esophagus along the lesser curvature of the stomach (44). These are located near the gastroesophageal junction and are often supplied by the same venous source as EV. Type 2 GOV extend from the esophagus along the gastric fundus and are often longer and more tortuous. In contrast, IGV occur in the absence of EV and are also classified into two types: IGV1 which are isolated to the fundus and IGV2 which are found in the body, antrum, or around the pylorus (43).
As mentioned, while GOV1 usually occur in continuity with EV and share a similar vascular anatomy, varices in the cardia and fundus (i.e., those classified as GOV2 and IGV1) have a rather unique supply. These cardiofundal varices are part of the so-called “left-sided circulation,” that is, they arise to the left of the patient’s midline, or more specifically to the left of the confluence of the splenic vein and mesenteric vein as they form the main portal vein (45). Most commonly, the afferent supply of GV comes from the splenic vein via the posterior gastric and left gastric vein (also known as the coronary vein) (45). These vessels then supply GV
themselves and are subsequently drained by the efferent venous system, which is most commonly through a gastrorenal shunt that empties into the left renal vein (45). This anatomic variability is important to consider as it pertains to the effectiveness of interventional strategies used for management.
Epidemiology GV are less common than EV, occurring in about 20% of patients with portal hypertension (46). Pathologic studies have reported rates as high as 40% whereas endoscopic studies report rates varying between 15-35% (21, 47). With the use of endoscopic ultrasound, rates as high as 5578% have been reported; though, it is unclear whether fundal varices seen using this modality carry a bleeding risk (48). GV in the absence of EV (i.e., IGV1 or 2 in the Sarin classification) occur in about 5-10% of patients (46). Gastric variceal bleeding accounts for 3-30% of variceal bleeding episodes, with bleeding risk related to their anatomic location (46). Type 1 GOV are the most common subtype, comprising 70% of GV, yet account for just 11% of GV bleeds. In comparison, type 1 IGV comprise less than 10% of all GV, yet 78% of this subtype bleeds (46). Type 2 IGV are uncommon, making up less than 5% of all GV, and bleeding occurs in just 5.7% of this subgroup (46). While reports on the natural history of GV are variable, in one study of 132 patients, bleeding risk at 1 year, 3 years and 5 years was estimated at 16%, 36% and 44%, respectively (49). In addition to anatomic location, other risk factors for bleeding are similar to those of EV; namely, large size (>5 mm), advanced liver disease, and endoscopic high-risk stigmata (49). Overall, compared to EV, GV bleed less frequently but when bleeding does occur it tends to be more severe (46).
Ectopic Varices Ectopic varices generally refer to dilated portosystemic collaterals occurring in unusual sites other than the gastroesophageal region. They can occur along the length of the luminal GI tract
from the gastric body (IGV2) to the rectum and include peristomal varices seen postoperatively. Several other extra-luminal ectopic sites of varices have been reported, including in the biliary tree, peritoneum, bladder, ovary, vagina, and diaphragm though this discussion will be limited to intraluminal sites (50).
Pathogenesis Similar to gastroesophageal varices, ectopic varices occur as a result of portal hypertension, be it related to intrahepatic disease or extrahepatic obstruction. In an attempt to decompress high portal pressures, these normally collapsed vessels become engorged and are at risk of bleeding. Less commonly, other causative mechanisms exist, including intra-abdominal surgery involving visceral organs and vasculature, venous outflow anomalies, vascular thrombosis, and intra-abdominal malignancy (50, 51). Surgical intervention involving structures drained by the systemic and portal systems may result in the formation of collaterals at unusual sites; the prototypic example being the formation of stomal varices after colectomy in patients with PSC (52). In addition, small bowel varices have also been reported post-pancreaticoduodenectomy with portal vein resection (53). Depending on the site, intra-abdominal thrombosis has been reported to lead to ectopic varices along the length of the gastrointestinal tract from the proximal duodenum to rectum.
Epidemiology Ectopic varices make up 2-5% of all variceal bleeding and occur more frequently in patients with extrahepatic portal hypertension (20-30%) than intrahepatic causes (1-5%) (54, 55). The prevalence of ectopic varices depends on the mode of testing used. Up to 40% of patients with intrahepatic portal hypertension undergoing angiography were found to have duodenal varices, whereas small bowel varices have been reported to occur in 8% of patients with cirrhosis undergoing capsule endoscopy (50, 56). Colonic varices have been reported in 3.4% of patients
with intrahepatic portal hypertension, and anorectal varices have a reported prevalence of 1040% in cirrhotic patients undergoing colonoscopy (57-59).
Small Intestinal Varices Most duodenal varices have their afferent supply via the portal or superior mesenteric vein and efferent drainage is directly into the inferior vena cava (60). They are seen in 0.2-0.4% of patients undergoing upper endoscopy and make up 17% of all ectopic variceal bleeding (54, 61). Patients with duodenal varices on upper endoscopy often have extrahepatic portal hypertension and, in fact, most patients with PVT or SVT identified on angiography also show duodenal varices (54). Varices in the jejunum and ileum are uncommon but when seen are often in the setting of patients with intrahepatic portal hypertension who have undergone prior intra-abdominal surgery (54, 55).
Colorectal Varices Colonic varices are rare but may develop in the absence of portal hypertension due to congenital or acquired anomalies of portosystemic anastomoses or arteriovenous fistulas (50). Rectal varices are most common, with reports suggesting they make up to 77% of prevalent ectopic varices (62). Like small bowel varices, they occur more frequently with extrahepatic portal vein obstruction (63-94%) compared to intrahepatic portal hypertension from cirrhosis (28-56%) (63, 64). While bleeding from rectal varices is rare, it can be massive and lifethreatening. Rebleeding rates of up to 10-20% despite portal decompression with transjugular intrahepatic portosystemic shunt (TIPS) have been reported, likely related to the complex efferent vascular pathways that exist at this location and, thus, multimodal therapy for effective control of bleeding may be necessary (44, 65-68).
Gastrointestinal Varices with Vascular Thrombosis
Varices occurring in the setting of PVT and SVT should be considered distinct from each other due to their disparate underlying etiologies. PVT can occur in patients with and without cirrhosis. PVT occurs in about 10% of patients with cirrhosis and is related to reduced portal flow into the liver as a result of increased intrahepatic vascular resistance (69-71). In fact, low portal flow is the most important risk factor for PVT in cirrhosis and predicts future PVT (72, 73). At presentation, the rates of variceal bleeding in patients with cirrhosis and PVT ranges from 39 to 50%, with most bleeding occurring from EV (74). Patients with cirrhosis-related PVT have a higher risk of bleeding than patients with non-cirrhotic PVT, and the presence of PVT is associated with a longer time to achieve endoscopic eradication of varices (75, 76). Noncirrhotic PVT is the second leading cause of portal hypertension in the Western world and in this group of patients, EV can be seen in up to 90% of patients and GV have a reported prevalence of 15-50% (77-79). Ectopic varices are more common in the setting of thrombosis than in portal hypertension secondary to cirrhosis alone, and have been reported to occur in approximately 30% of patients with splanchnic vein thrombosis, including isolated PVT with or without SVT or mesenteric vein thrombosis (63, 79). Up to 50% of patients with non-cirrhotic splanchnic vein thrombosis can present with portal hypertensive bleeding, with EV being the most common culprit (80). Secondary bleeds have however been reported to be more commonly related to GV (26%) or ectopic varices (33%) (80). Anticoagulation is warranted in the setting of acute PVT, thrombosis of the main portal vein or progressive PVT in liver transplant candidates, or in those with an underlying hypercoagulable state (80, 81). Data regarding the benefit of anticoagulation in chronic or non-occlusive PVT and in non-liver transplant candidates are less clear aside from the setting of a hypercoagulable state in which case treatment should be considered (44). In general, the bleeding risk in patients with cirrhotic PVT treated with vitamin K antagonists or low-molecular weight heparin is low and treatment may prevent extension and slow progression
of liver disease (44, 70). Furthermore, mortality risk is not associated with bleeding and is rather related to the thrombosis itself or underlying liver disease (82, 83). In general, endoscopic screening and variceal obliteration prior to initiation of anticoagulation is recommended. Subsequent endoscopic screening should occur 6 months after diagnosis and then yearly thereafter, with management of varices as per recommendations in patients with cirrhosis (44, 70).
SVT is most commonly caused by pancreatitis, pancreatic pseudocysts or neoplasms, and should be considered distinct from cirrhosis and PVT (84, 85). GV have been reported to occur in 15-57% of patients with SVT and bleeding is the presenting symptom in 45 to 72% of patients with SVT (86-89). Splenectomy, which eliminates collateral venous outflow, is the treatment of choice to stop active bleeding and prevent future bleeding from GV due to SVT (85, 88-90).
Conclusions In summary, gastrointestinal varices are a common consequence of portal hypertension that can occur with and without cirrhosis. Elevated portal pressures, as a result of structural and functional resistance to flow, a hyperdynamic circulation, or extrahepatic venous obstruction, lead to increased blood flow through a collateral venous system. Hemorrhage ensues when tension exerted on the thin wall of the varix exceeds its limit of elasticity. Gastroesophageal varices are the most common subtype occurring in 50% of patients with cirrhosis, and their presence and bleeding risk is correlated with severity of liver disease. Gastric varices are less common but tend to bleed more severely. Cardiofundal varices are complex anatomically and thus may require multimodal therapy for effective management. Isolated gastric varices and ectopic varices should prompt investigation for mesenteric thrombosis, particularly splenic vein thrombosis, which carries a different etiology, prognosis and therapeutic approach than gastrointestinal varices that occur due to portal vein thrombosis.
Conflict of Interest Statement: None
References 1.
Garcia-Tsao G, Friedman S, Iredale J, et al: Now there are many (stages) where before there was one: In search of a pathophysiological classification of cirrhosis. Hepatology 51:1445-1449, 2010
2.
Desmet VJ. Knodell RG, Ishak KG, et al: Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. J Hepatol 38:382-386, 2003
3.
Batts KP, Ludwig J: Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 19:1409-1417, 1995
4.
D'Amico G, Garcia-Tsao G, Pagliaro L: Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 44: 217-231, 2006
5.
Garcia-Tsao G, Sanyal AJ, Grace ND, et al: Practice Guidelines Committee of the American Association for the Study of Liver D, Practice Parameters Committee of the American College of G. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 46: 922-38, 2007
6.
Perello A, Escorsell A, Bru C, et al: Wedged hepatic venous pressure adequately reflects portal pressure in hepatitis C virus-related cirrhosis. Hepatology 30:1393-1397, 1999
7.
Groszmann RJ, Garcia-Tsao G, Bosch J, et al: Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 353:2254-2261, 2005
8.
Ripoll C, Groszmann R, Garcia-Tsao G, et al: Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 133: 481-488, 2007
9.
Garcia-Tsao G, Groszmann RJ, Fisher RL, et al: Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 5: 419-424, 1985
10.
de Franchis R, Baveno VIF: Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 63: 743-752, 2015
11.
Groszmann RJ, Bosch J, Grace ND, et al: Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 99: 1401-1407, 1990
12.
Bosch J, Garcia-Pagan JC: Prevention of variceal rebleeding. Lancet 361:952-4, 2003.
13.
Casado M, Bosch J, Garcia-Pagan JC, et al: Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology 114: 1296-1303, 1998
14.
Moitinho E, Escorsell A, Bandi JC, et al: Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology 117: 626-631, 1999
15.
Groszmann RJ, Wongcharatrawee S: The hepatic venous pressure gradient: anything worth doing should be done right. Hepatology 39: 280-282, 2004
16.
Carrion JA, Navasa M, Bosch J, et al: Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation. Liver Transpl 12: 1791-1798, 2006
17.
Vizzutti F, Arena U, Romanelli RG, et al: Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 45: 1290-1297, 2007
18.
Vorobioff JD, Groszmann RJ: Prevention of portal hypertension: from variceal development to clinical decompensation. Hepatology 61: 375-381, 2015
19.
Groszmann RJ, Abraldes JG: Portal hypertension: from bedside to bench. J Clin Gastroenterol 39: 125-130, 2005 (suppl)
20.
Bosch J, Abraldes JG, Fernandez M, et al: Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J Hepatol 53: 558-567, 2010
21.
Berzigotti A: Pathophysiology of variceal bleeding in cirrhotics. Ann Gastroenterol 14:150-157, 2001
22.
Garcia-Tsao G, Bosch J: Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 362: 823-382, 2010
23.
Abraldes JG, Iwakiri Y, Loureiro-Silva M, et al. Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state. Am J Physiol Gastrointest Liver Physiol 290: G980-987, 2006
24.
Bosch J, Berzigotti A, Garcia-Pagan JC, et al: The management of portal hypertension: rational basis, available treatments and future options. J Hepatol 48: 68-92, 2008 (suppl)
25.
Polio J, Groszmann RJ: Hemodynamic factors involved in the development and rupture of esophageal varices: a pathophysiologic approach to treatment. Semin Liver Dis 6: 318-331, 1986
26.
Polio J, Groszmann RJ, Reuben A, et al: Portal hypertension ameliorates arterial hypertension in spontaneously hypertensive rats. J Hepatol 8: 294-301, 1989
27.
Rigau J, Bosch J, Bordas JM, et al: Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage. Gastroenterology 96: 873-880, 1989
28.
Siringo S, Bolondi L, Gaiani S, et al: Timing of the first variceal hemorrhage in cirrhotic patients: prospective evaluation of Doppler flowmetry, endoscopy and clinical parameters. Hepatology 20: 66-73, 1994
29.
Zoli M, Merkel C, Magalotti D, et al: Evaluation of a new endoscopic index to predict first bleeding from the upper gastrointestinal tract in patients with cirrhosis. Hepatology 24: 1047-1052, 1996
30.
Noda T: Angioarchitectural study of esophageal varices. With special reference to variceal rupture. Virchows Arch A Pathol Anat Histopathol 404: 381-392, 1984
31.
Kovalak M, Lake J, Mattek N, et al: Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database. Gastrointest Endosc 65: 82-88, 2007
32.
Navasa M, Pares A, Bruguera M, et al: Portal hypertension in primary biliary cirrhosis. Relationship with histological features. J Hepatol 5: 292-298, 1987
33.
Merli M, Nicolini G, Angeloni S, et al: Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 38: 266-272, 2003
34.
D'Amico G, Pagliaro L, Bosch J: Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 19: 475-505, 1999
35.
El-Serag HB, Everhart JE. Improved survival after variceal hemorrhage over an 11-year period in the Department of Veterans Affairs. Am J Gastroenterol 95: 3566-3573, 2000
36.
D'Amico G, De Franchis R, Cooperative Study G: Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. Hepatology 38: 599-612, 2003
37.
Carbonell N, Pauwels A, Serfaty L, et al: Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 40: 652-659, 2004
38.
Reverter E, Tandon P, Augustin S, et al: A MELD-based model to determine risk of mortality among patients with acute variceal bleeding. Gastroenterology 146: 412-419, 2014
39.
Garcia-Tsao G, Abraldes JG, Berzigotti A, et al: Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology 65: 310-335, 2017
40.
Caldwell S: Gastric varices: is there a role for endoscopic cyanoacrylates, or are we entering the BRTO era? Am J Gastroenterol 107: 1784-1790, 2012
41.
Mishra SR, Chander Sharma B, Kumar A, et al: Endoscopic cyanoacrylate injection versus beta-blocker for secondary prophylaxis of gastric variceal bleed: a randomised controlled trial. Gut 59: 729-735, 2010
42.
Watanabe K, Kimura K, Matsutani S, et al: Portal hemodynamics in patients with gastric varices. A study in 230 patients with esophageal and/or gastric varices using portal vein catheterization. Gastroenterology 95: 434-440, 1988
43.
Sarin SK, Lahoti D, Saxena SP, et al: Prevalence, classification and natural history of gastric varices: a long-term follow-up study in 568 portal hypertension patients. Hepatology 16:1343-1349, 1992
44.
Henry Z, Uppal D, Saad W, et al: Gastric and ectopic varices. Clin Liver Dis 18: 371-388, 2014
45.
Saad WE: Vascular anatomy and the morphologic and hemodynamic classifications of gastric varices and spontaneous portosystemic shunts relevant to the BRTO procedure. Tech Vasc Interv Radiol 16: 60-100, 2013
46.
Classen M, Tytgat GNJ, Lightdale CJ (eds): Gastroenterological endoscopy (ed 2). New York, NY, Thieme, 2010
47.
Caletti G, Brocchi E, Baraldini M, et al: Assessment of portal hypertension by endoscopic ultrasonography. Gastrointest Endosc 36: 21-27, 1990 (suppl)
48.
Boustiere C, Dumas O, Jouffre C, et al: Endoscopic ultrasonography classification of gastric varices in patients with cirrhosis. Comparison with endoscopic findings. J Hepatol 19: 268-272, 1993
49.
Kim T, Shijo H, Kokawa H et al. Risk factors for hemorrhage from gastric fundal varices. Hepatology 25: 307-312, 1997
50.
Helmy A, Al Kahtani K, Al Fadda M: Updates in the pathogenesis, diagnosis and management of ectopic varices. Hepatol Int 2: 322-334, 2008
51.
Zaman L, Bebb JR, Dunlop SP, et al: Familial colonic varices--a cause of "polyposis" on barium enema. Br J Radiol 81: 17-19, 2008
52.
Wiesner RH, LaRusso NF, Dozois RR, et al: Peristomal varices after proctocolectomy in patients with primary sclerosing cholangitis. Gastroenterology 90(2): 316-322, 1986
53.
Bromfield EB, Altshuler L, Leiderman DB, et al. Cerebral metabolism and depression in patients with complex partial seizures. Arch Neurol 49: 617-623, 1992
54.
Norton ID, Andrews JC, Kamath PS: Management of ectopic varices. Hepatology 28: 1154-1158, 1998
55.
Lebrec D, Benhamou JP: Ectopic varices in portal hypertension. Clin Gastroenterol 14:105-121, 1985
56.
De Palma GD, Rega M, Masone S, et al. Mucosal abnormalities of the small bowel in patients with cirrhosis and portal hypertension: a capsule endoscopy study. Gastrointest Endosc 62: 529-534, 2005
57.
McCormack TT, Bailey HR, Simms JM, et al: Rectal varices are not piles. Br J Surg 71: 163, 1984
58.
Hosking SW, Smart HL, Johnson AG, et al: Anorectal varices, haemorrhoids, and portal hypertension. Lancet 1: 349-352, 1989
59.
Naveau S, Poynard T, Pauphilet C, et al: Rectal and colonic varices in cirrhosis. Lancet 1: 624, 1989
60.
Hashizume M, Tanoue K, Ohta M, et al: Vascular anatomy of duodenal varices: angiographic and histopathological assessments. Am J Gastroenterol 88: 1942-1945, 1993
61.
Al-Mofarreh M, Al-Moagel-Alfarag M, Ashoor T et al: Duodenal varices. Report of 13 cases. Z Gastroenterol 24: 673-680, 1986
62.
Chawla Y, Dilawari JB: Anorectal varices--their frequency in cirrhotic and non-cirrhotic portal hypertension. Gut 32: 309-311, 1991
63.
Ganguly S, Sarin SK, Bhatia V, et al: The prevalence and spectrum of colonic lesions in patients with cirrhotic and noncirrhotic portal hypertension. Hepatology 21: 1226-1231, 1995
64.
Misra SP, Dwivedi M, Misra V, et al: Colonic changes in patients with cirrhosis and in patients with extrahepatic portal vein obstruction. Endoscopy 37: 454-459, 2005
65.
Kochar N, Tripathi D, McAvoy NC, et al: Bleeding ectopic varices in cirrhosis: the role of transjugular intrahepatic portosystemic stent shunts. Aliment Pharmacol Ther 28: 294303, 2008
66.
Vangeli M, Patch D, Terreni N, et al: Bleeding ectopic varices--treatment with transjugular intrahepatic porto-systemic shunt (TIPS) and embolisation. J Hepatol 41: 560-566, 2004
67.
Shibata D, Brophy DP, Gordon FD, et al: Transjugular intrahepatic portosystemic shunt for treatment of bleeding ectopic varices with portal hypertension. Dis Colon Rectum 42: 1581-1585, 1999
68.
Nayar M, Saravanan R, Rowlands PC, et al: TIPSS in the treatment of ectopic variceal bleeding. Hepatogastroenterology 53: 584-587, 2006
69.
Rodriguez-Castro KI, Porte RJ, Nadal E, et al: Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review. Transplantation 94:1145-1153, 2012
70.
Harding DJ, Perera MT, Chen F, et al: Portal vein thrombosis in cirrhosis: Controversies and latest developments. World J Gastroenterol 21: 6769-6784, 2015
71.
Shah V: Molecular mechanisms of increased intrahepatic resistance in portal hypertension. J Clin Gastroenterol 41: 259-261, 2007 (suppl)
72.
Amitrano L, Guardascione MA, Ames PR: Coagulation abnormalities in cirrhotic patients with portal vein thrombosis. Clin Lab 53: 583-589, 2007
73.
Kinjo N, Kawanaka H, Akahoshi T, et al: Risk factors for portal venous thrombosis after splenectomy in patients with cirrhosis and portal hypertension. Br J Surg 97: 910-916, 2010
74.
Amitrano L, Guardascione MA, Brancaccio V, et al: Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 40: 736-741, 2004
75.
Merkel C, Bolognesi M, Bellon S, et al: Long-term follow-up study of adult patients with non-cirrhotic obstruction of the portal system: comparison with cirrhotic patients. J Hepato 15: 299-303, 1992
76.
Dell'Era A, Iannuzzi F, Fabris FM, et al: Impact of portal vein thrombosis on the efficacy of endoscopic variceal band ligation. Dig Liver Dis 46: 152-156, 2014
77.
Valla DC, Condat B, Lebrec D: Spectrum of portal vein thrombosis in the West. J Gastroenterol Hepatol 17: 224-227, 2002 (suppl)
78.
Amitrano L, Guardascione MA, Scaglione M, et al: Prognostic factors in noncirrhotic patients with splanchnic vein thromboses. Am J Gastroenterol 102: 2464-2470, 2007
79.
Sarin SK, Sollano JD, Chawla YK, et al: Consensus on extra-hepatic portal vein obstruction. Liver Int 26: 512-519, 2006
80.
Orr DW, Harrison PM, Devlin J, et al: Chronic mesenteric venous thrombosis: evaluation and determinants of survival during long-term follow-up. Clin Gastroenterol Hepatol 5: 80-86, 2007
81.
DeLeve LD, Valla DC, Garcia-Tsao G: American Association for the Study Liver D. Vascular disorders of the liver. Hepatology 49: 1729-1764, 2009
82.
Janssen HL, Wijnhoud A, Haagsma EB, et al: Extrahepatic portal vein thrombosis: aetiology and determinants of survival. Gut 49: 720-724, 2001
83.
Donadini MP, Dentali F, Ageno W: Splanchnic vein thrombosis: new risk factors and management. Thromb Res 129: 93-96, 2012 (suppl)
84.
Butler JR, Eckert GJ, Zyromski NJ, et al: Natural history of pancreatitis-induced splenic vein thrombosis: a systematic review and meta-analysis of its incidence and rate of gastrointestinal bleeding. HPB 13: 839-845, 2011
85.
Agarwal AK, Raj Kumar K, Agarwal S, et al: Significance of splenic vein thrombosis in chronic pancreatitis. Am J Surg 196: 149-154, 2008
86.
Heider TR, Azeem S, Galanko JA, et al: The natural history of pancreatitis-induced splenic vein thrombosis. Ann Surg 239: 876-880, 2004
87.
Bernades P, Baetz A, Levy P, et al: Splenic and portal venous obstruction in chronic pancreatitis. A prospective longitudinal study of a medical-surgical series of 266 patients. Dig Dis Sci 37: 340-346, 1992
88.
Sakorafas GH, Sarr MG, Farley DR, et al: The significance of sinistral portal hypertension complicating chronic pancreatitis. Am J Surg 179: 129-133, 2000
89.
Weber SM, Rikkers LF: Splenic vein thrombosis and gastrointestinal bleeding in chronic pancreatitis. World J Surg 27: 1271-1274, 2003
90.
Gunther RW, Vorwerk D, Thon HJ, et al: Balloon dilatation and insertion of a selfexpandable flexible metallic stent in a benign stricture of the left hepatic duct: case report. Cardiovasc Intervent Radiol 12: 69-71, 1989
Legend Figure 1.
Gastrointestinal varices are a consequence of portal hypertension and develop as a result of increased intrahepatic vascular resistance and increased flow through a hyperdynamic circulation. In patients with cirrhosis, increased intrahepatic vascular resistance occurs due to vascular obliteration by regenerative nodules and scar tissue compressing intrahepatic small vessels and is further aggravated by an imbalance between local vasoconstrictors and vasodilators. At the same time, increased blood flow through the splanchnic circulation due to overproduction of endogenous vasodilators and a hyperdynamic circulation lead to increased portal flow and contribute to the persistence of portal hypertension and progression of varices. Once portal pressures exceed 10 mmHg, varices develop and are at risk of growth and subsequent hemorrhage.