The adult survivor with variceal bleeding

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Abbreviations

bid

twice daily

EBL

endoscopic band ligation

i.v.

intravenously

NSBB

non-selective beta-receptor blocker or blockade

TIPS

transjugular intrahepatic portosystemic shunt

The Young Adult With Portal Hypertension and Varices

Portal hypertension complicated by variceal bleeding is a rare condition in young adults, but it is a frequent problem faced in transition clinics. These patients have some features that differentiate them from typical patients seen in adult liver clinics:

• The etiology of portal hypertension in pediatric and transitional patients is different than in adults. A substantial proportion are biliary atresia patients surviving with their native liver.1 In addition, noncirrhotic portal hypertension (mainly extrahepatic portal vein obstruction) is a much more common cause of portal hypertension in surviving pediatric liver patients than in adults. This is relevant because mortality from variceal bleeding is around 15% to 20% in patients with cirrhosis but is negligible in patients with noncirrhotic portal hypertension. This should be considered when assessing the trade‐offs of aggressive therapeutic options such as surgical shunts.

• The management of varices and variceal bleeding is different in pediatric patients than in adults. Firstly, it is important to note that the age for transition varies between centers, regions, and countries from 15 years of age to 21 years of age. Therefore, proposed interventions need to be tailored accordingly. Primary prophylaxis of variceal bleeding, either with endoscopic variceal ligation or with nonselective beta‐blockers (NSBB), is not recommended in children.2 Even after a variceal bleed, NSBBs are seldom used because there is a lack of information on dosing, efficacy, and safety of these drugs in children. Thus, many of these patients need to be started on prophylaxis for the first time in the transition clinic. Another specific feature is that surgical treatments for portal hypertension are now rarely seen in adults, but they are more common in pediatric patients. These include portosystemic shunts (mainly splenorenal shunts) or meso‐Rex bypass3 (in certain cases of extrahepatic portal vein obstruction). There are no standardized recommendations for the follow‐up of these patients, but they might benefit from surveillance of the patency of the shunts and, in the case of portosystemic shunts, surveillance for complications such as hepatic encephalopathy, hepatopulmonary syndrome, or portopulmonary hypertension.

• Evidence to guide the management of these patients is scarce. Young adults have been markedly underrepresented in randomized trials for varices; therefore, therapeutic decisions are based on extrapolations from data in older populations. Fundamentally, the physiology of an adolescent who is completing or has completed puberty approximates an adult; thus, the management strategies should not be different. However, concrete evidence to support this extrapolation is not available.

• Finally, the abrupt termination of parental involvement and transfer of sole responsibility for decision-making to the young adult undergoing transition from pediatric to adult care may not be well received, resulting in a greater risk that appropriate recommendations will not be followed. The patient's readiness for transition needs to be assessed.4

We will focus this review on the management of the young adult with esophageal varices and variceal bleeding. The management of gastric and ectopic varices have been recently reviewed elsewhere.5

Screening for Varices

Endoscopic screening is underused in children with portal hypertension because there are no definitive recommendations for primary prophylaxis.2 In adults, the current recommendation is to screen with endoscopy all patients with suspected portal hypertension. If no varices are found, endoscopy should be repeated in 2 to 3 years.

Primary Prevention of Esophageal Variceal Bleeding

Most data in the natural history and management of varices come from studies in adults with cirrhosis. This approach can be generalized in most cases to patients with noncirrhotic portal hypertension.

The risk of variceal bleeding is significant in patients with large varices or in patients with small varices who have high‐risk indicators (Child‐Pugh class C disease or red color signs on the varices). In these patients, prophyllaxis to prevent a first bleed is recommended. NSBBs and endoscopic band ligation (EBL) are the two available therapeutic options for primary prophylaxis in patients with large varices. In patients with small varices who require prophylaxis (high‐risk features), therapy with NSBBs is recommended.6 Despite the lack of evidence to support this extrapolation, the primary prevention of esophageal variceal bleeding in mid‐ to late adolescence need not be any different from adults.

Pharmacological Therapy

As compared to placebo, NSBBs (propranolol or nadolol) reduce the risk of first variceal bleeding and mortality in patients with large varices.7 Promising data suggests that the NSBB/anti‐alpha–adrenergic agent carvedilol may be a superior option for primary prophylaxis.8 NSBB‐associated side effects (hypotension, tiredness, breathlessness, poor memory, insomnia, impotence) have a major impact in a young population and may result in a lack of compliance, which is a major issue in transition clinics. Most of these symptoms improve by adjusting the dose, but they commonly lead to discontinuation of the medication.

Endoscopic Band Ligation

When EBL is compared to NSBB, meta‐analysis of available data suggests that EBL is superior to NSBB in reducing the occurrence of first variceal hemorrhage, with no differences in mortality.9 The strength of the conclusion that EBL is superior to NSBB, however, is significantly limited by the quality of the trials included in the analysis (Fig 1). The main adverse effect of EBL is bleeding induced by postbanding ulcers. Moreover, varices frequently reappear, needing re‐eradication. This means that patients require long‐term endoscopic surveillance every 6 to 12 months.

Figure 1.

Meta‐analysis of randomized controlled trials comparing endoscopic band ligation (EBL) with beta‐adrenergic blockers in the prevention of first variceal bleeding stratified according to trial size and publication status. No differences in the risk of bleeding could be demonstrated in full‐published trials with large sample size (over 100 patients). ##Carvedilol was used as beta‐blocker.

Current guidelines recommend either NSBB or banding ligation for patients with large varices.6 Patient's preferences and local resources should guide the therapeutic choice. There is little information in the literature on the long‐term effects of EBL, whereas the long‐term benefits of NSBB are well‐established.10 This might favor the choice of NSBB in young patients with a long life expectancy.

When Prophylaxis Fails: The Acute Bleeding Episode

Patients with acute variceal bleeding should be managed in an intensive care setting by a multidisciplinary team. The initial therapy should include hemodynamic resuscitation, vasoconstrictor therapy, antibiotics, and endoscopic hemostasis (Fig. 2).

Figure 2.

Summary of the recommendations for the initial management of acute variceal bleeding. bid, twice daily; i.v., intravenously.

General Management

Blood volume replacement should be initiated as soon as possible with plasma volume expanders, aiming to maintain the systolic blood pressure around 100 mmHg. Blood transfusion should follow a restrictive strategy targeting a hemoglobin of 7.0 mg/dL, except in patients with rapid ongoing bleeding or with ischemic heart disease.11 The use of 5 to 7 days of prophylactic antibiotics (i.v. quinolones or ceftriaxone) reduces the risk of mortality, bacterial infection, rebleeding, and duration of stay in hospital.12

Specific Therapy for Control of Bleeding

The combination of vasoactive drugs and endoscopic therapy is superior to either drug or endoscopy alone in the control of bleeding and the incidence of 5‐day rebleeding.13 Vasoactive drug therapy should be started as soon as possible. The selection of the vasoactive drug depends on local availability. Terlipressin, somatostatin, octreotide, or vapreotide are acceptable options. The current recommendation is to maintain the drug for 2 to 5 days.6 EBL is the endoscopic therapy of choice for the initial control of bleeding because it is associated with less adverse events and less mortality than sclerotherapy.

Management of Treatment Failures

In 10% to 20% of patients, variceal bleeding is unresponsive to initial treatment. In these cases, the patient should be offered a derivative treatment. Balloon tamponade should only be used in the case of a massive bleeding, for a short period of time (less than 24 hours) as a temporal bridge until definite treatment is instituted. Esophageal‐covered stents might be an alternative to balloon tamponade, with less severe complications despite longer periods of treatment.14

Both TIPS and surgical shunts are extremely effective rescue treatments.15 TIPS is first choice in patients with advanced liver disease. TIPS might be impossible in patients with complete portal vein thrombosis, especially in those with cavernous transformation of the portal vein. In these cases, a careful radiological assessment of the splanchnic vessels should inform the feasibility of splenorenal or mesocaval surgical shunts. The more physiological meso‐Rex bypass3 is the surgical treatment of choice in children with portal vein thrombosis and a patent intrahepatic left portal vein, but it has been seldom used after puberty. Overall, the good prognosis of variceal bleeding in noncirrhotic patients should be weighed in the decision to proceed with aggressive surgical treatments.

Stratified Approach to Acute Variceal Bleeding

Recent data suggest that early treatment with TIPS in high‐risk patients such as Child‐Turcotte‐Pugh (CTP) class C patients or CTP class B patients with active variceal bleeding has significantly less treatment failure and lower mortality than patients undergoing standard therapy.16 However, further data are needed to clarify the subgroup of patients who might benefit the most from this stratified approach that is logistically demanding in a real‐life setting.

Secondary Prophylaxis: Prevention of Recurrent Bleeding From Esophageal Varices

Secondary prophylaxis should start as soon as possible from day 6 of the index variceal bleed. Without it, patients have a 60% risk of experiencing recurrent hemorrhage within 2 years.6 NSBBs are the mainstay of pharmacological therapy and should be titrated to maximal tolerance. Alone, they reduce rebleeding rates and mortality. The addition of nitrates to NSBB further enhances portal pressure reduction but is poorly tolerated and not commonly utilized. EBL is the endoscopic treatment of choice, superior to sclerotherapy. EBL should be repeated every 1 to 2 weeks until variceal obliteration, then carried out in 1 to 3 months and every 6 to 12 months to evaluate for recurrence.17

The combination of NSBBs and EBL is more effective than either therapy alone.18 As compared to monotherapy, combination therapy decreases rebleeding (relative risk 0.68) and bleeding‐related mortality (relative risk 0.52). Patients who rebleed despite combination therapy, especially those with a major rebleed, should be considered for derivative therapy (TIPS if feasible, or a surgical shunt). Patients with poor liver function should be evaluated for liver transplantation.