Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

24. Portal Hypertension and Cirrhosis

Julie M. Sease


 Images Cirrhosis is a severe, chronic, irreversible disease associated with significant morbidity and mortality. However, the progression of cirrhosis secondary to alcohol abuse can be interrupted by abstinence. It is therefore imperative for the clinician to educate and support abstinence from alcohol as part of the overall treatment strategy of the underlying liver disease.

 Images Patients with cirrhosis should receive endoscopic screening for varices, and certain patients with varices should receive primary prophylaxis with nonselective β-adrenergic blockade therapy to prevent variceal hemorrhage.

 Images When nonselective β-adrenergic blocker therapy is used to prevent rebleeding, β-blocker therapy can be titrated to achieve a goal heart rate of 55 to 60 beats/min or the maximal tolerated dose.

 Images Octreotide is the preferred vasoactive agent for the medical management of variceal bleeding. Endoscopy employing endoscopic band ligation is the primary therapeutic tool for the management of acute variceal bleeding.

 Images The combination of spironolactone and furosemide is the recommended initial diuretic therapy for patients with ascites.

 Images All patients who have survived an episode of spontaneous bacterial peritonitis should receive long-term antibiotic prophylaxis.

 Images The mainstay of therapy of hepatic encephalopathy involves therapy to lower blood ammonia concentrations and includes diet therapy, lactulose, and antibiotics alone or in combination with lactulose.

Chronic liver injury causes damage to normal liver tissue resulting in the development of regenerative nodules surrounded by fibrous bands.1 Cirrhosis is an advanced stage of liver fibrosis. The advanced fibrosis of cirrhosis leads to shunting of the portal and arterial blood supply directly into hepatic outflow through the central veins, and exchange between hepatic sinusoids and hepatocytes is compromised. Clinical consequences of cirrhosis include impaired hepatocyte function, the increased intrahepatic resistance of portal hypertension, and hepatocellular carcinoma. Circulatory irregularities such as splanchnic vasodilation, vasoconstriction and hypoperfusion of the kidneys, water and salt retention, and increased cardiac output also occur. The word cirrhosis is derived from the Greek kirrhos, meaning orange-yellow, and refers to the color of the cirrhotic liver as seen on autopsy or during surgery.2

Images While cirrhosis has many causes (Table 24-1), in the Western world, excessive alcohol intake and hepatitis C are the most common causes.1,3 This chapter elucidates the pathophysiology of cirrhosis and the resultant effects on human anatomy and physiology. Treatment strategies for managing the most commonly encountered clinical complications of cirrhosis are discussed.

TABLE 24-1 Etiology of Cirrhosis



The exact prevalence of cirrhosis is unknown, but a reasonable estimate is that 1% of populations have histologically diagnosable cirrhosis.1 Cirrhosis was responsible for over 31,000 deaths in America in 2010, and chronic liver disease continues to be ranked 12th among the leading causes of death in the United States.4 Acute variceal bleeding and spontaneous bacterial peritonitis (SBP) are among the immediately life-threatening complications of cirrhosis. Associated conditions causing significant morbidity include ascites and hepatic encephalopathy (HE). Approximately 50% of patients with cirrhosis develop ascites during 10 years of observation and, within 2 years, nearly half of patients who develop ascites will die.5


Any discussion of cirrhosis must be based on a firm understanding of hepatic anatomy and vascular supply. Conceptually, the liver can be thought of as an elaborate blood filtration system receiving blood from the hepatic artery and the portal vein (Fig. 24-1), with portal blood originating from the small intestines.6 Blood enters the liver via the portal triad, which contains branches of the portal vein, hepatic artery, and bile ducts. It then drains through the sinusoidal spaces (also known as the space of Disse) of the hepatic lobule (Fig. 24-2), which are lined by the workhorses of the liver, the hepatocytes. Individual hepatocytes are arranged in plates that are one cell thick and organized around individual central veins. The six or more surfaces of each individual hepatocyte 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 veins, and then empties into larger hepatic veins and eventually into the inferior vena cava. Functional gradients of hepatocytes based on oxygen saturation have been reported. Hepatocytes closest to the portal triad, which contains the hepatic artery, have greater oxygen saturation than those hepatocytes nearer to the terminal hepatic venule. Blood flows past hepatocytes in zone one, then zone two, and finally zone three before entering the central vein. Hepatocytes in zone one are involved in gluconeogenesis, urea synthesis, and oxidative energy metabolism while those in zone three carry out the functions of glycolysis and lipogenesis.


FIGURE 24-1 The portal venous system.


FIGURE 24-2 The hepatic lobule.

Normally, hepatic stellate cells function to store vitamin A and help to maintain the normal matrix in the sinusoidal space.7 During chronic liver disease, however, hepatic stellate cells undergo an “activation” process, which is the central event in the development of hepatic fibrosis. Activation causes stellate cells to lose vitamin A, become highly proliferative, and synthesize fibrotic scar tissue, which accumulates in the sinusoidal space. This leads to loss of hepatocyte microvilli, loss of sinusoidal endothelial fenestrae, deterioration of hepatocyte function, and, if fibrosis progresses, eventual cirrhosis.

Cirrhosis causes changes to the splanchnic vascular bed as well as the systemic circulation.8 Splanchnic vasodilation, decreased responsiveness to vasoconstrictors, and the formation of new blood vessels contribute to an increased splanchnic blood flow, formation of gastroesophageal varices, and variceal bleeding. All of these components are part of the portal hypertensive syndrome. Portal hypertension is characterized by hypervolemia, increased cardiac index, hypotension, and decreased systemic vascular resistance. This is a so-called hyperkinetic syndrome that leads to a marked activation of neurohumoral vasoactive factors, a response that occurs in an effort to maintain the arterial blood pressure within normal limits. Activation of neurohumoral vasoactive factors is a main component in the pathophysiology of the ascites and renal dysfunction that often accompany chronic liver disease. Portal-systemic shunting may also occur and is involved in HE and other complications.

In summary, cirrhosis results from fibrotic changes within the hepatic sinusoids and results in changes in the levels of vasodilatory and vasoconstrictor mediators and an increase in blood flow to the splanchnic vasculature.


Cirrhosis and the pathophysiologic abnormalities that cause it result in the commonly encountered problems of ascites, portal hypertension, esophageal varices, HE, and coagulation disorders. Other less commonly seen problems in patients with cirrhosis include hepatorenal syndrome, hepatopulmonary syndrome, and endocrine dysfunction. These are discussed in Management of Portal Hypertension and Variceal Bleeding below.


Ascites is the accumulation of an excessive amount of fluid within the peritoneal cavity.9 It is the most commonly occurring major complication of cirrhosis.5 Approximately half of all cirrhotic patients develop ascites within 10 years of diagnosis. Several hypotheses have been offered to explain the mechanism for the development of ascites in decompensated cirrhosis.9 Most acceptable theories state that ascites formation begins as a result of the development of sinusoidal hypertension and portal hypertension. Portal hypertension activates vasodilatory mechanisms that are mediated mostly by nitric oxide overproduction. This leads to splanchnic and peripheral arteriolar vasodilation and, in advanced disease, a drop in arterial pressure. Baroreceptor-mediated activation of the renin–angiotensin–aldosterone system, activation of the sympathetic nervous system, and release of antidiuretic hormone occur in response to the resulting arterial hypotension in an effort to restore normal blood pressure (Fig. 24-3). These changes cause renal sodium and water retention. Additionally, ongoing splanchnic vasodilation increases splanchnic lymph production beyond the capacity of the lymph transportation system. Leakage of lymphatic fluid into the peritoneal cavity occurs. Persistent renal sodium and water retention, increased splanchnic vascular permeability, and lymph leakage into the peritoneal cavity combine to create the sustained ascites formation of end-stage liver disease.


FIGURE 24-3 Pathogenesis of ascites.

Portal Hypertension and Varices

Sinusoidal portal hypertension is most often caused by cirrhosis.10 It is associated with acute variceal bleeding, a medical emergency that carries a mortality rate of 10% to 20% at 6 weeks, and is among the most severe complications of cirrhosis.11 Portal hypertension is defined by the presence of a gradient of greater than 5 mm Hg between the portal and central venous pressures (see Fig. 24-1).10 This gradient is called the hepatic venous pressure gradient (HVPG). Esophageal and gastric varices and variceal bleeding may arise after a HVPG pressure gradient of 10 mm Hg is reached.

Progression to bleeding can be predicted by Child-Pugh score, size of varices, and the presence of red wale markings on the varices. First variceal hemorrhage occurs at an annual rate of about 15% and carries a mortality of 7% to 15%. Rebleeding is common following initial hemorrhage with a median rate of 60% and carries a mortality rate as high as 33%. Prevention of bleeding is a major goal in the therapy of portal hypertension, and strategies include both pharmacologic and surgical approaches.

Hepatic Encephalopathy

HE is a metabolically induced functional disturbance of the brain that is potentially reversible.12 Symptoms of HE are thought to result from an accumulation of gut-derived nitrogenous substances in the systemic circulation as a consequence of decreased hepatic functioning and shunting through portosystemic collaterals bypassing the liver.13 Once these substances enter the CNS, they cause alterations of neurotransmission that affect consciousness and behavior. Ammonia is the most commonly cited culprit in the pathogenesis of HE, but glutamine, benzodiazepine receptor agonists, aromatic amino acids, and manganese are also potential causes.12,13 Arterial ammonia levels are increased commonly in both acute and chronic liver diseases, but an established correlation between blood ammonia levels and mental status does not exist.13 Despite this, interventions to lower blood ammonia levels remain the mainstay of treatment for HE.

HE is now categorized as type A, B, or C based on nomenclature developed by the 11th World Congress of Gastroenterology.12 Type A is HE induced by acute liver failure, type B is due to portal-systemic bypass without associated intrinsic liver disease, and type C is HE that occurs in patients with cirrhosis. Minimal HE refers to cirrhotic patients who do not suffer clinically overt cognitive dysfunction but who are found to have cognitive impairment on psychological studies. The onset of HE in a patient with liver failure may be related to the presence of several known precipitating factors. In cases of HE associated with a precipitant, if that precipitant can be cured or discontinued, it may also be possible to discontinue treatment for HE. In many cases, no precipitant is found and, therefore, long-term treatment of HE may be required.


Signs and Symptoms

    • Asymptomatic

    • Hepatomegaly and splenomegaly

    • Pruritus, jaundice, palmar erythema, spider angiomata, and hyperpigmentation

    • Gynecomastia and reduced libido

    • Ascites, edema, pleural effusion, and respiratory difficulties

    • Malaise, anorexia, and weight loss

    • Encephalopathy

Laboratory Tests

    • Hypoalbuminemia

    • Elevated prothrombin time (PT)

    • Thrombocytopenia

    • Elevated alkaline phosphatase

    • Elevated aspartate transaminase (AST), alanine transaminase (ALT), and ã-glutamyl transpeptidase (GGT)

Coagulation Defects

The liver synthesizes most of the proteins that are responsible for the maintenance of hemostasis (the balance between coagulation and anticoagulation).14 Hepatocellular damage can lead to a disruption in hemostasis because of defects it may cause in the function of coagulation and fibrinolytic factors. These defects include a reduction in the synthesis of clotting factors, excessive fibrinolysis, disseminated intravascular coagulation, thrombocytopenia, and platelet dysfunction. Most coagulation factors are created in the liver, and the levels of these factors can be significantly reduced in chronic liver disease associated with extensive hepatocellular damage. Factor VII is the first factor to decrease as liver function declines due to its short half-life. A reduction in clotting factor VII is common in end-stage liver disease, affecting 60% of patients. Low factor VII activity is prognostic for reduced survival, and the prothrombin time (PT) is a standard component of the Child-Pugh scoring system. Accelerated intravascular coagulation and fibrinolysis can be detected in some patients with cirrhosis. The coexistence of sepsis, shock, surgery, trauma, or ascites may cause a progression from accelerated intravascular coagulation to disseminated intravascular coagulation. In patients with cirrhosis, disseminated intravascular coagulation involves increased release of procoagulants, impaired removal of activated coagulation factors and endotoxins produced by gut bacteria, and reduced synthesis of coagulation inhibitors. Both platelet number and function may also be affected in cirrhosis. Platelet numbers are reduced by multiple mechanisms, including splenomegaly due to portal hypertension and sequestration of platelets in the spleen, reduced hepatic production of thrombopoietin, bone marrow suppression, and increased platelet destruction. Mild to moderate thrombocytopenia occurs in 15% to 70% of patients with cirrhosis. The net effect of the coagulation disorders that occur in cirrhosis is the development of bleeding.


Cirrhotic patients may present in a variety of ways, from asymptomatic with abnormal radiographic or laboratory studies to decompensated with ascites, SBP, HE, or variceal bleeding.15

The approach to a patient with suspected liver disease begins with a thorough history and physical exam. Some presenting characteristics of patients with cirrhosis include anorexia, weight loss, weakness, fatigue, jaundice, pruritus, GI bleeding, coagulopathy, increasing abdominal girth with shifting flank dullness, mental status changes, and vascular spiders. Osteoporosis, as a result of vitamin D malabsorption and resultant calcium deficiency, can also occur.

A thorough history including risk factors that predispose patients to cirrhosis should be taken. Quantity and duration of alcohol intake should be determined. Risk factors for hepatitis B and C transmission should be inquired about. These include birthplace in endemic areas, sexual history, intranasal or IV drug use, body piercing or tattooing, and accidental contamination of body tissues or blood. Information concerning any history of transfusions, as well as any personal history of autoimmune or hepatic diseases, should be gathered. A family history should also be taken, looking especially for any family member with a prior history of autoimmune or hepatic diseases.

Laboratory Abnormalities

There are no laboratory or radiographic tests of hepatic function that can accurately diagnose cirrhosis. Despite this, liver function tests, a complete blood count with platelets, and a PT test should be performed if liver disease is suspected. Tests that measure the level of serum liver enzymes are usually referred to as liver function tests.16 However, these tests actually reflect hepatocyte integrity or cholestasis, not liver function.

Routine liver tests include alkaline phosphatase, bilirubin, AST, ALT, and GGT. Additional markers of hepatic synthetic activity include albumin and PT. Liver function tests are often the first step in the evaluation of patients who present with symptoms or signs suggestive of cirrhosis.15 The use of liver function tests in the diagnosis and management of cirrhosis is discussed in the following sections. It may be useful to group the tests into two broad categories: markers of hepatocyte integrity such as the transaminases and markers of liver function mass such as PT and albumin.16


The aminotransferases, AST and ALT, are enzymes that are highly concentrated in the liver. Liver injury, whether acute or chronic, results, at some point in the course of the disease, in increases in the serum concentrations of the aminotransferase enzymes. The degree of elevation, rate of rise, and nature of the course of alteration in aminotransferase serum levels are helpful in suggesting possible etiologies. Liver function tests will typically be elevated to the highest levels in acute viral, ischemic, or toxic liver injury. Chronic hepatitis and cirrhosis patients may present with elevated aminotransferase levels, but they may also present with aminotransferase levels within the normal reference range. The degree of aminotransferase level elevation is dependent on the course of the hepatic injury being experienced by the patients and also depends on when the enzyme levels are tested. In a landmark study by Cohen and Kaplan, alcoholic liver disease resulted in AST elevations of only six to seven times the upper limit of normal in 98% of patients.17 The ratio of AST to ALT also provides information in patients with suspected alcoholic liver disease. Seventy percent of patients with alcoholic liver disease in the study by Cohen and Kaplan had ratios greater than 2, whereas 92% of patients had ratios greater than 1.

Alkaline Phosphatase and γ-Glutamyl Transpeptidase

Elevated serum levels of alkaline phosphatase and GGT occur in cases of liver injury with a cholestatic pattern and therefore accompany conditions such as primary biliary cirrhosis, primary sclerosing cholangitis, drug-induced cholestasis, bile duct obstruction, autoimmune cholestatic liver disease, and metastatic cancer of the liver.16 Neither alkaline phosphatase nor GGT is found solely 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 concomitant elevation in GGT level increases clinical suspicion of hepatic etiology.

Child-Pugh Classification and Model for End-Stage Liver Disease Score

The Child-Pugh classification system has gained widespread acceptance as a means of quantifying the myriad effects of the cirrhotic process on the laboratory and clinical manifestations of this disease.18Recommended drug dosing adjustments for patients in liver failure, when available, are normally based on the Child-Pugh score. The newer Model for End-Stage Liver Disease (MELD) scoring system is now the accepted classification scheme used by the United Network for Organ Sharing in the allocation livers for transplantation.19 The Child-Pugh classification system employs a combination of physical and laboratory findings (Table 24-2), whereas the MELD score calculation takes into account a patient’s serum creatinine, bilirubin, international normalized ratio (INR), and etiology of liver disease, omitting the more subjective reports of ascites and encephalopathy used in the Child-Pugh system. The MELD scoring calculation* is as follows20:

TABLE 24-2 Criteria and Scoring for the Child-Pugh Grading of Chronic Liver Disease



or using SI units*:


These classification systems are important because they are used to assess and define the severity of the cirrhosis, and as a predictor for patient survival, surgical outcome, and risk of variceal bleeding.


Bilirubin is the product of the breakdown of hemoglobin molecules in the reticuloendothelial system.16 Elevations in serum conjugated bilirubin indicate that the liver has lost at least half of its excretory capacity and are usually a sign of liver disease. When found in conjunction with markedly elevated AST and ALT, conjugated hyperbilirubinemia indicates the possible presence of acute viral hepatitis, autoimmune hepatitis, toxic liver injury, or ischemic liver injury. Elevated conjugated bilirubin levels with concomitant increases in alkaline phosphatase and normal aminotransferase levels are a sign of cholestatic disease and possible cholestatic drug reactions. Causes of elevations in unconjugated bilirubin include hemolysis, Gilbert’s syndrome, hematoma reabsorption, and ineffective erythropoiesis. Causes of conjugated hyperbilirubinemia include bile duct obstruction, hepatitis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, total parenteral nutrition, drug toxins, and vanishing bile duct syndrome. When cirrhosis has been established, the degree of bilirubin elevation has prognostic significance and is used as a component of the Child-Pugh and MELD scoring systems for quantifying the degree of cirrhosis.18,20

Figure 24-4 describes a general algorithm for the interpretation of liver function tests. The algorithm first separates the tests into two categories based on the underlying pathology (pattern of elevations): obstructive (alkaline phosphatase, GGT, and bilirubin) versus hepatocellular (AST and ALT). If a hepatocellular pattern predominates, the magnitude of elevation provides diagnostic assistance. If the degree of elevation is greater than 10 times normal, the etiology is likely a result of drugs or other toxins, ischemia, or acute viral hepatitis.16 Elevations less than 10 times normal have a broad differential. Unfortunately, most liver enzyme abnormalities will fall into a mixed pattern providing limited diagnostic assistance.


FIGURE 24-4 Interpretation of liver function tests. (DDX, differential diagnosis.)

Albumin and Coagulation Factors

Albumin and coagulation proteins are markers of hepatic synthetic activity and are therefore used to estimate the level of hepatic functioning in cirrhosis. Albumin and PT are used in the Child-Pugh system for quantifying liver disease, and the INR is used in the MELD scoring system as a marker of coagulation.18,20 Albumin levels can be affected by a number of factors, including malnutrition, malabsorption, and protein losses from renal and intestinal sources.16

Coagulation factors I, II, V, VII, VIII, IX, X, XI, XII, and XIII are synthesized in the liver.14 Significantly reduced levels of coagulation factors II, V, VII, and XIII have been observed in patients with chronic liver disease resulting in PT prolongation and systemic bleeding unrelated to portal hypertension.


Thrombocytopenia (generally defined as a platelet count less than 150,000/mm3 [150 × 109/L]) is a common feature of chronic liver disease found in 15% to 70% of cirrhotic patients depending on the stage of liver disease and definition of thrombocytopenia. The etiology of thrombocytopenia in liver disease is multifactorial, involving primarily splenomegaly due to portal hypertension with pooling of platelets in the spleen. A decrease in thrombopoietin due to decreased hepatic synthesis occurs as well as an immune-mediated destruction of platelets. Additionally, bone marrow suppression related to the hepatitis C virus or interferon antiviral treatment may exist and lead to thrombocytopenia associated with the cirrhotic process.

Endoscopic and Radiographic Abnormalities

While no radiographic test is considered a diagnostic standard for cirrhosis, radiographic studies may be used to detect ascites, hepatosplenomegaly, hepatic or portal vein thromboses, and hepatocellular carcinoma.15Ultrasonography, because it does not require radiation exposure or IV contrast and is relatively low cost, should be the first radiographic study in the evaluation of a patient with suspected cirrhosis. Hepatic nodularity, irregularity, increased echogenicity, and atrophy are all ultrasonographic findings indicative of cirrhosis. Ascites may also be detected on ultrasound. Computed tomography and magnetic resonance imaging can demonstrate liver nodularity as well as atrophic and hypertrophic changes. Ascites and varices may also be detected on computed tomography or magnetic resonance imaging scans. Portal vein patency can be assessed by computer tomography imaging.

Liver Biopsy

Liver biopsy should be considered after a thorough noninvasive workup has failed to confirm a diagnosis in suspected cirrhosis. Liver biopsy has a sensitivity and specificity of 80% to 100% for an accurate diagnosis of cirrhosis and its etiology. The success of biopsy as a diagnostic tool is dependent on the number of histologic samples retrieved as well as the sampling method used.


General Approaches to Treatment

General approaches to therapy in cirrhosis should include the following:

   1. Identify and eliminate, where possible, the causes of cirrhosis (e.g., alcohol abuse).

   2. Assess the risk for variceal bleeding and begin pharmacologic prophylaxis when indicated. Prophylactic endoscopic therapy can be used for patients with high-risk medium and large varices as well as in patients with contraindications or intolerance to nonselective β-adrenergic blockers. Endoscopic therapy is also appropriate for patients suffering acute bleeding episodes. Variceal obliteration with endoscopic techniques in conjunction with pharmacologic intervention is the recommended treatment of choice in patients with acute bleeding.

   3. Evaluate the patient for clinical signs of ascites and manage with pharmacologic therapy (e.g., diuretics) and paracentesis. Careful monitoring for SBP should be used in patients with ascites who undergo acute deterioration.

   4. HE is a common complication of cirrhosis and requires clinical vigilance and treatment with dietary restriction, elimination of CNS depressants, and therapy to lower ammonia levels.

   5. Frequent monitoring for signs of hepatorenal syndrome, pulmonary insufficiency, and endocrine dysfunction is necessary.

Desired Outcomes

The desired therapeutic outcomes can be viewed in two categories: resolution of acute complications such as tamponade of bleeding and resolution of hemodynamic instability for an episode of acute variceal hemorrhage and prevention of complications through lowering of portal pressure with medical therapy using β-adrenergic blocker therapy or supporting abstinence from alcohol. Treatment end points and desired therapeutic outcomes are presented for each of the recommended therapies discussed.

Management of Portal Hypertension and Variceal Bleeding

The management of varices involves three strategies: (a) primary prophylaxis (prevention of the first bleeding episode); (b) treatment of acute variceal hemorrhage; and (c) secondary prophylaxis (prevention of rebleeding in patients who have previously bled).11

Primary Prophylaxis

β-Adrenergic Blockade The mainstay of primary prophylaxis is the use of nonselective β-adrenergic blocking agents such as propranolol or nadolol.10,11,21 These agents reduce portal pressure by reducing portal venous inflow via two mechanisms: a decrease in cardiac output through β1-adrenergic blockade and a decrease in splanchnic blood flow through β2-adrenergic blockade.10

Endoscopic Variceal Ligation (EVL) EVL is an endoscopic therapy that consists of placing rubber bands around varices until the varices are obliterated.21

Treatment Recommendations: Variceal Bleeding—Primary Prophylaxis

Images All patients with cirrhosis should be screened for varices on diagnosis.10,11,21 β-Adrenergic blocker therapy is not indicated in patients without varices to prevent the formation of varices. Patients with small varices plus risk factors for variceal hemorrhage including red wale marks or Child-Pugh class C should receive prophylaxis therapy with a nonselective β-adrenergic blocker. β-Adrenergic blocker therapy is recommended preferentially to EVL in this situation due to the technical difficulty of EVL in the treatment of small varices. β-Adrenergic blocker therapy is not recommended for patients with small varices in the absence of risk factors as there is insufficient evidence to support this therapy to slow the growth of varices in this scenario. All patients found to have medium to large varices that have not bled should receive primary prophylaxis therapy with a nonselective β-adrenergic blocker or EVL. The choice of treatment should be based on a consideration of resources and expertise as well as patient preferences and characteristics with a particular emphasis on side effects and contraindications.11 If β-adrenergic blocker therapy is chosen, initiate therapy with oral propranolol 20 mg twice daily or nadolol 20 to 40 mg once daily and titrate every 2 to 3 days to maximal tolerated dose to heart rates of 55 to 60 beats/min.10,21 Once a patient is started on nonselective β-adrenergic blocker therapy, it should be continued indefinitely. Following initiation and appropriate titration of the β-adrenergic blocker, further endoscopic surveillance is not needed. If EVL is chosen, it will be performed every 1 to 2 weeks until the obliteration of varices.21 Followup surveillance will occur at 1 to 3 months and again every 6 to 12 months thereafter.

Patients with contraindications to therapy with nonselective β-adrenergic blockers (i.e., those with asthma, insulin-dependent diabetes with episodes of hypoglycemia, and peripheral vascular disease) or intolerance to β-adrenergic blockers should be considered for alternative prophylactic therapy with EVL.22 Also, EVL may be considered as a possible first option for primary prophylaxis in patients with high-risk medium to large varices. Nitrates are no longer recommended as alternative therapy for primary prophylaxis against variceal bleeding in patients with intolerance to nonselective β-adrenergic blocker due to a potential for higher mortality with this therapy.21 At this time, there is also insufficient evidence to support the use of other therapies and procedures (such as combination nonselective β-adrenergic blocker therapy with isosorbide mononitrate, combination nonselective β-adrenergic blocker therapy with spironolactone, combination nonselective β-adrenergic blocker therapy with EVL, shunt surgery, and endoscopic sclerotherapy) for primary prevention of variceal hemorrhage.

Acute Variceal Hemorrhage

Variceal hemorrhage is a medical emergency that carries a mortality rate of 15% to 20%, requires admission to an intensive care unit, and is one of the most feared complications of cirrhosis.10,21 Treatment of acute variceal bleeding includes general stabilizing and assessment measures as well as specific measures to control the acute hemorrhage and prevent complications.

Initial treatment goals include (a) adequate blood volume resuscitation, (b) protection of airway from aspiration of blood, (c) correction of significant coagulopathy and/or thrombocytopenia with fresh-frozen plasma and platelets, (d) prophylaxis against SBP and other infections, (e) control of bleeding, (f) prevention of rebleeding, and (g) preservation of liver function.22 Prompt stabilization of blood volume with a goal of maintaining hemodynamic stability and a hemoglobin of 8 g/dL (80 g/L; 4.97 mmol/L) should be undertaken. Volume should be expanded to maintain a systolic blood pressure of 90 to 100 mm Hg and a heart rate of less than 100 beats/min, but vigorous resuscitation with saline solution should generally be avoided because this may lead to recurrent variceal hemorrhage or accumulation of ascites and/or fluid at other anatomic sites.21,22 Use of recombinant factor VIIa therapy is not recommended in cirrhotic patients with GI hemorrhage at this time. Airway management is critical in patients with variceal hemorrhage, especially those with concomitant HE or severe bleeding.22 Elective or more emergent intubation may be required prior to diagnostic endoscopy. Combination pharmacologic therapy plus endoscopic therapy with preferably EVL, or sclerotherapy if EVL is not technically feasible, is considered the most rational approach to the treatment of acute variceal bleeding.10,21

Vasoactive drug therapy (usually octreotide) is routinely used early to stop or slow bleeding for patient management as soon as a diagnosis of variceal bleeding is suspected, and potentially even before endoscopy. Antibiotic therapy to prevent SBP and other infections, as well as to prevent rebleeding and decrease mortality, should be implemented. Figure 24-5 presents an algorithm for the management of variceal hemorrhage.


FIGURE 24-5 Management of acute variceal hemorrhage.

Drugs employed to manage acute variceal bleeding in the United States include (a) the somatostatin analogue octreotide and (b) vasopressin. These agents work as splanchnic vasoconstrictors, thus decreasing portal blood flow and pressure.21 Agents available in other countries also include terlipressin, which is an analogue of vasopressin, and another somatostatin analogue, vapreotide.

Somatostatin and Octreotide

Somatostatin is a naturally occurring tetradecapeptide hormone, and octreotide is a synthetic octapeptide that shares a four–amino acid segment with somatostatin and has similar pharmacologic activity with greater potency and longer duration of action as compared with somatostatin.23 Somatostatin and octreotide cause a reduction in portal pressure and port-collateral blood flow through inducing splanchnic vasoconstriction without causing the systemic effects associated with vasopressin.22,23 The splanchnic vasoconstriction found with somatostatin and octreotide therapy is due to inhibition of the release of vasodilatory peptides such as glucagon; however, octreotide has a local vasoconstrictive effect confined to the splanchnic vasculature.22 Somatostatin and somatostatin analogues are associated with fewer side effects as compared with vasopressin. The side effects of somatostatin therapy may include sinus bradycardia, hypertension, arrhythmia, and abdominal pain.10 The currently recommended dosing of octreotide for variceal bleeding consists of an initial IV bolus of 50 mcg followed by a continuous IV infusion of 50 mcg/h. Because octreotide is safe for continuation for multiple days and because around half of early recurrent bleeding occurs within the first 3 to 5 days, guidelines suggest continuation of octreotide for 5 days after acute variceal bleeding.11,21


Vasopressin (also known as antidiuretic hormone) is a potent, nonselective vasoconstrictor that reduces portal pressure by causing splanchnic vasoconstriction, which reduces splanchnic blood flow.23Unfortunately, the vasoconstrictive effects of vasopressin are nonselective—the vasoconstriction is not restricted to the splanchnic vascular bed. Potent systemic vasoconstriction induces peripheral resistance, which reduces cardiac output, heart rate, and coronary blood flow. These effects on cardiac hemodynamics can lead to myocardial ischemia or infarction, arrhythmias, mesenteric ischemia, ischemia of the limbs, and cerebrovascular accidents. A meta-analysis comparing vasopressin and somatostatin in the management of acute esophageal variceal hemorrhage found somatostatin more efficacious for controlling acute hemorrhage from esophageal varices with significantly less adverse effects.24 Only four patients must be treated with somatostatin over vasopressin for one to derive additional benefit in terms of initial control of bleeding, and only nine patients need to be treated with somatostatin instead of vasopressin in order for one to experience benefit in terms of avoidance of rebleeding. Although somatostatin is not available in the United States today, its analogue octreotide is commonly used instead of vasopressin for acute variceal hemorrhage.

A recommended dosing strategy for vasopressin is a continuous IV infusion of 0.2 to 0.4 units/min, which can be increased to a maximal dose of 0.8 units/min.22 Vasopressin should only be used at the highest effective dose continuously for a maximum of 24 hours and should always be administered with IV nitroglycerin at a starting dose of 40 mcg/min (which can be increased to a maximum of 400 mcg/min and adjusted to maintain systolic blood pressure over 90 mm Hg) in order to minimize the risk of serious adverse events. With the addition of safer and equally effective treatment alternatives, vasopressin, alone or combined with nitroglycerin, can no longer be recommended as first-line therapy for the management of variceal hemorrhage.10,22 Terlipressin, a synthetic analogue of vasopressin, has fewer side effects and a longer duration of action than vasopressin. It reduces mortality in acute variceal hemorrhage, but is not currently available in the United States.10

Cirrhotic patients with active bleeding are at high risk of severe bacterial infections such as SBP.22 Short-term prophylactic antibiotic therapy to reduce the risk of infection during episodes of bleeding not only reduces the likelihood of development of SBP and other infections but also reduces the incidence of rebleeding and increases short-term survival.21 Prophylactic antibiotic therapy should be prescribed for all patients with cirrhosis and acute variceal bleeding.22 A short course (7 days maximum) of oral norfloxacin 400 mg twice daily or IV ciprofloxacin when the oral route is not available is recommended. Alternatively, in patients with severe cirrhosis in areas with high quinolone resistance, IV ceftriaxone 1 g/day may be preferable.

Clinical Controversy…

Whether nonselective β-blocker or EVL is best for primary prophylaxis against variceal bleeding remains unsettled.10 Some centers tend to perform EVL more readily in this indication. Others favor the more conservative approach of instituting a trial with nonselective β-blocker first, reserving EVL for patients unable to tolerate the β-blocker. Carvedilol is a nonselective β-blocker with α1-adrenergic activity that shows promise for potentially being more effective than EVL in preventing first variceal hemorrhage. Further research is needed before carvedilol can be routinely recommended for this indication, however.

Endoscopic Interventions: Sclerotherapy and Band Ligation

The Baveno V Consensus Report recommends that endoscopy be performed as soon as possible (at least within 12 hours) following admission in cases of upper GI bleeding in patients with features suggestive of cirrhosis.11Endoscopy is used to diagnose variceal bleeding, and endoscopic techniques, such as EVL and sclerotherapy, can be used in an attempt to stop variceal bleeding. EVL consists of placement of rubber bands around the varix through a clear plastic channel attached to the end of the endoscope.21 EVL can be repeated if hemorrhage is not controlled or in the event of early recurrence of bleeding. Endoscopic sclerotherapy involves injection of 1 to 4 mL of a sclerosing agent into the lumen of the varices to tamponade blood flow. EVL is more effective than sclerotherapy with greater control of hemorrhage, less risk for rebleeding, lower likelihood of adverse events, and lower mortality.10Consensus recommendation calls for EVL (in conjunction with pharmacologic therapy) as the recommended form of endoscopic therapy for acute variceal bleeding, although endoscopic sclerotherapy may be employed if ligation is technically difficult.11 Endoscopic injection of the tissue adhesive N-butyl cyanoacrylate is recommended to control acute gastric variceal bleeding from isolated gastric varices and gastroesophageal varices type 2 that extend beyond the cardia. EVL or tissue adhesive can be used for bleeding from gastroesophageal varices type 1.

Interventional and Surgical Treatment Approaches

Standard therapy fails to control initial bleeding or early rebleeding in 10% to 20% of patients with acute variceal hemorrhage.21 In these cases, a salvage procedure, such as balloon tamponade or transjugular intrahepatic portosystemic shunt (TIPS), is necessary. Balloon tamponade is effective in controlling variceal bleeding temporarily; however, rebleeding is common after balloon deflation, and complications result in mortality rates of up to 20% with balloon tamponade. Sengstaken-Blakemore tubes are recommended for use in esophageal variceal bleeding. Linton tubes are preferred for bleeding from fundal gastric varices. Balloon tamponade should be reserved as a temporizing measure until a more definitive treatment, such as TIPS, can be performed.

The TIPS procedure involves the placement of one or more stents between the hepatic vein and the portal vein (Fig. 24-6). TIPS (preferably with polytetrafluoroethylene-covered stents) is recommended for patients who fail to achieve hemostasis despite combined endoscopic and pharmacologic therapy.11 TIPS provides an effective decompressive shunt without laparotomy and can be employed regardless of Child-Pugh score, unlike shunt surgery, which is restricted to Child-Pugh class A patients.22 TIPS decreases the incidence of variceal rebleeding and decreases the incidence of deaths due to rebleeding.25There is a significantly increased rate of posttreatment encephalopathy found in TIPS-treated patients.


FIGURE 24-6 Transjugular intrahepatic portosystemic shunt (TIPS).

Treatment Recommendations: Variceal Hemorrhage

Patients require cautious resuscitation with colloids and blood products to correct intravascular losses and to reverse existing coagulopathies.10,11,21,22 Images Drug therapy with octreotide should be initiated early to control bleeding and facilitate diagnostic and therapeutic endoscopy. Therapy is initiated with an IV bolus of 50 mcg and is followed by a continuous infusion of 50 mcg/h for 3 to 5 days.21,22 Monitor patients for bradycardia, hypertension, arrhythmia, and abdominal pain.10 Endoscopy is recommended in any patient with suspected upper GI bleeding due to ruptured varices.10,11,21,22 EVL is the recommended form of endoscopic therapy, but endoscopic sclerotherapy may be employed if EVL is technically difficult. An additional endoscopic therapy option is injection of the tissue adhesive N-butyl cyanoacrylate for gastric varices.11 Short-term antibiotic prophylaxis (maximum 7 days) is recommended.11,22 Appropriate choices include norfloxacin 400 mg twice daily or IV ciprofloxacin if the oral route is unavailable.22 In patients with advanced cirrhosis in areas of high quinolone resistance, IV ceftriaxone 1 g daily may be preferred. Surgical shunts and TIPS are employed as salvage therapy in patients who have failed repeated endoscopy and vasoactive drug therapy.11

Secondary Prophylaxis

Because rebleeding after initial control of variceal hemorrhage occurs in a median of 60% of patients and because rebleeding carries a mortality rate of 33%, it is inappropriate to simply observe patients for evidence of further bleeding.10,22 Only patients who underwent shunt surgery or TIPS to control their initial acute bleeding require no further intervention as secondary prophylaxis. Patients who underwent one of these procedures to treat their initial bleeding should be referred for transplantation if they are a candidate. Candidates include those with a Child-Pugh score greater than or equal to 7 or MELD score greater than or equal to 15.22 Combination therapy with β-adrenergic blockers and chronic EVL to eradicate varices is the best treatment option for secondary prophylaxis of variceal bleeding.10,11,21,22Secondary prophylaxis should be started once vasoactive drug therapy is discontinued and as soon as possible (as early as day 6) following the acute bleeding event.10,11

Drug Therapy

The combination of EVL and a nonselective β-adrenergic blocking agent provides the most rational approach for secondary prophylaxis because nonselective β-adrenergic blocking agents can protect against variceal rebleeding before variceal obliteration can be accomplished through EVL, and β-adrenergic blocking agents will also delay variceal recurrence.21,22 The addition of isosorbide mononitrate to nonselective β-adrenergic blocker therapy reduces portal pressure more than β-adrenergic blocker alone, but there is no difference in the overall rate of rebleeding with this combination and side effects are more likely than with β-adrenergic blocker monotherapy (namely, headache and light-headedness).26 Pharmacologic therapy (either isosorbide mononitrate plus nonselective β-adrenergic blocker therapy or β-adrenergic blocker therapy alone) plus EVL is associated with lower rebleeding rates than either pharmacologic or EVL therapy alone.27,28

The lowest rate of variceal rebleeding occurs in patients when pharmacologic therapy leads to a reduction in HVPG of greater than 20% of baseline or to a measurement less than 12 mm Hg.10 Ideally, portal pressure monitoring would help to assess the response to nonselective β-adrenergic blocker therapy and identify responders from nonresponders earlier in the treatment course. In order to utilize the HVPG measurement for clinical decision making, the technique used to make this measurement would first have to be standardized.

Treatment Recommendations: Variceal Bleeding—Secondary Prophylaxis

The combination of EVL plus pharmacologic therapy to prevent rebleeding is currently considered the most rational therapeutic approach.21,22 Pharmacologic therapy should be initiated with a nonselective β-blocker such as propranolol 20 mg twice daily or nadolol at a dose of 20 to 40 mg once daily.21 Images β-Blocker therapy can be titrated to achieve a goal heart rate of 55 to 60 beats/min or the maximal tolerated dose. Monitor patients for evidence of heart failure, bronchospasm, and glucose intolerance, particularly hypoglycemia in patients with insulin-dependent diabetes. EVL should be conducted every 1 to 2 weeks until variceal obliteration, and then the patient should be followed by surveillance endoscopy in 1 to 3 months and then every 6 to 12 months. Combination therapy with nonselective β-blocker plus isosorbide mononitrate can be considered in patients who are unable to undergo EVL as well in patients who are hemodynamic nonresponders.11 Patients who cannot tolerate or who fail pharmacologic and endoscopic interventions can be considered for TIPS or surgical shunting to prevent bleeding. A summary of evidence-based treatment recommendations regarding portal hypertension and variceal bleeding is found in Table 24-3.

TABLE 24-3 Evidence-Based Table of Selected Treatment Recommendations: Variceal Bleeding in Portal Hypertension


Management of Ascites and Spontaneous Bacterial Peritonitis

Patients with cirrhosis experience overt fluid retention and ascites as liver disease progresses.9 The classic physical exam findings of ascites are a bulging abdomen with shifting flank dullness.5 The development of ascites in patients with cirrhosis is an indication of advanced liver disease and is a poor prognostic sign.5,9 The principle therapeutic goals for patients with ascites are to control the ascites; to prevent or relieve ascites-related symptoms such as dyspnea, abdominal pain, and abdominal distention; and to prevent life-threatening complications such as SBP and the hepatorenal syndrome.9 Treatment of ascites is expected to have little effect on survival, however.21 Workup includes a history and physical exam, abdominal paracentesis and/or ultrasound, and ascitic fluid analysis.5 The treatment of ascites is based on oral diuretics and is carried out in a slow, stepwise fashion.21 Treatment of ascites should be initiated only in stable patients (e.g., those without ongoing variceal hemorrhage, bacterial infection, or renal dysfunction).

SBP is an infection of ascitic fluid that occurs in the absence of any evidence of an intraabdominal, surgically treatable source of infection.5 It is a common complication that develops in 10% to 20% of patients hospitalized with severe liver disease, cirrhosis, and ascites.21 The key mechanism behind the development of SBP is thought to be bacterial translocation.29 Decreased motility of the GI tract with disturbances of the gut flora, changes in the structure of the GI tract, and reduced local and humoral immunity combine to lead to the free flow of microorganisms and endotoxins to the mesenteric lymph nodes. Most episodes of SBP are caused by Escherichia coliKlebsiella pneumonia, and pneumococci.5 Symptoms and signs of SBP include fever, abdominal pain, abdominal tenderness, rebound, encephalopathy, renal failure, acidosis, peripheral leukocytosis, and altered mental status.5,29 Paralytic ileus, hypotension, and hypothermia are poor prognostic indicators.29 Thirteen percent of patients with SBP present with no symptoms. For this reason, a diagnostic paracentesis with analysis of ascitic fluid should be performed in all patients admitted with ascites.5 SBP is diagnosed when there is possible ascitic fluid bacterial culture and ascitic fluid cell counts show an absolute polymorphonuclear (PMN) leukocyte count of greater than or equal to 250 cells/mm3 (250 × 106/L).

The following treatment guidelines for the management of adult patients with ascites and SBP were updated and approved by the Practice Guidelines Committee of the American Association for the Study of Liver Diseases (AASLD).


In adult patients with new-onset ascites as determined by physical exam or radiographic studies, abdominal paracentesis should be performed, and ascitic fluid analysis should include a cell count with differential, ascitic fluid total protein, and a serum-ascites albumin gradient (SAAG). If infection is suspected, ascitic fluid cultures should be obtained at the time of the paracentesis. The SAAG can accurately determine whether ascites is a result of portal hypertension or another process. If the SAAG is greater than or equal to 1.1 g/dL (11 g/L), the patient almost certainly has portal hypertension. The treatment of ascites secondary to portal hypertension is relatively straightforward and includes abstinence from alcohol, sodium restriction, and diuretics.

Images Abstinence from alcohol is an essential element of the overall treatment strategy. Abstinence from alcohol can result in improvement of the reversible component of alcoholic liver disease, resolution of ascites, or improved responsiveness of ascites to medical therapy. Patients with cirrhosis not caused by alcohol have less reversible liver disease, and, by the time ascites is present, these patients may be best managed with liver transplantation rather than protracted medical therapy.

Beyond avoidance of alcohol, the primary treatment of ascites due to portal hypertension and cirrhosis is salt restriction and oral diuretic therapy. Fluid loss and weight change depend directly on sodium balance in these patients. A goal of therapy is to increase urinary excretion of sodium to greater than 78 mmol/day. Evaluation of urinary sodium excretion, preferably utilizing a 24-hour urine collection, may be helpful, although this collection can be difficult. A random spot urine sodium concentration that is greater than the potassium concentration correlates very well with a 24-hour urinary sodium excretion over 78 mmol/day and is an easier test to complete. Severe hyponatremia, defined as serum sodium less than a threshold of 120 to 125 mEq/L (120 to 125 mmol/L), does warrant fluid restriction. However, rapid correction of asymptomatic hyponatremia is not recommended as patients with cirrhosis are usually asymptomatic until their serum sodium concentrations are less than 110 mEq/L (110 mmol/L) or unless the decline in serum sodium is rapid.

Diuretic Therapy The AASLD practice guidelines recommend that diuretic therapy be initiated with the combination of spironolactone and furosemide. At one time, spironolactone was commonly recommended for initial therapy as a single agent. However, due to the likelihood for development of drug-induced hyperkalemia with spironolactone when used as monotherapy, the drug is now recommended only for use as a lone diuretic agent in patients with minimal fluid overload. If tense ascites is present, paracentesis should be performed prior to institution of diuretic therapy and salt restriction. For patients who respond to diuretic therapy, this approach is preferred over the use of serial paracenteses. In patients with refractory ascites, serial paracenteses may be employed. Albumin infusion postparacentesis is controversial, but reasonable for extraction volumes exceeding 5 L. Laboratory tests for renal function and electrolytes need to be monitored during therapy. Referral for liver transplantation should be made in patients with refractory ascites. TIPS is a therapeutic modality for the treatment of refractory ascites that may be considered in appropriately selected patients. Peritoneovenous shunting may be considered in treatment refractory patients who are not candidates for paracenteses, transplant, or TIPS.

Spontaneous Bacterial Peritonitis

Relatively broad-spectrum antibiotic therapy that adequately covers the three most commonly encountered pathogens (E. coliK. pneumoniae, and pneumococci) is warranted in patients with documented or suspected SBP.5,21,29Empiric therapy should not be delayed while awaiting culture results. In some patients, signs and symptoms of infection are present such as fever, abdominal pain, and unexplained encephalopathy at the bacterascites stage (i.e., signs and symptoms are present before the PMN count in the ascitic fluid is elevated).5 In these patients, signs and symptoms of infection justify empiric antibiotic therapy until culture results are known, regardless of the PMN count in the ascitic fluid.

Cefotaxime 2 g every 8 hours, or a similar third-generation cephalosporin, is considered the drug of choice for SBP. A 5-day course of antibiotic therapy is as efficacious as 10 days of therapy. Ofloxacin 400 mg every 12 hours administered orally for an average of 8 days is an alternative for patients without vomiting, shock, significant HE, or serum creatinine over 3 mg/dL (265 μmol/L). IV ciprofloxacin offers another potential treatment alternative. Patients with SBP who previously received quinolone therapy as prophylaxis should be treated with an alternative agent since patients who have received quinolone therapy may become infected with quinolone-resistant flora.

Secondary bacterial peritonitis, ascitic fluid infection caused by a surgically treatable intraabdominal source, can masquerade as SBP. Free perforation should be considered when multiple or atypical organisms are cultured, a very high ascitic fluid PMN count is seen, or at least two of the following are seen on ascitic fluid analysis: total protein greater than 1 g/dL (10 g/L), lactate dehydrogenase greater than the upper limit of normal for serum, and glucose less than 50 mg/dL (2.8 mmol/L). A 48-hour followup PMN count that rises above pretreatment levels despite antibiotic treatment is indicative of secondary nonperforation peritonitis. Patients with free perforation or nonperforation secondary peritonitis should receive a third-generation cephalosporin plus anaerobic coverage in addition to undergoing laparotomy.

Treatment Recommendations: Ascites and Spontaneous Bacterial Peritonitis

Adult patients admitted to the hospital with new-onset ascites should have an abdominal paracentesis performed to establish the SAAG, the ascitic fluid cell count and differential, and the ascitic fluid total protein. If ascitic fluid infection is suspected, ascitic fluid should be cultured at the bedside. Images Patients who drink alcohol should be strongly discouraged from further alcohol use. Images Sodium restriction to 2,000 mg/day, together with spironolactone and furosemide, is the mainstay of therapy. Diuretic therapy should be initiated with single morning doses of spironolactone 100 mg and furosemide 40 mg administered orally. Titrate diuretic therapy every 3 to 5 days using the 100:40 mg dose ratio to attain adequate natriuresis and weight loss (reasonable daily weight loss goal is 0.5 kg). Maximum daily doses are 400 mg spironolactone and 160 mg furosemide. This combination ratio is used because it usually maintains normokalemia. Fluid restriction, unless the serum sodium is less than 120 to 125 mEq/L (120 to 125 mmol/L), and bedrest are not recommended. Utilize the random spot urine test to confirm a sodium concentration that is greater than the potassium concentration as this correlates very well with a 24-hour urinary sodium excretion over the goal of 78 mmol/day. Monitor serum potassium and renal function frequently. Avoid rapid correction of asymptomatic hyponatremia in patients with cirrhosis. If tense ascites is present, paracentesis should be performed prior to institution of diuretic therapy and salt restriction. For patients who respond to diuretic therapy, this approach is preferred over the use of serial paracenteses. Discontinue diuretic therapy in patients who experience uncontrolled or recurrent encephalopathy, severe hyponatremia (serum sodium less than 120 mEq/L [120 mmol/L]) despite fluid restriction, or renal insufficiency (serum creatinine greater than 2 mg/dL [177 μmol/L]). Serial paracenteses may be considered for patients with refractory ascites and albumin infusion of 6 to 8 g/L of fluid removed can be considered postparacentesis when paracentesis volumes exceed 5 L.

Patients with ascitic fluid PMN counts greater than or equal to 250 cells/mm3 (250 × 106/L) should receive empiric antibiotic therapy with IV cefotaxime 2 g every 8 hours or a similar third-generation cephalosporin. Oral ofloxacin 400 mg twice daily may be an alternative option in patients without prior exposure to quinolones, vomiting, shock, severe encephalopathy, or serum creatinine over 3 mg/dL (265 μmol/L). Patients with ascitic fluid PMN counts less than 250 cells/mm3 (250 × 106/L) but with signs and symptoms of infection (symptoms such as abdominal pain, abdominal tenderness, and fever) should also receive empiric antibiotic treatment. Patients with ascitic fluid PMN counts greater than or equal to 250 cells/mm3 (250 × 106/L) and suspicion of SBP should also receive 1.5 g of albumin per kilogram body weight within 6 hours of detection and 1 g of albumin per kilogram body weight on day 3 if they also have a serum creatinine over 1 mg/dL (88 μmol/L), blood urea nitrogen over 30 mg/dL (10.7 mmol/L), or total bilirubin over 4 mg/dL (68.4 μmol/L).

Images All patients who have survived an episode of SBP should receive long-term antibiotic prophylaxis with daily norfloxacin 400 mg or double strength trimethoprim–sulfamethoxazole. Long-term prophylaxis should also be considered for the prevention of SBP in patients with low-protein ascites (less than 1.5 g/dL [15 g/L]) who also have one of the following: serum creatinine greater than or equal to 1.2 mg/dL (106 μmol/L), blood urea nitrogen greater than or equal to 25 mg/dL (8.9 mmol/L), serum sodium less than or equal to 130 mEq/L (130 mmol/L), or Child-Pugh score of greater than or equal to 9 with bilirubin greater than or equal to 3 mg/dL (51.3 μmol/L). Short-term prophylaxis (7 days) is indicated in patients with cirrhosis and GI hemorrhage. A summary of evidence-based treatment recommendations regarding ascites and SBP is found in Table 24-4.

TABLE 24-4 Evidence-Based Table of Selected Treatment Recommendations: Ascites and Spontaneous Bacterial Peritonitis


Management of Hepatic Encephalopathy

The clinical manifestations of HE vary widely.30 Patients with minimal HE do not suffer from clinically overt cognitive dysfunction; nevertheless, it adversely affects their ability to function socially and perform in the workplace, and it may also affect their ability to drive safely.31 Episodic HE refers to precipitated, spontaneous, or recurrent acute episodes of HE. Recurrent HE refers to two spontaneous or precipitated episodes of HE that occur within 1 year. Persistent HE refers to mild, severe, or treatment-dependent symptoms that are chronic in nature and negatively impact a patient’s quality of life.

The prevalence of HE among cirrhotics is variable but may be found in up to 70% of patients. To determine the severity of HE, a grading system that relates neurologic and neuromuscular signs can be used (Table 24-5). The primary substances thought to be involved in the development of HE are ammonia, glutamate, manganese, and the α-aminobutyric acid (GABA)-benzodiazepine receptor agonists.30,31

TABLE 24-5 Grading System for Hepatic Encephalopathy


Episodic HE may develop in a clinically stable cirrhotic patient as the result of a precipitating event.31 Table 24-6 lists the most commonly encountered precipitating factors and suggests general treatment alternatives. Table 24-7describes the treatment goals for patients with HE and contrasts the differences between episodic and persistent HE. The general approach to the management of HE is to first identify and treat any precipitating factors, and, when associated with a precipitant, the clinical features of HE may resolve after the precipitating factor is treated or removed.13,31

TABLE 24-6 Portosystemic Encephalopathy: Precipitating Factors and Therapy


TABLE 24-7 Treatment Goals: Episodic and Persistent Hepatic Encephalopathy


Treatment approaches for episodic and persistent HE include (a) reducing ammonia blood concentrations by dietary restrictions and drug therapy aimed at inhibiting ammonia production or enhancing its removal and (b) inhibiting the GABA-benzodiazepine receptors.13 Additionally, treatment for persistent HE should include avoidance and prevention of precipitating factors in an effort to avoid acute decompensation.


Images Treatment interventions to reduce ammonia blood concentrations are recommended in patients with HE. Decreasing ammonia blood concentrations by reducing the nitrogenous load from the gut remains a mainstay of therapy for patients with HE. Treatment options most commonly used to decrease ammonia load from the gut include nutritional management, nonabsorbable disaccharides, and antibiotics.

Guidelines for nutritional support of patients with liver disease have been published by the European Society for Parenteral and Enteral Nutrition.32 Protein withdrawal is a cornerstone of treatment for patients during acute episodes of HE.13 However, prolonged restriction can lead to malnutrition and poorer prognosis among HE patients. Therefore, once successful reversal of HE symptoms is achieved, protein is added back to the diet in combination with other therapies until a target of 1 to 1.5 g/kg/day is reached. Vegetable-source and dairy-source protein may be preferable to meat-source protein because the latter contains a higher calorie-to-nitrogen ratio. Also, the higher fiber content of vegetable protein lowers colonic pH, increasing catharsis. Most patients will tolerate at least 1 g/kg/day of standard proteins without becoming encephalopathic.33 Branched-chain amino acid formulations may provide a better-tolerated source of protein in those patients with protein intolerance.13 Bowel cleansing using cathartics or lactulose enemas (see following discussion) results in rapid removal of ammonia substrate from the colon and may be combined with dietary intervention to help the patient eliminate ammonia and tolerate dietary protein.

The use of lactulose, a nonabsorbable disaccharide, is standard therapy for both acute and chronic HE. Lactulose, when administered orally through ingestion or a nasogastric tube, passes through the GI tract and reaches the colon unchanged. It can also be administered by retention enema. Lactulose is metabolized by gut flora into acetic acid and lactic acid, which lower colonic pH and create a cathartic effect.

Lactulose administration lowers ammonia levels in the blood in several ways: (a) through creation of a laxative effect that reduces the time period available for ammonia absorption, (b) through leaching of ammonia from the circulation into the colon and increasing bacterial uptake of ammonia by colonic bacteria, and (c) through reducing ammonia production by the small intestine by interfering directly with the uptake of glutamine by the intestinal wall and its subsequent metabolism to ammonia.34

Clinical Controversy…

Whether lactulose retains benefit once antibiotic therapy is begun for recurrent HE has been an area of uncertainty.12 This controversy stems from concern over whether or not antibiotic-altered gut flora is able to metabolize lactulose appropriately. Rifaximin has been established as the second-line agent of choice for patients with recurrent HE. A placebo-controlled trial examining rifaximin’s effectiveness for maintaining remission in patients with a history of recurrent HE found significant improvement among patients allocated to receive rifaximin.35 In this study, 90% of patients received concomitant lactulose therapy. Hence, at least in the case of rifaximin, it seems that continuing lactulose may be an appropriate therapeutic choice.

Inhibiting the activity of urease-producing bacteria by using neomycin or metronidazole can decrease production of ammonia.13 Neomycin at doses of 3 to 6 g daily can be given for 1 to 2 weeks during an acute episode of HE. For persistent HE, a dose of 1 to 2 g daily could be used with periodic renal and annual auditory monitoring. Despite poor absorption, chronic use of neomycin can lead to irreversible ototoxicity, nephrotoxicity, and the possibility of staphylococcal superinfection. As such, neomycin should not be routinely recommended.34 Metronidazole initiated at 250 mg twice daily may also produce a favorable clinical response in HE.13 However, neurotoxicity caused by impaired hepatic clearance of the drug may be problematic. Helicobacter pylori eradication is not routinely recommended as a way to improve ammonia levels or symptoms of encephalopathy.

Rifaximin is a synthetic antibiotic structurally similar to rifamycin with a systemic absorption of only 0.4%.34 It lowers blood ammonia levels and improves neuropsychiatric symptoms in HE. In a randomized, double-blind, placebo-controlled trial, patients in remission from recurrent HE were randomized to either rifaximin 550 mg twice daily or placebo for 6 months.35 Rifaximin significantly reduced the risk of a recurrent episode of HE as well as hospitalization due to HE. Lactulose was used concomitantly in 90% of patients in this study. The incidence of adverse effects was similar between rifaximin and placebo with the most common serious adverse events reported being nausea and diarrhea.

Zinc is a cofactor of urea cycle enzymes and can be deficient in cirrhotic patients, especially in cases of malnourishment.13 Zinc acetate 220 mg twice daily is recommended for patients with zinc deficiency.

Drugs Affecting Neurotransmission

The GABA-receptor complex is the primary inhibitory neural network within the CNS. An enhanced GABA-ergic tone and an increased amount of endogenous benzodiazepines may contribute to HE. Flumazenil 1 mg IV bolus may be considered for short-term therapy in refractory patients with suspected benzodiazepine intake, but cannot be recommended for routine clinical use.

Alterations of dopaminergic neurotransmission have also been thought to play a role in the symptoms of HE, particularly the extrapyramidal signs. Improvements of extrapyramidal symptoms have been reported with bromocriptine therapy. Bromocriptine 30 mg twice daily is indicated for chronic HE treatment in patients who are unresponsive to other therapies. Prolactin levels may become elevated during bromocriptine treatment.

Treatment Recommendations: Hepatic Encephalopathy

Treatment recommendations depend on the type of HE being managed: episodic HE, persistent HE, or minimal HE.21 The general approach to the management of HE is first to identify patients with acute episodic HE and then to provide aggressive management of any precipitating events (see Table 24-7).13 When the precipitating event has been discovered and appropriate therapy initiated, steps to rapidly reverse the encephalopathy should be implemented.

Images The mainstay of therapy of HE involves measures to lower blood ammonia concentrations and includes diet therapy, lactulose, and antibiotics alone or in combination with lactulose. Other commonly used adjunctive therapies include zinc replacement in patients with zinc deficiency, flumazenil, and possibly bromocriptine.

In patients with episodic HE, protein is withheld or limited while maintaining the total caloric intake until the clinical situation improves. Then dietary protein is titrated back up based on tolerance, increasing gradually to a total of 1 to 1.5 g/kg/day. Consider the substitution of meat-source protein with vegetable or dairy protein. Zinc acetate supplementation at a dose of 220 mg twice daily is recommended for long-term management in patients with cirrhosis who are zinc deficient.

In episodic HE, lactulose is initiated at a dose of 45 mL orally every hour (or by retention enema: 300 mL lactulose syrup in 1 L water held for 60 minutes) until catharsis begins. The dose is then decreased to 15 to 45 mL orally every 8 to 12 hours and titrated to produce two to three soft stools per day. The enema is retained for 1 hour with the patient in the Trendelenburg position. For chronic encephalopathy, dosing is the same except that the initial hourly administration is not required. Patients are maintained on this regimen to prevent recurrence of episodic HE. Monitor electrolytes periodically, follow patients for changes in mental status, and titrate to the number of stools as already described.

Rifaximin 550 mg twice daily plus lactulose has been proven superior to lactulose alone in patients with a history of recurrent HE.35 Because of its more favorable adverse effect profile, rifaximin is now considered the next line of therapy for recurrent HE over either metronidazole or neomycin.21

Systemic Complications

In addition to the more common complications of chronic liver disease discussed earlier, other complications can occur, including hepatorenal syndrome, hepatopulmonary syndrome, coagulation disorders, and endocrine dysfunction.

Hepatorenal syndrome, which is a functional renal failure in the setting of cirrhosis, occurs in the absence of structural kidney damage.36 It develops in patients with cirrhosis as a result of intense renal vasoconstriction, which results from extreme systemic vasodilation. The resultant reduction in blood supply to the kidneys causes avid sodium retention and oliguria. As liver disease progresses, systemic vasodilation worsens and, subsequently, increased renal vasoconstriction occurs and renal blood flow is further decreased. As this occurs, the heart’s response becomes insufficient to maintain perfusion pressure, which the kidneys rely heavily on at this point to maintain adequate blood flow. Hepatorenal syndrome is common and develops in approximately 20% of hospitalized patients with cirrhosis.

Management of hepatorenal syndrome begins with a first step of discontinuing diuretics and any other medication that could potentially decrease effective blood volume and to expand the intravascular volume with IV albumin at a dose of 1 g/kg up to a maximum of 100 g.21 Precipitating factors such as infection, fluid loss, and blood loss should be investigated and treated if found. Liver transplantation is the only definitive therapy for hepatorenal syndrome and the only therapy that will prolong survival. Therapies used to bridge patients until transplantation include arteriolar vasoconstrictor-based treatments with terlipressin or midodrine plus octreotide used in addition to IV albumin infusion as already discussed.

Hepatopulmonary syndrome affects somewhere between 5% and 32% of patients with cirrhosis.37 This abnormality is characterized by a defect in arterial oxygenation, which is caused by the pulmonary vascular dilation that occurs in the presence of liver disease. Less commonly, pleural and pulmonary arteriovenous shunting can occur as well as portopulmonary venous anastomoses. These patients present with dyspnea on exertion, at rest, or both. Cirrhotic patients with these findings should be evaluated for hepatopulmonary syndrome, which is diagnosed based on the presence of arterial hypoxemia. Arterial hypoxemia is defined based on measurements of the partial pressure of oxygen that are performed with patients sitting and at rest. Testing for an increased alveolar–arterial oxygen gradient is also particularly important as this gradient can rise abnormally before the patient’s partial pressure of oxygen measurement becomes abnormally low. Long-term management requires supportive therapy with supplemental oxygen. The prognosis for these patients is poor. Ultimately, liver transplantation offers the best chance for long-term recovery.

Correction of the coagulopathy is essential for patients actively bleeding. The pathophysiology of the coagulopathy is complex and involves impaired synthesis of clotting factors, excessive fibrinolysis, disseminated intravascular coagulation, thrombocytopenia, and platelet dysfunction. Acute therapy involves platelet transfusions for thrombocytopenia and fresh-frozen plasma for prolongation of the PT because of clotting factor deficiencies.21

The presence of cirrhosis can produce abnormal circulating levels of various hormones.38 Hypogonadism, diabetes mellitus, osteoporosis, and thyroid disorders are among the endocrine disorders that may develop related to advanced liver disease. Erectile dysfunction related to hypogonadism can be treated with the administration of testosterone and the removal of causative factors such as alcohol.

Liver Transplantation

The complications seen in patients with chronic liver disease are essentially functional as a secondary effect of the circulatory and metabolic changes that accompany liver failure. Consequently, liver transplantation is the only treatment that can offer a cure for complications of end-stage cirrhosis.


Cirrhosis modulates the behavior of drugs in the body by inducing kinetic alterations in drug absorption, distribution, and clearance.39 Additionally, patients with cirrhosis may exhibit pharmacodynamic changes with increased sensitivity to the effects of certain drugs, namely, opiates, benzodiazepines, and nonsteroidal antiinflammatory drugs. These pharmacodynamic changes are separate and distinct from the enhancement of drug effects seen in cirrhosis patients as a result of pharmacokinetic changes. Hepatic drug clearance is primarily dependent on protein binding, hepatic blood flow, and metabolic enzyme activity. The pathophysiologic changes that occur in patients with cirrhosis, including reduced liver blood flow, intrahepatic and extrahepatic portal-systemic shunting, diminished metabolic and synthetic function, and capillarization of the sinusoids, can have a significant impact on each of these factors. The consequence of these changes is a reduction in intrinsic metabolic activity, a reduction in the delivery of blood to the liver that decreases clearance and prolongs half-life, and a reduction in the degree of protein binding that increases the fraction of unbound drug in the serum. Finally, patients with cirrhosis frequently accumulate large amounts of interstitial fluid resulting in substantial changes in the volume of distribution, which also prolongs drug half-life. These changes occur most commonly in combination in patients with cirrhosis and are dynamic throughout the disease course. The effect that these changes will have depends on the drug and the type of biotransformation that the drug undergoes.

Drugs with a high extraction ratio (high-extraction drugs) are dependent on blood flow for metabolism, and the rate of metabolism will be sensitive to changes in blood flow. Drugs with a low extraction ratio (low-extraction drugs) are dependent on intrinsic metabolic activity for metabolism, and the rate of metabolism will reflect changes in intrinsic clearance and protein binding. Furthermore, hepatic biotransformation involves two types of metabolic processes: phase I reactions and phase II reactions. Phase I reactions involve the cytochrome P450 system and include hydrolysis, oxidation, dealkylation, and reduction reactions. Phase II reactions involve conjugation of the drug with an endogenous molecule such as sulfate or an amino acid, rendering it more water soluble and enhancing its elimination. Drugs metabolized by phase I reactions, especially oxidation, tend to be significantly impaired in patients with cirrhosis, whereas drugs eliminated by conjugation are relatively unaffected.

The variability and complexity of the interaction between the extent and severity of liver disease and individual characteristics of the drug make it difficult to predict the degree of pharmacokinetic perturbation in an individual patient. Unfortunately, there are no sensitive and specific clinical or biochemical markers that allow us to quantify the extent of liver insufficiency or the degree of metabolic activity. In addition, renal insufficiency and alterations that commonly accompany cirrhosis further complicate empiric dosing recommendations in these patients. Dosing recommendations are most commonly nonspecific, with recommendations labeled for patients with mild to moderate liver impairment. Dosing information for patients with more severe liver impairment is not available. As a result, when patients with cirrhosis require therapy with drugs that undergo hepatic metabolism (e.g., benzodiazepines), monitoring response to therapy and anticipating drug accumulation and enhanced effects is essential. In the case of benzodiazepines, selection of an agent such as lorazepam, an intermediate-acting agent that is metabolized via conjugation and has no active metabolites, is easier to monitor than a drug such as diazepam, a long-acting benzodiazepine that is oxidized in the liver and has an active metabolite with a long half-life of its own.


Table 24-8 summarizes the management approach for patients with cirrhosis and includes possible adverse drug effects. Cirrhosis is generally a chronic progressive disease that requires aggressive medical management to prevent or delay common complications. Table 24-8 also lists monitoring criteria that need to be carefully followed in order to achieve the maximum benefit from the medical therapies employed and prevent adverse effects. A therapeutic plan including therapeutic end points for each medical and diet therapy needs to be developed and discussed with the patient.

TABLE 24-8 Drug Monitoring Guidelines





    1. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008; 371(9615):838–851.

    2. Guha IN, Iredale JP. Clinical and diagnostic aspects of cirrhosis. In: Rodés J, Benhamou J, Blei A, eds. Textbook of Hepatology: From Basic Science to Clinical Practice, 3rd ed. Malden, MA: Blackwell Publishing, 2007.

    3. Abboud G, Kaplowitz N. Drug-induced liver injury. Drug Saf 2007;30(4):277–294.

    4. Murphy SL, Xu J, Kochanek KD. Deaths: Preliminary data for 2010. Natl Vital Stat Rep 2012;60(4):1–52.

    5. Runyon BA. Management of adult patients with ascites due to cirrhosis: An update. Hepatology 2009;49(6):2087–2107.

    6. Khalili M, Liao CE, Nquyen T. Liver disease. In: McPhee SJ, Hammer GD, eds. Pathophysiology of Disease, 6th ed. New York: McGraw-Hill, 2010, [chapter 14].

    7. Friedman SL. Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88:125–172.

    8. Bosch J, Berzigotti A, Garcia-Pagan JC, et al. The management of portal hypertension: Rational basis, available treatments and future options. J Hepatol 2008;48:S68–S92.

    9. Kashani A, Landaverde C, Medici V, et al. Fluid retention in cirrhosis: Pathophysiology and management. Q J Med 2008;101:71–85.

   10. Bari K, Garcia-Tsao G. Treatment of portal hypertension. World J Gastroenterol 2012;18(11):1166–1175.

   11. de Franchis R. Evolving consensus in portal hypertension: Report of the Baveno V consensus workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010;53(4):762–768.

   12. Cash WJ, McConville P, McDermott E, McCormick PA, Callender ME, McDougall NI. Current concepts in the assessment and treatment of hepatic encephalopathy. Q J Med 2010;103:9–16.

   13. Blei AT, Cordoba J, Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy. Am J Gastroenterol 2001;96:1968–1976.

   14. Peck-Radosavljevic M. Review article: Coagulation disorders in chronic liver disease. Aliment Pharmacol Ther 2007;26(Suppl 1):21–28.

   15. Heidelbaugh JJ, Bruderly M. Cirrhosis and chronic liver failure, I: Diagnosis and evaluation. Am Fam Physician 2006;74:756–762, 781.

   16. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: A guide for clinicians. Can Med Assoc J 2005;172(3): 367–379.

   17. Cohen JA, Kaplan MM. The SGOT/SGPT ratio—An indicator of alcoholic disease. Dig Dis Sci 1979;24:835–838.

   18. Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophagus varices. Br J Surg 1973;60:646–649.

   19. About the MELD/PELD Calculator,

   20. MELD/PELD Calculator Documentation,

   21. Garcia-Tsao G, Lim J, Members of the Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: Recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol 2009;104:1802–1829.

   22. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46(3):922–938.

   23. de Franchis R. Somatostatin, somatostatin analogues and other vasoactive drugs in the treatment of bleeding oesophageal varices. Dig Liver Dis 2005;36(Suppl 1): S93–S100.

   24. Imperiale TF, Teran JC, McCullough AJ. A meta-analysis of somatostatin versus vasopressin in the management of acute esophageal variceal hemorrhage. Gastroenterology 1995;109(4):1289–1294.

   25. Zheng M, Chen Y, Bai J, et al. Transjugular intrahepatic portosystemic shunt versus endoscopic therapy in the secondary prophylaxis of variceal rebleeding in cirrhotic patients meta-analysis update. J Clin Gastroenterol 2008; 42(5):507–516.

   26. Gluud LL, Langholz E, Drag A. Meta-analysis: Isosorbide-mononitrate alone or with either β-blockers or endoscopic therapy for the management of oesophageal varices. Aliment Pharmacol Ther 2010;32:859–871.

   27. Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010; 362:823–832.

   28. Gonzalez R, Zamora J, Gomez-Camarero J, Molinero LM, Bañares R, Albillos A. Meta-analysis: Combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109–122.

   29. Koulaouzidis A, Bhat S, Saeed AA. Spontaneous bacterial peritonitis. World J Gastroenterol 2009;15(9):1042–1049.

   30. Mas A. Hepatic encephalopathy: From pathophysiology to treatment. Digestion 2006;73(Suppl 1):86–93.

   31. Stewart CA, Cerhan J. Hepatic encephalopathy: A dynamic or static condition. Metab Brain Dis 2005;20(3):193–204.

   32. Plauth M, Cabré E, Kondrup J, et al. ESPEN guidelines on parenteral nutrition: Hepatology. Clin Nutr 2009;28(4): 436–444.

   33. Charlton M. Branched-chain amino acid enriched supplements as therapy for liver disease. J Nutr 2006;136:295S–298S.

   34. Morgan MY, Blei A, Grüngreiff K, et al. The treatment of hepatic encephalopathy. Metab Brain Dis 2007;22:389–405.

   35. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010;362:1071–1081.

   36. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008;48:2064–2077.

   37. Rodriquez-Roisin R, Krowka MJ. Hepatopulmonary syndrome—A liver-induced lung vascular disorder. N Engl J Med 2008;358:2378–2387.

   38. Minemura M, Tajri K, Shimizu Y. Systemic abnormalities in liver disease. World J Gastroenterol 2009;15(24):2960–2974.

   39. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008;64:1147–1161.