135

found that when propranolol was tapered off, the risk of variceal hemorrhage

increased from 4% (while on propranolol therapy) to 24% (after propranolol

withdrawal), and was comparable to the risk of bleeding in an untreated population

(22% in the placebo group from the previous study). Importantly, patients who

abruptly discontinued β-blockers experienced increased mortality compared with the

untreated population (48% vs. 21%; p < 0.05).

135 Therefore, avoiding sudden

discontinuation of β-blockers in this population is essential.

The AASLD/ACG guidelines recommend nonselective β-blockers for primary

prophylaxis in patients with small varices that have not bled, but are at increased risk

of hemorrhage (Child–Turcotte–Pugh class B or C or presence of red wale marks on

varices). Patients with medium or large varices that have not bled but are at a high

risk of hemorrhage (Child–Turcotte–Pugh class B or C or variceal red wale markings

on endoscopy), nonselective β-blockers or EVL may be recommended. In contrast,

patients with medium or large varices that have not bled and are not at the highest

risk of hemorrhage (Child–Turcotte–Pugh class A patients and no red signs),

nonselective β-blockers are preferred and EVL should be considered in patients with

contraindications, intolerance, or noncompliance to β-blockers. The β-blocker should

be titrated to the maximal tolerated dose.

92

Isosorbide-5-Mononitrate

Isosorbide-5-mononitrate monotherapy for primary prophylaxis for variceal

hemorrhage has not proven to be effective.

136,137 Garcia-Pagan et al.

137 conducted a

prospective, multicenter, double-blind, randomized, controlled trial evaluating

whether isosorbide-5-mononitrate prevented variceal bleeding in cirrhotic patients

with gastroesophageal varices, who had contraindications or could not tolerate βblockers. Patients received isosorbide-5-mononitrate or placebo. No significant

differences were noted in the 1- and 2-year actuarial probability of bleeding or

survival between the two treatment groups.

137

When combined with a β-blocker, isosorbide-5-mononitrate caused a greater

reduction in the hepatic venous pressure gradient than propranolol alone.

138 Merkel et

al.

139 examined the value of combining nadolol and isosorbide-5-mononitrate for

primary prevention of variceal bleeding. Patients in the nadolol monotherapy group

received between 40 and 160 mg/day titrated to achieve a 20% to 25% decrease in

resting heart rate. Patients in the combination group received nadolol and isosorbide5-mononitrate 10 to 20 mg orally BID. The overall risk of variceal bleeding was

18% in the nadolol group compared with 7.5% in the combined treatment group (p =

0.03). However, a higher number of patients had to be withdrawn from the

combination therapy group compared with the nadolol monotherapy group (eight vs.

four patients) because of side effects.

139 The AASLD and ACG guidelines suggest

that nitrates (either alone or in combination with β-blockers), shunt therapy, or

sclerotherapy should not be used in the primary prophylaxis of variceal

hemorrhage.

92

Depending on the size of C.V.’s varices on endoscopy and the risk of hemorrhage,

C.V. should have been given propranolol 10 mg 3 times a day or nadolol 20 mg daily

titrated to reduce the resting heart rate to 55 to 60 beats/minute (or by 25%), or EVL

to prevent or delay the first episode of variceal bleeding.

SECONDARY PROPHYLAXIS

CASE 25-2, QUESTION 6: C.V.’s hepatologist would like to start treatment to prevent further variceal

hemorrhage. What are the long-term objectives for the treatment of C.V.? What treatment approaches can be

used to prevent a recurrence of bleeding (secondary prevention)?

Secondary prevention or secondary prophylaxis is when therapy is used to prevent

re-bleeding once it has occurred. All patients who survive a variceal bleeding

episode should receive therapy to prevent recurrent episodes. It is important that the

initiation of β-blockers be delayed until after recovery of the initial variceal

hemorrhage. Initiation of a β-blocker during the treatment of an acute bleed would

block the patient’s acute tachycardia in response to his or her hypotension, which

may adversely impact survival. The benefit of nonselective β-blockers in the

prevention of re-bleeding episodes has been demonstrated by a number of

trials.

113,140,141 For example, Colombo et al.

140

randomized cirrhotic patients with a

history of variceal hemorrhage to propranolol, atenolol, or placebo. Oral

propranolol was titrated until the resting pulse rate was reduced by ~25%, and

atenolol was given at a fixed dose of 100 mg daily. The incidence of re-bleeding was

significantly lower in patients receiving propranolol than those receiving placebo (p

= 0.01). Bleeding-free survival was higher for patients on active drugs than for those

on placebo (propranolol vs. placebo, p = 0.01; atenolol vs. placebo, p = 0.05).

140

Eradication of varices by endoscopic procedures is also effective in preventing

recurrent variceal bleeding.

15,141 A study by de la Pena et al.

141 showed that nadolol

plus EVL (n = 43) reduced the incidence of variceal re-bleeding compared with EVL

alone (n = 37). Variceal bleeding recurrence rate was 14% in the EVL plus nadolol

group and 38% in the EVL alone group (p = 0.006). Mortality was similar in both

groups and the actuarial probability of variceal recurrence at 1 year was lower in the

EVL plus nadolol group than in the EVL alone group (54% vs. 77%; p = 0.06). The

adverse effects in the β-blocker group were higher, and led to the withdrawal of 20%

to 30% of the patients.

141

A meta-analysis of randomized trials

142

reported that compared with EVL alone,

EVL combined with β-blockers ± isosorbide mononitrate reduced overall rebleeding (32% vs. 17%, respectively; p < 0.01) with no significant difference in

mortality or complications. When comparing drug therapy alone to combination

therapy with EVL and β-blockers ± isosorbide mononitrate, combination therapy

showed a trend toward lower re-bleeding (29% vs. 37%, respectively; NS), but no

effect on mortality. Combination therapy

p. 550

p. 551

with EVL plus β-blockers ± isosorbide mononitrate is effective in preventing rebleeding. Drug therapy alone is an alternative.

142

TIPS is an option for those patients who fail both EVL and prophylaxis with βblocker therapy. In a randomized study of Child–Turcotte–Pugh class B and C

cirrhotic patients surviving their first episode of variceal hemorrhage, Escorsell et

al.

143

reported a lower rate of re-bleeding (13% vs. 39%; p = 0.007) and higher rate

of encephalopathy (38% vs. 14%, p = 0.007) in patients treated with TIPS versus

those treated with the combination of propranolol and isosorbide-5-mononitrate. The

2-year re-bleeding probability was also lower in the TIPS group (13% vs. 49%; p =

0.01). Of note, drug therapy improved the Child–Turcotte–Pugh class more frequently

than with TIPS (72% vs. 45%; p = 0.04) and at lower costs.

143

The AASLD/ACG guidelines suggest the use of a combination of nonselective βblockers plus EVL for secondary prophylaxis. TIPS should be considered in patients

who are Child–Turcotte–Pugh class A or B who experience recurrent variceal

hemorrhage despite combination pharmacological and endoscopic therapy.

86,92

Since C.V. has a history of recurrent upper GI bleeding, the best option to prevent

further bleeding is to initiate a nonselective β-blocker and begin EVL. The β-blocker

should be titrated to reduce the resting heart rate to 55 to 60 beats/minute or by 25%.

EVL should be repeated every 1 to 2 weeks until obliteration with a repeat

endoscopy performed 1 to 3 months after obliteration and then every 6 to 12 months

to check for variceal recurrence.

92

If this combination fails to prevent variceal

hemorrhage, then TIPS would be considered as a therapeutic option.

86

HEPATIC ENCEPHALOPATHY

CASE 25-3

QUESTION 1: R.C., a 57-year-old man, was admitted to the hospital because of nausea, vomiting, and

abdominal pain. He had a long history of alcohol abuse, with multiple hospital admissions for alcoholic gastritis

and alcohol withdrawal. Physical examination revealed a cachectic male patient (weighing 55 kg) with clouded

mentation, who was not responsive to questions about name and place. Tense ascites and edema were noted,

and the liver was percussed at 9 cm below the right costal margin. The spleen was not palpated, and no active

bowelsounds were heard. Laboratory results on admission included the following:

Na, 132 mEq/L

K, 3.7 mEq/L

Cl, 98 mEq/L

Bicarbonate, 27 mEq/L

BUN, 24 mg/dL

SCr, 1.4 mg/dL

Hgb, 9.2 g/dL

Hct, 24.1%

AST, 520 IU

Alkaline phosphatase, 218 IU

Lactate dehydrogenase (LDH), 305 IU

Total bilirubin, 3.5 mg/dL

PT, 22 seconds (INR, 1.8)

A 70-g protein, 2,000-kcal diet was ordered. Furosemide 40 mg IV every 12 hours was ordered in an attempt

to reduce the edema and ascites. Morphine sulfate and prochlorperazine were ordered for his abdominal pain

and nausea, respectively. Two days after admission, R.C. had an episode of hematemesis. He became mentally

confused and at times nonresponsive to verbal command. An NG tube was inserted and coffee-ground material

was produced on continuous suctioning. Saline lavage was continued until the aspirate became clear. The next

morning, R.C. was still in a confused mental state. He demonstrated prominent asterixis, and fetor hepaticus

was noted on his breath. On the second day of his hospitalization, laboratory data were as follows:

Hgb, 7.4 g/dL

Hct, 21.2%

K, 3.1 mEq/L

SCr, 1.4 mg/dL

BUN, 36 mg/dL

PT, 22 seconds (INR, 1.8)

Guaiac positive stool

Hepatic encephalopathy and upper GI bleeding were added to his problem list.

What aspects of R.C.’s history are compatible with a diagnosis of hepatic encephalopathy? What

classification of hepatic encephalopathy does he fall into?

Hepatic encephalopathy (HE) is a spectrum of central nervous system (CNS)

abnormalities ranging from subclinical alterations to coma and caused by advanced

liver disease and/or portosystemic shunting of blood. According to the guidelines by

the American Association for the Study of Liver Diseases (AALSD) and the

European Association for the Study of the Liver (EASL) for HE in Chronic Liver

Disease, HE is classified according to four criteria: (1) underlying disease (Acute

Liver Failure [Type A]; resulting from portosystemic bypass or shunting [Type B];

from cirrhosis [Type C]), (2) severity of manifestations, (3) according to time course

(episodic, recurrent, or persistent HE), and (4) according to precipitating factors

(nonprecipitated or precipitated).

144

The gold standard to measure the severity of HE is by the West Haven Criteria

(WHC), and patients with significant altered consciousness by the Glasgow Coma

Scale (GCS). For more detail on WHC criteria and GCS, please refer to the

AASLD/EASL 2014 guidelines at aasld.org

(https://www.aasld.org/sites/default/files/guideline_documents/141022_AASLD_GuideliThe ISHEN (International Society for Hepatic Encephalopathy and Nitrogen

Metabolism) consensus classifies patients as having Minimal Hepatic

Encephalopathy (MHE) and Grade I hepatic encephalopathy (WHC) as Covert

Hepatic Encephalopathy (CHE), whereas those with apparent clinical abnormalities

as Overt Hepatic Encephalopathy (OHE). The ISHEN consensus defines the onset of

disorientation or asterixis as the onset of OHE.

145 This chapter will focus on the

treatment of OHE in cirrhosis.

During the early phase of HE, the altered mental state may present as a slight

derangement of judgment, and change in personality, sleep pattern, or mood.

Drowsiness and confusion become more prominent as the HE progresses. Finally,

unresponsiveness to arousal and deep coma ensue. Asterixis, or flapping tremor, is

often present in the early to middle stages of HE that precede stupor or coma.