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The liver is situated under the right diaphragm in the lower part of the right rib cage. The left lobe of the liver is in the epigastrium and is therefore not protected by the rib cage. The normal liver is firm and has a smooth surface.
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The liver parenchyma is divided into functional units called lobules (Figures 42-1 and 42-2). Each lobule is 1–2 mm in diameter and is made up of a maze-like arrangement of interconnected plates of hepatocytes separated by endothelium-lined sinusoids (Figure 42-2). The liver cell plates are arranged radially around the central vein; the liver cells that surround a portal tract comprise the limiting plate. Liver cell plates are normally one hepatocyte in thickness. Individual hepatocytes are large, with a central round nucleus, a prominent nucleolus, and abundant granular cytoplasm.
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The liver cells are separated from the sinusoids by a narrow space (space of Disse) that contains connective tissue and represents the scant interstitial compartment of the liver. Specialized cells of the macrophage system (Kupffer cells) are present in the sinusoids scattered among the endothelial cells.
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The biliary system begins at the biliary canaliculi, which are small channels lined by the complex microvilli of surrounding liver cells. The biliary canaliculi form the intralobular bile ductules (canals of Hering), which drain into the bile ducts in the portal tract.
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The normal liver has a huge reserve functional capacity. When the liver is normal, about 80% of it can be removed without compromising function. The liver has synthetic, excretory, and metabolic functions.
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The liver is the source of plasma albumin; many plasma globulins, including α1-antitrypsin (α-antiprotease); and many proteins of the coagulation cascade.
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Many substances are excreted by the liver in bile. The main component of bile is bilirubin. Cholesterol, urobilinogen, and bile acids are also present in bile.
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The liver plays a central role in the metabolism of fat, carbohydrates, and protein and in detoxification.
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Free fatty acids from adipose tissue and medium- or short-chain fatty acids absorbed in the intestine are brought to the liver. Triglycerides, cholesterol, and phospholipids are synthesized in the liver from the fatty acids and complexed with specific lipid acceptor proteins to form very-low-density lipoproteins that enter the plasma. The liver also metabolizes intermediate- and low-density lipoproteins (Chapter 20: The Blood Vessels).
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Carbohydrate Metabolism
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The liver is the main source of plasma glucose. Following a meal, glucose is derived from intestinal absorption. In the fasting state, glucose is derived from glycogenolysis and gluconeogenesis in the liver. The liver is the main body storage site for glycogen. When there is a glucose deficiency, the liver metabolizes fatty acids to form ketone bodies, which represent an alternative energy source for many tissues.
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In addition to its synthetic function, the liver is the central organ in protein catabolism and synthesis of urea. Urea is secreted by the liver into the plasma for excretion by the kidney.
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The liver plays a vital role in detoxifying noxious nitrogenous compounds derived from the intestine, as well as many drugs and chemicals.
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Pain is an uncommon symptom of liver disease and occurs only in conditions such as acute hepatitis and right ventricular failure when rapid enlargement of the liver occurs. Pain—commonly constant in the lower right chest region—is the result of stretching of the liver capsule. Pain may be referred to the right shoulder.
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Alteration in Liver Size
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Most liver diseases are associated with hepatomegaly. When the liver enlarges, its inferior edge becomes palpable below the right costal margin. Enlargement is usually diffuse but may be localized if due to a focal lesion such as neoplasm or abscess. The enlarged liver of heart failure is firm, tender, and has a smooth surface. That of cirrhosis has an increased firmness (hard) and a nodular surface.
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Shrinkage of the liver occurs in massive liver necrosis and some forms of cirrhosis. A shrunken liver recedes further under the right lower ribs. It can be detected clinically by a decrease in the area of liver dullness on percussion of the right lower chest.
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Abnormal Liver Function Tests
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An abnormality in a liver function test detected on routine blood examination is a common method of presentation of liver disease. Patients with asymptomatic chronic liver disease (eg, chronic hepatitis, cirrhosis) may show decreased serum albumin, increased enzyme levels, or an increased prothrombin time. Patients with mass lesions in the liver or partial bile duct obstruction may have an elevated alkaline phosphatase level in serum. As the frequency of routine blood testing increases, more patients with abnormal tests such as these will need to be evaluated for asymptomatic liver disease.
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Jaundice (hyperbilirubinemia) is an increase in the plasma bilirubin above its normal upper limit of 0.8 mg/dL. Bilirubin is derived from breakdown of hemoglobin in the reticuloendothelial system (see Chapter 1: Cell Degeneration & Necrosis). Jaundice may be classified according to the type of bilirubin that accumulates—conjugated or unconjugated hyperbilirubinemia; or according to cause—hemolytic, hepatocellular, or obstructive.
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(Increased red cell breakdown.) Excessive hemolysis leads to increased production of bilirubin, and jaundice results when the load exceeds the capacity of the liver for conjugation (this usually signifies a severe degree of hemolysis). The bilirubin that accumulates in the plasma is unconjugated (not water-soluble), complexed with albumin, and does not appear in urine (acholuric jaundice). Increased amounts of bilirubin are excreted into the intestine, resulting in increased amounts of urobilinogen in feces and urine (Table 42-5). The causes of hemolytic jaundice are discussed in Chapter 25: Blood: II. Hemolytic Anemias; Polycythemia.
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Hepatocellular Abnormality
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Defective Hepatic Uptake of Bilirubin
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Unconjugated bilirubin in the plasma is carried into the liver cell by intracellular transport proteins. Absence of these proteins results in failure of bilirubin uptake, leading to unconjugated hyperbilirubinemia (Table 42-5). The most common cause is Gilbert's syndrome, inherited as an autosomal dominant trait and characterized by transient episodes of mild jaundice, usually precipitated by intercurrent illness. Patients with Gilbert's syndrome also have a partial conjugation defect (see below). There is no structural abnormality, and patients have a normal life expectancy.
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Abnormal Conjugation of Bilirubin
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Conjugation of bilirubin to bilirubin glucuronide is effected by UDP-glucuronyl transferase. Deficiency of this enzyme results in unconjugated hyperbilirubinemia (Table 42-5).
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Neonates (Neonatal or Physiologic Jaundice)
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Mild jaundice in the first few days after birth is common and is the result of immaturity of the liver enzyme system. The enzyme deficiency is more extreme with increasing degrees of prematurity, and neonatal jaundice can reach dangerous levels in very premature babies.
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Crigler-Najjar Syndrome
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This is a very rare autosomal recessive disease characterized by complete absence of the enzyme in the homozygous patient (type A disease). It causes severe jaundice with kernicterus and death in early life. A less severe form of Crigler-Najjar syndrome (type B) in which the enzyme deficiency is partial is compatible with more prolonged survival.
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In Gilbert's syndrome there is a partial deficiency of glucuronyl transferase.
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Drugs may interfere with this enzyme system. Novobiocin is an example.
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Hepatocellular Damage
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Acute or chronic hepatocellular damage leads to jaundice when the number of liver cells is reduced enough so that bilirubin metabolism becomes abnormal. Jaundice is generally more severe in acute liver failure than chronic liver failure. Patients with jaundice due to hepatocellular damage commonly have cholestasis superimposed on the failure of conjugation, producing a mixed conjugated and unconjugated hyperbilirubinemia.
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Obstruction or Impaired Excretion of Bili-Rubin
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After conjugation, bilirubin is excreted by the liver cell into the biliary canaliculus, and from there it passes to the bile ducts and the intestine. Failure of transfer of bilirubin glucuronide from the liver cell into the canaliculus occurs as an inherited disease in Dubin-Johnson syndrome and Rotor's syndrome. The defect is usually partial. Dubin-Johnson syndrome is characterized by conjugated hyperbilirubinemia (Table 42-5) and accumulation of pigment (probably lipofuscin) in the hepatocytes, imparting a dark brown to black color to the liver. There is no obvious cholestasis in the liver. Rotor's syndrome is identical except for the absence of pigment. These diseases are usually mild and are compatible with a normal life span.
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Obstruction at the Intrahepatic Level (Cholestasis)
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Obstruction to the flow of bile in the intralobular biliary canaliculi is called intrahepatic cholestasis. Bile accumulates in the lobule within dilated biliary canaliculi and hepatocytes. The bile ductules in the portal tract and the larger bile ducts are normal. The cause is unknown, but many cases show abnormalities in the actin cytoskeleton of the hepatocyte microvilli bordering the biliary canaliculi.
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Intrahepatic cholestasis occurs (1) in viral hepatitis; (2) in alcoholic liver disease; (3) as a toxic reaction to drugs, including androgens (methyltestosterone), anabolic steroids, oral contraceptives, and phenothiazines; (4) in benign familial cholestatic jaundice, a rare familial disease in which recurrent attacks of cholestatic jaundice represent the only abnormality; and (5) during pregnancy (recurrent jaundice of pregnancy), most commonly in the last trimester. Spontaneous reversal of cholestasis occurs after delivery, and the disorder is probably due to increased sex hormone levels in pregnancy affecting susceptible individuals.
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In general, all of these causes of cholestasis are associated with severe jaundice, which usually reverses spontaneously and is not associated with liver failure.
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Extrahepatic Obstruction
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To cause jaundice, obstruction must involve both main hepatic ducts, the common hepatic duct, or the common bile duct. Obstruction of a smaller duct in one lobe of the liver does not cause jaundice because the normally draining lobe can compensate by increasing the excretion of bilirubin. Partial biliary obstruction may result in an elevated serum alkaline phosphatase level.
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Complete obstructive jaundice prevents entry of bilirubin into the intestine, producing pale clay-colored or chalky stools. Absence of bilirubin in the gut also results in absence of fecal and urinary urobilinogen (Table 42-5). Regurgitation of conjugated bilirubin into the plasma produces conjugated hyperbilirubinemia, which in turn leads to excretion of a dark brown urine containing bilirubin.
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Histologically, large bile duct obstruction produces dilation of bile ductules, which are plugged with bile and frequently rupture, leading to bile lakes in the lobule. Stagnant bile commonly becomes infected, leading to cholangitis with neutrophil infiltration and progressive fibrosis around the dilated bile ducts in the portal areas. In chronic cases, fibrosis may be so marked as to produce fine granularity of the liver (secondary biliary cirrhosis).
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Jaundice is diagnosed clinically by yellow discoloration caused by deposition of bilurubin pigment in elastic fibers of the interstitial tissues, most easily seen in the scleras. Jaundice must always be confirmed by serum bilirubin measurement because other pigments such as carotene may cause yellow discoloration of skin and eyes.
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Deposition of bilirubin by itself does not cause symptoms. However, patients with cholestasis and obstructive jaundice frequently have intense pruritus believed to be caused by bile acids, which are also present in elevated levels in the plasma.
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Bilirubin is dangerous when it crosses the blood-brain barrier because it has a toxic effect on brain cells, causing kernicterus. Kernicterus occurs only when there is an increased level of free unconjugated bilirubin (not complexed to plasma proteins) in plasma during the neonatal period (see Chapter 1: Cell Degeneration & Necrosis).
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Hepatocellular Failure
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Because of its tremendous functional reserve, liver failure occurs only when there is extensive liver disease destroying over 80% of the organ.
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Acute liver failure most commonly results from acute massive liver cell necrosis caused by viral hepatitis and toxic drugs and chemicals, but it may also follow acute fatty change of the liver (see Chapter 1: Cell Degeneration & Necrosis). Reye's syndrome is a disease of uncertain causation occurring mainly in children and characterized by acute liver failure with encephalopathy. There is acute fatty change in many organs, including the liver, kidney, and heart. Reye's syndrome has been linked to the administration of aspirin to children with acute viral illnesses such as chickenpox and influenza. Acute fatty liver of pregnancy in the last trimester is characterized by microvacuolar acute fatty change and acute liver failure. High-dosage intravenous tetracycline therapy was a cause of acute fatty liver in the past.
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Acute liver failure is characterized by (1) jaundice; (2) hypoglycemia; (3) a bleeding tendency due to disseminated intravascular coagulation and failure of synthesis of clotting factors in the liver; (4) electrolyte and acid-base disturbances (hypokalemia is the most dangerous); (5) hepatic encephalopathy; (6) hepatorenal syndrome; and (7) elevation of serum enzymes (lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT); see Table 42-2) in cases associated with extensive necrosis of liver cells.
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Acute liver failure has a very high mortality rate. Patients who recover usually do so completely, with regeneration of liver in cases of massive necrosis and rapid reversal of the fatty change in acute fatty liver.
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Chronic Liver Failure
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Chronic liver failure usually results from cirrhosis, which is associated with progressive necrosis of liver cells, fibrosis, and nodular regeneration.
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The effects of chronic liver failure can be listed as follows:
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Decreased synthesis of albumin, leading to low serum albumin levels, edema, and ascites.
Decreased levels of prothrombin and of factors VII, IX, and X, resulting in a bleeding tendency.
Portal hypertension (see below).
Hepatic encephalopathy (see below).
Hepatorenal syndrome (see below).
Endocrine changes caused by disordered metabolism of certain hormones. Accumulation of estrogens causes gynecomastia, testicular atrophy, and small vascular telangiectasias in the skin (spider angiomas). Failure of aldosterone metabolism causes sodium and water retention and contributes to edema. Failure of metabolism of antidiuretic hormone contributes to inappropriately high serum levels of antidiuretic hormone (ADH) in some cases, causing hyponatremia.
Fetor hepaticus—a breath like that of “a freshly opened corpse”—believed to be due to deficient methionine catabolism.
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Portal hypertension is elevation of portal venous pressure above the upper limit of normal of 12 mm Hg. Most cases result from obstruction to the outflow of blood from the portal system. More rarely, portal hypertension results from transmission of arterial pressure to the portal circulation through arteriovenous fistulas, or, in some cases of massive splenomegaly, through dilated splenic sinusoids.
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Portal hypertension resulting from obstruction may be classified according to the level of obstruction.
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Presinusoidal portal hypertension may be caused by obstruction of the extrahepatic portal vein by thrombosis, neoplasms, or inflammation; or by obstruction of intrahepatic portal venous radicals, as occurs in schistosomiasis, biliary cirrhosis, and congenital hepatic fibrosis. Idiopathic portal hypertension is also presinusoidal, but the mechanism is unknown.
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Sinusoidal portal hypertension accounts for over 90% of cases and is caused by cirrhosis of the liver in which fibrosis and distortion restrict the portal circulation and lead to establishment of hepatic arterioportal venous anastomoses.
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Postsinusoidal portal hypertension occurs when the hepatic venous radicles are obstructed by thrombosis (Budd-Chiari syndrome) or neoplasm, commonly hepatocellular carcinoma. Right ventricular failure and constrictive pericarditis also produce functional postsinusoidal obstruction.
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Effects of Portal Hypertension
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Splenic enlargement is caused by passive venous congestion.
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Development of Portosystemic Venous Anastomoses, Bypassing the Obstructed Portal Circulation
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Venous anastomoses occur wherever the portal and systemic venous drainages commingle, resulting in dilated, tortuous veins at the following sites: (1) in the lower esophagus and stomach (gastroesophageal varices)—these frequently rupture, causing severe upper gastrointestinal bleeding (see Chapter 37: The Esophagus); (2) in the rectum (hemorrhoids); and (3) around the umbilicus, where the collateral veins radiate outward in the abdominal wall (caput medusae).
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Entry of portal venous blood into the systemic circulation through these collateral channels may result in hepatic encephalopathy because blood bypassing the liver eludes detoxification. Portacaval anastomoses created surgically to relieve portal hypertension may have the same effect.
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Ascites is due to increased transudation of fluid across the peritoneal membrane, particularly over the surface of the liver. The major factor leading to severe ascites in chronic liver disease is a decrease in serum albumin level, with portal hypertension playing only a contributory role.
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Hepatic Encephalopathy
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Hepatic encephalopathy is characterized by cerebral dysfunction (hypersomnia, delirium, flapping tremors of the hands) leading to convulsions, coma, and death. It may occur in both acute and chronic liver disease and is usually accompanied by other evidence of liver failure. In patients with extensive portosystemic venous anastomoses, hepatic encephalopathy may occur in isolation.
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The pathogenesis of hepatic encephalopathy is unclear, but it is believed that nitrogenous products of intestinal bacteria accumulate in the systemic blood, having bypassed the liver through portosystemic anastomoses or having undergone deficient detoxification by the failing liver cells. These nitrogenous products then cross the blood-brain barrier, causing edema and neuronal degeneration.
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Substances suspected of being involved in the pathogenesis of hepatic encephalopathy are (1) ammonia, which is present in high plasma and cerebrospinal fluid concentrations in patients with liver failure; and (2) amides like octopamine, which act as false neurotransmitters.
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Hepatorenal syndrome is the occurrence of acute renal failure in a patient with liver disease.
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The mechanism by which renal failure occurs is uncertain. There are no pathologic changes in the kidneys, and when these kidneys are transplanted into normal individuals, they function normally. Renal failure has features similar to those of prerenal failure occurring in hypovolemic shock, with production of a small volume of concentrated urine. This has led to the hypothesis that hepatorenal syndrome is the result of an alteration in distribution of blood flow in the kidneys, caused perhaps by the effect of false neurotransmitters on the sympathetic nervous system.
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The occurrence of hepatorenal syndrome is an ominous sign in a patient with liver disease.
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Hepatocellular Necrosis
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Liver cell necrosis is a common manifestation of many liver diseases. If severe, it causes acute or chronic liver failure. In many diseases, however, necrosis is subclinical and revealed only by elevations of liver enzyme concentrations in serum (Table 42-2) or by histologic changes in a liver biopsy.
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Different liver diseases cause different patterns of liver cell necrosis. Recognition of these patterns is useful in diagnosis (Figure 42-5).
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Focal liver cell necrosis is randomly occurring necrosis of single cells or small clusters of cells in all areas of liver lobules. Not all lobules are involved. Its presence is recognized in biopsies by (1) acidophilic (Councilman) bodies, which are necrotic liver cells with pyknotic or lysed nuclei and coagulated pink-staining cytoplasm; and (2) areas of lysed liver cells surrounded by collections of Kupffer cells and inflammatory cells.
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Focal necrosis is commonly seen in viral hepatitis, toxic damage, and bacteremic infections.
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Zonal liver cell necrosis is necrosis of liver cells occurring in identical regions in all liver lobules. The causes differ according to the zone involved. Centrizonal necrosis, which involves the cells around the central hepatic vein, occurs in viral hepatitis, carbon tetrachloride and chloroform toxicity, and anoxic states such as cardiac failure and shock. Midzonal necrosis is uncommon and occurs in yellow fever. Peripheral zonal necrosis, which involves liver cells around the portal tracts, occurs in eclampsia and phosphorus poisoning.
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Submassive & Massive Necrosis
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Submassive necrosis is the occurrence of liver cell necrosis that extends across lobular boundaries, often bridging portal areas and central veins (bridging necrosis). The most severe form is massive liver necrosis, in which large confluent areas of liver undergo necrosis, leaving only small islands of viable liver cells intact. Massive necrosis is characterized by sudden decrease in size of the liver, which appears soft, yellow, and flabby, with a wrinkled capsule (sometimes called “acute yellow atrophy”). Areas of residual viable liver are seen as mottled dark brown areas contrasting with the necrotic yellow zones.
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Massive liver necrosis is commonly caused by hepatitis viruses (usually B or C, and very rarely A). It is less commonly due to drugs (halothane, acetaminophen, isoniazid, methyldopa) or toxic chemicals (Amanita phalloides mushrooms, chlorinated hydrocarbon insecticides, chloroform, carbon tetrachloride).
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Patients with submassive and massive liver necrosis present with acute liver failure of variable severity. Serum enzyme levels are greatly elevated. The mortality rate is high, but those who recover show regeneration of a normal liver.
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Congenital defects in bilirubin uptake, conjugation, or excretion have already been considered (see Jaundice, above). Congenital anomalies of the bile ducts are described later along with biliary tract disease (Chapter 44: The Extrahepatic Biliary System).
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Congenital Hepatic Fibrosis
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Congenital hepatic fibrosis is uncommon and is usually associated with polycystic renal disease. It is characterized by fibrosis connecting adjacent portal tracts. It is not true cirrhosis because the basic liver lobular architecture is intact, with central veins present in the center of the nodules demarcated by fibrosis.
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There is usually also an abnormal proliferation of bile ducts that appear grossly as microcystic structures (bile duct hamartomas; Meyenberg complexes). Larger cysts lined by biliary epithelium may occur; when cysts are conspicuous, the condition is termed congenital polycystic disease of the liver.
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Congenital hepatic fibrosis usually presents as an incidental finding in a patient with polycystic renal disease. Rarely, portal fibrosis causes a presinusoidal type of portal hypertension associated with ascites and esophageal varices.
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Chronic Hepatic Venous Congestion
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Chronic venous congestion of the liver occurs in right heart failure and is most marked in patients with tricuspid incompetence and constrictive pericarditis. The liver is enlarged; the increased systemic venous pressure is transmitted to the central hepatic vein, and there is congestion of the centrilobular sinusoids. With prolonged congestion, the liver cells around the central vein undergo necrosis. The periportal areas are normal or show fatty change (Figure 42-6).
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Grossly, the regular alternation of the red congested central area and the normal (brown) or fatty (yellow) periportal zone produces a characteristic mottled appearance that resembles the cut surface of a nutmeg (“nutmeg liver”). Prolonged congestion leads to fibrosis around the central vein, producing a finely granular liver (cardiac sclerosis or, incorrectly, “cardiac cirrhosis”).
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Clinically, passive congestion is characterized by tender enlargement of the liver. Mild abnormalities in liver function are common, but liver failure almost never occurs.
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Infarction of the Liver
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Because of the liver's dual blood supply from the portal vein and hepatic artery, either of which can independently sustain the liver, infarction rarely occurs. Infarction may occur when the hepatic artery becomes suddenly occluded beyond the origin of the gastroduodenal and right gastric arteries. Occlusion may be caused by thrombosis, atherosclerosis, polyarteritis nodosa, or accidental ligation at surgery. Portal vein occlusion usually does not cause infarction.
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This rare clinical syndrome is caused by extensive occlusion of hepatic venous radicles by fibrosis, thrombosis, or neoplasm. The changes in the liver are those of severe chronic venous congestion, characterized by the presence of erythrocytes in the sinusoids and space of Disse in the centrizonal region. This is associated with extensive fibrosis and nodular regeneration. Clinically, patients present with an enlarged liver and portal hypertension; ascites is commonly a prominent feature.
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Viruses that primarily infect the liver include hepatitis A, hepatitis B, hepatitis C, delta hepatitis, and hepatitis E viruses. Hepatitis also occurs as part of systemic viral infection in yellow fever (uncommon in the United States; common in parts of Africa and South America), infectious mononucleosis (Epstein-Barr virus), cytomegalovirus infection, herpes simplex, and varicella-zoster infection.
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The hepatitis viruses and their broad clinical and epidemiologic features are described in the following sections, followed by a discussion of the clinical syndromes that may result from infection with these viruses.
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Hepatitis A is caused by an ribonucleic acid (RNA) enterovirus measuring 27 nm in diameter that has been identified in the stools of patients and infected volunteers and in the liver of marmosets (the animal model for the disease). It is usually transmitted via the fecal-oral route and has a short incubation period (2–6 weeks). Explosive epidemics have been recorded after fecal contamination of water, milk, and shellfish (where untreated sewage spills into coastal waters). Parenteral transmission is rare, occurring only in the transient acute viremic phase.
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Hepatitis A has a global incidence, highest in low socioeconomic populations where fecal-oral transmission is greatest.
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Hepatitis A is usually a mild acute illness with recovery occurring in a few weeks. It is rarely fatal in the few cases complicated by massive necrosis, does not progress to chronic hepatitis, and there is no carrier state. IgM antibodies appear early in the acute phase, rise rapidly, and wane during the convalescent period. IgG antibodies appear later in the illness, rise rapidly, and remain elevated throughout life (Figure 42-7). The presence of IgG antibody against hepatitis A virus is evidence of previous infection. More than 30% of the United States population have antibodies but give no history of hepatitis, suggesting that subclinical infection is common.
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Hepatitis B is caused by a deoxyribonucleic acid (DNA) virus (Figure 42-8) composed of (1) an inner core synthesized in the hepatocyte nucleus and containing the hepatitis B core antigen (HBcAg), hepatitis B e antigen (HBeAg), DNA, and DNA polymerase; and (2) an outer envelope that is synthesized in the hepatocyte cytoplasm and contains the hepatitis B surface antigen (HBsAg). The entire particle measures 42 nm in diameter and is called the Dane particle. There is excess production of the envelope, free forms of which appear in the blood; these measure 22 nm in size and have a spherical or tubular structure. These envelope particles were first discovered in the blood of an Australian aborigine with hepatitis B (HBsAg is therefore also called Australia antigen). HBsAg itself is not infective because the nucleic acid core of the virus is required for infection.
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In developed countries, hepatitis B is usually transmitted in blood or blood products from an individual with active disease or a carrier. Transfer may occur with shared needles, mainly among drug abusers (most hospitals now use disposable needles), during sexual intercourse, by accidental spillage of specimens in the laboratory, and by transfusion of blood products. Routine screening of blood products for hepatitis B coupled with a trend away from use of paid blood donors has greatly reduced the incidence of hepatitis B transmission via blood transfusion. Several epidemics of hepatitis B infection have occurred among patients and staff of renal dialysis units.
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Hepatitis B has a long (6 weeks to 6 months) incubation period. Illness is of varying severity and often subclinical. However, the risk of a complicated course, death, chronic disease, or a carrier state is much greater than in hepatitis A.
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The appearance of the various hepatitis B antigens and antibodies (Figure 42-7) is important from a diagnostic standpoint. HBsAg appears first, late in the incubation period, and is followed by HBeAg. The presence of HBeAg and hepatitis B-DNA in the serum correlate well with the presence of infective Dane particles in the blood, and they are indications of infectivity. In patients who recover, both HBsAg and HBeAg disappear at the onset of clinical recovery. The first antibody to appear is anti-HBc during the acute illness, followed by anti-HBe and anti-HBs. The presence of anti-HBe in the blood indicates absence of the infective Dane particle; such patients are usually not infective. Testing for all antigens and antibodies permits diagnosis at all stages of the illness. If the testing includes only HBsAg and anti-HBs, there is a window period during the recovery phase when both of these are negative and the diagnosis may be missed.
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Hepatitis B-infected hepatocytes may be identified (1) in biopsy material by the presence of hepatocytes with ground-glass cytoplasm (Figure 42-9A); (2) by Shikata orcein stain, which selectively stains hepatitis B-infected cells; and (3) by immunoperoxidase stains using labeled antibodies against HBsAg (Figure 42-9B). The third method is the most specific.
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Hepatitis C is caused by a single-stranded RNA virus. Infected patients develop anti-hepatitis C virus (HCV) antibodies that can be detected in the serum by immunoassays. Before serologic testing was routinely available, hepatitis C was responsible for over 90% of cases of hepatitis associated with transfusion of blood products in the United States. The disease also occurs among drug abusers, in transplant recipients, and in renal dialysis units. The incubation period varies between 2 weeks and 6 months.
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Hepatitis C has clinical features almost identical to those of hepatitis B except for a higher incidence of chronic hepatitis, which occurs in 50% of those infected. Cirrhosis complicates 20%. Interferon therapy is useful in controlling chronic hepatitis C.
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The delta hepatitis agent is an RNA virus that has the envelope of hepatitis B virus but an antigenically distinct core of delta antigen. It appears to be a “defective” virus that uses hepatitis B virus as a “helper” because it is incapable of causing infection in the absence of hepatitis B virus. Transmission is parenterally, by blood transfusions or intravenous drug abuse. Delta hepatitis is uncommon in the United States but has been reported more frequently in Africa and the Mediterranean region.
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Delta hepatitis occurs (1) as an acute disease along with hepatitis B or (2) as acute or chronic hepatitis in a chronic carrier of HBsAg. The diagnosis is made by demonstration of the antigenically unique delta agent in the blood or in liver cells. Delta virus increases the severity of an attack of acute hepatitis B and increases the risk of chronic hepatitis and cirrhosis when compared with hepatitis B infection alone.
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Hepatitis E is an uncommon infection occurring mainly in Central America and India. A few imported cases have been reported in the United States. Hepatitis E resembles hepatitis A in having a primarily enteric mode of transmission.
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Clinicopathologic Syndromes
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The clinicopathologic features of viral hepatitis are considered here as a group (Table 42-6). It is important to note that hepatitis A and probably hepatitis E are mild diseases associated with few deaths and no chronic phase. The other viruses cause much more severe illness with a chronic phase and a carrier state.
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Acute Viral Hepatitis
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All the hepatitis viruses, replicating within the liver cell, cause damage, either as a direct effect or via an immunologic response against cells bearing viral antigens. Damaged cells show diffuse swelling (ballooning; Figure 42-11). Focal or centrizonal necrosis follows. Single necrotic liver cells have coagulated pink cytoplasm and show pyknosis or karyolysis (Councilman body). There is a lymphocytic and plasma cell infiltrate in the portal tracts (Figure 42-11). In a few cases, liver cell necrosis is more extensive, traversing lobular boundaries. Some of these patients have a prolonged course and delayed recovery. However, it is difficult to predict chronic disease based on any histologic features in acute hepatitis.
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Acute hepatitis is associated with sudden onset of fever, loss of appetite, vomiting, jaundice, and tender enlargement of the liver. Jaundice is caused by a combination of liver cell dysfunction and cholestasis. Bile is present in the urine in most cases, and urinary urobilinogen levels are increased (Table 42-5). Liver enzymes (aminotransferases and lactate dehydrogenase) enter the bloodstream from the necrotic cells, appearing early in the course of illness. A few patients develop extrahepatic manifestations such as lymph node enlargement, skin rashes, and joint pains that probably result from circulating immune complexes.
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Acute viral hepatitis is frequently subclinical or associated with a flu-like illness (anicteric hepatitis). It can then be diagnosed only by liver function tests (elevated liver enzymes, increased urinary urobilinogen) or hepatitis antibody testing. Antibody testing is the only means of identifying the specific virus.
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Clinical recovery occurs within 2–3 weeks in most cases. Return of biochemical abnormalities to normal may take months. Recovery is associated with liver cell regeneration.
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Cholestatic Viral Hepatitis
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A clinical variant of acute viral hepatitis is characterized by severe intrahepatic cholestasis, with deep jaundice, bilirubin in the urine, and absence of urobilinogen in urine and feces. The chances of complete recovery are not reduced by this complication.
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Fulminant Viral Hepatitis
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A fulminant course characterized by acute liver failure associated with massive or submassive liver cell necrosis occurs in about 1% of cases of hepatitis B and hepatitis C and more rarely in hepatitis A. Patients with coinfection with hepatitis B and delta virus have a greater incidence than those with hepatitis B alone. The mortality rate is high. Survivors regenerate a normal liver and do not have chronic liver disease.
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Chronic Viral Hepatitis
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Chronic viral hepatitis is defined as the presence, in viral hepatitis, of a clinical, biochemical, or serologic abnormality lasting over 6 months. Chronic hepatitis is caused by viruses B, C, and delta, but not by hepatitis A or E. An identical clinicopathologic syndrome occurs as a toxic reaction to certain drugs (oxyphenisatin, methyldopa, isoniazid) and in Wilson's disease, α1-antitrypsin deficiency, and autoimmune chronic active hepatitis. Diagnosis of viral etiology is by serologic tests for the specific viruses.
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Clinically, chronic hepatitis is characterized by a spectrum of disease, which can be characterized in increasing severity as follows: (1) Asymptomatic carrier state with normal liver histology. Here, viral serology is positive and virus can be demonstrated in hepatocytes. There are no symptoms, biochemical abnormalities, or histologic evidence of inflammation; (2) minimal chronic hepatitis (previously called chronic persistent hepatitis), which is characterized by minimal symptoms and/or mild biochemical abnormalities (eg, slightly elevated enzyme levels), and the presence of lymphocytes and plasma cells in the portal triad. Portal chronic inflammation is mild and restricted to the portal triads without extension into the liver lobule across the limiting plate. There is little or no active hepatocyte necrosis and minimal fibrosis; (3) chronic active hepatitis, which is characterized by continuing necrosis of liver cells. The portal tracts show severe chronic inflammation with lymphocytes and plasma cells extending into the liver lobule (Figure 42-12), disrupting the limiting plate of hepatocytes. Liver cells in the periphery of the liver lobule are entrapped in the inflammation and undergo necrosis (piecemeal necrosis). Portal fibrosis occurs and progressively increases. Cirrhosis results in the most severe cases.
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Patients with chronic hepatitis may have disease that progresses at varying rates. Some patients have minimal disease for many years; others progress rapidly through severely progressive active hepatitis to the onset of cirrhosis. The activity of chronic hepatitis may also change, either spontaneously or with treatment. Remission of active disease frequently has histologic features of minimal disease.
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The main causes of death in chronic hepatitis are (1) cirrhosis of the liver with chronic liver failure or the effects of portal hypertension and (2) development of hepatocellular carcinoma (see Chapter 43: The Liver: II. Toxic & Metabolic Diseases; Neoplasms).
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Prevention of Viral Hepatitis
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Preventive measures against viral hepatitis may be necessary (1) for individuals with known exposure to hepatitis A virus-contaminated food or water; (2) for hospital employees exposed to blood products, who are at risk for developing hepatitis B and C; and (3) for patients receiving transfused blood and blood products, again at risk for hepatitis B and C.
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Hyperimmune gamma globulin provides passive protection against hepatitis A and can be used to prevent a clinical attack of hepatitis A after exposure to the virus. The use of pooled hyperimmune gamma globulin (a blood product) itself carries a risk of hepatitis B and C transmission.
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A recombinant DNA hepatitis B vaccine is effective in preventing hepatitis B infection and has been recommended for high-risk groups such as hospital employees who have contact with patients' blood and tissues.
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Screening of blood donors for hepatitis B and C has virtually eradicated transmission of viral hepatitis via blood transfusion.
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Bacterial Infections of the Liver
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Nonsuppurative Infections
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Nonsuppurative bacterial infections of the liver occur as a result of bacteremia associated with any systemic bacterial infection. Liver involvement may provide a means of diagnosis, such as finding caseous granulomas in a liver biopsy specimen from a patient with miliary tuberculosis. Systemic infections such as typhoid fever, brucellosis, and leptospirosis may produce focal necrosis and inflammation in the liver. Apart from minor abnormalities in liver function tests (eg, slight elevation of transaminases, bilirubin, or alkaline phosphatase), these nonsuppurative infections do not usually cause any clinical features. Leptospirosis is an exception because it commonly causes jaundice.
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Pyogenic Liver Abscess
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In areas where Entamoeba histolytica is not prevalent, most liver abscesses are caused by pyogenic organisms. Many different bacteria may be involved, most commonly Escherichia coli, other gram-negative bacilli, anaerobic bacilli, Staphylococcus aureus, and streptococci. Culture of pus is necessary for etiologic diagnosis and often reveals a mixed flora.
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Bacteria may reach the liver in the course of a systemic bacteremia in the hepatic artery or from the intestine along the bile duct or portal vein (Figure 42-13). Liver abscesses are walled-off collections of pus with liquefactive necrosis of liver cells and neutrophil accumulation. About 50% of cases have multiple abscesses.
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Clinically, patients present with high fever, right-sided upper abdominal pain, and hepatomegaly. Pyogenic abscess is a focal lesion and not usually associated with abnormalities in liver function tests except elevation of serum alkaline phosphatase. Treatment consists of drainage of the abscess followed by antibiotic therapy directed by culture and antibiotic sensitivity of the bacteria isolated from the pus.
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Parasitic Infections of the Liver
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Hepatic amebiasis is caused by the entry of amebic trophozoites into portal venous radicles in the colonic submucosa, whence they are carried to the liver. Hepatic infection usually occurs in patients with subclinical or chronic intestinal amebic infection and very rarely during an attack of acute amebic colitis. About half of patients with hepatic amebiasis give no history suggestive of preceding amebic colitis.
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When they reach the liver, the amebas cause focal enzymatic necrosis of hepatocytes. In the early stage of the disease, there are multiple microabscesses throughout the liver (Note: Although the term “abscess” is used, amebic liver abscesses are not true abscesses because they contain few neutrophils and are composed of liquefied liver cells.) The patient presents at this stage with high fever, right upper abdominal pain, and tender hepatomegaly. This stage of the disease is sometimes called amebic hepatitis. With progression, the microabscesses coalesce to form larger abscesses.
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Grossly, amebic abscesses are large, lined by an irregular wall, and contain amebic “pus,” which has the typical reddish-brown hue (likened to anchovy paste) of liquefied liver (Figure 42-14). Trophozoites of Entamoeba histolytica may be found in the abscess wall.
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Diagnosis is based on clinical findings, which include fever, pain in the lower right chest, with hepatomegaly and marked tenderness. Chest x-ray, ultrasonography, computer tomography (CT) scan, elevated serum titers of amebic antibodies, and the finding of trophozoites in aspirated pus are useful for confirmation. Liver function tests are usually normal except for an elevated serum alkaline phosphatase level.
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Without treatment, amebic liver abscess has a high mortality rate. Deaths are due to (1) rupture into the free peritoneal cavity; (2) rupture into the pleural cavity and lung; (3) rupture into the pericardial sac (in left lobe abscesses), causing acute pericardial tamponade; and (4) systemic spread of trophozoites, resulting in amebic abscesses in the brain and lung.
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Treatment is with the highly effective amebicidal drug metronidazole. Drainage is required for large abscesses.
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Hepatic Schistosomiasis
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Schistosomiasis of the liver complicates intestinal schistosomiasis. Schistosoma mansoni, which causes colonic infection in the Middle East, and Schistosoma japonicum, which causes small intestinal infection in the Far East, are the species involved. The adult worms live in the intestinal venous plexuses and produce eggs that are carried via the portal vein to the liver, where they are deposited in the portal areas. They produce granulomas in the acute phase followed by pipestem fibrosis of the portal areas in the chronic phase. The finding of schistosome ova in the fibrous portal tracts is diagnostic.
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Hepatic schistosomiasis causes portal hypertension and ascites and is an important cause of these conditions in endemic areas.
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Hydatid cysts occur in humans as a result of accidental infection by ova of Echinococcus granulosus. The liver is the most common site for hydatid cysts, which may reach a large size and may be multiple. Histologic examination shows a thick, acellular laminated eosinophilic wall with an inner surface lined by the germinal epithelium of the larva. The cysts are filled with a granular fluid that is characterized by numerous small larval capsules containing scoleces (brood capsules).
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Patients present with a cystic mass in the liver. The diagnosis is made by the typical radiologic appearance (calcified wall). During surgical removal, care must be taken to avoid spillage of cyst contents into the peritoneal cavity, since the cyst fluid is highly antigenic and may lead to anaphylactic shock.
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Oriental Cholangiohepatitis
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Infection of the bile ducts with Clonorchis sinensis is common in eastern Asia. The flukes attach with their suckers to the bil-duct wall and cause inflammation and strictures of the bile ducts and fibrosis of the surrounding liver. The dilated bile ducts proximal to the narrowed segments contain numerous crumbling black calculi. Flukes and ova may be found (Figure 42-15). In some cases, the etiologic agent is not known. Patients present with episodes of fever and right upper abdominal pain. The diagnosis is usually based on the radiologic appearance. Surgical resection of the affected areas may be necessary.
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