Upon completion of the chapter, the reader will be able to:
1. Describe the epidemiology and social impact of portal hypertension and cirrhosis.
2. Explain the pathophysiology of cirrhosis and portal hypertension.
3. Outline the progression of liver damage from excessive alcohol intake.
4. Identify the signs and symptoms of liver disease in a given patient.
5. Describe the consequences associated with decreased hepatic function.
6. List the treatment goals for a patient with portal hypertension and its complications.
7. Evaluate patient history and physical exam findings to determine the etiology of cirrhosis.
8. Recommend a specific treatment regimen that includes lifestyle changes, pharmacologic therapy, and nonpharmacologic therapy.
Portal hypertension is the precipitating factor for the complications of cirrhotic liver disease: ascites, spontaneous bacterial peritonitis (SBP), variceal bleeding, and hepatic encephalopathy (HE). Lowering portal pressure can reduce the complications of cirrhosis and decrease morbidity and mortality.
Chronic excessive ingestion of ethanol causes progressive liver damage because both ethanol and its metabolic products are direct hepatotoxins.
Cirrhosis is irreversible; treatments are directed at limiting disease progression and minimizing complications.
Nonselective β-blockers are first-line treatment for preventing variceal bleeding; they vasoconstrict the splanchnic bed through multiple mechanisms.
The goals of treating ascites are to minimize acute discomfort, reequilibrate ascitic fluid, and prevent SBP. Treatment should modify the underlying disease pathology; without directed therapy, fluid will rapidly reaccumulate.
Cirrhosis is a high aldosterone state; spironolactone is a direct aldosterone antagonist and a primary treatment for ascites.
During acute variceal hemorrhage, it is crucial to control bleeding, prevent rebleeding, and avoid acute complications such as SBP.
Long-term antibiotic prophylaxis for SBP decreases mortality in patients with a history of SBP or low-protein ascites (ascitic fluid albumin less than 1 g/dL [10 g/L]).
Lactulose is the foundation of pharmacologic therapy to prevent and treat HE. It binds ammonia in its ionic form in the gut and facilitates its excretion.
Cirrhosis is the progressive replacement of normal hepatic cells with fibrous scar tissue. This scarring is accompanied by the loss of viable hepatocytes, which are the functional cells of the liver. Progressive cirrhosis is irreversible and leads to portal hypertension, which is in turn responsible for many of the complications of advanced liver disease. These consequences include (but are not limited to)spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), andvariceal bleeding.1
EPIDEMIOLOGY AND ETIOLOGY
Cirrhosis is the result of long-term insult to the liver, so damage is typically not evident clinically until the fourth decade of life. Chronic liver disease and cirrhosis combined were the 12th leading cause of death in the United States in 2002. In patients between the ages of 25 and 64 years, damage from excessive alcohol use accounted for over one-half of the deaths.2 Alcoholic liver disease and viral hepatitis C are the most common causes of cirrhosis in the United States, whereas hepatitis B accounts for the majority of cases worldwide.3 Once cirrhosis is diagnosed, the disease progression is relentless, regardless of the initial insult to the liver.
Variations occur, but cirrhosis secondary to alcohol abuse typically develops after 10 or more years of daily ingestion of 80 g of ethyl alcohol; this is an average of 6 to 8 drinks per day (a drink is equivalent to 1 ounce [30 mL] of hard liquor, 4 ounces [120 mL] of wine, or a 12-ounce [360-mL] beer).4 With equivalent alcohol intake, women usually develop cirrhosis more quickly than men do. Differences in the rate of alcohol metabolism may account for this gender disparity; women metabolize less alcohol in the GI tract; this allows delivery of higher levels of ethanol (which is directly hepatotoxic) to the liver.5 Genetic factors also play a role in development of alcoholic liver disease; some persons will progress to cirrhosis with much less cumulative alcohol intake than that of a typical cirrhotic patient (either fewer drinks per day, or faster disease development), while others do not develop the disease with even more excessive intake.
Infection with one or more strains of viral hepatitis causes an acute inflammation of the liver, whereas chronic infection with hepatitis B or C can lead to cirrhosis. Hepatitis B and C are common in IV drug users and can also be transmitted through sexual contact, but many cases of hepatitis C are idiopathic.6,7 See Chapter 24 (Viral Hepatitis) for a complete discussion of infectious hepatitis.
Approximately 30% of patients with cirrhosis experience variceal bleeding at some point during the course of the disease. Variceal bleeding carries a remarkably high mortality rate. Up to 55% of patients with advanced disease die from their first episode. Mortality correlates with disease severity; risk factors include poor liver function, large varices, and red signs (wales) on endoscopic examination.8 More than two-thirds of patients who survive the first incidence of variceal bleeding experience a repeat episode.
Development of ascites in cirrhotic patients is a particularly ominous marker; 1-year mortality after initial presentation with ascites is approximately 50%.9 In addition to the high mortality rate, cirrhosis carries an enormous economic and social burden from hospitalizations, lost wages, and decreased productivity, not to mention the emotional strain of the disease on both patients and families.
Determining the specific cause of cirrhosis requires examination of both physical presentation and a thorough past medical history. An accurate social history is particularly important because few factors in the physical and laboratory examination aid in determining disease etiology. Understanding the cause of a patient’s cirrhosis is imperative because it can affect therapeutic options and treatment decisions, even though cirrhosis itself cannot be reversed.
Portal Hypertension and Cirrhosis
The portal vein is the primary vessel leading into the liver; it receives the deoxygenated venous blood flow from the splanchnic bed (intestines, stomach, pancreas, and spleen) (Fig. 22–1). Portal flow accounts for approximately 75% of all the blood delivered to the liver. The hepatic artery provides the remaining 25% of the blood supply in the form of oxygenated blood from the abdominal aorta. Normal portal vein pressure is between 5 and 10 mm Hg; this level maintains blood flow to the liver at approximately 1 to 1.5 L/min. Portal hypertension occurs when the hepatic venous pressure gradient (the pressure difference between the portal vein and the inferior vena cava) exceeds 10 to 12 mm Hg.10,11
Portal hypertension is a consequence of increased resistance to blood flow through the portal vein. This is usually due to restructuring of intrahepatic tissue (sinusoidal damage) but may also be caused by presinusoidal damage such as portal vein occlusion from trauma, malignancy, or thrombosis. The third (and the least common) cause of portal hypertension is outflow obstruction of the hepatic vein. This latter damage is posthepatic, and normal liver structure is maintained. This chapter will focus on portal hypertension caused by intrahepatic damage from cirrhosis.
Sinusoidal damage from cirrhosis is the most common cause of portal hypertension. The sinusoids are porous vessels within the liver that surround radiating rows of hepatocytes, which are the basic functional cells of the liver (Fig. 22–2). Progressive destruction of hepatocytes and an increase in fibroblasts and connective tissue surrounding the hepatocytes culminate in cirrhosis. Fibrosis and regenerative nodules of scar tissue modify the basic architecture of the liver, disrupting and reducing hepatic blood flow as well as normal liver function. Reduced hepatic blood flow alters the normal metabolic breakdown processes and decreases protein synthesis within the liver.
FIGURE 22–1. The portal venous system. (From Sease JM, Timm EJ, Stragand JJ. Portal hypertension and cirrhosis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 634, with permission.)
FIGURE 22–2. Relationship of sinusoids to hepatocytes and the venous system. (From Sease JM, Timm EJ, Stragand JJ. Portal hypertension and cirrhosis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 634, with permission.)
The sinusoids transport both portal and arterial blood to the hepatocytes. The systemic blood delivered to the liver contains nutrients, drugs, and ingested toxins. The liver processes nutrients (carbohydrates, proteins, lipids, vitamins, and minerals) for either immediate use or for storage, while drugs and toxins are broken down through a variety of metabolic processes. Changes in hepatic blood flow can significantly alter metabolism. Processing of drugs eliminated by first-pass metabolism is reduced, extending the half-life. In the case of prodrugs that are activated by the liver, the time to therapeutic effect is delayed. The liver also processes metabolic waste products for excretion. In cirrhosis, bilirubin (from the enzymatic breakdown of heme) can accumulate; this causes jaundice (yellowing of the skin), scleral icterus (yellowing of the sclera), and tea-colored urine (urinary bilirubin excretion).
Changes in steroid hormone production, as well as changes in the conversion and handling of steroids are also prominent features of cirrhosis. These changes can result in decreased libido, gynecomastia (development of breast tissue in men), testicular atrophy, and features of feminization in male patients. Another deleterious effect of changes in sex hormone metabolism is the development of spider angiomata (nevi). Spider angiomata are vascular lesions found mainly on the trunk. The lesion has a central arteriole (body) surrounded by radiating “legs.” When blanched, the lesions fill from the center body outward toward the legs. Spider angiomata are not specific to cirrhosis, but the number and size do correlate with disease severity, and their presence relates to risk of variceal hemorrhage.12
Increased intrahepatic resistance to portal flow increases pressure on the entire splanchnic bed; an enlarged spleen (splenomegaly) is a common finding in cirrhotic patients. Splenic sequestration secondary to splenomegaly is one of the causes of thrombocytopenia in cirrhotic patients. Portal hypertension mediates systemic and splanchnic arterial vasodilation through production of nitric oxide and other vasodilators in an attempt to counteract the increased pressure gradient. Nitric oxide causes a fall in systemic arterial pressure; unfortunately, this activates both the rennin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, as well as increasing antidiuretic hormone (vasopressin) production.13 The activation of these systems is an attempt to maintain arterial blood pressure through increases in renal sodium and water retention. Increased systemic and portal pressure put increased pressure on the vascular system. As a consequence, the umbilical vein, which is usually eradicated in infancy, may become patent and increase blood flow to the abdominal veins. These prominent veins, which are visible on the surface of the abdomen, are called caput medusae because they resemble the head of the mythical Gorgon Medusa.
The aim of pharmacologic treatment in portal hypertension is to decrease portal pressure and reduce the effects of sympathetic activation.
Ascites is the accumulation of fluid in the peritoneal space and is often one of the first signs of decompensated liver disease. Ascites is the most common complication of cirrhosis and portends a dire prognosis.14
The pathophysiologic mechanisms of portal hypertension and of cirrhosis itself are entwined with the mechanisms of ascites (Fig. 22-3). Cirrhotic changes and subsequent decreases in synthetic function lead to decreased albumin production (hypoalbuminemia). Albumin is the primary intravascular protein responsible for maintaining oncotic pressure within the vascular system; low serum albumin levels combined with increased capillary permeability allow fluid to leak from the vascular space into body tissues. This results in peripheral edema, ascites, and fluid in the pulmonary system. Obstruction of hepatic sinusoids and hepatic lymph nodes allows fluid to seep into the peritoneal cavity, further contributing to ascitic fluid formation.
FIGURE 22–3. Factors involved in the development of ascites. (From Chung RT, Podolsky DK. Cirrhosis and its complications. In: Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill, 2005: 1858-1869, with permission.)
As previously discussed, the nitric oxide released in reaction to portal hypertension dilates the systemic arterial system, causing a decrease in blood pressure. There is also a decrease in renal perfusion from the lowered effective intravascular volume. The kidney reacts by activating the RAAS, which increases plasma renin activity, aldosterone production, and sodium retention. This increase in intravascular volume furthers the imbalance of intravascular oncotic pressure, allowing even more fluid to escape to the extravascular spaces, furthering ascites and peripheral edema.
Vasodilation and decreased arterial pressure are also detected centrally. The sympathetic nervous system is activated to increase blood pressure, which in turn increases portal pressure. Unchecked, these combined effects enable the cycle of portal pressure and ascites to continue, creating a self-perpetuating loop of ascites formation.
Most patients with large ascites also retain sodium and water avidly, partially due to activation of antidiuretic hormone. Patients may become hyponatremic if there is a decrease in free water excretion. Untreated, this can lead to a decrease in renal function and the hepatorenal syndrome (HRS).4,13
Type 1 HRS is characterized by rapid deterioration of renal function in the presence of decompensated cirrhosis. HRS is not reversible with volume repletion and is rapidly fatal, with a 50% mortality rate at 14 days if left untreated. Renal artery vasoconstriction (stimulated by activation of the sympathetic nervous system) and decreased mean arterial pressure (mediated by nitric oxide) combine to decrease renal perfusion and precipitate renal failure in patients with cirrhosis. The kidneys attempt to counteract this drop in renal perfusion by activating the RAAS. Production of renin stimulates a cascade that causes fluid retention and peripheral vasoconstriction in an attempt to increase blood flow to the kidneys. Production of prostaglandin E2 and prostacyclin are increased to stimulate renal vasodilation. HRS develops when these mechanisms are overwhelmed and renal perfusion drops acutely. SBP is often implicated as a trigger for HRS, and nonsteroidal anti-inflammatory drugs (NSAIDs) can precipitate HRS by inhibiting prostaglandins.
The splanchnic system drains venous blood from the GI tract to the liver. In portal hypertension, there is increased resistance to drainage from the originating organ so collateral vessels (varices) develop in the esophagus, stomach, and rectum to compensate for the increased blood volume. Varices divert blood meant for hepatic circulation back to the systemic circulation; this has the unintended deleterious effect of decreasing clearance of medications and potential toxins through loss of first-pass metabolism. Varices are weak superficial vessels, so any additional increase in pressure can cause these vessels to rupture and bleed.15
Spontaneous Bacterial Peritonitis
SBP is an acute bacterial infection of peritoneal (ascitic) fluid in the absence of intra-abdominal infection or intestinal perforation. Estimates of the prevalence of SBP in patients with ascites range from 10% to 30%.16 The peritoneal cavity is usually a sterile space. One proposed mechanism of bacterial contamination is translocation of intestinal bacteria into the peritoneal cavity, which then seeds the ascitic fluid.17 Bacterial translocation correlates with the delay in intestinal transit time and increased intestinal wall permeability observed in cirrhotic patients. Another possible mechanism is the hematogenous spread of bacteria into the peritoneal space.18 Enteric gram-negative aerobes are the most common bacteria isolated from ascitic fluid, usually Escherichia coli or Klebsiella pneumoniae. Streptococcus pneumoniae is the most common gram-positive pathogen associated with SBP.19 Once a bacterial pathogen has been identified, the antibiotic spectrum can be narrowed; SBP is rarely polymicrobial.
Decreased cognition, confusion, and changes in behavior combined with physical signs such as asterixis (characteristic flapping of hands upon extension of arms with wrist flexion) indicate HE. To objectively stage the degree of impairment, the patient should be assessed in five distinct categories:
1. Level of consciousness
2. Cognition (e.g., attention, memory, and disorientation)
3. Behavior (e.g., mood, anger, and paranoia)
4. Motor function (e.g., coordination, reflexes, and asterixis)
5. Response to psychometric tests
Changes in mental status may be acute and therefore possibly reversible. Identifiable triggers can often be detected and reversed in acute HE. Changes may also be of a more chronic, insidious nature. Patients rarely recover from chronic HE.
Numerous factors, many of them poorly understood, are involved in the development of HE. In severe hepatic disease, systemic circulation bypasses the liver, so many of the substances normally metabolized by the liver remain in the systemic circulation and accumulate to toxic levels. In excess, these metabolic byproducts, especially nitrogenous waste, cause alterations in CNS functioning.20
Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic byproduct of protein catabolism and is also generated by bacteria in the GI tract. In a normally functioning liver, hepatocytes take up ammonia and degrade it to form urea, which is later renally excreted. In patients with cirrhosis, this conversion to urea is retarded and ammonia accumulates, resulting in encephalopathy. The decrease in urea formation is manifest on laboratory assessment as decreased blood urea nitrogen (BUN), but BUN levels do not correlate with degree of HE. Patients with HE commonly have elevated serum ammonia concentrations, but again, the levels do not correlate well with the degree of CNS impairment.20
False neurotransmitters resulting from increased levels of aromatic amino acids, γ-aminobutyric acid and endogenous benzodiazepines have also been implicated in HE. These substances bind to both the y-aminobutyric acid and benzodiazepine receptors and act as agonists at the active receptor sites.20
Patients with previously stable cirrhosis who develop acute encephalopathy often have an identifiable precipitating event that can account for the increased production and/or decreased elimination of these toxins. Infections, variceal hemorrhage, renal insufficiency, electrolyte abnormalities, and increased dietary protein have all been associated with acute development of HE.
Bleeding Diathesis and Synthetic Failure
Coagulopathies signal end-stage liver disease. The liver manufactures coagulation factors essential for blood clotting and maintenance ofblood homeostasis. With advanced disease, the liver is unable to synthesize these proteins, resulting in extended clotting times (e.g., prothrombin time) and bleeding irregularities.21 Thrombocytopenia is another coagulation abnormality seen in advanced liver disease. This is a result of decreased platelet production in the bone marrow (triggered by a lack of thrombopoietin stimulation by the liver) as well as the splenic sequestration of formed platelets. Macrocytic anemia may also occur because of decreased intake, metabolism, and storage of folate and vitamin B12. In individuals who continue to drink, blood abnormalities are also aggravated further because ethanol is toxic to bone marrow.
Alcoholic Liver Disease
The course of alcoholic liver disease moves through several distinct phases from development of fatty liver to the development of alcoholic hepatitis and cirrhosis. Fatty liver and alcoholic hepatitis may be reversible with cessation of alcohol intake, but cirrhosis itself is irreversible. Although the scarring of cirrhosis is permanent, maintaining abstinence from alcohol can still decrease complications and slow progression to end-stage liver disease.22 Continuing to imbibe ethanol speeds the advancement of liver dysfunction and its complications.
Metabolism of ethanol begins even prior to absorption, as alcohol dehydrogenase (ADH) within the gastric mucosa oxidizes a portion of ingested alcohol to acetaldehyde. The remaining alcohol is rapidly absorbed from the GI tract, and since it is highly lipid soluble, it enters the body tissues quite easily. ADH oxidizes ethanol in body tissues, primarily the liver, producing hypoxic damage.25 High levels of ethanol saturate the ADH enzyme system; when the ADH system is overwhelmed, the microsomal ethanol oxidizing system must take over the detoxification process. The microsomal ethanol oxidizing system is an inducible cytochrome P-450 (CYP 450) enzyme system; it participates in phase 1 metabolism and also produces acetaldehyde as its end product.24,25 Acetaldehyde exerts direct toxic effects on the liver by damaging hepatocytes, inducing fibrosis, and by directly coupling to proteins, interfering with their intended actions. Metabolism of large amounts of ethanol shifts hepatic metabolic processes away from oxidation and toward reduction. These changes in metabolism account for the fatty liver, hypertriglyceridemia, and acidemia observed in alcoholic liver disease.
Less Common Causes of Cirrhosis
Genetics and metabolic risk factors mediate other less common causes of cirrhosis. These diseases vary widely in prevalence, disease progression, and treatment options.
Primary biliary cirrhosis is characterized by progressive inflammatory destruction of the bile ducts. This immune-mediated inflammation of the intrahepatic bile ducts results in remodeling and scarring, causing retention of bile within the liver and subsequent hepatocellular damage and cirrhosis. The number of patients affected with primary biliary cirrhosis is difficult to estimate because many people are asymptomatic; it is often diagnosed incidentally during a routine health care visit.
Nonalcoholic fatty liver disease (NAFLD) begins with asymptomatic fatty liver but may progress to cirrhosis. NAFLD is a disease of exclusion; elimination of any possible viral, genetic, or environmental causes must be made prior to making this diagnosis. NAFLD is directly related to numerous metabolic abnormalities. Risk factors include diabetes mellitus, dyslipidemia, obesity, and other conditions associated with increased hepatic fat.26
Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis.
Wilson’s disease is another autosomal recessive disease that leads to cirrhosis through protein abnormalities. The protein that is responsible for facilitating copper excretion in the bile is faulty, so copper accumulates in hepatic tissue. High copper levels within hepatocytes are toxic, and fibrosis and cirrhosis may develop in untreated patients. Those with Wilson’s disease usually present with symptoms of liver and/or neurologic disease while still in their teens.
A third autosomal recessive genetic disease is α1-antitrypsin deficiency. Abnormalities in the α1-antitrypsin protein impair its secretion from the liver. α1-Antitrypsin deficiency causes cirrhosis in children as well as adults; adults usually have concomitant pulmonary disease such as chronic obstructive pulmonary disease.
CLINICAL PRESENTATION AND DIAGNOSIS
Diagnosis of Cirrhosis
In some cases, cirrhosis is diagnosed incidentally before the patient develops symptoms or acute complications. Other patients may have decompensated cirrhosis at initial presentation; they may present with variceal bleeding, ascites, SBP, or HE. At diagnosis, patients may have some, all, or none of the laboratory abnormalities and/or signs and symptoms that are associated with cirrhosis.28
Ultrasound examination is used routinely to evaluate cirrhosis; a small, nodular liver with increased echogenicity is consistent with cirrhosis. Liver biopsy is the only way to diagnose cirrhosis definitively, but this is often deferred in lieu of a presumptive diagnosis. Because it is an invasive procedure, the decision to perform a biopsy is based on the expected clinical utility of the biopsy results. If the results have the potential to change the course of treatment, it may be advisable to perform a biopsy. The modified Child-Pugh and Model for End-Stage Liver Disease (MELD) classification systems (Table 22–1) are used to classify disease severity and evaluate the need for transplantation.
Clinical Presentation of Cirrhosis and Complications of Portal Hypertension
• Most signs and symptoms that bring a patient to the attention of medical personnel are specific to the complication the patient is experiencing at that time. The signs and symptoms vary with severity and suddenness of onset.
• Patients with cirrhosis may exhibit nonspecific symptoms such as fatigue and weakness but may be asymptomatic until acute complications develop.
• Nonspecific symptoms include anorexia, fatigue, and changes in libido and sleep patterns. Patients may also experience easy bruising and may bleed from minor injuries. Pruritus may be present, particularly with biliary involvement.
• Patients with ascites may complain of abdominal pain, nausea, increasing tightness and fullness in the abdomen, shortness of breath and early satiety.
• Hemorrhage from esophageal or gastric varices may be associated with melena, pallor, fatigue, and weakness from blood loss. Patients often present with nausea, vomiting, and hematemesis because blood in the Gl tract is nauseating. Bleeding from rectal varices may present as hematochezia.
• In patients with bleeding varices, digestion of swallowed blood represents a high protein load; this causes nausea and can precipitate symptoms of HE.
• In patients with HE, neurologic changes can be overwhelming or so subtle that they are not clinically apparent except during a targeted clinical evaluation.
• Patients with HE may complain of disruption of sleep patterns and day-to-night inversion; patients have delayed to-bed and wake times, which may progress to complete inversion of the normal diurnal cycle.
• If SBP occurs, symptoms of infection may include fever, chills, abdominal pain, and mental status changes.
• Nonspecific signs on physical exam include jaundice, scleral icterus, tea-colored urine, bruising, hepatomegaly, splenomegaly, spider angiomata, caput medusae, palmar erythema, gynecomastia, and testicular atrophy.
• Ascites can be detected by increased abdominal girth accompanied by shifting dullness and a fluid wave.
• Signs ofvariceal bleeding depend on the degree of blood loss and abruptness of onset. Rapid and massive blood loss is more likely to result in hemodynamic instability than is slow, steady bleeding. Signs of acute bleeding may include pallor, hypotension, tachycardia, mental status changes, and hematemesis.
• Markers of hepatic encephalopathy (HE) include decreased cognition, confusion, changes in behavior, and asterixis.
• Patients with SBP may present with fever, painful tympanic abdomen, and changes in mental status.
• Decreases in clotting factors may manifest as abnormal bruising and bleeding.
• Dupuytren contracture is a contraction of the palmar fascia that usually affects the fourth and fifth digits.27 It is not specific to cirrhosis and can also be seen in repetitive use injuries.
• Hepatocellular damage manifests as elevated serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]). The degree of transaminase elevation does not correlate with the remaining functional metabolic capacity of the liver. An AST level two-fold higher than ALT is suggestive of alcoholic liver damage.
• Elevated alkaline phosphatase is nonspecific and may correlate with liver or bone disease; it tends to be elevated in biliary tract disease.
• γ-Glutamyl transferase (GGT) is specific to the bile ducts, and in conjunction with an elevated alkaline phosphatase, suggests hepatic disease. Extremely elevated GGT levels further indicate obstructive biliary disease. GGT is also elevated in those who drink three or more alcoholic drinks daily.
• Increased total, direct, and indirect bilirubin concentrations indicate defects in transport, conjugation, or excretion of bilirubin.
• Lactate dehydrogenase (LDH) is a nonspecific marker of hepatocyte damage; disproportionate elevation of LDH indicates ischemic injury.
• Thrombocytopenia may occur because of decreased platelet production and splenic platelet sequestration.
• Anemia (decreased hemoglobin and hematocrit) occurs as a result ofvariceal bleeding, decreased erythrocyte production, and hypersplenism.
• Elevated prothrombin time (PT) and international normalized ratio (INR) are coagulation derangements that indicate loss of synthetic capacity in the liver and correlate with functional loss of hepatocytes.
• Decreased serum albumin and total protein occur in chronic liver damage due to loss of synthetic capacity within the liver.
• The serum albumin-to-ascites gradient is 1.1 g/dL (11 g/L) or greater caused by portal hypertension.
• Increased blood ammonia concentration is characteristic of HE, but levels do not correlate well with the degree of impairment.
• Increased serum creatinine signaling a decline in renal function may be seen with hepatorenal syndrome.
• Signs and symptoms of SBP in a patient with cirrhosis and ascites should prompt a diagnostic paracentesis (Fig. 22–5). In SBP, there is decreased total serum protein, elevated white blood cell count (with left shift), and the ascitic fluid contains at least 250/mm3 (250 × 106/L) neutrophils. Bacterial culture of ascitic fluid may be positive, but lack of growth does not exclude the diagnosis.
Patients with ascites or known varices must be assumed to have portal hypertension and are treated as such, even if direct measurements of portal pressure have not been made.29
Table 22–1 Child-Pugh and MELD Classifications for Determining Severity of Liver Damage
Diagnosis of Ascites
In obese patients or those with only small amounts of fluid accumulation, ultrasound evaluation may be necessary to detect ascites with certainty. Analysis of ascitic fluid obtained during paracentesis provides diagnostic clues to the etiology of the ascites. Diagnostic evaluation should include cell count with differential, albumin, total protein, Gram stain, and bacterial cultures. In patients without an established diagnosis of liver disease, the serum ascites-albumin gradient (SAAG) is sensitive in determining if the ascites is caused by portal hypertension.22 SAAG compares the serum albumin concentration to the ascitic fluid albumin concentration:
Albserum – Albascites = SAAG
A value of 1.1 g/dL or greater (11 g/L or greater) identifies portal hypertension as the cause of the ascites with 97% accuracy.22,30 In portal hypertension, the ascitic fluid is low in albumin; this balances the oncotic pressure gradient with the hydrostatic pressure gradient of portal hypertension. The differential diagnoses for SAAG values less than 1.1 g/dL (less than 11 g/L) include peritoneal carcinoma, peritoneal infection (tuberculosis, fungal, or cytomegalovirus), and nephrotic syndrome. Serum albumin measurements should be made at the same time ascitic fluid is obtained for an accurate comparison.22
TREATMENT OF CIRRHOSIS, PORTAL HYPERTENSION, AND COMPLICATIONS
Recognizing and treating the cause of cirrhosis is paramount. Cirrhosis is irreversible; treatments are directed at limiting disease progression and minimizing1 complications. The immediate treatment goals are to stabilize acute complications such as variceal bleeding and prevent SBP. Once life-threatening conditions have stabilized, the focus shifts to preventing complications and preventing further liver damage. Complication prevention involves both primary and secondary prophylaxis. To determine appropriate prophylactic therapy, a careful analysis of patient characteristics and disease history is mandatory. The sections that follow concentrate on treatment and prevention of cirrhotic complications.
Lifestyle modifications can limit disease complications and slow further liver damage. Avoidance of additional hepatic insult is critical for successful cirrhosis treatment. The only proven treatment for alcoholic liver disease is the immediate cessation of alcohol consumption. Patients who have cirrhosis from etiologies other than alcoholic liver disease should also abstain from alcohol consumption to prevent further liver damage.
All patients with ascites require counseling on dietary sodium restriction. Salt intake should be limited to less than 800 mg sodium (2 g sodium chloride) per day. More stringent restriction may cause faster mobilization of ascitic fluid, but adherence to such strict limits is very difficult. Ascites usually responds well to sodium restriction accompanied by diuretic therapy.14,22,31,32 The goal of therapy is to achieve urinary sodium excretion of at least 78 mEq (78 mmol) per day.22 While a 24-hour urine collection will provide this information, a spot urine sodium:potassium ratio greater than 1 provides the same information and is much less cumbersome to perform.
Medication use must be monitored carefully for potential hepatotoxicity. Hepatically metabolized medications have the potential to accumulate in patients with liver disease. Little guidance is available on drug dosing in hepatic impairment because these patients have historically been excluded from drug trials. Daily acetaminophen use should not exceed 2 g. Dietary supplements, herbal remedies, and nutraceuticals have not been well studied in hepatic impairment and cannot be recommended.
In patients with variceal bleeding, nasogastric (NG) suction reduces the risk of aspirating stomach contents. Aspiration pneumonia is a major cause of death in patients with variceal bleeding. NG suction is also helpful in decreasing vomiting during acute episodes of variceal bleeding.33,34 Blood within the GI tract is very nauseating; removal of the blood can decrease vomiting.
Patient Encounter, Part 1
ES is a 44-year-old Hispanic man who presents to the emergency department with complaints of abdominal pain and fatigue.
Chief complaint: “My belly feels tight”
HPI: Increasing feelings of fullness and abdominal tightness that have become noticeable over the past 2 weeks, accompanied by nausea and decreased food intake, but without vomiting
PMH: Hypertension × 15 years, acute pancreatitis × 2 episodes
PSH: No surgeries
SH: Married, currently separated; denies tobacco and illicit drug use; for the past 20 years typically drinks a 12-pack of beer daily and several shots of tequila; use has recently increased due to depression over marital separation
FH: Father with cirrhosis, died at age 45 from coronary disease; mother alive at age 62 with type 2 diabetes mellitus, hypertension, hyperlipidemia, and gastroesophageal reflux disease
Outpatient Meds: Chlorthalidone 25 mg daily
ROS: (+) Anorexia and nausea; denies vomiting, constipation, or diarrhea; patient reports moderate shortness of breath and dyspnea on exertion
VS: BP 125/75 mm Hg, P 84 bpm, T 37.3°C (99.1 °F), RR 18/min, oxygen saturation 98% on room air
HEENT: PERRL, EOMI, (+) sclera icterus
CV: RRR, no murmurs, rubs, or gallops
Chest: CTA bilaterally, no crackles or wheezes
Abd: Tense, distended abdomen that is tender to palpation, decreased bowel sounds, (+) hepatosplenomegaly
Ext: 2+ pedal pulses, 2+ pitting edema
What are this patient’s risk factors for liver disease?
Identify features of his presentation that are consistent with cirrhosis.
Endoscopic band ligation and sclerotherapy are both means to stop acutely bleeding varices. Endoscopic band ligation is the application of a stricture around the varix, whereas sclerotherapy involves injecting the varix with substances designed to decrease blood flow to the area and prevent rebleeding. Endoscopic band ligation has replaced sclerotherapy as the preferred endoscopic treatment and is effective in stopping acute variceal bleeding in up to 90% of patients.35 It is the standard of care for secondary prophylaxis of repeat bleeding in patients with a history of either esophageal or gastric variceal bleeding. Endoscopic band ligation is best used in conjunction with pharmacologic treatment.36–38
Balloon tamponade involves the application of direct pressure to the area of bleeding with an inflatable balloon attached to an NG tube. It is an option for patients in whom drug therapy and band ligation fail to stop variceal bleeding. Balloon tamponade is used only when other methods have failed. Once the direct pressure of the balloon is removed, rebleeding often occurs, so balloon tamponade is only a temporary measure prior to more definitive treatment such as shunting.11
During episodes of acute HE, temporary protein restriction to decrease ammonia production can be a useful adjuvant to pharmacologic therapy. Long-term protein restriction in cirrhotic patients is not recommended. Cirrhotic patients are already in a nutritionally deficient state, and prolonged protein restriction will exacerbate the problem.20
Vaccination against hepatitis A and B is recommended in patients with underlying cirrhosis to prevent additional liver damage from an acute viral infection.39 Pneumococcal and influenza vaccination may also be appropriate and can reduce hospitalizations due to influenza or pneumonia.
Shunts are long-term solutions to decrease elevated portal pressure. Shunts divert blood flow either through or around the diseased liver, depending on the location and type of shunt employed. Transjugular intrahepatic portosystemic shunts (TIPS) create a communication pathway between the intrahepatic portal vein and the hepatic vein. TIPS procedures have an advantage over surgically inserted shunts because they are placed through the vascular system rather than through a more invasive surgical procedure, but they still carry a risk of bleeding and infection. TIPS placement is associated with an improvement in HRS but an increased incidence of HE.40 HE associated with TIPS placement results from decreased detoxification of nitrogenous waste products because the shunt allows blood to evade metabolic processing.
Drug therapy targeted to reduce portal hypertension and cirrhosis can alleviate symptoms and prevent complications but cannot reverse cirrhosis. Drug therapy is available to treat the complications of ascites, varices, SBP, HE, HRS, and coagulation abnormalities.
Nonselective β-blockers such as propranolol and nadolol are first-line treatments to reduce portal hypertension. They reduce bleeding and decrease mortality in patients with known varices. Use of β-blockers for primary prevention of variceal formation is controversial.
Only nonselective β-blockers reduce bleeding complications in patients with known varices. Blockade of β1 receptors reduces cardiac output and splanchnic blood flow. β2-Adrenergic blockade prevents β2-receptor-mediated splanchnic vasodilation while allowing unopposed a-adrenergic effects; this enhances vasoconstriction of both the systemic and splanchnic vascular beds. The combination of β1 and β2effects makes the nonselective β-blockers preferable to cardioselective agents in treating portal hypertension.1,35,41 Cardioselective β-blockers do lose their cardioselectivity at higher doses, but most patients with cirrhosis cannot tolerate the high doses.
Because β-blockers decrease blood pressure and heart rate, they should be started at low doses to increase tolerability Propranolol is hepatically metabolized, and its half-life and pharmacologic effects are prolonged in portal hypertension. A reasonable starting dose of propranolol is 10 mg two to three times daily.
Doses should be titrated as tolerated with the goal of decreasing heart rate by 25% or to approximately 55 to 60 bpm.11,35 Heart rate is not an accurate marker for portal pressure reduction, but it is the acknowledged surrogate marker for effectiveness because there are no other acceptable alternatives.
Nitrates have been suggested in patients who do not achieve therapeutic goals (heart rate reduction) with β-blocker therapy alone. Trials to evaluate the effects of nitrates (e.g., isosorbide mononitrate) on portal pressure, both alone and in combination with β-blockers, show enhanced reduction of portal pressure; however, there is an increase in mortality when nitrates are used alone. Adverse effects are significantly higher in patients treated with the combination of nonselective β-blockers and nitrates as opposed to β-blocker monotherapy.42,43 The current evidence only supports use of the combination to prevent rebleeding, not for primary prophylaxis. Unfortunately, β-blockers either alone or in combination may be intolerable for many patients with cirrhosis.
The goals of treating ascites are to minimize acute discomfort, reequilibrate ascitic fluid, and prevent SBP. Treatment should modify the underlying disease pathology; without directed therapy, fluid will rapidly reaccumulate.
In the case of tense ascites, relief of acute discomfort may be accomplished by therapeutic paracentesis. Often the removal of just 1 to 2 L of ascitic fluid provides relief from pain and fullness. When removing 5 L or more of fluid at one time, volume resuscitation with 8 to 10 g of albumin given IV should be provided for each liter of fluid removed. Large-volume paracentesis without albumin administration is a known precipitant of HRS, secondary to decreased perfusion. If less than 5 L of fluid is removed in a hemodynamically stable patient, albumin use is not warranted.22
Diuretics are often required in addition to sodium restriction (see Nonpharmacologic Therapy). Spironolactone and furosemide form the basis of pharmacologic therapy for ascites. Spironolactone is an aldosterone antagonist and counteracts the effects of activation of the RAAS. In hepatic disease, not only is aldosterone production increased, but the half-life is prolonged because of decreased hepatic metabolism. Spironolactone also acts to conserve the potassium that would otherwise be excreted because of elevated aldosterone levels.
Patient Encounter, Part 2
In the emergency department, a chest x-ray was normal. The following laboratory test results were obtained:
Sodium 128 mEq/L (mmol/L)
Potassium 3.1 mEq/L (mmol/L)
Chloride 106 mEq/L (mmol/L)
Bicarbonate 24 mEq/L (mmol/L)
BUN 10 mg/dL (3.57 mmol/L)
Scr 1.1 mg/dL (97 μmol/L)
Glucose 145 mg/dL (8.0 mmol/L)
Hemoglobin 12.5 g/dL (125 g/L or 7.75 mmol/L)
Hematocrit 38% (0.38)
WBC 7.4 × 103/mm3 (× 109L)
Platelets 118 × 103/mm3 (× 109L)
Albumin 2.7 g/dL (27 g/L)
Total bilirubin 2.3 mg/dL (39.3 μmol/L)
Alkphos 177 IU/L (2.95 μKat/L)
AST 443 IU/L (7.38 ιKat/L)
ALT 206 IU/L (3.43 ιKat/L)
GGT 185 IU/L (3.1 ιKat/L)
LDH 203 IU/L (3.38 ιKat/L)
PT 29 seconds
Which of these values are consistent with the diagnosis of cirrhosis?
What (if anything) in the current presentation implies the underlying cause of the disease?
Which of the laboratory results are suggestive of complications related to cirrhosis?
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyl transferase; INR, International Normalized Ratio; IU, international units; LDH, lactate dehydrogenase; PT, prothrombin time.
Spironolactone is usually used in combination with a loop diuretic (e.g., furosemide) for more potent diuresis. A ratio of 40 mg furosemide (the most commonly used loop diuretic) to each 100 mg spironolactone can usually maintain serum potassium concentrations within the normal range. Therapy is commonly initiated with oral spironolactone 100 mg and furosemide 40 mg/day.
Doses should be titrated at intervals no more frequent than every 2 to 3 days. Because spironolactone is used for its antialdosterone effects, much higher doses (up to 400 mg/day) are needed than those used when treating hypertension. If intolerable side effects such as gynecomastia occur with spironolactone, other potassium-sparing diuretics may be used, but clinical trials have not shown equivalent efficacy.22
The target in treating ascites is to cause a fluid loss of approximately 0.5 L/day.22 Because ascites equilibrates with vascular fluid at a much slower rate than does peripheral edema, aggressive diuresis is associated with intravascular volume depletion and should be avoided unless patients have concomitant peripheral edema. Patients with peripheral edema in addition to ascites may require increasing furosemide doses until euvolemia is achieved; IV diuretics are often necessary.22 Diuretic therapy in cirrhosis is typically lifelong.
Unfortunately, variceal bleeding is common in cirrhotic patients; it accounts for between 10% and 30% of all cases of upper GI hemorrhage. During acute variceal hemorrhage, it is crucial to control bleeding, prevent rebleeding, and avoid acute complications such as SBP; mortality from first bleeding episode is up to 55%, and patients must be treated aggressively. A treatment algorithm for acute variceal bleeding is depicted in Figure 22–4.
Patient Encounter, Part 3
ES is found to have ascites. Therapeutic paracentesis is ordered to relieve shortness of breath and abdominal pain; 4 L of ascitic fluid is removed.
What are the goals for treating ascites in this patient?
What lifestyle modifications should the patient make that may decrease his risk of hospitalization and death from cirrhosis?
What pharmacologic options are available to treat ascites in this patient?
Octreotide is a synthetic analogue of somatostatin; it causes selective vasoconstriction of the splanchnic bed, decreasing portal venous pressure with few serious side effects. Vasopressin has also been used to achieve this effect, but since vasopressin causes nonselective vasoconstriction, it carries the risk of systemic consequences, which limits its usefulness.
The recommended octreotide dose is a 50- to 100-mcg IV loading dose followed by a continuous IV infusion of 25 to 50 mcg/hour. Therapy should continue for at least 24 to 72 hours after bleeding has stopped. Some clinicians continue octreotide for a full 5 days since this is the time frame during which the risk of rebleeding is highest. Octreotide combined with endoscopic therapy results in decreased rebleeding rates and transfusion needs when compared to endoscopic treatment alone.35
Spontaneous Bacterial Peritonitis
Initiation of prophylactic antibiotic therapy to prevent SBP is recommended during acute variceal bleeding; this is typically initiated with a fluoroquinolone (e.g., ciprofloxacin 500 mg twice daily for 7 days) or an IV third-generation cepha-losporin. Some institutions would not use a fluoroquinolone antibiotic in patients who have been on long-term prophylactic therapy with that class of drugs. Prophylactic antibiotic therapy reduces in-hospital infections and mortality in patients hospitalized for variceal bleeding.44
If the presence of SBP is suspected, empiric antibiotic therapy with a broad-spectrum anti-infective agent should be initiated after ascitic fluid collection, pending cultures and susceptibilities (Fig. 22-5).45,46In the setting of presumed infection, delaying treatment while awaiting laboratory confirmation is inappropriate and may result in death. The initial antibiotic should be an IV third-generation cephalosporin (e.g., cefotaxime 2 g every 8 hours, ceftriaxone 1 g every 24 hours), an IV extended-spectrum penicillin (e.g., piperacillin-tazobactam 3.375 g every 6 hours or 4.5 g every 8 hours), or a fluoroquinolone (e.g., ciprofloxacin 400 mg IV every 12 hours), because these agents cover the most common gram-negative and gram-positive agents implicated in SBP. Third-generation cephalosporins are usually recommended as first-line therapy. Fluoroquinolones may be used if resistant (extended-spectrum β-lactamase positive) organisms are suspected based on local susceptibility patterns or patient history. Once an infectious agent has been identified, antibiotic coverage can be narrowed to an agent that is highly active against that particular organism.
SBP has been identified as a cause of HRS. The risk of renal failure is lessened with IV albumin therapy, dosed at 1.5 g/kg of body weight initially, followed by 1 g/kg of body weight on day 3 of SBP therapy.47
FIGURE 22–4. Treatment algorithm for active Gl bleeding resulting from portal hypertension. (Adapted from Schiano TD, Bodenheimer HC. Complications of chronic liver disease. In: Friedman SL, McQuaid KR, Grendell JH, eds. Current Diagnosis and Treatment in Gastroenterology, 2nd ed. New York: McGraw-Hill, 2003, p. 649, with permission).
FIGURE 22–5. Approach to the patient with ascites and spontaneous bacterial peritonitis (SBP). (BUN, blood urea nitrogen; Na, sodium; PMN polymorphonuclear leukocyte; TIPS, transjugular intrahepatic portosystemic shunt.) (From Chung RT, Podolsky DK. Cirrhosis and its complications. In: Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine, 17th ed. New York: McGraw-Hill, 2005: 1858-1869, with permission.) *lf PMN is greater than 250/μL but culture is negative (culture-negative neutrocytic ascites) begin empiric antibiotics and retap after 48 hours. If culture is positive but PMN less than 250/μL, treat as if PMN greater than 250/μL (presumed SBP). If polymicrobial infection exists, exclude SBP.
Patient Encounter, Part 4
ES is brought to the emergency department by ambulance 2 months after the initial presentation.
Chief Complaint: “I’ve been vomiting black stuff and I’m really tired.”
HPI: Hematemesis for the past 2 days, worsening today and accompanied by profound weakness; patient is continuing to drink alcohol at the same rate as he was at his first visit.
Outpatient Meds: Spironolactone 100 mg daily; furosemide 40 mg daily
ROS: (+) Nausea, coffee-ground emesis, and melena; denies constipation or diarrhea; (+) bilateral lower extremity edema
VS: BP 98/60 mm Hg, P 122 bpm, T 37.1°C (98.8°F), RR 21/min, oxygen saturation 91% on room air
CV: Tachycardia; no murmurs, rubs, or gallops
Chest: CTA bilaterally
Abd: Mildly distended, tender to deep palpation, decreased bowel sounds, (+) hepatosplenomegaly and fecal occult blood test
Ext: Decreased pedal pulses, 3+ pitting edema
What are the immediate treatment goals for ES? How will these goals be achieved?
Does this presentation warrant prophylaxis to prevent further disease complications? If so, what therapy is appropriate for this patient?
Patients who have previously experienced SBP and those with low-protein ascites (ascitic fluid albumin less than 1 g/dL [less than 10 g/L]) are candidates for long-term prophylactic antibiotic therapy.Recommended regimens include either a single trimethoprim-sulfamethoxazole double-strength tablet 5 days per week (Monday through Friday) or ciprofloxacin 750 mg once weekly.19,46
Lactulose is the foundation of pharmacologic therapy to prevent and treat HE. It is a nondigestible synthetic disaccharide laxative that is hydrolyzed in the gut to an osmotically active compound that draws water into the colon and stimulates defecation. Lactulose lowers colonic pH, which favors the conversion of ammonia (NH3 to ammonium (NH4+).48 Ammonium is ionic and cannot cross back into systemic circulation; it is eliminated in the feces.Lactulose is usually initiated at 15 to 30 mL two to three times per day and titrated to a therapeutic goal of two to four soft bowel movements daily.20,49,50
Prior to the introduction of lactulose, neomycin was the only treatment available for HE. Neomycin exerts its antibiotic action in the gut, thereby eliminating urease-producing bacteria. Elimination of these organisms decreases ammonia production. Although neomycin is classified as a nonabsorbable antibiotic, patients with cirrhosis have been shown to have detectable plasma concentrations. This is thought to be due to decreased integrity of the intestinal mucosa and may lead to nephrotoxicity. Neomycin is given orally in doses of 3 to 6 g daily.
Rifaximin is another nonabsorbable antibiotic that is used extensively in Europe as first-line therapy for HE. Rifaximin therapy has been shown to be both efficacious and well tolerated, but the expense in the United States (where it is not licensed for HE) may be prohibitive for long-term use. Rifaximin given at the typical dose of 1,200 mg/day costs approximately tenfold more than lactulose.
Evidence for the false transmitter theory as the cause of encephalopathy is demonstrated by the fact that administration of flumazenil (a benzodiazepine antagonist) has resulted in functional improvement. Unfortunately, long-term benefit has not been shown, and since flumazenil can only be administered parenterally, it is not an appropriate choice for clinical use. Its use is limited to the research setting.
HRS is a life-threatening complication of cirrhosis. Targeted treatment increases volume within the central venous system. Peripheral vasoconstriction redistributes fluid from the periphery to the venous system, and the fluid is contained thereby increases in oncotic pressure from albumin administration. The ultimate goal is to increase renal perfusion.
A common regimen involves administration of albumin 1 g/kg on day one, followed by 20 to 40 g on subsequent treatment days. This regimen is used in combination with midodrine (an α-agonist) and octreotide. Midodrine is typically initiated at 7.5 mg three times daily, and octreotide is administered subcutaneously (as opposed to IV during variceal bleeding) 100 mcg three times daily. Both of these regimens can be titrated as tolerated to achieve increases in mean arterial pressure of 15 mm Hg or greater.
Terlipressin, a vasopressin analog available in Europe, has been used with success in patients with HRS, but it is not currently available in the United States.
Vitamin K is essential for the production of coagulation factors within the liver. Elevated clotting times from decreased protein synthesis are indistinguishable from those produced by low vitamin K levels resulting from malnutrition or poor intestinal absorption. Vitamin K1 (phytonadione) 10 mg given subcutaneously daily for 3 days can help to establish whether the prolonged bleeding time results from loss of synthetic function in the liver or vitamin K deficiency. It is unusual to completely reverse clotting abnormalities, but most patients experience a decrease in international normalized ratio (INR), conferring a decreased risk of bleeding.
Patient Encounter, Part 5
During the hospital stay, ES had endoscopic band ligation to treat esophageal and gastric varices. Propranolol 20 mg three times a day was initiated; IV furosemide 60 mg twice daily resolved the pedal edema. Prescriptions for spironolactone 200 mg daily and furosemide 40 mg twice daily were provided at discharge. Three weeks later, ES is brought to clinic by his daughter who states that he is confused and “hasn’t been himself.” She is unsure if he has been taking his medication but says he continues to drink and has been eating poorly. Patient will only speak to staff in Spanish.
What are the presenting signs and symptoms of hepatic encephalopathy (HE)?
What factors could contribute to HE in this patient?
What is the prognosis for this patient who has developed ascites, variceal bleeding, and HE within 3 months?
• Reevaluate the pharmacotherapy regimen at each visit to assess adherence, effectiveness, adverse events, and need for drug titration.
• Determine adherence to lifestyle changes such as cessation of ethanol intake and avoidance of over-the-counter medications (particularly NSAIDs) and herbal remedies that may exacerbate complications of cirrhosis.
• Assess the effectiveness of β-blocker therapy by measuring heart rate. Heart rate reduction of 25% from baseline or to 55 to 60 bpm is desirable. Ask the patient specific, directed questions regarding adverse effects of β-blockers; inquire about symptoms of orthostatic hypotension (e.g., lightheadedness, dizziness, or fainting).
• Evaluate effectiveness of diuretic therapy with regard to ascitic fluid accumulation and development of peripheral edema. Ask the patient directed questions about abdominal girth, fullness, tenderness, and pain. Weigh the patient at each visit, and ask the patient to keep a weight diary. Assess for peripheral edema at each visit.
• Assess dietary sodium intake by patient food recall. Objectively measure dietary sodium adherence using spot urine sodium-to-potassium ratio. Assess for appropriate sodium excretion.
Patient Care and Monitoring
1. Obtain a complete history of alcohol intake and hepatotoxic drug use, including over-the-counter products and dietary supplements.
2. At each encounter, ask the patient specific questions about adherence to prescribed therapy, dietary restrictions and cessation of alcohol intake.
3. At each visit, evaluate the pharmacotherapy regimen for appropriate drug choice and dose, nonprescription drug use, adverse effects, and use of potentially hepatotoxic medications.
4. Question the patient about adverse effects, since hepatically metabolized medications may accumulate and cause adverse effects.
5. Consider antibiotic prophylaxis for SBP in patients with low-protein ascites or prior SBP.
6. Conduct a review of systems and physical examination at each visit to determine if the patient has had progression of complications.
7. Ask specific questions about bleeding, bruising, and fatigue. There is a direct link between loss of synthetic function and disease progression.
8. Refer the patient to substance abuse counseling for education about alcohol cessation if appropriate.
9. Provide education regarding dietary sodium restriction at each visit; consider referral to a dietician if appropriate.
• Obtain complete blood count and prothrombin time (PT)/INR to assess for anemia, thrombocytopenia, or coagulopathy. Ask about increases in bruising, bleeding, or development of hematemesis, hematochezia, or melena to assess for bleeding.
• Review biopsy reports and laboratory data. Transaminases and blood ammonia levels do not correlate well with disease progression, but increased coagulation times are markers of loss of synthetic function.
• Evaluate for signs and symptoms of HE. Mental status changes may be subtle; questioning family members or caregivers about confusion or personality changes may reveal mild HE even if the patient is unaware of the deficits.
• In patients taking lactulose therapy, titrate the dose to achieve two to four soft bowel movements daily.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
1. Lubel JS, Angus PW. Modern management of portal hypertension. Int Med J 2005;35:45-49.
2. Anderson RN, Smith BL. Deaths: Leading causes for 2002. Natl Vital Stat Rep 2005;53:17.
3. National Digestive Diseases Information Clearinghouse. Cirrhosis of the liver. NIH Publication No. 04-1134. Bethesda, MD: Author; 2003(December).
4. Lelbach WK. Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse. Ann NY Acad Sei 1975;252:85-105.
5. Frezza M, DiPadova C, Pozzato G, et al. High blood alcohol levels in women. The role of decreased alcohol dehydrogenase activity and first pass metabolism. N Engl J Med 1990;322:95-99.
6. Alter MJ, Hadler SC, Margolis HS, et al. The changing epidemiology of hepatitis B in the United States. Need for alternative vaccination strategies. JAMA 1990;263:1218-1222.
7. Alter MJ, Gerety RJ, Smallwood LA, et al. Sporadic non-A, non-B hepatitis: Frequency and epidemiology in an urban U.S. population. J Infect Dis 1982;145:886-893.
8. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. N Engl J Med 1988;319:983-989.
9. Krige JEJ, Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system: Portal hypertension 2: Ascites, encephalopathy, and other conditions. BMJ 2001;322:416-418.
10. Krige JEJ, Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system: Portal hypertension 1: Varices. BMJ 2001;322:348-351.
11. DeFranchis R. Updating consensus in portal hypertension: Report of the Baveno III workshop on definitions, methodology and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846-852.
12. Zaman A, Hapke R, Flora K, et al. Factors predicting the presence of esophageal or gastric varices in patient with advanced liver disease. Am J Gastroenterol 1999;94:3292-3296.
13. Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities of sodium and water retention in cirrhosis. N Engl J Med 1998;339:533-541.
14. Gines P, Cardena A, Arroyo V, Rodes J. Management of cirrhosis and ascites. N Engl J Med 2004;350:1646-1654.
15. Sarin SK, Lahoti D, Saxena SP, et al. Prevalence, classification and natural history of gastric varices: A long-term follow-up study in 568 portal hypertension patients. Hepatology 1992;16:1343-1349.
16. Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: A consensus document. J Hepatol 2000;32:142-145.
17. Guarner C, Runyon BA. Spontaneous bacterial periton it is: Pathogenesis, diagnosis, and management. Gastroenterology 1995;3:311-328.
18. Such J, Frances R, Munoz C, et al. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology 2002;36:135-141.
19. Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: A consensus document. J Hepatol 2000;32:142-153.
20. Blei AT, Cordoba J. The Practice Parameters Committee of the American College of Gastroenterology. Hepatic encephalopathy practice guidelines. Am J Gastroenterol 2001;96:1968-1976.
21. Robert A, Chazouilleres O. Prothrombin time in liver failure: Time, ratio, activity percentage, or international normalized ratio. Hepatology 1996;24:1392-1394.
22. Runyon BA. American Association for the Study of Liver Diseases (AASLD) practice guideline: Management of adult patients with ascites due to cirrhosis. Hepatology 2004;39:841-856.
23. Lieber CS. Biochemical and molecular basis of alcohol-induced injury to liver and other tissues. N Engl J Med 1988;319:1639-1650.
24. Tsutsumi M, Lasker JM, Shimuzu M, et al. The intralobular distribution of ethanol inducible P450IIE1 in rat and human liver. Hepatology 1989;10:437-446.
25. Tsutsumi M, Lasker JM, Takahashi T, Lieber CS. In vivo induction of hepatic P4502E1 by ethanol: Role of increased enzyme synthesis. Arch Biochem Biophys 1993;304(1):209-218.
26. Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 2002;35:373-379.
27. Attali P, Ink O, Pelletier G, et al. Dupuytren’s contracture, alcohol consumption, and chronic liver disease. Arch Intern Med 1987;147:1065-1067.
28. Bravo A, Sheth S, Chopra S. Liver biopsy. N Engl J Med 2001;344:-495-500.
29. Garcia-Tsao G, Groszmann RJ, Fisher RL, et al. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985;5:419-424.
30. Runyon BA, Montano A, Akrivadis E, et al. The serum ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med 1992;117:215-220.
31. Runyon BA. Care of patients with ascites. N Engl J Med 1994;330:337-342.
32. Runyon BA. Management of adult patients with ascites caused by cirrhosis. Hepatology 1998;27:264-272.
33. D’Amico G, Morabito A, Pagliaro L. Six week prognostic indicators in upper gastrointestinal hemorrhage in cirrhotics. Front Gastrointest Res 1986;9:247.
34. Garden OJ, Motyl H, Gilmour WH, et al. Prediction of outcome following acute variceal haemorrhage. Br J Surg 1985;72:91-95.
35. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001;345:669-681.
36. Grace ND, American College of Gastroenterology Practice Parameters Committee. Diagnosis and treatment of gastrointestinal bleeding secondary to portal hypertension. Am J Gastroenterol 1997;92:1081-1091.
37. Lo GH, Lai KH, Cheng JS, et al. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: A prospective, randomized trial. Hepatology 2000;32:461-465.
38. De La Pena J, Brullet E, Sanchez-Hernandez E, et al. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: A multicenter trial. Hepatology 2005;41:572-578.
39. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Recomm Rep; 2002 (May 10);51(RR-6): 1-78.
40. Boyer TD, Haskal ZJ. American Association for the Study of Liver Diseases (AASLD) practice guideline: The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology 2005;41:386-401.
41. Pagliaro L, D’Amico G, Sorensen TI, et al. Prevention of first bleeding in cirrhosis. A meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med 1992;117:59-70.
42. Merkel C, Sacerdoti D, Bolognesi M, et al. Hemodynamic evaluation of the addition of isosorbide-5 -mononitrate to nadolol in cirrhotic patients with insufficient response to the beta-blocker alone. Hepatology 1997;26:34-39.
43. Gournay J, Masliah C, Martin T, et al. Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding. Hepatology 2000;6:1239-1245.
44. Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L. Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding. Cochrane Database Syst Rev 2002;(2):CD002907.
45. Such J, Runyon BA. Spontaneous bacterial peritonitis. Clin Infect Dis 1998;27:669-674.
46. Soares-Weiser K, Brezis M, Tur-Kaspa R, et al. Antibiotic prophylaxis of bacterial infections in cirrhotic inpatients: A meta-analysis of randomized controlled trials. Scand J Gastroenterol 2003;38:193-200.
47. Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403-409.
48. Pasricha PJ. Treatment of disorders of bowel motility and water flux; antiemetics; agents used in biliary and pancreatic disease. In: Brunton LL, LAZO JS, Parker KL, eds. Goodman & Gilman’s the Pharmacologic Basis of Therapeutics, 11th ed. New York: McGraw-Hill, 2005:1335-1358.
49. Mortensen PB. The effect of oral-administered lactulose on colonic nitrogen metabolism and excretion. Hepatology 1992;16:1350-1356.
50. Mortensen PB, Holtug K, Bonnen H, Clausen MR. The degradation of amino acids, proteins, and blood to short-chain fatty acids in colon is prevented by lactulose. Gastroenterology 1990;98:353-360.