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| CECIL |
| TEXT BOOK of MEDICINE |
Section XIII Diseases of the Liver, Gallbladder, and Bile Ducts
| 157 CIRRHOSIS AND ITS SEQUELAE Guadalupe Garcia-Tsao • |
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Definition
Cirrhosis, which can be the final stage of any chronic liver disease, is a diffuse process characterized by fibrosis and conversion of normal architecture to structurally abnormal nodules (Fig. 157-1). These “regenerative” nodules lack normal lobular organization and are surrounded by fibrous tissue. The process involves the whole liver and is essentially irreversible. Although cirrhosis is histologically an “all or nothing” diagnosis, clinically it can be classified by its status as compensated or decompensated. Decompensated cirrhosis is defined by the presence of ascites, variceal bleeding, encephalopathy, or jaundice, which are complications that result from the main consequences of cirrhosis: portal hypertension and liver insufficiency.
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| FIGURE 157-1 • Gross and microscopic images of a normal and cirrhotic liver. A, Gross image of a normal liver with a smooth surface and homogeneous texture. B, Microscopically, liver sinusoids are organized and vascular structures are normally distributed. C, Gross image of a cirrhotic liver. The liver has an orange-tawny color with an irregular surface and a nodular texture. D, Microscopically, the architecture is disorganized and there are regenerative nodules surrounded by fibrous tissue. |
Epidemiology
Because many patients with cirrhosis are asymptomatic until decompensation occurs, it is very difficult to assess the real prevalence and incidence of cirrhosis in the general population. The prevalence of chronic liver disease/cirrhosis worldwide is estimated to be 100 (range, 25 to 400) per 100,000 subjects, but it varies widely by country and by region.
Cirrhosis is an important cause of morbidity and mortality worldwide and in the United States. According to the World Health Organization, about 800,000 people die of cirrhosis annually. In the United States, cirrhosis accounts for about 27,000 deaths each year, or a death rate of 9.4 per 100,000, which makes it the 12th leading cause of death overall. Importantly, chronic liver disease and cirrhosis are the seventh leading cause of death in the United States in individuals between 25 and 64 years of age, with a death rate of 19.9 per 100,000. Because chronic liver disease affects people in their most productive years of life, it has a significant impact on the economy as a result of premature death, illness, and disability.
Any chronic liver disease can lead to cirrhosis (Table 157-1). Chronic viral hepatitis C and alcoholic liver disease are the most common causes of cirrhosis, followed by nonalcoholic fatty liver disease and chronic hepatitis B (Chapters 152 and 156). However, the many other causes of cirrhosis include cholestatic and autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis (Chapter 159), autoimmune hepatitis (Chapter 152), and metabolic diseases such as hemochromatosis, Wilson's disease, and α1-antitrypsin deficiency (Chapter 154). When all the causes have been investigated and excluded, cirrhosis is considered “cryptogenic.” Many cases of cryptogenic cirrhosis are now thought to be due to nonalcoholic fatty liver disease (Chapter 156).
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It is important to mention that although the entity termed “primary biliary cirrhosis” assumes the presence of cirrhosis, this term is actually misleading. Primary biliary cirrhosis (Chapter 159) is an immune-mediated cholestatic chronic liver disease that is characterized by progressive destruction of intrahepatic bile ducts and progresses over time from an initial stage in which fibrosis is minimal (stage 1) to a final stage in which there is well-established cirrhosis (stage 4).
Pathobiology
Liver Fibrosis/Cirrhosis
The key pathogenic feature underlying liver fibrosis and cirrhosis is activation of hepatic stellate cells. Hepatic stellate cells, which are known as Ito cells or perisinusoidal cells, are located in the space of Disse between hepatocytes and sinusoidal endothelial cells. Normally, hepatic stellate cells are quiescent and serve as the main storage site for retinoids (vitamin A). In response to injury, hepatic stellate cells become activated, as a result of which they lose their vitamin A deposits, proliferate, develop a prominent rough endoplasmic reticulum, and secrete extracellular matrix (collagen types I and III, sulfated proteoglycans, and glycoproteins). Additionally, they become contractile hepatic myofibroblasts.
Unlike other capillaries, normal hepatic sinusoids lack a basement membrane. The sinusoidal endothelial cells themselves contain large fenestrae (100 to 200 nm in diameter) that allow the passage of large molecules with molecular weights up to 250,000. Collagen deposition in the space of Disse, as occurs in cirrhosis, leads to defenestration of the sinusoidal endothelial cells (“capillarization” of the sinusoids), thereby altering exchange between plasma and hepatocytes and resulting in a decreased sinusoidal diameter that is further exacerbated by the contraction of stellate cells.
Complications of Cirrhosis
The two main consequences of cirrhosis are portal hypertension, with the accompanying hyperdynamic circulatory state, and liver insufficiency (Fig. 157-2). The development of varices and ascites is a direct consequence of portal hypertension and the hyperdynamic circulatory state, whereas jaundice occurs as a result of an inability of the liver to excrete bilirubin (i.e., liver insufficiency). Encephalopathy is the result of both portal hypertension and liver insufficiency. Ascites, in turn, can become complicated by infection, which is called spontaneous bacterial peritonitis, and by functional renal failure, which is called hepatorenal syndrome.
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| FIGURE 157-2 • Complications of cirrhosis result from portal hypertension or liver insufficiency. Varices and variceal hemorrhage are a direct consequence of portal hypertension. Ascites results from sinusoidal portal hypertension and can be complicated by infection (spontaneous bacterial peritonitis [SBP]) or renal dysfunction (hepatorenal syndrome [HRS]). Hepatic encephalopathy results from portosystemic shunting (i.e., portal hypertension) and liver insufficiency. Jaundice results solely from liver insufficiency. |
Portal Hypertension and the Hyperdynamic Circulatory State
In cirrhosis, portal hypertension results from both an increase in resistance to portal flow and an increase in portal venous inflow. The initial mechanism is increased sinusoidal vascular resistance secondary to (1) deposition of fibrous tissue and subsequent compression by regenerative nodules (fixed component) and (2) active vasoconstriction (functional component), which is amenable to the action of vasodilators such as nitroprusside and is caused by a deficiency in intrahepatic nitric oxide (NO), as well as enhanced activity of vasoconstrictors.
Early in the portal hypertensive process, the spleen grows and sequesters platelets and other formed blood cells, thereby leading to hypersplenism. In addition, vessels that normally drain into the portal system, such as the coronary vein, reverse their flow and shunt blood away from the portal system to the systemic circulation. These portosystemic collaterals are insufficient to decompress the portal venous system and offer additional resistance to portal flow. As collaterals develop, an increase in portal blood inflow maintains the portal hypertensive state as a result of splanchnic vasodilation, which in turn is secondary to increased production of NO. Thus, the paradox in portal hypertension is that a deficiency of NO in the intrahepatic vasculature leads to vasoconstriction and increased resistance whereas overproduction of NO in the extrahepatic circulation leads to vasodilation and increased flow.
In addition to splanchnic vasodilation, there is systemic vasodilation, which by causing a decreased effective arterial blood volume, leads to activation of neurohumoral systems, retention of sodium, expansion of plasma volume, and development of a hyperdynamic circulatory state. This hyperdynamic circulatory state maintains the portal hypertension, thereby leading to the formation and growth of varices, and plays an important role in the development of all other complications of cirrhosis.
Varices and Variceal Hemorrhage
The complication of cirrhosis that results most directly from portal hypertension is the development of portal-systemic collaterals, the most relevant of which are those that form through dilation of the coronary and gastric veins and constitute gastroesophageal varices. The initial formation of esophageal collaterals depends on a threshold portal pressure, which is a hepatic venous pressure gradient of 10 to 12 mm Hg, below which varices do not develop.
Development of a hyperdynamic circulatory state leads to further dilation and growth of varices and eventually to their rupture and variceal hemorrhage, one of the most dreaded complications of portal hypertension. Tension in a varix determines variceal rupture and is directly proportional to variceal diameter and intravariceal pressure and inversely proportional to variceal wall thickness.
Ascites and Hepatorenal Syndrome
Ascites in cirrhosis is secondary to sinusoidal hypertension and retention of sodium. Cirrhosis leads to sinusoidal hypertension by blocking hepatic venous outflow both anatomically by fibrosis and regenerative nodules and functionally by increased postsinusoidal vascular tone. Similar to the formation of esophageal varices, a threshold hepatic venous pressure gradient of 12 mm Hg is needed for the formation of ascites. In addition, retention of sodium replenishes the intravascular volume and allows the continuous formation of ascites. Retention of sodium results from vasodilation that is mostly due to an increase in NO production; NO inhibition in experimental animals increases urinary sodium excretion and lowers plasma aldosterone levels. With progression of cirrhosis and portal hypertension, vasodilation is more pronounced, thereby leading to further activation of the renin-angiotensin-aldosterone and sympathetic nervous systems and resulting in further sodium retention (refractory ascites), water retention (hyponatremia), and renal vasoconstriction (hepatorenal syndrome).
Spontaneous Bacterial Peritonitis
Spontaneous bacterial peritonitis, which is an infection of ascitic fluid, occurs in the absence of perforation of a hollow viscus or an intra-abdominal inflammatory focus such as an abscess, acute pancreatitis, or cholecystitis. Bacterial translocation, or the migration of bacteria from the intestinal lumen to mesenteric lymph nodes and other extraintestinal sites, is the main mechanism implicated in spontaneous bacterial peritonitis. Impaired local and systemic immune defenses are a major element in promoting bacterial translocation and, together with shunting of blood away from the hepatic Kupffer cells through portosystemic collaterals, allow a transient bacteremia to become more prolonged, thereby colonizing ascitic fluid. Spontaneous bacterial peritonitis occurs in patients with reduced ascites defense mechanisms, such as a low complement level in ascitic fluid. Another factor that promotes bacterial translocation in cirrhosis is bacterial overgrowth attributed to a decrease in small bowel motility and intestinal transit time. Infections, particularly from gram-negative bacteria, can precipitate renal dysfunction through worsening of the hyperdynamic circulatory state.
Encephalopathy
Ammonia, a toxin normally removed by the liver, plays a key role in the pathogenesis of hepatic encephalopathy. In cirrhosis, ammonia accumulates in the systemic circulation because of shunting of blood through portosystemic collaterals and decreased liver metabolism (i.e., liver insufficiency). The presence of large amounts of ammonia in the brain damages supporting brain cells or astrocytes and leads to structural changes characteristic of hepatic encephalopathy (Alzheimer's type II astrocytosis). Ammonia results in upregulation of astrocytic peripheral-type benzodiazepine receptors, the most potent stimulants of neurosteroid production. Neurosteroids are the major modulators of γ-aminobutyric acid, which results in cortical depression and hepatic encephalopathy. Other toxins, such as manganese, also accumulate in the brain, particularly the globus pallidus, where they lead to impaired motor function.
Jaundice
Jaundice (Chapters 149 and 150) in cirrhosis is a reflection of the inability of the liver to excrete bilirubin and is therefore the result of liver insufficiency. However, in cholestatic diseases leading to cirrhosis (e.g., primary biliary cirrhosis, primary sclerosing cholangitis, vanishing bile duct syndrome), jaundice is more likely due to biliary damage than liver insufficiency. Other indicators of liver insufficiency, such as the prothrombin time or the presence of encephalopathy, help determine the most likely contributor to hyperbilirubinemia (Chapter 150).
Cardiopulmonary Complications
The hyperdynamic circulatory state eventually results in high-output heart failure with decreased peripheral utilization of oxygen, a complication that has been referred to as cirrhotic cardiomyopathy. Vasodilation at the level of the pulmonary circulation leads to arterial hypoxemia, the hallmark of hepatopulmonary syndrome. Normal pulmonary capillaries are 8 μm in diameter, and red blood cells (slightly <8 μm) pass through them one cell at a time, thereby facilitating oxygenation. In hepatopulmonary syndrome, the pulmonary capillaries are dilated up to 500 μm, so passage of red cells through the pulmonary capillaries may be many cells thick. As a result, a large number of red cells are not oxygenated, which causes the equivalent of a right-to-left shunt.
Conversely, portopulmonary hypertension occurs when the pulmonary bed is exposed to vasoconstrictive substances that may be produced in the splanchnic circulation and bypass metabolism by the liver; the initial result is reversible pulmonary hypertension. However, because these factors result in endothelial proliferation, vasoconstriction, in situ thrombosis, and obliteration of vessels, irreversible pulmonary hypertension ensues.
Clinical Manifestations
The clinical manifestations of cirrhosis range widely, depending on the stage of cirrhosis, from an asymptomatic patient with no signs of chronic liver disease to a patient who is confused and jaundiced and has severe muscle wasting and ascites. The natural history of cirrhosis is characterized by an initial phase, termed “compensated” cirrhosis, followed by a rapidly progressive phase marked by the development of complications of portal hypertension or liver dysfunction (or both), termed “decompensated” cirrhosis (Fig. 157-3). In the compensated phase, portal pressure may be normal or below the threshold level identified for the development of varices or ascites. As the disease progresses, portal pressure increases and liver function decreases, thereby resulting in the development of ascites, portal hypertensive gastrointestinal (GI) bleeding, encephalopathy, and jaundice. The development of any of these complications marks the transition from a compensated to a decompensated phase. Progression to death may be accelerated by the development of other complications such as recurrent GI bleeding, renal impairment (refractory ascites, hepatorenal syndrome), hepatopulmonary syndrome, and sepsis (spontaneous bacterial peritonitis). The development of hepatocellular carcinoma (Chapter 206) may accelerate the course of the disease at any stage (see Fig. 157-3). Transition from a compensated to a decompensated stage occurs at a rate of approximately 5 to 7% per year. The median time to decompensation, or the time at which half the patients with compensated cirrhosis will become decompensated, is about 6 years.
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| FIGURE 157-3 • Natural history of cirrhosis. Any chronic liver disease will lead to cirrhosis. Initially, cirrhosis will be compensated (median survival, 9 years), but once complications (ascites, variceal hemorrhage, encephalopathy, jaundice) develop, it becomes decompensated (median survival, 1.6 years). Hepatocellular carcinoma (HCC) can develop at any stage and precipitate decompensation and death. |
Compensated Cirrhosis
In this stage, cirrhosis is mostly asymptomatic and is diagnosed either (1) when a liver biopsy is performed during the evaluation of chronic liver disease or (2) fortuitously during routine physical examination, biochemical testing, imaging for other reasons, or abdominal surgery. Nonspecific fatigue, decreased libido, or sleep disturbances may be the only complaints.
About 40% of patients with compensated cirrhosis have esophageal varices. Nonbleeding gastroesophageal varices are asymptomatic, and their presence (without bleeding) does not denote decompensation.
Decompensated Cirrhosis
At this stage there are signs of decompensation: ascites, variceal hemorrhage, jaundice, hepatic encephalopathy, or any combination of these findings. Ascites, which is the most frequent sign of decompensation, is present in 80% of patients with decompensated cirrhosis.
Variceal Hemorrhage
Gastroesophageal varices are present in approximately 50% of patients with newly diagnosed cirrhosis. The prevalence of varices correlates with the severity of liver disease and ranges from 40% in Child A cirrhotic patients (Table 157-2) to 85% in Child C cirrhotic patients.
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Both the development of varices and the growth of small varices occur at a rate of 7 to 8% per year. The incidence of a first variceal hemorrhage in patients with small varices is about 5% per year, whereas medium and large varices bleed at a rate of approximately 15% per year. Large varices, severe liver disease, and red wale markings on varices are independent predictors of variceal hemorrhage. Bleeding from gastroesophageal varices can be manifested as overt hematemesis or melena, or both (Chapter 137).
Ascites and Hepatorenal Syndrome
Ascites (Chapter 145) is the most common cause of decompensation in cirrhosis and occurs at a rate of 7 to 10% per year. The most frequent symptoms associated with ascites are increased abdominal girth, which is often described by the patient as tightness of the belt or garments around the waist, and recent weight gain. When present in small to moderate amounts, ascites can be identified on examination by bulging flanks, flank dullness, and shifting dullness (Chapter 149).
Hepatorenal syndrome is divided into two types based on clinical characteristics and prognosis. Type 1 hepatorenal syndrome is rapidly progressive renal failure in which a doubling of serum creatinine (or halving of creatinine clearance) occurs within a 2-week period. Type 2 hepatorenal syndrome is more slowly progressive and associated with ascites that is refractory to diuretics. Patients with hepatorenal syndrome usually have tense ascites that responds poorly to diuretics, but no specific symptoms or signs typify this entity.
Spontaneous Bacterial Peritonitis
About a third of cirrhotic patients are admitted for or acquire bacterial infections during hospitalization, the most common being spontaneous bacterial peritonitis. The two most important predictors of the development of bacterial infection are the severity of liver disease and admission for GI hemorrhage. The most frequent clinical manifestations of spontaneous bacterial peritonitis are fever, jaundice, and abdominal pain. On physical examination there is typically abdominal tenderness, with or without rebound tenderness, or ileus (or both). However, patients with spontaneous bacterial peritonitis may have just encephalopathy or evidence of shock. Up to a third of patients may be entirely asymptomatic.
Hepatic Encephalopathy
Hepatic encephalopathy, which is the neuropsychiatric manifestation of cirrhosis, occurs at a rate of approximately 2 to 3% per year. Hepatic encephalopathy associated with cirrhosis is of gradual onset and rarely fatal. Clinically, it is characterized by alterations in consciousness and behavior ranging from inversion of the sleep/wake pattern and forgetfulness (stage 1); to confusion, bizarre behavior, and disorientation (stage 2); to lethargy and profound disorientation (stage 3); to coma (stage 4) (Chapter 158). On physical examination, early stages may demonstrate only a distal tremor, but the hallmark of hepatic encephalopathy is the presence of asterixis (Chapter 149). Additionally, patients with hepatic encephalopathy may have sweet-smelling breath, a characteristic termed fetor hepaticus.
Pulmonary Complications
Hepatopulmonary syndrome is associated with exertional dyspnea, which can lead to extreme debilitation. Clubbing of the fingers, cyanosis, and vascular spiders may be seen on physical examination. Hepatopulmonary syndrome is present in approximately 5 to 10% of patients awaiting liver transplantation.
Portopulmonary hypertension is manifested as exertional dyspnea, syncope, and chest pain. On examination, an accentuated second sound and right ventricular heave are prominent (Chapter 67).
Diagnosis
The diagnosis of cirrhosis should be considered in any patient with chronic liver disease. In asymptomatic patients with compensated cirrhosis, typical signs of cirrhosis may not be present, and the diagnosis may often require histologic confirmation by liver biopsy, which is the “gold standard” for the diagnosis of cirrhosis. In patients with symptoms or signs of chronic liver disease, however, the presence of cirrhosis can frequently be confirmed noninvasively by imaging studies without the need for liver biopsy.
Physical Examination
On physical examination, stigmata of cirrhosis consist of muscle atrophy, mainly involving the bitemporal muscle regions and the thenar and hypothenar eminences; spider angiomas, mostly on the trunk, face, and upper limbs; and palmar erythema involving the thenar and the hypothenar eminences and the tips of the fingers. Although muscular atrophy is a marker of liver insufficiency, spider angiomas and palmar erythema are markers of vasodilation and a hyperdynamic circulation. Males may have hair loss on the chest and abdomen, gynecomastia, and testicular atrophy. Petechiae and ecchymoses may be present as a result of thrombocytopenia or a prolonged prothrombin time. Dupuytren's contracture, which is a thickening of the palmar fascia, occurs mostly in alcoholic cirrhosis. A pathognomonic feature of cirrhosis is the finding on abdominal examination of a small right liver lobe, with a span of less than 7 cm on percussion, and a palpable left lobe that is nodular with increased consistency. Splenomegaly may also be present and is indicative of portal hypertension. Collateral circulation on the abdominal wall (caput medusae) may also develop as a consequence of portal hypertension. Absence of any of the aforementioned physical findings does not exclude cirrhosis.
Laboratory Tests
Laboratory test results suggestive of cirrhosis include even subtle abnormalities in serum levels of albumin or bilirubin or elevation of the international normalized ratio. The most sensitive and specific laboratory finding suggestive of cirrhosis in the setting of chronic liver disease is a low platelet count (<150,000/mm3), which occurs as a result of portal hypertension and hypersplenism. Other serum markers that are often abnormal include levels of aspartate and alanine aminotransferase, alkaline phosphatase, γ-glutamyl transpeptidase, hyaluronic acid, α2-macroglobulin, haptoglobin, and apolipoprotein A. Although attempts have been made to use such markers to predict the presence of cirrhosis, none have sufficient sensitivity and specificity to be useful clinically.
Imaging Studies
Confirmatory imaging tests include computed tomography, ultrasound, and magnetic resonance imaging. Findings consistent with cirrhosis include a nodular contour of the liver, a small liver with or without hypertrophy of the left/caudate lobe, splenomegaly, and in particular, identification of intra-abdominal collateral vessels indicative of portal hypertension. On a liver-spleen scan, findings consistent with cirrhosis are heterogeneous colloid uptake by a small liver, splenomegaly, and colloid shift to the bone marrow. Typical findings on any of these imaging studies together with a compatible clinical picture are indicative of the presence of cirrhosis; a liver biopsy is not required unless the degree of inflammation or other features require investigation.
In decompensated cirrhosis, detection of ascites, variceal bleeding, or encephalopathy in the setting of chronic liver disease essentially establishes the diagnosis of cirrhosis; a liver biopsy is not necessary to establish the diagnosis. Patients with decompensated cirrhosis often exhibit malnutrition, more severe muscle wasting, more numerous vascular spiders, and hypotension and tachycardia as a result of the hyperdynamic circulatory state.
Portal Pressure Measurements
Direct measurements of portal pressure involve catheterization of the portal vein, are cumbersome, and may be associated with complications. Hepatic vein catheterization with measurement of wedged and free pressure is the simplest, safest, most reproducible, and most widely used method to indirectly measure portal pressure. Portal pressure measurements are expressed as the hepatic venous pressure gradient: the gradient between wedged hepatic venous pressure, which is a measure of sinusoidal pressure, and free hepatic or inferior vena cava pressure, which is used as an internal zero reference point. In a patient with clinical evidence of portal hypertension (e.g., varices), the hepatic venous pressure gradient is useful in the differential diagnosis of the cause of portal hypertension: it will be normal in prehepatic causes of portal hypertension, such as portal vein thrombosis (Chapter 158), and in intrahepatic but presinusoidal causes, such as schistosomiasis (Chapter 376), but will be abnormal in sinusoidal causes of portal hypertension, such as cirrhosis, and in postsinusoidal causes, such as veno-occlusive disease. Not unexpectedly, the hepatic venous pressure gradient predicts the development of complications of portal hypertension, and its reduction on pharmacologic therapy predicts a favorable outcome in patients with cirrhosis.
Complications of Cirrhosis
Varices and Variceal Hemorrhage
Upper GI endoscopy (Chapters 136 and 137) remains the main method for diagnosing varices and variceal hemorrhage. Varices are classified as small (straight, minimally elevated veins above the esophageal mucosal surface), medium (tortuous veins occupying less than a third of the esophageal lumen), or large (occupying more than a third of the esophageal lumen). The diagnosis of variceal hemorrhage is made when diagnostic esophagogastroduodenoscopy shows one of the following: active bleeding from a varix, a “white nipple” overlying a varix, clots overlying a varix, or varices with no other potential source of bleeding.
Ascites
The most common cause of ascites is cirrhosis, which accounts for 80% of cases; peritoneal malignancy (e.g., peritoneal metastases from GI tumors or ovarian cancer; Chapter 145), heart failure (Chapter 57), and peritoneal tuberculosis (Chapters 145, 155, and 345) account for another 15% of cases. The initial, most cost-effective, and least invasive method to confirm the presence of ascites is abdominal ultrasonography.
Diagnostic paracentesis is a safe procedure that should be performed in every patient with new-onset ascites, even in those with coagulopathy. Ultrasound guidance should be used in patients in whom percussion cannot locate the ascites or in whom a first paracentesis attempt does not yield fluid. The fluid in a patient with new-onset ascites should always be evaluated for albumin (with simultaneous estimation of serum albumin), total protein, polymorphonuclear (PMN) blood cell count, bacteriologic cultures, and cytology. The PMN cell count and bacteriologic culture are useful to exclude infection (spontaneous or secondary bacterial peritonitis), and cytologic evaluation is needed if peritoneal carcinomatosis is suspected. Depending on the clinical setting, additional tests can be performed on the fluid: glucose and lactate dehydrogenase levels (if secondary bacterial peritonitis is suspected), smear and culture for acid-fast bacilli (if peritoneal tuberculosis is suspected), and an amylase level (if pancreatic ascites is suspected).
The serum-ascites albumin gradient and ascites protein levels are useful in the differential diagnosis of ascites (Table 157-3). The serum-ascites albumin gradient correlates with sinusoidal pressure and will therefore be elevated (>1.1 g/dL) in patients in whom the source of ascites is the hepatic sinusoid (e.g., cirrhosis or cardiac ascites). Protein levels in ascitic fluid are an indirect marker of the integrity of the hepatic sinusoids: normal sinusoids are permeable structures that “leak” protein, whereas sinusoids in cirrhosis are “capillarized” and do not leak as much protein. The three main causes of ascites—cirrhosis, peritoneal malignancy or tuberculosis, and heart failure—can easily be distinguished by combining the results of both the serum-ascites albumin gradient and ascites total protein content. Cirrhotic ascites typically has a high serum-ascites albumin gradient and low protein, cardiac ascites has a high serum-ascites albumin gradient and high protein, and ascites secondary to peritoneal malignancy typically has a low serum-ascites albumin gradient and high protein.
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Hepatorenal Syndrome
Hepatorenal syndrome represents the extreme of the spectrum of abnormalities that lead to cirrhotic ascites and is characterized by maximal peripheral vasodilation as well as maximal activation of hormones that cause the retention of sodium and water and vasoconstriction of renal arteries. Ascites unresponsive to diuretics is universal, and dilutional hyponatremia is almost always present.
Hepatorenal syndrome, which is a diagnosis of exclusion, should be made only after discontinuing diuretics, expanding intravascular volume with albumin, and excluding or treating any condition that leads to worsening of the hemodynamic status of the cirrhotic patient. The differential diagnosis includes conditions that worsen vasodilation, such as sepsis, the use of vasodilators, and large-volume paracentesis not accompanied by albumin infusion; conditions that decrease effective arterial blood volume, such as fluid losses through overdiuresis or diarrhea (often induced by overdoses of lactulose); conditions that induce renal vasoconstriction, such as nonsteroidal anti-inflammatory drugs; and nephrotoxic insults, such as from aminoglycosides.
Spontaneous Bacterial Peritonitis
A high index of suspicion and early diagnosis are key in the management of spontaneous bacterial peritonitis. Diagnostic paracentesis should be performed in any patient with symptoms or signs of spontaneous bacterial peritonitis, including unexplained encephalopathy and renal dysfunction. Because spontaneous bacterial peritonitis is often asymptomatic and frequently community acquired, diagnostic paracentesis should be performed when any cirrhotic patient is admitted to the hospital, regardless of the cause for admission.
The diagnosis of spontaneous bacterial peritonitis is established by an ascitic fluid PMN count greater than 250/mm3. Bacteria can be isolated from ascitic fluid in only 40 to 50% of cases, even with sensitive methods such as inoculation directly into a blood culture bottle. Spontaneous bacterial peritonitis is mostly a monobacterial infection, usually with gram-negative enteric organisms. Anaerobes and fungi very rarely cause spontaneous bacterial peritonitis; their presence, as well as a polymicrobial infection, should raise suspicion of secondary bacterial peritonitis.
Hepatic Encephalopathy
The diagnosis of hepatic encephalopathy is clinical and based on the history and physical examination showing alterations in consciousness and behavior, as well as the presence of asterixis. Ammonia levels are unreliable, and there is poor correlation between the stage of hepatic encephalopathy and ammonia blood levels. Therefore, measurements of ammonia are not useful. Psychometric tests and an electroencephalogram are typically used in research but are not useful for clinical diagnosis. Minimal hepatic encephalopathy, formerly called “subclinical” hepatic encephalopathy, which occurs in about 30 to 70% of patients who have cirrhosis without overt hepatic encephalopathy, is detected by psychometric and neuropsychological testing of attention (e.g., number connection test, digit symbol test) and psychomotor function (e.g., grooved pegboard) alone. However, screening of cirrhotic patients for asymptomatic hepatic encephalopathy is not recommended because diagnostic tests are not standardized and the benefits of treatment are unknown.
Hepatopulmonary Syndrome and Portopulmonary Hypertension
The diagnostic criteria for hepatopulmonary syndrome are arterial hypoxemia with a Pao2less than 80 mm Hg or an alveolar arterial oxygen gradient greater than 15 mm Hg, along with evidence of pulmonary vascular shunting on contrast echocardiography (Chapter 53) or a 99mTc-labeled macroaggregated albumin scan demonstrating abnormal shunting of radioactivity to the brain. Portopulmonary hypertension is diagnosed by the presence of mean pulmonary arterial pressure higher than 25 mm Hg on right heart catheterization, provided that pulmonary capillary wedge pressure is less than 15 mm Hg.
Treatment
Treatment of cirrhosis should ideally be aimed at interrupting or reversing fibrosis. However, antifibrotic drugs have not been shown to reverse fibrosis consistently or improve outcomes in cirrhotic patients. Treatment of compensated cirrhosis is currently directed at preventing the development of decompensation by (1) treating the underlying liver disease (e.g., antiviral therapy for hepatitis C or B) to reduce fibrosis and prevent decompensation; (2) avoiding factors that could worsen liver disease, such as alcohol and hepatotoxic drugs; and (3) screening for varices (to prevent variceal hemorrhage) and for hepatocellular carcinoma (to treat at an early stage) (Fig. 157-4). Treatment of decompensated cirrhosis is directed toward specific decompensating events.
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| FIGURE 157-4 • Summary of the management of compensated and decompensated cirrhosis. AFP = α-fetoprotein; BM = bowel movement; EGD = esophagogastroduodenoscopy; GI = gastrointestinal; HCC = hepatocellular carcinoma; INR = international normalized ratio; Na = sodium; NSAIDs = nonsteroidal anti-inflammatory drugs; SBP = spontaneous bacterial peritonitis; US = ultrasound. |
■ Varices and Variceal Bleeding
Reducing portal pressure decreases the risk for the development of varices and variceal hemorrhage, as well as the risk for ascites and death. Nonselective β-adrenergic blockers (propranolol, nadolol) reduce portal pressure by producing splanchnic vasoconstriction and decreasing portal venous inflow. In patients with cirrhosis and medium/large varices that have never bled, nonselective β-blockers significantly reduce the risk for first variceal hemorrhage, and their use in this setting is considered the standard of care.1 Propranolol should be initiated at a dose of 20 mg orally twice a day, whereas nadolol should be initiated at a dose of 20 mg orally every day. The dose should be titrated to produce a resting heart rate of about 55 to 60 beats per minute. In patients who cannot tolerate or have contraindications to β-blockers, particularly those with large varices with red wale marks, endoscopic variceal ligation is indicated. Ligation is a local therapy that aims to obliterate varices by placement of rubber rings on variceal columns. In patients with no varices, nonselective β-blockers do not prevent the development of varices and are associated with more side effects.2 In patients with small varices, data are insufficient to recommend therapy with nonselective β-blockers. Endoscopy should be repeated every 2 to 3 years in patients with no varices, every 1 to 2 years in patients with small varices, and sooner in patients with decompensated disease so that effective therapy can be instituted before the varices grow in size and bleed.
Patients with cirrhosis and variceal hemorrhage require resuscitation in an intensive care unit. However, overtransfusion and volume overexpansion should be avoided because they can precipitate rebleeding. Prophylactic antibiotics should be used in this setting not only to prevent bacterial infections but also to decrease rebleeding3 and death. The recommended antibiotic is oral norfloxacin at a dose of 400 mg twice daily for 5 to 7 days, although ciprofloxacin (orally at a dose of 500 mg twice daily or intravenously at a dose of 400 mg twice daily) for 5 to 7 days is a reasonable alternative.
The most effective specific therapy for the control of active variceal hemorrhage is the combination of a vasoconstrictor with endoscopic therapy. Safe vasoconstrictors include terlipressin, somatostatin, and the somatostatin analogues octreotide and vapreotide; they can be initiated at admission to the hospital and continued for 2 to 5 days. The vasoconstrictor currently available in the United States is octreotide, which is used as a 50-μg bolus followed by an infusion at 50 μg/hr.
After control of hemorrhage, the 1-year recurrence of hemorrhage without treatment is very high at about 60%. Therefore, therapy to prevent rebleeding should be instituted before the patient is discharged. The lowest rebleeding rates (about 10%) are observed in patients who achieve a significant reduction in the hepatic venous pressure gradient with pharmacologic therapy (β-blockers, at the same dose recommended for prevention of first hemorrhage, with or without isosorbide mononitrate at stepwise dosing starting at 20 mg/day and increased as tolerated up to 40 mg twice a day); however, because hepatic venous pressure gradient measurements are not widely used, the next best results (rebleeding rates of 14 to 23%) are obtained with the combination of nonselective β-blockers (propranolol or nadolol) and endoscopic variceal ligation.4 The dose of β-blockers should be the maximal dose tolerated, and endoscopic variceal ligation should be repeated every 2 to 4 weeks until the varices are obliterated.
Shunt therapy should be used in patients whose variceal bleeding has persisted or recurred despite combined pharmacologic and endoscopic therapy. Shunt therapy is most commonly accomplished with a transjugular intrahepatic portosystemic shunt (TIPS) to connect the portal vein to the hepatic vein, bypass the liver, and normalize portal pressure; however, TIPS can also cause complications or worsen hepatic encephalopathy and liver failure. Moreover, TIPS stents can occlude, but newer polytetrafluoroethylene-covered stents are associated with lower occlusion rates and lower rates of hepatic encephalopathy.5
Ascites
Salt restriction and diuretics constitute the mainstay of management of ascites. Dietary sodium intake should be restricted to 2 g/day. A more restrictive diet is not recommended and may compromise nutritional status. Fluid restriction is not required unless the serum sodium concentration is below 125 mEq/L.
Spironolactone, which is more effective than loop diuretics, should be started at a dose of 100 mg/day (once a day in the morning). The dose should be adjusted every 3 to 4 days to a maximal effective dose of 400 mg/day. If weight loss is inadequate or if hyperkalemia develops, furosemide can be added at an escalated dose from 40 to 160 mg/day. The goal is weight loss of 1 kg in the first week and 2 kg/wk subsequently. However, diuretics should be reduced if the rate of weight loss is greater than 0.5 kg/day or more than 1 kg/day in patients with peripheral edema. Side effects of diuretic therapy include electrolyte abnormalities, renal dysfunction, encephalopathy, and painful gynecomastia (with spironolactone).
In the 10 to 20% of patients with ascites who are refractory to diuretics, large-volume paracentesis, aimed at removing all or most of the fluid, plus albumin at a dose of 6 to 8 g intravenously per liter of ascites removed, particularly when more than 5 L is removed at once, is a reasonable approach. The frequency of large-volume paracentesis is dictated by the rapidity at which the ascites reaccumulates. TIPS with uncovered stents has been more effective than large-volume paracentesis plus albumin in preventing recurrent ascites but is associated with a higher rate of encephalopathy without a significant improvement in survival.6 In patients requiring frequent large-volume paracentesis (more than twice per month), polytetrafluoroethylene-covered TIPS stents should be considered. A peritoneovenous shunt, using a subcutaneously placed silicone tube that transfers ascites from the peritoneal cavity to the systemic circulation, can be used in patients who are not candidates for TIPS or liver transplantation.
Hepatorenal Syndrome
Because hepatorenal syndrome is functional renal failure that results from hemodynamic abnormalities secondary to end-stage liver disease and severe portal hypertension, the mainstay of therapy is liver transplantation (Chapter 158). Therapies that have been used to “bridge” a patient to transplantation include vasoconstrictors plus albumin, TIPS, and extracorporeal albumin dialysis, which is an experimental hemofiltration dialysis method that uses an albumin dialysate. Evidence for the use of these treatments is not strong, and randomized trials will be necessary to determine the best therapeutic strategy for hepatorenal syndrome. The largest experience is with the combination of potent vasoconstrictors (terlipressin, octreotide plus midodrine, noradrenaline), which act by ameliorating the vasodilatory state of advanced cirrhosis, plus intravenous albumin (25 to 50 g/day), which acts by expanding arterial blood volume. The most investigated drug is terlipressin, used at a dose 0.5 to 2.0 mg intravenously every 4 to 6 hours. Because terlipressin is not yet available in the United States, the most used combination is octreotide (100 to 200 μg subcutaneously three times a day) plus midodrine (7.5 to 12.5 mg orally three times a day), with the dose adjusted to obtain an increase of at least 15 mm Hg in mean arterial pressure. Improvements may become clinically noticeable at day 7.
Spontaneous Bacterial Peritonitis
Empirical antibiotic therapy with an intravenous third-generation cephalosporin (e.g., cefotaxime, 2 g intravenously every 12 hours, or ceftriaxone, 1 to 2 g intravenously every 24 hours) or amoxicillin–clavulanic acid (1 g/0.5 g intravenously every 8 hours) should be initiated as soon as the diagnosis is established and before culture results are available; the minimal duration of therapy should be 5 days. Aminoglycosides should be avoided because of the high incidence of renal toxicity in cirrhotic patients. Repeat diagnostic paracentesis should be performed 2 days after starting antibiotics, by which time the number of PMN neutrophils in ascitic fluid should have decreased by more than 25% from baseline. Lack of response should prompt further investigations to exclude secondary peritonitis. The renal dysfunction associated with spontaneous bacterial peritonitis can be prevented by the intravenous administration of albumin, particularly in patients who have any evidence of renal dysfunction (blood urea nitrogen >30 mg/dL and/or creatinine >1 mg/dL) or serum bilirubin greater than 4 mg/dL at the time of diagnosis. Albumin has been used at a dose of 1.5 g/kg of body weight at diagnosis, repeated on the third day at a dose of 1 g/kg of body weight. However, this dosing is empirical and should probably not exceed 100 g per dose.
The administration of nonabsorbable (or poorly absorbable) antibiotics can prevent the development of spontaneous bacterial peritonitis and other infections in cirrhosis by selectively eliminating gram-negative organisms in the gut. However, the widespread use of prophylactic norfloxacin is associated with a higher rate of infections by antibiotic-resistant organisms. Long-term antibiotic prophylaxis is justified only in two groups: cirrhotic patients hospitalized with GI hemorrhage (short-term prophylaxis) and patients who have recovered from a previous episode of spontaneous bacterial peritonitis (long-term prophylaxis), in whom the recommended antibiotic is oral norfloxacin at a dose of 400 mg/day.
Hepatic Encephalopathy
Treatment of hepatic encephalopathy involves identifying and treating the precipitating factor and reducing the ammonia level. Precipitating factors include infections, overdiuresis, GI bleeding, a high oral protein load, and constipation. Narcotics and sedatives contribute to hepatic encephalopathy by directly depressing brain function further. TIPS is a common precipitant of hepatic encephalopathy; hepatic occlusion or reduction of the shunt may be required. Agents aimed at decreasing ammonia production in the gut are lactulose (15 to 30 mL orally twice daily adjusted to obtain two to three soft bowel movements per day) or orally administered nonabsorbable antibiotics such as neomycin (500 mg to 1 g three times per day), metronidazole (250 mg two to four times per day), or rifaximin (400 mg three times per day). l-Ornithine, l-aspartate, and benzoate may increase ammonia fixation in the liver. Switching dietary protein from an animal source to a vegetable source may be beneficial, but protein restriction is not necessary and should not be used long-term7
Pulmonary Complications
Hepatopulmonary syndrome rarely resolves spontaneously, and medical therapy is disappointing. TIPS is not generally recommended. The only viable treatment is liver transplantation (Chapter 158).
By comparison, portopulmonary hypertension is not an indication for liver transplantation. In fact, a mean pulmonary arterial pressure higher than 50 mm Hg is an absolute contraindication to liver transplantation.
Surgical Therapy
Liver Transplantation
Orthotopic liver transplantation (Chapter 158), which is the definitive therapy for cirrhosis, is indicated when the risk of dying from liver disease is greater than the risk of dying from transplantation, as determined by a Child-Pugh score of 7 or higher (see Table 157-2) or a Model for End-Stage Liver Disease (MELD) score of 15 or higher. MELD (see Table 158-4), which is a mathematical model that estimates the risk for 3-month mortality, is used to determine the priority for liver transplantation. The number of available deceased donor organs is lower than the number of patients awaiting liver transplantation; as a result, 15 to 20% of patients awaiting liver transplantation in the United States die before an organ becomes available.
Primary Prevention
Treatment of the underlying liver disease, before the development of cirrhosis, is a primary prevention strategy. Because the major causes of cirrhosis are related to lifestyle choices such as injection drug use (Chapter 32), alcohol consumption (Chapter 31), and unprotected sex, primary prevention programs that focus on encouraging alcohol abstinence, reducing high-risk behavior for hepatitis virus infection, and vaccinating for hepatitis B are even better prevention strategies.
Prognosis
The outcome of cirrhosis depends on the patient's stage. Patients with compensated cirrhosis die of liver disease only after transition to a decompensated stage. The 10-year survival rate of patients who remain in a compensated stage is approximately 90%, whereas their likelihood of decompensation is 50% at 10 years. Inception cohort studies of patients with compensated cirrhosis show a median survival of all patients, including those in whom decompensation develops over time, of about 10 years, whereas the median survival after decompensation is around 2 years.
Four clinical stages of cirrhosis have recently been identified, each with a different prognosis. In stage 1, or patients without varices or ascites, mortality is about 1% per year. Stage 2 patients, or those with varices but without ascites or bleeding, have a mortality rate of about 4% per year. Stage 3 patients have ascites with or without esophageal varices that have never bled; their mortality rate while remaining in this stage is 20% per year. Stage 4 patients, or those with portal hypertensive GI bleeding with or without ascites, have a 1-year mortality rate of 57%, with nearly half of these deaths occurring within 6 weeks after the initial episode of bleeding. Stages 1 and 2 correspond to compensated cirrhosis, whereas stages 3 and 4 are decompensated cirrhosis. Hepatocellular carcinoma develops at a fairly constant rate of 3% per year and is associated with a worse outcome at whatever stage it develops.
Predictors of survival are different in compensated and decompensated patients, with parameters of portal hypertension (varices, splenomegaly, platelet count, gamma globulin) assuming greater importance in compensated patients, whereas renal dysfunction, bleeding, and hepatocellular carcinoma are important predictive factors in patients with decompensated cirrhosis. In clinical practice, the Child-Pugh score is applicable to all cirrhotic patients, and the MELD score is used in decompensated patients to determine priority for liver transplantation.
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