Section X. The Liver, Biliary Tract, & Pancreas

All kinds of viral hepatitis (Chapter 42: The Liver: I. Structure & Function; Infections) are very common throughout the world, although the prevalence of Virus A hepatitis is greatest in developing countries. Chronic Virus B infection is most common in Far East Asia and Africa. Ethyl alcohol abuse is a worldwide problem (see Chapter 12: Disorders Due to Chemical Agents); in the United States, it is estimated that 10% of the population is affected by alcoholism. Liver and pancreatic disease are major complications of alcoholism (Chapters 43: The Liver: II. Toxic & Metabolic Diseases; Neoplasms and 45: The Exocrine Pancreas). Gallstone disease (Chapter 44: The Extrahepatic Biliary System) is common, particularly in middle-aged women.

The endocrine pancreas is discussed in this section rather than in the endocrine section because neoplasms of the islets of Langerhans enter the differential diagnosis of pancreatic tumors (Chapters 45: The Exocrine Pancreas and 46: The Endocrine Pancreas (Islets of Langerhans)). Diabetes mellitus (Chapter 46: The Endocrine Pancreas (Islets of Langerhans)) is a very common disease, affecting an estimated 2% of the population of the United States.

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.

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.

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.

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.

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.

Synthetic Functions

The liver is the source of plasma albumin; many plasma globulins, including α1-antitrypsin (α-antiprotease); and many proteins of the coagulation cascade.

Excretory Functions

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.

Metabolic Functions

The liver plays a central role in the metabolism of fat, carbohydrates, and protein and in detoxification.

Fat Metabolism

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).

Carbohydrate Metabolism

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.

Protein Metabolism

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.

Detoxification

The liver plays a vital role in detoxifying noxious nitrogenous compounds derived from the intestine, as well as many drugs and chemicals.

An enlarged liver can usually be palpated below the costal margin. Any alteration in its normally smooth surface may then be assessed.

Ultrasonography, computerized tomography, and magnetic resonance imaging disclose mass lesions in the liver or dilation of the biliary system. Hepatic blood flow can be investigated by arteriography and isotope scans. Gallium scanning is useful in detecting neoplasms and abscesses in the liver.

Liver biopsy is a relatively safe method of obtaining tissue for histologic examination (Table 42-1). Blind biopsy using a cutting needle is indicated for diffuse lesions of the liver. Radiologically directed fine-needle aspiration biopsy is indicated when it is necessary to examine a localized lesion.

Liver function tests are summarized in Table 42-2.

(Table 42-3)

Pain

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.

Alteration in Liver Size

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.

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.

Abnormal Liver Function Tests

(Table 42-2)

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.

Jaundice

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.

Etiology

(Table 42-4)

Hemolysis

(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.

Hepatocellular Abnormality

Defective Hepatic Uptake of Bilirubin

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.

Abnormal Conjugation of Bilirubin

Conjugation of bilirubin to bilirubin glucuronide is effected by UDP-glucuronyl transferase. Deficiency of this enzyme results in unconjugated hyperbilirubinemia (Table 42-5).

Neonates (Neonatal or Physiologic Jaundice)

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.

Crigler-Najjar Syndrome

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.

Gilbert's syndrome

In Gilbert's syndrome there is a partial deficiency of glucuronyl transferase.

Drugs

Drugs may interfere with this enzyme system. Novobiocin is an example.

Hepatocellular Damage

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.

Obstruction or Impaired Excretion of Bili-Rubin

Defective Excretion

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.

Obstruction at the Intrahepatic Level (Cholestasis)

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.

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.

In general, all of these causes of cholestasis are associated with severe jaundice, which usually reverses spontaneously and is not associated with liver failure.

Extrahepatic Obstruction

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.

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.

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).

Effects of Jaundice

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.

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.

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).

Hepatocellular Failure

(Figure 42-3)

Because of its tremendous functional reserve, liver failure occurs only when there is extensive liver disease destroying over 80% of the organ.

Acute Liver Failure

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.

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.

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.

Chronic Liver Failure

Chronic liver failure usually results from cirrhosis, which is associated with progressive necrosis of liver cells, fibrosis, and nodular regeneration.

The effects of chronic liver failure can be listed as follows:

1.  Decreased synthesis of albumin, leading to low serum albumin levels, edema, and ascites.

2. Decreased levels of prothrombin and of factors VII, IX, and X, resulting in a bleeding tendency.

3. Portal hypertension (see below).

4. Hepatic encephalopathy (see below).

5. Hepatorenal syndrome (see below).

6. 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.

7.  Fetor hepaticus—a breath like that of “a freshly opened corpse”—believed to be due to deficient methionine catabolism.

Portal Hypertension

(Figure 42-4)

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.

Classification

Portal hypertension resulting from obstruction may be classified according to the level of obstruction.

Presinusoidal

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.

Sinusoidal

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.

Postsinusoidal

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.

Effects of Portal Hypertension

Splenomegaly

Splenic enlargement is caused by passive venous congestion.

Development of Portosystemic Venous Anastomoses, Bypassing the Obstructed Portal Circulation

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).

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.

Ascites

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.

Hepatic Encephalopathy

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.

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.

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.

Hepatorenal Syndrome

Hepatorenal syndrome is the occurrence of acute renal failure in a patient with liver disease.

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.

The occurrence of hepatorenal syndrome is an ominous sign in a patient with liver disease.

Hepatocellular Necrosis

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.

Different liver diseases cause different patterns of liver cell necrosis. Recognition of these patterns is useful in diagnosis (Figure 42-5).

Focal Necrosis

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.

Focal necrosis is commonly seen in viral hepatitis, toxic damage, and bacteremic infections.

Zonal Necrosis

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.

Submassive & Massive Necrosis

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.

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).

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.

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).

Congenital Hepatic Fibrosis

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.

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.

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.

Chronic Hepatic Venous Congestion

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).

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”).

Clinically, passive congestion is characterized by tender enlargement of the liver. Mild abnormalities in liver function are common, but liver failure almost never occurs.

Infarction of the Liver

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.

Budd-Chiari Syndrome

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.

Viral Hepatitis

Etiology

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.

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.

Hepatitis A

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.

Hepatitis A has a global incidence, highest in low socioeconomic populations where fecal-oral transmission is greatest.

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.

Hepatitis B

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.

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.

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.

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.

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.

Hepatitis C

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.

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.

Delta Hepatitis

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.

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.

Hepatitis E

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.

Clinicopathologic Syndromes

(Figure 42-10)

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.

Acute Viral Hepatitis

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.

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.

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.

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.

Cholestatic Viral Hepatitis

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.

Fulminant Viral Hepatitis

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.

Chronic Viral Hepatitis

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.

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.

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.

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).

Prevention of Viral Hepatitis

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.

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.

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.

Screening of blood donors for hepatitis B and C has virtually eradicated transmission of viral hepatitis via blood transfusion.

Bacterial Infections of the Liver

Nonsuppurative Infections

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.

Pyogenic Liver Abscess

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.

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.

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.

Parasitic Infections of the Liver

Hepatic Amebiasis

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.

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.

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.

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.

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.

Treatment is with the highly effective amebicidal drug metronidazole. Drainage is required for large abscesses.

Hepatic Schistosomiasis

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.

Hepatic schistosomiasis causes portal hypertension and ascites and is an important cause of these conditions in endemic areas.

Hydatid Cyst

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).

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.

Oriental Cholangiohepatitis

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.

Incidence & Pathogenesis

Chronic alcoholism is a major problem in almost every society (see also Chapter 12: Disorders Due to Chemical Agents). In developed countries, it has been estimated that about 10% of the population consume potentially harmful amounts of ethyl alcohol. The habit often begins in the teen years and continues throughout life. The incidence is increasing, and in developed countries chronic liver disease and accidents associated with alcoholism are among the 10 most common causes of death. Alcoholic liver disease is most common in middle-aged men, but there is an increasing incidence among women and in the young.

The greater the amount and the longer the duration of alcohol consumption, the greater the risk of liver disease. Most patients with chronic alcoholic liver disease have consumed about 150 g or more of ethyl alcohol daily for over 10 years (a standard 750 mL bottle of 80-proof whisky contains about 300 g of alcohol).

Not all heavy drinkers develop liver disease. About 50% of alcoholics have no detectable liver disease, 30% have alcoholic hepatitis, and 20% develop cirrhosis. Prediction of liver disease in individual cases is uncertain.

Alcohol is metabolized in the hepatocyte cytoplasm by the reduced nicotinamide adenine dinucleotide (NADH)-dependent enzyme alcohol dehydrogenase into acetaldehyde. Acetaldehyde or a related substance is believed to exert a toxic effect on liver cells. Malnutrition, which frequently coexists with alcoholism, may aggravate the liver injury.

Clinicopathologic Syndromes

Alcoholic liver disease may be manifested as fatty liver, alcoholic hepatitis, or alcoholic cirrhosis (Figure 43-1). These lesions may coexist.

Fatty Liver

(See Chapter 1: Cell Degeneration & Necrosis.) Fatty liver is a common early manifestation of alcohol injury. It is the result of decreased fatty acid oxidation, increased synthesis of triglycerides, and impaired secretion of lipoproteins by the liver cell. Fat accumulates first as small globules that coalesce, increasing in size and pushing the hepatocyte nucleus to one side.

Clinically, fatty liver causes diffuse liver enlargement. Liver function is normal even when there is severe fatty change. Fatty liver is reversible if the patient stops drinking at this stage.

Acute Alcoholic Hepatitis (Acute Sclerosing Hyaline Necrosis of the Liver)

Acute alcoholic hepatitis is characterized pathologically by (1) focal lytic necrosis of hepatocytes, causing an increase in serum enzyme levels; (2) cholestasis with jaundice; (3) neutrophilic infiltration of the sinusoids and around necrotic liver cells; (4) sclerosis around the central venule, initially as fine fibrils in the space of Disse and later as coarse fibrosis that may obliterate central veins; and (5) the presence of eosinophilic waxy alcoholic hyalin—Mallory bodies—in the cytoplasm of liver cells (Figure 43-2). Hyalin is a fibrillar material derived from the cell's cytoskeleton; it stains positively for cytokeratin and ubiquitin by the immunoperoxidase technique. Hyalin is not specific for alcoholic liver injury as it is also found in biliary cirrhosis, Indian childhood cirrhosis, Wilson's disease, and liver cell carcinoma.

Clinically, patients present with an acute onset of fever, jaundice, tender enlargement of the liver, and ascites, commonly after a recent bout of heavy drinking. With severe alcoholic hepatitis, encephalopathy and death may occur. Symptoms and most of the pathologic features resolve with cessation of drinking, but the fibrosis increases progressively with each episode.

Chronic Alcoholic Liver Disease

Chronic ingestion of alcohol is associated with progressive fibrosis in the centrizonal region of the liver and distortion of liver architecture by fibrous bands that may connect portal areas and central veins; this differs from cirrhosis in the absence of true regenerative nodules. Progression may slow or come to a halt if alcohol ingestion is discontinued.

Alcoholic Cirrhosis

See later discussions of Cirrhosis of the Liver and Alcoholic Cirrhosis.

Many drugs and other chemical substances cause liver damage by a variety of mechanisms (Table 43-1).

Predictable (Dose-Related) Toxicity

Agents in this group cause liver cell necrosis in all individuals at a predictable dose level. Acetaminophen, which is normally metabolized by the glutathione reductase system, is an example of this phenomenon. In overdosage, the glutathione becomes exhausted, and alternative metabolic pathways yield toxic products. Salicylates in high doses and cytotoxic anticancer drugs such as methotrexate also cause liver cell necrosis. Carbon tetrachloride and chloroform, which are used in industry, also cause liver cell necrosis (Figure 43-3).

Tetracycline in high intravenous dosages has been reported to cause acute microvacuolar fatty change in the liver, with liver failure and a high mortality rate.

Unpredictable (Idiosyncratic) Toxicity

Some hepatotoxic drugs cause liver injury in an unpredictable manner, usually unrelated to dose and in only a small percentage of susceptible individuals. Injury is manifested in a variety of ways.

Massive Hepatocellular Necrosis

Isoniazid, halothane, and methyldopa may cause submassive or massive liver necrosis, with acute liver failure. Lesser degrees of liver necrosis have been reported following exposure to other antituberculous drugs and antidepressants.

Isoniazid-induced necrosis is important because of the recommendation that this drug be used for chemoprophylaxis in all patients who give a positive tuberculin skin test. Massive necrosis occurs in only 0.1% of patients taking isoniazid; the risk is insignificant in individuals under 30 years of age and rises after that.

Halothane is an anesthetic agent that causes massive necrosis in a small number of patients. More than one exposure is usually necessary.

Cholestasis

Cholestasis is caused by anabolic steroids, oral contraceptives, phenothiazines, and oral antidiabetic drugs. Clinically, patients present with deep jaundice of the obstructive type. Liver biopsy shows cholestasis with minimal inflammation and necrosis. The bile ducts in the portal areas are normal, and radiologic studies show lack of dilation of the intrahepatic biliary system.

Acute Hepatitis

Acute hepatitis indistinguishable clinically and pathologically from viral hepatitis has been reported as a complication of isoniazid (in about 1% of patients taking the drug), phenytoin, and salicylates.

Fatty Change

Fatty change occurs as an idiosyncratic effect of methotrexate, valproic acid, and corticosteroids.

Chronic Hepatitis

Chronic hepatitis of a type that is very difficult to distinguish clinically and pathologically from viral and autoimmune chronic active hepatitis occurs with methyldopa and oxyphenisatin. The disease may progress to cirrhosis.

Granulomatous Hepatitis

Noncaseating epithelioid cell granulomas occur with a variety of drugs. Distinction from sarcoidosis is possible only by clinical means.

Mass Lesions

Mass lesions in the liver, including liver cell adenoma and focal nodular hyperplasia, have been attributed to oral contraceptives and anabolic steroids. A few cases of liver cell carcinoma have been reported in oral contraceptive users, but a causal relationship has not been established. Vinyl chloride and thorium dioxide (Thorotrast—a radiologic dye used in the past) are associated with angiosarcoma of the liver.

Malnutrition (kwashiorkor) is associated with fatty liver and nutritional cirrhosis. Indian childhood cirrhosis is now thought to be the result of malnutrition. The exact mechanism by which undernutrition causes cirrhosis is uncertain.

At the other extreme, obese patients treated with ileoileal bypass (no longer performed) developed liver disease characterized by fatty change and sclerosing hyaline necrosis very similar to alcoholic liver disease. The mechanism of liver injury after ileal bypass is uncertain.

The role of immunologic hypersensitivity in liver disease is difficult to evaluate. Immune injury probably contributes to the changes seen in viral hepatitis and in several types of drug-induced liver injuries. There is strong evidence that nonviral chronic active hepatitis and primary biliary cirrhosis are the result of injuries mediated by immune mechanisms.

Autoimmune Chronic Active Hepatitis (“Lupoid Hepatitis”)

Immune-mediated and viral chronic active hepatitis have identical clinical and pathologic features. Patients with autoimmune chronic active hepatitis have negative viral serologic tests. Anti-smooth muscle antibody and antinuclear antibodies are frequently present in the serum, and the lupus erythematosus (LE) cell test is positive (hence “lupoid” hepatitis). Immune-mediated chronic active hepatitis has no relationship to systemic lupus erythematosus.

In contrast to its viral counterpart, immune-mediated chronic active hepatitis occurs more frequently in women. The disease has a bad prognosis, progressing to cirrhosis in the majority of cases. Corticosteroids are sometimes of value in treatment.

Primary Biliary Cirrhosis

Primary biliary cirrhosis occurs predominantly (over 90% of cases) in middle-aged women. The exact cause is uncertain, but immunologic injury is strongly suspected. Primary biliary cirrhosis is associated with other immunologic diseases such as progressive systemic sclerosis and Sjögren's syndrome and is characterized by the presence in serum of several autoantibodies, the most specific of which is antimitochondrial antibody; when present in the serum in a titer in excess of 1:160, it is diagnostic of primary biliary cirrhosis.

Histologically, the diagnostic changes are in the portal tracts. Lymphocytes and plasma cells surround, infiltrate, and appear to actively destroy the walls of the bile ductules. Epithelioid cell granulomas with Langhans' giant cells occur in 30% of cases. Initial bile duct proliferation is followed by progressive destruction. In the final stage of the disease, bile ducts are absent from the portal tracts, which show marked fibrosis. Even in the terminal phase, primary biliary cirrhosis shows only moderate fibrosis. It does not show nodular regeneration of the liver and is therefore not a true cirrhosis despite its name.

Hepatic parenchymal changes are nonspecific and consist of cholestasis and Kupffer cell hyperplasia. Hyalin may be present in the peripheral zonal liver cells.

Clinically, patients present with slowly progressive biliary obstruction. The onset is insidious; pruritus is the most common first symptom, resulting from accumulation of bile salts in the blood. Serum alkaline phosphatase is elevated early, but jaundice occurs later, usually 6–18 months after onset. Most patients have elevated serum triglyceride and cholesterol levels, and many develop xanthomas in the skin. There is an increased risk of atherosclerosis. Portal hypertension and liver failure may occur 5–15 years after onset.

Cirrhosis of the liver is a pathologic entity characterized by (1) necrosis of liver cells, slowly progressive over a long period and ultimately causing chronic liver failure and death; (2) fibrosis, which involves both central veins and portal areas; (3) regenerative nodules, the result of hyperplasia of surviving liver cells; (4) distortion of normal hepatic lobular architecture; and (5) diffuse involvement of the whole liver. A regenerative nodule is an abnormal mass of liver cells without a normal cord pattern or central venule and surrounded completely by fibrosis (Figure 43-4).

Pathology

Grossly, the liver is enlarged in the early stages, but later it becomes smaller because of cell loss and fibrous contraction. It is much firmer than normal. Nodularity is the most characteristic feature (Figure 43-5). Depending on whether the nodules are more or less than 3 mm in size, cirrhosis is classified as macronodular, micronodular, or mixed.

Histologically, regenerative nodules are characteristic. They are composed of hyperplastic liver cells organized into irregular plates. Liver cells often show enlargement, with atypical nuclei—a picture sometimes called “dysplasia” because of the suspicion that such changes are a precursor of liver cell carcinoma.

The vasculature of the liver is greatly distorted. The fibrous bands obstruct the portal venous radicles and lead to abnormal fistulous communications between portal veins and hepatic arterioles, resulting in portal hypertension.

Clinical Features

Cirrhosis is manifested clinically by features of chronic liver failure and portal hypertension (Figure 43-6). Common presenting symptoms include hematemesis due to rupture of gastroesophageal varices and ascites. Cirrhosis is an irreversible and progressive disease that ultimately causes death. The rate of progression is variable.

Cirrhosis is a premalignant lesion. The risk of hepatocellular carcinoma is greatest in cirrhosis caused by hemochromatosis, virus-induced cirrhosis, cryptogenic cirrhosis, and alcoholic cirrhosis, in order of decreasing hazard.

Etiologic Types of Cirrhosis

(Table 43-2)

The terminology of this disorder is confusing and unsatisfactory. Characterizing cirrhosis as micronodular and macronodular according to the size of the nodules is of little value because the size of nodules does not correlate with etiology. The terms portal cirrhosis and Laennec's cirrhosis are no longer used; both denoted micronodular cirrhosis of the alcoholic type. The term postnecrotic cirrhosis should no longer be used because all forms of cirrhosis are associated with necrosis of liver cells and are therefore postnecrotic.

Cirrhosis is most usefully classified according to its causes. All etiologic classifications include a group called cryptogenic cirrhosis (cirrhosis of unknown cause). The incidence of cryptogenic cirrhosis depends on how diligently the cause is sought and how rigorous the criteria are for assigning specific causes to individual cases.

Cryptogenic Cirrhosis

Hepatic cirrhosis is said to be cryptogenic when complete evaluation of the patient has failed to identify a cause. Cryptogenic cirrhosis may include cirrhosis following immune-mediated chronic active hepatitis or following injury due to drugs or chemicals—because there is no way to identify these causes with certainty. Many patients with cirrhosis give a history of drug ingestion, but it is difficult to establish a causal role for the drugs.

Alcoholic Cirrhosis

Alcoholic cirrhosis is frequently associated with evidence of fatty change or acute alcoholic hepatitis. Alcoholic cirrhosis is typically a fatty micronodular cirrhosis (Figure 43-4). In patients who stop drinking, the nodules are not infrequently larger and fat is absent.

Alcoholic cirrhosis tends to have a slow rate of progression, particularly if the patient stops drinking. The disease is irreversible and causes death.

Virus-Induced Cirrhosis

Cirrhosis may follow chronic active hepatitis resulting from infection with hepatitis B and C viruses. Patients who present with cirrhosis may or may not give a history of hepatitis. Typically, virus-induced cirrhosis is macronodular. Features of chronic active hepatitis may coexist. Virus-induced cirrhosis tends to progress rapidly, with death due to chronic liver failure, portal hypertension, or hepatocellular carcinoma.

Cirrhosis caused by hepatitis B virus may be identified by the presence of hepatitis B (HB)sAg in the serum and in liver cells; orcein stains and immunoperoxidase stains for HBsAg are positive. A few cases of cirrhosis due to hepatitis B show coinfection with delta hepatitis that can be demonstrated by immunologic techniques. Patients with cirrhosis caused by hepatitis C have anti-hepatitis c virus (HCV) antibody in their serum.

Biliary Cirrhosis

Primary biliary cirrhosis causes portal fibrosis, but the changes fall short of the definition of true cirrhosis because regenerative nodules are usually absent (Figure 43-7).

Secondary biliary cirrhosis occurs in patients with prolonged large bile duct obstruction (gallstones, stricture, tumor, cholangitis). Marked cholestasis causes liver cell necrosis, and prolonged cholangitis leads to portal fibrosis (Figure 43-7). Biliary cirrhosis causes a fine nodularity (micronodules). Features of chronic liver failure and portal hypertension occur late.

Hemochromatosis

Hemochromatosis results from iron overload in the body as demonstrated by increased serum iron, ferritin, and saturation of iron-binding protein; increased iron stores in the bone marrow; and the presence of iron in liver cells.

Etiology

Hereditary Hemochromatosis

This is a familial disease with autosomal recessive inheritance of an abnormal gene located on chromosome 6 in close linkage with human leukocyte antigen (HLA)-A3. The disease occurs in homozygotes; heterozygotes show slightly elevated serum iron levels. The mechanism by which the abnormal gene causes iron overload is not certain but is believed to involve increased intestinal iron absorption.

Secondary Hemochromatosis

Secondary hemochromatosis is the occurrence of iron overload due to recognizable causes such as the following:

Increased Dietary Intake of Iron

This occurs in the Bantu tribe of Africa, who use iron cooking utensils (“Bantu siderosis”). The excessive use of iron-containing drugs and iron-rich wine and beer may also cause iron overload.

Iron Infusions

Usually in the form of repeated blood transfusions for patients with chronic anemias.

Liver Disease

Particularly alcoholic cirrhosis, which is associated with increased iron absorption. The resulting iron deposition in liver cells may contribute to further liver cell damage.

Chronic Hemolytic Anemias

Thalassemia is the most common cause of secondary hemochromatosis. Iron overload is due to repeated blood transfusions and stimulation of intestinal iron absorption by erythroid hyperplasia in the bone marrow.

Liver Changes in Hemochromatosis

Iron is deposited as hemosiderin in the cytoplasm of Kupffer cells and hepatocytes. Hemosiderin appears as golden brown granules in routine microscopic sections (see Chapter 1: Cell Degeneration & Necrosis). The Prussian blue stain for iron produces an intense blue color. The most accurate assessment of hepatic iron load is by quantitative assay of iron content in a liver biopsy. Patients with hereditary hemochromatosis show marked elevation of hepatic iron (> 10,000 μg/g of liver dry weight; normal is < 1000 μg/g of liver dry weight).

Accumulation of iron in hepatocytes causes cellular degeneration, functional impairment, and clinical disease. This occurs early in idiopathic hemochromatosis and later in secondary forms of hemochromatosis. The mechanism by which stored iron causes cell damage is uncertain. It is believed that free iron accumulates in the cytoplasm when the capacity for storage as ferritin and hemosiderin is exhausted. Free ferric iron undergoes reduction, causing abnormal electron transfers and the formation of toxic oxygen-based free radicals.

Initially, the liver is slightly enlarged. Over a long period of time, there is progressive loss of liver cells accompanied by fibrosis—leading to cirrhosis, which is commonly macronodular. Hepatic hemochromatosis progresses rapidly and may be complicated by hepatocellular carcinoma.

Changes in Extrahepatic Tissues

Iron deposition occurs in many other tissues: The pancreas, myocardium, skin, endocrine glands, and joints are commonly affected, producing the extrahepatic clinical manifestations of hemochromatosis (Figure 43-8). Increased pigmentation of the skin and pancreatic islet destruction result in bronze diabetes, which is an alternative name for hemochromatosis.

Wilson's Disease

Wilson's disease is an autosomal recessive disorder characterized by (1) defective excretion of copper into bile; (2) increase in total body copper, resulting from unchanged absorption in the face of decreased biliary excretion; (3) accumulation of copper in the cytoplasm of liver cells, complexed to an abnormal protein; (4) decreased ceruloplasmin level in plasma; and (5) increased “free” copper in plasma, causing increased urinary excretion of copper and deposition of copper both in cells and in connective tissue. The primary defect is in the liver cell and is corrected by liver transplantation.

Liver Changes in Wilson's Disease

Liver involvement is responsible for the dominant clinical features. Intracellular copper produces an injury manifested as a progressive microvacuolar fatty change and focal liver cell necrosis. It may present, usually in late childhood, as acute hepatitis clinically resembling viral hepatitis. With continuing liver cell necrosis, it progresses to fibrosis and finally to cirrhosis with chronic liver failure. Increased copper levels in the liver can be demonstrated biochemically. Histochemical methods (rubeanic acid stain) are not always positive because of the abnormal protein binding of the copper in liver cells.

Extrahepatic Changes in Wilson's Disease

Copper deposition in the brain involves the basal ganglia (particularly the lenticular nucleus), thalamus, red nucleus, and dentate nucleus of the cerebellum, all of which show atrophy, slight brown discoloration, and cavitation. Microscopically, the neurons are decreased in number, representing chronic cell necrosis. Reactive astrocytic proliferation is present. These changes produce clinical features of extrapyramidal dysfunction. Wilson's disease is also called hepatolenticular degeneration.

Deposition of copper in Descemet's membrane at the sclerocorneal junction is important for clinical diagnosis because it produces a characteristic greenish-brown ring (Kayser-Fleischer ring) at the corneal edge. This is not seen with the naked eye until a late stage of the disease but can be recognized early by slit-lamp examination. Copper deposition in the eye does not cause visual impairment.

Alpha1-Antitrypsin Deficiency

(See also Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases)

Severe α1-antitrypsin (α-antiprotease) deficiency occurs in homozygous PiZZ individuals and is a rare cause of cirrhosis, usually with onset during childhood. The abnormal gene results in hepatic synthesis of an abnormal α1-antitrypsin molecule that accumulates in the liver cell cytoplasm, appearing as eosinophilic globules. These globules are present in liver cells in the peripheral part of the lobule and stain positively with periodic acid-Schiff (PAS) stain. They also stain by immunoperoxidase methods using antibody against α1-antitrypsin. The demonstration of these globules establishes the diagnosis, which can be further confirmed by absence of α1-antitrypsin in the blood.

Galactosemia

Galactosemia is a rare inherited disease caused by deficiency of galactose-1-phosphate uridyl transferase. Galactose metabolites accumulate in the liver, causing injury. Affected patients present in early infancy following feeding of milk (which contains lactose, a disaccharide of glucose and galactose). Cholestasis, fatty change, and cirrhosis progress rapidly to liver failure. Galactosemia is also associated with cataracts and mental retardation.

Galactosemia is routinely looked for in neonatal screening tests. Diagnosis in a neonate followed by administration of a diet that contains no milk products prevents liver damage.

Benign Neoplasms

Benign neoplasms of the liver are not uncommon as incidental findings at autopsy and are becoming increasingly important because modern radiologic imaging procedures are now able to detect small tumors, raising the question of whether such tumors are benign or malignant, primary or secondary.

Cavernous Hemangioma

Hemangiomas are common incidental findings at surgery, radiologic examination, and autopsy. Histologically, they are composed of large endothelium-lined spaces filled with blood.

Peliosis Hepatis

Peliosis hepatis is a rare degenerative condition associated with multiple blood-filled spaces in the liver, many of which lack an endothelial lining. It may be associated with use of anabolic steroids. There is an increased incidence of peliosis in patients with acquired immunodeficiency disease (AIDS).

Sclerosing Bile Duct Adenoma

Bile duct adenoma is uncommon and usually presents as an incidental finding at surgery. It appears as a firm, gray-white nodule situated beneath the capsule. Over 90% are less than 1 cm in diameter. Histologically, bile duct adenoma is composed of irregular glands surrounded by collagen. Distinction from metastatic adenocarcinoma can be difficult.

Liver Cell Adenoma

Liver cell adenoma is a rare benign neoplasm that occurs mainly in women taking oral contraceptives and athletes taking anabolic steroids; some tumors have regressed when these drugs were withdrawn.

The tumors may be multiple and large and may have foci of hemorrhage and necrosis. Microscopically, liver cell adenomas are composed of cytologically benign hepatocytes arranged in thickened cords. Bile ducts and portal tracts are absent. The distinction from a well-differentiated hepatocellular carcinoma may be difficult.

Clinically, patients may present with a mass, sudden pain due to infarction, or hemorrhage due to rupture through the liver capsule.

Focal Nodular Hyperplasia

Focal nodular hyperplasia is another mass lesion of the liver that has been etiologically related to oral contraceptives. It is not a true neoplasm; the mechanism by which it arises is unknown.

Focal nodular hyperplasia most frequently presents as a solitary solid mass lesion, usually subcapsular, well circumscribed, and only rarely larger than 5 cm. On cut section, it is gray-white and typically has a central scar with bands of fibrosis radiating to the periphery.

Microscopically, nodules of liver tissue are separated by fibrous bands in which portal tracts containing bile ductules can be identified. The lesion resembles a neoplasm grossly and localized cirrhosis microscopically.

Malignant Neoplasms

Malignant neoplasms may arise in the liver from (1) hepatocytes (hepatocellular carcinoma), (2) intrahepatic bile ductules (cholangiocarcinoma), and (3) mesenchymal elements such as blood vessels (angiosarcoma and hemangioendothelioma).

Hepatocellular Carcinoma

Incidence

Hepatocellular carcinoma (sometimes inappropriately called hepatoma) has a marked geographic variation in incidence, being common in the Far East and certain parts of Africa (Chapter 17: Neoplasia: I. Classification, Nomenclature, & Epidemiology of Neoplasms; Table 43-3), where in some areas it is the most common type of cancer. It is uncommon in Western Europe and North America (about 8000 cases a year in the United States).

Etiology

The cause is unknown, but several factors have been implicated: (1) Aflatoxin, a product of the fungus Aspergillus flavus, which grows on improperly stored grain and nuts (including peanuts), is toxic to liver cells. It is present in high levels in grain in Africa and Asia, leading to the suggestion that chronic ingestion of aflatoxin may be at least partially responsible for the high incidence of liver cell carcinoma in these areas; (2) Hepatitis B virus infection is strongly suspected of causing hepatocellular carcinoma. African and Far East countries where hepatocellular carcinoma is common have high rates of hepatitis carriers, probably with vertical transmission of the virus from generation to generation; and (3) Hepatitis C virus infection is also associated with hepatocellular carcinoma.

Over 80% of patients who develop hepatocellular carcinoma have cirrhosis of the liver. The increased cell turnover in regenerative nodules of cirrhosis is associated with cytologic abnormalities that have been interpreted as premalignant dysplastic changes. While all types of cirrhosis may be complicated by carcinoma, the association is greatest with hemochromatosis, virus-induced cirrhosis, and alcoholic cirrhosis.

Pathology

Grossly, hepatocellular carcinoma may present as a large solitary mass (Figure 43-9), as multiple nodules, or as a diffusely infiltrative lesion. Microscopically, the neoplasm is composed of abnormal liver cells of variable differentiation. The better differentiated tumors are composed of cells resembling liver cells arranged in cords separated by sinusoids (Figure 43-10). The cells have enlarged nuclei that show prominent nucleoli and hyperchromatism and may contain bile in the cytoplasm. The less well differentiated tumors have sheets of anaplastic cells. Invasion of hepatic venous radicles is a typical feature that permits differentiation from adenoma. It may be difficult to distinguish a poorly differentiated hepatocellular carcinoma from metastatic carcinoma. Rarely, venous involvement is so extensive as to produce Budd-Chiari syndrome. Even more rarely, a tumor thrombus extends along the hepatic vein into the inferior vena cava and up into the right atrium.

Immunohistochemical stains may show the presence of alpha-fetoprotein (AFP) in the neoplastic cells. Hepatocellular carcinoma also secretes AFP into the blood; elevated levels are present in 90% of patients, making serum AFP assay an important diagnostic test. (Note: AFP levels may be slightly elevated in some cases of hepatitis and cirrhosis, as well as in some germ cell neoplasms of the gonads.)

Hepatocellular carcinoma tends to metastasize early via lymphatics to regional lymph nodes and via the bloodstream to produce lung metastases. Metastases to other sites occur terminally.

A rare variant, fibrolamellar carcinoma, has a better prognosis than the usual hepatocellular carcinoma. This occurs mainly in younger females, has no AFP elevation, and is usually a grossly encapsulated mass. The entity is defined by the presence of large polygonal cells with abundant eosinophilic cytoplasm separated by broad fibrous bands.

Clinical Features

(Figure 43-11)

Hepatocellular carcinoma should be suspected when a patient with known cirrhosis presents with any new symptom such as pain, loss of weight, fever, increasing liver size, or increasing ascites. About 20% of patients present with intraperitoneal hemorrhage. Rarely, hepatocellular carcinoma may secrete an ectopic hormone, causing hypoglycemia (insulin-like polypeptide), polycythemia (erythropoietin), or hypercalcemia (parathyroid hormone-like polypeptide).

Surgical resection is rarely undertaken for the treatment of hepatocellular carcinoma, and chemotherapy and radiotherapy are not very effective. Progression is extremely rapid, and most patients are dead within 1 year. The median survival after diagnosis is 2 months; the 5-year survival rate is almost nil.

Cholangiocarcinoma

Cholangiocarcinoma arises in the intrahepatic bile ductules. It is uncommon in the United States and Europe but has a relatively high incidence in the Far East, where infection with the liver fluke, Clonorchis sinensis, is thought to be a predisposing factor. Cholangiocarcinoma is not associated with cirrhosis.

Grossly, cholangiocarcinoma presents features indistinguishable from those of hepatocellular carcinoma. Histologically, it is an adenocarcinoma that shows mucin secretion. The presence of cytoplasmic mucin permits differentiation from hepatocellular carcinoma, which does not secrete mucin. Marked sclerosis is common. Differentiation from metastatic adenocarcinoma is almost impossible on histologic grounds alone. Serum AFP levels are normal.

The clinical presentation is with a liver mass. The progress of disease is often slow, but bloodstream spread ultimately occurs, and the prognosis is poor.

Malignant Vascular Neoplasms

Angiosarcoma

Hepatic angiosarcoma is a highly malignant rare neoplasm that has been linked etiologically to polyvinyl chloride, which is used extensively in the plastics industry; and to Thorotrast, a thorium dioxide-containing radiographic dye that was used several decades ago. Thorium was deposited as refractile crystals in the portal tracts and acted as a carcinogen.

Patients present with rapid liver enlargement. The tumor appears as a solid, often very large hemorrhagic mass composed histologically of intercommunicating vascular spaces lined by malignant endothelial cells.

Epithelioid Hemangioendothelioma

This rare malignant neoplasm of endothelial cells has a slower rate of progression than angiosarcoma. It produces a diffusely infiltrative mass with marked fibrosis. Metastases occur late, and death occurs 10–15 years after diagnosis.

Metastatic Neoplasms

Metastases account for most neoplasms involving the liver. Virtually any malignant neoplasm in the body can metastasize to the liver; those from the gastrointestinal tract (via the portal vein), breast, and lung and malignant melanoma are most common.

Metastatic carcinoma characteristically produces massive liver enlargement with multiple nodules (Figure 43-12). However, differentiation of hepatocellular carcinoma from metastatic carcinoma is sometimes very difficult. The following features are helpful: (1) Grossly, the nodules of metastatic carcinoma often show central necrosis and umbilication; (2) The presence of cirrhosis favors hepatocellular carcinoma; (3) The demonstration of AFP in tumor cells or in the blood is almost pathognomonic of hepatocellular carcinoma. (4) Invasion of hepatic veins favors hepatocellular carcinoma.

If metastatic spread is from an adenocarcinoma, distinction from primary cholangiocarcinoma of the liver may be impossible unless a primary adenocarcinoma is found elsewhere in the body.

Liver Neoplasms in Infancy

Several rare neoplasms have been described as occurring in the liver in infancy.

Infantile hemangioendothelioma is a benign neoplasm of endothelial cells characterized by anastomosing vascular spaces. It is often large and tends to shunt blood from the arterial to the venous side, acting as an arteriovenous fistula and leading to a hyperdynamic circulation; the usual presentation is heart failure in infancy.

Mesenchymal hamartoma also produces a mass—often a large mass—in the liver. It is solid, with areas of cystic change; microscopically, mesenchymal hamartoma is composed of bile duct-like structures admixed with disorganized mesenchymal elements. It is benign. Surgical removal is curative.

Hepatoblastoma is a malignant neoplasm composed of primitive cells that resemble fetal liver cells. Mesenchymal elements such as bone are present in most cases. AFP is present both in tumor cells and in the blood. This tumor commonly presents as marked liver enlargement in infancy. It has a poor prognosis.

The extrahepatic biliary system is composed of the bile ducts and the gallbladder (Figure 44-1). In 70% of patients, the common bile duct and pancreatic duct join at the ampulla of Vater and have a common duodenal opening. In the other 30%, the pancreatic and bile ducts open separately. The common bile duct has a luminal diameter of 0.5–0.7 cm in the adult.

Histologically, the entire biliary tract is lined by mucus-secreting columnar epithelium. In the gallbladder, the epithelium is thrown up into delicate folds, and mucous glands are buried deeply in the smooth muscle wall (Aschoff-Rokitansky sinuses).

The biliary system stores and delivers the bile secreted by the liver into the duodenum, with the gallbladder acting as a reservoir in which the bile is stored and concentrated (from about 1000 mL/d down to 50 mL/d). The gallbladder is not required for adequate functioning of the system. Bile is an alkaline fluid that contains the excretory bilirubin pigments, bile acids and bile salts, cholesterol, inorganic ions, and mucus. Cholesterol, which is insoluble in water, is maintained in solution by the formation of complexes with the hydrophilic bile salts and lecithin.

Pain

Several types of pain occur in diseases of the extrahepatic biliary system. Biliary colic is severe intermittent pain in the right upper abdomen that radiates to the back and right shoulder. It is caused by increased muscular contraction of the bile duct and occurs when there is bile duct obstruction. Vague epigastric pain (dyspepsia), which may be aggravated by ingestion of fatty foods, is common in patients with gallstones and chronic cholecystitis. The mechanism of this pain is unknown. Constant right upper abdominal pain, often severe, occurs in acute cholecystitis when extension of inflammation involves the pain-sensitive parietal peritoneum.

Obstructive Jaundice

(Figure 44-2)

Obstruction of the common bile duct results in obstructive jaundice. The biliary system undergoes dilation proximal to the obstruction, and bile backs up in the liver (cholestasis). The gallbladder undergoes enlargement when it is normal; in patients who have gallstones and fibrotic thickening of the gallbladder wall, gallbladder enlargement does not occur (Courvoisier's law).

Cholecystography & Cholangiography

The biliary tract may be outlined by a radiopaque dye, permitting evaluation of its anatomy. The dye may be given orally or intravenously to be excreted in bile. Oral cholecystography and intravenous cholangiography have a high failure rate in patients with obstructive jaundice because the dye is not excreted in adequate amounts in the bile. Dye may also be injected into the common bile duct through an endoscope in the duodenum (endoscopic retrograde cholangiopancreatography, ERCP) or directly into the dilated intrahepatic ducts in patients with obstructive jaundice (transhepatic cholangiography, THC). ERCP also permits the taking of biopsy specimens from the terminal part of the common bile duct and samples of bile for cytologic study.

Other Radiologic Techniques

Ultrasonography and computerized tomography are extremely accurate in detecting dilated bile ducts, calculi in the biliary system, and masses in the head of the pancreas and bile ducts. When a mass is present, a fine needle may be passed into it under radiologic guidance and material aspirated for cytologic diagnosis (fine-needle aspiration biopsy). Hepatobiliary (HIDA) scans utilize an agent that is rapidly excreted into bile, permitting evaluation of the biliary tract.

Functional Evaluation

Tests to evaluate obstructive jaundice have been considered in Chapter 42: The Liver: I. Structure & Function; Infections. Chemical examination of bile is of little clinical diagnostic value and is rarely performed.

Anatomic Variations of the Biliary System

Minor variations in the way in which the common hepatic, cystic, and common bile ducts connect are very common and frequently associated with varying distributions of the arteries supplying the biliary system and liver. Recognition of these normal variations is important at cholecystectomy in order to prevent accidental ligation of ducts and blood vessels.

Anatomic abnormalities of the gallbladder include absence, duplication with the presence of two gallbladders, intrahepatic location, and floating gallbladder surrounded by peritoneum and connected to the inferior surface of the liver by a pedicle. A peculiar abnormality is a focal concentric narrowing of the body of the gallbladder, producing an expanded fundus (“phrygian cap” gallbladder).

Biliary Atresia

Biliary atresia is the most common cause of neonatal obstructive jaundice. Atresia is failure of development of the lumen in the epithelial cord that ultimately becomes the bile ducts; this failure may be complete or incomplete. The cause of atresia is controversial; some authorities believe it is the result of an intrauterine infection. Atresia commonly involves the extrahepatic bile ducts only; more rarely, the intrahepatic ducts are involved. Complete atresia involving the entire system is associated with a high mortality rate. The liver shows the features of severe large bile duct obstruction with secondary biliary cirrhosis.

Without treatment, death occurs in infancy. Surgical treatment may be successful in cases where atresia is partial. In cases where atresia involves intrahepatic ducts, liver transplantation represents the only hope of survival.

Choledochal Cyst

Choledochal cyst, although uncommon, is the most frequent cause of obstructive jaundice in older children. Choledochal cysts are caused by focal dilation, often massive, of the common bile duct. The wall is thick and fibrotic, and the cavity contains bile. Rarely, dilation of intrahepatic bile ducts (Caroli's disease) may coexist.

Women are more commonly affected. Clinical presentation is with pain, jaundice, and a cystic mass in the right upper quadrant.

Most gallbladder diseases are associated with the formation of gallstones (cholelithiasis). Gallstones are usually formed in the gallbladder and rarely in the common bile duct.

Etiology & Incidence

(Table 44-1)

Cholesterol-Based Gallstones

Pure, mixed, and combined cholesterol-based gallstones are common and are formed when the concentration of cholesterol is increased or when bile salts are decreased. (Bile salts keep cholesterol in solution.) Women are more apt to be affected. Middle age, obesity, and multiparity (“fat, fertile females in their forties and fifties”) increase the risk to as high as 20%. Oral contraceptives increase biliary cholesterol excretion and predispose to gallstones. Three fourths of Native American women develop gallstones. The incidence is also high in South American and Mexican women.

In patients with terminal ileal disease such as Crohn's disease or those who have undergone ileal resection and ileal bypass surgery, failure of bile salt reabsorption in the terminal ileum is associated with decreased bile salt levels in bile and formation of gallstones.

Patients with diabetes mellitus also have an increased incidence of cholesterol gallstones, probably related to increased cholesterol levels in bile.

Pigment (Bilirubin) Stones

These are uncommon and occur (1) in patients suffering from chronic hemolytic anemias such as sickle cell disease and thalassemia, in whom bilirubin excretion is greatly increased; and (2) in patients with parasitic infestations, most commonly Clonorchis sinensis, in whom the parasite ova form a nidus for pigment stones (see Oriental Cholangiohepatitis, Chapter 42: The Liver: I. Structure & Function; Infections).

Clinicopathologic Syndromes

(Figure 44-3)

Asymptomatic Gallstones

Thirty percent or more of patients with gallstones have no symptoms, and gallstones are frequently found incidentally at radiologic examination. Only about 25% of gallstones contain sufficient calcium to be visible on plain x-rays, but ultrasonography and computerized tomography are highly effective at detecting gallstones. The presence of asymptomatic gallstones is not an indication for surgical removal.

Acute Cholecystitis

Acute cholecystitis rarely occurs in the absence of gallstones. In 80% of cases, a stone is found obstructing the cystic duct, leading to stasis of bile in the gallbladder. The residual bile becomes highly concentrated and causes a chemical acute inflammation. The damaged gallbladder is then susceptible to infection by bacteria; Escherichia coli and other gram-negative bacilli are cultured from the bile in 80% of cases.

Pathologically, the gallbladder shows congestion, thickening of the wall by edema, mucosal ulceration, and fibrinous exudation. Large numbers of neutrophils are present. The gallbladder may become filled with pus (empyema of the gallbladder). In severe cases, necrosis of the wall occurs, with greenish-black discoloration (gangrenous cholecystitis). Perforation may lead to local abscess formation or to generalized peritonitis.

Clinically, acute cholecystitis produces acute onset of fever and right upper quadrant pain. An enlarged, tender gallbladder is palpable in 40% of cases; mild jaundice may be seen in about 20%. Treatment is with antibiotics and surgical drainage or cholecystectomy.

Chronic Cholecystitis

Chronic cholecystitis almost never occurs without gallstones. Pathologically, the gallbladder is contracted and its wall thickened by fibrosis (Figure 44-4), with infiltration by lymphocytes, plasma cells, and macrophages. Calcification may occur in the wall; when extensive, the gallbladder is outlined on abdominal x-ray (porcelain gallbladder). The mucosa of the gallbladder may be near normal or thinned by pressure of a stone, or it may show yellow flecks due to accumulation of cholesterol-filled foamy macrophages in the mucosa (cholesterolosis).

Symptoms are usually vague; abdominal pain, often related to the ingestion of fatty foods, is the most common feature. Biliary colic—severe intermittent right upper quadrant pain—may occur when the cystic duct is obstructed.

Movement of Gallstones

Migration of gall-stones from the gallbladder may cause obstruction or fistula formation.

1. Cystic duct obstruction is characterized by distention of the gallbladder with watery bile (hydrops) or mucus (mucocele). Acute cholecystitis also complicates duct obstruction.

2. Common bile duct obstruction may be intermittent, with attacks of biliary colic, jaundice, and high fever due to cholangitis (Charcot's triad of symptoms). Less commonly, obstruction is complete, leading to deep jaundice. In patients with obstructive jaundice resulting from stones, the presence of chronic cholecystitis prevents dilation of the gallbladder (Courvoisier's law; see Figure 44-2). Impaction of a gallstone in the ampulla of Vater may obstruct the pancreatic duct, leading to acute pancreatitis.

3. Fistulous tracts develop rarely between the gallbladder and intestine due to the chronic inflammation. A large gallstone may then pass directly through such a cholecystoenteric fistula into the intestine, causing intestinal obstruction (gallstone ileus).

Fibrous strictures of the common bile duct are an important cause of obstructive jaundice. They occur (1) after biliary surgery, most frequently cholecystectomy; (2) after external trauma (rarely); and (3) following inflammation, either caused by a gallstone in the bile duct or chronic pancreatitis.

Sclerosing cholangitis is a rare specific disease that occurs in patients with chronic ulcerative colitis. Its cause is unknown, but immunologic injury is thought to be involved. The large bile ducts both within and outside the liver undergo irregular fibrosis with narrowing, leading to obstructive jaundice. Sclerosing cholangitis is difficult to distinguish from bile duct carcinoma.

Fibrous strictures of the biliary system, both intrahepatic and extrahepatic, occur in Clonorchis sinensis infection. Multiple strictures of the bile duct are associated with irregular dilation of the biliary system and the presence of numerous pigment stones and sludge containing parasites and ova.

Benign Neoplasms

Benign neoplasms are rare in the biliary system. Papillary adenoma, which may occur at the ampulla of Vater or in the gallbladder, is the most common type. It presents as a polyp.

The biliary tract is a site in which granular cell tumors occur. Granular cell tumors are believed to be variants of schwannomas and are composed of large cells containing an abundance of granular cytoplasm. Although rare, these neoplasms are important because they cause stenosis of the common bile duct and resemble bile duct carcinoma.

Carcinoma of the Gallbladder

Carcinomas of the gallbladder and biliary tree are relatively uncommon—less than 1% of causes of cancer in the United States. Gallbladder carcinoma is much more common in women, following the sex distribution of gallstones (80% of gallbladder carcinomas are associated with gallstones), and occurs with high frequency among Native Americans and persons of Central and South American origin. Chronic cholecystitis with extensive calcification of the wall (porcelain gallbladder) is associated with a 25% incidence of carcinoma.

Grossly, gallbladder carcinoma presents as a polypoid mass that projects into the lumen, with infiltration of the wall (Figure 44-5). In some cases, the infiltrative component dominates, producing thickening of the wall. Histologically, it is an adenocarcinoma of variable differentiation frequently associated with marked fibrosis and a tendency to perineural invasion.

Most cases of gallbladder carcinoma are found in patients being evaluated for gallstones. In advanced disease, there is weight loss, a palpable mass, or evidence of metastases. The prognosis depends on the stage. Tumors confined to the gallbladder have a good prognosis. When there is extension through the wall of the gallbladder into the liver or peritoneum with or without evidence of metastatic disease, the 5-year survival rate is close to zero.

Carcinoma of the Bile Ducts

Although uncommon, bile duct carcinoma represents an important cause of obstructive jaundice in adults. Tumors may involve the hepatic ducts at the hilum of the liver (Klatskin tumor) or the common bile duct, most commonly at its terminal portion (at the ampulla of Vater; Figure 44-6).

Bile duct carcinoma tends to cause obstructive jaundice at an early stage. Histologically, these tumors are usually well differentiated and associated with marked sclerosis.

Bile duct carcinoma grows slowly, with local extension along the biliary system and neighboring structures. Lymph node involvement is early, but bloodstream metastasis usually occurs late. The ultimate prognosis is poor, although many patients have a long survival.

The pancreas is situated retroperitoneally in the upper abdomen. It is divided into the head, which lies in the curve of the duodenum; the body, which is situated horizontally in the upper retroperitoneum; and the tail, which extends leftward to the hilum of the spleen.

The pancreas has two functional components: exocrine and endocrine.

1.  The exocrine pancreas contains acini that secrete a variety of enzymes into the pancreatic ducts. The main pancreatic duct opens at the duodenal papilla and in 70% of patients joins with the terminal common bile duct at the ampulla of Vater. An accessory (minor) pancreatic duct usually opens independently into the duodenum proximal to the papilla.

2.  The endocrine pancreas is composed of the islets of Langerhans, distributed throughout the pancreas with a maximum density in the tail and containing several different hormone-producing cell types (Chapter 46: The Endocrine Pancreas (Islets of Langerhans)).

Pain

Acute or chronic inflammation of the pancreas is associated with pain, often severe and constant, situated deep in the epigastric region and frequently radiating to the back.

Failure of Exocrine Secretion

Failure of exocrine pancreatic function leads to maldigestion of fat (lack of lipase), which results in steatorrhea. Lack of pancreatic proteolytic enzymes, although important in protein digestion, can be compensated for by gastric and intestinal proteases.

Changes in Pancreatic Hormone Production

See Chapter 46: The Endocrine Pancreas (Islets of Langerhans).

Assessment of Structure

The pancreas is not easily evaluated clinically because it becomes palpable only when it contains a large mass. Plain abdominal x-ray is useful for demonstration of pancreatic calcification, which is a feature of chronic pancreatitis. Ultrasonography and computerized tomography permit visualization of the pancreas and detection of mass lesions. It is also possible to cannulate the pancreatic duct via an endoscope in the duodenum and inject dye to permit evaluation of the duct system (endoscopic retrograde cholangiopancreatography (ERCP)).

Percutaneous fine-needle aspiration biopsy under radiologic control is a safe method of obtaining cytologic material for diagnosis of mass lesions of the pancreas.

Assessment of Function

Elevated serum levels of amylase and lipase provide evidence of necrosis of pancreatic cells, as in acute pancreatitis. It is more difficult to test the adequacy of secretion of enzymes by the pancreas into the duodenum, and failure of exocrine secretion is usually deduced by the occurrence of maldigestion (steatorrhea). Assays for hormones secreted by the pancreatic islets are useful in diseases of the endocrine pancreas.

Ectopic Pancreatic Tissue

Ectopic pancreatic tissue is present in about 2% of persons, usually discovered as an incidental finding at autopsy. In descending order of frequency, ectopic pancreas is found in the stomach, duodenum, jejunum, and Meckel's diverticula. Because ectopic pancreatic tissue is a developmental mass composed of disorganized pancreatic acini, ducts, and muscle that do not belong in these locations, the term choristoma may be used.

Maldevelopment of the Pancreas

Pancreatic developmental abnormalities are uncommon. The most important is a rare malformation of the head of the pancreas, which results in a complete collar of pancreatic tissue around the second part of the duodenum (annular pancreas); this may result in duodenal constriction and obstruction.

Cystic Fibrosis (Mucoviscidosis; Fibrocystic Disease)

Cystic fibrosis is a common congenital disease that is inherited as an autosomal recessive trait and affects one in 2000 Caucasian infants. It is rare in blacks and Asians. The genetic defect of cystic fibrosis is a three-base deletion removing phenylalanine 508 from the 1480-amino-acid coding region in the long arm of chromosome 7. The mutation is present in 75% of cases. About 2–5% of the population of the United States are heterozygous carriers of the abnormal gene.

The disease is characterized by abnormally viscous secretion of exocrine glands throughout the body. The basic defect is an impermeability of epithelial cell membrane to chloride ions. The cystic fibrosis allele codes for a membrane-associated protein that serves as a chloride channel. This defect results in (1) increased salt content of sweat and (2) decreased water content of respiratory, intestinal, and pancreatic exocrine secretion, leading to increased viscosity.

The pathologic changes in cystic fibrosis are the result of obstruction of ducts of exocrine glands by the viscid mucus (hence the alternative name mucoviscidosis) (Figure 45-1). Pancreatic abnormalities are present in 80% of patients. Pancreatic ducts are plugged with mucus, leading to chronic inflammation, with atrophy of acini, fibrosis, and dilation of ducts (hence the term fibrocystic disease). Lack of pancreatic lipase in the intestine causes maldigestion of fat, leading to steatorrhea.

Pulmonary changes (see Chapter 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases) are the most serious manifestation of cystic fibrosis. Bronchial mucus plugs lead to collapse of the lung, recurrent infections—including lung abscess—and ultimately fibrosis and bronchiectasis.

Increased amounts of viscid intestinal mucus in the lumen may result in intestinal obstruction in the neonatal period (meconium ileus). Bile duct obstruction may result in jaundice; changes in the vas deferens and seminal vesicles may cause infertility in the male.

The diagnosis is established by determination of electrolyte levels in sweat. A sweat sodium level in excess of 60 meq/L is diagnostic in a patient with clinical features of cystic fibrosis.

Most patients with cystic fibrosis die of pulmonary complications. Twenty years ago, survival beyond infancy was unusual; today, most individuals survive to adulthood, although life expectancy is still much less than normal. Detection of heterozygous carriers of the cystic fibrosis allele is now possible.

Acute Pancreatitis

Acute pancreatitis is a clinical syndrome resulting from the escape of activated pancreatic digestive enzymes from the duct system into the parenchyma. It is associated with extensive destruction of pancreatic and peripancreatic tissue and acute inflammation.

Acute pancreatitis is a common and important medical emergency, accounting for about one in every 500 admissions to general hospital emergency rooms.

Etiology

In about 25% of cases of acute pancreatitis, no etiologic factor can be identified. Infectious agents are usually not involved, although mild nonnecrotizing acute pancreatitis occurs in association with some viral diseases—commonly mumps and cytomegalovirus infection.

Factors associated with acute pancreatitis are shown in Figure 45-2 and discussed briefly below.

Biliary Tract Calculi

Biliary tract calculi are present in about 50% of cases and may obstruct the terminal bile duct. Reflux of bile or infected duodenal contents into the pancreatic duct has been suggested as a mechanism leading to pancreatitis in bile duct disease. Obstruction of the pancreatic duct may occur when a calculus becomes lodged in the ampulla of Vater. Acute pancreatitis complicating gallstones is chiefly a disorder of women because of the female preponderance of gallstone disease.

Alcoholism

Alcoholism as a cause of acute pancreatitis occurs with varying frequency in different parts of the world. It is common in the United States, being involved in 65% of cases of acute pancreatitis; in Europe, the incidence is 5–20%. Acute pancreatitis commonly occurs after a bout of heavy drinking. A direct toxic effect of alcohol on pancreatic acinar cells has been postulated.

Hypercalcemia

Hypercalcemia, as occurs in primary hyperparathyroidism, is complicated by acute pancreatitis in about 10% of cases. A high plasma calcium concentration is thought to stimulate activation of trypsinogen in the pancreatic duct.

Hyperlipidemias

The hyperlipidemias—particularly those types associated with increased plasma levels of chylomicrons—are complicated by acute pancreatitis. It is postulated that free fatty acids liberated by the action of pancreatic lipase produce acinar injury.

Shock and Hypothermia

In shock and hypothermia, decreased perfusion of the pancreas may lead to cellular degeneration, release of pancreatic enzymes, and acute pancreatitis.

Drugs and Radiation

Thiazide diuretics, corticosteroids, anticancer agents, and other drugs may also cause acute pancreatitis. Radiation to the retroperitoneum for treatment of malignant neoplasms is an uncommon cause of acute pancreatitis.

Pathogenesis

The pathologic changes in acute pancreatitis are the result of the action of pancreatic enzymes on the pancreas and surrounding tissues (Figure 45-3). Trypsin and chymotrypsin activate phospholipase and elastase as well as kinins, complement, the coagulation cascade, and plasmin, leading to acute inflammation, thrombosis, and hemorrhage. Elastase contributes to vascular injury. Phospholipases act on cell membranes, causing cell injury. Pancreatic lipase acts on surrounding adipose tissue, causing enzymatic fat necrosis (see Chapter 1: Cell Degeneration & Necrosis).

In addition to a local action, pancreatic enzymes enter the bloodstream. Circulating amylase does not contribute to cell injury; however, phospholipases are thought to contribute to the production of adult respiratory distress syndrome by interfering with the normal function of pulmonary surfactant. Rarely, high serum lipase levels are associated with fat necrosis at sites distant from the pancreas.

Pathology

Acute pancreatitis is characterized by widespread necrosis in tissues subjected to the effect of extravasated pancreatic enzymes. Necrosis of pancreatic parenchyma is initially coagulative but the necrotic cells rapidly undergo liquefaction. Vascular necrosis and disruption result in hemorrhage. Fat necrosis appears as chalky white foci that may be calcified, usually in and around the pancreas, omentum, and mesentery (Figure 45-3). Rarely, fat necrosis extends down the retroperitoneum and into the mediastinum. In severe cases, massive liquefactive necrosis of the pancreas occurs, resulting in a pancreatic abscess.

In very severe cases, death may occur before an adequate inflammatory response can be mobilized. Neutrophils predominate when the inflammation becomes established.

The peritoneal cavity sometimes contains a brownish serous fluid (pancreatic ascites). This fluid contains altered blood, fat globules (“chicken broth”), and very high levels of amylase.

Clinical Features

Acute pancreatitis usually presents as a medical emergency. Patients develop severe constant epigastric pain, frequently referred to the back, accompanied by vomiting and shock. Shock is caused by peripheral circulatory failure resulting from hemorrhage and the entry of kinins into the bloodstream (Figure 45-2). Mild jaundice may be present. In severe pancreatitis, there is discoloration due to hemorrhage in the subcutaneous tissue around the umbilicus (Cullen's sign) and in the flanks (Turner's sign). Activation of the plasma coagulation cascade may lead to disseminated intravascular coagulation.

Laboratory Studies

There is an almost immediate (within hours) elevation of the serum amylase, often to 10–20 times the normal upper level; amylase levels return to normal in 2–3 days. Serum lipase is increased later, usually after 72 hours. Hypocalcemia is present in severe cases and is a bad prognostic sign. Transient glycosuria is present in the acute stage in about 10% of cases as a result of islet dysfunction. Permanent diabetes mellitus almost never follows a single attack of acute pancreatitis.

Complications

Most patients recover from the acute attack with proper supportive care, and the pancreas regenerates and returns almost to normal, with mild residual scarring. In severe cases, death may occur in the acute phase as a consequence of pancreatic abscess, severe hemorrhage, shock, disseminated intravascular coagulation, or respiratory distress syndrome.

Pancreatic pseudocyst (see below) may follow weeks to months after recovery from an acute attack.

Chronic Pancreatitis

Chronic pancreatitis is a chronic disease characterized by progressive destruction of the parenchyma with chronic inflammation, fibrosis, stenosis and dilation of the duct system, and eventually impairment of pancreatic function.

Etiology

Chronic alcoholism and biliary tract calculi are the two main conditions that are associated with chronic pancreatitis. In the United States, alcoholism is believed to be implicated in about 40% of cases and biliary tract disease in 20%. In 30–40% of cases, no etiologic factors are identified. Some cases follow recurrent acute episodes; cystic fibrosis is a specific type of chronic pancreatitis described earlier.

Pathology

(Figure 45-4)

Chronic pancreatitis is characterized by shrinkage of the pancreas as a result of fibrosis and atrophy of acinar structures. The changes usually involve the gland diffusely; more rarely, a firm, localized mass forms that is difficult to distinguish grossly from carcinoma.

The pancreatic ducts show multiple areas of stenosis with irregular dilation distally. Ducts are filled with inspissated secretions that may undergo calcification to form calculi (Figure 45-5). Diffuse calcification imparts a rock-hard consistency to the gland.

Microscopically, there is acinar loss with marked fibrosis. At the end stage there are almost no recognizable acini, and the gland is composed of dilated ducts separated by collagen. Islets tend to withstand destruction better than acini. A variable lymphocytic infiltrate is present.

Clinical Features

Pain is the dominant symptom. It may be constant or intermittent and can be so severe as to lead to narcotic dependence. In many cases, pain is associated with acute exacerbations, and the patients are asymptomatic between relapses. When pain is caused by dilation of the duct system, surgical correction by draining the dilated duct system may provide relief.

Pancreatic exocrine insufficiency due to failure of secretion of pancreatic juice leads to steatorrhea, malabsorption of fat-soluble vitamins, and weight loss. Endocrine insufficiency (diabetes mellitus) occurs in about 30% of cases.

The course is variable. Many patients have recurrent attacks of severe pain, vomiting, and elevation of serum amylase, due probably to repeated acute episodes (chronic relapsing pancreatitis). Acute attacks may be followed by formation of pancreatic pseudocysts (see below).

In about 5% of patients with severe sclerosing chronic pancreatitis affecting the head of the pancreas, obstruction of the common bile duct leads to deep jaundice. This condition is difficult to differentiate from jaundice due to pancreatic carcinoma.

The diagnosis of chronic pancreatitis is made on clinical grounds. There are no specific laboratory tests, but the presence of calcification on x-ray provides supportive evidence. In chronic disease, the amount of residual pancreatic tissue may be insufficient to cause elevation of serum amylase.

Treatment & Prognosis

Treatment of chronic pancreatitis consists of management of the pain, malabsorption, and diabetes. When pain cannot be controlled by drugs, surgery to drain the pancreatic duct (by creating an opening between the duct and a loop of jejunum, ie, pancreaticojejunostomy) often has good results. Malabsorption and diabetes mellitus can be controlled by dietary supplements and insulin if necessary. The complications of diabetes mellitus represent the main threat to life.

A variety of lesions enter into the differential diagnosis of pancreatic cysts revealed by computerized tomography.

Pancreatic Pseudocyst

Pancreatic pseudocyst is the most common type of cyst found in the pancreas. A pseudocyst is usually a solitary fluid-filled unilocular structure of variable size lined by a wall composed of collagen and inflamed granulation tissue. It is called a pseudocyst because it does not have an epithelial lining. Pseudocysts usually occur after an attack of acute necrotizing pancreatitis or during chronic relapsing pancreatitis and probably represent the end result of hemorrhagic necrosis, with the liquefied material walled off by granulation tissue and fibrosis. They contain brownish serous fluid composed of pancreatic juice with a high enzyme content and altered blood. Most pseudocysts occur in and around the pancreas; rarely, when pancreatic enzyme leakage produces necrosis away from the pancreas, pseudocysts may occur at a considerable distance from the pancreas (eg, in the right iliac fossa).

Patients with pseudocysts present with an abdominal mass, and most give a history of abdominal pain suggestive of acute or chronic pancreatitis. Other patients give only a history of alcoholism.

Treatment consists of establishing surgical drainage of the cyst either into the stomach or into a loop of jejunum.

Complications of pancreatic pseudocyst include (1) acute rupture of the cyst into the intestine, most commonly the stomach and transverse colon, producing intestinal hemorrhage, which may be severe; (2) secondary infection, leading to the formation of an abscess; and (3) compression of the common bile duct, causing obstructive jaundice.

Congenital Cysts

Rarely, maldevelopment of parts of the pancreatic duct system produces multiple cysts ranging in size from very small to 5 cm in diameter. These are true cysts, lined by epithelium and filled with serous fluid.

Congenital pancreatic cysts are often associated with polycystic renal disease and congenital hepatic fibrosis. Congenital pancreatic cysts also occur in von Hippel-Lindau disease (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Neoplastic Cysts

Serous Cystadenoma

Serous cystadenoma is a rare solitary, benign cystic neoplasm of the pancreas. It may reach large size but rarely causes symptoms, and it is most commonly an incidental finding at abdominal surgery or radiography. It consists of multiple small locules lined by cuboidal epithelium, the cells of which contain abundant glycogen (also called microcystic, serous, and glycogen-rich cystadenoma). With very rare exceptions, it does not undergo malignant change.

Mucinous Cystadenoma & Cystadenocarcinoma

Mucinous cystic neoplasms are more common than serous cystadenoma. They are usually solitary, unilocular, and often very large. The cysts are lined by tall columnar epithelium and contain a glairy mucinous fluid. The malignant counterpart shows cytologic atypia, stratification of cells, and invasion of the capsule. Mucinous cystadenocarcinoma behaves like a slowly growing low-grade malignant neoplasm. The 5-year survival rate after complete surgical removal is about 70%.

Carcinoma of the pancreas is understood to involve the exocrine pancreas; islet cell neoplasms are classified separately.

Incidence & Etiology

Approximately 25,000 patients annually in the United States die from pancreatic carcinoma, accounting for 6% of cancer deaths; the incidence is slightly higher in men than in women and is increasing. Pancreatic carcinoma occurs mainly after age 50 years.

The etiology is unknown. There is a sixfold increased risk in diabetic women but not in diabetic men. A large number of dietary factors have been proposed, including decaffeinated coffee and high-fat diets. Cigarette smokers show a fivefold increase in incidence. Expression of the K-ras oncogene is present in many pancreatic carcinomas.

Pathology

(Figure 45-6)

Carcinomas occur throughout the pancreas: 70% in the head, 20% in the body, and 10% in the tail; 99% take origin from the ducts (ductal carcinoma; Figure 45-7) and the remainder from the acini (acinar cell carcinoma).

Grossly, pancreatic carcinoma presents as a hard infiltrative mass (Figure 45-8) that obstructs the pancreatic duct, frequently causing chronic pancreatitis in the distal gland. Carcinomas of the head tend to obstruct the common bile duct early in their course and present at a stage when the tumor is small. Tumors in the body and tail tend to present late and be very large. Pancreatic carcinoma frequently evokes marked fibrosis; it may distort the duodenal loop, producing a typical “inverted 3” appearance on barium x-ray studies.

Microscopically, over 90% of cases are well-differentiated adenocarcinomas, associated with marked fibrosis. Perineural invasion is common (Figure 45-9). The remaining 10% include adenosquamous carcinomas, anaplastic carcinomas—which contain spindle cells and pleomorphic giant cells (sarcomatoid and pleomorphic carcinomas)—and acinar cell carcinomas. Rarely, acinar cell carcinomas secrete lipase into the bloodstream and cause fat necrosis in the subcutaneous tissue and bone marrow throughout the body.

Spread

The tumor tends to infiltrate into surrounding structures. Spread along the perineural fascial spaces is a typical feature. Lymphatic involvement occurs early, with metastasis to regional lymph nodes. Bloodstream spread also occurs early, with the liver being the most common site of secondary deposits.

Clinical Features

Carcinoma of the head of the pancreas presents with common bile duct obstruction. (Courvoisier's law: Obstructive jaundice in the presence of a dilated gallbladder usually indicates carcinoma of the head of the pancreas.) Carcinoma of the body and tail presents at a late stage with an abdominal mass, severe weight loss, and anemia. A high proportion of patients present with evidence of metastatic disease, most often in the liver. Skin rashes and lytic bone lesions due to fat necrosis may be present in lipase-secreting acinar cell carcinomas.

Carcinoembryonic antigen levels in the serum are elevated in some cases; this is not a specific finding, as colon, lung, and other cancers may also show elevated levels. The presence of a more specific pancreatic oncofetal antigen has been reported recently in a high proportion of cases, but data are preliminary. Computerized tomography is effective in establishing the presence of a solid mass. Percutaneous fine-needle aspiration of the mass under radiologic guidance provides tissue for cytologic examination and is an excellent method of making the diagnosis.

A common paraneoplastic manifestation in patients with carcinoma of the pancreas is superficial thrombophlebitis in the leg veins (Trousseau's syndrome). Rarely, patients with pancreatic carcinoma develop disseminated intravascular coagulation, due probably to thromboplastic substances present in the mucinous product of the adenocarcinoma.

Treatment & Prognosis

Most pancreatic carcinomas are inoperable at presentation. Small carcinomas confined to the head of the pancreas may be cured by total pancreaticoduodenectomy (Whipple procedure). Chemotherapy and radiotherapy are ineffective. The prognosis is dismal: Mean survival is 6 months after diagnosis, and the overall 5-year survival rate is less than 5%.

The islets of Langerhans are microscopic structures 50–250 μm in diameter. They are scattered throughout the pancreas, with a maximum density in the tail. The islets appear to have a great reserve capacity; islet dysfunction is not a major problem even after 90% of the pancreas is removed in a distal pancreatectomy. The islets are not connected to the exocrine duct system; the hormonal products are secreted directly into the bloodstream.

Microscopically, the islets are composed of small uniform cells with round nuclei and scant cytoplasm. Routine microscopy does not permit differentiation of the various types of cells contained within the islets; this requires immunohistochemistry (Table 46-1 and Figure 46-1).

The most important hormone secreted by the pancreas is insulin. The B (beta) cells of the islets are the only source of insulin in the body, and failure of secretion of adequate amounts of insulin results in diabetes mellitus.

Glucagon, secreted by the A (alpha) cells, also plays a role in glucose metabolism. The role of glucagon is a less vital one, and absence of glucagon has not been shown to cause clinical disease. The physiologic functions of pancreatic polypeptide (PP) and vasoactive intestinal polypeptide (VIP) have not been elucidated, and the amount of somatostatin and gastrin normally secreted by the pancreatic islets is thought to be too small to be of any physiologic significance. However, excessive secretion of any of these hormones by pathologic islets causes specific clinical syndromes.

Assessment of islet structure is very difficult because of their small size and scattered distribution in the pancreas. Only large islet cell neoplasms are distinguishable on computerized tomography. The main tests of islet function are serum assays of the various hormones secreted by the islets.

Diabetes mellitus is a chronic disease characterized by relative or absolute deficiency of insulin, resulting in glucose intolerance. It occurs in 4–5 million persons in the United States (approximately 2% of the population).

Normal Insulin Metabolism

Insulin is a polypeptide composed of an A chain, with 21 amino acids, and a B chain, with 30 amino acids (Figure 46-2). It is released from the B cell by a variety of stimuli (Figure 46-2), the most important of which—from a physiologic standpoint—is glucose. Amino acids and drugs of the sulfonylurea group also stimulate insulin release. Insulin is transported in the plasma with the alpha and beta globulins; no specific transport protein has been identified.

Insulin release occurs in three phases: (1) Basal secretion is responsible for the fasting level of insulin in serum; (2) initial rapid secretion after a meal is due to release of stored insulin in the B cells within 10 minutes after eating; and (3) delayed release after meals is due to stimulation of insulin synthesis in response to ingested glucose.

Insulin interacts with target cells that have insulin receptors on their plasma membranes (Figure 46-3). Important target cells are liver, muscle, and fat, although receptors have been demonstrated in many other cells. The number of insulin receptors on individual cells is variable, and the affinity of the receptor to insulin also varies.

The binding of insulin to receptors triggers a chain of events in the cell that mediates the action of the hormone; it is believed that small peptides act as second messengers to activate insulin-dependent enzyme systems.

Metabolic Actions of Insulin

(Figure 46-3)

The major biochemical function of insulin is to regulate the transfer of glucose from the plasma into the cytoplasm of cells.

After a large meal, high insulin levels in the blood induce the tissues to take up and store glucose. Glycogenesis is stimulated in the liver and in skeletal muscle, and lipogenesis increases in adipose tissue. In this state, free glucose represents the major source of immediate energy for muscle cells.

In the fasting state, low levels of insulin result in mobilization of body stores to satisfy energy needs of the body. Glycogenolysis and proteolysis in liver and skeletal muscle provide glucose; lipolysis in adipose tissue produces free fatty acids, which enter the circulation and are metabolized to ketone bodies in the liver. The cells of the body, with the exception of brain cells, utilize fatty acids and ketone bodies for energy in states of low insulin secretion. Brain cells are dependent on a continuous supply of glucose for metabolic needs; in the fasting state, this is supplied mainly by gluconeogenesis from amino acids.

Etiology of Diabetes Mellitus

(Table 46-2)

Diabetes mellitus is caused by a relative or absolute deficiency of insulin. In primary diabetes (95% of cases), there is no underlying disease process that might explain insulin deficiency. Primary diabetes is of two types: I and II (see below and Table 46-3). The remaining 5% of cases of secondary diabetes are due either to pancreatic destruction or to the presence of increased levels of hormones that antagonize the action of insulin.

There is an absolute deficiency of insulin in type I primary diabetes and in those cases of secondary diabetes associated with destruction of the pancreas. In type II primary diabetes—and in the presence of increased levels of antagonistic hormones—the insulin deficiency is relative, and serum insulin levels are usually normal and may even be elevated.

Type I Diabetes Mellitus

Type I diabetes mellitus (insulin-dependent diabetes mellitus [IDDM]) is due to destruction of pancreatic B cells. Plasma insulin levels are very low, and ketoacidosis develops if the patients do not receive exogenous insulin. Rarely, in the early stage of type I diabetes, there may be enough insulin to prevent ketoacidosis, and the patients are not insulin-dependent (this is sometimes known as “type I diabetes in evolution”). The disease affects young patients (juvenile-onset diabetes mellitus), most commonly under 30 years of age, and there is a significant association with human leukocyte antigen (HLA)-B8, -B15, -DR3, and -DR4. The HLA-D locus is closely associated with genes that confer increased susceptibility to type I diabetes. Ninety-five percent of patients with type I diabetes express DR3, DR4, or the heterozygous DR3/DR4 state. Increased susceptibility has also been linked with (1) the absence of aspartic acid in position 57 of the DQβ chain and (2) the presence of the DQw8 allele. The genetic predisposition to type I diabetes is shown by the history of diabetes in about 20% of first-degree relatives—which is not as strong as in type II diabetes.

The cause of B cell destruction in type I diabetes is unknown. A few cases have followed viral infections, most commonly with coxsackievirus B or mumps virus, and several viruses have been shown to cause B cell damage when inoculated into mice. Despite these findings, the role of viruses in the etiology of human diabetes is thought to be that of an inciting factor for autoimmunity.

Autoimmunity is believed to be the major mechanism involved. Islet cell autoantibodies are present in the serum of 90% of newly diagnosed cases. Such antibodies are directed against several cell components, including cytoplasmic and membrane antigens or against insulin itself (IgG and IgE antibodies). Sensitized T lymphocytes with activity against B cells have also been demonstrated in some patients. Microscopic examination of the islets in patients with early type I diabetes shows the presence of a lymphocytic infiltrate in the islet (“insulitis”). One hypothesis is that a mild viral injury of B cells induces an autoimmune reaction against the injured cells. HLA-linked immune response genes may explain the genetic susceptibility; HLA-B8, -B15, -DR3, and -DR4, in addition to their association with diabetes, also occur at increased frequency in Graves' disease, Addison's disease, and pernicious anemia, all of which are characterized by the presence of autoantibodies.

Toxins such as nitrophenylureas (in rat poisons) and cyanide from spoiled food have been implicated in B cell destruction in rare cases.

Type II Diabetes Mellitus

The etiology of type II diabetes (non-insulin-dependent diabetes mellitus [NIDDM]) is even less clearly understood. Two factors have been identified.

Impaired Insulin Release

Basal secretion of insulin is often normal, but the rapid release of insulin that follows a meal is greatly impaired, resulting in failure of normal handling of a carbohydrate load. The delayed phase of insulin secretion is also normal in the early stages but impaired in advanced disease. However, some level of insulin secretion is maintained in most patients, so that the abnormality of glucose metabolism is limited, and ketoacidosis is uncommon. In these patients, insulin secretion can be stimulated by drugs such as sulfonylureas. Exogenous insulin is therefore not essential in treatment. Most patients with type II diabetes first develop disease in adult life (adult-onset diabetes). A subgroup of type II diabetes develops disease at a young age (maturity-onset diabetes of the young [MODY]). These patients have an autosomal dominant single-gene inheritance pattern.

It has been suggested that inheritance of a defective pattern of insulin secretion is responsible for the familial tendency of diabetes. The mechanism of inheritance is highly complex and probably involves multiple genes except in maturity-onset diabetes of the young. The genetic factor is very strong in type II diabetes, with a history of diabetes present in about 50% of first-degree relatives.

Insulin Resistance

A defect in the tissue response to insulin is believed to play a major role. This phenomenon is called insulin resistance and is caused by defective insulin receptors on the target cells.

Insulin resistance occurs in association with obesity and pregnancy. In normal individuals who become obese or pregnant, the B cells secrete increased amounts of insulin to compensate. Patients who have a genetic susceptibility to diabetes cannot compensate because of their inherent defect in insulin secretion. Thus, type II diabetes is frequently precipitated by obesity and pregnancy.

In a few patients with extreme insulin resistance, antibodies against the receptors have been demonstrated in the plasma. These antibodies are mostly of the IgG class and may act in a manner analogous to the action of antiacetylcholine-receptor antibodies in myasthenia gravis. Decreased numbers of insulin receptors, defective binding of insulin to receptors, and abnormalities in the series of cellular events that follow insulin binding have also been postulated as causes of insulin resistance.

Pathology

The pathologic changes in the pancreatic islets in diabetes mellitus are variable from one patient to another and are not specific for diabetes. In type I diabetes, there is frequently a lymphocytic infiltration of the islets in the early phase, followed by a decrease in the total number and size of the islets due to a progressive loss of B cells.

The changes in type II diabetes are often minimal in the early stages. In advanced disease, there may be fibrosis and amyloid deposition in the islets; in diabetes, the amyloid appears to consist in part of precipitated insulin. Similar changes in the islets are sometimes present in elderly nondiabetic patients and are not considered diagnostic for diabetes.

Clinical Features

The classic symptoms of diabetes mellitus result from abnormal glucose metabolism. The lack of insulin activity results in failure of transfer of glucose from the plasma into the cells (“starvation in the midst of plenty”). The body responds as if it were in the fasting state, with stimulation of glycogenolysis, gluconeogenesis, and lipolysis producing ketone bodies (Figure 46-4).

The glucose absorbed during a meal is not metabolized at the normal rate and therefore accumulates in the blood (hyperglycemia) to be excreted in the urine (glycosuria). Glucose in the urine causes osmotic diuresis, leading to increased urine production (polyuria). The fluid loss and hyperglycemia increase the osmolarity of the plasma, stimulating the thirst center (polydipsia). Stimulation of protein breakdown to provide amino acids for gluconeogenesis results in muscle wasting and weight loss. These classic symptoms occur only in patients with severe insulin deficiency, most commonly in type I diabetes.

Many patients with type II diabetes do not have these symptoms and present with one of the complications of diabetes (see below).

Diagnosis

The diagnosis of diabetes mellitus is most certain when there is fasting hyperglycemia. This is defined as a plasma glucose level of > 7.8 mmol/L (> 140 mg/dL) on at least two occasions following an overnight fast.

In mild cases, the patient may have a fasting plasma glucose in the normal range, with the abnormality restricted to deficient handling of a glucose load as assessed in the 75 g oral glucose tolerance test (Figure 46-5). Diabetes is diagnosed in this test if the plasma glucose is > 11.1 mmol/L (> 200 mg/dL) at 2 hours and > 11.1 mmol/L (> 200 mg/dL) on at least one other occasion during the 2-hour test. If the glucose tolerance test is negative, diabetes is excluded. The interpretation of a positive test must take into account the possibility that a false-positive test may result from epinephrine released by the stress associated with the test.

Patients who have a 2-hour plasma glucose concentration between 7.8 and 11.1 mmol/L (140–200 mg/dL) and one other value > 11.1 mmol.L (> 200 mg/dL) during the test are diagnosed as having impaired glucose tolerance. Ten to 25 percent of patients with impaired glucose tolerance will develop overt diabetes.

The presence of glycosuria is of no value in the initial diagnosis of diabetes because there are many causes of glycosuria other than diabetes.

All of the above tests provide information about the patient's glucose metabolism only at the time of the test. Estimation of glycosylated hemoglobin (HbA1c) levels in blood is used as a guide to the degree of control over a long period. The level of HbA1c is dependent on the serum glucose concentration and is increased in uncontrolled diabetes. HbA1c, once formed, remains in the erythrocyte for the 120-day life span of the cell; HbA1c levels thus provide an indication of blood glucose elevation in the previous 2–3 months. Normal HbA1c is around 4% of total hemoglobin.

Acute Complications

Diabetic Ketoacidosis

Ketoacidosis occurs in severe diabetes, where insulin levels are greatly reduced and glucagon levels are increased. It is common in untreated type I diabetes but rare in type II diabetes, where insulin levels, although functionally inadequate, are still sufficient to prevent ketone body formation.

In the absence of insulin, lipolysis is stimulated (Figure 46-4), releasing free fatty acids that are oxidized in the liver cell to form acetylcoenzyme A. The entry of acetyl-CoA into the citric acid cycle is defective in diabetes. As a result, acetyl-CoA is converted in the liver to acetoacetate, β-hydroxybutyrate, and acetone (collectively called ketone bodies). Glucagon excess is an important factor in the pathogenesis of ketoacidosis. While insulin lack mobilizes free fatty acids from adipose tissue, oxidation of fatty acids to ketones in the liver cell is induced by glucagon via its stimulatory effect on the hepatic carnitine-palmitoyltransferase system. Glucagon also stimulates gluconeogenesis, aggravating the hyperglycemia. The ketone bodies enter the blood (ketonemia, ketosis) and represent an important source of energy for skeletal muscle that cannot utilize glucose effectively in diabetes. They also spill over to be excreted in the urine (ketonuria).

Ketone bodies are moderately strong acids and cause a metabolic acidosis with decreased blood pH and low serum bicarbonate. Respiration is stimulated, washing out carbon dioxide and leading to a decrease in Pco2. An acid urine is excreted.

Clinically, patients present with altered consciousness as a result of general failure of energy production and acidosis. Coma occurs in severe cases. Marked volume depletion is usually present. The diagnosis is established by the presence of glycosuria, hyperglycemia, ketonemia, and ketonuria. Treatment requires aggressive fluid replacement, correction of electrolyte imbalance, and insulin therapy.

Hyperosmolar Nonketotic Coma

Patients who develop hyperosmolar coma are usually elderly, with severe uncontrolled diabetes. The disorder results from extremely high serum glucose levels that cause osmotic diuresis and marked fluid depletion, increasing plasma osmolarity. Hyperosmolar coma is treated with aggressive fluid replacement and insulin. It is associated with a high mortality rate.

Hypoglycemic Coma

Hypoglycemic coma is not a direct complication of diabetes but rather a complication of therapy. In treating diabetes it is essential to balance the insulin dose and the dietary intake of carbohydrate (“glucose dose”). A fall in blood glucose may follow overdosage of insulin but is seen more often when the usual daily schedule of insulin injections is given and one or more meals is missed or lost by vomiting (ie, when the “glucose dose” is reduced).

Chronic Complications

(Table 46-4)

Diabetic Microangiopathy (Small Vessel Disease)

Microangiopathy is one of the most characteristic and most important pathologic changes in diabetes. It is characterized by diffuse thickening of the basement membranes of capillaries throughout the body. The kidney (Figure 46-6), retina, skin, and skeletal muscles are commonly involved. A similar change involves other basement membranes in renal tubules, placenta, and peripheral nerves. Basement membrane thickening in capillaries is associated with increased permeability to fluid and protein macromolecules.

The structure of the thick basement membrane in diabetics is abnormal. Increased amounts of collagen and laminin and decreased proteoglycans have been demonstrated. It has been suggested that prolonged elevation of serum glucose increases glycosylation of basement membrane proteins in a manner similar to glycosylation of hemoglobin. This would explain why strict control of diabetes decreases the incidence and severity of microangiopathy. It is widely accepted—although not proved—that tight control of diabetes decreases the risk of microangiopathy.

Large Vessel Disease

Diabetes mellitus is a major risk factor for development of atherosclerotic vascular disease; myocardial infarction and cerebral arterial occlusion (stroke) represent two of the most common causes of death in diabetics. The increased incidence of hyperlipidemia (both hypertriglyceridemia and hypercholesterolemia) in diabetes contributes to the development of atherosclerosis.

Neuropathy and Cataract

Neuropathy and cataract in diabetic patients are believed to result from accumulation of sorbitol within nerve or lens tissue. The enzyme aldose reductase produces sorbitol in these tissues when glucose levels are high, and the accumulated sorbitol, which is osmotically active and nondiffusible, produces cellular swelling or death. It is postulated that nerve and lens tissue (and perhaps small vessels and kidney) may be particularly vulnerable to this effect because glucose can enter these cells even in low-insulin states—unlike other cells of the body, which require normal plasma levels of insulin for entry of glucose. Trials of drugs that inhibit aldose reductase are under way as a possible means of combating some of the chronic effects of diabetes.

Other Complications

Other complications include a general increased susceptibility to infection (Chapter 7: Deficiencies of the Host Response) and impaired wound healing (Chapter 6: Healing & Repair). Chronic foot ulcers are a common and difficult problem.

Clinical Course

The average life expectancy of diabetics is reduced by 9 years for males and 7 years for females when compared with nondiabetics. The reduction is greatest when the onset of disease is at a young age.

Quality of life is seriously affected for all diabetics because of the many disabling complications. In addition, the requirement for strict dietary control and continuous drug treatment for many patients calls for a continuous emotional struggle.

Causes of death in diabetes (in order of frequency) are myocardial infarction, renal failure, cerebrovascular accidents, infections, ketoacidosis, hyperosmolar coma, and hypoglycemia.

Treatment

Type I diabetics require insulin treatment for life. Oral agents that act by stimulating the B cells are not effective in these patients because of their B cell-depleted state. Type II diabetics can be managed with measures to decrease insulin resistance, such as decreasing body weight by diet, and by stimulation of the pancreatic B cells with oral antidiabetic agents such as sulfonylureas. In many type II diabetics, insulin is also necessary for good control. An essential component of treatment is ensuring good control by repeated examinations of blood and urine for glucose. Serum HbA1c levels are useful for checking longer term control.

In animals, transplantation of pancreatic islets has resulted in a cure of experimental diabetes, but this method of treatment is not yet routinely available for treatment of humans.

Excess secretion (Figure 46-7) of any one or several of the hormones of the islets of Langerhans may be caused by islet cell neoplasms or hyperplasia.

Islet Cell Neoplasms

Adenomas derived from the islet cells are relatively common. In 10–15% of cases, multiple adenomas are present. Islet cell carcinomas occur, but less frequently.

Grossly, islet cell neoplasms are firm nodules that typically have a yellowish-brown color. They vary in size from microscopic (microadenomas) to large masses that may weigh several kilograms. They may or may not show encapsulation.

Microscopically, islet cell neoplasms are composed of uniform small cells arranged in nests and trabeculae separated by endothelium-lined vascular spaces. The islet cell origin of a pancreatic neoplasm can be established (1) by the presence of membrane-bound, electron-dense neurosecretory granules in the cytoplasm on electron microscopy; and (2) by positive staining for neuron-specific enolase, chromogranin, or specific hormones by immunoperoxidase techniques.

Differentiation of adenomas from carcinomas of islet cells is difficult by light microscopic examination. Invasion of the capsule and cytologic atypia are common in neoplasms that show benign behavior and cannot be used as evidence of malignant change. Conversely, islet cell carcinomas may be well circumscribed and have little cytologic atypia. Features that favor a diagnosis of carcinoma are extensive invasion of the pancreatic stroma or peripancreatic tissue, venous involvement, and perineural invasion. The only definite evidence of malignancy is the presence of metastatic lesions.

Islet cell adenomas are cured by surgical excision; carcinomas tend to grow slowly but are difficult to control if surgery fails. Even in the presence of metastatic disease, patients may survive several years because of the slow growth rate of islet cell carcinoma.

Most islet cell neoplasms are composed of one cell type; less commonly, multiple cell types are involved. The diagnosis of the cell type is impossible by routine light microscopy and requires (1) electron microscopy, which demonstrates characteristic granules of the different cells; (2) serum assay for the different pancreatic hormones; and (3) demonstration of hormone in the tumor cells by immunoperoxidase techniques. Some islet cell neoplasms do not produce sufficient hormone to be detectable in serum (nonfunctional islet cell neoplasms).

Islet Cell Hyperplasia

Diffuse hyperplasia of the islets is a rare cause of hypersecretion of pancreatic hormones, and there is some doubt about whether it is a real entity. Islet cell hyperplasia is characterized by the presence of islets in the size range 300–700 μm. Islets measuring less than 300 μm are normal; those above 700 μm are microadenomas. Microscopically, hyperplastic islets resemble normal islets; immunohistochemical studies sometimes show a dominance of one cell type.

In adults, the most common situation in which hyperplastic islets are found is in the pancreas adjacent to an islet cell neoplasm. The finding of hyperplastic islets in a surgically removed pancreas should therefore lead to a careful search for an adenoma in the remaining pancreas. Marked islet cell hyperplasia (of insulin-producing B cells) is also seen in fetuses born of diabetic mothers as a fetal response to the high glucose environment.

Clinical Features of Pancreatic Hormone Excess

The clinical features of hypersecretion of the islets depend on which hormone is secreted in excess and to what degree. In most cases, hypersecretion is restricted to one hormone; rarely, two or more hormones are involved.

Hyperinsulinism

The most common clinical syndrome associated with hyperfunctioning islets is hyperinsulinism. Seventy percent of cases are caused by solitary B cell adenomas (insulinomas); 10% by multiple adenomas; 10% by carcinomas; and 10% by islet cell hyperplasia.

Increased insulin secretion is characterized (1) by hypoglycemia, precipitated by fasting or exercise and causing dizziness, confusion, and excessive sweating which, if sustained, are followed by convulsions, coma, and death; (2) by prompt relief of symptoms after glucose administration; and (3) by a plasma glucose level under 40 mg/dL during an attack. The fasting plasma glucose is also decreased to less than half of normal. This symptom complex is known as Whipple's triad.

The diagnosis is established by the finding of an inappropriately high serum insulin level during a period of hypoglycemia.

Glucagon Excess

Glucagon stimulates glycogenolysis and gluconeogenesis, serving to maintain glucose levels between meals. Hyperfunction of A cells is rare and caused by an islet cell neoplasm (glucagonoma), 70% of which are carcinomas and 30% adenomas. Two thirds of patients with carcinomas present with evidence of metastases, commonly in the liver.

Clinically, patients have mild diabetes mellitus due to the insulin antagonistic action of glucagon and a typical erythematous necrotizing migratory skin eruption. Alopecia, increased skin pigmentation, and glossitis are less common manifestations.

The diagnosis is made by finding an elevated serum glucagon level.

Gastrin Excess

Gastrin hypersecretion is second in frequency to hyperinsulinism among this group of diseases. It is usually caused by an islet cell neoplasm composed of G cells (gastrinoma), 70% of which are malignant. In 10% of cases, islet cell hyperplasia is present but no neoplasm is found in the pancreas. In 1% of cases, a microadenoma measuring about 1 mm in diameter is the cause. Gastrinomas rarely occur also in the duodenal and gastric wall.

Secretion of large amounts of gastrin leads to Zollinger-Ellison syndrome, characterized by continuous hypersecretion of gastric acid, causing a low pH of gastric juice. The resting acid secretion is greater than 60% of the maximum acid secretion in response to an injection of histamine or pentagastrin. Unrelenting, recurrent peptic ulcers occur in the stomach, duodenum, esophagus, and jejunum in 90% of patients. Severe diarrhea and hypokalemia—induced by the hyperacidity—are present in 30% of patients. Diarrhea may be associated with malabsorption of fat and steatorrhea due to inactivation of lipase by the low pH in the duodenum. Ten percent of patients with Zollinger-Ellison syndrome present with diarrhea and have no peptic ulcer disease. The gastric mucosal folds are commonly thickened.

The diagnosis of Zollinger-Ellison syndrome is made by demonstrating high serum gastrin levels. It can be distinguished from other causes of elevated serum gastrin by a paradoxic increase in gastrin levels in response to intravenous secretin and calcium injections.

Somatostatin Excess

D cell neoplasms of the pancreas (somatostatinomas) are very rare. Eighty percent are malignant. Clinically, mild diabetes mellitus resulting from impaired release of insulin is the most constant feature; diarrhea and gallstones also occur commonly.

Diagnosis by demonstration of an elevated serum level is difficult because of the short half-life of somatostatin.

Vasoactive Intestinal Polypeptide Excess

Excess secretion of vasoactive intestinal polypeptide (VIP) is rare and caused by a D1 cell neoplasm of the islets (VIPoma). Clinically, the polypeptide stimulates intestinal secretion by an unknown mechanism, causing watery diarrhea with hypokalemia and alkalosis (WDHA syndrome; Verner-Morrison syndrome). The diagnosis is established by demonstrating elevated VIP levels in the serum and in an extract of the tumor.

Pancreatic Polypeptide Excess

Pancreatic polypeptide (PP)-producing neoplasms are extremely rare. They may be present in patients with no clinical symptoms. Some patients have watery diarrhea and hypokalemia; others have peptic ulcer disease.