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and HCV infection, alcoholic cirrhosis, and food contaminants (e.g., aatoxins), is the fth most common cancer and third leading cause of cancer-related mortality worldwide. Cholangiocarcinoma occurs primarily in older persons with a history of chronic disorders of the bile ducts. Although primary tumors of the liver are relatively rare in developed countries of the world, the liver shares with the lung the distinction of being the most common site of metastatic tumors.
body of the pancreas lies beneath the stomach. The tail touches the spleen. The pancreas is virtually hidden because of its posterior position; unlike many other organs, it cannot be palpated. Because of the position of the pancreas and its large functional reserve, symptoms from conditions such as cancer of the pancreas do not usually appear until the disorder is far advanced. The pancreas is both an endocrine and exocrine organ. Its function as an endocrine organ is discussed in Chapter 33. The exocrine pancreas is made up of lobules that consist of acinar cells, which secrete digestive enzymes into a system of microscopic ducts. These ducts empty into the main pancreatic duct, which extends from left to right through the substance of the pancreas. The main pancreatic duct and the bile duct unite to form the hepatopancreatic ampulla, which empties into the duodenum. The sphincter of the pancreatic duct controls the ow of pancreatic secretions into the bile duct (see Fig. 30-16).
Gallbladder
Right and left hepatic ducts Common hepatic duct Spiral valve in cystic duct
Liver
Pylorus Pancreas
Cystic duct (Common) bile duct Accessory pancreatic duct Hepatopancreatic ampulla Duodenum Descending part of duodenum Bile duct Sphincter of bile duct
Main pancreatic duct Major duodenal papilla Sphincter of pancreatic duct Hepatopancreatic ampulla Pancreatic duct
FIGURE 30-16. (A) Extrahepatic bile passages, gallbladder, and pancreatic ducts. (B) Entry of bile duct and pancreatic duct into the hepatopancreatic ampulla, which opens into the duodenum.
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function; it is assumed to be a by-product of bile salt formation, and its presence is linked to the excretory function of bile. Normally insoluble in water, cholesterol is rendered soluble by the action of bile salts and lecithin, which combine with it to form micelles. In the gallbladder, water and electrolytes are absorbed from the liver bile, causing the bile to become more concentrated. Because neither lecithin nor bile salts are absorbed in the gallbladder, their concentration increases along with that of cholesterol; in this way, the solubility of cholesterol is maintained. Entrance of food into the intestine causes the gallbladder to contract and the sphincter of the bile duct to relax, such that bile stored in the gallbladder moves into the duodenum. The stimulus for gallbladder contraction is primarily hormonal. Products of food digestion, particularly lipids, stimulate the release of a gastrointestinal hormone called cholecystokinin from the mucosa of the duodenum. Cholecystokinin provides a strong stimulus for gallbladder contraction. The role of other gastrointestinal hormones in bile release is less clearly understood. Passage of bile into the intestine is regulated largely by the pressure in the common duct. Normally, the gallbladder regulates this pressure. It collects and stores bile as it relaxes and the pressure in the common bile duct decreases, and it empties bile into the intestine as the gallbladder contracts, producing an increase in common duct pressure. After gallbladder surgery, the pressure in the common duct changes, causing the common duct to dilate. The ow of bile then is regulated by the sphincters in the common duct. Two common disorders of the biliary system are cholelithiasis (i.e., gallstones) and inammation of the gallbladder (cholecystitis) or common bile duct (cholangitis). At least 10% of adults have gallstones.3,4 There is an increased prevalence with age, and approximately twice as many white women as men have gallstones.3 In both circumstances, hypersecretion of biliary cholesterol appears to play a major role.
FIGURE 30-17. Cholesterol gallstones. The gallbladder has been opened to reveal numerous yellow cholesterol gallstones. (From Rubin R., Rubin E. [2008]. The liver and biliary system. In Rubin R., Strayer D.S. [Eds.], Rubins pathology: Clinicopathologic foundations of medicine [5th ed., p. 668]. Philadelphia: Lippincott Williams & Wilkins.)
Cholelithiasis
Cholelithiasis or gallstones is caused by precipitation of substances contained in bile, mainly cholesterol and bilirubin. Approximately 80% of gallstones are composed primarily of cholesterol; the other 20% are black or brown pigment stones consisting of calcium salts with bilirubin.3 Pigment stones containing bilirubin are seen in persons with hemolytic disease (e.g., sickle cell disease) and hepatic cirrhosis. Many stones have a mixed composition. Figure 30-17 shows a gallbladder with numerous cholesterol gallstones. Three factors contribute to the formation of gallstones: abnormalities in the composition of bile, stasis of bile, and inammation of the gallbladder.3,4 The formation of cholesterol stones is associated with obesity and occurs more frequently in women, especially women who have had multiple pregnancies or who are taking oral contraceptives. All of these factors cause the liver to excrete more cholesterol into the bile. Estrogen reduces the synthesis of bile acid in women. Gallbladder sludge
(thickened gallbladder mucoprotein with tiny trapped cholesterol crystals) is thought to be a precursor of gallstones. Sludge frequently occurs with pregnancy, starvation, and rapid weight loss. Drugs that lower serum cholesterol levels, such as clobrate, also cause increased cholesterol excretion into the bile. Malabsorption disorders stemming from ileal disease or intestinal bypass surgery tend to interfere with the absorption of bile salts, which are needed to maintain the solubility of cholesterol. Inammation of the gallbladder alters the absorptive characteristics of the mucosal layer, allowing excessive absorption of water and bile salts. Cholesterol gallstones are extremely common among Native Americans, which suggests that a genetic component may have a role in gallstone formation. Many persons with gallstones have no symptoms. Gallstones cause symptoms when they obstruct bile ow.47,48 Small stones (i.e., 8 mm in diameter) pass into the common duct, producing symptoms of indigestion and biliary colic. Larger stones are more likely to obstruct ow and cause jaundice. The pain of biliary colic is usually located in the upper right quadrant or epigastric area and may be referred to the upper back, right shoulder, or midscapular region. Typically the pain is abrupt in onset, increases steadily in intensity, persists for 2 to 8 hours, and is followed by soreness in the upper right quadrant.
Acute Cholecystitis
Acute cholecystitis is a diffuse inammation of the gallbladder, usually secondary to obstruction of the gallbladder outlet. Most cases of acute cholecystitis (85% to
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90%) are associated with the presence of gallstones (calculous cholecystitis).3,4,4850 The remaining cases (acalculous cholecystitis) are associated with sepsis, severe trauma, or infection of the gallbladder. Acute acalculous cholecystitis, which involves ischemic rather than inammatory changes associated with stones, can rapidly progress to gangrene and perforation.48 Acute calculous cholecystitis occurs when a stone becomes impacted in the cystic duct and inammation develops behind the obstruction. It has been theorized that obstruction of the cystic duct leads to the release of mucosal phospholipase from the epithelium of the gallbladder. These lipases, in turn, lead to disruption of the normal glycoprotein mucous layer, exposing the mucosal epithelium to the destructive action of concentrated bile salts.3,4 Acute acalculous cholecystitis is thought to result from ischemia. The cystic artery is an end artery with essentially no collateral circulation.3 Contributing factors may include inammation and edema of the gallbladder wall, stasis of bile, and conditions that lead to cystic duct obstruction in the absence of frank stone formation. Risk factors for acute acalculous cholecystitis include sepsis with hypotension and multisystem organ failure, immunosuppression, major trauma and burns, diabetes mellitus, and infections.3,48 Persons with acute cholecystitis usually experience an acute onset of upper right quadrant or epigastric pain, frequently associated with mild fever, anorexia, nausea, vomiting.4850 Whereas in biliary colic the cystic duct obstruction is transient, in acute cholecystitis it is persistent. Persons with calculous cholecystitis usually, but not always, have experienced previous episodes of biliary pain. The pain may appear with remarkable suddenness and constitute a surgical emergency. In the absence of medical attention, the attack usually subsides in 7 to 10 days and frequently within 24 hours. In persons who recover, recurrence is common. The onset of acalculous cholecystitis tends to be more insidious because the manifestations are obscured by the underlying conditions precipitating the attack. In the severely ill patient, early recognition is crucial because a delay in treatment can prove life-threatening. Persons with acute cholecystitis usually have an elevated white blood cell count and many have mild elevations in AST, ALT, alkaline phosphatase, and bilirubin.
gallbladder, which in chronic cholecystitis usually contains stones, may be enlarged, shrunken, or of normal size.
Chronic Cholecystitis
Chronic cholecystitis results from repeated episodes of acute cholecystitis or chronic irritation of the gallbladder by stones.3,4 It is characterized by varying degrees of chronic inammation. Gallstones almost always are present. Cholelithiasis with chronic cholecystitis may be associated with acute exacerbations of gallbladder inammation, common duct stones, pancreatitis, and, rarely, carcinoma of the gallbladder. The manifestations of chronic cholecystitis are more vague than those of acute cholecystitis. There may be intolerance to fatty foods, belching, and other indications of discomfort. Often, there are episodes of colicky pain with obstruction of biliary ow caused by gallstones. The
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Ultrasonography, CT scans, and radionuclide imaging may be used to demonstrate dilation of bile ducts and impaired blood ow. Endoscopic ultrasonography and magnetic resonance cholangiography are used for detecting common duct stones. Both percutaneous transhepatic cholangiography (PTC) and endoscopic retrograde cholangiopancreatography (ERCP) provide a direct means for determining the cause, location, and extent of obstruction. PTC involves the injection of dye directly into the biliary tree. It requires the insertion of a thin, exible needle through a small incision in the skin with advancement into the biliary tree. ERCP involves the passage of an endoscope into the duodenum and the passage of a catheter into the hepatopancreatic ampulla. ERCP can be used to enlarge the opening of the sphincter of the bile duct, which may allow the lodged stone to pass, or an instrument may be inserted into the bile duct to remove the stone. Common duct stones in persons with cholelithiasis usually are treated by stone extraction followed by laparoscopic cholecystectomy. Antibiotic therapy, with an agent that enters the bile, is used to treat the infection. Emergency decompression of the common duct, usually by ERCP, may be necessary for persons who are septic or fail to improve with antibiotic treatment.
Acute Pancreatitis
Acute pancreatitis represents a reversible inammatory process of the pancreatic acini brought about by premature activation of pancreatic enzymes.5256 Although the disease process may be limited to pancreatic tissue, it also can involve peripancreatic tissues or those of more distant organs. The pathogenesis of acute pancreatitis involves the autodigestion of pancreatic tissue by inappropriately activated pancreatic enzymes. The process is thought to begin with the activation of trypsin. Once activated, trypsin can then activate a variety of digestive enzymes that cause pancreatic injury, resulting in an intense inflammatory response. The acute inflammatory response itself causes substantial tissue damage and may progress beyond the pancreas to produce a systemic inammatory response syndrome and multiorgan failure (see Chapter 20). Although a number of factors are associated with the development of acute pancreatitis, most cases result from gallstones (stones in the common duct) or alcohol abuse.5255 In the case of biliary tract obstruction due to gallstones, pancreatic duct obstruction or biliary reux is believed to activate the enzymes in the pancreatic duct system. The precise mechanisms whereby alcohol exerts its action are largely unknown. Alcohol is known to be a potent stimulator of pancreatic secretions, and it also is known to cause partial obstruction of the sphincter of the pancreatic duct. Acute pancreatitis also is associated with hyperlipidemia, hypercalcemia, infections (particularly viral), abdominal and surgical trauma, and drugs such as thiazide diuretics. Clinical Features. The manifestations of acute pancreatitis can range from mild with minimal organ dysfunction to severe and life-threatening. Overall, about 20% of persons with acute pancreatitis have a severe course, and 10% to 30% of those with severe pancreatitis die.54,55 Abdominal pain is a cardinal manifestation of acute pancreatitis. The pain is usually located in the epigastric or periumbilical region and may radiate to the back, chest, or ank areas. Physical examination ndings are variable and include fever, tachycardia, hypotension, severe abdominal tenderness, respiratory distress, and abdominal distention. Recognized markers of severe disease include laboratory values that measure the inammatory response (e.g., C-reactive protein), scoring systems that assess inammation or organ failure, and ndings on imaging studies. Clinical ndings such as thirst, poor urine output, progressive tachycardia, tachypnea, hypoxemia, agitation, confusion, a rising hematocrit level, and lack of improvement in symptoms within the rst 48 hours are warning signs of impending severe disease. Complications include the systemic inammatory response, acute respiratory distress syndrome, acute tubular necrosis, and organ failure. An important disturbance related to acute pancreatitis is the loss of a large volume of uid into the retroperitoneal and peripancreatic spaces and the abdominal cavity. Signs of hypocalcemia may develop, probably as a result
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of the precipitation of serum calcium in the areas of fat necrosis. Serum amylase and serum lipase are the laboratory markers most commonly used to establish a diagnosis of acute pancreatitis. The serum lipase may remain elevated slightly longer than amylase. However, the level of elevation of the serum amylase or lipase does not correlate with the severity of the disorder. The white blood cell count may be increased, and hyperglycemia and an elevated serum bilirubin level may be present. Determination of the cause is important in guiding the immediate management and preventing recurrence. Abdominal ultrasonography is usually performed to assess for gallstones. CT scans and dynamic contrast-enhanced CT of the pancreas are used to detect necrosis and uid accumulation. Treatment measures depend on the severity of the disease. Persons who present with persistent or severe pain, vomiting, dehydration, or signs of impending severe acute pancreatitis require hospitalization. Treatment measures are directed at pain relief, putting the pancreas to rest by withholding oral foods and uids, and restoration of lost plasma volume. Meperidine rather than morphine usually is given for pain relief because it causes fewer spasms of the sphincter of the pancreatic duct. Gastric suction is instituted to treat distention of the bowel and prevent further stimulation of the secretion of pancreatic enzymes. Intravenous uids and electrolytes are administered to replace those lost from the circulation and to combat hypotension and shock. Intravenous colloid solutions are given to replace the uid that has become sequestered in the abdomen and retroperitoneal space. Complications. Sequelae in persons surviving an episode of severe acute pancreatitis include uid collections and infection.54 In 40% to 60% of persons with acute necrotizing pancreatitis, the necrotic debris becomes infected, usually by gram-negative organisms from the alimentary canal, further complicating the condition.52 Fluid collections with a high level of pancreatic enzymes are usually associated with pancreatic duct disruptions and may eventually form pseudocysts (a collection of pancreatic uid enclosed in a layer of inammatory tissue). A pseudocyst most often is connected to a pancreatic duct, so that it continues to increase in mass. The symptoms depend on its location; for example, jaundice may occur when a cyst develops near the head of the pancreas, close to the common duct. Pseudocysts may resolve or, if they persist, may require surgical intervention.
pancreatitis is long-term alcohol abuse. Less common causes are long-standing obstruction of the pancreatic duct by pseudocysts, calculi, or neoplasms; autoimmune chronic pancreatitis, which occurs in association with autoimmune disorders such as Sjgren syndrome, primary sclerosing cholangitis, and inammatory bowel disease; idiopathic chronic pancreatitis, associated with cystic brosis (discussed in Chapter 23); and hereditary pancreatitis, a rare autosomal dominant disorder that is associated with both acute and chronic pancreatitis. Clinical Features. Chronic pancreatitis is manifested in episodes that are similar, albeit of lesser severity, to those of acute pancreatitis. Patients have persistent, recurring episodes of epigastric and upper left quadrant pain; the attacks often are precipitated by alcohol abuse or overeating. Anorexia, nausea, vomiting, constipation, and atulence are common. Eventually the disease progresses to the extent that endocrine and exocrine pancreatic functions become decient. At this point, signs of diabetes mellitus and the malabsorption syndrome (e.g., weight loss, fatty stools [steatorrhea]) become apparent. Treatment consists of measures to treat coexisting biliary tract disease. A low-fat diet usually is prescribed. The signs of malabsorption may be treated with pancreatic enzymes. When diabetes is present, it is treated with insulin. Alcohol is forbidden because it frequently precipitates attacks. Because of the frequent episodes of pain, narcotic addiction is a potential problem in persons with chronic pancreatitis. Surgical intervention sometimes is needed to relieve the pain and usually focuses on relieving any obstruction that may be present.
Chronic Pancreatitis
Chronic pancreatitis is characterized by progressive and permanent destruction of the exocrine pancreas, brosis, and, in the later stages, destruction of the endocrine pancreas.3,4,57,58 Most factors that cause acute pancreatitis can also cause chronic pancreatitis. However, the chief distinction between the two conditions is the irreversibility of pancreatic function that is characteristic of chronic pancreatitis. By far the most common cause of chronic
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manifestations depend on the size and location of the tumor as well as its metastasis. Pain, jaundice, and weight loss constitute the classic presentation of the disease. The most common pain is a dull epigastric pain often accompanied by back pain, often worse in the supine position, and relieved by sitting forward. Although the tumor can arise anywhere in the pancreas, the most frequent site is the head (60%), followed by the body (10%) and tail (5%). The pancreas is diffusely involved in the remaining 25%.53 Because of the proximity of the pancreas to the common duct and the hepatopancreatic ampulla, cancer of the head of the pancreas tends to obstruct bile ow. Jaundice frequently is the presenting symptom of a person with cancer of the head of the pancreas, and it usually is accompanied by complaints of pain and pruritus. Cancer of the body of the pancreas usually impinges on the celiac ganglion, causing pain. The pain usually worsens with ingestion of food or assumption of the supine position. Cancer of the tail of the pancreas usually has metastasized before symptoms appear. Migratory thrombophlebitis (deep vein thrombosis) develops in about 10% of persons with pancreatic cancer, particularly when the tumor involves the body or tail of the pancreas.53 Thrombi develop in multiple veins, including the deep veins of the legs, the subclavian vein, the inferior and superior mesentery veins, and even the vena cava. It is not uncommon for the migratory thrombophlebitis to provide the rst evidence of pancreatic cancer, although it may present in other cancers as well. The mechanism responsible for the hypercoagulable state is largely unclear, but may relate to activation of clotting factors by proteases released from the tumor cells.53 Patient history, physical examination, and elevated serum bilirubin and alkaline phosphate levels may suggest the presence of pancreatic cancer but are not diagnostic.5961 The serum cancer antigen (CA) 19-9, a Lewis blood group antigen, may help conrm the diagnosis in symptomatic patients and may help predict prognosis and recurrence after resection. However, CA 19-9 lacks the sensitivity and specificity to screen asymptomatic patients effectively.60 Ultrasonography and CT scanning are the most frequently used diagnostic methods to conrm the disease. Intravenous and oral contrastenhanced spiral CT is the preferred method for imaging the pancreas. Percutaneous ne needle aspiration cytology of the pancreas has been one of the major advances in the diagnosis of pancreatic cancer. Unfortunately, the smaller and more curable tumors are most likely to be missed by this procedure. ERCP may be used for evaluation of persons with suspected pancreatic cancer and obstructive jaundice. Most cancers of the pancreas have metastasized at the time of diagnosis. Surgical resection of the tumor is done when the tumor is localized or as a palliative measure. Radiation therapy may be useful when the disease is localized but not resectable. The use of irradiation and chemotherapy for pancreatic cancer continues to be investigated. Pain control is one of the most important aspects in the management of persons with end-stage pancreatic cancer.
In summary, the biliary tract serves as a passageway for the delivery of bile from the liver to the intestine. This tract consists of the bile ducts and gallbladder. The most common causes of biliary tract disease are cholelithiasis and cholecystitis. Three factors contribute to the development of cholelithiasis: abnormalities in the composition of bile, stasis of bile, and inammation of the gallbladder. Cholelithiasis predisposes to obstruction of bile ow, causing biliary colic and acute or chronic cholecystitis. Cancer of the gallbladder, which has a poor 5-year survival rate, occurs in 2% of persons with biliary tract disease. The pancreas is an endocrine and exocrine organ. The exocrine pancreas produces digestive enzymes that are secreted in an inactive form and transported to the small intestine through the main pancreatic duct, which usually empties into the hepatopancreatic ampulla and then into the duodenum through the sphincter of the bile duct. The most common diseases of the exocrine pancreas are acute and chronic forms of pancreatitis and cancer. Acute and chronic pancreatitis are associated with biliary reux and chronic alcoholism. Acute pancreatitis is an inammatory condition of the pancreas due to inappropriate activation of pancreatic enzymes, with manifestations that can range from mild to severe and life-threatening. Chronic pancreatitis causes progressive destruction of the endocrine and exocrine pancreas. It is characterized by episodes of pain and epigastric distress that are similar to but less severe than those that occur with acute pancreatitis. Cancer of the pancreas is the fourth leading cause of cancer death in the United States. It usually is far advanced at the time of diagnosis, and the 5-year survival rate is 4% to 5%.
REVIEW EXERCISES
1. A 24-year-old woman reports to her health care professional with complaints of a yellow discoloration of her skin, loss of appetite, and a feeling of upper gastric discomfort. She denies use of intravenous drugs and has not received blood products. She cannot recall eating uncooked shellsh or drinking water that might have been contaminated. She has a daughter who attends day care. A. What tests could be done to conrm a diagnosis of hepatitis A? B. What is the most common mode of transmission for hepatitis A? It is suggested that the source might be through the day care center that her daughter attends. Explain. C. What methods could be used to protect other family members from getting the disease? 2. A 56-year-old man with a history of heavy alcohol consumption and a previous diagnosis of alcoholic cirrhosis and portal hypertension is admitted to the