Pancreatic Disease

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[edit] Pancreatic Disease

Norton J. Greenberger

[edit] ACUTE PANCREATITIS

[edit] Epidemiology and Etiology

The incidence of pancreatitis varies in different countries and depends on etiologic factors (e.g., alcohol, gallstones), metabolic factors, and drugs (Box 106-1). In the United States, acute pancreatitis is related to alcohol ingestion more often than to gallstones, whereas in England the opposite is true. Pancreatitis is classified as acute or chronic. An attack is defined as acute if the patient becomes asymptomatic after recovery, whereas with chronic pancreatitis the patient has persistent pain or insufficient exocrine or endocrine pancreatic function. Autopsy surveys in the United States indicate that the overall prevalence of acute pancreatitis is approximately 0.5%; the annual death rate is an estimated 1.5 per 100,000, or approximately 4000 cases per year.

[edit] Pathophysiology

Many causative factors exist in the pathogenesis of acute pancreatitis, but the mechanism by which the conditions trigger pancreatic inflammation have not been clearly elucidated. The final common pathway is thought to be autodigestion by activated enzymes. The autodigestion theory postulates that proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase, phospholipase) are activated within the pancreas rather than the intestinal lumen. A variety of factors (e.g., endotoxins, exotoxins, viral infections, ischemia, noxae, direct trauma) activate these proenzymes. Activated enzymes then digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and parenchymal cell necrosis. In addition, activation of bradykinin peptides and vasoactive substances (e.g., histamine) produces vasodilation, increased vascular permeability, and edema. Thus a cascade of events culminates in the development of acute necrotizing pancreatitis. A second theory postulates that inappropriate release of pancreatic lysosomal hydrolases activates zymogens and autodigestion. Several factors normally protect the pancreatic acinar cell: (1) zymogens and lysosomal hydrolases are packaged in intracellular organelles; (2) pancreatic tissue and juice contain inhibitors of pancreatic trypsin; and (3) plasma contains antiproteases (e.g., α₁-antitrypsin, α₂-macroglobulin).

The two most common causes of acute pancreatitis are alcohol ingestion and gallstones. Alcoholic pancreatitis develops in susceptible persons after heavy ethanol ingestion for many years. Chronic alcoholism may produce proteinaceous plugs in the small pancreatic ducts, causing atrophy of pancreatic parenchyma drained by the obstructed duct. Thus in first episodes of alcohol-associated acute pancreatitis, approximately 50% of patients already have evidence of chronic pancreatic disease. Patients with gallstone pancreatitis frequently have occult gallstones in their feces. Certain clinical features suggest the diagnosis of gallstone-associated pancreatitis. Drugs have also been implicated as a cause of acute pancreatitis (Box 106-2).

[edit] Patient Evaluation

[edit] History.

Abdominal pain is the cardinal symptom of acute pancreatitis. This pain may vary from a mild and tolerable discomfort to severe, constant, and incapacitating distress. Characteristically the pain, which is steady and boring, is in the epigastrium and periumbilical region and often radiates to the back as well as to the chest, flanks, and lower abdomen. Pancreatic pain frequently is more intense when the patient is supine, and patients often obtain relief by sitting with the trunk flexed and knees drawn up. Nausea, vomiting, and abdominal distention from gastric and intestinal hypomotility and chemical peritonitis are frequent complaints.

[edit] Physical Examination.

The patient is typically distressed and anxious. Low-grade fever, tachycardia, and hypotension are common. Shock may result from (1) hypovolemia secondary to exudation of blood and plasma proteins in the retroperitoneal space (i.e., a retroperitoneal burn); (2) increased formation and release of kinin peptides, which cause vasodilation and increased vascular permeability; (3) impairment of myocardial contractility by kinins and other poorly characterized peptides; and (4) systemic effects of proteolytic and lipolytic enzymes released into the circulation. Jaundice occurs in approximately 10% of patients and usually is caused by edema of the pancreatic head with compression of the intrapancreatic portion of the common bile duct. Abdominal tenderness and muscle rigidity are present to a variable degree, but when compared with the intense pain, these signs may be unimpressive. Bowel sounds usually are diminished or absent. A pancreatic pseudocyst may be palpable in the upper abdomen. A faint blue discoloration around the umbilicus (Cullen's sign) may result from hemoperitoneum. A blue, red, purple, or green-blue discoloration of the flanks (Turner's sign) reflects tissue catabolism of hemoglobin. The last two findings are uncommon but indicate severe necrotizing pancreatitis. Approximately 10% to 20% of patients develop pulmonary findings, which include atelectasis, basilar rales, mediastinal abscesses, and pleural effusion, most often left sided. Erythematous skin nodules that mimic erythema nodosum may result from subcutaneous fat necrosis.

Findings that indicate severe disease include hypotension, tachycardia greater than 130 beats/min, altered sensorium, abnormal physical examination of the lungs, and Cullen's and Turner's signs.

[edit] Laboratory Studies and Diagnostic Procedures

The diagnosis of acute pancreatitis usually is established by an increased serum amylase level exceeding two times the upper limit of normal values. No definite correlation exists between the severity of pancreatitis and the degree of serum amylase elevation. In acute pancreatitis the serum amylase usually is elevated within 24 hours and remains so for 1 to 3 days. Levels return to normal values within 3 to 5 days unless there is extensive pancreatic necrosis, incomplete ductal obstruction, or pseudocyst formation. Approximately 75% of patients with acute pancreatitis have an elevated serum amylase. Normal values, however, may occur if (1) there is a delay of 2 to 5 days in obtaining appropriate blood samples; (2) the underlying disorder is chronic pancreatitis with an acute exacerbation rather than acute pancreatitis; and (3) hypertriglyceridemia is present. Serum lipase levels are increased in approximately 70% to 85% of patients, and lipase may be the best enzyme to measure for the diagnosis of acute pancreatitis. If both serum amylase and serum lipase levels are determined, one test is abnormal in approximately 80% to 85% of patients with acute pancreatitis.

Serum amylase is often elevated in other conditions (Box 106-3). The enzyme is found in many organs besides the pancreas (salivary glands, liver, small intestine, kidney, fallopian tubes) and can be produced by various tumors (carcinoma of lung, esophagus, breast, and ovary). No blood test is reliable for the diagnosis of acute pancreatitis in patients with renal failure. The serum amylase can become elevated when the creatinine clearance is less than 50 ml/min. In such patients the serum amylase is usually less than 500 IU/L in the absence of other objective evidence of pancreatitis. A serum amylase may be spuriously normal in certain conditions (e.g., hypertriglyceridemia). In this setting, values for urine amylase and serum lipase are often abnormal, thus supporting the diagnosis of acute pancreatitis. Imaging procedures such as ultrasound and computed tomography (CT) scan are helpful in further confirming the diagnosis (Fig. 106-1). Imaging techniques show a diffusely enlarged pancreas in 70% to 90% of patients during an acute attack. In patients with clinical findings suggesting a severe attack (Box 106-4), a contrast-enhanced CT scan provides the best means to visualize the pancreas and is very accurate in diagnosing pancreatitis and detecting its local complications. More than 90% of CT scans performed within 72 hours of admission are abnormal in patients with acute pancreatitis. Identification of pancreatic and peripancreatic necrosis by dynamic CT scanning is useful in distinguishing between mild and severe pancreatitis. Areas of the pancreas not enhanced by contrast are thought to be necrotic, and the extent of pancreatic necrosis does correlate with severity of disease. The vast majority of patients with acute pancreatitis do not require a CT scan, which should be reserved for patients with more than three prognostic signs, one or more major factors, or evidence of one or more systems undergoing organ failure.^[1][2]

Figure 106-1 Normal pancreas and pancreatitis. A, Normal pancreas (black arrows) and normal landmarks. Portal vein (large white arrow), splenic vein (white arrowhead), superior mesenteric artery (top curved arrow), and aorta (lower curved arrow).B, Ultrasound demonstrating enlarged pancreas outlined by arrows in acute pancreatitis. C, Dynamic (contrast-enhanced) CT scan showing normal pancreas (arrows).D, CT scan showing a necrotic pancreas (thick arrows) impinging on the superior mesenteric artery and vein (thin arrows).E, Dynamic CT in acute pancreatitis showing viable pancreas (curved arrow) and necrotic pancreas (broad arrow).F, CT scan in acute pancreatitis showing enlarged pancreas and peripancreatic fluid collection (arrow).

Other routine studies in patients with acute pancreatitis include chest radiograph, electrocardiogram (ECG), arterial blood gases, and routine serum chemistries. Careful attention is given to the white blood cell count, blood glucose, liver tests, blood urea nitrogen (BUN), serum calcium, serum albumin, and arterial oxygen pressure, which are also of prognostic value (see Box 106-4).

[edit] Differential Diagnosis

Any severe acute pain in the abdomen or back should suggest acute pancreatitis. The diagnosis usually is considered when a patient has severe and constant abdominal pain, nausea, emesis, fever, tachycardia, and abnormal findings on abdominal examination. Laboratory studies frequently reveal leukocytosis, abnormal radiographs of the abdomen, hyperglycemia, hypocalcemia, increased BUN levels, and decreased serum albumin values. The diagnosis usually is confirmed by finding an elevated serum amylase or serum lipase. The diagnosis should be considered in terms of definite, probable, and possible pancreatitis (Table 106-1). Acute appendicitis must be considered in all patients with acute abdominal pain (Box 106-5). Localization of pain to the right lower quadrant, low-grade fever, and moderate leukocytosis point to the diagnosis of acute appendicitis. It may be quite difficult to distinguish between acute cholecystitis and acute pancreatitis, since an increased serum amylase may be found in both disorders. The pain of biliary tract origin is more right sided and gradual in onset, and ileus usually is absent; these clues suggest acute cholecystitis. A perforated duodenal ulcer is usually diagnosed by free intraperitoneal air, which is present in more than 75% of patients. Alcoholic hepatitis should be considered in patients with a history of excessive alcohol ingestion, hepatomegaly, and elevated values for mean corpuscular volume (MCV), γ-glutamyltransferase (GGT), and serum aspartate transaminase (AST) and an AST/ALT (alanine) ratio greater than 3:1. The diagnosis of intestinal obstruction caused by mechanicalfactors is suggested by a history of colicky abdominal pain, compatible findings on physical examination of the abdomen, and radiographs of the abdomen showing characteristic changes of mechanical obstruction. Acute mesenteric vascular occlusion should be considered in elderly debilitated patients with a history of weight loss, postprandial abdominal pain, and an abdominal bruit who present with brisk leukocytosis, abdominal distention, and bloody diarrhea. Arteriography in such patients frequently shows evidence of vascular occlusion in two or more major arteries. Serum amylase levels are increased in approximately 25% of patients. In patients with systemic lupus erythematosus (SLE) or polyarteritis nodosa, it may be difficult to differentiate abdominal pain caused by vasculitis and gut ischemia (with or without infarction) from pain caused by pancreatitis.

Table 106-1 Diagnosis of Acute Pancreatitis

✢All three are not present.

†If 1 to 3 and either 4 or 5 are positive, a definite diagnosis of acute pancreatitis is established.

Diabetic ketoacidosis often is accompanied by abdominal pain, leukocytosis, and elevated serum amylase levels, thus simulating acute pancreatitis. However, the serum amylase frequently is of salivary and not of pancreatic origin.^[3] Metabolic acidosis can result in elevated serum amylase levels (especially salivary isoamylase). The serum lipase level is not elevated in diabetic ketoacidosis, however, and with an imaging procedure is useful in excluding a diagnosis of acute pancreatitis. Renal colic usually is associated with an abnormal urinalysis and sonogram and often with an abnormal intravenous pyelogram. All patients with acute abdominal pain must have a chest film examination to exclude acute pneumonia, which can mimic a surgical abdomen. A constellation of the following clinical features should suggest the diagnosis of gallstone-associated acute pancreatitis: (1) age over 50 years; (2) female; (3) serum amylase over 1000 U; (4) serum AST over 100 U; and (5) serum bilirubin over 2 mg/dl. If all five features are present, there is an 85% probability the diagnosis is gallstone pancreatitis.

Although the vast majority of patients with acute pancreatitis recover without major complication, 5% to 10% develop severe pancreatitis. Accordingly, it is important to identify factors that increase the likelihood of a fatal outcome in patients with acute pancreatitis (see Box 106-4). Patients with severe acute pancreatitis need to be hospitalized in the intensive care unit (ICU), and consultation with a surgeon and gastroenterologist is indicated.

[edit] Management and Complications

In most patients with acute pancreatitis (85% to 90%) the disease is self-limited and subsides spontaneously, usually within 3 to 5 days after treatment is initiated. Medical treatment is aimed at reducing pancreatic secretion and, in essence, putting the pancreas at rest. Conventional measures include (1) analgesics for pain; (2) intravenous (IV) fluids and colloids to maintain normal intravascular volume and correct electrolyte abnormalities; (3) no oral alimentation; and (4) nasogastric suction. Since nasogastric suction offers no clear-cut advantages in the treatment of mild to moderately severe acute pancreatitis, however, its use should be considered elective rather than mandatory. The patient with mild to moderate pancreatitis usually requires treatment with IV fluids, no oral intake, and possibly nasogastric suction for 3 to 5 days. A clear-liquid diet frequently is started on the fifth day and a regular diet by the seventh day.

No drugs have been demonstrated to improve the course of mild, moderate, or severe pancreatitis. The list includesanticholinergic drugs (which are contraindicated), antibiotics (except for infected pancreatic necrosis and other infections), somatostatin analogs (e.g., octreotide), H₂ receptor antagonists (H₂RAs, H₂ blockers), calcitonin, and lexiplafant, an inhibitor of platelet-activating factor.

The patient with fulminant pancreatitis requires intensive therapy. This usually includes large amounts of IV fluids, treatment of cardiovascular collapse and respiratory insufficiency, and management of hypocalcemia. Removal of toxic pancreatic exudate from the peritoneal cavity may alter the course of the disease, although controlled trials of peritoneal lavage have not established that this procedure is effective. In patients with failure in one or more organ systems (Box 106-6), intensive supportive therapy, preferably in an ICU, is indicated. Such patients with severe acute pancreatitis usually require parenteral nutrition. Consultation with a surgeon or gastroenterologist should be obtained.

In patients acutely ill with severe pancreatitis and major risk factors, pancreatic abscess or infected pancreatic necrosis needs to be excluded, usually by CT-guided biopsy, aspiration of pancreatic tissue, and preparation of appropriate cultures.^[4] Infected pancreatic necrosis should be removed by debridement; this is done surgically because it is difficult to evacuate solid infected material by percutaneous catheter drainage. Current evidence favors the use of prophylactic antibiotics in severe acute pancreatitis. Results of four randomized trials^[5][6] restricted to patients with prognostically severe acute pancreatitis demonstrated improved outcome (i.e., decreased rate of infection, reduced mortality) with antibiotic treatment. The carbapenem group of antibiotics, including imipenem, has a very broad spectrum, including activity against Pseudomonas, Staphylococcus, and Enterococcus, and achieves good penetration into pancreatic tissue. Secondary infection of necrotic pancreatic tissue (abscess, pseudocyst, obstructed biliary passages with ascending cholangitis complicating choledocholithiasis) contributes to much of the late mortalityfrom pancreatitis, so appropriate antibiotic therapy of established infections is especially important. The optimum treatment of patients with severe pancreatitis and sterile pancreatic necrosis is controversial. If such patients develop organ failure or have acute physiologic and chronic health evaluation scores (APACHE II, a scale used to assess severity of illness) greater than 13, surgical debridement is reasonable because the mortality in this setting can be as high as 40%.

[edit] PSEUDOCYST

Pseudocysts of the pancreas are collections of tissue, fluid, debris, pancreatic enzymes, and blood that develop over 1 to 4 weeks after the onset of acute pancreatitis. In contrast to true cysts, pseudocysts do not have an epithelial lining, and the walls consist of necrotic, granulation, and fibrous tissue. Disruption of the pancreatic ductal system is common. Transient edema and fluid collections within the pancreas may give rise to epigastric pain, a palpable abdominal mass, and distortion or displacement of the upper gastrointestinal (UGI) tract on barium study, thus mimicking a pancreatic pseudocyst. The use of ultrasonography and CT scanning should permit differentiation between an edematous and inflamed pancreas and an actual pseudocyst.

[edit] Etiology

Pseudocysts are preceded by pancreatitis in approximately 90% of cases. In several reports the incidence of acute and chronic alcoholism in patients with pseudocysts has ranged from 88% to 93%. Gallbladder disease was identified in approximately 5% and trauma in approximately 10% of cases; other etiologic factors rarely exist.

[edit] Clinical Presentation

Pseudocysts develop in 10% to 15% of patients with acute pancreatitis. Pseudocysts are solitary lesions in more than 90% of patients and multiple in less than 10%. Approximately 90% of pseudocysts are located in the body or tail of the pancreas and 10% in the head.^[7] Abdominal pain is a cardinal symptom and is present in more than 90% of patients. Nausea and vomiting, anorexia, and weight loss are common symptoms, whereas diarrhea and fever occur infrequently. A palpable mass, often tender and usually in the midabdomen or left upper quadrant, is present in approximately 50% of patients. On the basis of physical examination alone, however, it is difficult to differentiate between an edematous, inflamed pancreas (which can give rise to a palpable mass) and a pseudocyst. Ascites is present in approximately 20% and jaundice in 10% of patients.

Several laboratory tests are important in the evaluation of patients with pseudocysts. Serum amylase is elevated in approximately 75% of patients. The WBC is 12,000/mm³ or higher in approximately half of patients, the blood sugar is elevated in one third, and the hemoglobin level is less than 10 gm/dl in approximately one fourth of patients. Chest x-ray evidence of pulmonary and pleural disease is found in approximately 25% of such patients. The serum bilirubin is elevated to values greater than 2 mg/dl in approximately 10% of patients, usually from compression of the intrapancreatic portion of the common bile duct. Ultrasound, CT scan, and endoscopic retrograde cholangiopancreatography (ERCP) help identify pancreatic pseudocyst (Fig. 106-2).

Figure 106-2 Pseudocyst of pancreas. A, Ultrasound showing large pancreatic pseudocyst (arrows).B, CT scan showing well-encapsulated pseudocyst (arrow).C, ERCP showing a disrupted pancreatic duct (thin arrows) communicating directly with pancreatic pseudocyst (broad arrow).

[edit] Differential Diagnosis

The diagnosis of pseudocyst often is difficult, however, because the clinical features, physical examination, and conventional radiologic evaluations are both insensitive and nonspecific. An ultrasound or CT scan should be obtained to confirm the diagnosis. The differential diagnosis of pancreatic cysts includes (1) pseudocysts, (2) retention cysts, (3) neoplasms (e.g., cystadenoma, cystadenocarcinoma), (4) congenital causes, and (5) desmoids.

In studies using serial ultrasound or CT scan, pseudocysts resolved in 25% to 40% of patients. However, pseudocysts greater than 5 cm and present for longer than 6 weeks infrequently disappear. Persistent pseudocysts can be treated by CT-guided percutaneous drainage (if the location is favorable) or by surgical or endoscopic cystogastrostomy or cystoenterostomy.

[edit] Natural History and Complications

The major complications of pseudocyst include pain, rupture with and without bleeding, gastrointestinal bleeding, abscess, and pancreatic ascites. Rupture with hemorrhage is the most serious, with mortality rates of 50% to 60%. Pancreatic abscess can occur (1) because of communication of the pseudocyst with the colon; (2) after inadequate surgical drainage of a pseudocyst; (3) after needling a pseudocyst; and (4) with infected severe pancreatic necrosis. In addition, pancreatic abscess is much more common in patients with severe pancreatitis. In a representative series, pancreatic abscess occurred in 28 of 330 patients with pancreatitis. The cause of pancreatitis in patients with pancreatic abscess most often was surgery; alcoholism and biliary tract disease caused only 6.6% and 3.0%, respectively. In patients with lethal pancreatitis, evidence of pancreatic abscess is found at autopsy in more than 90%. The incidence of pancreatic abscess rises appreciably with an increasing number of risk factors present in a given case, being less than 3% with fewer than three risk factors and greater than 50% with five or more risk factors. Characteristic signs of pancreatic abscess are the development of fever, tachycardia, leukocytosis, toxicity, and rapid deterioration after initial stabilization. Serial CT scans may provide additional evidence to support a diagnosis of infected pseudocyst and pancreatic abscess, but the absence of telltale gas on a CT scan does not exclude a diagnosis of pancreatic abscess.

Pancreatic ascites occurs because of one of two factors: (1) disruption of the main pancreatic duct or (2) a leaking pseudocyst. The diagnosis is established by the triad of findings of (1) persistently increased serum amylase; (2) elevated ascitic fluid amylase; and (3) increased ascitic fluid protein concentration (more than 3 gm/dl). Patients frequently require surgery.

[edit] Management

If the patient is stable and serial ultrasound examinations show that the pseudocyst is decreasing in size, observation only is indicated. However, patients with an expanding pseudocyst or those complicated by rupture, hemorrhage, or abscess should undergo surgery. Elective cyst drainage usually is indicated if pseudocysts persist for longer than 6 weeks. ERCP may be important in this setting because a leaking pancreatic duct can be identified and treated by stenting (see Fig. 106-2, C). The long-acting somatostatin analog octreotide, which inhibits pancreatic secretion, is also useful in these patients.

[edit] CHRONIC PANCREATITIS

[edit] Epidemiology and Etiology

Chronic pancreatitis is usually characterized by recurring or persistent abdominal pain with or without steatorrhea or diabetes. Morphologically, chronic pancreatitis is characterized by irregular sclerosis with destruction and permanent loss of pancreatic parenchyma that may be focal, segmental, or diffuse and with variable dilation of the pancreatic ducts.

Chronic pancreatitis may present as episodes of acute inflammation superimposed on a previously injured pancreas or as chronic damage with persistent pain or malabsorption.Box 106-7 lists the causes of both chronic pancreatitis and pancreatic exocrine insufficiency. Patients with chronic pancreatic damage of mild to moderate severity usually come to medical attention because of chronic abdominal pain. Often the only abnormal laboratory test at this stage of the disease is a test of pancreatic exocrine function such as the secretin test. Patients with extensive chronic pancreatic damage frequently present with diarrhea, steatorrhea, and weight loss; these patients have pancreatic exocrine insufficiency. Because of the enormous reserve capacity of the pancreas, malabsorption is a late manifestation of chronic pancreatitis resulting only when more than 90% of the exocrine pancreas is destroyed.

In several patients with hereditary chronic pancreatitis, researchers were able to identify a genetic defect that affects the gene and coding for trypsinogen. The defect seems to allow trypsinogen to resist the effect of trypsin inhibitor and thus become spontaneously activated and remain activated. This continual activation of digestive enzymes within the gland is believed to lead to continued injury and ultimately chronic pancreatitis.^[8]

In the United States, alcohol is by far the most common cause of clinically apparent pancreatic exocrine insufficiency, whereas cystic fibrosis (CF) accounts for the majority of cases in children. Approximately 85% of CF patients have impaired pancreatic exocrine function. With improved treatment of their pulmonary problems, an increasing number of CF patients are reaching adulthood, when their pancreatic exocrine insufficiency can become clinically relevant. In adult patients 20 to 40 years of age with exocrine pancreatic insufficiency without obvious cause, the diagnosis of CF should be excluded. In recent studies of patients with idiopathic chronic pancreatitis, an appreciable number of patients had gene mutations of CF, and classic stigmata of CF, such as abnormal spirometry or respiratory tract disease, were usually absent.^[9] In adult patients over age 40 with pancreatic insufficiency without obvious cause, pancreatic cancer needs to be excluded (Box 106-8). In up to 25% of U.S. adults with chronic pancreatitis, the disorder is idiopathic.

[edit] Pathophysiology

The pancreas has an enormous reserve capacity for the digestion of nutrients. An inverse relationship exists between intraduodenal and intrajejunal levels of lipase and development of steatorrhea, as well as between intraluminal trypsin and chymotrypsin levels and the development of azotorrhea (increased nitrogen in the stool) and creatorrhea (undigested muscle fibers in the stool).^[10] Steatorrhea, azotorrhea, and creatorrhea are late manifestations of pancreatic exocrine insufficiency and develop when the capacity of the exocrine pancreas to secrete these enzymes is less than 10% of normal values. Thus patients may have evidence of exocrine dysfunction, that is, an impaired response to intravenously injected secretin or secretin plus cholecystokinin or an abnormal pancreatic ductal system demonstrated by ERCP but without any obvious impairment in digestive function.

Many patients with chronic pancreatitis have persistent abdominal pain as the major manifestation of their disease. Pain in chronic pancreatitis may be caused by (1) persistence of pseudocysts with perifocal inflammation, (2) dilation of the pancreatic duct from elevated ductal pressures, (3) continued pancreatic parenchymal inflammatory processes, (4) pressure of an enlarged or inflamed gland on retroperitoneal structures, and (5) infiltration or entrapment of sensory nerves.^[11] Pseudocysts can be important in the pathogenesis of pancreatic pain, as evidenced by the repeated observation that up to 50% of patients with chronic pancreatitis have obtained pain relief by simple drainage of pseudocysts. Therefore, in all patients with chronic pancreatic pain, imaging studies (preferably a CT scan) are performed to rule out an underlying pseudocyst. An abnormal pancreatic ductal system is frequently documented in patients with chronic pancreatitis, although no consistent relationship exists between severity of pain and presence of strictured or dilated ducts. Some patients with pancreatic pain and stenotic ducts may obtain relief, however, when the pancreatic ductal system is stented.

Studies support the concept of an enteropancreatic axis. After initiation of intraluminal digestions by pancreatic enzymes, increased levels of proteases in the duodenal and jejunal lumen act in a feedback manner to decrease release of cholecystokinin from the small bowel mucosa, which in turn results in decreased stimulation of the pancreas. This concept has led to the use of pharmacologic doses of pancreatic enzymes, rich in protease content, in the treatment of persistent pain in patients with chronic pancreatitis.

[edit] Patient Evaluation

[edit] History.

Although patients with chronic pancreatitis may have symptoms identical to those found in patients with acute pancreatitis, patients with chronic pancreatitis often complain of persistent or recurring pain. Although many patients may have severe epigastric pain that radiates through to the back, the pain pattern often is atypical. The pain may be maximal in the right upper or left upper quadrant, in the back, or diffuse throughout the abdomen; it may even be referred to the anterior chest or flank. Characteristically the pain is severe, persistent, deep seated, unresponsive to antacids or food ingestion, and increased by alcohol ingestion or heavy meals (especially foods rich in fat). Often the pain is so severe as to require the frequent use of narcotics. Nausea, vomiting, and abdominal distention are seen less frequently and usually are secondary to the pain and use of medications (especially narcotics), which decrease gastric and intestinal motility.

Weight loss, diarrhea, and steatorrhea frequently are present. However, clinically apparent deficiencies of fat-soluble vitamins are noted less frequently than in patients with steatorrhea secondary to small bowel disease. The stool characteristically has an oily appearance and may cling to the sides of the toilet bowl.

[edit] Physical Examination.

The physical findings in patients with chronic pancreatitis or pancreatic exocrine insufficiency usually are not impressive. Indeed, the disparity between the severity of the abdominal pain and the paucity of physical findings is remarkable. Abdominal tenderness and mild fevermay be seen, especially in those with episodes of acute superimposed on chronic pancreatitis. Weight loss may be profound. Jaundice may be noted in 10% to 20% of patients from obstruction of the common bile duct secondary to edema or fibrosis of the duct above or in the head of the pancreas. Ascites and a palpable abdominal mass (pseudocyst) may be noted in 2% to 5% of patients. Patients with severe malabsorption often show evidence of malnutrition with cachexia, muscle wasting, edema, and stigmata of vitamin deficiencies.

[edit] Laboratory Studies and Diagnostic Procedures

Several studies can be used to evaluate pancreatic exocrine function, but many of these are not widely available. Direct tests of pancreatic secretory capacity include the secretin test or the secretin plus cholecystokinin test. These tests are usually available only in academic health centers. A reliable test to document evidence of intraluminal maldigestion is to examine stools for evidence of fatty acid globules and for crystals and undigested muscle fibers (creatorrhea). The finding of more than five muscle fibers in the stool provides strong evidence of impaired intraluminal digestion. Although a very specific test, this test is rather insensitive in that positivity requires that more than 95% of the exocrine pancreas has been destroyed.

Several diagnostic procedures are available to image the pancreas. The simplest test is the plain film of the abdomen; if this shows evidence of pancreatic calcification, it establishes the diagnosis of chronic pancreatitis (Fig. 106-3). Ultrasound studies may reveal evidence of pancreatic calcification (before it is evident on the plain film), enlargement of the pancreas, or irregularities in the pancreas. The CT scan is the diagnostic procedure of choice to evaluate the pancreas in patients with suspected chronic pancreatitis. In addition to showing evidence of calcification, it may show evidence of duct dilation, focal enlargement, fluid collections, biliary ductal dilation, alterations of peripancreatic fat, or fascia. A normal-appearing pancreas appears in only 10% of the patients with chronic pancreatitis. ERCP often shows varying degrees of ductular dilation and may show marked dilation of areas of stenosis as well.

Figure 106-3 Calcification in pancreas.

[edit] Differential Diagnosis

First, the etiology of pancreatic insufficiency must be identified (see Box 106-7). In adults past age 40 and especially past age 60 who present with evidence of pancreatic malabsorption (steatorrhea, creatorrhea) the diagnosis of pancreatic cancer must be excluded. If the classic diagnostic triad for pancreatic exocrine insufficiency (steatorrhea, pancreatic calcification, diabetes mellitus) is present, no need exists for additional tests of pancreatic secretory capacity. Unfortunately, only one fourth of the patients with pancreatic exocrine insufficiency manifest the diagnostic triad, so other tests are often needed (e.g., qualitative examination of stool). The criteria for diagnosis of chronic pancreatitis are shown in Box 106-9. Absorption of vitamin B₁₂ (Schilling test) is often done, since over 40% of patients with pancreatic exocrine insufficiency have impaired absorption of vitamin B₁₂. In patients with malabsorption, as evidenced by the presence of steatorrhea, tests must confirm that mucosal function is normal. These include a normald-xylose test, normal small bowel radiographs, and a normal small bowel biopsy. An important parameter that confirms the presence of malabsorption due to pancreatic exocrine insufficiency is a positive response to pancreatic enzyme replacement therapy. Such a positive response is characterized by gain in weight and amelioration of diarrhea, steatorrhea, and creatorrhea.

In patients with chronic pancreatitis manifested only by chronic abdominal pain, it is important to exclude other painful conditions and to confirm that patients are not surreptitiously using alcohol. If available, the secretin test is useful in establishing the diagnosis of chronic pancreatitis, since patients with pain from chronic pancreatitis almost invariably have a peak bicarbonate concentration less than 80 mEq/L.

The differential diagnosis of pain in chronic pancreatitis should include (1) pseudocysts, (2) peptic ulcer disease, (3) cholelithiasis, (4) pancreatic cancer, (5) biliary tract obstruction, (6) pancreatic stones, and (7) narcotic addiction. The latter is an important issue and can usually be diagnosed by taking a careful history and trying to wean the patient off narcotics under clonidine cover. This usually requires hospitalization and administration of clonidine (usually as a patch, but at least in a dosage of 5 μg/kg). Because the drug may cause hypotension, it should be done in a hospital setting, where the narcotic dosage can be reduced by 20% to 25% each day.

[edit] Management and Complications

Management of patients with pancreatogenous steatorrhea usually starts with pancreatic enzymes that have both potent lipase and protease content, with 6 to 18 capsules per day depending on the lipase and protease content of the enzyme preparation (Fig. 106-4). If diarrhea or steatorrhea persists, the fat content in the diet should be reduced. If problems persist with steatorrhea or diarrhea, either bicarbonate or an H₂ RA can be added. The evidence that H₂ RAs bring about additional improvement in this setting is still somewhat controversial.

Figure 106-4 Management of pancreatogenous steatorrhea. H₂RA, Histamine receptor antagonist; PPI, proton pump inhibitor.

The management of pain in chronic pancreatitis requires an understanding of the natural history of this problem. A classic study evaluated 245 patients with chronic pancreatitis and persistent pain for an average of 10 years.^[12] Alcohol was the etiologic factor in 173 patients, 58 had idiopathic chronic pancreatitis, and 14 had various rare disorders. Regardless of medical or surgical therapy, 85% of the patients obtained lasting pain relief within 4½ years. In many patients, pain relief was accompanied by further pancreatic dysfunction and the development of malabsorption. The physician must ensure that the use of alcohol is discontinued in all patients with chronic pancreatitis, especially those with persistent pain. This simple expedient will result in pain relief in approximately 50% of patients with chronic pancreatitis.

Because evidence supports an enteropancreatic axis, a trial of high-dose pancreatic enzyme therapy rich in pancreatic proteases should be considered in all patients who have pain from chronic pancreatitis (Fig. 106-5).^[13][5][6] This should include pancreatic enzyme therapy (18 to 24 capsules per day), and the capsules should not be enteric coated or slow release. The patients most likely to respond to pancreatic enzyme replacement therapy are females with idiopathic pancreatitis, in whom a response rate of about 75% may be seen. By contrast, the response rate is much less in males (20% to 25%), male alcoholics (12% to 15%), and males and females with severe chronic pancreatitis (25%). In all patients with chronic pancreatitis and persistent pain, it is important to exclude the presence of the pseudocyst, since drainage of the pseudocyst often results in amelioration of pain. Risk of narcotic addiction is high, and the pain in such patients should be controlled by using nonnarcotic analgesics. Drugs such as Darvon plus Tylenol combinations or nonsteroidals such as ketorolac, taken orally, are often effective. A regular schedule of Extra Strength Tylenol (1 gm every 8 hours) is also effective. Patients who have been alcoholic should be cautioned about using even small doses of alcohol if they are taking 3 gm of Tylenol per day.

Figure 106-5 Management of chronic pancreatic pain. HCO₃, Bicarbonate.

Serious complications of chronic pancreatitis include pancreatogenous ascites, which can result from a leaking pseudocyst or a disrupted pancreatic duct (Box 106-10). Common bile duct obstruction is associated with abnormal liver function tests and development of secondary biliary cirrhosis. Accordingly, in all patients with chronic pancreatitis who have persistent and sustained elevation of the serum alkaline phosphatase to values greater than twice normal for more than 2 months, studies should be undertaken to evaluate for extrahepatic biliary tract obstruction, usually with ERCP. If this shows evidence of a stricture, a liver biopsy should be performed. If this suggests secondary biliary cirrhosis, the biliary tract obstruction should be decompressed.

[edit] PANCREATIC CANCER

[edit] Epidemiology

Carcinoma of the pancreas, one of the most dreaded of all tumors, strikes adults in all age groups; the peak age of risk is about 60 years. The overall incidence has risen 300% over the past 30 years, and pancreatic cancer now ranks as the fourth most common tumor behind lung, colorectal, and breast cancer. The disease attacks men twice as frequently as women.

Only a few risk factors have been clearly identified as predisposing to the development of pancreatic cancer. These include cigarette smoking, diabetes, and chronic pancreatitis.^[14] However, the vast majority of patients with this tumor have none of these risk factors. This inability to identify subgroups at risk for the disease is one of the major problems limiting the development of screening techniques for early detection.

[edit] Pathophysiology

The clinical presentation of pancreatic carcinoma, at least initially, can be quite variable (Box 106-11). The most common presentation (new onset, obscure and unrelenting abdominal pain) results from an enlarging mass in the pancreas causing pressure on retroperitoneal structures and the stomach and duodenum. Presentation with diarrhea and malabsorption can be caused by a localized obstruction of the main pancreatic duct and head of the pancreas, resulting in pancreatic exocrine insufficiency and steatorrhea with diarrhea. New onset of an irritable bowel–type syndrome in any patient past 50 with no prior history of such a disorder should always suggest pancreatic cancer. Pancreatic cancers located at the head of the pancreas often cause obstruction of the common bile duct, resulting in new onset of jaundice with obstructive features. Approximately 40% of patients with pancreatic carcinoma have an abnormal blood glucose level detected within 2 years before diagnosis. Therefore, in any patient past age 50 who develops signs of unexplained carbohydrate intolerance, especially if this is accompanied by abdominal pain or weight loss, the diagnosis of pancreatic carcinoma should be excluded.

[edit] Patient Evaluation

[edit] History.

Persistent abdominal pain, weight loss, and unremitting jaundice are the outstanding symptoms of pancreatic carcinoma. The site of the lesion, however, greatly influences the character and time of onset of symptoms. Obscure abdominal pain is one of the most difficult of all symptoms to evaluate. Clues to a pancreatic origin include a persistent gnawing, boring upper abdominal discomfort referred through to the back. This upper abdominal pain may have no particular exacerbating or relieving factors. If there is already some mechanical compromise to gastric emptying, the patient may complain of vague abdominal distress and fullness made worse by eating. Cancer in the body or tail of the pancreas frequently produces more severe pain, and its unrelenting nature should suggest pancreatic cancer, especially if the pain is worse when lying supine and relieved by sitting forward. Although painless jaundice is touted as a presentation of pancreatic cancer, more often the patient complains of vague abdominal distress that may be difficult to characterize. In adults over age 50 presenting with irritable bowel–type symptoms without any prior such history, and especially if this is accompanied by weight loss, the diagnosis of pancreatic cancer should be considered. Similarly, new onset of malabsorption with stigmata of pancreatic exocrine insufficiency in adults past age 50 without an obvious reason for pancreatic insufficiency should also suggest pancreatic cancer. Patients with anaplastic carcinoma of the pancreas have a lesion that grows rapidly and spreads quickly to distant locations, and this can result in evidence of malignant ascites or metastatic carcinoma at presentation. Finally, patients with obstructive type jaundice often complain of intense and persistent pruritus.

[edit] Physical Examination.

Pertinent physical findings in the patient with suspected pancreatic cancer include (1) jaundice; (2) excoriations or scratching that may reflect pruritus; (3) evidence of recent weight loss; (4) Virchow supraclavicular adenopathy; (5) hepatomegaly, especially with the palpable left lobe of the liver; (6) a palpable gallbladder (Courvoisier's sign), which occurs in one fourth to one third of patients; (7) palpable periumbilical (Sister Mary Joseph) lymph nodes; (8) splenomegaly, which may be caused by splenic vein thrombosis because of invasion of the splenic artery and vein by the tumor; and (9) new detection of a left upper quadrant bruit, again due to invasion of the splenic artery or vein (this occurs in approximately 25% of patients with carcinoma of pancreatic body and tail).

[edit] Laboratory Studies and Diagnostic Procedures

Routine studies to obtain in patients suspected of harboring a pancreatic cancer include CBC, chemistry profile, and chest film. A disproportionately elevated serum alkaline phosphatase may provide an initial clue to the presence of metastatic disease. In patients with classic obstructive jaundice the serum transaminases, are less than 400 IU, if elevated. The serum alkaline phosphatase may be 2 to 10 times normal, and markers for viral hepatitis should be negative. Key tests to confirm suspected pancreatic cancer include ultrasound, CT scan, ERCP, CT-guided biopsy of a pancreatic mass lesion, and arteriography if surgery is contemplated (Fig. 106-6).

Figure 106-6 CT scan demonstrating mass in pancreas.

For a patient with obstructive-type jaundice the ultrasound study is an important initial consideration. The presence of dilated intrahepatic ducts suggests a mechanical, obstructive process, whereas the absence of dilated ducts indicates intrahepatic cholestasis. CT scan, especially contrast-enhanced (dynamic) scan, is abnormal in approximately 90% of the patients with carcinoma of the pancreas, especially if the lesion is more than 2 cm in diameter. When an obvious lesion is detected by CT scanning, a CT-guided percutaneous biopsy may establish the diagnosis. ERCP may also provide important diagnostic information as well as affording an opportunity to decompress the obstructed bile duct. If CT scanning shows evidence of potentially resectable disease, an arteriogram can assist the surgeon and exclude sheathing of the pancreaticoduodenal artery and splenic vein thrombosis, which preclude a curative resection if present.

[edit] Differential Diagnosis

For any patient presenting with new onset of persistent abdominal pain, jaundice with obstructive-type liver tests, new onset of diarrhea, and malabsorption, the diagnosis of pancreatic carcinoma must be considered. In patients past age 60 with jaundice and obstructive-type liver tests, the differential diagnosis in 80% of cases lies between pancreatic cancer and choledocholithiasis, with viral hepatitis, posttransfusion hepatitis, drug-induced jaundice, and alcoholic liver disease in the other 20%. Therefore, if the history suggests none of the latter four disorders, an imaging procedure can determine whether the biliary ducts are dilated and, if so, further studies are indicated. Choledocholithiasis is rarely painless. Carcinoma of the ampulla of Vater can mimic many of the features of carcinoma of the pancreas but has a much better prognosis. This condition is diagnosed by ERCP, which reveals a tumor protruding into the duodenal lumen. CT-guided percutaneous biopsy of the pancreas is an effective means of establishing the diagnosis and provides positive results in approximately 85% of patients. For pancreatic duct adenocarcinomas, ERCP has a sensitivity of approximately 90% and a similar specificity. Arteriography has a sensitivity of approximately 65%, with a specificity of 90% for vessel sheathing and splenic vein thrombosis.

[edit] Management

For patients with a lesion demonstrable by CT scan that measures less than 3 cm and in whom arteriography shows no evidence of vessel involvement or metastases, exploration with planning for Whipple's procedure is recommended. If the operative findings confirm a lesion that is 3 cm or less in size with no adenopathy and no extension, Whipple's procedure results in a 2-year survival of up to 40%. The resectability rate in patients with pancreatic carcinoma is only about 20% because of the presence of small metastases at presentation not detectable by CT scan. The 5-year survival rate is still only 5% or less in patients with nonresectable lesions. For patients with obstructive jaundice and evidence of metastases or nonresectability, it is reasonable to attempt stenting of the common bile duct to relieve symptoms and sequelae of high-grade extrahepatic obstruction. If a carcinoma of the pancreatic head is causing gastric outlet obstruction, exploration and a gastric bypass procedure as well as cholecystojejunostomy are reasonable. These procedures are palliative and will not affect the patient's long-term survival. Only 10% of patients with pancreatic cancer survive 1 year. No effective chemotherapy or radiation therapy exists for carcinoma of the pancreas. Approximately 15% of patients will respond briefly to chemotherapy. The addition of radiotherapy to chemotherapy results in an increased survival of only 1 to 2 months.

[edit] Glucagonoma Syndrome

Tumors of the pancreatic alpha cells result in high levels of circulating glucagon. This syndrome is associated with angular cheilitis, glossitis, and necrolytic migratory erythema—intertriginous, red, scaling, arcuate, erosive lesions in the body folds. The lesions are often confused with candidiasis. Skin biopsy is often diagnostic of glucagonoma syndrome. Diabetes, anemia, and weight loss are commonly seen. Removal of the tumor results in healing of the cutaneous lesions.

[edit] REFERENCES