Section 4: Disorders of the Pancreas

GENERAL CONSIDERATIONS

As emphasized in Chap. 341, the etiologies as well as 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, genetic mutations, 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.

The incidence of acute pancreatitis is about 5–35 per 100,000 new cases per year worldwide, with a mortality rate of about 3%. The incidence of chronic pancreatitis is about 4–8 per 100,000 persons with a prevalence of 26–42 cases per 100,000. The number of patients admitted to the hospital who suffer with both acute and chronic pancreatitis in the United States is largely increasing and is now estimated to be 274,119 for acute pancreatitis and 19,724 for chronic pancreatitis. Acute pancreatitis is the most common gastrointestinal diagnosis requiring hospitalization in the United States. Acute and chronic pancreatic disease costs an estimated $3 billion annually in health care expenditures. These numbers may underestimate 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 diagnosis of acute pancreatitis is generally clearly defined based on a combination of laboratory, imaging, and clinical symptoms. The diagnosis of chronic pancreatitis, especially in mild disease, is hampered by the relative inaccessibility of the pancreas to direct examination and the nonspecificity of the abdominal pain associated with chronic pancreatitis. 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 (PEI), 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 advanced pancreatic disease (i.e., pancreatic calcification, steatorrhea, or diabetes mellitus) than in patients with occult disease. Invasive, direct tests of pancreatic secretory function (secretin tests) are the most sensitive and specific tests to detect early chronic pancreatic disease when imaging is equivocal or normal.

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 340-1 and Fig. 340-1. At some institutions, pancreatic function tests are available and performed if the diagnosis of chronic pancreatic disease remains a possibility after noninvasive tests (ultrasound, computed tomography [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 using direct stimulation of the pancreas with secretin are the most sensitive.

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 (3× ULN) in combination with epigastric pain strongly suggest the diagnosis of acute pancreatitis. In acute pancreatitis, the serum amylase and lipase are usually elevated within 24 h of onset and remain 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 lipase and amylase levels. The values may be normal if (1) there is a delay (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 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 340-2), 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). Isoamylase determinations do not accurately distinguish elevated blood amylase levels from pancreatic or nonpancreatic sources. In patients with unexplained hyperamylasemia, measurement of macroamylase can avoid numerous tests in patients with this rare disorder.

Elevation of ascitic fluid amylase occurs in acute pancreatitis as well as in (1) 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 is the single best enzyme to measure for the diagnosis of acute pancreatitis. No single blood test is reliable for the diagnosis of acute pancreatitis in patients with renal failure. Pancreatic enzyme elevations are usually less than three times the upper limit of normal. 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 <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 test for acute pancreatitis in renal disease is serum lipase.

Studies Pertaining to Pancreatic Structure

RADIOLOGIC TESTS

Plain films of the abdomen, which once provided useful information in patients with acute and chronic pancreatitis, have been superseded by other more detailed imaging procedures (ultrasound, EUS, CT, MRCP).

Ultrasonography can provide important information in patients with acute pancreatitis, chronic pancreatitis, pseudocysts, and pancreatic carcinoma. Sonographic changes 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 a smooth, round fluid collection. Pancreatic carcinoma distorts the usual landmarks, and mass lesions >3.0 cm are usually detected as localized, solid lesions. US is often the initial investigation for most patients with suspected pancreatic disease. However, obesity and excess intestinal bowel gas can interfere with pancreatic imaging by US studies.

Computed tomography is the best imaging study for initial evaluation of a suspected pancreatic disorder and for the assessment of 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 Chap. 341, Figs. 341-1, 341-2, and 341-4), and pancreatic neoplasms. Acute pancreatitis is characterized by (1) enlargement of the pancreatic outline, (2) distortion of the pancreatic contour, and/or (3) a pancreatic fluid 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. CT provides clear images much more rapidly and essentially negates artifact caused by patient movement. If acute pancreatitis is confirmed with serology and physical examination findings, CT scan in the first 3 days is not recommended to avoid overuse and minimize costs. The major benefit of CT in acute pancreatitis is the diagnosis of pancreatic necrosis in patients not responding to conservative management within 72 h.

Endoscopic ultrasonography 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 replaced ERCP for diagnostic purposes. 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 5–10% of post-ERCP pancreatitis observed. EUS is also helpful in detecting common bile duct stones in acute pancreatitis. Pancreatic masses can also be biopsied via EUS in cases with suspected pancreas cancer, and one can deliver nerve-blocking agents through EUS fine-needle injection in patients suffering from pancreatic pain from chronic pancreatitis or cancer. EUS has been studied as a diagnostic modality for chronic pancreatitis. Criteria for abnormalities on EUS in severe chronic pancreatic disease have been developed. There is general agreement that the presence of five or more of the nine criteria listed in Table 340-3 is highly predictive of chronic pancreatitis. Recent studies comparing EUS and ERCP to the secretin test in patients with unexplained abdominal pain suspected of having chronic pancreatitis show similar 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.

MRI and MRCP are now being used to view the bile ducts, pancreatic duct, and the pancreas parenchyma in both acute pancreatitis and chronic pancreatitis. For diagnostic imaging in chronic pancreatitis, 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. Secretin-enhanced MRCP is emerging as a method to better evaluate ductal changes. In anteroposterior imaging, T2 imaging of fluid collections can differentiate necrotic debris from fluid in suspected walled-off necrosis, and T1 imaging can diagnose hemorrhage in suspected pseudoaneurysm rupture.

As mentioned, EUS and MRCP have largely replaced ERCP in the diagnostic evaluation of pancreatic disease. As these techniques become more refined, especially with the administration of secretin, they may well be the diagnostic tests of choice to evaluate the pancreatic duct. ERCP is primarily of therapeutic value after CT, EUS, or MRCP has detected abnormalities requiring invasive endoscopic treatment. ERCP can also be helpful at clarification of equivocal findings discovered with other imaging techniques (see Chap. 341, Fig. 341-1). Pancreatic carcinoma is characterized by stenosis or obstruction of either the pancreatic duct or the common bile duct; both ductal systems are often abnormal (double-duct sign). In chronic pancreatitis, ERCP abnormalities in the main pancreatic duct and side branches have been outlined by the Cambridge classification. 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 sequelae of a recent 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 the majority of patients, and clinical pancreatitis in 5–10% of patients. Recent data suggest that pancreatic duct stenting and rectal indomethacin can decrease the incidence of ERCP-induced pancreatitis. ERCP should not be done for diagnostic purposes and should especially be avoided in high-risk patients.

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 340-1) can be divided into the following:

1. Direct stimulation of the pancreas by IV infusion of secretin followed by collection and measurement of duodenal contents

   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 h. The most reproducible measurement, giving the highest level of discrimination between normal subjects and patients with chronic PEI, appears to be the maximal bicarbonate concentration. A cutoff point below 80 mmol/L is considered abnormal and suggestive of abnormal secretory function that is most commonly observed in early chronic pancreatitis.

   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, whereas 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 emphasized that an abnormal secretin test result suggests that pancreatic ductal secretory function is abnormal. This is commonly observed in chronic pancreatitis.

2. Measurement of fecal pancreatic enzymes such as elastase

   Measurement of intraluminal digestion products (i.e., undigested muscle fibers, stool fat, and fecal nitrogen) is discussed in Chap. 318. The amount of human elastase in stool reflects the pancreatic output of this proteolytic enzyme. Decreased elastase-1 activity (FE-1) in stool is an excellent test to detect severe PEI in patients with chronic pancreatitis and cystic fibrosis. FE-1 levels >200 μg/g are normal, levels of 100–200 μg/g are considered mild, and levels <100 μg/g are severe for PEI. Although the test is simple and noninvasive, it can give false-positive results and has a low sensitivity. Fecal levels <50 μg/g are definitive for PEI 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. 318 and 341.

FURTHER READING

GENERAL CONSIDERATIONS

The pancreas secretes 1500–3000 mL of isosmotic alkaline (pH >8) fluid per day containing about 20 enzymes. The pancreatic secretions provide the enzymes and bicarbonate needed to affect the major digestive activity of the gastrointestinal tract and provide an optimal pH for the function of these enzymes.

REGULATION OF PANCREATIC SECRETION

The exocrine pancreas is influenced by intimately interacting hormonal and neural systems. Gastric acid is the stimulus for the release of secretin from the duodenal mucosa (S cells), which stimulates the secretion of water and electrolytes from pancreatic ductal cells. Release of cholecystokinin (CCK) from the duodenal and proximal jejunal mucosa (Ito cells) is largely triggered by long-chain fatty acids, essential amino acids (tryptophan, phenylalanine, valine, methionine), and gastric acid itself. CCK evokes an enzyme-rich secretion from acinar cells in the pancreas. The parasympathetic nervous system (via the vagus nerve) exerts significant control over pancreatic secretion. Secretion evoked by secretin and CCK depends on permissive roles of vagal afferent and efferent pathways. This is particularly true for enzyme secretion, whereas water and bicarbonate secretions are heavily dependent on the hormonal effects of secretin and to a lesser extent CCK. Also, vagal stimulation affects the release of vasoactive intestinal peptide (VIP), a secretin agonist. Pancreatic exocrine secretion is also influenced by inhibitory neuropeptides such as somatostatin, pancreatic polypeptide, peptide YY, neuropeptide Y, enkephalin, pancreastatin, calcitonin gene–related peptides, glucagon, and galanin. Although pancreatic polypeptide and peptide YY may act primarily on nerves outside the pancreas, somatostatin acts at multiple sites. Nitric oxide (NO) is also an important neurotransmitter.

WATER AND ELECTROLYTE SECRETION

Bicarbonate is the ion of primary physiologic importance within pancreatic secretion. The ductal cells secrete bicarbonate predominantly derived from plasma (93%) more than from intracellular metabolism (7%). Bicarbonate enters the duct lumen through the sodium bicarbonate cotransporter with depolarization caused by chloride efflux through the cystic fibrosis transmembrane conductance regulator (CFTR). Secretin and VIP bind at the basolateral surface and cause an increase in secondary messenger intracellular cyclic AMP, and act on the apical surface of the ductal cells opening the CFTR in promoting secretion. CCK, acting as a neuromodulator, markedly potentiates the stimulatory effects of secretin. Acetylcholine also plays an important role in ductal cell secretion. Intraluminal bicarbonate secreted from the ductal cells helps neutralize gastric acid and creates the appropriate pH for the activity of pancreatic enzymes and bile salts on ingested food.

ENZYME SECRETION

The acinar cell is highly compartmentalized and is concerned with the secretion of pancreatic enzymes. Proteins synthesized by the rough endoplasmic reticulum are processed in the Golgi and then targeted to the appropriate site, whether that be zymogen granules, lysosomes, or other cell compartments. The zymogen granules migrate to the apical region of the acinar cell awaiting the appropriate neural or hormonal stimulatory response. The pancreas secretes amylolytic, lipolytic, and proteolytic enzymes into the duct lumen. Amylolytic enzymes, such as amylase, hydrolyze starch to oligosaccharides and to the disaccharide maltose. The lipolytic enzymes include lipase, phospholipase A₂, and cholesterol esterase. Bile salts inhibit lipase in isolation, but colipase, another constituent of pancreatic secretion, binds to lipase and prevents this inhibition. Bile salts activate phospholipase A and cholesterol esterase. Proteolytic enzymes include endopeptidases (trypsin, chymotrypsin), which act on internal peptide bonds of proteins and polypeptides; exopeptidases (carboxypeptidases, aminopeptidases), which act on the free carboxyl- and amino-terminal ends of peptides, respectively; and elastase. The proteolytic enzymes are secreted as inactive zymogen precursors. Ribonucleases (deoxyribonucleases, ribonuclease) are also secreted. Enterokinase, an enzyme found in the duodenal mucosa, cleaves the lysine-isoleucine bond of trypsinogen to form trypsin. Trypsin then activates the other proteolytic zymogens and phospholipase A₂ in a cascade phenomenon. All pancreatic enzymes have pH optima in the alkaline range. The nervous system initiates pancreatic enzyme secretion. The neurologic stimulation is cholinergic, involving extrinsic innervation by the vagus nerve and subsequent innervation by intrapancreatic cholinergic nerves. The stimulatory neurotransmitters are acetylcholine and gastrin-releasing peptides. These neurotransmitters activate calcium-dependent secondary messenger systems, resulting in the release of zymogens into the pancreas duct. VIP is present in intrapancreatic nerves and potentiates the effect of acetylcholine. In contrast to other species, there are no CCK receptors on acinar cells in humans. CCK in physiologic concentrations stimulates pancreatic secretion by stimulating afferent vagal and intrapancreatic nerves.

AUTOPROTECTION OF THE PANCREAS

Autodigestion of the pancreas is prevented by (1) the packaging of pancreatic proteases in precursor (proenzyme) form, (2) intracellular calcium homeostasis (low intracellular calcium in the cytosol of the acinar cell promotes the destruction of spontaneously activated trypsin), (3) acid-base balance, and (4) the synthesis of protective protease inhibitors (pancreatic secretory trypsin inhibitor [PSTI] or SPINK1), which can bind and inactivate about 20% of intracellular trypsin activity. Chymotrypsin C can also lyse and inactivate trypsin. These protease inhibitors are found in the acinar cell, the pancreatic secretions, and the α₁- and α₂-globulin fractions of plasma. Loss of any of these four protective mechanisms leads to premature enzyme activation, autodigestion, and acute pancreatitis.

ENTEROPANCREATIC AXIS AND FEEDBACK INHIBITION

Pancreatic enzyme secretion is controlled, at least in part, by a negative feedback mechanism induced by the presence of active serine proteases in the duodenum. To illustrate, perfusion of the duodenal lumen with phenylalanine (stimulates early digestion) causes a prompt increase in plasma CCK levels as well as increased secretion of chymotrypsin and other pancreatic enzymes. However, simultaneous perfusion with trypsin (stimulates late digestion) blunts both responses. Conversely, perfusion of the duodenal lumen with protease inhibitors actually leads to enzyme hypersecretion. The available evidence supports the concept that the duodenum contains a peptide called CCK-releasing factor (CCK-RF) that is involved in stimulating CCK release. It appears that serine proteases inhibit pancreatic secretion by inactivating a CCK-releasing peptide in the lumen of the small intestine. Thus, the integrative result of both bicarbonate and enzyme secretion depends on a feedback process for both bicarbonate and pancreatic enzymes. Acidification of the duodenum releases secretin, which stimulates vagal and other neural pathways to activate pancreatic duct cells, which secrete bicarbonate. This bicarbonate then neutralizes the duodenal acid, and the feedback loop is completed. Dietary proteins bind proteases, thereby leading to an increase in free CCK-RF. CCK is then released into the blood in physiologic concentrations, acting primarily through the neural pathways (vagal-vagal). This leads to acetylcholine-mediated pancreatic enzyme secretion. Proteases continue to be secreted from the pancreas until the protein within the duodenum is digested. At this point, pancreatic protease secretion is reduced to basic levels, thus completing this step in the feedback process.

GENERAL CONSIDERATIONS IN ACUTE PANCREATITIS

Recent U.S. estimates from the Nationwide Inpatient Sample report that acute pancreatitis is the most common inpatient principal gastrointestinal diagnosis. The incidence of acute pancreatitis also varies in different countries and depends on cause (e.g., alcohol, gallstones, metabolic factors, drugs [Table 341-1]). The annual incidence ranges from 13 to 45 cases per 100,000 persons. Acute pancreatitis results in >250,000 hospitalizations per year. The median length of hospital stay is 4 days, with a median hospital cost of $6096 and a mortality of 1%. The estimated cost annually approaches $2.6 billion. Hospitalization rates increase with age, which are 88% higher among blacks, and are higher among males than females. The age-adjusted rate of hospital discharges with an acute pancreatitis diagnosis increased 62% between 1988 and 2004. From 2000 to 2009, the rate increased 30%. Thus, acute pancreatitis is increasing and is a significant burden on health care costs and resource utilization.

ETIOLOGY AND PATHOGENESIS IN ACUTE PANCREATITIS

There are many causes of acute pancreatitis (Table 341-1), but the mechanisms by which these conditions trigger pancreatic inflammation have not been fully elucidated. Gallstones and alcohol account for 80–90% of the acute pancreatitis cases in the United States. Gallstones continue to be the leading cause of acute pancreatitis in most series (30–60%). The risk of acute pancreatitis in patients with at least one gallstone <5 mm in diameter is fourfold greater than that in patients with larger stones. Alcohol is the second most common cause, responsible for 15–30% of cases in the United States. The incidence of pancreatitis in alcoholics is surprisingly low (5/100,000), indicating that in addition to the amount of alcohol ingested, other factors affect a person’s susceptibility to pancreatic injury such as cigarette smoking. Acute pancreatitis occurs in 5–10% of patients following endoscopic retrograde cholangiopancreatography (ERCP). Use of a prophylactic pancreatic duct stent and rectal nonsteroidal anti-inflammatory drugs (NSAIDs, indomethicin) has been shown to reduce pancreatitis after ERCP. Risk factors for post-ERCP pancreatitis include minor papilla sphincterotomy, sphincter of Oddi dysfunction, prior history of post-ERCP pancreatitis, age <60 years, >2 contrast injections into the pancreatic duct, and endoscopic trainee involvement.

Hypertriglyceridemia is the cause of acute pancreatitis in 1.3–3.8% of cases; serum triglyceride levels are usually >1000 mg/dL. Most patients with hypertriglyceridemia, when subsequently examined, show evidence of an underlying derangement in lipid metabolism, probably unrelated to pancreatitis. Such patients are prone to recurrent episodes of pancreatitis. Any factor (e.g., drugs or alcohol) that causes an abrupt increase in serum triglycerides can precipitate a bout of acute pancreatitis. Patients with a deficiency of apolipoprotein CII have an increased incidence of pancreatitis; apolipoprotein CII activates lipoprotein lipase, which is important in clearing chylomicrons from the bloodstream. Patients with diabetes mellitus who have developed ketoacidosis and patients who are on certain medications such as oral contraceptives may also develop high triglyceride levels. Approximately 0.1–2% of cases of acute pancreatitis are drug related. Drugs cause pancreatitis either by a hypersensitivity reaction or by the generation of a toxic metabolite, although in some cases, it is not clear which of these mechanisms is operative (Table 341-1).

Pathologically, acute pancreatitis varies from interstitial pancreatitis (pancreas blood supply maintained), which is generally self-limited to necrotizing pancreatitis (pancreas blood supply interrupted), in which the extent of necrosis may correlate with the severity of the attack and its systemic complications. Autodigestion is a currently accepted pathogenic theory; according to this theory, pancreatitis results when proteolytic enzymes (e.g., trypsinogen, chymotrypsinogen, proelastase, and lipolytic enzymes such as phospholipase A₂) are activated in the pancreas acinar cell rather than in the intestinal lumen. A number of factors (e.g., endotoxins, exotoxins, viral infections, ischemia, oxidative stress, lysosomal calcium, and direct trauma) are believed to facilitate premature activation of trypsin. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also can activate other enzymes, such as elastase and phospholipase A₂. Spontaneous activation of trypsin also can occur.

ACTIVATION OF PANCREATIC ENZYMES IN THE PATHOGENESIS OF ACUTE PANCREATITIS

Several recent studies have suggested that pancreatitis is a disease that evolves in three phases. The initial phase is characterized by intrapancreatic digestive enzyme activation and acinar cell injury. Trypsin activation appears to be mediated by lysosomal hydrolases such as cathepsin B that become colocalized with digestive enzymes in intracellular organelles; it is currently believed that acinar cell injury is the consequence of trypsin activation. The second phase of pancreatitis involves the activation, chemoattraction, and sequestration of leukocytes and macrophages in the pancreas, resulting in an enhanced intrapancreatic inflammatory reaction. Neutrophil depletion induced by prior administration of an antineutrophil serum has been shown to reduce the severity of experimentally induced pancreatitis. There is also evidence to support the concept that neutrophils can activate trypsinogen. Thus, intrapancreatic acinar cell activation of trypsinogen could be a two-step process (i.e., an early neutrophil-independent and a later neutrophil-dependent phase). The third phase of pancreatitis is due to the effects of activated proteolytic enzymes and cytokines, released by the inflamed pancreas, on distant organs. Activated proteolytic enzymes, especially trypsin, not only digest pancreatic and peripancreatic tissues but also activate other enzymes such as elastase and phospholipase A₂. The active enzymes and cytokines then digest cellular membranes and cause proteolysis, edema, interstitial hemorrhage, vascular damage, coagulation necrosis, fat necrosis, and parenchymal cell necrosis. Cellular injury and death result in the liberation of bradykinin peptides, vasoactive substances, and histamine that can produce vasodilation, increased vascular permeability, and edema with profound effects on many organs. The systemic inflammatory response syndrome (SIRS) and acute respiratory distress syndrome (ARDS), as well as multiorgan failure, may occur as a result of this cascade of local and distant effects.

A number of genetic factors can increase the susceptibility and/or modify the severity of pancreatic injury in acute pancreatitis, recurrent pancreatitis, and chronic pancreatitis. All of the major genetic susceptibility factors center on the control of trypsin activity within the pancreatic acinar cell, in part because they were identified as candidate genes linked to intrapancreatic trypsin control. Five genetic variants have been identified as being associated with susceptibility to pancreatitis. The genes that have been identified include (1) cationic trypsinogen gene (PRSS1), (2) pancreatic secretory trypsin inhibitor (SPINK1), (3) the cystic fibrosis transmembrane conductance regulator gene (CFTR), (4) the chymotrypsin C gene (CTRC), and (5) the calcium-sensing receptor (CASR). Investigations of other genetic variants are currently under way, and new genes will be added to this list in the future. Multiple medical, ethical, and psychological issues arise when these genes are discovered, and referral to genetic counselors is recommended.

APPROACH TO THE PATIENT WITH ACUTE PANCREATITIS

LABORATORY DATA IN ACUTE PANCREATITIS

Serum amylase and lipase values threefold or more above normal virtually clinch the diagnosis if gut perforation, ischemia, and infarction are excluded. Serum lipase is the preferred test. However, it should be noted that there is no correlation between the severity of pancreatitis and the degree of serum lipase and amylase elevations. After 3–7 days, even with continuing evidence of pancreatitis, total serum amylase values tend to return toward normal. However, pancreatic lipase levels may remain elevated for 7–14 days. It should be recognized that amylase elevations in serum and urine occur in many conditions other than pancreatitis (see Chap. 340, Table 340-2). Importantly, patients with acidemia (arterial pH ≤7.32) may have spurious elevations in serum amylase. This finding explains why patients with diabetic ketoacidosis may have marked elevations in serum amylase without any other evidence of acute pancreatitis. Serum lipase activity increases in parallel with amylase activity and is more specific than amylase. A serum lipase measurement can be instrumental in differentiating a pancreatic or nonpancreatic cause for hyperamylasemia. Leukocytosis (15,000–20,000 leukocytes/μL) occurs frequently. Patients with more severe disease may show hemoconcentration with hematocrit values >44% and/or prerenal azotemia with a blood urea nitrogen (BUN) level >22 mg/dL resulting from loss of plasma into the retroperitoneal space and peritoneal cavity.

Hemoconcentration may be the harbinger of more severe disease (i.e., pancreatic necrosis), whereas azotemia is a significant risk factor for mortality. Hyperglycemia is common and is due to multiple factors, including decreased insulin release, increased glucagon release, and an increased output of adrenal glucocorticoids and catecholamines. Hypocalcemia occurs in ~25% of patients, and its pathogenesis is incompletely understood. Although earlier studies suggested that the response of the parathyroid gland to a decrease in serum calcium is impaired, subsequent observations have failed to confirm this phenomenon. Intraperitoneal saponification of calcium by fatty acids in areas of fat necrosis occurs occasionally, with large amounts (up to 6.0 g) dissolved or suspended in ascitic fluid. Such “soap formation” may also be significant in patients with pancreatitis, mild hypocalcemia, and little or no obvious ascites. Hyperbilirubinemia (serum bilirubin >4.0 mg/dL) occurs in ~10% of patients. However, jaundice is transient, and serum bilirubin levels return to normal in 4–7 days. Serum alkaline phosphatase and aspartate aminotransferase levels are also transiently elevated, and they parallel serum bilirubin values and may point to gallbladder-related disease or inflammation in the pancreatic head. Hypertriglyceridemia occurs in 5–10% of patients, and serum amylase levels in these individuals are often spuriously normal (Chap. 340). Approximately 5–10% of patients have hypoxemia (arterial PO₂ ≤60 mm Hg), which may herald the onset of ARDS. Finally, the electrocardiogram is occasionally abnormal in acute pancreatitis with ST-segment and T-wave abnormalities simulating myocardial ischemia.

An abdominal ultrasound is recommended in the emergency ward as the initial diagnostic imaging modality and is most useful to evaluate for gallstone disease and the pancreatic head.

The Revised Atlanta criteria have clearly outlined the morphologic features of acute pancreatitis on computed tomography (CT) scan as follows: (1) interstitial pancreatitis, (2) necrotizing pancreatitis, (3) acute pancreatic fluid collection, (4) pancreatic pseudocyst, (5) acute necrotic collection (ANC), and (6) walled-off necrosis (WON) (Table 341-2 and Fig. 341-1). Radiologic studies useful in the diagnosis of acute pancreatitis are discussed in Chap. 340 and listed in Table 340-1.

DIAGNOSIS OF ACUTE PANCREATITIS

Any severe acute pain in the abdomen or back should suggest the possibility of acute pancreatitis. The diagnosis is established by two of the following three criteria: (1) typical abdominal pain in the epigastrium that may radiate to the back, (2) threefold or greater elevation in serum lipase and/or amylase, and (3) confirmatory findings of acute pancreatitis on cross-sectional abdominal imaging. Patients also have associated nausea, emesis, fever, tachycardia, and abnormal findings on abdominal examination. Laboratory studies may reveal leukocytosis, hypocalcemia, and hyperglycemia. Although not required for diagnosis, markers of severity may include hemoconcentration (hematocrit >44%), admission azotemia (BUN >22 mg/dL), SIRS, and signs of organ failure (Table 341-3).

The differential diagnosis should include the following disorders: (1) perforated viscus, especially peptic ulcer; (2) acute cholecystitis and biliary colic; (3) acute intestinal obstruction; (4) mesenteric vascular occlusion; (5) renal colic; (6) inferior myocardial infarction; (7) dissecting aortic aneurysm; (8) connective tissue disorders with vasculitis; (9) pneumonia; and (10) diabetic ketoacidosis. It may be difficult to differentiate acute cholecystitis from acute pancreatitis, because an elevated serum amylase may be found in both disorders. Pain of biliary tract origin is more right sided or epigastric than periumbilical or left upper quadrant and can be more severe; ileus is usually absent. Ultrasound is helpful in establishing the diagnosis of cholelithiasis and cholecystitis. Intestinal obstruction due to mechanical factors can be differentiated from pancreatitis by the history of crescendo-decrescendo pain, findings on abdominal examination, and CT of the abdomen showing changes characteristic of mechanical obstruction. Acute mesenteric vascular occlusion is usually suspected in elderly debilitated patients with brisk leukocytosis, abdominal distention, and bloody diarrhea, confirmed by CT or magnetic resonance angiography. Vasculitides secondary to systemic lupus erythematosus and polyarteritis nodosa may be confused with pancreatitis, especially because pancreatitis may develop as a complication of these diseases. Diabetic ketoacidosis is often accompanied by abdominal pain and elevated total serum amylase levels, thus closely mimicking acute pancreatitis. However, the serum lipase level is not elevated in diabetic ketoacidosis.

CLINICAL COURSE, DEFINITIONS, AND CLASSIFICATIONS IN ACUTE PANCREATITIS

The Revised Atlanta Criteria (1) defines phases of acute pancreatitis, (2) outlines severity of acute pancreatitis, and (3) clarifies imaging definitions as outlined below.

Phases of Acute Pancreatitis

Two phases of acute pancreatitis have been defined, early (<2 weeks) and late (>2 weeks), which primarily describes the hospital course of the disease. In the early phase of acute pancreatitis, which lasts 1–2 weeks, severity is defined by clinical parameters rather than morphologic findings. Most patients exhibit SIRS, and if this persists, patients are predisposed to organ failure. Three organ systems should be assessed to define organ failure: respiratory, cardiovascular, and renal. Organ failure is defined as a score of 2 or more for one of these three organ systems using the modified Marshall scoring system. Persistent organ failure (>48 h) is the most important clinical finding in regard to severity of the acute pancreatitis episode. Organ failure that affects more than one organ is considered multisystem organ failure. CT imaging is usually not needed or recommended during the first 48 h of admission in acute pancreatitis.

The late phase is characterized by a protracted course of illness and may require imaging to evaluate for local complications. The important clinical parameter of severity, as in the early phase, is persistent organ failure. These patients may require supportive measures such as renal dialysis, ventilator support, or need for supplemental nutrition via the nasojejunal or parenteral route. The radiographic feature of greatest importance to recognize in this phase is the development of necrotizing pancreatitis on CT imaging. Necrosis generally prolongs hospitalization and, if infected, may require operative, endoscopic, or percutaneous intervention.

Severity of Acute Pancreatitis

Three severity classifications have also been defined: mild, moderately severe, and severe. Mild acute pancreatitis is without local complications or organ failure. Most patients with interstitial acute pancreatitis have mild pancreatitis. In mild acute pancreatitis, the disease is self-limited and subsides spontaneously, usually within 3–7 days after treatment is instituted. Oral intake can be resumed if the patient is hungry, has normal bowel function, and is without nausea and vomiting. Typically, a clear or full liquid diet has been recommended for the initial meal; however, a low-fat solid diet is a reasonable choice following recovery from mild acute pancreatitis.

Moderately severe acute pancreatitis is characterized by transient organ failure (resolves in <48 h) or local or systemic complications in the absence of persistent organ failure. These patients may or may not have necrosis, but may develop a local complication such as a fluid collection that requires a prolonged hospitalization >1 week.

Severe acute pancreatitis is characterized by persistent organ failure (>48 h). Organ failure can be single or multiple. A CT scan or magnetic resonance imaging (MRI) should be obtained to assess for necrosis and/or complications. If a local complication is encountered, management is dictated by clinical symptoms, evidence of infection, maturity of fluid collection, and clinical stability of the patient. Prophylactic antibiotics are not recommended.

IMAGING IN ACUTE PANCREATITIS

Two types of pancreatitis are recognized on imaging as interstitial or necrotizing based on pancreatic perfusion. CT imaging is best evaluated 3–5 days into hospitalization when patients are not responding to supportive care to look for local complications such as necrosis. Recent studies report the overutilization of CT imaging in acute pancreatitis and its inability to be better than clinical judgment in the early days of acute pancreatitis management. The Revised Atlanta criteria also outline the terminology for local complications and fluid collections along with a CT imaging template to guide reporting of findings. Local morphologic features are summarized in Table 341-1. Interstitial pancreatitis occurs in 90–95% of admissions for acute pancreatitis and is characterized by diffuse gland enlargement, homogenous contrast enhancement, and mild inflammatory changes or peripancreatic stranding. Symptoms generally resolve with a week of hospitalization. Necrotizing pancreatitis occurs in 5–10% of acute pancreatitis admissions and does not evolve until several days of hospitalization. It is characterized by lack of pancreatic parenchymal enhancement by intravenous contrast agent and/or presence of findings of peripancreatic necrosis. According to the Revised Atlanta criteria, the natural history of pancreatic and peripancreatic necrosis is variable because it may remain solid or liquefy, remain sterile or become infected, and persist or disappear over time. CT identification of local complications, particularly necrosis, is critical in patients who are not responding to therapy because patients with infected and sterile necrosis are at greatest risk of mortality (Figs. 341-1B, 341-2, and 341-3). The median prevalence of organ failure is 54% in necrotizing pancreatitis. The prevalence of organ failure is perhaps slightly higher in infected versus sterile necrosis. With single-organ system failure, the mortality is 3–10% but increases to 47% with multisystem organ failure.

OVERVIEW

We will briefly outline the management of patients with acute pancreatitis from the time of diagnosis in the emergency ward to ongoing hospital admission and, finally, to time of discharge, highlighting salient features based on severity and complications. It is important to note that 85–90% of cases of acute pancreatitis are self-limited and subside spontaneously, usually within 3–7 days after initiation of treatment, and do not exhibit organ failure or local complications.

The management of acute pancreatitis begins in the emergency ward. After a diagnosis has been confirmed, aggressive fluid resuscitation is initiated, intravenous analgesics are administered, severity is assessed, and a search for etiologies that may impact acute care is begun. Patients who do not respond to aggressive fluid resuscitation in the emergency ward should be considered for admission to a step-down or intensive care unit for aggressive fluid resuscitation, hemodynamic monitoring, and management of necrosis or organ failure.

FLUID RESUSCITATION AND MONITORING RESPONSE TO THERAPY IN ACUTE PANCREATITIS

The most important treatment intervention for acute pancreatitis is safe, aggressive intravenous fluid resuscitation. The patient is made NPO to rest the pancreas and is given intravenous narcotic analgesics to control abdominal pain and supplemental oxygen (2 L) via nasal cannula.

Intravenous fluids of lactated Ringer’s or normal saline are initially bolused at 15–20 mL/kg (1050–1400 mL), followed by 2–3 mL/kg per hour (200–250 mL/h), to maintain urine output >0.5 mL/kg per hour. Serial bedside evaluations are required every 6–8 h to assess vital signs, oxygen saturation, and change in physical examination to optimize fluid resuscitation. Lactated Ringer’s solution has been shown to decrease systemic inflammation (lower CRP levels from admission) and may be a better crystalloid than normal saline. A targeted resuscitation strategy with measurement of hematocrit and BUN every 8–12 h is recommended to ensure adequacy of fluid resuscitation and monitor response to therapy, noting less aggressive resuscitation strategy may be needed in milder forms of pancreatitis. A rising BUN during hospitalization is not only associated with inadequate hydration but also higher in-hospital mortality.

A decrease in hematocrit and BUN during the first 12–24 h is strong evidence that sufficient fluids are being administered. Serial measurements and bedside assessment for fluid overload are continued, and fluid rates are maintained at the current rate. Adjustments in fluid resuscitation may be required in patients with cardiac, pulmonary, or renal disease. A rise in hematocrit or BUN during serial measurement should be treated with a repeat volume challenge with a 2-L crystalloid bolus followed by increasing the fluid rate by 1.5 mg/kg per hour. If the BUN or hematocrit fails to respond (i.e., remains elevated or does not decrease) to this bolus challenge and increase in fluid rate, consideration of transfer to an intensive care unit is strongly recommended for hemodynamic monitoring.

ASSESSMENT OF SEVERITY AND HOSPITAL TRIAGE IN ACUTE PANCREATITIS

Severity of acute pancreatitis should be determined in the emergency ward to assist in patient triage to a regular hospital ward or step-down unit or direct admission to an intensive care unit. The Bedside Index of Severity in Acute Pancreatitis (BISAP) incorporates five clinical and laboratory parameters obtained within the first 24 h of hospitalization (Table 341-3)—BUN >25 mg/dL, impaired mental status (Glasgow coma score <15), SIRS, age >60 years, and pleural effusion on radiography—that can be useful in assessing severity. Presence of three or more of these factors was associated with substantially increased risk for in-hospital mortality among patients with acute pancreatitis. In addition, an elevated hematocrit >44% and admission BUN >22 mg/dL are also associated with more severe acute pancreatitis. Incorporating these indices with the overall patient response to initial fluid resuscitation in the emergency ward can be useful at triaging patients to the appropriate hospital acute care setting.

In general, patients with lower BISAP scores, hematocrits, and admission BUNs tend to respond to initial management and are triaged to a regular hospital ward for ongoing care. If SIRS is not present at 24 h, the patient is unlikely to develop organ failure or necrosis. Therefore, patients with persistent SIRS at 24 h or underlying comorbid illnesses (e.g., chronic obstructive pulmonary disease, congestive heart failure) should be considered for a step-down unit setting if available. Patients with higher BISAP scores and elevations in hematocrit and admission BUN that do not respond to initial fluid resuscitation and exhibit evidence of respiratory failure, hypotension, or organ failure should be considered for direct admission to an intensive care unit.

SPECIAL CONSIDERATIONS BASED ON ETIOLOGY IN ACUTE PANCREATIC MANAGEMENT

A careful history, review of medications, selected laboratory studies (liver profile, serum triglycerides, serum calcium), and an abdominal ultrasound are recommended in the emergency ward to assess for etiologies that may impact acute management. An abdominal ultrasound is the initial imaging modality of choice and will evaluate the gallbladder and common duct and assess the pancreatic head.

Gallstone Pancreatitis

Patients with evidence of ascending cholangitis (rising white blood cell count, increasing liver enzymes) should undergo ERCP within 24–48 h of admission. Patients with gallstone pancreatitis are at increased risk of recurrence, and consideration should be given to performing a cholecystectomy during the same admission or within 4–6 weeks of discharge. An alternative for patients who are not surgical candidates would be to perform an endoscopic biliary sphincterotomy before discharge.

Hypertriglyeridemia

Serum triglycerides >1000 mg/dL are associated with acute pancreatitis. Initial therapy may include insulin, heparin, or plasmapheresis. Outpatient therapies include control of diabetes if present, administration of lipid-lowering agents, weight loss, and avoidance of drugs that elevate lipid levels.

Other potential etiologies that may impact acute hospital care include hypercalcemia, autoimmune pancreatitis (AIP), post-ERCP pancreatitis, and drug-induced pancreatitis. Treatment of hyperparathyroidism or malignancy is effective at reducing serum calcium. AIP is responsive to glucocorticoid administration. Pancreatic duct stenting and rectal indomethacin administration are effective at decreasing pancreatitis after ERCP. Drugs that cause pancreatitis should be discontinued. Multiple drugs have been implicated, but only about 30 have been challenged (Class 1A) and found to be causative.

NUTRITIONAL THERAPY IN ACUTE PANCREATITIS

A low-fat solid diet can be administered to subjects with mild acute pancreatitis after the abdominal pain has resolved. Enteral nutrition should be considered 2–3 days after admission in subjects with more severe pancreatitis instead of total parenteral nutrition (TPN). Enteral feeding maintains gut barrier integrity, limits bacterial translocation, is less expensive, and has fewer complications than TPN. The choice of gastric versus nasojejunal enteral feeding is currently under investigation.

MANAGEMENT OF LOCAL COMPLICATIONS IN ACUTE PANCREATITIS

Patients exhibiting signs of clinical deterioration despite aggressive fluid resuscitation and hemodynamic monitoring should be assessed for local complications, which may include necrosis, pseudocyst formation, pancreas duct disruption, peripancreatic vascular complications, and extrapancreatic infections (Table 341-4). A multidisciplinary team approach is recommended including gastroenterology, surgery, interventional radiology, and intensive care specialists, and consideration should also be made for transfer to a pancreas center.

Necrosis in Acute Pancreatitis

The management of necrosis requires a multidisciplinary team approach. The benefits of percutaneous aspiration of necrosis with Gram stain and culture should be considered or discussed if there are ongoing signs of possible pancreatic infection such as sustained leukocytosis, fever, or organ failure. There is currently no role for prophylactic antibiotics in necrotizing pancreatitis. It is reasonable to start broad-spectrum antibiotics in a patient who appears septic while awaiting the results of Gram stain and cultures. If cultures are negative, the antibiotics should be discontinued to minimize the risk of developing opportunistic or fungal superinfection. Repeated fine-needle aspiration and Gram stain with culture of pancreatic necrosis may be done every 5–7 days in the presence of persistent fever. Repeated CT or MRI imaging should also be considered with any change in clinical course to monitor for complications (e.g., thromboses, hemorrhage, abdominal compartment syndrome).

In general, sterile necrosis is most often managed conservatively unless complications arise. Once a diagnosis of infected necrosis is established and an organism identified, targeted antibiotics should be instituted. Pancreatic debridement (necrosectomy) should be considered for definitive management of infected necrosis, but clinical decisions are generally influenced by response to antibiotic treatment and overall clinical condition. Symptomatic local complications as outlined in the Revised Atlanta criteria may require definitive therapy.

A step-up approach (percutaneous or endoscopic transgastric drainage followed, if necessary, by open necrosectomy) has been successfully reported by some pancreatic centers. One-third of the patients successfully treated with the step-up approach did not require major abdominal surgery. A randomized trial reported advantages to an initial endoscopic approach compared to an initial surgical necrosectomy approach in select patients requiring intervention for symptomatic WON. Taken together, a more conservative approach to the management of infected pancreatic necrosis has evolved under the close supervision of a multidisciplinary team. If conservative therapy can be safely implemented for 4–6 weeks, to allow the pancreatic collections to resolve or “wall-off,” surgical or endoscopic intervention is generally much safer and better tolerated by the patient.

Pseudocyst in Acute Pancreatitis

The incidence of pseudocyst is low, and most acute collections resolve over time. Less than 10% of patients have persistent fluid collections after 6 weeks that would meet the definition of a pseudocyst. Only symptomatic collections should be drained with surgery or endoscopy or by percutaneous route.

Pancreatic Duct Obstruction in Acute Pancreatitis

Pancreatic duct disruption may present with symptoms of increasing abdominal pain or shortness of breath in the setting of an enlarging fluid collection. Diagnosis can be confirmed on magnetic resonance cholangiopancreatography (MRCP) or ERCP. Placement of a bridging pancreatic stent for at least 6 weeks is >90% effective at resolving the leak. Nonbridging stents are less effective (25–50%).

Pervascular Complications in Acute Pancreatitis

Perivascular complications may include splenic vein thrombosis with gastric varices and pseudoaneurysms. Gastric varices bleed <5% of the time. Life-threatening bleeding from a ruptured pseudoaneurysm can be diagnosed and treated with mesenteric angiography and embolization.

Etrapancreatic Infections

Hospital-acquired infections occur in up to 20% of patients with acute pancreatitis. Patients should be continually monitored for the development pneumonia, urinary tract infection, and line infection. Continued culturing of urine, monitoring of chest x-rays, and routine changing of intravenous lines are important during hospitalization.

FOLLOW UP CARE IN ACUTE PANCREATITIS

Hospitalizations for moderately severe and severe acute pancreatitis can be prolonged and last weeks to months and often involve a period of intensive care unit admission and outpatient rehabilitation or subacute nursing care. Follow-up evaluation should assess for development of diabetes, exocrine insufficiency, recurrent cholangitis, or development of infected fluid collections. As mentioned previously, cholecystectomy should be performed during hospitalization or within 4–6 weeks of discharge if possible for patients with uncomplicated gallstone pancreatitis.

RECURRENT PANCREATITIS

Approximately 25% of patients who have had an attack of acute pancreatitis have a recurrence. The two most common etiologic factors are alcohol and cholelithiasis. In patients with recurrent pancreatitis without an obvious cause, the differential diagnosis should encompass occult biliary tract disease including microlithiasis, hypertriglyceridemia, drugs, pancreatic cancer, pancreas divisum, and cystic fibrosis (Table 341-1). In one series of 31 patients diagnosed initially as having idiopathic or recurrent acute pancreatitis, 23 were found to have occult gallstone disease. Thus, approximately two-thirds of patients with recurrent acute pancreatitis without an obvious cause actually have occult gallstone disease due to microlithiasis. Genetic defects as in hereditary pancreatitis and cystic fibrosis mutations can result in recurrent pancreatitis. Other diseases of the biliary tree and pancreatic ducts that can cause acute pancreatitis include choledochocele; ampullary tumors; pancreas divisum; and pancreatic duct stones, stricture, and tumor. Approximately 2–4% of patients with pancreatic carcinoma present with acute pancreatitis.

PANCREATITIS IN PATIENTS WITH AIDS

The incidence of acute pancreatitis is theoretically increased in patients with AIDS for two reasons: (1) the high incidence of infections involving the pancreas such as infections with cytomegalovirus, Cryptosporidium, and the Mycobacterium avium complex; and (2) the frequent use by patients with AIDS of medications such as didanosine, pentamidine, trimethoprim-sulfamethoxazole, and protease inhibitors. It should be noted that the incidence has been markedly reduced due to advances in therapy (Chap. 197).

PATHOPHYSIOLOGY OF CHRONIC PANCREATITIS

Chronic pancreatitis is a disease process characterized by irreversible damage to the pancreas as distinct from the reversible changes noted in acute pancreatitis (Table 341-4). The events that initiate and then perpetuate the inflammatory process in the pancreas are becoming more clearly understood. Irrespective of the mechanism of injury, it is becoming apparent that stellate cell activation that results in cytokine expression and production of extracellular matrix proteins cause acute and chronic inflammation and collagen deposition in the pancreas. Thus, the condition is defined by the presence of histologic abnormalities, including chronic inflammation, fibrosis, and progressive destruction of both exocrine and eventually endocrine tissue (atrophy). A number of etiologies have been associated with chronic pancreatitis resulting in the cardinal manifestations of the disease such as abdominal pain, steatorrhea, weight loss, and diabetes mellitus (Table 341-5).

Although alcohol has been believed to be the primary cause of chronic pancreatitis, other factors contribute to the disease because not all heavy consumers of alcohol develop pancreatic disease. There is also a strong association between smoking and chronic pancreatitis. Cigarette smoke leads to an increased susceptibility to pancreatic autodigestion and predisposes to dysregulation of duct cell CFTR function. Smoking is an independent, dose-dependent risk factor for chronic pancreatitis and recurrent acute pancreatitis. Both continued alcohol and smoking exposure are associated with pancreatic fibrosis, calcifications, and progression of disease.

Recent characterization of pancreatic stellate cells (PSCs) has added insight into the underlying cellular responses behind development of chronic pancreatitis. Specifically, PSCs are believed to play a role in maintaining normal pancreatic architecture that can shift toward fibrogenesis in the case of chronic pancreatitis. The sentinel acute pancreatitis event (SAPE) hypothesis uniformly describes the events in the pathogenesis of chronic pancreatitis. It is believed that alcohol or additional stimuli lead to matrix metalloproteinase–mediated destruction of normal collagen in pancreatic parenchyma, which later allows for pancreatic remodeling. Proinflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin 1 (IL-1), and interleukin 6 (IL-6), as well as oxidant complexes, are able to induce PSC activity with subsequent new collagen synthesis. In addition to being stimulated by cytokines, oxidants, or growth factors, PSCs also possess transforming growth factor β (TGF-β)–mediated self-activating autocrine pathways that may explain disease progression in chronic pancreatitis even after removal of noxious stimuli.

ETIOLOGIC CONSIDERATIONS IN CHRONIC PANCREATITIS

Among adults in the United States, alcoholism is the most common cause of clinically apparent chronic pancreatitis, whereas cystic fibrosis is the most frequent cause in children. As many as 25% of adults in the United States with chronic pancreatitis have the idiopathic form. Recent investigations have indicated that up to 15% of patients with idiopathic pancreatitis may have pancreatitis due to genetic defects (Table 341-5).

Whitcomb and associates studied several large families with hereditary chronic pancreatitis and were able to identify a genetic defect that affects the gene encoding for trypsinogen. Several additional defects of this gene have also been described. The defect prevents the destruction of prematurely activated trypsin and allows it to be resistant to the intracellular protective effect of trypsin inhibitor. It is hypothesized that this continual activation of digestive enzymes within the gland leads to acute injury and, finally, chronic pancreatitis. Since the initial discovery of the PRSS1 mutation defect, other genetic diseases have been detected (Table 341-5).

Several other groups of investigators have documented mutations of CFTR. This gene functions as a cyclic AMP–regulated chloride channel. In patients with cystic fibrosis, the high concentration of macromolecules can block the pancreatic ducts. It must be appreciated, however, that there is a great deal of heterogeneity in relationship to the CFTR gene defect. More than 1000 putative mutations of the CFTR gene have been identified. Attempts to elucidate the relationship between the genotype and pancreatic manifestations have been hampered by the number of mutations. The ability to detect CFTR mutations has led to the recognition that the clinical spectrum of the disease is broader than previously thought. Two studies have clarified the association between mutations of the CFTR gene and another monosymptomatic form of cystic fibrosis (i.e., chronic pancreatitis). It is estimated that in patients with idiopathic pancreatitis, the frequency of a single CFTR mutation is 11 times the expected frequency and the frequency of two mutant alleles is 80 times the expected frequency. In these studies, the patients were adults when the diagnosis of pancreatitis was made; none had any clinical evidence of pulmonary disease, and sweat test results were not diagnostic of cystic fibrosis. The prevalence of such mutations is unclear, and further studies are certainly needed. In addition, the therapeutic and prognostic implication of these findings with respect to managing pancreatitis remains to be determined. Long-term follow-up of affected patients is needed. CFTR mutations are common in the general population. It is unclear whether the CFTR mutation alone can lead to pancreatitis as an autosomal recessive disease. A study evaluated 39 patients with idiopathic chronic pancreatitis to assess the risk associated with these mutations. Patients with two CFTR mutations (compound heterozygotes) demonstrated CFTR function at a level between that seen in typical cystic fibrosis and cystic fibrosis carriers and had a fortyfold increased risk of pancreatitis. The presence of an N34S SPINK1 mutation increased the risk twentyfold. A combination of two CFTR mutations and an N34S SPINK1 mutation increased the risk of pancreatitis 900-fold. Knowledge of the genetic defects and downstream alterations in protein expression has led to the development of novel genetic therapy in cystic fibrosis children that potentiates the CFTR channel resulting in improvement in lung function, quality of life, and weight gain. Table 341-5 lists recognized causes of chronic pancreatitis and pancreatic exocrine insufficiency.

AUTOMIMMUNE PANCREATITIS

AIP is an uncommon disorder of presumed autoimmune causation with characteristic laboratory, histologic, and morphologic findings (Table 341-6). The nomenclature has recently been simplified to include AIP and idiopathic duct centric pancreatitis (IDCP). In AIP, the pancreas is involved as part of an IgG4 systemic disease (Chap. 361) and meets HISORt criteria as defined below. The characteristic pancreatic histopathologic findings include lymphoplasmacytic infiltrate, storiform fibrosis, and abundant IgG4 cells. IDCP is histologically confirmed IDCP with granulocytic infiltration of the duct wall (termed GEL), but without IgG4 positive cells and systemic involvement. It is a disorder limited to the pancreas only.

Although AIP was initially described as a primary pancreatic disorder, it is now recognized that it is associated with other disorders of presumed autoimmune etiology, and this has been termed IgG4-related disease (Chap. 361). The clinical features include IgG4-associated cholangitis, rheumatoid arthritis, Sjögren’s syndrome, ulcerative colitis, mediastinal fibrosis and adenopathy, autoimmune thyroiditis, tubulointerstitial nephritis, retroperitoneal fibrosis, chronic periaortitis, chronic sclerosing sialadenitis, and Mikulicz’s disease. Mild symptoms, usually abdominal pain, and recurrent acute pancreatitis are unusual. Furthermore, AIP is not a common cause of idiopathic recurrent pancreatitis.

Weight loss from pancreatic atrophy and new onset of diabetes may also occur in patients that smoke and consume alcohol. An obstructive pattern on liver tests is common (i.e., disproportionately elevated serum alkaline phosphatase and minimally elevated serum aminotransferases). Elevated serum levels of IgG4 provide a marker for the disease, particularly in Western populations. Serum IgG4 is elevated in 2/3 of those with AIP. CT scans reveal abnormalities in the majority of patients and include diffuse enlargement, focal enlargement, and a distinct enlargement at the head of the pancreas. ERCP or MRCP reveals strictures in the bile duct in more than one-third of patients with AIP; these may include common bile duct strictures, intrahepatic bile duct strictures, or proximal bile duct strictures, with accompanying narrowing of the pancreatic portion of the bile duct. This has been termed autoimmune IgG4 cholangitis. Characteristic histologic findings include extensive lymphoplasmacytic infiltrates with dense fibrosis around pancreatic ducts, as well as a lymphoplasmacytic infiltration, resulting in an obliterative phlebitis.

The Mayo Clinic HISORt criteria indicate that AIP can be diagnosed by the presence of at least one or more of the following: (1) histology; (2) imaging; (3) serology (elevated serum IgG4 levels); (4) other organ involvement; and (5) response to glucocorticoid therapy, with improvement in pancreatic and extrapancreatic manifestations.

Glucocorticoids have shown efficacy in alleviating symptoms, decreasing the size of the pancreas, and reversing histopathologic features in patients with AIP. Patients may respond dramatically to glucocorticoid therapy within a 2- to 4-week period. Prednisone is usually administered at an initial dose of 40 mg/d for 4 weeks followed by a taper of the daily dosage by 5 mg/wk based on monitoring of clinical parameters. Relief of symptoms, serial changes in abdominal imaging and improvements in liver tests are parameters to follow. A poor response to glucocorticoids over a 2- to 4-week period should raise suspicion of pancreatic cancer or other forms of chronic pancreatitis. A recent multicenter international report reviewed 1064 patients with AIP. Clinical remission was achieved in 99% of AIP and 92% of IDCP patients with steroids. However, disease relapse occurred in 31% of AIP and 9% of IDCP patients. For treatment of disease relapse in AIP, glucocorticoids were successful in 201 of 295 (68%) patients, and azathioprine was successful in 52 of 58 patients (85%). A small number of patients responded favorably to 6-mercaptapurine, rituximab, cyclosporine, and cyclophosphamide. AIP and IDCP are highly responsive to initial glucocorticoid treatment. Relapse is common in AIP patients, especially those with biliary tract strictures. Most relapses occur after glucocorticoids are discontinued. Patients with refractory symptoms and strictures generally require immunomodulator therapy as noted above. Rituximab, a monoclonal antibody directed against B cells has been shown to be very effective at inducing and maintaining remission. Appearance of interval cancers following a diagnosis of AIP is uncommon.

CLINICAL AND RADIOLOGIC FEATURES OF CHRONIC PANCREATITIS

Patients with chronic pancreatitis seek medical attention predominantly because of two symptoms: abdominal pain or maldigestion and weight loss. The abdominal pain may be quite variable in location, severity, and frequency. The pain can be constant or intermittent with frequent pain-free intervals. Eating may exacerbate the pain, leading to a fear of eating with consequent weight loss. The spectrum of abdominal pain ranges from mild to quite severe, with narcotic dependence as a frequent consequence. Maldigestion is manifested as chronic diarrhea, steatorrhea, weight loss, and fatigue. Patients with chronic abdominal pain may or may not progress to maldigestion, and ~20% of patients will present with symptoms of maldigestion without a history of abdominal pain. Patients with chronic pancreatitis have significant morbidity and mortality and use appreciable amounts of societal resources. Despite steatorrhea, clinically apparent deficiencies of fat-soluble vitamins are surprisingly uncommon. Physical findings in these patients are usually unimpressive, so that there is a disparity between the severity of abdominal pain and the physical signs that usually consist of some mild tenderness.

The diagnosis of early or mild chronic pancreatitis can be challenging because there is no biomarker for the disease. In contrast to acute pancreatitis, the serum amylase and lipase levels are usually not strikingly elevated in chronic pancreatitis. Elevation of serum bilirubin and alkaline phosphatase may indicate cholestasis secondary to common bile duct stricture caused by chronic inflammation. Many patients have impaired glucose tolerance with elevated fasting blood glucose levels. The fecal elastase-1 and small-bowel biopsy are useful in the evaluation of patients with suspected pancreatic steatorrhea. The fecal elastase level will be abnormal and small-bowel histology will be normal in such patients. A decrease of fecal elastase level to <100 μg per gram of stool strongly suggests severe pancreatic exocrine insufficiency.

The radiographic evaluation of a patient with suspected chronic pancreatitis usually proceeds from a noninvasive to more invasive approach. Abdominal CT imaging (Fig. 341-4A, B) is the initial modality of choice, followed by MRI (Fig. 341-4C), endoscopic ultrasound, and pancreas function testing. In addition to excluding a pseudocyst and pancreatic cancer, CT may show calcification, dilated ducts, or an atrophic pancreas. Although abdominal CT scanning and MRCP greatly aid in the diagnosis of pancreatic disease, the diagnostic test with the best sensitivity and specificity is the hormone stimulation test using secretin. The secretin test becomes abnormal when ≥60% of the pancreatic exocrine function has been lost. This usually correlates well with the onset of chronic abdominal pain. The role of endoscopic ultrasonography (EUS) in diagnosing early chronic pancreatitis is still being defined. A total of nine endosonographic features have been described in chronic pancreatitis. The presence of five or more features is considered diagnostic of chronic pancreatitis. EUS is not a sensitive enough test for detecting early chronic pancreatitis alone (Chap. 340) and may show positive features in patients who have dyspepsia or even normal aging individuals. Recent data suggest that EUS can be combined with endoscopic pancreatic function testing (EUS-ePFT) during a single endoscopy to screen for chronic pancreatitis in patients with chronic abdominal pain. Diffuse calcifications noted on plain film of the abdomen usually indicate significant damage to the pancreas and are pathognomic for chronic pancreatitis (Fig. 341-4A). Although alcohol is by far the most common cause of pancreatic calcification, such calcification may also be noted in hereditary pancreatitis, posttraumatic pancreatitis, hypercalcemic pancreatitis, idiopathic chronic pancreatitis, and tropical pancreatitis.

COMPLICATIONS OF CHRONIC PANCREATITIS

The complications of chronic pancreatitis are protean and are listed in Table 341-7. Although most patients have impaired glucose tolerance, diabetic ketoacidosis and diabetic coma are uncommon. Likewise, end-organ damage (retinopathy, neuropathy, nephropathy) is also uncommon. A nondiabetic retinopathy may be due to either vitamin A and/or zinc deficiency. Gastrointestinal bleeding may occur from peptic ulceration, gastritis, a pseudocyst eroding into the duodenum, arterial bleeding into the pancreatic duct (hemosuccus pancreaticus), or ruptured varices secondary to splenic vein thrombosis due to chronic inflammation of the tail of the pancreas. Jaundice, cholestasis, and biliary cirrhosis may occur from the chronic inflammatory reaction around the intrapancreatic portion of the common bile duct. Twenty years after the diagnosis of calcific chronic pancreatitis, the cumulative risk of pancreatic carcinoma is 4%. Patients with hereditary pancreatitis are at a tenfold higher risk for pancreatic cancer.

TREATMENT OF CHRONIC PANCREATITIS

HERIDITARY PANCREATITIS

Hereditary pancreatitis is a rare disease that is similar to chronic pancreatitis except for an early age of onset and evidence of hereditary factors. A genomewide search using genetic linkage analysis identified the hereditary pancreatitis gene on chromosome 7. Mutations in ion codons 29 (exon 2) and 122 (exon 3) of the cationic trypsinogen gene cause autosomal dominant forms of hereditary pancreatitis. The codon 122 mutations lead to a substitution of the corresponding arginine with another amino acid, usually histidine. This substitution, when it occurs, eliminates a fail-safe trypsin self-destruction site necessary to eliminate trypsin that is prematurely activated within the acinar cell. These patients have recurring attacks of severe abdominal pain that may last from a few days to a few weeks. The serum amylase and lipase levels may be elevated during acute attacks but are usually normal. Patients frequently develop pancreatic calcification, diabetes mellitus, and steatorrhea; in addition, they have an increased incidence of pancreatic carcinoma, with the cumulative incidence being as high as 40% by age 70 years. A recent natural history study of hereditary pancreatitis in >200 patients from France reported that abdominal pain started in childhood at age 10 years, steatorrhea developed at age 29 years, diabetes at age 38 years, and pancreatic carcinoma at age 55 years. Such patients often require surgical ductal decompression for pain relief. Abdominal complaints in relatives of patients with hereditary pancreatitis should raise the question of pancreatic disease.

PSTI, or SPINK1, is a 56-amino-acid peptide that specifically inhibits trypsin by physically blocking its active site. SPINK1 acts as the first line of defense against prematurely activated trypsinogen in the acinar cell. Recently, it has been shown that the frequency of SPINK1 mutations in patients with idiopathic chronic pancreatitis is markedly increased, suggesting that these mutations may be associated with pancreatitis.

PANCREATIC ENDOCRINE TUMORS

Chap. 80.

ANNULAR PANCREAS

When the ventral pancreatic anlage fails to migrate correctly to make contact with the dorsal anlage, the result may be a ring of pancreatic tissue encircling the duodenum. Such an annular pancreas may cause intestinal obstruction in the neonate or the adult. Symptoms of postprandial fullness, epigastric pain, nausea, and vomiting may be present for years before the diagnosis is entertained. The radiographic findings are symmetric dilation of the proximal duodenum with bulging of the recesses on either side of the annular band, effacement but not destruction of the duodenal mucosa, accentuation of the findings in the right anterior oblique position, and lack of change on repeated examinations. The differential diagnosis should include duodenal webs, tumors of the pancreas or duodenum, postbulbar peptic ulcer, regional enteritis, and adhesions. Patients with annular pancreas have an increased incidence of pancreatitis and peptic ulcer. Because of these and other potential complications, the treatment is surgical even if the condition has been present for years. Retrocolic duodenojejeunostomy is the procedure of choice, although some surgeons advocate Billroth II gastrectomy, gastroenterostomy, and vagotomy.

PANCREAS DIVISUM

Pancreas divisum is present in 7–10% of the population and occurs when the embryologic ventral and dorsal pancreatic anlagen fail to fuse, so that pancreatic drainage is accomplished mainly through the accessory papilla. Pancreas divisum is the most common congenital anatomic variant of the human pancreas. Current evidence indicates that this anomaly does not predispose to the development of pancreatitis in the great majority of patients who harbor it. However, the combination of pancreas divisum and a small accessory orifice could result in dorsal duct obstruction. The challenge is to identify this subset of patients with dorsal duct pathology. Cannulation of the dorsal duct by ERCP is not as easily done as is cannulation of the ventral duct. Patients with pancreatitis and pancreas divisum demonstrated by MRCP or ERCP should be treated with conservative measures. In many of these patients, pancreatitis is idiopathic and unrelated to the pancreas divisum. Endoscopic or surgical intervention is indicated only if pancreatitis recurs and no other cause can be found. If marked dilation of the dorsal duct can be demonstrated, surgical ductal decompression should be performed. It should be stressed that the ERCP/MRCP appearance of pancreas divisum (i.e., a small-caliber ventral duct with an arborizing pattern) may be mistaken as representing an obstructed main pancreatic duct secondary to a mass lesion.

MACROAMYLASEMIA

In macroamylasemia, amylase circulates in the blood in a polymer form too large to be easily excreted by the kidney. Patients with this condition demonstrate an elevated serum amylase value and a low urinary amylase value. The presence of macroamylase can be documented by chromatography of the serum. The prevalence of macroamylasemia is 1.5% of the nonalcoholic general adult hospital population. Usually macroamylasemia is an incidental finding and is not related to disease of the pancreas or other organs. Macrolipasemia has now been documented in a few patients with cirrhosis or non-Hodgkin’s lymphoma. In these patients, the pancreas appeared normal on ultrasound and CT examination. Lipase was shown to be complexed with immunoglobulin A. Thus, the possibility of both macroamylasemia and macrolipasemia should be considered in patients with elevated blood levels of these enzymes.

ACKNOWLEDGMENT

This chapter represents a revised version of chapters by Drs. Norton J. Greenberger, Phillip P. Toskes, and Bechien Wu that were in previous editions of Harrison’s.