Role of endoscopy in management of gastrointestinal complications of portal hypertension

Abstract

The management of patients with gastrointestinal complications of portal hypertension is often complex and challenging. The endoscopy plays an important role in the management of these patients. The role of endoscopy is both diagnostic and interventional and in the last years the techniques have undergone a rapid expansion with the advent of different and novel endoscopic modalities, with consequent improvement of investigation and treatment of these patients. The choice of best therapeutic strategy depends on many factors: baseline disease, patient’s clinical performance and the timing when it is done if in emergency or a prophylactic approaches. In this review we evaluate the endoscopic management of patients with the gastrointestinal complications of portal hypertension.

Core tip: Endoscopy plays a primary role in the staging, diagnosis and treatment of gastrointestinal complications of portal hypertension. In this review, we summarize data from randomized clinical trials or prospective studies together with meta-analytical data, when applicable, to present the most updated recommendations on endoscopic management of the gastrointestinal complications of portal hypertension.

INTRODUCTION

Portal hypertension is defined as a pathologic increase in portal vein to inferior vena cava pressure gradient greater than 5 mmHg. According to anatomic location, the diseases causing portal hypertension are classified as pre-hepatic if involve portal, splenic or mesenteric veins, intra-hepatic if cause acute or chronic liver diseases, and post-hepatic if interfere with the venous outflow of the liver. The most prevalent cause of portal hypertension is liver cirrhosis with greater resistance to portal flow. Hepatic venous pressure gradient (HVPG) is an indirect measurement of portal hypertension which is obtained by placing a catheter in the hepatic vein or by occluding a large branch of hepatic vein by inflating a balloon. Portal hypertension likely causes the development of varices and hemodynamic and mucosal changes in the entire gastrointestinal (GI) tract. Varices are present in the 50% of cirrhotic patients[1-4]. Bleeding occurs in approximately 5%-15% of patients, depends on the size of varices. Other predictors of bleeding may be the presence of red wale mark and decompensated cirrhosis[5]. The variceal bleeding mortality is around 20% at 6 wk despite improvement in therapy over the last decade thanks to the development of endoscopical and pharmacological therapies and antibiotic prophylaxis[6-8].

In the patients with portal hypertension the gut mucosa undergoes microcirculatory changes, such as submucosal angiogenesis and vascular ectasia, that impair its integrity and promote its susceptibility to damage. Stomach changes can cause bleeding [portal hypertensive gastropathy (PHG)], usually the involvement of small bowel is asymptomatic (portal hypertensive enteropathy), but sometimes can cause occult blood loss, finally colon involvement (portal hypertensive colopathy) is often associated with bleeding and the symptoms are similar to inflammatory bowel disease[9].

The aim of this paper is to review the interventional and diagnostic role of endoscopy in patients with GI complications of portal hypertension.

ESOPHAGEAL VARICES

Primary prophylaxis

The goal of primary prophylaxis is to prevent first bleeding episode and consequently improve survival through decreasing bleeding-related death. All cirrhotic patients should be screened for varices through endoscopy to detect the patients that need a prophylactic treatment[10,11]. The Child-Pugh (C-P) score suggests that risk factors of bleeding are the presence of red wale marks, the size of varices and the liver disease severity[5].

Typically, one of two approaches is used for primary prophylaxis: pharmacologic prophylaxis using a non-selective beta-adrenergic blockers (NSBBs) or with endoscopic band ligation (EBL).

EBL consists in the placement of rubber rings on variceal columns which are sucked into a plastic hollow cylinder attached to the tip of the endoscope. Endoscopic ligation causes occlusion of the varix and then thrombosis with ischemic necrosis of the mucosa. Multiple-shot devices have largely replaced the original single-shot ligators, since the procedure is much simpler and faster with multi shot devices. Endoscopic variceal ligation is associated with complications such as hemorrhage, chest pain, dysphagia, and odynophagia and ulceration of the mucosa. There are only few studies that have evaluated the risk of bleeding from ligation-induced ulcers. Schepke et al[12] found that the incidence of bleeding from ligation ulcers after EBL was 6.7%. Another retrospective data analysis of EBL described hemorrhage from ligation ulcers as 5.7%, irrespective of the indication[13]. Endoscopic variceal ligation sessions are usually repeated at 1-2 wk intervals until complete obliteration[11]. A randomized, controlled trial of bimonthly vs biweekly EBL (primary and secondary prophylaxis) found that EBL bimonthly had a higher total eradication rate, lower recurrence rate, and lower rate of additional treatment than biweekly EBL and that the patients treated bi-monthly showed better ulceration healing in the second and third treatments than the patients treated bi-weekly[14]. This approach may decrease the risk of bleeding or perforation.

NSBBs can be used in patients that present cirrhosis, small varices and risk of bleeding according to C-P score[10,11]. It’s known that patients with small varices with red signs on its wall or with C-P score class C, have the same risk of bleeding of patients with large varices[5]. In patients with medium/large varices either NSBBs or EBL are an appropriate choice for primary prophylaxis of bleeding[10,11]. A systematic review of 11 randomized controlled trials (RCTs) about prevention of variceal hemorrhage,has compared NSBBs with placebo or non active treatment, and has shown a 9% absolute risk reduction of first variceal bleeding at two years[15]. A significant reduction in mortality was also seen with NSBBs use[16]. The use of NSBBs is limited by their side-effect profile, which includes hypotension, fatigue, lethargy, depression, and dyspnea in patients with associated pulmonary disease. Around 15%-20% of patients suffer from intolerable side effects that require discontinuation of the drug[17].

A meta-analysis of 5 trials comparing prophylactic EBL with controls found that EBL decreases the risk of variceal hemorrhage and the mortality related to hemorrhage[18]. The treatment choice is based on patient preference, local resources and side effects[10]. A Cochrane meta-analysis that included 19 RCTs, has compared prophylactic EBL with NSBBs and has shown a slight beneficial effect for EBL, without different bleeding-related mortality in the two arms[19].

Evolving data suggest novel uses for endoscopic ultrasonography (EUS) in patients with esophageal varices, in fact a RCT has shown that in the treatment of esophageal varices EUS-guided injection sclerotherapy is most safe and efficacious respect to endoscopic injection therapy[20].

In patients treated with NSBBs endoscopic follow-up isn’t necessary, conversely in patients treated with EBL, is necessary repeat endoscopy every one or two weeks until obliteration, 1-3 mo after obliteration and finally every year to check for variceal recurrence[11]. In patients with small varices and who not receive NSBBs, is necessary repeat endoscopy in two years. In the case of hepatic decompensation, endoscopy should be repeated every year and in cirrhotic patients without the presence of varices on the initial endoscopy it should be repeated every three years[10,11].

Acute variceal bleeding

Ruptured esophageal varices cause 70% of all upper GI bleeding episodes in patients with portal hypertension. Therefore, a variceal origin should be suspected in any cirrhotic patient that presents a GI bleeding[7]. In patients with hematemesis or hemodynamic instability, an endoscopic evaluation should be done in the first 12 h after admission[10,11].

The use of new drugs, which are able to decrease portal pressure, the novel and specialized endoscopic endoscopic therapy, the use of antibiotics and the interventional radiologic procedures improved the survival in the last 25 years[6]. Mortality during the bleeding episode remains high and ranges from 24% in unselected cirrhotic variceal bleeders to about 16% among those receiving the current standard of care (band ligation + vasoactive drugs + antibiotics)[21-23]. For the treatment of acute bleeding related to variceal the current recommendation is to combine antibiotic prophylaxis, hemodynamic stabilization, the use of drugs and the treatment through endoscopy[11]. It’s important maintaining hemodynamic stability and a hemoglobin of 8 g/dL[11]. The restitution of lost blood causes an increasing in portal pressure to levels higher respect to baseline[24]. A recently RCT showed that a restrictive transfusion strategy in patients with portal hypertensive bleeding reduced further bleeding, need for rescue therapy and length of stay in the hospital. In the restrictive-strategy group the hemoglobin threshold for transfusion was 7 g/dL per deciliter with a target range of 7 to 9 g/dL per deciliter[25]. Antibiotic prophylaxis is a standard practice, in fact it is known that is able to decrease the rate of bacteria infections and the incidence of rebleeding, and increase the survival[26,27]. The combination of endoscopic and pharmacological therapy is the most common approach for treatment of acute variceal bleeding[10,11]. For example a meta-analysis of 8 RCTs has shown that vasoactive drugs enhance the efficacy of endoscopic therapy respect to endoscopic therapy alone, without evidence of side effects or mortality[28].

EBL is the best endoscopic therapy for active bleeding because respect to endoscopic sclerotherapy (ES), allows a greater control of bleeding, the possible adverse events are lower and improves the survival[10,29,30]. When EBL is not technically feasible, endoscopic sclerotherapy is recommended[10]. Endoscopic ultrasound allows a more effective distribution of sclerosant, the injection of sclerosant agents can be realized into esophageal varices, and causes a decrease of the recurrence rate[31].

Emergency injection of acrylate glue could be also an effective method for treat the bleeding of esophageal varices[32]. Vaso-active medications decrease portal blood flow which relate closely to variceal pressure and include vasopressine, somatostatin, and their analogs (terlipressin and octreotide, respectively). Vasoactive therapy should be continued for 5 d to prevent the rebleeding[10], the reason behind this treatment is that a higher portal pressure is associated with a prognosis less favorable[33].

Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy, are at high risk for treatment failure and a poor prognosis and early use of PTFE-covered TIPS (within 72 h) markedly and significantly reduces failures to control bleeding or rebleeding and improves survival[34].

Secondary prophylaxis

Over 70% of patients experience recurrent variceal bleeding within one year of their index bleed[35,36]. To prevent recurrent bleeding all surviving patients should receive prophylactic treatments[11]. Available treatments for preventing variceal rebleeding include pharmacological therapy, endoscopic therapy, transjugular intra-hepatic porto-systemic shunt (TIPS) and surgical shunting. A recently meta-analysis showed that NSBBs and EBL are similarly able to reduce upper GI bleeding, variceal rebleeding and bleeding-related mortality, but the overall mortality rate was only lowered with NSBBs[37]. The beneficial effect of b-blockers goes beyond the reduction in the variceal bleeding risk and is probably related to an improvement of other complications of portal hypertension.

A combination of NSBBs and endoscopic therapy is the currently recommended first line treatment for the prevention of variceal rebleeding[10,11]. Band ligation is the endoscopic therapy of choice and has replaced injection sclerotherapy because it is safer and more effective[38]. EBL should be repeated every 1-2 wk until obliteration, the first surveillance endoscopy is performed 1-3 mo after obliteration and then every 6-12 mo to check for variceal recurrence and NSBBs should be adjusted to the maximal tolerated dose[10,11].

Recently, a meta-analysis of 9 trials has confirmed that the combination of EBL and drug treatment reduces the risk of overall and variceal rebleeding, but not overall mortality, when compared with b-blockers or EBL alone[39]. However, data evaluating this issue are not very strong. Lo and de la Pena, have shown that adding b-blockers to EBL reduces the risk of rebleeding and variceal recurrence but this effect was not confirmed in a third study[40-42]. Another two trials failed to show a clear-cut benefit from adding EBL to combined pharmacological therapy with nadolol plus isosorbide mononitrate[43,44].

In cirrhotic patients that are unable or that refuse EBL, NSBBs is a valid option, in fact causes a reduction in portal pressure and a slight increase of side effects[11,45]. TIPS should be considered in patients who are Child A or B who experience recurrent variceal hemorrhage despite combination pharmacological and endoscopic therapy[10,11]. The use of polytetrafluoroethylene (PTFE)-covered stents significantly decreased the rates of obstruction and re-intervention[46]. Surgical shunt prevents rebleeding but markedly increases the risk of hepatic encephalopathy[47].

Rescue therapy

In about 10% of patients, despite urgent endoscopic, variceal bleeding cannot be controlled and thus they may be candidates for salvage therapy[11]. A TIPS is suggested in patients with uncontrolled hemorrhage from esophageal varices with bleeding recurs[11,48-50]. Balloon tamponade (BT) is a temporary measure in patients with uncontrollable bleeding[10]. The main complications associated with BT include aspiration pneumonia in unventilated patients, esophageal ulcers, esophageal tears and airway obstruction with fatal complications in 6%-20% of cases[50].

Fully covered self-expanding metal stent (FCSEMS) placement have been recently proposed as rescue therapy[51], their use allow the stabilization of the patients until is performed the definitive therapy. Preliminary studies showed an high success rate, with minor complications[51-54]. Recently the hemostatic powder TC-325 was used as rescue therapy with good results[55].

GASTRIC VARICES

Seventeen percent of patients with hepatic cirrhosis are affected by gastric varices (GV)[56]. Gastric varices are classified according their location in: esophago-gastric varices, i.e., esophageal varices extending either from the gastroesophageal junction to the small curvature of the stomach (GOV1), or to the fundus (GOV2); and isolated gastric varices (IGV), located in the stomach (IGV2) or elsewhere in the fundus (IGV1); GOV1 represent 75% of GV, GOV2, IVG1 and IGV2 represent respectively 21%, 1% and 4% of GV[57]. GOV1 constitute an extension of esophageal varices[10]. GV bleed less frequently than esophageal varices and with a reported incidence of bleeding of about 25% in 2 years. Fundal varices, however, had a significantly higher bleeding incidence (78% for IGV1 and 55% for GOV2), than GOV1 and IGV2 (10%)[56]. Risk factors for GV bleeding include red color spots, larger nodular GV, fundal location and an advanced Child-Pugh class[56,58].

Primary prophylaxis

Little data have been reported about the primary prophylaxis of GV bleeding. Recently a RCT has compared the injection of cyanoacrylate glue with NSBBs in primary prophylaxis of GV bleeding and showed that cyanoacrylate therapy is more efficacious than NSBBs in preventing gastric variceal bleeding[59].

Acute variceal bleeding

Gastric varices bleeding is less frequent, but more severe than esophageal varices bleeding, therefore it can be more challenging to treat. The management of acute GV bleeding is similarly to the management of esophageal varices bleeding, and include antibiotic prophylaxis, management of euvolemic status and early use of vasoactive drugs[10,11]. The use of cyanoacrylate glue injection resulted in an high percentage of success (i.e., bleeding cessation)[60]. A small RCTs compared cyanoacrylate glue injection with EBL and ES and showed that cyanoacrylate injection is as effective as (or more than) ligation in acute bleeding[61,62]. Leaking of glue (4.4%), sepsis (1.3%), systemic embolism (2%-3%) represent the more common complications related to this treatment[63,64].

A new technique of treatment was introduced in last years, EUS-guided therapy of gastric fundal varices with a combination of cyanoacrylate glue and coil injection that reduced the risk of glue embolization. Coils act as a scaffold to sustain the cyanoacrylate glue within the varix and decrease the amount of glue injection. In a retrospective cohort study this technique was successful in all patients without procedure-related complications[65]. A recently study that compared the treatment of GV by using EUS-guided cyanoacrylate injection or EUS-guided coil application showed that both techniques are effective in the obliteration of localized GV. EUS-guided coil required fewer endoscopies and tended to have fewer adverse events compared with EUS-guided cyanoacrylate injection[66].

TIPS is considered in patients with hemorrhage from fundal varices that can’t be controlled or with bleeding that recurs despite the therapy[11]. Fibrin sealant (a solution of fibrinogen and thrombin) has been injected for arrest of variceal bleeding in small uncontrolled series[67,68]. Thrombin has been evaluated for use in endoscopic hemostasis of variceal bleeding. In 2 retrospective studies, thrombin achieved hemostasis in bleeding gastric varices in 75% to 94%[69,70].

Secondary prophylaxis

Cyanoacrylate injection is the most frequent treatment for secondary prophylaxis of GV[10]. Rebleeding rates after an acute GV bleeding episode treated with tissue adhesives range from 7%-65%[71]. After initial hemostasis with tissue adhesives, repeated sessions are performed from two to four weeks until is achieved the endoscopic obliteration. Two RCTs compared cyanoacrylate injection with variceal band ligation, showing that cyanoacrylate injection reduced the rebleeding rates[61,62]. Another study compared cyanoacrylate injection with sclerotherapy and showed a greater control of initial hemostasis and a lower rebleeding rates with cyanoacrylate[72]. TIPS is considered when patients show hemorrhage that can not be controlled or in whom bleeding recurs[11,73].

PHG

The prevalence of PHG, in patients with severe liver disease, ranges between the 11% and 80% and is a potential cause of bleeding[74]. PHG is classified as mild when the only change consists of a snakeskin mosaic pattern, and it is classified as severe when in addition to the mosaic pattern, flat or bulging red or black-brown spots are seen, and/or when there is active hemorrhage[75]. Acute bleeding from PHG is a rare event, with an incidence less than 3%, the incidence of chronic bleeding is around 10%-15%[76]. At the current time, there is not enough data to recommend primary prophylaxis of bleeding from PHG in cirrhotic patients[77].

In the case of acute haemorrhage are administered vasoactive drugs such as vasopressin and its analogue and terlipressin, this drugs are able to control haemorrhage[78-80]. In rare cases, the medical therapy is unable to control bleeding and in this cases limited data suggests the endoscopic thermal therapy[81]. Moreover TIPS is employed in the treatment of PHG with improvement of both mild and severe forms and reduction in endoscopic severity as well as transfusion requirement[82]. Recently haemostatic powder (Hemospray) has been evaluated in patients with acute bleeding due to PHG. This haemostatic powder, which acts by forming a barrier over them bleeding site and enhancing the concentration of clotting factors, was successfully used in four patients actively bleeding from PHG[83]. In patients who have previously experienced clinically significant GI blood loss, NSBBs should be used for prevention of recurrent bleeding[10].

GASTRIC ANTRAL VASCULAR ECTASIA

Gastric antral vascular ectasia (GAVE) is a disorder of the stomach that is characterized by the presence of dilated and fragile blood vessels. In patients with cirrhosis GAVE is less detected compared to PHG[84,85]. There are 2 types of GAVE based on distinctive endoscopic appearances. The classic manifestation consists of appearance of multiple flat, linear, erythematous strips of ectatic vessels radiating from the pylorus to the antrum. The second type is punctate, with punctate red spots scattered throughout the antrum and tends to be more associated with liver cirrhosis[86]. It is reasonable to not treat GAVE lesions that are asymptomatic[77]. Neodymium-yttrium-aluminum garnet laser coagulation is used to control GAVE-related bleeding, in fact is able to reduce the need of blood transfusions in 50%-80% of cases. The disadvantages of this technique are the high cost and the need of a long training period[87-89].

Argon plasma coagulation (APC) is a thermoablative method, which produces thermal coagulation by the use of electric current with high frequency that is passed through with argon gas without contact with the mucosa. APC treatment have an efficacy ranging from 90% to 100%, without the need of blood transfusions with an increase of hemoglobin level in most patients[90,91]. The most frequently complication of APC treatment is the intestinal gas distension, more serious adverse events are antral stenosis and upper GI hemorrhage[91]. Argon plasma coagulation is frequently associated with recurrence of bleeding in 30%-60% of cases, in the medium to long term period[91,92]. The use of EBL has been recently demonstrated for GAVE treatment[93].

EBL may more reliably obliterate vascular structures in the deep mucosa and submucosa, thus reducing the need for further treatments. Ligation bands are applied to abnormal-appearing mucosa in the antrum. First is treated the distal antrum, after the ligation bands are applied more proximally until most of the abnormal mucosa is treated. Wells et al[93], in a retrospective study, found that EBL reduced recurrent bleeding and required less treatment sessions and hospital admissions compared to APC treatment[93]. This finding is in accordance with other two studies[94,95].

Recently studies examined the use of radiofrequency ablation (RFA) for the treatment of GAVE[96,97]. These two studies suggests that endoscopic mucosal ablation by using the RFA with HALO system is a viable option for the treatment of chronic bleeding related to GAVE[96,97]. Additional therapy for GAVE includes cryotherapy, cyanoacrylate spray and surgical antrectomy[98-101].

ECTOPIC VARICES

Ectopic varices are those varices which are not located in the gastro-esophageal area, are less common and occur in different sites, such as in the jejunum or ileum (18%),in the duodenum (17%) or in the colon (14%), in the rectum (8%), and finally in the peritoneum (9%)[102,103].

Duodenal varices

Duodenal varices (DV) were reported to be the second cause of ectopic variceal bleeding after the rectal location[104]. They are most commonly noted in the duodenal bulb followed by the second part of the duodenum[102,104]. Bleeding due to DV is usually massive, with a mortality rate around the 40% at the first episode[105,106]. Different sclerosant agents are used for endoscopic injection therapy, for example Seo et al[107] have been shown how bleeding duodenal varices can be eradicated with injection of ethanolamine. Liu et al[106] in a five-year retrospective study reported the successful treatment with cyanoacrylate injection in 4 patients with bleeding due to DV. Some authors have reported also the successful EBL of DV bleeding[108-110]. If rebleeding occur after endoscopic therapy, and TIPS are used as rescue therapy with good results[111,112].

Small-bowel varices

An uncommon, difficult to treat and sometimes fatal manifestation of portal hypertension is the hemorrhage associated with small-bowel varices. In fact, 8.1% of patients with portal hypertension who underwent to capsule endoscopy present small-bowel varices[113]. When the terminal ileum is intubated on colonoscopy the 18% of patients with portal hypertension, present terminal ileal varices[114]. Double-balloon enteroscopy (DBE) allows to display whole small bowel and perform endoscopic surgeries in patients with bleeding small-bowel varices. Enteroscopic and colonscopic sclerotherapy of jejunal and ileal varices has been described[115-118]. TIPS is the first line treatment for refractory variceal bleeding[119].

Colonic varices

The most common sites of colonic varices are the rectum and cecum[105]. The rate of colonic variceal bleeding in liver cirrhosis is approximately 1%-8%[120]. Several interventional therapies like endoscopic variceal ligation, glue injection, TIPS, BRTO, colonic resection have been reported[121-126].

Rectal varices

Rectal varices are one of the most important causes of bleeding in portal hypertension, they occur in 44% to 89% of cirrhosis[127-129]. The endoscopic options for treatment of rectal varices are injection therapies using sclerosants or cyanoacrylate glue and band ligation[130-133]. Recently EUS-guided approach has been used in management of rectal varices. The advantages to use EUS-guided therapy are different and include the ability to treat directly the varix and visualize deeper collateral vessels. The EUS-guided therapy with sclerosant or coil embolization showed good results[134-136].

PORTAL HYPERTENSIVE BILIOPATHY

Portal hypertensive biliopathy (PHB) is an abnormalities of all biliary tract including intra-hepatic and extra-hepatic bile ducts, cystic duct and gallbladder. The frequency of PHB in patients with extra-hepatic portal venous obstruction (EHPVO), is greater respect to patients with cirrhosis[137]. EUS could be useful in patients with cirrhosis to identify CBD varices or bile duct stones[138].

The extraction of CBD stones by endoscopic sphincterotomy is the normally treatment applied in patients with CBD stones. Endoscopic treatment is the best treatment for patients with dominant biliary stricture, but without a shuntable vein. Porto-systemic shunt is performed in patients with dominant biliary strictures with a shuntable vein[139,140].

PORTAL HYPERTENSIVE ENTEROPATHY

Portal hypertensive enteropathy (PHE) is defined as the presence of several red spots like arterovenous malformations, patchy hyperemia of the mucosa, diffuse mucosal edema, spontaneous bleeding from the mucosa or small bowel varices[141-143]. Due to the difficult access to the small bowel, in the past the diagnosis of PHE was very difficult, but with the introduction of capsule endoscopy and DBE, PHE seems more common and has been seen that in cirrhotic patients may cause chronic GI bleeding with portal hypertension[144,145]. PHG is mostly asymptomatic, although it may bleed acutely leading to hematemesis and/or melena.

PORTAL HYPERTENSIVE COLOPATHY

Portal hypertensive colopathy (PHC) is characterized by erythema of the colonic mucosa and vascular lesions including telangiectasias, cherry-red spots and angiodysplasia-like lesions. The prevalence of PHC in patients with cirrhosis ranging between 25%-70%[146-148]. Portal hypertension seems to play an important role, and there is an association with a hyperkinetic circulatory state[149]. Lower GI bleeding due to PHC is estimated up to 9%[150-152]. In patients with chronic lower GI bleeding secondary to PHC, as reported the treatment with NSBBs is effective[153]. In patients with acute bleeding, vasoactive medications, such as octreotide or terlipressin, could be effective[153]. TIPS has been used as a rescue therapy in patients with refractory GI bleeding[154].