Disorders involving the pancreas are generally divided into 2 categories. One group includes diseases of the exocrine portion of the pancreas, which secretes digestive enzymes into the gastrointestinal tract. The other category includes the disorders of the endocrine portion of the pancreas, which contains beta cells for secretion of insulin, alpha cells for secretion of glucagon, and delta cells for secretion of somatostatin. The cells that secrete hormones are arranged in islets within the exocrine pancreas.

The most frequently encountered disorders of the exocrine pancreas are pancreatitis and pancreatic neoplasms (usually cancer). Pancreatitis may be acute, or chronic with recurrent bouts of acute pancreatitis. Pancreatic tumors of the exocrine pancreas almost always originate in the pancreatic ductal epithelium. The major disease of the endocrine pancreas is diabetes mellitus (DM). Several neoplasms are also associated with the endocrine pancreas but are much rarer than those associated with the exocrine pancreas.

Description

Acute pancreatitis is a potentially lethal disorder associated with intracellular activation of digestive enzymes in the pancreas. This results in autodigestion of the pancreatic tissue by the powerful enzymes normally secreted into the gastrointestinal tract to degrade ingested foods. The damage to the pancreas can produce inflammation, edema, necrosis, hemorrhage, and liquefaction, and may obstruct the pancreatic duct and block the flow of pancreatic enzymes into the gastrointestinal tract. The obstruction further enhances the progression of acute pancreatitis. Clinically, a bout of acute pancreatitis is characterized by midepigastric pain frequently radiating to the back, nausea, and vomiting.

The cause of acute pancreatitis in the majority of the cases is either alcohol abuse or gallstones. There are, however, other causes, such as hypertriglyceridemia, hypercalcemia, selected infections, obstructing pancreatic tumors, and trauma to the pancreas. Hereditary forms of acute pancreatitis have also been described due to mutations in the trypsinogen gene or the trypsin inhibitor gene. In addition, many medications have been associated with the development of acute pancreatitis. Selected examples are asparaginase, azathioprine, estrogens, furosemide, sulfonamides, tetracycline, and thiazide diuretics. The mechanism of pancreatic injury following ingestion of these medications may be related to hypersensitivity to the drug or accumulation of a toxic drug metabolite in the pancreas. In about 20% of cases of acute pancreatitis, a specific cause cannot be identified. This is known as idiopathic acute pancreatitis.

Diagnosis

A large number of potential markers (carboxyester lipase, carboxypeptidase, trypsin, trypsinogen-2, pancreatitis-associated protein, trypsinogen activation peptide, C-reactive protein, and tumor necrosis factor) are discussed in the literature as possible for the diagnosis of acute pancreatitis; however, none of them are typically available in most hospital laboratories. In fact, acute pancreatitis is not solely diagnosed by a biochemical marker but rather by a combination of history, clinical presentation, and radiologic and laboratory findings (Table 17–1).

Nonspecific laboratory findings include, but are not limited to, aminotransferase elevations, mild-to-moderate leukocytosis with a shift toward immature forms, hyperglycemia, mild hyperbilirubinemia, and a decreased serum calcium level.

More specific biochemical tests used for the diagnosis are amylase and lipase. Historically, an amylase level greater than 3× the upper limit of normal was considered diagnostic for acute pancreatitis, and lipase findings were helpful but not as useful. The problem with lipase was the existence of a number of different assay methods and no standardization between them. This has changed. Current assays for lipase are more standardized, and the lipase assay has several characteristics that make it a better marker for acute pancreatitis.

Temporally, in acute pancreatitis, amylase will rise and fall over a shorter period of time (rise over 6-24 hours, peak at 48 hours, and normalize in 5-7 days). Lipase has different temporal kinetics (rise over 4-8 hours, peak at 24 hours, and normalize in 8-14 days). Therefore, it is more possible to miss an amylase elevation than a lipase elevation. In addition, despite the fact that neither marker is organ specific for the pancreas, lipase has relatively greater pancreas specificity than amylase. There are a larger number of conditions that can result in non-pancreatitis hyperamylasemia than there are that can result in hyperlipasemia. Conditions associated with non-pancreatitis increases in both amylase and lipase include biliary disease, intestinal obstruction, pancreatic pseudocyst, and renal impairment. Clinical conditions associated with elevations in amylase without a corresponding increase in lipase include macroamylasemia, ruptured ectopic pregnancy, salivary gland disease, and abdominal and thoracic malignancies. Renal failure is the most common extrapancreatic condition associated with an elevated serum lipase level. About 80% of patients with renal failure have lipase levels 2 to 3 times the upper limit of the reference range, and about 5% have an elevation more than 5 times the upper limit of normal.

Amylase elevation greater than 3× the upper limit of normal is the cutoff often cited for the diagnosis of acute pancreatitis. Test characteristics for amylase in the diagnosis of acute pancreatitis range from 45% to 85% for sensitivity with specificities ranging from 90% to 99%. Test characteristics for lipase elevations have sensitivities and specificities greater than 95% for the diagnosis of acute pancreatitis.

In cases of hyperamylasemia where the clinical presentation does not support the diagnosis of acute pancreatitis, a urine amylase level may have clinical utility.

A urine amylase determination may be helpful in diagnosing pancreatic disorders, especially when the serum amylase level is normal or slightly elevated. As a general rule, urine amylase rises within 24 hours after an increase in serum amylase, and remains high for 7 to 10 days after the serum level returns to normal. Renal excretion of amylase depends on the glomerular filtration rate and, consequently, the urine amylase correlates with the creatinine clearance (CC). In acute pancreatitis, the clearance of amylase into the urine may be increased compared with creatinine, resulting in an increased (amylase/creatinine clearance [A/CC]) ratio. The A/CC ratio is determined using the following formula:

Determination of the A/CC ratio involves simultaneous collection of serum and urine specimens but does not require a timed or complete 24-hour urine collection. The A/CC ratio becomes abnormal 1 to 2 days after an elevation of the serum amylase, and typically remains abnormal for as long as the urine amylase is high. Like the urine amylase level, the A/CC ratio remains elevated for 7 to 10 days after the serum amylase level returns to normal.

Macroamylasemia is an established cause for an elevated serum amylase value. Macroamylase is a complex of alpha-amylase and other molecules, which may be proteins or carbohydrates. Because of its large molecular size, macroamylase is not filtered by the glomerulus in the kidney. Consequently, it accumulates in the serum, and produces a chronically elevated serum amylase level. The presence of macroamylase has been shown to account for an elevated serum amylase level in 1% to 3% of patients. Because macroamylase does not enter the urine, the urine amylase level is normal or low, unlike the situation in acute and chronic pancreatitis in which the urine amylase level is usually elevated along with the serum activity. Thus, patients with macroamylasemia have a combination of elevated serum amylase levels and normal or low urine amylase levels.

Both pancreatic and salivary amylase have more than 1 isoenzyme alpha-amylase can be pancreatic or salivary. Amylase can be separated into its component isoenzymes by selective enzymatic or chemical inhibition and by electrophoresis. In acute pancreatitis, there is an increase in pancreas-derived isoenzymes in almost all patients, but isoenzyme analysis is rarely required for diagnosis.

A number of laboratory tests and computed tomography may be useful to assess prognosis in patients with acute pancreatitis. One system to assign prognosis in acute pancreatitis is the simplified Glasgow criteria. Features associated with a worse prognosis include age >55 years, white blood cell count >15,000/μL, LD >600 U/L, glucose >180 mg/dL, albumin <3.2 g/dL, calcium <8 mg/dL, arterial PO₂ <60 mm Hg, and BUN >45 mg/dL.

Description

Following an attack of acute pancreatitis, the patient may experience a complete recovery, have an additional recurrence without permanent damage to the pancreas, or suffer multiple recurrences leading to chronic pancreatitis and significant damage to the organ. In chronic pancreatitis, the cells that generate the digestive enzymes are destroyed and replaced with scar tissue, and the pancreatic ducts become dilated and filled with precipitated protein. Chronic pancreatitis can be divided into chronic calcifying pancreatitis and obstructive pancreatitis. Since chronic disease follows from recurrence of acute pancreatitis, chronic pancreatitis has various causes in adults. In the United States, the majority of cases of chronic pancreatitis are due to prolonged excessive alcohol consumption. Malnutrition-induced pancreatitis is more common in underdeveloped areas of the world. In children, the most common cause of chronic pancreatitis is cystic fibrosis (see Chapter 7).

Diagnosis

The diagnosis of chronic pancreatitis may be challenging because the disease can evolve subclinically over an extended period. The patient with chronic pancreatitis often has impaired glucose tolerance (IGT) or, in severe cases, DM. Additional manifestations include abdominal pain, weight loss, pancreatic calcifications on x-ray, and steatorrhea. The sensitivity of laboratory tests to diagnose chronic pancreatitis depends on the extent of pancreatic tissue destruction and the length of time over which the damage has occurred.

An elevated serum amylase level is much less informative to make a diagnosis of chronic pancreatitis than it is in the diagnosis of acute pancreatitis. In about one half of the patients with chronic pancreatitis, the serum amylase level remains within the normal range. In other patients with the disorder, the values may be borderline or only slightly elevated, raising the possibility of a nonpancreatic cause for the elevated amylase. In chronic pancreatitis, the urine amylase level may be elevated when the serum amylase is within the normal range or only slightly elevated. Measurement of a 72-hour fecal fat provides an index of pancreatic exocrine function. It is increased in severe chronic pancreatitis. However, the fecal fat test is neither sensitive nor specific. More recently, measurement of fecal elastase (decreased in chronic pancreatitis) and serum levels of trypsinogen (decreased in chronic pancreatitis) have been used as additional tests of pancreatic function.

The bentiromide test is a noninvasive test for assessing pancreatic function in patients suspected to have chronic pancreatitis. The test is based on the hydrolysis by chymotrypsin of a synthetic tripeptide, N-benzoyl-L-tyrosyl-p-aminobenzoic acid. The tripeptide, variously called bentiromide, NBT-PBA, or BTP, is administered orally, along with a test meal to stimulate pancreatic secretion. Chymotrypsin cleaves the p-aminobenzoic acid (PABA) molecule from the bentiromide in the duodenum. The PABA moiety is absorbed into the portal circulation, conjugated in the liver, and excreted by the kidneys as an arylamine. In the bentiromide test, the arylamines are quantitated in a 6-hour urine specimen, with the time started after the oral intake of bentiromide and the test meal. Decreased excretion (<50% of the test dose) suggests decreased absorption from the duodenum, which can occur with deficient activity of pancreatic chymotrypsin. The sensitivity of the test for diagnosis of chronic pancreatitis depends on the severity of the disease, with greater sensitivity of the test correlating with greater disease severity. Many nonpancreatic conditions, especially diseases of the kidney, are associated with a false-positive test result by decreasing the conjugation and/or excretion of the PABA metabolite in the urine. Conversely, a number of drugs (acetaminophen, lidocaine, procainamide, sunscreens containing PABA, and pancreatic enzyme supplements, as examples) may produce a falsely normal result in a patient with chronic pancreatitis, because these products can increase the amount of arylamine in the urine.

Imaging studies including abdominal plain films may demonstrate calcifications. Ultrasound and computed tomography scans are relatively sensitive and specific. Duodenal intubation using endoscopic retrograde cholangiopancreatography (ERCP), with injection of x-ray contrast medium into the common bile duct and pancreatic ducts, is the most sensitive test, but the test itself may induce pancreatitis and should therefore be reserved for selected cases. More recently endoscopic ultrasound has gained favor, and it is equally sensitive and specific for chronic pancreatitis as ERCP.

Exocrine Pancreas Neoplasms

Description

Masses within the pancreas can be either nonneoplastic or neoplastic. The nonneoplastic masses are almost always cystic. However, both benign and malignant pancreatic tumors may be cystic. A cyst can be congenital from abnormal development, but more often, it is a collection of pancreatic secretions and tissue debris following bouts of pancreatitis, and is known as a pseudocyst. In contrast to true cysts, pseudocysts lack an epithelial lining. Pancreatic cancer affects more than 30,000 adults in the United States annually and is usually rapidly fatal. The great majority of these tumors arise in the exocrine pancreas and histologically are ductal adenocarcinomas.

Diagnosis

CA 19-9 is the most widely used pancreatic tumor marker. CA 19-9 antigen is present in the normal adult and fetal pancreas, and it is also found in the esophagus, stomach, small intestine, gallbladder, bile duct, and salivary glands. For the diagnosis of pancreatic cancer, the reported sensitivity ranges from 70% to 92% with a specificity that ranges from 68% to 92%. The marker’s sensitivity is proportional to tumor size. Measuring the level of the CA 19-9 may be useful in patients with pancreatic cancer. In patients with early stage tumors, the CA 19-9 level is often normal. Therefore, the marker is of little value as a screening test. In patients with more advanced tumors, the CA 19-9 level is often elevated, and this finding may be helpful in suggesting a diagnosis of pancreatic cancer. CA 19-9 is most useful as an aid to monitor the patient response to therapy. However, CA 19-9 is not specific to pancreatic cancer and may be elevated in other types of gastrointestinal cancers and in some nonneoplastic disorders as well. Of note, CA 19-9 requires the presence of the Lewis blood group antigen for it to be expressed. Therefore, CA 19-9 will be naturally undetectable in 7% to 10% of the population.

Endocrine Pancreas Neoplasms