633

C HAP T E R

39 Portal Hypertension and Cirrhosis

JULIE M. SEASE, EDWARD G. TIMM, AND JAMES J. STRAGAND

on three criteria: diffuse disease, presence of fibrosis, and replacement

KEY CONCEPTS of normal liver architecture by abnormal nodules.3 As fibrotic tissue
replaces normal hepatic parenchyma, resistance to blood flow results
 Cirrhosis is a severe, chronic, irreversible disease associated in the clinical problems of portal hypertension and the development of
with significant morbidity and mortality. However, the progres- varices and ascites. Hepatocyte loss and intrahepatic shunting of blood
sion of cirrhosis secondary to alcohol abuse can be interrupted result in diminished metabolic and synthetic function which leads to
by abstinence. Consequently, it is imperative for the clinician to hepatic encephalopathy and coagulopathy.
educate and support abstinence from alcohol as part of the  While cirrhosis has many causes (Table 39–1), in the United
overall treatment strategy of the underlying liver disease. States, excessive alcohol intake and hepatitis B and C are the most
 Patients with cirrhosis and portal hypertension should be consid- common causes.1,3 This chapter elucidates the pathophysiology of
ered for endoscopic screening and patients with varices should cirrhosis and the resultant effects on human anatomy and physiology.
receive primary prophylaxis with β-adrenergic blockade therapy. Treatment strategies for managing the most commonly encountered
clinical complications of cirrhosis are discussed.
 When nonselective β-adrenergic blocker therapy is used to pre-
vent rebleeding, it is essential that the dose be titrated to
achieve a heart rate goal of 60 beats per minute (beats/min) EPIDEMIOLOGY
or a heart rate that is 25% lower than the baseline heart rate.
The exact prevalence of cirrhosis is unknown, with nearly 30% to
 Octreotide is the preferred vasoactive agent employed in the 40% of diagnoses being made on autopsy.3 Cirrhosis is responsible for
medical management of variceal bleeding. Endoscopy employ- more than 26,000 deaths each year in America and chronic liver
ing endoscopic band ligation is the primary therapeutic tool in disease is currently ranked twelfth among the leading causes of death
the management of acute variceal bleeding. in the United States.4 Acute variceal bleeding and spontaneous bacte-
 The combination of spironolactone and furosemide is the rec- rial peritonitis are among the immediately life-threatening complica-
ommended initial diuretic therapy for patients with ascites. tions of cirrhosis. Associated conditions causing significant morbidity
include ascites and hepatic encephalopathy. Approximately 50% of
 All patients who have survived an episode of spontaneous bac- patients with cirrhosis develop ascites during 10 years of observation
terial peritonitis should receive long-term antibiotic prophylaxis. and half of the cirrhotic patients who develop ascites will die within 2
 The mainstay of therapy of hepatic encephalopathy involves years of diagnosis.5
therapy to lower blood ammonia concentrations, and includes
diet therapy, lactulose, and antibiotics alone or in combination PATHOPHYSIOLOGY OF CIRRHOSIS
with lactulose.
Any discussion of cirrhosis must be based on a firm understanding
of hepatic anatomy and vascular supply. Conceptually, the liver can
Chronic liver disease and exposure to hepatotoxic substances causes be thought of as an elaborate blood filtration system receiving blood
damage to normal liver tissue resulting in an inflammatory response from the hepatic artery and the portal vein (Fig. 39–1) with portal
and abnormal collagen secretion. The initial result of this inflamma- blood originating from the mesenteric, gastric, splenic, and pancre-
tion and collagen secretion is hepatic fibrosis.1 Fibrosis, defined as the atic veins. Blood enters the liver via the portal triad which contains
excessive accumulation of proteins, such as collagen, in the liver’s branches of the portal vein and hepatic artery, bile ducts, and
extracellular matrix, is currently considered a wound-healing response lymphatic and nerve tissue. It then drains through the sinusoidal
to chronic liver injury. If fibrotic liver disease advances, collagen bands spaces of the hepatic lobule (Fig. 39–2), which are lined by the
progress to bridging fibrosis and eventually frank hepatic cirrhosis.2 workhorses of the liver, the hepatocytes. Individual hepatocytes are
The word cirrhosis is derived from the Greek kirrhos, meaning orange- arranged in plates 1 cell thick, expanding from the portal veins to the
colored, and refers to the yellow-orange hue of the cirrhotic liver seen terminal hepatic venules. The six or more surfaces of each individual
by the pathologist or surgeon. Cirrhosis is defined histologically based hepatocyte either make contact with adjacent hepatocytes, border
the bile canaliculi, or are exposed to the sinusoidal space. Filtered
blood travels into the terminal hepatic venules, also called central
Learning objectives, review questions, veins, and then empties into larger hepatic veins and eventually into
and other resources can be found at the inferior vena cava. The hepatic lobule can be subdivided into
www.pharmacotherapyonline.com. three functional zones based on relative oxygen supply. The hepatic
artery supplies oxygen-rich blood to the portal triad. Hepatocytes at

Copyright © 2008, 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
 634

TABLE 39-1 Etiology of Cirrhosis

Inferior vena cava
Hepatic vein
SECTION 4

Chronic alcohol consumption

Chronic viral hepatitis (types B, C, and D) Left
Metabolic liver disease Liver gastric vein
Hemochromatosis
Wilson disease Stomach
α1-Antitrypsin deficiency
Nonalcoholic steatohepatitis (“fatty liver”)
Cholestatic liver diseases
Primary biliary cirrhosis
Gastrointestinal Disorders

Secondary biliary cirrhosis (possible causes: gallstones, strictures, parasitic infection)

Primary sclerosing cholangitis (associated with ulcerative colitis and cholangio- Portal
carcinoma) vein
Budd-Chiari syndrome
Splenic vein
Severe congestive heart failure and constrictive pericarditis
Inferior vena cava Spleen
Drugs and herbals
Isoniazid, methyldopa, amiodarone, methotrexate, phenothiazine, estrogen, Left renal vein
Right renal vein
anabolic steroids, black cohosh, Jamaican bush tea

Inferior
the periphery therefore receive a higher level of oxygen than the cells
mesenteric vein
near the terminal hepatic venules.6 Superior
mesenteric vein
In areas of hepatocellular injury, regardless of the nature of the
inciting agent, hepatic stellate cells undergo an abnormal transfor-
mation. Stellate cells normally reside in the sinusoidal space and are
involved in the storage of retinoids like vitamin A. However, when
hepatic injury occurs, stellate cells in the affected areas begin to
resemble fibroblasts, express contractile proteins, and become a
major source of collagen and other matrix proteins that proliferate FIGURE 39-1. The portal venous system.

Hepatic cell
Hepatocytes
Liver
Lymph vessel lobule

3 Terminal
1 2 hepatic
Sinusoid venule

Portal vein Portal vein

Bile duct
Hepatic artery Hepatic artery

Bile duct

Terminal hepatic venule

FIGURE 39-2. The hepatic lobule. 1, 2, and 3 indicate thte three functional zones based on relative oxygen supply (1 being the highest).
 635
during fibrosis, eventually causing the permanent hepatic scarring
Cirrhosis/
characteristic of cirrhosis.1 The progressive deposition of fibrous

CHAPTER 39
portal hypertension
material within the sinusoids disrupts the normal blood flow
through the hepatic lobule. Resistance to portal blood flow increases Nitric oxide
as fibrous tissue accumulates resulting in persistent and progressive
elevations in portal blood pressures or portal hypertension. Systemic/splanchnic vasodilation
Changes occur in cirrhosis to the vasodilatory and vasoconstrict-
ing mediators that regulate the hepatic sinusoidal blood flow. A Effective arterial blood volume

decrease in the production of nitric oxide, which acts as a vasodila-

Activation of renin–angiotensin–aldosterone system
tor, and an increase in the levels of endogenous vasoconstrictors,

Portal Hypertension and Cirrhosis

such as endothelin, combine to increase the resistance to blood flow
through the sinusoidal space. Concurrently, there also appears to be Hyperdynamic circulation Sodium and water retention Renal vasoconstriction
an increase in the blood flow to the splanchnic vasculature through
a nitric oxide-mediated effect on the splanchnic arteriole.7,8 These Ascites
pathophysiologic changes mark the current and past targets of
pharmacologic therapy for the treatment of portal hypertension and
FIGURE 39-3. Pathogenesis of ascites.
prevention of variceal bleeding.
In summary, cirrhosis results in elevation of portal blood pres-
portal venous pressure is 12 mm Hg greater than vena cava pressure.7
sure because of fibrotic changes within the hepatic sinusoids,
Hemorrhage from varices occurs in 25% to 40% of patients with
changes in the levels of vasodilatory and vasoconstrictor mediators,
cirrhosis, and each episode of bleeding carries a 25% to 30% risk of
and an increase in blood flow to the splanchnic vasculature.
death.11 Rebleeding is common following initial hemorrhage, espe-
cially within the first 72 hours. More than 50% of recurrent bleeding
ANATOMIC AND PHYSIOLOGIC EFFECTS episodes occur within the first 10 days of the initial bleed and risk
OF CIRRHOSIS returns to baseline after 6 weeks.11 The risk of bleeding from esoph-
ageal varices is related to the tension on the variceal wall, which, in
Cirrhosis and the pathophysiologic abnormalities that cause it result turn, is related to portal vein pressure and, ultimately, to the degree of
in the commonly encountered problems of ascites, portal hyperten- cirrhosis.7 It should be apparent from this understanding that the
sion, esophageal varices, hepatic encephalopathy, and coagulation primary strategy for the treatment of esophageal varices is the reduc-
disorders. Other, less commonly seen problems in patients with tion of portal hypertension by pharmacologic and surgical approaches.
cirrhosis include hepatorenal syndrome, hepatopulmonary syn-
drome, and endocrine dysfunction. HEPATIC ENCEPHALOPATHY
Hepatic encephalopathy (HE) can be defined as a central nervous
ASCITES
system disturbance with a wide range of neuropsychiatric symptoms,
Ascites, from the Greek askos, meaning water bag or wineskin, is the and which is associated with hepatic insufficiency and liver failure.12,13
pathologic accumulation of lymph fluid within the peritoneal cavity. Symptoms of HE are thought to result from an accumulation of gut-
It is one of the earliest and most common presentations of cirrhosis.9 derived nitrogenous substances in the systemic circulation as a conse-
More than 50% of cirrhotic patients develop ascites within 10 years of quence of decreased hepatic functioning and shunting through porto-
diagnosis.5 The mechanism for the development of ascites is multifac- systemic collaterals bypassing the liver. Once these substances enter the
torial. Recent theory states that severe portal hypertension and hepatic central nervous system, they cause alterations of neurotransmission
insufficiency lead to splanchnic arterial vasodilation and decreased that affect consciousness and behavior.12 Ammonia is the most com-
peripheral resistance. The resulting systemic hypotension causes monly cited culprit in the pathogenesis of HE, but glutamate, benzo-
increased activity of the sympathetic nervous system and renin– diazepine receptor agonists, and manganese have also been recognized
angiotensin–aldosterone system, which causes increased sodium and as potential causes.12,13 Arterial ammonia levels are increased com-
water retention and vasoconstrictor production (Fig. 39–3). Although monly in both acute and chronic liver disease, but an established
vascular resistance is increased in most major vascular territories correlation between blood ammonia levels and mental status does not
(kidney, brain, skin, and muscle) by this increase in vasoconstrictor exist.12 Despite this, interventions to lower blood ammonia levels
release, the splanchnic vasculature does not seem to have the same remain the mainstay of treatment for HE.
response. Instead, splanchnic arterial dilation occurs and causes a HE is now categorized as type A, B, or C, based on nomenclature
rapid inflow of arterial blood into the liver and other splanchnic developed by the 11th World Congress of Gastroenterology. Type A
organs. Hydrostatic pressure increases leading to excessive splanchnic is HE induced by acute liver failure; type B is a result of portal–
lymph production and leakage. The leaked fluid accumulates in the systemic bypass without associated intrinsic liver disease; and type C
abdominal cavity, forming ascites, which is continuously perpetuated is HE that occurs in patients with cirrhosis. The duration and
by ongoing sodium and water retention by the kidneys.10 characteristics of HE are classified as episodic, persistent, and mini-
mal. Episodic HE occurs spontaneously or is precipitated by a clinical
PORTAL HYPERTENSION AND VARICES factor, such as gastrointestinal bleeding. Recurrent HE is defined by
two episodes of spontaneous or precipitated HE occurring within 1
The most important clinical sequelae of portal hypertension are the year, and the hallmark of persistent HE is chronic cognitive deficits
development of varices or alternative routes of blood flow from the that decrease a patient’s quality of life. Minimal HE refers to cirrhotic
portal to the systemic circulation, bypassing the liver (see Fig. 39–1). patients who do not suffer clinically overt cognitive dysfunction, but
Varices decompress the portal venous system and return blood to the who are found to have cognitive impairment on psychological stud-
systemic circulation. Varices can occur at any level of the gastrointes- ies.13 HE associated with chronic liver failure has a gradual onset, is
tinal tract; however, the route with the most clinical significance is commonly associated with known precipitating factors, and has a
through the left gastric vein with the development of esophageal poor prognosis with the need for long-term treatment of the under-
varices. Patients with cirrhosis are at risk for variceal bleeding when lying liver disease.12
 636

COAGULATION DEFECTS LABORATORY ABNORMALITIES

SECTION 4

Complex coagulation derangements can occur in cirrhosis. These There are no laboratory or radiographic tests of hepatic function
defects include a reduction in the synthesis of clotting factors, exces- despite the commonly ordered liver function tests. These commonly
sive fibrinolysis, disseminated intravascular coagulation, thrombocy- measured markers are substances produced by the liver and released
topenia, and platelet dysfunction. Vitamin K-dependent clotting into the bloodstream during hepatocellular injury, and are more
factors, including factor VII, are affected early and occur with suffi- correctly termed liver dysfunction tests. True liver function tests that
cient frequency and rapidity that the prothrombin time is a standard assess the ability of the liver to eliminate substances that undergo
component of the Child-Pugh scoring system discussed in the follow- hepatic metabolism, such as the 14C-aminopyrine breath test, are
ing section. In fact, a reduction in clotting factor VII is so common in limited by complexity and availability.
end-stage liver disease that it affects 75% to 85% of patients.14 The
Gastrointestinal Disorders

Routine liver tests include alkaline phosphatase, bilirubin, aspar-

presence of activated clotting factors in cirrhosis creates a low-grade tate transaminase (AST), alanine transaminase (ALT), and γ-glutamyl
disseminated intravascular coagulation-like state with fibrinolysis. In transpeptidase (GGT). Additional markers of hepatic synthetic activ-
addition, the portal hypertension of cirrhosis is accompanied by a ity include albumin and prothrombin time. Liver function tests are
qualitative and quantitative reduction in platelets with mild to mod- often the first step in the evaluation of patients who present with
erate thrombocytopenia occurring in 49% to 64% of patients with symptoms or signs suggestive of cirrhosis. Liver function tests are
end-stage liver disease.14 The net effect of these events is the develop- typically elevated in chronic inflammatory liver disease such as
ment of bleeding diathesis. hepatitis C, but may be normal in patients with a previous toxic
exposure or resolved infectious process such as hepatitis B.
The use of liver function tests in the diagnosis and management
CLINICAL PRESENTATION of cirrhosis is discussed in the following sections. It is useful to
group the tests into two broad categories: markers of hepatocyte
Cirrhotic patients may present in a variety of ways, from asympto- damage, such as the transaminases, and markers of hepatocellular
matic patients with abnormal laboratory tests noted on routine synthetic function, such as prothrombin time and albumin.
blood tests to acute life-threatening hemorrhage in an emergency
room. The approach to a patient with suspected liver disease begins
Aminotransferases
with a thorough history and physical examination. Table 39–2
describes some of the typical presenting characteristics of patients The aminotransferases, AST and ALT, are enzymes located in the
with cirrhosis.3,15 Clinical jaundice is often a late manifestation of cytoplasm of hepatocytes and their levels are elevated with hepato-
cirrhosis and its absence does not exclude the diagnosis. cellular injury. The degree of elevation and rate of rise in amino-
A thorough history of alcohol or drug use, with the input of transferase serum levels is helpful in suggesting possible etiologies.
family and friends is important, as the patient often underestimates The highest levels are typically seen in acute viral, ischemic, or toxic
the amount of alcohol consumed. Family history can also provide liver injury.17 In contrast, alcoholic liver disease resulted in AST
clues regarding problems such as hemochromatosis. The social elevations of only 6 to 7 times the upper limit of normal in 98% of
history provides information regarding potential occupational patients in a landmark study by Cohen and Kaplan.18
exposures to toxic agents. A history of acute pain and fever may The ratio of AST to ALT also provides information in patients
indicate an obstructive process caused by gallstones, or an inflam- with suspected alcoholic liver disease. Seventy percent of patients
matory condition such as viral or alcoholic hepatitis. with alcoholic liver disease had ratios greater than 2 compared to
The classic clinical signs of cirrhosis, such as palmar erythema, only 4% of patients with viral hepatitis.18
spider angiomata, and gynecomastia, are neither sensitive nor spe-
cific for this disease.15,16 Only a combination of physical and labora- Alkaline Phosphatase and
tory findings provides a reasonable indicator of liver disease. A γ-Glutamyl Transpeptidase
decreased albumin level was the most common finding in patients
Elevated serum levels of alkaline phosphatase and GGT occur as a
with cirrhosis, but was nonspecific and occurred in a variety of
result of the bile flow obstruction that accompanies conditions such
conditions. An elevated prothrombin time was the single most
as primary biliary cirrhosis, primary sclerosing cholangitis, drug-
reliable manifestation of cirrhosis. The combination of thrombocy-
induced cholestasis, gallstone disease, and autoimmune cholestatic
topenia, encephalopathy, and ascites was found in just over half of
liver disease. Neither alkaline phosphatase nor GGT are found solely
cirrhotics, but had the highest predictive value.12
in the liver, and elevations in either of these biomarkers can occur
in a variety of disease states, affecting other bodily tissues. However,
the combination of an elevation in alkaline phosphatase level with a
TABLE 39-2 Clinical Presentation of Cirrhosis concomitant elevation in GGT level is considered to be both a
Signs and symptoms sensitive and specific marker of cholestatic liver disease.17
Asymptomatic
Hepatomegaly, splenomegaly Child-Pugh Classification and Mayo End-Stage
Pruritus, jaundice, palmar erythema, spider angiomata, hyperpigmentation Liver Disease Score
Gynecomastia, reduced libido
Ascites, edema, pleural effusion, and respiratory difficulties The Child-Pugh classification system has gained widespread accep-
Malaise, anorexia, and weight loss tance as a means of quantifying the myriad effects of the cirrhotic
Encephalopathy process on the laboratory and clinical manifestations of this dis-
Laboratory tests ease.19 Recommended drug-dosing adjustments for patients in liver
Hypoalbuminemia failure, when available, are normally based upon the Child-Pugh
Elevated prothrombin time score. The newer Mayo End-Stage Liver Disease (MELD) scoring
Thrombocytopenia system is now the accepted classification scheme used by the United
Elevated alkaline phosphatase Network for Organ Sharing (UNOS) in the allocation livers for
Elevated aspartate transaminase (AST), alanine transaminase (ALT), and
transplantation.20 The Child-Pugh classification system employs a
γ-glutamyl transpeptidase (GGT)
combination of physical and laboratory findings (Table 39–3),
 637

TABLE 39-3 Criteria and Scoring for the Child-Pugh Grading of

Pattern of abnormal

CHAPTER 39
Chronic Liver Disease liver function test
Score 1 2 3
Bilirubin (mg/dL) 1–2 2–3 >3 Obstructive Hepatocellular
Albumin (mg/dL) >3.5 2.8–3.5 < 2.8 (alkaline, phosphatase, GGT, bilirubin) (AST/ALT)
Ascites None Mild Moderate
Encephalopathy (grade) None 1 and 2 3 and 4 Imaging Magnitude
(ultrasound, CT scan)
Prothrombin time (seconds prolonged) 1–4 4–6 >6
Grade A, < 7 points; grade B, 7–9 points; grade C, 10–15 points.
Dilated Nondilated ≥ 20  Normal < 20  Normal

Portal Hypertension and Cirrhosis

biliary tree biliary tree
whereas the MELD score calculation takes into account a patient’s
serum creatinine, bilirubin, international normalized ratio (INR),
Gallstones/ Intrahepatic process Hepatitis Broad DDX
and etiology of liver disease, omitting the more subjective reports of Malignancy Drugs
ascites and encephalopathy used in the Child-Pugh system. The Ischemia
Drugs
MELD scoring calculation is as follows21: Primary biliary cirrhosis
Hepatitis
MELD score = 0.957 × Loge(creatinine mg/dL) + 0.378 × Malignancy
Loge(bilirubin mg/dL) +
1.120 × Loge(INR) + 0.643 FIGURE 39-4. Interpretation of liver function tests. (CT, computed tomog-
raphy; DDX, differential diagnosis.)
These classification systems are important because they are used
to assess and define the severity of the cirrhosis, and as a predictor When cirrhosis has been established, the degree of bilirubin
for patient survival, surgical outcome, and risk of variceal bleeding. elevation has prognostic significance and is used as a component of
the Child-Pugh and MELD scoring systems for quantifying the
degree of cirrhosis.
CLINICAL CONTROVERSY Figure 39–4 describes a general algorithm for the interpretation
The Child-Pugh classification system has been used for decades to of liver function tests. The algorithm first separates the tests into
quantify liver impairment in patients with cirrhosis. A problem two categories based on the underlying pathology (pattern of
with this system is that it relies on subjective scoring components elevations): obstructive (alkaline phosphatase, GGT, and bilirubin)
related to ascites and encephalopathy, leading to the possibility of versus hepatocellular (AST and ALT). If a hepatocellular pattern
interpretation differences and scoring disparities. UNOS now predominates, the magnitude of elevation provides diagnostic assis-
employs the MELD scoring system, which relies solely on objective tance. If the degree of elevation is ≥20 times normal, the etiology is
laboratory measurements, to stratify the severity of a patient’s liver likely a result of drugs or other toxins, ischemia, or acute viral
dysfunction and assist with transplant allocation. Controversy hepatitis. Elevations <20 times normal have a broad differential.
surrounds whether or not the Child-Pugh scoring system should Unfortunately, most liver enzyme abnormalities will fall into a
be abandoned for the more objective MELD scoring system to mixed pattern, providing limited diagnostic assistance.
describe the severity of a patient’s liver dysfunction, assist with
clinical decision making, and eventually guide drug dosing. Albumin and Coagulation Factors
Albumin and coagulation proteins are markers of hepatic synthetic
Bilirubin activity and are therefore used to estimate the level of functioning
Bilirubin is a breakdown product of hemoglobin derived from hepatocytes in cirrhosis. They are both used in the Child-Pugh
senescent red blood cells. Elevations of the serum bilirubin are system for liver disease and the INR is used in the MELD scoring
common in end-stage liver disease and obstruction of the common system as a marker of coagulation. Albumin levels can be affected by
bile duct caused by gallstones or malignancy; however, there are a number of factors, including the patient’s nutritional status, acute
other causes of an elevated bilirubin (Table 39–4). illnesses, which result in redistribution of albumin, and protein
losses from renal and intestinal sources.
Coagulation factors I, II, V, VII, VIII, IX, X, XI, XII, and XIII are
TABLE 39-4 Etiology of Hyperbilirubinemia
synthesized in the liver and, when circulating levels of factors I, V,
Etiology Diagnosis VII, IX, and X are sufficiently reduced, the prothrombin time (PT)
Unconjugated bilirubin becomes prolonged. PT prolongation is related to the severity of
Excessive production Hemolysis liver disease and decreased synthetic activity in the liver. The PT is
Immature enzyme systems Jaundice of newborn used as one of the prognostic factors found in the Child-Pugh
Jaundice of prematurity scoring system. Likewise, the INR, which is calculated based upon
Inherited defects Gilbert syndrome the PT, is used in the MELD system.22 The PT has also been used in
Crigler-Najjar syndrome acute liver disease as an outcome measurement in acetaminophen
Drug effects overdose and acute alcoholic hepatitis.23
Conjugated bilirubin
Impaired intrahepatic excretion
Hepatocellular disease Hepatitis, cirrhosis, drugs
Thrombocytopenia
Intrahepatic cholestasis Drugs, pregnancy Thrombocytopenia (generally defined as a platelet count less than
Congenital Dubin-Johnson syndrome 150,000) is a common feature of chronic liver disease found in 30%
Rotor syndrome to 64% of cirrhotic patients. The etiology of thrombocytopenia in
Obstruction liver disease is multifactorial involving primarily splenomegaly
Extrahepatic Calculus, stricture, neoplasm
caused by portal hypertension with pooling of platelets in the
Intrahepatic Sclerosing cholangitis, cirrhosis, neoplasm
spleen. A decrease in thrombopoietin as a consequence of decreased
 638
hepatic synthesis occurs, as well as an immune-mediated destruc- end points and desired therapeutic outcomes are presented for each
tion of platelets. Additionally, bone marrow suppression may exist of the recommended therapies discussed.
SECTION 4

related to alcohol, folate deficiency, and drug therapies, and lead to

thrombocytopenia associated with the cirrhotic process.22 ■ PORTAL HYPERTENSION AND
VARICEAL BLEEDING
ENDOSCOPIC AND Portal hypertension is characterized by an increased gradient
RADIOGRAPHIC ABNORMALITIES between the portal venous and central venous pressures which leads
The use of imaging techniques can provide useful information to esophageal and gastric varices. Once the gradient increases above
regarding the presence of liver disease and portal hypertension. The 12 mm Hg, variceal bleeding can occur causing a potentially life-
threatening complication of cirrhosis.11 Mortality from the first
Gastrointestinal Disorders

modality chosen is often determined by the clinical presentation.

Examples include the use of ultrasound for the detection of gall- incidence of variceal bleeding is approximately 50%.24 In one study,
stones and biliary duct abnormalities in patients presenting with varices arose in 5% of cirrhotic patients within 1 year and in 28%
acute pain and jaundice, or endoscopic retrograde cholangiopan- within 3 years. The 2-year risk of variceal bleeding was 12% and the
creatography (ERCP) for patients with known choledocholithiasis. 30-day mortality of variceal bleeding ranged from 20% to 29%.
Upper endoscopy can be used to detect the presence of esophageal Progression was predicted by the Child-Pugh scoring system.25
or gastric varices as an indicator of portal hypertension. Computed
tomography is a sensitive means of detecting hepatic metastases and ■ MANAGEMENT OF PORTAL
is used for directing liver biopsy. HYPERTENSION AND VARICEAL BLEEDING
The management of varices involves three strategies: (a) primary
LIVER BIOPSY prophylaxis (prevention of the first bleeding episode); (b) treatment
of acute variceal hemorrhage; and (c) secondary prophylaxis, pre-
Liver biopsy plays a central role in the diagnosis and staging of liver
vention of rebleeding in patients who have previously bled.8
disease. However, for the diagnosis of cirrhosis, percutaneous liver
biopsy has a significant false-negative rate because of the presence of
regenerating nodules within the liver. Primary Prophylaxis
β-Adrenergic Blockade The mainstay of primary prophylaxis is
the use of nonselective β-adrenergic blocking agents such as pro-
TREATMENT pranolol or nadolol.11 These agents reduce portal pressure by
reducing portal venous inflow via two mechanisms: a decrease in
Cirrhosis cardiac output through β1-adrenergic blockade and a decrease in
splanchnic blood flow through β2-adrenergic blockade.26
■ GENERAL APPROACHES TO TREATMENT Meta-analysis of 12 trials assessing the effectiveness of the β-
adrenergic blockers propranolol and nadolol demonstrated the effec-
The clinical manifestations of cirrhosis are protean and it is difficult
tiveness of these agents in the prevention of bleeding over a median
to provide overall management guidelines. General approaches to
follow up of 2 years and a trend toward a reduction in mortality. The
therapy should include:
average reduction in the incidence of initial bleeding achieved by
1. Identifying and eliminating, where possible, the causes of cir- nonselective β-adrenergic blockade is approximately 25%. Benefit
rhosis (e.g., alcohol abuse). was proven irrespective of variceal size or the presence of ascites.27
2. Assessing the risk for variceal bleeding and beginning pharma- Nadolol reduces the rate of growth of small esophageal varices in
cologic prophylaxis when indicated. Reserve prophylactic patients with cirrhosis.28 However, β-adrenergic blocker therapy does
endoscopic therapy for patients with contraindications or not prevent the formation of first varices and prophylactic therapy is
intolerance to β-adrenergic blockers. Endoscopic therapy is not recommended until an assessment of esophageal varices is
also appropriate for patients suffering acute bleeding episodes. made.7,26 Once started, β-adrenergic blocker therapy should be con-
Variceal obliteration with endoscopic techniques is the recom- tinued for life unless it is not tolerated.29
mended treatment of choice in patients with acute bleeding.
3. Evaluating the patient for clinical signs of ascites and managing Treatment Recommendations: Variceal
with pharmacologic therapy (e.g., diuretics and paracentesis). Bleeding—Primary Prophylaxis
Careful monitoring for spontaneous bacterial peritonitis should  All patients with cirrhosis should be screened for varices upon
be used in patients with ascites who undergo acute deterioration. diagnosis and all patients found to have varices, regardless of variceal
4. Monitoring for hepatic encephalopathy, which is a common size, should receive prophylaxis therapy with a  nonselective β-
complication of cirrhosis that requires clinical vigilance and adrenergic blocker.7 Initiate therapy with oral propranolol 10 mg
treatment with dietary restriction, elimination of central ner- three times daily or nadolol 20 mg once daily and titrate to a
vous system depressants, and therapy to lower ammonia levels. reduction in the resting heart rate of 20% to 25%, an absolute heart
rate of 55 to 60 beats/min, or the development of adverse effects.
5. Monitoring frequently for signs of hepatorenal syndrome, pul-
Patients with contraindications or intolerance to β-adrenergic block-
monary insufficiency, and endocrine dysfunction is necessary.
ers should be considered for alternative prophylactic therapy.30 Endo-
scopic band ligation (EBL) is superior to both β-adrenergic blockers
■ DESIRED OUTCOMES and nitrates for preventing first bleeding.31–36 Because EBL does not
The desired therapeutic outcomes can be viewed in two categories: improve survival and long-term benefits are still uncertain, use of EBL
resolution of acute complications, such as tamponade of bleeding and for primary prophylaxis should be reserved for patients with contra-
resolution of hemodynamic instability for an episode of acute indications or intolerance to β-adrenergic blockers.7 Nitrates are no
variceal hemorrhage; and prevention of complications, through low- longer recommended as alternative therapy for primary prophylaxis
ering of portal pressure with medical therapy using β-adrenergic against variceal bleeding in patients with intolerance to β-adrenergic
blocker therapy, or supporting abstinence from alcohol. Treatment blockers.7 Additionally, there is insufficient evidence to recommend
 639
use of nitrates in addition to β-adrenergic blockers in an attempt to troduodenoscopy (EGD) employing endoscopic injection sclerother-
further lower portal pressure.7,37 At this time, there is also insufficient apy (EIS) or endoscopic band ligation (EBL) of varices as the primary

CHAPTER 39
evidence to support the use of other agents which decrease hepatic diagnostic and treatment strategy for upper GI tract hemorrhage
resistance and blood flow such as carvedilol, prazosin, irbesartan, or secondary to portal hypertension and varices.38
losartan in the management of portal hypertension.8 Nonselective β- Fluid resuscitation involves colloids initially and subsequent blood
adrenergic blocker therapy remains the mainstay of therapy in portal products after blood bank matching procedures are completed.
hypertension patients with known varices to avoid first variceal Packed red blood cells, fresh-frozen plasma, and platelets may be
bleeding. employed both as volume expanders and corrective therapy for
underlying clotting abnormalities. Vasoactive drug therapy (somato-
■ ACUTE VARICEAL HEMORRHAGE statin, octreotide, or terlipressin) to stop or slow bleeding is routinely

Portal Hypertension and Cirrhosis

used early in patient management to allow stabilization of the patient
Variceal hemorrhage typically presents with hematemesis or melena. and to permit endoscopy to proceed under more favorable condi-
Important risk factors include active alcohol abuse, use of nonsteroidal tions. Antibiotic therapy to prevent sepsis should also be imple-
antiinflammatory agents or aspirin, or previous variceal hemorrhage.30 mented early, especially for patients with signs of infection or ascites.
It is important to note, however, that variceal bleeding secondary to Figure 39–5 presents an algorithm for the management of variceal
portal hypertension can occur in patients without signs of liver disease; hemorrhage.
for example, in patients with portal vein thrombosis. The initial
assessment should determine the severity of the bleeding, severity of
other organ dysfunction, and the severity of the liver disease.30 Drug Therapy
Drugs employed to manage acute variceal bleeding include octreo-
Management of Acute Variceal Hemorrhage tide or somatostatin, vasopressin, and terlipressin (triglycyl-lysine
vasopressin). These agents work as splanchnic vasoconstrictors thus
Initial treatment goals include (a) adequate fluid resuscitation; decreasing portal blood flow and pressure.39,40
(b) correction of coagulopathy and thrombocytopenia; (c) control of
bleeding; (d) prevention of rebleeding; and (e) preservation of liver Somatostatin and Octreotide Somatostatin is a naturally occur-
function. Prompt stabilization and aggressive fluid resuscitation of ring 14-amino-acid peptide with a half-life of 1 minute, necessitating
patients with active bleeding is followed by endoscopic examination. continuous intravenous infusion; octreotide is its more potent syn-
General resuscitation measures should be applied in the initial man- thetic octapeptide analog with a half-life of 10 to 22 minutes, which
agement of variceal hemorrhage. Airway management is critical in can be dosed via intravenous infusion or subcutaneous injection.
patients with variceal hemorrhage because of depressed reflexes and/ Somatostatin and octreotide decrease splanchnic arterial blood flow
or combative behavior associated with drug and alcohol use. The with a subsequent decrease in portal inflow through inhibition of
endoscopic approach to bleeding also requires a quiet and coopera- vasodilatory gastrointestinal peptides including glucagon, vasoactive
tive patient, and elective intubation for airway control and adequate intestinal peptide, calcitonin gene-related peptide, and substance P.
sedation is often necessary. Clinical practice guidelines approved by Somatostatin and octreotide are associated with few side effects.41
the American College of Gastroenterology recommend esophagogas- Unlike vasopressin, systemic vasoconstriction and elevations in blood

Acute bleed

Resuscitation
ABCs
Sedation

Somatostatin
Octreotide
Prophylactic antibiotic therapy

Endoscopy: Diagnostic and therapeutic

Nonportal hypertension source Portal hypertension gastropathy Isolated gastric varices Esophageal varices

Treat Somatostatin Tamponade Octreotide for 5 days and

Octreotide Octreotide endoscopy banding or
TIPS sclerotherapy

If unresolved—TIPS

Rebleeding No rebleeding

Continue endoscopy
Child-Pugh A or early B Child-Pugh ȕ-blockers

Surgical shunt/TIPS TIPS

FIGURE 39-5. Management of acute variceal hemorrhage. (TIPS, transjugular intrahepatic portosystemic shunt.)
 640
pressure are not seen because the vasoconstriction that occurs with observed throughout therapy for signs and symptoms of spontane-
somatostatin and octreotide is selective for the mesenteric circulation. ous bacterial peritonitis.49
SECTION 4

Clinical trial data with somatostatin and octreotide are somewhat

conflicting. For somatostatin, meta-analysis of clinical trials has been
performed for studies comparing the drug with both placebo and
Endoscopic Interventions: Sclerotherapy
vasopressin. Somatostatin controlled bleeding better than vaso- and Band Ligation
pressin, and had a superior side effect profile, but, oddly, was not  The American College of Gastroenterology published clinical
found to control bleeding better when trials comparing the drug to practice guidelines in 1997 recommending EGD employing EIS or
placebo were analyzed.42,43 A meta-analysis of 13 studies comparing EBL of varices as the primary diagnostic and treatment strategy for
octreotide with terlipressin, vasopressin, or placebo found improved upper GI tract hemorrhage secondary to portal hypertension and
Gastrointestinal Disorders

control of bleeding with octreotide over each of the other three varices.38 Since that time, the Baveno IV Consensus Report was
therapeutic options. Efficacy was similar to sclerotherapy with fewer published stating that EBL is the recommended form of endoscopic
side effects than terlipressin or vasopressin.44 therapy for acute variceal bleeding, although EIS may be employed if
Vasopressin (also known as antidiuretic hormone) is a potent, ligation is technically difficult.7 EIS involves injection of 1 to 4 mL of
nonselective vasoconstrictor that has been recommended for many a sclerosing agent into the lumen of the varices to tamponade blood
years for the management of acute variceal bleeding. Vasopressin flow. EBL consists of placement of rubber bands around the varix
reduces portal pressure by causing splanchnic vasoconstriction, through a clear plastic channel attached to the end of the endoscope.
which reduces splanchnic blood flow. Unfortunately, the vasocon- After the rubber bands are in place, the varix will slough off after 48
strictive effects of vasopressin are nonselective—the vasoconstriction to 72 hours. Endoscopic approaches can successfully stop bleeding in
produced is not restricted to the splanchnic vascular bed. Potent up to 95% of cases, but rebleeding may occur in 50% of cases.30
systemic vasoconstriction occurs in the coronary and mesenteric Various clinical trials have been completed comparing the effec-
circulation as well, resulting in hypertension, severe headaches, tiveness of EBL, EIS, and drug therapy to control variceal bleeding.
coronary ischemia, myocardial infarction, and arrhythmias. A meta- In a meta-analysis of 15 trials comparing EIS with vasoactive drug
analysis of 15 randomized controlled clinical trials of vasopressin for therapy, the rates of treatment failure and mortality were found to
variceal hemorrhage demonstrated that vasopressin was significantly be similar between treatment strategies, while EIS was related to
more effective than no treatment; however, control of hemorrhage significantly more adverse effects as compared to somatostatin.50 In
was achieved in only 50% of the bleeding episodes.42 Adverse effects a trial comparing EBL and somatostatin, EBL was found superior at
were reported in 45% of patients, and vasopressin was discontinued controlling bleeding and adverse effects were similar.51 A meta-
in 25% of patients secondary to adverse effects. To minimize adverse analysis of 13 randomized controlled trials comparing EBL, EIS, and
effects associated with the peripheral vasoconstriction secondary to vasoactive drug therapy found EBL to be the most effective treat-
vasopressin, and to further lower portal pressure, the combination of ment option with EIS and drug therapy being equally effective, but
vasopressin and intravenous nitroglycerin has been evaluated.9 The significantly less effective than EBL.52 Endoscopic injection of the
combination trended toward improved control of hemorrhage with tissue adhesive n-butyl 2-cyanoacrylate has been found to control
reduced side effects when compared to vasopressin alone. However, active bleeding as well as EBL, and was associated with a lower rate
with the recent addition of safer and equally effective treatment of rebleeding in one trial.53
alternatives, vasopressin, alone or combined with nitroglycerin, can
no longer be recommended as first-line therapy for the management
of variceal hemorrhage.30
Interventional and Surgical
Terlipressin (Glypressin), a triglycyl-lysine vasopressin, is a syn- Treatment Approaches
thetic prodrug of vasopressin with intrinsic vasoconstrictor activity If standard therapy fails to control bleeding (after two failed endo-
that was developed in an attempt to provide an analog of vaso- scopic procedures, further attempts are unlikely to be of benefit) a
pressin with lower toxicity. It is the preferred drug in Europe for salvage procedure, such as balloon tamponade, transjugular intrahe-
acute variceal bleeding, is the only drug shown to reduce mortality, patic portosystemic shunting (TIPS), or surgical shunting is neces-
but is not currently available in the United States.30 sary. Sengstaken-Blakemore tubes are balloon devices designed to
The glycyl residues are enzymatically cleaved in vivo, resulting in tamponade gastric and esophageal varices that can be effective in
the slow conversion into lysine vasopressin. This process results in 70% to 90% of cases of variceal bleeding.30 However, these devices
the availability of lysine vasopressin with a longer half-life, permit- have a 10% to 30% complication rate and will be ineffective if the
ting intermittent intravenous dosing every 4 hours.30 Terlipressin bleeding source is nonvariceal, a situation which occurs in 10% to
produces a marked and sustained reduction in portal pressure, 50% of patients with portal hypertension.30 Balloon tamponade
effectively controls variceal bleeding, and causes few side effects even should be reserved as a temporizing measure until a TIPS procedure
among patients with initial treatment failure with standard somato- or surgical shunt can be performed.49
statin therapy.45,46 Its prolonged biologic effect allows intravenous In patients with acute variceal bleeding refractory to pharmacologic
administration as an intermittent infusion every 4 hours, whereas or endoscopic therapy, a decrease in portal pressure through use of the
somatostatin requires administration as a continuous intravenous TIPS procedure is effective in controlling bleeding and preventing
infusion.47 Terlipressin is better tolerated and equally effective as rebleeding.54 The TIPS procedure involves the placement of one or
compared to sclerotherapy.45 Cirrhotic patients with active bleeding more stents between the hepatic vein and the portal vein (Fig. 39–6).
are at high risk of infection and sepsis secondary to aspiration, the This procedure is widely used because it provides an effective decom-
placement of multiple intravascular access devices, sclerotherapy, pressive shunt without laparotomy, and can be employed regardless of
translocation, and defects in humoral and cellular immunity.30 Child-Pugh score. Survival rates with TIPS in patients refractory to
Prophylactic antibiotic therapy to reduce the risk of sepsis during endoscopic treatment are comparable to rates achieved with porta-
episodes of bleeding is reported to decrease the incidence of rebleed- caval shunts.30 Patients undergoing TIPS experience a 30% incidence
ing and to increase short-term survival.48 Prophylactic antibiotic of encephalopathy, and approximately 50% of shunts malfunction.49
therapy should be instituted upon admission for variceal bleeding.7 Various surgical shunts have been developed and are effective for
All patients with variceal hemorrhage should be screened for infec- the prevention of recurrent variceal hemorrhage in patients refractory
tion and pan cultured. Patients should be evaluated at admission and to β-adrenergic blockade and endoscopy.49
 641
55
Hepatic Inferior events, 22% versus 9% compared to untreated controls, with 5.7%
vein vena cava requiring discontinuation of β-adrenergic blockade therapy.

CHAPTER 39
When considering the benefits associated with β-adrenergic block-
ers, it is important to appreciate that at least 30% of cirrhotic patients
will not achieve a reduction in portal pressures sufficient to prevent
bleeding even with adequate β-adrenergic blockade.31 Use of a long-
Stent
acting β-blocker (such as nadolol) is usually recommended to
improve compliance, and gradual, individualized dose escalation may
help to minimize side effects. Ideally, portal pressure monitoring can
help to assess the response to β-adrenergic blocker therapy and

Portal Hypertension and Cirrhosis

identify nonresponders earlier in the treatment course. A decrease in
hepatic venous pressure gradient (HVPG) to <12 mm Hg or a
reduction of more than 20% from baseline are considered therapeutic
Portal targets.8
vein

FIGURE 39-6. Transjugular intrahepatic portosystemic shunt (TIPS). CLINICAL CONTROVERSY

The procedure for measuring portal pressures is invasive, expen-
Treatment Recommendations: sive, and not available in most facilities. Additionally, the cost-
Variceal Hemorrhage effectiveness of this approach (baseline and posttherapy) has not
Patients require prompt resuscitation with colloids and blood prod- been compared with simply monitoring heart rate reduction
ucts to correct intravascular losses and to reverse existing coagulopa- with β-blockers.56 However, for patients who fail to achieve
thies.  Drug therapy with octreotide or somatostatin should be sufficient reductions in portal pressure with β-blocker therapy
initiated early to control bleeding and facilitate diagnostic and thera- alone, combination therapy with nitrates may more effectively
peutic endoscopy. Based on availability, octreotide is preferred. Ther- lower portal pressure potentially reducing bleeding rates.57 Con-
apy is initiated with an IV bolus of 50 to 100 mcg and is followed by troversy currently surrounds whether or not routine HVPG
a continuous infusion of 25 mcg/h, up to a maximum rate of 50 mcg/ monitoring should be employed in secondary prophylaxis
h. Monitor patients for hypo- or hyperglycemia, especially patients patients so as to better identify those with insufficient portal
with diabetes, and assess for cardiac conduction abnormalities. Vaso- pressure lowering on standard β-adrenergic blocker therapy
pressin is no longer recommended for control of variceal bleeding. who may potentially benefit from the addition of nitrate therapy.
Endoscopy is recommended in any patient with upper gastrointesti-
nal bleeding caused by ruptured varices. EBL is the recommended Comparisons of β-adrenergic blocker therapy alone with EIS
form of endoscopic therapy but EIS may also be employed and an suggest that less variceal rebleeding is seen with EIS, but this benefit
additional endoscopic therapy option is injection of the tissue adhe- is offset by an increase in complications.58 However, β-adrenergic
sive n-butyl 2-cyanoacrylate.7 Antibiotic prophylaxis is recommended blocker therapy in combination with nitrates is more effective than
if ascites is present and EIS is planned. Appropriate choices include a EIS at lower risk of rebleeding with fewer side effects.59 Several
third-generation cephalosporin (e.g., ceftazidime or ceftriaxone), a studies have been conducted comparing EIS with EBL at preventing
penicillin/β-lactamase inhibitor combination (e.g., piperacillin-tazo- rebleeding. EBL is safer and more effective at decreasing the rate of
bactam), or a fluoroquinolone (e.g., ofloxacin). Surgical shunts and recurrent bleeding. EBL requires fewer sessions to obliterate varices
TIPS are employed as salvage therapy in patients who have failed and improves survival as compared to EIS.60–62 Combined drug
repeated endoscopy and vasoactive drug therapy. therapy with nadolol plus isosorbide mononitrate was more effec-
tive than EBL at preventing rebleeding than EBL with a lower rate of
Secondary Prophylaxis: Prevention of Rebleeding Because
major complications.57 More studies are required to make combina-
the risk of rebleeding after initial control of variceal hemorrhage can
tion therapy with a β-adrenergic blocker and a nitrate the definitive
approach 80%, and rebleeding significantly increases the risk of
choice over EBL for prevention of rebleeding. Current guidelines
death, it is inappropriate to simply observe patients for evidence of
suggest that a combination of drug therapy and EBL is likely the best
further bleeding. Traditionally, pharmacologic therapy using β-
therapeutic choice for secondary prophylaxis at this time.
adrenergic blockers was recommended as the initial approach for
prevention of rebleeding. Combination therapy with β-adrenergic Shunting. When drug therapy and endoscopy fail, alternatives
blockers and chronic EBL to eradicate varices has been recognized include TIPS placement or shunt surgery. Regular documentation of
as the likely best treatment option for secondary prophylaxis of patency and the requirement of repeat procedures make it an unsuit-
variceal bleeding.7 Alternatives for the secondary prevention of able long-term solution. In patients with well-compensated hepatic
rebleeding include surgical or interventional shunting. function (Child-Pugh grade A or B) surgical shunting is an excellent
option.
Drug Therapy. Drug therapy of variceal hemorrhage is less expen-
sive, offers fewer serious complications, and is usually preferred by Treatment Recommendations: Secondary Prophylaxis The
patients. In patients without contraindications, β-adrenergic block- preferred initial approach to secondary prophylaxis is currently unset-
ing agents should be the initial step in secondary prophylaxis, along tled with both pharmacotherapy and interventional procedures being
with EBL.7,30 A meta-analysis of 11 randomized controlled clinical accepted means. Endoscopic therapy using either EIS or EBL and
trials demonstrated a significant 21% reduction in rebleeding with β- pharmacologic therapy are both effective in reducing the risk of rebleed-
blockers as compared to untreated controls, and a 5.4% improve- ing. As a consequence of decreased complications, bleeding, and possi-
ment in the 2-year overall survival rate.55 Secondary prophylaxis with bly mortality, EBL has emerged as the endoscopic treatment of
β-adrenergic blockade therapy also resulted in a significant 7.4% choice.60–62  Either EBL alone or the combination of EBL with
reduction in death as a consequence of rebleeding. Propranolol was pharmacologic therapy can be considered appropriate initial therapy.
used in 10 trials; nadolol was used in one trial. Patients treated with Pharmacologic therapy should be initiated with a nonselective β-blocker
β-adrenergic blocking agents experienced significantly more adverse such as propranolol 20 mg three times a day, or nadolol at a dose of 20
 642

TABLE 39-5 Evidence-Based Table of Selected Treatment portosystemic collaterals), suppression of the reticuloendothelial
Recommendations: Variceal Bleeding in system, and bacterial overgrowth of the ascitic fluid. Ascitic fluid
SECTION 4

Portal Hypertension offers a favorable growth medium as a result of leukocyte dysfunc-

tion and decreased ascitic fluid defenses as a result of a decreased
Recommendation Grade
albumin content.64 Consequently, most episodes of SBP are caused
Prevention of variceal bleeding by gram-negative Enterobacteriaceae, with Escherichia coli the most
Nonselective β-blockers should be initiated in patients with 1A commonly isolated. The clinical presentation of SBP can vary from
medium or large esophageal varices patients who present with all of the signs and symptoms of perito-
EBL should be offered to patients who have contraindications or 5D
nitis, including fever, leukocytosis, abdominal pain, hypoactive or
intolerance to nonselective β-blockers
absent bowel sounds, and rebound tenderness, to those patients
Treatment of variceal bleeding
Gastrointestinal Disorders

Antibiotic prophylaxis should be instituted on admission 1A who have no signs or symptoms at all. For this reason, a diagnostic
Vasoactive drugs should be started as soon as possible, prior to 1A paracentesis with analysis of ascitic fluid should be performed in all
endoscopy, and maintained for 2–5 days patients admitted with ascites and in patients with cirrhosis who
EBL is the recommended form of endoscopic therapy for acute 1A suddenly deteriorate.5,9 Spontaneous bacterial peritonitis is diag-
esophageal variceal bleeding and should be used in conjunction nosed when ascitic fluid cell counts show an absolute polymorpho-
with vasoactive drug therapy nuclear (PMN) leukocyte count of ≥250 cells/mm3.64
Secondary prophylaxis of variceal bleeding
Nonselective β-blockers, EBL, or both should be used for preven- 1A
tion of recurrent variceal bleeding Management of Ascites and Spontaneous
EBL, endoscopic band ligation.
Bacterial Peritonitis
Recommendation Grading: Level of Evidence 1 = highest; 5 = lowest and Grade of Recommendation: The following treatment guidelines for the management of adult
1 = strongest; D = weakest.
patients with ascites and spontaneous bacterial peritonitis were
Data from DeFranchis R. Updating consensus in portal hypertension. Report of the Baveno III
consensus workshop on definitions, methodology and therapeutic strategies in portal hypertension. developed and approved by the Practice Guidelines Committee of
J Hepatol 2000;33:846–852. the American Association for the Study of Liver Diseases (AASLD).5

to 40 mg once daily, and titrated weekly to achieve a goal heart rate of 55 Ascites In adult patients with new-onset ascites as determined by
to 60 beats/min or a heart rate that is 25% lower than the baseline heart physical examination or radiographic studies, abdominal paracentesis
rate. Assessment of portal pressures can identify nonresponders for should be performed and ascitic fluid analysis should include a cell
whom combination therapy with β -blockers and nitrates may be count with differential and a serum-ascites albumin gradient (SAG).
attempted to achieve portal pressure gradients <12 mm Hg. Monitor If infection is suspected, ascitic fluid cultures should be obtained at
patients for evidence of heart failure, bronchospasm, and glucose intol- the time of the paracentesis. The SAG can accurately determine
erance, particularly hypoglycemia in patients with insulin-dependent whether ascites is a result of portal hypertension or another process.
diabetes. Table 39–5 summarizes the evidence-based treatment recom- If the SAG is >1.1 g/dL, portal hypertension is present with 97%
mendations regarding portal hypertension and variceal bleeding. accuracy.5 If the SAG is <1.1 g/dL, with similar certainty, the patient
does not have portal hypertension. This is important because patients
■ ASCITES AND SPONTANEOUS without portal hypertension will not respond to salt restriction and
BACTERIAL PERITONITIS diuretics. The treatment of ascites secondary to portal hypertension is
relatively straightforward and includes abstinence from alcohol,
Patients with cirrhosis fail to maintain normal extracellular fluid sodium restriction, and diuretics. This strategy is effective in approx-
volumes secondary to abnormal sodium and fluid retention and an imately 90% of patients. Fifteen percent of patients will respond to
impaired capacity to eliminate water.9 The classic physical examina- dietary sodium restriction alone, and an additional 75% of patients
tion findings of ascites are a distended abdomen with a fluid thrill or will respond to the addition of diuretics.65
shifting dullness. The development of ascites in patients with cirrho-  Abstinence from alcohol is an essential element of the overall
sis is an indication of advanced liver disease and is a poor prognostic treatment strategy. Abstinence from alcohol can result in improve-
sign. The principal therapeutic goal for patients with ascites is to ment of the reversible component of alcoholic liver disease and
improve the patient’s sense of well-being and quality of life by normalize portal pressures in some patients.5 Even in those patients
minimizing respiratory difficulties, loss of appetite, and discomfort with cirrhosis from another cause (e.g., autoimmune hepatitis) absti-
from abdominal distension or leg swelling. Treatment of ascites is nence from alcohol can reverse alcohol-related effects and result in
expected to have little effect on survival, however.63 Pleural effusions substantial improvement of the underlying liver disease. Patients with
are common, and in some cases can be the primary manifestation of cirrhosis not caused by alcohol have less reversible liver disease, and
the fluid retention. Workup includes a history and physical examina- by the time ascites is present, given the poor prognosis, these patients
tion, laboratory tests to assess liver function, abdominal ultrasound may be best managed with liver transplantation rather than pro-
to rule out hepatocellular carcinoma, endoscopy to evaluate esoph- tracted medical therapy.5
ageal and gastric varices, abdominal paracentesis with analysis of Beyond avoidance of alcohol, the primary treatment of ascites
ascitic fluid, and a complete evaluation of circulatory and renal caused by portal hypertension and cirrhosis is salt restriction and
function. Treatment of ascites has risks. Depending on the treatment oral diuretic therapy.5 Fluid loss and weight change depend directly
approach and the goals selected, significant adverse reactions can on sodium balance in these patients. To monitor them appropri-
occur, including electrolyte disturbances, acid–base abnormalities, ately, evaluation of urinary sodium excretion, using a 24-hour urine
hepatic encephalopathy, hypovolemia, and renal insufficiency. collection, is recommended.5 However, severe hyponatremia, serum
Spontaneous bacterial peritonitis (SBP), infection of preexisting sodium <120 mEq/L, does warrant fluid restriction; rapid correc-
ascitic fluid, in the absence of any evidence of a primary intraab- tion of asymptomatic hyponatremia (patients with cirrhosis usually
dominal source of infection, is a common complication in patients are not symptomatic until their serum sodium concentrations are
with ascites, developing in 10% to 25% of patients followed pro- <110 mEq/L) is not recommended.
spectively for at least 1 year.9 The pathogenesis of SBP is unknown,
but presumably results from altered gut permeability (cirrhosis Diuretic Therapy  The AASLD practice guidelines recommend
permits enteric organisms direct access to the bloodstream via the that diuretic therapy be initiated with the combination of spirono-
 643
lactone and furosemide. At one time, spironolactone was commonly patients with ascites and no gastrointestinal bleeding, a total ascitic
recommended for initial therapy as a single agent. However, because protein <1 g/dL, and a serum bilirubin >2.5 mg/dL.5 Antibiotic

CHAPTER 39
of the likelihood for development of drug-induced hyperkalemia prophylaxis should be limited only to patients in one of the above
with spironolactone when used as monotherapy, the drug is now high-risk groups as selective intestinal decontamination does pro-
only recommended for use as a lone diuretic agent in patients with mote the growth of resistant gut flora. Additionally, prophylaxis
minimal fluid overload.5 If tense ascites is present, paracentesis regimens should be continued long-term only in patients who have
should be performed prior to institution of diuretic therapy and salt survived an episode of SBP or possibly in those with ascites whose
restriction.5 For patients who respond to diuretic therapy, this total ascitic protein is <1 g/dL and serum bilirubin is >2.5 mg/dL.5
approach is preferred over the use of serial paracenteses.5 In patients
with refractory ascites, serial paracenteses may be employed. Albu- Treatment Recommendations: Ascites and

Portal Hypertension and Cirrhosis

min infusion postparacentesis is controversial, but reasonable for Spontaneous Bacterial Peritonitis
extraction volumes exceeding 5 L.5 Laboratory tests for renal func-
tion and electrolytes need to be monitored during therapy. Liver Adult patients admitted to the hospital with new-onset ascites should
transplantation should be considered in patients with refractory have an abdominal paracentesis performed to establish the serum-
ascites. For patients who are not transplant candidates and who fail ascites albumin gradient, the ascitic fluid PMN count, and to obtain
repeated paracentesis because of loculated ascites, TIPS or peritoneal ascitic fluid cultures. Patients who drink alcohol should be strongly
venous shunts may be considered. Both of these procedures have discouraged from further alcohol use.  Sodium restriction to 2,000
significant complication rates and are not recommended for the mg/day, together with spironolactone and furosemide, is the main-
routine treatment of ascites.5 stay of therapy. Diuretic therapy should be initiated with single
morning doses of spironolactone 100 mg and furosemide 40 mg
Spontaneous Bacterial Peritonitis Relatively broad-spectrum administered orally with the goal of a 0.5-kg maximum daily weight
antibiotic therapy that adequately covers the three most commonly loss. Titrate diuretic therapy using the 100-mg:40-mg ratio, to a
encountered pathogens (E. coli, Klebsiella pneumoniae, and Strepto- maximum daily dose of 400 mg spironolactone and 160 mg furo-
coccus pneumoniae) is warranted in patients with documented or semide. This combination ratio is used because it usually maintains
suspected SBP.5 Delaying antibiotic therapy while awaiting evidence normokalemia. Fluid restriction, unless the serum sodium is <120
of a positive ascitic fluid culture is not recommended and can result mEq/L, and bedrest are not recommended. Monitor urinary sodium
in overwhelming infection and death.5 In some patients, signs and excretion using a 24-hour urine collection, and monitor serum
symptoms of infection are present such as fever, abdominal pain, potassium and renal function frequently. Avoid rapid correction of
and encephalopathy at the bacterascites stage (i.e., signs and symp- asymptomatic hyponatremia in patients with cirrhosis. If tense
toms are present before the PMN count in the ascitic fluid is ascites is present, a 4- to 6-L paracentesis should be performed prior
elevated). In these patients, signs and symptoms of infection justify to institution of diuretic therapy and salt restriction. For patients
empiric antibiotic therapy until culture results are known, regardless who respond to diuretic therapy, this approach is preferred over the
of the PMN count in the ascitic fluid.5 use of serial paracenteses. Discontinue diuretic therapy in patients
Cefotaxime, or a similar third-generation cephalosporin, is consid- who experience encephalopathy, severe hyponatremia (serum
ered the drug of choice for SBP.5 Cefotaxime is more effective than sodium <120 mEq/L) despite fluid restriction, or renal insufficiency
aztreonam or the combination of ampicillin and tobramycin.9 A 5- (serum creatinine >2 mg/dL). Serial paracenteses may be considered
day course of antibiotic therapy was as efficacious as 10 days of for patients with refractory ascites with albumin infusion postpara-
therapy in a randomized trial involving 100 patients with SBP.66 centesis when volumes exceeding 5 L are removed.
Fluoroquinolone antibiotics provide good activity against the usual Patients with documented SBP, positive ascitic fluid cultures, or
pathogens encountered in SBP, excellent oral bioavailability, and high ascitic fluid PMN count ≥250 cells/mm3, regardless of symptoms,
penetration into ascitic fluid. Ofloxacin 400 mg every 12 hours should receive broad-spectrum empiric antibiotic therapy with cefo-
administered orally is equivalent to intravenous cefotaxime for treat- taxime 2 g every 8 hours, or a similar third-generation cepha-
ment of SBP in patients without vomiting, shock, significant hepatic losporin, plus albumin 1.5 g/kg within 6 hours of admission and 1 g/
encephalopathy, or serum creatinine over 3 mg/dL.67 For many kg on day 3. Patients with ascitic fluid PMN counts <250 cells/mm3,
patients, oral ofloxacin therapy offers a simple, cost-effective alterna- but with signs and symptoms of infection (abdominal pain, tender-
tive to intravenous therapy with third-generation cephalosporins. ness, fever, encephalopathy, renal failure, acidosis, or peripheral
Secondary bacterial peritonitis, ascitic fluid infection caused by a leukocytosis), should also receive empiric antibiotic treatment with
treatable intraabdominal source, can masquerade as SBP and should cefotaxime 2 g every 8 hours, or a similar third-generation cepha-
be considered when multiple or atypical organisms are cultured, a losporin. Short-term prophylaxis should be considered for the pre-
very high ascitic fluid PMN count is seen, or in patients who fail to vention of SBP in patients with low-protein ascites (<1 g/dL) and in
respond to appropriate antibiotic therapy. A dramatic clinical patients with variceal hemorrhage.5
response is typical of uncomplicated SBP once treatment is initiated.  All patients who have survived an episode of SBP should
A followup paracentesis revealing a PMN count that continues to rise receive long-term antibiotic prophylaxis.5 Table 39–6 summarizes
despite antibiotic therapy can be helpful in detecting secondary the evidence-based treatment recommendations regarding ascites
peritonitis.5 and SBP.
 Antibiotic therapy for the prevention of SBP should be consid-
ered in all patients who are at high risk for this complication,
including those who have experienced a prior episode of SBP or ■ HEPATIC ENCEPHALOPATHY
variceal hemorrhage, and those with low-protein ascites (<1 g/dL). The clinical manifestations of HE vary widely.68 Patients with
Patients with gastrointestinal hemorrhage should receive short- minimal HE often experience only minor motor and attentional
term (7 days) norfloxacin twice daily or trimethoprim-sulfameth- deficits and compensate on their own without the need for therapy.
oxazole to prevent SBP. An intravenous quinolone can be used for Those with persistent HE who have more significant deficits that
patients actively bleeding.5 Patients who survive an episode of SBP impact activities of daily living can benefit from intervention.12
should receive long-term prophylaxis with norfloxacin or trimetho- The prevalence of HE among cirrhotics is variable but may be
prim-sulfamethoxazole.5 It may also be appropriate to provide found in up to 70% of patients.13 To determine the severity of HE, a
antibiotic prophylaxis (either short-term or long-term) to those grading system that relates neurologic and neuromuscular signs can
 644

TABLE 39-6 Evidence-Based Table of Selected Treatment commonly encountered precipitating factors and suggests general
Recommendations: Ascites and Spontaneous treatment alternatives.12,13,68 Table 39–9 describes the treatment goals
SECTION 4

Bacterial Peritonitis for patients with HE and contrasts the differences between episodic
and persistent HE. The general approach to the management of HE is
Recommendation Grade
to first identify and treat any precipitating factors, which often results
Ascites in prompt resolution of the encephalopathy. The development of
Initial therapeutic paracentesis should be performed in patients II-3 mental status changes in cirrhosis is associated with increased mor-
with tense ascites bidity and mortality.12 However, universal treatment of patients with
Sodium restriction of 2,000 mg/day should be instituted, as well as I
subclinical HE is not recommended because the consequences of
oral diuretic therapy with spironolactone and furosemide
motor and attention deficits are considered minor, and prevention of
Diuretic-sensitive patients should be treated with sodium restriction III
Gastrointestinal Disorders

and diuretics rather than serial paracentesis progression to more severe HE has not been studied.12
Refractory ascites Treatment approaches for episodic and persistent HE include
Serial therapeutic paracenteses may be performed III (a) reducing ammonia blood concentrations by dietary restrictions
Postparacenteses albumin infusion of 8–10 g/L of fluid removed II-2 and drug therapy aimed at inhibiting ammonia production or
can be considered if more than 4–5 L are removed during enhancing its removal and (b) inhibition of the GABA–benzodiaze-
paracenteses pine receptors. Additionally, treatment for persistent HE should
Treatment of SBP include avoidance and prevention of precipitating factors in an
If ascitic fluid PMN counts are greater than 250 cells/mm3, empiric I effort to avoid acute decompensation.12
antibiotic therapy should be instituted (cefotaxime 2 g every 8 hours)
If ascitic fluid PMN counts are less than 250 cells/mm3, but signs or II-3 Hyperammonemia  Despite criticisms of the ammonia
symptoms of infection exist, empiric antibiotic therapy should be hypothesis, treatment interventions to reduce ammonia blood con-
initiated while awaiting culture results centrations are beneficial in patients with HE.12 Decreasing ammo-
Ofloxacin 400 mg twice daily may be substituted for cefotaxime in I nia blood concentrations by limiting its availability and production,
patients without vomiting, shock, grade II or higher encephalopa- or by enhancing its metabolism, remains a mainstay of therapy for
thy, or serum creatinine greater than 3 mg/dL patients with both episodic and persistent HE.12
If ascitic fluid PMN counts are greater than 250 cells/mm3 and I
Decreasing ammonia blood concentrations can be attempted by
clinical suspicion of SBP is present, 1.5 g/kg albumin should be
infused within 6 hours of detection and 1 g/kg albumin infusion
reducing ammonia production or by decreasing the availability of
should also be given on day 3 ammonia in the colon. Limiting dietary protein acutely usually results
Prophylaxis against SBP in a lowering of ammonia concentrations and improvement in HE.
Twice-daily norfloxacin or trimethoprim-sulfamethoxazole should I Guidelines for nutritional support of patients with liver disease
be used for 7 days to prevent SBP in cirrhosis patients with have been published by the European Society for Parenteral and
gastrointestinal hemorrhage; intravenous quinolone therapy may Enteral Nutrition.69 Protein withdrawal is a cornerstone of treatment
be used in active bleeding for patients during acute episodes of HE. However, prolonged restric-
Patients who survive an episode of SBP should receive long-term I tion can lead to malnutrition and poorer prognosis among HE
prophylaxis with either daily norfloxacin or trimethoprim-sulfa- patients.12,70 Therefore, once successful reversal of HE symptoms is
methoxazole
achieved, protein is added back to the diet initially with 0.5 to 0.6 g/
Short-term or long-term prophylaxis may be justified in patients I
kg per day and advanced by 0.25 to 0.5 g/kg per day every 3 to 5 days
with ascites whose ascitic total protein is less than 1g/dL or whose
serum bilirubin is greater than 2.5 mg/dL until either a target of 1 to 1.5 g/kg per day is reached or progression
of HE occurs.69 Vegetable-source protein may be preferable to ani-
PMN, polymorphonuclear leukocyte; SBP, spontaneous bacterial peritonitis. mal-source protein because it contains fewer aromatic amino acids
Recommendation Grading: I = randomized controlled trials; II-1 = controlled trials without
randomization; II-2 = cohort or case-control analytic studies; II-3 = multiple time series, dramatic
(phenylalanine, tryptophan, and tyrosine) and methionine which,
uncontrolled experiments; III = opinions of authorities, descriptive epidemiology. when elevated in the serum, can worsen the symptoms of HE.12,69,70
Data from Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology Also, the higher fiber content of vegetable protein increases colonic
2004;39(3):841–856. transit time and lowers colonic pH secondary to its fermentation by
colonic bacteria.12,69 Most patients will tolerate at least 1 g/kg per day
be used (Table 39–7). Presently, the primary substances thought to be of standard proteins without becoming encephalopathic.70 Branched-
involved in the development of HE are ammonia, manganese, and the chain amino acid formulations may provide a better tolerated source
γ-aminobutyric acid (GABA)–benzodiazepine receptors.12,68 of protein in those patients with protein intolerance.12 Bowel cleans-
ing using cathartics or lactulose enemas (see below) results in rapid
Management of Hepatic Encephalopathy removal of ammonia substrate from the colon and may be combined
Episodic HE usually develops in a clinically stable cirrhotic patient as with dietary intervention to help patient eliminate ammonia and
the result of an acute precipitating event.12 Table 39–8 lists the most tolerate dietary protein.

TABLE 39-7 Grading System for Hepatic Encephalopathies

Electroencephalogram
Grade Level of Consciousness Personality/Intellect Neurologic Abnormalities Abnormalities
0 Normal Normal None None
Minimal Normal Normal Psychological only None
1 Inverted sleep patterns/restless Forgetful, mild confusion, agitation, irritable Tremor, apraxia, incoordination, impaired Triphasic waves
handwriting
2 Lethargic, slow responses Disorientation for time, amnesia, decreased Asterixis, dysarthria, ataxia, hypoactive reflexes Triphasic waves
inhibitions, inappropriate behavior
3 Somnolent but arousable, Disorientation for place, aggressive Asterixis, hyperactive reflexes, Babinski sign, Triphasic waves
confused muscle rigidity
4 Coma/unarousable None Decerebrate Delta activity
 645
12
TABLE 39-8 Portosystemic Encephalopathy: Precipitating Factors ing. Despite poor absorption, chronic use of neomycin can lead to
irreversible ototoxicity, nephrotoxicity, and the possibility of staphy-

CHAPTER 39
and Therapy
lococcal superinfection. As such, neomycin should not be considered
Factor Therapy Alternatives
first-line therapy for HE. In patients with an inadequate response to
Gastrointestinal bleeding lactulose alone, combination therapy with neomycin may be tried.12
Variceal Band ligation/sclerotherapy Metronidazole 250 mg twice daily may also produce a favorable
Octreotide clinical response in HE.12 However, neurotoxicity caused by impaired
Nonvariceal Endoscopic therapy
hepatic clearance of the drug may be problematic.12
Proton pump inhibitors
It has been speculated that ammonia generated by Helicobacter
Infection/sepsis Antibiotics
Paracentesis
pylori in the stomach is associated with precipitating or worsening HE

Portal Hypertension and Cirrhosis

Electrolyte abnormalities Discontinue diuretics in patients with cirrhosis.74 However, a prospective clinical trial
Fluid and electrolyte replacement showed no significant improvement in mental status or serum ammo-
Sedative ingestion Discontinue sedatives/tranquilizers nia levels in patients with HE who underwent H. pylori eradication.75
Consider reversal (flumazenil/naloxone) Consequently, routine eradication of H. pylori is not recommended.12
Dietary excesses Limit daily protein Enhancing ammonia removal by stimulating its detoxification by
Lactulose supporting alternative metabolic pathways can reduce blood ammonia
Constipation Cathartics concentrations. L-Ornithine L-aspartate stimulates residual hepatic
Bowel cleansing/enema urea cycle activity and promotes peripheral glutamine synthesis.76 The
Renal insufficiency Discontinue diuretics effectiveness of intravenous L-ornithine L-aspartate at reducing blood
Discontinue nonsteroidal antiinflammatory
ammonia and improving the clinical symptoms of hepatic encepha-
drugs, nephrotoxic antibiotics
Fluid resuscitation
lopathy in cirrhosis patients has been studied and proven to be
effective in patients with grade 1 and grade 2 HE with clinical response
rates similar to those of lactulose.77 Oral L-ornithine L-aspartate is
The use of lactulose, a nonabsorbable disaccharide (and Lactinol, effective at reducing blood ammonia and improving clinical symp-
which is not available in the United States), is standard therapy for toms in patients with grade 2 HE.78
both acute and chronic HE.12 Lactulose, when administered orally, Zinc is a cofactor of urea cycle enzymes and can be deficient in
passes through the gastrointestinal tract and reaches the colon cirrhotic patients, especially in cases of malnourishment. Both
unchanged.12,71 For patients unable to take lactulose orally or via tube supportive and nonsupportive studies evaluating the efficacy of zinc
administration, it may be administered as an enema.12 Lactulose replacement at decreasing ammonia levels and improving symp-
increases osmotic pressure in the colon and also undergoes fermenta- toms of HE have been published.12 In a controlled trial in cirrhotic
tion by gut flora resulting in production of organic acids which lower patients with mild HE, the administration of zinc sulfate 600 mg/
colonic pH. Together, these actions increase peristalsis and exert a day for 3 months resulted in increased urea formation and lower
cathartic effect.71 ammonia levels, along with improvement in psychological test
Acidification of the colon through lactulose administration lowers scores.79 Zinc supplementation is recommended for long-term
ammonia levels in the blood in several ways: (a) it supplies carbohy- management in patients with cirrhosis who are zinc deficient.12
drate to the gut thereby decreasing amino acid breakdown; (b) it Inhibition of GABA–Benzodiazepine Receptors The GABA-
changes bacterial flora metabolism in the gut reducing protein degra- receptor complex is the primary inhibitory neural network within the
dation; (c) it supplies energy for the growth of the bacterial mass in central nervous system. An enhanced GABAergic tone and an
the gut (nitrogen-containing compounds are used in this growth increased amount of endogenous benzodiazepines have been postu-
process and therefore expended); and (d) it decreases bacterial urea lated to contribute to HE.12 Based on evidence of an increase in
degradation.71 Lactulose also enhances the net movement of ammo- benzodiazepine receptor ligands in patients with hepatic encephalop-
nia from the blood into the bowel.12 More than 30 clinical trials have athy, flumazenil has been evaluated for the treatment of HE. Among
demonstrated the efficacy of lactulose in the management of acute five prospective, placebo-controlled trials, three reported benefit with
HE, and more than 20 studies support its use in chronic HE.15 Clinical flumazenil, whereas two found no difference when compared to
improvement is noted in approximately 86% of patients with acute placebo. With dosages of 0.2 to 15 mg IV, response rates were
HE, and in approximately 77% of patients with chronic HE. variable, ranging from 17% to 78%; improvements, however, were
Inhibiting the activity of urease-producing bacteria by using neo- often transient.80 Flumazenil, which is only available in an intrave-
mycin or metronidazole can decrease production of ammonia.72,73 nous dosage form, may be considered for short-term therapy in
Neomycin at doses of 3 to 6 g daily can be given for 1 to 2 weeks refractory patients with suspected benzodiazepine intake, but cannot
during an acute episode of HE.12 For persistent HE, a dose of 1 to 2 g be recommended for routine clinical use.
daily could be used with periodic renal and annual auditory monitor-
Treatment Recommendations:
Hepatic Encephalopathy
TABLE 39-9 Treatment Goals: Episodic and Persistent Hepatic
Encephalopathy (HE) Treatment recommendations depend on the type of HE being
managed, episodic HE, persistent HE, or minimal HE. The general
Episodic HE Persistent HE
approach to the management of HE is to first identify patients with
Control precipitating factor Reverse encephalopathy acute episodic HE and then to provide aggressive management of
Reverse encephalopathy Avoid recurrence any precipitating events (see Table 39–8). When the precipitating
Hospital/inpatient therapy Home/outpatient therapy event has been discovered and appropriate therapy initiated, steps
Maintain fluid and hemodynamic support Manage persistent neuropsychiatric
to rapidly reverse the encephalopathy should be implemented.
abnormalities
Remember that the altered sensorium associated with HE itself is
Manage chronic liver disease
Expect normal mentation after recovery High prevalence of abnormal menta-
associated with increased morbidity and mortality.
tion after recovery  The mainstay of therapy of HE involves measures to lower
blood ammonia concentrations, and includes diet therapy, lactu-
 646
lose, and antibiotics, alone or in combination with lactulose. Other abnormal ventilation-to-perfusion ratio, the presence of arterial venous
adjunctive therapies include zinc replacement in patients with zinc shunts, and changes in the alveolar–arterial membrane.82 These
SECTION 4

deficiency. patients present with dyspnea, and arterial oxygenation is often

In patients with episodic HE, protein is withheld or limited to 10 impaired. In the absence of intrinsic cardiopulmonary disease, cirrhotic
to 20 g/day while maintaining the total caloric intake, until the patients with these findings should be evaluated for hepatopulmonary
clinical situation improves. Titrate protein based on tolerance, syndrome which is diagnosed based upon the presence of arterial
increasing intake in increments of 10 to 20 g/day every 3 to 5 days hypoxemia, an increased alveolar–arterial oxygen gradient, and intra-
to a total of 1 to 1.5 g/kg per day. In patients with persistent HE, pulmonary vasodilation.82 Long-term management requires control of
restrict protein to 40 g/day. Consider the addition of dietary fiber to ascites (see Management of Ascites and Spontaneous Bacterial Perito-
animal-source protein diets. nitis above), supportive therapy with supplemental oxygen, and opti-
Gastrointestinal Disorders

In episodic HE, lactulose is initiated at a dose of 45 mL orally every mizing fluid status. The prognosis for these patients is poor. Ultimately,
hour (or by retention enema, 300 mL lactulose syrup in 1 L water, liver transplantation offers the best chance for long-term recovery.
held for 60 minutes) until catharsis begins. The dose is then decreased Coagulation disorders are common in patients with chronic liver
to 15 to 45 mL orally every 8 to 12 hours (enemas every 6 to 8 hours) disease. These disorders increase the risk of bleeding and tend to
and titrated to produce two to three soft, acidic stools per day. become more profound as the liver failure becomes more severe.
Patients are maintained on this regimen to prevent recurrence of Correction of the coagulopathy is essential for patients actively
episodic HE. Monitor electrolytes periodically, follow patients for bleeding (see Management of Acute Variceal Hemorrhage above),
changes in mental status, and titrate to the number of stools as above. but is not required for patients who present with only minor symp-
Antibiotic therapy with either metronidazole or neomycin is toms such as bruising or nose bleeds and who are not actively
reserved for patients who have not responded to diet and lactulose bleeding. The pathophysiology of the coagulopathy is complex and
therapy, where the combination may provide additive effects and involves impaired synthesis of clotting factors, excessive fibrinolysis,
improved clinical response. Zinc acetate supplementation at a dose disseminated intravascular coagulation, thrombocytopenia, and
of 220 mg twice daily is recommended for long-term management platelet dysfunction.14 Acute therapy involves platelet transfusions for
in patients with cirrhosis who are zinc deficient. thrombocytopenia, and fresh-frozen plasma for prolongation of the
Other adjunctive therapies that may be considered for patients prothrombin time because of clotting factor deficiencies. Long-term
refractory to standard therapy include L-ornithine L-aspartate or management of cirrhotic patients with identified coagulopathies is
flumazenil 0.2 mg up to 15 mg IV. Universal treatment of patients supportive for the management of the underlying cause of cirrhosis;
with minimal HE is not recommended; however, therapy to for example, encouraging abstinence from alcohol.
improve performance of daily activities, or in patients with more The presence of cirrhosis can produce abnormal regulation and
significant deficits, may be considered with close monitoring for function of multiple endocrine systems.83 Most common are femini-
adverse effects. Finally, supportive measures to manage the under- zation and hypogonadism, and hypothyroidism. Cirrhosis perturbs
lying liver failure need to be implemented. the hypothalamic–pituitary axis, which is required for normal regula-
tion of sex and thyroid hormones. In men with cirrhosis, testosterone
■ SYSTEMIC COMPLICATIONS levels are depressed, while estrogen levels are increased. The clinical
manifestations of these changes include loss of libido, muscle wasting,
In addition to the more common complications of chronic liver and gynecomastia. These clinical findings are commonly seen and
disease discussed above, a number of other complications can have been reported to occur in up to 60% of cirrhotic patients.83 In
occur, including hepatorenal syndrome, hepatopulmonary syn-
women, feminization changes are less-well studied. Alcohol use com-
drome, coagulation disorders, and endocrine dysfunction.
plicates and can worsen sex hormone abnormalities.
Hepatorenal syndrome, functional renal failure in the setting of
Both central and peripheral defects in thyroid secretion are noted
cirrhosis in the absence of intrinsic renal disease, occurs in patients
in patients with cirrhosis. Alcohol plays a major role with direct toxic
with cirrhosis as a result of intense vasoconstriction within the renal
effects on the thyroid gland. Management includes thyroid hormone
cortical vasculature. It is common and develops in approximately
replacement for hypothyroidism with the usual doses (levothyroxine
40% of patients with cirrhosis and ascites within 5 years.81 The
50 to 100 mcg/day) and oral testosterone replacement (testosterone
resultant reduction in blood supply to the kidneys causes avid 200 mg three times daily) may be attempted to decrease prevalence of
sodium retention and oliguria. The pathophysiologic mechanism gynecomastia. Routine hormone replacement has not been shown to
responsible for these effects is unknown, but is linked to both the impact survival or disease progression.83
increased vasoconstrictor and decreased vasodilator factors acting on
the renal circulation. The three predominant factors involved in this
process include the hemodynamic changes that decrease renal perfu- ■ LIVER TRANSPLANTATION
sion pressure, a stimulated renal sympathetic nervous system, and an The complications seen in patients with chronic liver disease are
increased synthesis of humoral and renal vasoactive mediators.81 essentially functional as a secondary effect of the circulatory and
Management of hepatorenal syndrome consists of excluding all metabolic changes that accompany liver failure. Consequently, liver
other potential nephrotoxins, such as nonsteroidal antiinflammatory transplantation is the only treatment that can offer a cure for complica-
agents and aminoglycosides, and assessment for prerenal azotemia tions of end-stage cirrhosis. However, patient selection, evaluation, and
secondary to overaggressive diuretic use. Withholding diuretic therapy pre- and postsurgical management are beyond the scope of this review.
and administering a fluid challenge of up to 1.5 L is recommended for
early diagnosis and therapy.81 Other therapies studied in the manage-
ment of hepatorenal syndrome include low (subpressor)-dose dopa- PHARMACOKINETIC AND
mine, ornipressin, terlipressin, and midodrine in combination with PHARAMACODYNAMIC CHANGES
octreotide, misoprostol, n-acetylcysteine, and dialysis.81 Liver trans- IN LIVER FAILURE
plantation, which if successful results in full recovery of renal function,
remains the treatment of choice for refractory hepatorenal syndrome. Cirrhosis modulates the behavior of drugs in the body by inducing
Hepatopulmonary syndrome affects somewhere between 10% and kinetic alterations in drug absorption, distribution, and clearance.
70% of patients with cirrhosis.82 This abnormality is caused by alter- Additionally, patients with cirrhosis may exhibit pharmacodynamic
ations in lung mechanics caused by edema and tense ascites, an changes with increased sensitivity to the effects of certain drugs,
 647
namely opiates, benzodiazepines, and nonsteroidal antiinflammatory activity. In addition, renal insufficiency and alterations that com-
drugs (NSAIDs). These pharmacodynamic changes are separate and monly accompany cirrhosis further complicate empiric dosing rec-

CHAPTER 39
distinct from the enhancement of drug effects seen in cirrhosis ommendations in these patients.84 Dosing recommendations are
patients as a result of pharmacokinetic changes.84 Hepatic drug most commonly nonspecific, with recommendations labeled for
clearance is primarily dependent upon protein binding, hepatic blood patients with mild to moderate liver impairment. Dosing information
flow, and metabolic enzyme activity.85 The pathophysiologic changes for patients with more severe liver impairment is not available. As a
that occur in patients with cirrhosis, including reduced liver blood result, when patients with cirrhosis require therapy with drugs that
flow, altered microcirculatory distribution of blood flow within the undergo hepatic metabolism (e.g., benzodiazepines), monitoring
liver, diminished metabolic and synthetic function, and changes in response to therapy and anticipating drug accumulation and
the endothelial lining of the sinusoids, can have a significant impact enhanced effects is essential. In the case of benzodiazepines, selection

Portal Hypertension and Cirrhosis

on each of these factors. The consequence of these changes is a of an agent such as lorazepam, an intermediate-acting agent that is
reduction in intrinsic metabolic activity, a reduction in the delivery of metabolized via conjugation and has no active metabolites, is easier to
blood to the liver that decreases clearance and prolongs half-life, and monitor than a drug such as diazepam, a long-acting benzodiazepine
a reduction in the degree of protein binding that increases the fraction that is oxidized in the liver and has an active metabolite with a long
of unbound drug in the serum. Finally, patients with cirrhosis half-life of its own. Up-to-date drug dosing recommendation infor-
frequently accumulate large amounts of interstitial fluid resulting in mation for patients with liver disease has been published.87
substantial changes in the volume of distribution, which also prolongs
drug half-life. These changes occur most commonly in combination PHARMACOECONOMIC CONSIDERATIONS
in patients with cirrhosis and are dynamic throughout the disease
course. The effect that these changes will have depends on the drug A number of issues related to the drug therapy and monitoring of
and the type of biotransformation that the drug undergoes. cirrhosis have been studied over the years. Two such studies, both
Drugs with a high extraction ratio (high-extraction drugs) are related to the prevention of variceal bleeding and published recently,
dependent on blood flow for metabolism and the rate of metabolism are mentioned here. A recent analysis provides evidence that HVPG
is sensitive to changes in blood flow. Drugs with a low extraction ratio monitoring is not cost-effective for use in patients with varices and no
(low-extraction drugs) are dependent on intrinsic metabolic activity history of variceal bleeding as compared to treatment with standard β-
for metabolism and the rate of metabolism reflects changes in intrin- blocker therapy without invasive monitoring.88 A cost-utility evalua-
sic clearance and protein binding.84,85 Furthermore, hepatic biotrans- tion of secondary prophylaxis therapies concluded that patients are best
formation involves two types of metabolic processes: phase I reactions served by treatment with either EBL or EBL plus medical management
and phase II reactions. Phase I reactions involve the cytochrome P450 as compared to TIPS placement.89 Because treatment approaches for
system and include hydrolysis, oxidation, dealkylation, and reduction patients with cirrhosis can range from supportive medical therapy, to
reactions. Phase II reactions involve conjugation of the drug with an repeated endoscopic procedures with serious complications, to liver
endogenous molecule such as sulfate or an amino acid, rendering it transplantation, the need for application of economic analysis is obvi-
more water soluble and enhancing its elimination. Drugs metabolized ous. Of critical importance is the question of when, in the course of
by phase I reactions, especially oxidation, tend to be significantly chronic liver disease, are the various treatment interventions employed
impaired in patients with cirrhosis, whereas drugs eliminated by and should liver transplantation be attempted earlier, thereby avoiding
conjugation are relatively unaffected.86 most of the complications associated with chronic liver disease.
The variability and complexity of the interaction between the
extent and severity of liver disease and individual characteristics of the
drug makes it very difficult to predict the degree of pharmacokinetic EVALUATION OF THERAPEUTIC OUTCOMES
perturbation in an individual patient. Unfortunately, there are no
sensitive and specific clinical or biochemical markers that allow us to Table 39–10 summarizes the management approach for patients with
quantify the extent of liver insufficiency or the degree of metabolic cirrhosis, including monitoring parameters and therapeutic out-

TABLE 39-10 Management Approach and Outcome Assessments

Complication Treatment Approach Monitoring Parameter Outcome Assessment
Ascites Diet, diuretics, paracentesis, TIPS Daily assessment of weight Prevent or eliminate ascites and its secondary
complications
Spontaneous bacte- Antibiotic therapy, prophylaxis if undergoing Evidence of clinical deterioration (e.g., abdom- Prevent/treat infection to decrease mortality
rial peritonitis paracentesis inal pain, fever, anorexia, malaise, fatigue)
Variceal bleeding Pharmacologic prophylaxis Child-Pugh score, endoscopy, CBC Appropriate reduction in heart rate and portal
pressure
Endoscopy, vasoactive drug therapy (octreo- CBC, evidence of overt bleeding Acute: control acute bleed
tide), ligation or sclerotherapy, volume resus- Chronic: variceal obliteration, reduce portal
citation, pharmacologic prophylaxis pressures
Coagulation disorders Blood products (PPF, platelets), vitamin K CBC, prothrombin time, platelet count Normalize PT time, maintain/improve hemostasis
Hepatic Ammonia reduction (lactulose, cathartics), elim- Grade of encephalopathy, EEG, psychological Maintain functional capacity, prevent hospitaliza-
encephalopathy ination of drugs causing CNS depression, limit testing, mental status changes, concurrent tion for encephalopathy, decrease ammonia
excess protein in diet drug therapy levels, provide adequate nutrition
Hepatorenal syn- Eliminate concurrent nephrotoxins (NSAIDs), Serum and urine electrolytes, concurrent drug Prevent progressive renal injury by preventing
drome decrease or discontinue diuretics, volume therapy dehydration and avoiding other nephrotoxins
resuscitation, liver transplantation Liver transplantation for refractory hepatorenal
syndrome
Hepatopulmonary Paracentesis, O2 therapy Dyspnea, presence of ascites Acute: relief of dyspnea and hypoxia
syndrome Chronic: manage ascites as above
CBC, complete blood cell count; CNS, central nervous system; EEG, electroencephalogram; PT, prothrombin time; NSAID, nonsteroidal antiinflammatory drug; PPF, plasma protein fraction; TIPS, transjugular
intrahepatic portosystemic shunt.
 648
comes. Cirrhosis is generally a chronic progressive disease that 18. Cohen JA, Kaplan MM. The SGOT/SGPT ratio—An indicator of
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SECTION 4

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20. Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor
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