As emphasized in Chap. 313, the etiologies as well as the clinical manifestations of pancreatitis are quite varied. Although it is well-appreciated that pancreatitis is frequently secondary to biliary tract disease and alcohol abuse, it can also be caused by drugs, trauma, and viral infections and is associated with metabolic and connective tissue disorders. In ∼30% of patients with acute pancreatitis and 25−40% of patients with chronic pancreatitis, the etiology initially can be obscure.
Although good data exist concerning the incidence of acute pancreatitis (about 5−35/100,000 new cases per year worldwide, with a mortality rate of about 3%), the number of patients who suffer with acute pancreatitis is largely increasing and is now estimated to be 70 hospitalizations/100,000 persons annually, resulting in >200,000 new cases of acute pancreatitis per year in the United States. Only one prospective study on the incidence of chronic pancreatitis is available; it showed an incidence of 8.2 new cases per 100,000 per year and a prevalence of 26.4 cases per 100,000. These numbers probably underestimate considerably the true incidence and prevalence, because non alcohol−induced pancreatitis has been largely ignored. At autopsy, the prevalence of chronic pancreatitis ranges from 0.04 to 5%. The relative inaccessibility of the pancreas to direct examination and the nonspecificity of the abdominal pain associated with pancreatitis make the diagnosis of pancreatitis difficult and usually dependent on elevation of blood amylase and/or lipase levels. Many patients with chronic pancreatitis do not have elevated blood amylase or lipase levels. Some patients with chronic pancreatitis develop signs and symptoms of pancreatic exocrine insufficiency, and, thus, objective evidence for pancreatic disease can be demonstrated. However, there is a very large reservoir of pancreatic exocrine function. More than 90% of the pancreas must be damaged before maldigestion of fat and protein is manifested. Noninvasive, indirect tests of pancreatic exocrine function (fecal elastase) are much more likely to give abnormal results in patients with obvious pancreatic disease (i.e., pancreatic calcification, steatorrhea, or diabetes mellitus, than in patients with occult disease). Thus, the number of patients who have subclinical exocrine dysfunction (<90% loss of function) is unknown.
Tests Useful in the Diagnosis of Pancreatic Disease
Several tests have proved of value in the evaluation of pancreatic disease. Examples of specific tests and their usefulness in the diagnosis of acute and chronic pancreatitis are summarized in Table 312-1 and Fig. 312-1. At some institutions, pancreatic-function tests are available and performed if the diagnosis of pancreatic disease remains a possibility after noninvasive tests [ultrasound, CT, magnetic resonance cholangiopancreatography (MRCP)] or invasive tests [endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasonography (EUS)] have given normal or inconclusive results. In this regard, tests employing direct stimulation of the pancreas are the most sensitive.
Table 312-1 Tests Useful in the Diagnosis of Acute and Chronic Pancreatitis and Pancreatic Tumors |Favorite Table|Download (.pdf)
Table 312-1 Tests Useful in the Diagnosis of Acute and Chronic Pancreatitis and Pancreatic Tumors
|Pancreatic Enzymes in Body Fluids|
|1. Serum||Pancreatic inflammation leads to increased enzyme levels||Simple; 20–40% false negatives and positives; reliable if test results are three times the upper limit of normal|
|2. Urine||Renal clearance of amylase is increased in acute pancreatitis||Infrequently used|
|3. Ascitic fluid||Disruption of gland or main pancreatic duct leads to increased amylase concentration||Can help establish diagnosis of acute pancreatitis; false positives occur with intestinal obstruction and perforated ulcer|
|4. Pleural fluid||Exudative pleural effusion with pancreatitis||False positives occur with carcinoma of the lung and esophageal perforation|
|Serum lipase||Pancreatic inflammation leads to increased enzyme levels||New methods have greatly simplified determination; positive in 70–85% of cases|
|Studies Pertaining to Pancreatic Structure|
|Radiologic and radionuclide tests|
|1. Plain film of the abdomen||Can be abnormal in acute and chronic pancreatitis||Simple; normal in >50% of cases of both acute and chronic pancreatitis|
|2. Upper GI x rays||Now obsolete|
|3. Ultrasonography (US)||Can provide information on edema, inflammation, calcification, pseudocysts, and mass lesions||Simple, noninvasive; sequential studies quite feasible; useful in diagnosis of pseudocyst limited by interference by bowel gas|
|4. CT scan||Permits detailed visualization of pancreas and surrounding structures, pancreatic fluid collection, pseudocyst, degree of necrosis||Useful in the diagnosis of pancreatic calcification, dilated pancreatic ducts, and pancreatic tumors; may not be able to distinguish between inflammatory and neoplastic mass lesions|
|5. Endoscopic retrograde cholangiopancreatography (ERCP)||Cannulation of pancreatic and common bile duct permits visualization of pancreatic-biliary ductal system||Can provide diagnostic data in 60–85% of cases; differentiation of chronic pancreatitis from pancreatic carcinoma may be difficult; now considered primarily a therapeutic procedure|
|6. Endoscopic ultrasonography (EUS)||High-frequency transducer employed with EUS can produce very high-resolution images and depict changes in the pancreatic duct and parenchyma with great detail||Can be used to assess chronic pancreatitis and pancreatic carcinoma|
|7. Magnetic resonance cholangiopancreatography||Three-dimensional rendering has been used to produce very good images of the pancreatic duct by a noninvasive technique||Has largely replaced ERCP as a diagnostic test|
|Pancreatic biopsy with US or CT guidance||Percutaneous aspiration biopsy with skinny needle and localization of lesion by US||High diagnostic yield; laparotomy avoided; can be done with EUS requires special technical skills|
|Tests of Exocrine Pancreatic Function|
|Direct stimulation of the pancreas with analysis of duodenal contents|
|1. Secretin-pancreozymin (CCK) test||Secretin leads to increased output of pancreatic juice and HCO3–; CCK leads to increased output of pancreatic enzymes; pancreatic secretory response is related to the functional mass of pancreatic tissue||Sensitive enough to detect occult disease; involves duodenal intubation and fluoroscopy; poorly defined normal enzyme response; overlap in chronic pancreatitis; large secretory reserve capacity of the pancreas, currently done at only a few medical centers|
|2. Endoscopic secretin—CCK test||Replaces need for tube placement duodenum||Sensitive enough to detect occult disease; avoids intubation and fluoroscopy; requires sedation|
|Measurement of intraluminal digestion products|
|1. Microscopic examination of stool for undigested meat fibers and fat||Lack of proteolytic and lipolytic enzymes causes decreased digestion of meat fibers and triglycerides||Simple, reliable; not sensitive enough to detect milder cases of pancreatic insufficiency|
|2. Quantitative stool fat determination||Lack of lipolytic enzymes brings about impaired fat digestion||Reliable, reference standard for defining severity of malabsorption; does not distinguish between maldigestion and malabsorption|
|3. Fecal nitrogen||Lack of proteolytic enzymes leads to impaired protein digestion, resulting in an increase in stool nitrogen||Does not distinguish between maldigestion and malabsorption; low sensitivity|
|Measurement of pancreatic enzymes in feces|
|1. Elastase||Pancreatic secretion of proteolytic enzymes; not degraded in intestine||Good sensitivity if stools not liquid|
A step-wise diagnostic approach to the patient with suspected chronic pancreatitis (CP). Endoscopic ultrasonography (EUS) and magnetic resonance cholangiopancreatography (sMRCP/MRCP) are appropriate diagnostic alternatives to endoscopic retrograde cholangiopancreatography (ERCP).
Pancreatic Enzymes in Body Fluids
The serum amylase and lipase levels are widely used as screening tests for acute pancreatitis in the patient with acute abdominal pain or back pain. Values greater than three times the upper limit of normal virtually clinch the diagnosis if gut perforation or infarction is excluded. In acute pancreatitis, the serum amylase and lipase are usually elevated within 24 hours of onset and remains so for 3−7 days. Levels usually return to normal within 7 days unless there is pancreatic ductal disruption, ductal obstruction, or pseudocyst formation. Approximately 85% of patients with acute pancreatitis have a threefold or greater elevated serum amylase and lipase levels. The values may be normal if (1) there is a delay (of 2−5 days) before blood samples are obtained, (2) the underlying disorder is chronic pancreatitis rather than acute pancreatitis, or (3) hypertriglyceridemia is present. Patients with hypertriglyceridemia and proven pancreatitis have been found to have spuriously low levels of amylase and perhaps lipase activity. In the absence of objective evidence of pancreatitis by abdominal ultrasound, CT scan, MRCP, or EUS, mild to moderate elevations of amylase, and/or lipase are not helpful in making a diagnosis of chronic pancreatitis.
The serum amylase can be elevated in other conditions (Table 312-2), in part because the enzyme is found in many organs. In addition to the pancreas and salivary glands, small quantities of amylase are found in the tissues of the fallopian tubes, lung, thyroid, and tonsils and can be produced by various tumors (carcinomas of the lung, esophagus, breast, and ovary). Urinary amylase measurements, including the amylase/creatinine clearance ratio, are no more sensitive or specific than blood amylase levels and are rarely employed. Isoamylase determinations do not accurately distinguish elevated blood amylase levels due to bona fide pancreatitis from elevated blood amylase levels due to a nonpancreatic source of amylase, especially when the blood amylase level is only moderately elevated.
Table 312-2 Causes of Hyperamylasemia and Hyperamylasuria |Favorite Table|Download (.pdf)
Table 312-2 Causes of Hyperamylasemia and Hyperamylasuria
- I. Pancreatitis
- A. Acute
- B. Chronic: ductal obstruction
- C. Complications of pancreatitis
- 1. Pancreatic pseudocyst
- 2. Pancreatogenous ascites
- 3. Pancreatic abscess
- Pancreatic necrosis
- II. Pancreatic trauma
- III. Pancreatic carcinoma
- I. Renal insufficiency
- II. Salivary gland lesions
- A. Mumps
- B. Calculus
- C. Irradiation sialadenitis
- D. Maxillofacial surgery
- III. “Tumor” hyperamylasemia
- A. Carcinoma of the lung
- B. Carcinoma of the esophagus
- C. Breast carcinoma, ovarian carcinoma
- IV. Macroamylasemia
- V. Burns
- VI. Diabetic ketoacidosis
- VII. Pregnancy
- VIII. Renal transplantation
- IX. Cerebral trauma
- X. Drugs: morphine
|Other Abdominal Disorders|
- I. Biliary tract disease: cholecystitis, choledocholithiasis
- II. Intraabdominal disease
- A. Perforated or penetrating peptic ulcer
- B. Intestinal obstruction or infarction
- C. Ruptured ectopic pregnancy
- D. Peritonitis
- E. Aortic aneurysm
- F. Chronic liver disease
- G. Postoperative hyperamylasemia
Elevation of ascitic fluid amylase occurs in acute pancreatitis as well as in (1) pancreatogenous ascites due to disruption of the main pancreatic duct or a leaking pseudocyst and (2) other abdominal disorders that simulate pancreatitis (e.g., intestinal obstruction, intestinal infarction, or perforated peptic ulcer). Elevation of pleural fluid amylase can occur in acute pancreatitis, chronic pancreatitis, carcinoma of the lung, and esophageal perforation.
Lipase may now be the single best enzyme to measure for the diagnosis of acute pancreatitis. Improvements in substrates and technology offer clinicians improved options, especially when a turbidimetric assay is used. The newer lipase assays have colipase as a cofactor and are fully automated.
No single blood test is reliable for the diagnosis of acute pancreatitis in patients with renal failure. Determining whether a patient with renal failure and abdominal pain has pancreatitis remains a difficult clinical problem. One study found that serum amylase levels were elevated in patients with renal dysfunction only when creatinine clearance was <0.8 mL/s (<50 mL/min). In such patients, the serum amylase level was invariably <8.3 μkat/L (<500 IU/L) in the absence of objective evidence of acute pancreatitis. In that study, serum lipase and trypsin levels paralleled serum amylase values. With these limitations in mind, the recommended screening tests for acute pancreatitis are serum lipase and serum amylase levels. Serum lipase and amylase values greater than three times normal are highly specific.
Studies Pertaining to Pancreatic Structure
Plain films of the abdomen, which once provided useful information in patients with acute and chronic pancreatitis, have been superceded by other detailed imaging procedures (US, EUS, CT, MRCP).
Ultrasonography can provide important information in patients with acute pancreatitis, chronic pancreatitis, pseudocysts, and pancreatic carcinoma. Echographic appearances can indicate the presence of edema, inflammation, and calcification (not obvious on plain films of the abdomen), as well as pseudocysts, mass lesions, and gallstones. In acute pancreatitis, the pancreas is characteristically enlarged. In pancreatic pseudocyst, the usual appearance is primarily that of smooth, round fluid collection. Pancreatic carcinoma distorts the usual landmarks, and mass lesions >3.0 cm are usually detected as localized, solid lesions. Ultrasound is often the initial investigation for most patients with suspected pancreatic disease. However, obesity, excess small- and large-bowel gas can interfere with pancreatic imaging by ultrasound studies.
CT is the best imaging study for initial evaluation of a suspected pancreatic disorder and for the complications of acute and chronic pancreatitis. It is especially useful in the detection of pancreatic and peripancreatic acute fluid collections, fluid-containing lesions such as pseudocysts, walled-off necrosis, calcium deposits (see Chapter 313, Figs. 313-1, 313-2, and 313-4), and pancreatic neoplasms. Most lesions are characterized by (1) enlargement of the pancreatic outline, (2) distortion of the pancreatic contour, and/or (3) a fluid filling that has a different attenuation coefficient than normal pancreas. Oral, water-soluble contrast agents are used to opacify the stomach and duodenum during CT scans; this strategy permits more precise delineation of various organs as well as mass lesions. Dynamic CT (using rapid IV administration of contrast) is useful in estimating the extent of pancreatic necrosis and in predicting morbidity and mortality. Spiral (helical) CT provides clear images much more rapidly and essentially negates artifact caused by patient movement.
EUS produces high-resolution images of the pancreatic parenchyma and pancreatic duct with a transducer fixed to an endoscope that can be directed onto the surface of the pancreas through the stomach or duodenum. EUS and MRCP have largely replaced ERCP for diagnostic purposes in many centers. EUS allows one to obtain information about the pancreatic duct as well as the parenchyma and has few procedure-related complications associated with it, in contrast to the 5−20% of post-ERCP pancreatitis observed. EUS is also helpful in detecting common bile duct stones. Pancreatic masses can be biopsied via EUS and one can deliver nerve-blocking agents through EUS fine-needle injection. Criteria for abnormalities on EUS in severe chronic pancreatic disease have been developed. Currently, chronic pancreatitis is considered diagnosed by EUS if five or more criteria listed in Table 312-3 are present. Recent studies comparing EUS and ERCP to the secretin test in patients with unexplained abdominal pain suspected of having chronic pancreatitis show equivalent diagnostic accuracy in detecting early changes of chronic pancreatitis. The exact role of EUS versus CT, ERCP, or function testing in the early diagnosis of chronic pancreatitis has yet to be clearly defined.
Table 312-3 Endoscopic Ultrasonographic Criteria for Chronic Pancreatitis |Favorite Table|Download (.pdf)
Table 312-3 Endoscopic Ultrasonographic Criteria for Chronic Pancreatitis
|Echogenic ductal walls||Echogenic foci|
|Irregular ductal walls||Calcifications|
|Visible side branches||Cyst|
MRCP/MRI is now being used to view the bile ducts, pancreatic duct, and the pancreas parenchyma. Non breath−holding and three-dimensional turbo spin-echo techniques are being used to produce superb MRCP images. The main pancreatic duct and common bile duct can be seen well, but there is still a question as to whether changes can be detected consistently in the secondary ducts. The secondary ducts are not visualized in a normal pancreas. MRCP may be particularly useful to evaluate the pancreatic duct in high-risk patients such as the elderly because this is a noninvasive procedure. Secretin enhanced MRCP is currently under investigation but is emerging as a method to better evaluate ductal changes.
Both EUS and MRCP have largely replaced diagnostic ERCP in most patients. As these techniques become more refined, they may well be the diagnostic tests of choice to evaluate the pancreatic duct. ERCP is still needed for treatment of bile duct and pancreatic duct lesions. ERCP is primarily of therapeutic value after CT, EUS, or MRCP have detected abnormalities requiring invasive endoscopic treatment. ERCP can also be helpful at clarification of equivocal findings discovered with other imaging techniques (see Chap. 313, Figs. 313-1C, 313-3D, and 313-4B). Pancreatic carcinoma is characterized by stenosis or obstruction of either the pancreatic duct or the common bile duct; both ductal systems are often abnormal. In chronic pancreatitis, ERCP abnormalities include (1) luminal narrowing; (2) irregularities in the ductal system with stenosis, dilation, sacculation, and ectasia; and (3) blockage of the pancreatic duct by calcium deposits. The presence of ductal stenosis and irregularity can make it difficult to distinguish chronic pancreatitis from carcinoma. It is important to be aware that ERCP changes interpreted as indicating chronic pancreatitis actually may be due to the effects of aging on the pancreatic duct or to the fact that the procedure was performed within several weeks of an attack of acute pancreatitis. Although aging may cause impressive ductal alterations, it does not affect the results of pancreatic function tests (i.e., the secretin test). Elevated serum amylase levels after ERCP have been reported in 25−75% of patients, and clinical pancreatitis in 5−20% of patients. There are no satisfactory means to pharmacologically prevent ERCP-induced pancreatitis, despite many agents such as octreotide and nitroglycerin having been suggested and evaluated. The best way to prevent ERCP-induced pancreatitis is to not perform this procedure for diagnostic purposes in high-risk patients, especially in women with acute relapsing pancreatitis in whom there is no evidence of biliary obstruction and patients with unexplained abdominal pain but no other abnormalities. If no lesion is found in the biliary and/or pancreatic ducts in a patient with repeated attacks of acute pancreatitis, manometric studies of the sphincter of Oddi may be indicated. Such studies, however, do increase the risk of post-ERCP/manometry acute pancreatitis. Such pancreatitis appears to be more common in patients with a nondilated pancreatic duct.
Pancreatic Biopsy with Radiologic Guidance
Percutaneous aspiration biopsy or a trucut biopsy of a pancreatic mass often distinguishes a pancreatic inflammatory mass from a pancreatic neoplasm.
Tests of Exocrine Pancreatic Function
Pancreatic function tests (Table 312-1) can be divided into the following:
Direct stimulation of the pancreas by IV infusion of secretin or secretin plus cholecystokinin (CCK) followed by collection and measurement of duodenal contents
Study of intraluminal digestion products, such as undigested meat fibers, stool fat, and fecal nitrogen
Measurement of fecal pancreatic enzymes such as elastase
The secretin test, used to detect diffuse pancreatic disease, is based on the physiologic principle that the pancreatic secretory response is directly related to the functional mass of pancreatic tissue. In the standard assay, secretin is given IV in a dose of 0.2 μg/kg of synthetic human secretin as a bolus. Normal values for the standard secretin test are (1) volume output >2 mL/kg per hour, (2) bicarbonate (HCO3−) concentration >80 mmol/L, and (3) HCO3− output >10 mmol/L in 1 hour. The most reproducible measurement, giving the highest level of discrimination between normal subjects and patients with chronic pancreatic exocrine insufficiency, appears to be the maximal bicarbonate concentration.
There may be a dissociation between the results of the secretin test and other tests of absorptive function. For example, patients with chronic pancreatitis often have abnormally low outputs of HCO3− after secretin but have normal fecal fat excretion. Thus the secretin test measures the secretory capacity of ductular epithelium, while fecal fat excretion indirectly reflects intraluminal lipolytic activity. Steatorrhea does not occur until intraluminal levels of lipase are markedly reduced, underscoring the fact that only small amounts of enzymes are necessary for intraluminal digestive activities. It must be noted that, an abnormal secretin test result suggests only that chronic pancreatic damage is present.
Measurement of intraluminal digestion products (i.e., undigested muscle fibers, stool fat, and fecal nitrogen) is discussed in Chap. 294. The amount of human elastase in stool reflects the pancreatic output of this proteolytic enzyme. Decreased elastase activity in stool is an excellent test to detect severe pancreatic exocrine insufficiency in patients with chronic pancreatitis and cystic fibrosis provided that the stool specimen is solid.
Tests useful in the diagnosis of exocrine pancreatic insufficiency and the differential diagnosis of malabsorption are also discussed in Chaps. 294 and 313.