Professional Documents
Culture Documents
MD
, Wael Saad,
MD
KEYWORDS
Ectopic varices Gastric varices Duodenal varices Rectal varices TIPS
BRTO Portal vein thrombosis Splenic vein thrombosis
Edson Guzman
KEY POINTS
There is significant heterogeneity underlying the formation of gastric and ectopic varices;
therefore, standardization of treatment is difficult.
Acute management of gastric and ectopic variceal bleeding should include medical management with octreotide or vasopressin analogues and may require temporizing measures administered endoscopically or via balloon tamponade.
Follow-up of acute gastric and ectopic variceal bleed should involve a combination of
endoscopic and radiographic staging to determine the best treatment modality based
on the underlying cause and vascular anatomy.
Endoscopic obliteration with cyanoacrylate injection, transjugular intrahepatic portosystemic shunt, and balloon-occluded retrograde transvenous obliteration are potential therapies for gastric and ectopic varices whether alone or in combination; but each of these
interventions has unique limitations, risks, benefits, and appropriate follow-up measures.
Anticoagulation for portal vein thrombosis should be considered in both noncirrhotic and
cirrhotic patients once the bleeding risk has been controlled; but for isolated splenic vein
thrombosis, splenectomy, rather than anticoagulation, should be considered in symptomatic patients.
To understand the venous structure of the portal-collateral pathways, it helps to understand their embryologic development. Fig. 1 shows the changes over time of the
developing portal venous system in the embryo and fetus. The portal venous system
begins as the paired vitelline and umbilical veins surrounding the liver bud with both
emptying directly into the sinus venosus. Extensive embryologic remodeling of these
Disclosures: None.
a
Division of Gastroenterology and Hepatology, University of Virginia Health System, PO
Box 800708, Charlottesville, VA 22908-0708, USA; b Division of Vascular and Interventional
Radiology, University of Virginia Health System, PO Box 800170, Charlottesville, VA 22908, USA
* Corresponding author.
E-mail address: shc5c@virginia.edu
Clin Liver Dis 18 (2014) 371388
http://dx.doi.org/10.1016/j.cld.2014.01.002
1089-3261/14/$ see front matter 2014 Elsevier Inc. All rights reserved.
liver.theclinics.com
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Henry et al
vessels into the portal system and simultaneous remodeling of the paired right and left
cardinal veins into the renal/adrenal/gonadal veins (subcardinal) and the azygous/
hemiazygos veins (supracardinal) lead ultimately to the mature venous system. The
development of these systems is important when approaching gastric varices (GV)
and ectopic varices (ECV) because the connections that arise are often related to their
anatomic origins. For example, in patients with splenic vein thrombosis (SVT) and subsequent GV, the hypertensive short gastric veins in the fundus of the stomach, which
originate from the vitelline veins, often communicate with the azygous vein, which originates from the supracardinal veins, through small portosystemic collaterals in the
distal esophagus.1 Understanding these anastomoses and the direction of these
veins afferent and efferent flow based on their anatomy can help guide therapeutic
interventions, which the authors note in future sections of this review.2
GV IN CIRRHOSIS
In patients with cirrhosis and no underlying splanchnic vein thrombosis, studies have
found the prevalence of GV to be 17% to 25% compared with a prevalence of esophageal varices (EV) of 50% to 60%.3,4 GV bleed less frequently than EV but tend to be
more severe.4 Fundal varices tend to bleed more often than varices in the cardia or
antrum.4 The natural history of GV has rarely been reported; but in one study of 132
patients, the bleeding risk was estimated at 16%, 36%, and 44% at 1 year, 3 years,
and 5 years, respectively. The presence of a red spot, a varix greater than 5 mm in
size, and advanced Child-Pugh class were all found to be predictors of bleeding.3
The absence of forward flow in the splenic vein has also recently been established
as a predictor of GV bleeding, with a 5-year risk of 59% versus 39% when compared
with those with forward flow.5 This finding is consistent with a much earlier study that
noted, in comparison with EV, GV are much more likely to have reversed or to-and-fro
flow in the splenic vein.6
The management of GV in patients with cirrhosis depends greatly on how they are
classified because this can provide a guide for the prognosis and treatment approach.
The most common system used is the Sarin classification (Fig. 2).4 Using this classification system helped identify gastric fundal varices as higher-risk lesions for bleeding
and has guided other studies in evaluating responses to different therapies. For
instance, sclerotherapy for GV has not had the same success that it had in the treatment of EV, except in subsets of patients with gastroesophageal varices (GOV) 1.
Physiologically, this makes sense because, as the Sarin classification has shown,
GOV1 GV are located near the gastroesophageal junction and are often fed from
the same venous source as EV. However, with fundal varices, GOV2 and IGV 1, the
Sarin classification does not truly describe the underlying vascular heterogeneity,
=
Fig. 1. The embryologic development of the portal venous and systemic venous circulation
of the abdomen. In gold are the vitelline veins that merge over time to form the intrahepatic portal and hepatic veins as well as the superior portion of the intrahepatic inferior
vena cava (IVC). These veins also form the main portal vein and go on to form the splenic
and mesenteric veins. In red are the umbilical veins. Over time, the right umbilical vein atrophies and the left umbilical vein maintains a connection to the left portal venous system
and forms the ductus venosus with the vitelline veins; the ductus venosus becomes the ligamentum venosum and the umbilical vein atrophies after birth. This vestigial link explains
the presence of a recanalized umbilical vein in portal hypertension. Colored teal blue are
the paired subcardinal veins, which merge over time to form the abdominal IVC and bilateral renal, adrenal, and gonadal veins. In green are the azygous and hemiazygos veins,
which are derived from the supracardinal veins and run inferiorly into the abdomen where
the hemiazygos connects into the left adrenal vein. These vestigial connections should atrophy over time but are likely the source of small portosystemic collaterals in portal hypertension1 and likely play a role in gastrorenal shunt formation.2 SVC, superior vena cava.
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Fig. 2. The Sarin endoscopic classification for GV.4 GOV, gastroesophageal varices; IGV,
isolated GV.
which has made it difficult to use this system alone to standardize an approach to
treatment and highlights the need for a better understanding of the vascular anatomy.
Clinical investigators in the 1980s and 1990s, especially in Japan, can be credited
with bringing a new appreciation of the architecture of the venous collateral bed underlying cardiofundal varices; these typically involve collaterals arising from the short
gastric veins and the posterior gastric veins leading to an outflow trunk that ends in the
left renal vein.6 This study also highlights the difference between a right-sided portal
circulation and a left-sided portal circulation in relation to GV. Proposed vascular classifications are based on the afferent veins feeding the varices combined with the
venous outflow tract, whether it is through a direct shunt or multiple small collaterals
(Figs. 3 and 4).7,8 The vascular classifications can be used in conjunction with the
endoscopic classification to determine the best therapy.
The management strategies for bleeding GV have varied over the years but are
generally categorized into either endoscopic or radiologic approaches. Appropriate
Fig. 3. The Kiyosue vascular classification of GV.7 Type 1 refers to a single afferent vein for
either the right or left portal circulation; type 2 refers to multiple afferent vessels contributing to the varix; type 3 is consistent with type 2 with the addition of small afferent vessels
in direct continuity with the outflow track. Type A consists of a gastrorenal shunt (GRS) as
the sole outflow; type B describes the presence of a GRS in conjunction with small peridiaphragmatic portosystemic collaterals; type C describes the presence of both a GRS and
direct gastro-caval shunt; type D consists of small portosystemic collaterals as the sole
outflow track. Types 1, 2, and 3 can be combined with types A, B, C, and D to describe
the inflow and outflow of a GV.
medical management of acute GV bleeding is unclear because there are no trials specifically evaluating the use of octreotide or vasopressin analogues; however, the diversion of splanchnic blood flow should decrease bleeding similar to the effect seen in
acute esophageal variceal bleeding and should be considered in this population.
Balloon tamponade is likely a more effective method to stop bleeding in the acute
setting; however, this usually must be followed up by more definitive endoscopic or
vascular therapy.
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Fig. 4. Saad-Caldwell vascular classification of GV.8 Type 1a with left-sided (left gastric vein)
afferent flow into GV and no gastrorenal shunt (GRS), outflow through small portosystemic
collaterals, type 1b with left-sided afferent flow and dominant GRS as outflow; type 2a with
right-sided (short gastric vein) afferent flow into GVand outflow through small portosystemic collaterals, type 2b with right-sided afferent flow and dominant GRS as outflow; type 3a with mixed
(left and right) afferent flow and outflow through small portosystemic collaterals, type 3b with
mixed afferent flow and dominant GRS as outflow. This classification includes a type 4a and
4b, which are the same as 3a and 3b but with the inclusion of portal vein thrombosis. CGV, cardial
GV; FGV, fundal GV; IVC, inferior vena cava; LGV, left gastric vein; LRV, left renal vein; MV, mesenteric vein (superior mesenteric vein); PV, portal vein; SGV, short gastric vein; SV, splenic vein.
Endoscopic Treatment of GV
Transjugular intrahepatic portosystemic shunt (TIPS) has been evaluated in the treatment of GV. In comparison with EV, large GV often have lower portal pressures and
lower portosystemic gradients before TIPS placement.6,18 In a study from 1997, results of TIPS procedures in patients with EV and/or GV were compared revealing
that EV had a notable reduction in size after TIPS, as would be expected; but 50%
of GV did not change in size despite achieving a portosystemic gradient less than
12 mm Hg.19 These findings were again noted in a study from 2007 comparing cyanoacrylate injection with TIPS for the treatment of GV. Despite a slightly lower rebleeding
rate in the TIPS group when follow-up endoscopy was performed, those that underwent glue injection had a much lower rate of persistent GV compared with the TIPS
group, 20% versus 57%, respectively.14 This phenomenon is likely caused by the
presence of spontaneous shunts, such as gastrorenal and splenorenal shunts.6
In a study from 2003, TIPS had a lower 30-day rate of rebleeding when compared
with cyanoacrylate injection, 15% versus 30%, respectively. But there was no mortality difference between the groups, and the cost analysis at 6 months revealed a significant benefit of glue injection over TIPS.20 In the authors own data, they found a
lower 1-year rebleeding rate in the cyanoacrylate group compared with the TIPS
group, 10% and 25% respectively, and also showed no mortality difference.21 The authors did, however, show an increased morbidity with TIPS caused by hepatic encephalopathy. In an earlier study with this same population, the authors also found
a cost benefit to cyanoacrylate treatment when compared with noncyanoacrylate
therapy.22 Although TIPS remains a common and widely accepted means of managing GV bleeding, its application remains problematic in many patients; it is sometimes
ineffective.18,23 This ineffectiveness is especially so in patients with far-left shunts, in
whom transhepatic occlusion of the shunt, usually performed by delivering a coil
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through the TIPS, may be challenging. In addition, TIPS may be less effective in patients with a low transhepatic pressure gradient because of effective decompression
through the spontaneous gastrorenal shunt and possibly detrimental in those with
marginal hepatic reserve.18,19,24
Balloon-Occluded Retrograde Transvenous Obliteration Treatment of GV
Prophylactic therapy for GV has not been evaluated extensively; however, Mishra and
colleagues40 compared cyanoacrylate glue injection with beta-blocker therapy for
both primary and secondary prophylaxis of GV bleeding. For secondary prophylaxis,
repeat glue injection until obliteration of varices had a much lower rebleeding rate
compared with standard beta-blockade therapy titrated to pulse, 15% versus 55%,
respectively. As expected, the beta-blocker group had a better reduction in portal
pressures; however, this did not affect the results. Also, beta-blockade had a much
higher mortality compared with the glue injection group, 25% versus 3%, respectively.
In a study comparing glue injection, beta blockade, and no therapy for primary prophylaxis of first GV bleed, the 2-year bleeding rates were 13%, 28%, and 45%, respectively, suggesting that glue injection is superior to beta-blockade, again despite
large decreases in portal pressure with beta-blocker therapy.41
DUODENAL VARICES
ECV are the cause for bleeding in 1% to 5% of patients with intrahepatic portal hypertension and in 20% to 30% of those with extrahepatic portal hypertension and make
up 2% to 5% of all variceal bleeding.42,43 Duodenal varices (DV) make up 17% of all
ECV bleeding.42 They have a prevalence of 0.2% to 0.4% in all patients undergoing
upper endoscopy.44,45 Because it is rare, there are no controlled trials evaluating
DV; however, as with GV, there are varying anatomic considerations to DV. In the
largest series of patients with DV, 3 of 14 patients had acute bleeding and underwent
endoscopic injection of cyanoacrylate along with one other patient with a red spot on a
duodenal varix. All 3 acutely bleeding patients achieved initial hemostasis, and there
were no rebleeds among all 4.46 Two other case reports reveal success with cyanoacrylate injection with no rebleeding out to 1 year, and another investigator reports success in a single case with thrombin injection.4749 Most DV have an afferent venous
supply from either the portal vein or the superior mesenteric vein with an outflow track
directly into the inferior vena cava, making TIPS and BRTO possible.44,50 In one case
of failed endoscopic management, rescue BRTO was performed for DV bleeding with
complete obliteration of the varix after 3 months of follow-up and no rebleeding.51
Another series of 5 patients who underwent BRTO for DV reported 100% technical
success and no rebleeding out to 1 year.50 TIPS has also been successful in one
case report of DV in the setting of cirrhosis as a bridge to transplant.52 Other reports
on the general use of TIPS for all kinds of ECV bleeding have shown modest results in
the patients with DV.53 Because of the lack of randomized trials, an exact recommendation for the treatment of DV cannot be made; but the evidence noted here suggests
that, similar to GV, there are many viable modalities with similar rates of success.
COLORECTAL VARICES
Rectal varices (RV) are the most prevalent of the ECV, with rates reported as high as
77% of all ECV. Their prevalence in patients with cirrhosis is between 28% and 56%,
whereas their prevalence in extrahepatic portal vein obstruction is 63% to 94%.5456
Bleeding from RV is rare but can be massive and fatal.57,58 Most of the data on management are related to TIPS placement in these patients; however, there are a few
case reports and case series on endoscopic therapies, BRTO, and even surgical management. Endoscopically there are case reports of cyanoacrylate use as well as band
ligation. In contrast to GV, band ligation shows superior results with excellent initial hemostasis and low rebleeding rates compared with glue injection.5860 There have been
case reports of standard BRTO therapy as well as a transumbilical approach to a
BRTO procedure; in both cases, the RV were completely obliterated and there was
no rebleeding.61,62 There have been many retrospective studies evaluating TIPS results in these patients; although initial hemostasis results are quite good, there are
rebleeding rates from 10% to 20% despite adequately reduced portal pressure.53,6365 This finding is similar to the findings in some patients with GV after
TIPS and suggests that, because of the complex vascular outflow pathways seen in
these varices, TIPS alone may not be effective. In some cases, BRTO or TIPS with
direct embolization of the varix may be necessary.
GV AND ECV IN PORTAL VEIN THROMBOSIS
Cirrhotic patients with PVT and variceal bleeding have a much worse prognosis.6669
In addition, PVT is much more prevalent in cirrhotic patients when compared with the
general population, with an average prevalence around 10% and a range between
2.1% and 23.0%.70 There are only a few studies that remark on the incidence of
PVT, one with a cumulative incidence of 7.4% and another with an annual incidence
of 16%.71,72 The rates of variceal bleeding in cirrhotic patients with PVT range from
about 39% to 50% at presentation; however, most of these bleeds are secondary
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to EV.73 There are very little data regarding gastric variceal bleeding or ectopic variceal
bleeding in cirrhotic patients with PVT; of the data available, there are only case reports or very small case series.
A case report of DV and GV in a patient with cirrhosis and PVT noted hemostasis
without rebleeding out to 1 year after endoscopic injection of Histoacryl.47 TIPS (usually along with postprocedure anticoagulation) is also a viable option in these patients,
even with occlusive PVT provided intrahepatic portal branches can be visualized.74
This approach has the advantage of offering variceal decompression but carries technical challenges and an increased risk of hepatic decompensation with higher MELD
scores.19 There are a few prospective trials that have evaluated the use of anticoagulation in PVT related to cirrhosis and have noted very few bleeding events.71,74,75 In
one of these studies, there was a significantly higher rate of recanalization in patients
on anticoagulation; variceal bleeding was worse in patients that did not receive anticoagulation compared with those that did.74 Certainly, long-term anticoagulation
needs to be considered in this population, especially in patients with an underlying
thrombophilia.
Noncirrhotic PVT and GV/ECV Bleeding
SVT must also be considered separate from PVT and cirrhosis because the underlying
cause is much different. The most common causes of isolated SVT are chronic
pancreatitis, acute pancreatitis, pancreatic pseudocyst, and neoplasm, with pancreatitis the most frequent cause.1,9397 The overall incidence of SVT ranges from 13%
to 45%, with most of these studies evaluating populations of patients with pancreatitis. It is estimated that 60% of cases of SVT are caused by pancreatitis.94,9799 The
incidence of GV in SVT ranges from 15% to almost 57%, with higher rates in studies
that looked specifically at acute and chronic pancreatitis.1,93,94,98,99 The presenting
symptom in patients with SVT is gastrointestinal bleeding in 45% to 72% of cases.97
Heider and colleagues93 looked at a large group of patients with pancreatitis over a
10-year period and noted 53 that had SVT. Of these 53 patients, they initially reported
that 41 of them were noted to have GV, a prevalence of almost 80%; however, most of
these were noted on computed tomography findings. On further analysis, only 36 of
these 53 patients underwent esophagogastroduodenoscopy (EGD); of those patients,
only 11 had endoscopically notable GV, or about 30%. Another study by Agarwal and
colleagues98 evaluated the incidence and management of SVT in patients with chronic
pancreatitis. There was an incidence of SVT of 22% and, within that group, an incidence of all varices of 41%. Of those with GV, 43% experienced a bleeding event.
The definitive treatment of GV bleeding in the setting of SVT is splenectomy; however,
performing splenectomy in all patients with SVT is a contentious subject.93,96,98 Heider
and colleagues93 found that, in their patients with SVT, the overall bleeding risk was only
4%; however, the patients that bled were all patients with GV on EGD. Additionally,
Agarwal and colleagues98 noted a bleeding rate from varices (EV vs GV not specified)
of approximately 10% and also noted that, in patients who underwent splenectomy,
there was no GV bleeding out to 2 years compared with a 14% GV bleeding rate in those
who did not. This finding suggests that splenectomy may prevent GV bleeding.
SUMMARY
In conclusion, GV and ECV have several underlying causes and, therefore, cannot be
treated with any one particular intervention. Acute management of both GV and ECV
should focus on the stabilization of patients while concurrently attempting to define
the underlying cause so that therapy can be tailored to the individual. More randomized controlled trials are needed in the future to better define the subsets of
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populations that may benefit from one intervention as compared with another. For patients with GV secondary to cirrhosis, the authors recommend the approach shown in
(Fig. 5). This approach outlines the need for flexibility in treatment options depending
on each patients unique vascular anatomy. A similar algorithm should be used for
ectopic variceal bleeding, with an initial focus on stabilization and optimization of
coagulation parameters followed by endoscopic assessment and assessment of
Fig. 5. Algorithm for management of gastric variceal bleeding. Enbucrilate (N-2-butylcyanoacrylate), procoagulants (recombinant factor VII, aminocaproic acid). Management
of ectopic variceal bleeding should follow the same algorithm with the exception that
endoscopic management is different depending on varix location. a Temporizing measures
only. b Cyanoacrylate glue injection may not be available at all institutions, and a riskbenefit discussion should be held with patients regarding embolic risk without knowing
the underlying vascular anatomy. EUS, endoscopic ultrasound; GR, gastrorenal; Hct,
hematocrit; HPS, hepatopulmonary syndrome; PFO, patent foramen ovale.
vascular anatomy. The treatment will vary based on the underlying vascular anatomy
and location of the ectopic varices (rectal, duodenal).
In patients whose presenting symptom of SVT is gastric variceal bleeding, then
splenectomy, after stabilization, should be the therapy of choice because it can relieve
active bleeding and will prevent further bleeding.95,9799 In patients with SVT who simply have GV but have not experienced bleeding, the authors would recommend a
more measured approach with regular screening endoscopies. If GV seem to be
increasing in size or begin showing high-risk marks, then prophylactic splenectomy
should be considered.
For all patients with PVT, whether cirrhotic or noncirrhotic, a hypercoagulable
workup should be performed. In acute PVT, anticoagulation should be strongly
considered for 3 to 6 months with the goal of recanalization of the portal vein once
bleeding has been controlled. Patients with acute GV or ECV bleeding should be
treated endoscopically before anticoagulation and should undergo variceal surveillance on a regular basis. TIPS after mechanical thrombectomy may be beneficial in
some patients; however, long-term anticoagulation may still be needed because of
underlying thrombophilia.
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