Section 4: Disorders of the Pancreas

GENERAL CONSIDERATIONS

Globally, pancreatic disorders, including acute and chronic pancreatitis, pancreatic cysts, and pancreatic cancer, are challenging to manage and associated with a high burden on health care resources. The relationships between these diseases continues to be poorly understood, but there is encouraging progress. Acute pancreatitis is one of the most common reasons for hospitalizations in gastroenterology, and there is increasing evidence of long-term sequelae including diabetes, exocrine pancreas insufficiency, and pancreas cancer. Chronic pancreatitis, an irreversible disease of the pancreas, is associated with poor quality of life, largely related to abdominal pain, and associated exocrine insufficiency. Pancreatic cysts, mostly incidental, are increasingly detected on cross-sectional abdominal imaging studies. Although a small number and specific types of pancreatic cysts can progress to pancreatic cancer, diagnostic uncertainty can introduce unwanted anxiety to patients and treating physicians. Meanwhile, with persistently high mortality rates, the incidence of pancreatic adenocarcinoma is increasing and is the seventh leading cause of cancer-related death in the industrialized world and the third most common in the United States.

As emphasized in Chap. 348, the etiologies and clinical manifestations of pancreatitis are quite varied. Although it is well-appreciated that acute pancreatitis is frequently secondary to biliary tract disease and alcohol abuse, it can also be caused by drugs, genetic mutations, and trauma. In ~30% of patients with acute pancreatitis and 25–40% of patients with chronic pancreatitis, the etiology is initially unexplained.

The global pooled incidence of acute pancreatitis is ~33.7 cases (95% confidence interval [CI], 23.3–48.8) with 1.16 deaths (95% CI, 0.85–1.6) per 100,000 person-years. The global pooled incidence of chronic pancreatitis is ~9.6 cases (95% CI, 7.9–11.8) with 0.09 attributable deaths (95% CI, 0.02–0.5) per 100,000 person-years. In the United States, the number of patients admitted to the hospital with acute pancreatitis is increasing, with estimated rates of almost 300,000 annually, whereas the number of patients hospitalized for chronic pancreatitis is decreasing, with recent estimates of ~13,000 admissions per year. Chronic pancreatitis has an annual prevalence of 42–73 cases per 100,000 adults in the United States, although higher prevalence rates (0.04–5%) have been noted among adults at autopsy. Together, acute and chronic pancreatic disease costs an estimated $3 billion annually in health care expenditures.

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 exocrine pancreatic insufficiency (EPI), 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 (e.g., 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 (e.g., secretin stimulation test) are the most sensitive and specific tests to detect early chronic pancreatic disease when imaging is equivocal or normal.

The increasing utilization of cross-sectional imaging modalities with their improved resolution has contributed to a high prevalence (2–5% with computed tomography [CT] scans, 20–30% with magnetic resonance imaging [MRI]) of incidentally detected pancreatic cysts. The most common cyst type encountered is an intraductal papillary mucinous neoplasm (IPMN), which is classified as a precancerous mucinous cyst. In the absence of high-risk features, radiographic surveillance is typically recommended (Fig. 347-1). Mucinous cystic neoplasms (MCNs) are a less commonly encountered mucinous cyst. Among the neoplastic cysts, serous cystadenomas have a negligible risk of progression to malignancy. Other infrequent neoplastic cysts include neuroendocrine tumors and solid pseudopapillary neoplasms. The most commonly encountered benign cyst is a pseudocyst, which can occur in patients with a history of acute or chronic pancreatitis. It is often difficult to accurately predict the risk of malignant transformation of precancerous pancreatic cysts, and there is an increasing number of patients on imaging surveillance protocols burdening the health care systems in the industrialized world.

TESTS USEFUL IN THE DIAGNOSIS OF PANCREATIC DISEASE

Several tests are 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 347-1 and Fig. 347-2. At some institutions, pancreatic function tests are available and performed if the diagnosis of chronic pancreatitis remains a possibility after noninvasive tests (i.e., ultrasound, CT Scan, MRI with magnetic resonance cholangiopancreatography [MRCP]) or invasive tests (i.e., endoscopic retrograde cholangiopancreatography [ERCP], endoscopic ultrasound [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. Lipase is very specific for the pancreas, and 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 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 acute 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, contrast-enhanced CT scan, MRI with MRCP, or EUS, mild to moderate elevations of amylase and/or lipase are not helpful in making a diagnosis of chronic pancreatitis.

It should be noted that the serum amylase can be elevated in other conditions (Table 347-2), 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, the 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. It is important to acknowledge that levels are often mildly elevated in the setting of renal disease, so determining whether a patient with renal failure and abdominal pain has pancreatitis remains a challenging 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, but a high index of clinical suspicion is needed based on symptoms. Elevations in serum lipase >3× ULN due to nonpancreatic etiology can be observed in hepatobiliary or gastrointestinal malignancies, septicemia, liver cirrhosis, systemic lupus erythematosus, severe head injury, chronic alcoholism, diabetes mellitus, and post-ERCP without any associated evidence of pancreatitis.

Studies Pertaining to Pancreatic Structure

RADIOLOGIC TESTS

Plain films of the abdomen rarely provide useful information related to pancreatic disease and have been superseded by more detailed imaging studies (ultrasound, EUS, CT, and MRI with MRCP).

Ultrasonography (US) can provide important information in the initial emergency ward evaluation of patients with acute pancreatitis, chronic pancreatitis, pseudocysts, and pancreatic adenocarcinoma. Sonographic changes can indicate the presence of edema, inflammation, and calcification (not obvious on plain films of the abdomen), as well as gallstones, biliary dilation, pseudocysts, and mass lesions. In acute pancreatitis, the pancreas is characteristically enlarged. In pancreatic pseudocyst, the usual appearance is primarily that of a smooth, round fluid collection. Pancreatic adenocarcinoma 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, limiting its sensitivity.

CT with intravenous contrast is the best imaging study 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 (see Chap. 348, Figs. 348-1, 348-2, and 348-4), and pancreatic neoplasms. Acute pancreatitis is characterized by (1) enlargement of the pancreas, (2) distortion of the pancreatic contour with peripancreatic stranding of adjacent fat tissue, and/or (3) the presence of pancreatic fluid that has a different attenuation coefficient than normal pancreas. When possible, CT scans should ideally be performed with oral and intravenous contrast to detect areas of pancreatic necrosis. The major benefit of CT scan in acute pancreatitis is the diagnosis of pancreatic necrosis in patients not responding to conservative management within 72 h. It may take 48–72 h to develop perfusion defects indicative of pancreatic necrosis. Therefore, if acute pancreatitis is confirmed with serology and physical examination findings, CT scan in the first 3 days is not recommended to minimize risk of contrast-induced nephropathy and unnecessary health care costs. Improved imaging technology and increased resolution are facilitated by multiphasic CT scans using multidetector technology (MDCT) in which a pancreas protocol consisting of dual-phase scanning with intravenous contrast is utilized for the detection and staging of pancreatic cancers. While the sensitivity of MDCT for detecting smaller (≤2 cm) lesions is lower, the reported overall sensitivity for pancreatic cancers is 76–97%. The contraindications to using intravenous contrast include renal failure (serum creatinine >2 mg/dL) and a history of severe allergic reaction to iodinated contrast agents. In situations where EUS is not available, CT-guided percutaneous aspiration or biopsy of a pancreatic mass can be performed. Prior to the major advance of EUS-guided fine-needle aspiration (FNA), CT-guided biopsy was utilized in the preceding decades and is regarded as a safe procedure.

MRI and MRCP provide excellent imaging of the bile duct, pancreatic duct, and pancreas parenchyma in both acute pancreatitis and chronic pancreatitis. MRI is better than transabdominal US and CT scans and comparable to EUS in the detection of choledocholithiasis. Similar to CT, MRI can evaluate for the severity of acute pancreatitis. Moreover, T2-weighted MRI of fluid collections can differentiate necrotic debris from fluid in suspected walled-off necrosis, and T1 imaging can diagnose hemorrhage in suspected pseudoaneurysm rupture. In chronic pancreatitis, secretin-enhanced MRCP is a method to enhance the evaluation of major and minor ductal changes. While imaging is comparable to CT for evaluating pancreatic mass lesions, MRI with MRCP is the preferred imaging modality for evaluating pancreatic cystic lesions. Nephrogenic systemic fibrosis has been described in patients with chronic renal failure following exposure to the gadolinium contrast, but incidence rates are extraordinarily low with contemporary contrast agents.

EUS produces high-resolution images of the bile duct, 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 is not beneficial for the evaluation of pancreas during acute pancreatitis. It is preferable to perform EUS after the resolution of acute pancreatitis (~4 weeks) to detect any predisposing factors, including malignancy, choledocholithiasis, pancreatic divisum, or ampullary lesions. EUS can be combined with ERCP in a single session and is increasingly preferred for the diagnosis and management of choledocholithiasis in acute pancreatitis and pancreatic neoplasm with biliary obstruction. 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 347-3 is highly predictive of chronic pancreatitis in the correct clinical context. The sensitivity of EUS (81%; 95% CI, 70–89%) to diagnose chronic pancreatitis is comparable to that of MRI/MRCP (78%; 95% CI, 69–85%) and better than CT (75%; 95% CI, 66–83%); however, nonspecific changes are commonly seen in the pancreas that may be attributable to cigarette smoking, diabetes, or normal aging. EUS also facilitates the delivery of nerve-blocking agents via fine-needle injection in patients suffering from pancreatic pain from chronic pancreatitis (celiac plexus block) or cancer (celiac plexus neurolysis). When clinically suspected, EUS imaging is more sensitive than MDCT for the detection of pancreatic malignancy and permits fine-needle aspiration/biopsy (FNA/B). Currently, EUS-guided FNA/B is the diagnostic modality of choice for the acquisition of diagnostic tissue and cyst fluid in patients with pancreatic masses and cystic lesions, respectively.

Although a pancreatogram during ERCP is the most specific and sensitive test for evaluating the ductal anatomy, EUS and MRI/MRCP have largely replaced ERCP in the diagnostic evaluation of pancreatic disease to avoid the risk of complications. Therefore, ERCP is primarily of therapeutic value after CT, EUS, or MRI and MRCP has detected abnormalities requiring endoscopic treatment. ERCP is the most sensitive modality for the detection of bile duct stones. In the management of acute biliary pancreatitis, ERCP should not be unduly delayed in patients with high clinical suspicion of biliary obstruction. In chronic pancreatitis, ERCP abnormalities in the main pancreatic duct and side branches have been outlined by the Cambridge classification (Fig. 347-2). The presence of ductal stenosis and irregularity can make it difficult to distinguish chronic pancreatitis from pancreatic adenocarcinoma. 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, sequelae of a recent attack of acute pancreatitis, or changes secondary to placement of pancreatic duct stent. Although aging may cause impressive ductal alterations, it does not affect the results of pancreatic secretin function tests. Pancreatic adenocarcinoma 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). When indicated, ERCP permits acquisition of diagnostic tissue as in biopsy of ampullary lesions or biliary brushings for distal bile duct strictures. Elevated serum amylase levels after ERCP have been reported in the majority of patients, and clinical pancreatitis has been reported in 5–10% of patients. Until recently, pancreatic duct stents were commonly placed to prevent post-ERCP pancreatitis. However, recent data suggest that periprocedural administration of rectal indomethacin can decrease the incidence of post-ERCP pancreatitis. Studies are currently underway comparing rectal indomethacin alone versus combination with prophylactic pancreatic duct stents to prevent post-ERCP pancreatitis.

TESTS OF EXOCRINE PANCREATIC FUNCTION

Pancreatic function tests (Table 347-1) 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 h, (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 pancreas dysfunction, appears to be the maximal bicarbonate concentration. A cutoff point <80 mmol/L is considered abnormal and suggestive of reduced secretory function that is most commonly observed in early chronic pancreatitis.

2. 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. The secretin test directly 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 an early abnormality in chronic pancreatitis but should not be considered diagnostic and must be interpreted within the proper clinical context (for example, a patient with recurrent attacks of pancreatitis and persistent abdominal pain and Cambridge 2 changes on imaging)

3. 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. 325. The amount of human elastase in stool reflects the pancreatic output of this proteolytic enzyme. Decreased fecal elastase-1 (FE-1) activity in stool is a test to detect severe EPI 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-moderate EPI, and levels <100 μg/g are severe EPI. Although the test is simple and noninvasive, it can yield false-positive results if stools are not formed and should not generally be used for the evaluation of a patient with diarrhea. False-positive results have also been observed in diabetes and irritable bowel syndrome.

Tests useful in the diagnosis of EPI and the differential diagnosis of malabsorption are also discussed in Chaps. 325 and 348.

FURTHER READING

BIOCHEMISTRY AND PHYSIOLOGY OF PANCREATIC EXOCRINE SECRETION

GENERAL CONSIDERATIONS

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

REGULATION OF PANCREATIC SECRETION

Secretions from the exocrine pancreas are highly regulated by neurohormonal systems in a phasic manner (cephalic, gastric, and intestinal phases). 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, particularly during the cephalic phase. Secretion evoked by secretin and CCK depends on the 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 including somatostatin, pancreatic polypeptide, peptide YY, neuropeptide Y, enkephalin, pancreastatin, calcitonin gene–related peptides, glucagon, and galanin. Pancreatic polypeptide and peptide YY may act primarily on nerves outside the pancreas, while somatostatin acts at multiple sites.

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, which promotes 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, increases the solubility of fatty acids and bile acids, maintains an optimal pH for pancreatic and brush border enzymes, and prevents intestinal mucosal damage.

ENZYME SECRETION

The acinar cell is highly compartmentalized for the production and secretion of pancreatic enzymes. Proteins synthesized by the rough endoplasmic reticulum are processed in the Golgi and then targeted to the appropriate site: 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 (“brush border”), cleaves the lysine-isoleucine bond of trypsinogen to form trypsin. Trypsin then activates the other proteolytic zymogens and phospholipase A₂ in a cascade. 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 the 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 ~20% of intracellular trypsin activity. Chymotrypsin C can also lyse and inactivate trypsin. These protease inhibitors are found in acinar cells, 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 ultimately 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 and nutrients in the distal small intestine. For example, 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. 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. Additional hormonal feedback inhibition of pancreatic enzyme secretion occurs via peptide YY and glucagon-like peptide-1 following lipid or carbohydrate exposure to the ileum.

ACUTE PANCREATITIS

GENERAL CONSIDERATIONS

Recent U.S. estimates indicate that acute pancreatitis is the most common inpatient principal gastrointestinal diagnosis, responsible for >250,000 hospitalizations per year. The annual incidence ranges from 15–45/100,000 persons, depending on the distribution of etiologies (e.g., alcohol, gallstones, metabolic factors, drugs [Table 348-1]) and country of study. The median length of hospital stay is 4 days, with a median hospital cost of ~$6000 and a mortality of ~1%. The estimated cost annually approaches $3 billion. Hospitalization rates increase with age and are higher among blacks and men. The age-adjusted rate of hospital discharges with an acute pancreatitis diagnosis increased by 62% between 1988 and 2004. From 2000 to 2009, the rate increased by 30%. Thus, the incidence of acute pancreatitis continues to rise and is associated with substantial health care costs.

ETIOLOGY AND PATHOGENESIS

There are many causes of acute pancreatitis (Table 348-1), and the mechanisms by which each of these conditions triggers pancreatic inflammation have not been fully elucidated. Gallstones and alcohol account for 80–90% of identified cases of acute pancreatitis 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 and genetic predisposition. Acute pancreatitis occurs in 5–10% of patients following endoscopic retrograde cholangiopancreatography (ERCP); however, this risk can be decreased with proper patient selection and the use of a prophylactic pancreatic duct stent and/or rectal nonsteroidal anti-inflammatory drugs (NSAIDs; indomethacin). Risk factors for post-ERCP pancreatitis include minor papilla sphincterotomy, suspected sphincter of Oddi dysfunction, prior history of post-ERCP pancreatitis, age <60 years, more than two contrast injections into the pancreatic duct, and endoscopist experience.

Hypertriglyceridemia is the cause of acute pancreatitis in 1–4% of cases; serum triglyceride levels are usually >1000 mg/dL. Most patients with hypertriglyceridemic pancreatitis have undiagnosed or uncontrolled diabetes mellitus. An additional subset has an underlying derangement in lipid metabolism, probably unrelated to pancreatitis. Such patients are prone to recurrent episodes of pancreatitis. Any factor (e.g., alcohol or medications, such as oral contraceptives) that causes an abrupt increase in serum triglycerides can potentially 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. Although frequently entertained, <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 348-1).

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

ACTIVATION OF PANCREATIC ENZYMES IN THE PATHOGENESIS OF ACUTE PANCREATITIS

Several 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 cellular necrosis in the parenchyma. 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 other 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 acute pancreatitis, and chronic pancreatitis. All 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. Six 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), (5) the calcium-sensing receptor (CASR), and (6) claudin-2 (CLDN2). Among these variants, only PRSS1 mutations are sufficient to precipitate acute pancreatitis in the absence of other risk factors, whereas the other variants are disease modifiers. Investigations of other genetic variants are currently underway, and new genes will be added to this list in the future.

LABORATORY DATA

Serum amylase and lipase values threefold or more above normal are strongly supportive of the diagnosis if alternate etiologies, including gut perforation, ischemia, and infarction, are excluded. However, it should be noted that there is no correlation between the severity of pancreatitis and the degree of serum lipase and amylase elevations or serial trends. 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. 347, Table 347-2). 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. On the other hand, serum amylase levels can be spuriously low in the setting of severe hypertriglyceridemia. Serum lipase activity increases in parallel with amylase activity and is more specific than amylase, making it the preferred test. 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, 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 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 transaminase levels may also be transiently elevated and parallel serum bilirubin values. Elevations of alanine aminotransferase (ALT) >3× the upper limit of normal are strongly associated with a gallstone etiology in patients with acute pancreatitis. Approximately 5–10% of patients have hypoxemia (arterial PO₂ ≤60 mmHg), 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 gallstones and common bile duct dilation.

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 348-2 and Fig. 348-1). Radiologic studies useful in the diagnosis of acute pancreatitis are discussed in Chap. 347 and listed in Table 347-1.

DIAGNOSIS

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. 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 348-3).

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 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 often not elevated in diabetic ketoacidosis, and pancreas imaging is normal.

CLINICAL COURSE, DEFINITIONS, AND CLASSIFICATIONS

The Revised Atlanta Criteria define (1) phases of acute pancreatitis, (2) severity of acute pancreatitis, and (3) radiographic 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 describe 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 regarding 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 critical 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 a 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 is associated with prolonged hospitalization and, if infected, may require intervention (percutaneous, endoscopic, and/or surgical).

Severity of Acute Pancreatitis

Three classes of severity have 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 onset. 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 (i.e., it 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. As with mild acute pancreatitis, the mortality rate for these patients remains low.

Severe acute pancreatitis is characterized by persistent organ failure (>48 h), involving one or more organs. 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, the maturity of fluid collection, and clinical stability of the patient. Prophylactic antibiotics are no longer recommended for severe acute pancreatitis.

Imaging in Acute Pancreatitis

Two types of pancreatitis are recognized on imaging as interstitial or necrotizing based on pancreatic perfusion. CT imaging with IV contrast is best evaluated 3–5 days into hospitalization if patients are not responding to supportive care to assess for local complications such as necrosis. Recent studies report the overutilization of CT imaging within 72 h for acute pancreatitis, including those with a mild severity of disease. 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 348-2. 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 may 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. 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. Importantly, those with only extrapancreatic necrosis have a more favorable prognosis than patients with pancreatic necrosis (with or without extrapancreatic necrosis). 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. 348-1 and 348-2). The median prevalence of organ failure is >50% in necrotizing pancreatitis, and is perhaps slightly higher in infected versus sterile necrosis. With single-organ system failure, the mortality is 3–10%, but increases to nearly 50% with multiorgan failure.

ACUTE PANCREATITIS MANAGEMENT

The management of patients with acute pancreatitis from the time of diagnosis in the emergency ward to hospital discharge is briefly reviewed, highlighting salient features based on severity and complications. It is important to recognize that 85–90% of cases of acute pancreatitis are self-limited and subside spontaneously, usually within 3–7 days after onset, 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, early and aggressive fluid resuscitation is critical. Additionally, 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 any organ failure.

Fluid Resuscitation and Monitoring Response to Therapy

The most important treatment intervention for acute pancreatitis is early, aggressive intravenous fluid resuscitation to prevent systemic complications from the secondary systemic inflammatory response. The patient is initially made NPO to minimize nutrient-induced stimulation of the pancreas and is given intravenous narcotic analgesics to control abdominal pain and supplemental oxygen (as needed).

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 C-reactive protein 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 that a 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

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 348-3)—BUN >25 mg/dL, impaired mental status (Glasgow coma scale score <15), SIRS, age >60 years, and pleural effusion on radiography—that can be useful in assessing severity. The 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 can be safely 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 who 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

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, common bile duct, and 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 in mild acute pancreatitis. An alternative for patients who are not surgical candidates would be to perform an endoscopic biliary sphincterotomy before discharge.

HYPERTRIGLYCERIDEMIA

Serum triglycerides >1000 mg/dL are associated with acute pancreatitis. Initial therapy should focus on treatment of hyperglycemia with intravenous insulin, which often corrects the hypertriglyceridemia. Adjunct therapies may also include heparin or plasmapheresis, but there is no compelling evidence these measures improve clinical outcomes. 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 and post-ERCP pancreatitis. Treatment of hyperparathyroidism or malignancy is effective at reducing serum calcium. 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 rechallenged (Class 1A) and found to be causative.

Nutritional Therapy

A low-fat solid diet can be administered to subjects with mild acute pancreatitis once they are able to eat. 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. Gastric feeding is safe; the benefits of nasojejunal enteral feeding over gastric feeding remains under investigation.

Management of Local Complications

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 348-4). 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 tertiary pancreas center of excellence.

NECROSIS

The management of necrosis requires a multidisciplinary team approach. Percutaneous fine-needle aspiration of necrosis with Gram stain and culture was previously performed to evaluate for infected pancreatic necrosis in those with sustained leukocytosis, fever, or organ failure. However, the current use of this technique varies depending on institutional preference, with many abandoning this diagnostic test to avoid potentially contaminating an otherwise sterile collection, particularly when culture results will not lead to a clinical decision to de-escalate antimicrobial therapy. Even though there is currently no role for prophylactic antibiotics in necrotizing pancreatitis, empiric antibiotics should be considered in those with clinical decompensation. Prophylactic antibiotics do not lead to improved survival and may promote the development of opportunistic fungal infections. 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 drainage and/or debridement (necrosectomy) should be considered for definitive management of infected necrosis, but clinical decisions are ultimately influenced by the clinical response since almost two-thirds of patients respond to antibiotic treatment with or without percutaneous drainage. Symptomatic local complications as outlined in the Revised Atlanta Criteria typically require definitive therapy.

A step-up approach (percutaneous or endoscopic transgastric/transduodenal drainage followed, if necessary, by surgical 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, it is recommended to do so for 4–6 weeks to allow the pancreatic collections to either resolve or evolve to develop a more organized boundary (i.e., to “wall off”) so that surgical or endoscopic intervention is generally safer and more effective.

PSEUDOCYST

The incidence of pseudocyst is low, and most acute collections resolve over time. Less than 10% of patients have persistent fluid collections after 4 weeks that would meet the definition of a pseudocyst. Only symptomatic collections require intervention with endoscopic or surgical drainage.

PANCREATIC DUCT DISRUPTION

Pancreatic duct disruption may present with symptoms of increasing abdominal pain or shortness of breath in the setting of an enlarging fluid collection resulting in pancreatic ascites (ascitic fluid has high amylase level). 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 with or without parenteral nutrition and octreotide. Nonbridging stents are less effective (25–50%) but should be considered with parenteral nutrition and octreotide prior to surgical intervention.

PERIVASCULAR COMPLICATIONS

Perivascular complications may include splenic vein thrombosis with gastric varices and pseudoaneurysms, as well as portal and superior mesenteric vein thromboses. Gastric varices rarely bleed but can be life-threatening. Similarly, life-threatening bleeding from a ruptured pseudoaneurysm can be diagnosed and treated with mesenteric angiography and embolization.

EXTRAPANCREATIC INFECTIONS

Hospital-acquired infections occur in up to 20% of patients with acute pancreatitis. Patients should be continually monitored for the development of 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

Hospitalizations for moderately severe and severe acute pancreatitis can be prolonged and last weeks to months and often involve periods of intensive care unit admission and outpatient rehabilitation or subacute nursing care. Follow-up evaluation should assess for development of diabetes, exocrine pancreatic insufficiency, recurrent cholangitis, or infected fluid collections. As mentioned previously, cholecystectomy should be performed during the initial hospitalization for acute gallstone pancreatitis with mild clinical severity. For patients with necrotizing gallstone pancreatitis, the timing of cholecystectomy needs to be individualized.

RECURRENT ACUTE 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, pancreatic cancer, and hereditary pancreatitis (Table 348-1). 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 cancer 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 pentamidine, trimethoprim-sulfamethoxazole, and protease inhibitors. The incidence has been markedly reduced due to advances in therapy, including the disuse of didanosine (Chap. 202).

CHRONIC PANCREATITIS AND EXOCRINE PANCREATIC INSUFFICIENCY

PATHOPHYSIOLOGY

Chronic pancreatitis is a disease process characterized by irreversible damage to the pancreas, in contrast to the reversible changes noted in acute pancreatitis (Table 348-4). 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 leads to cytokine expression and production of extracellular matrix proteins that contribute to acute and chronic inflammation and collagen deposition in the pancreas. This condition is defined by the presence of histologic abnormalities, including chronic inflammation, fibrosis, and progressive destruction (atrophy) of both exocrine and endocrine tissue. 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, diabetes mellitus, and, less commonly, pancreatic cancer (Table 348-5).

Even in individuals in whom alcohol is believed to be the primary cause of chronic pancreatitis, other factors are likely required for the development and progression of disease, which explains why 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 disease progression, including pancreatic fibrosis and calcifications.

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 shifts toward fibrogenesis in those who develop 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, can 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

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, including a subset of patients who do not develop clinical manifestations until later in life (idiopathic late-onset chronic pancreatitis). Recent investigations have indicated that up to 15% of patients with chronic pancreatitis previously classified as having idiopathic pancreatitis may have an underlying genetic predisposition (Table 348-5).

The prototypical genetic defect was identified in the cationic trypsinogen gene (PRSS1) by studying several large families with chronic pancreatitis. Additional pathogenic and nonpathogenic mutations have been identified in this gene. 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 disease modifiers have been identified (Table 348-5).

The CFTR 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 1700 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 large number and different classes of CFTR 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, 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 needed. In addition, the therapeutic and prognostic implication of these findings with respect to managing pancreatitis remains to be determined. CFTR mutations are common in the general population, so 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 a separate genetic mutation (N34S SPINK1) 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 therapies in children with cystic fibrosis that potentiate the CFTR channel, resulting in improvement in lung function, quality of life, and weight gain. Some studies have shown that use of CFTR modulators may reduce the frequency of acute pancreatitis in heterozygous carriers Table 348-5. lists other recognized causes of chronic pancreatitis.

AUTOIMMUNE PANCREATITIS

Autoimmune pancreatitis (AIP) refers to a form of chronic pancreatitis with distinct histopathology and several unique differences in the clinical phenotype (Table 348-6). Currently, two subtypes of AIP are recognized, type 1 AIP and idiopathic duct-centric chronic pancreatitis (IDCP, also referred to as type 2 AIP). Type 1 AIP is identified as the pancreatic manifestation of a multiorgan syndrome currently referred to as IgG4-related disease (Chap. 368). The characteristic histopathologic findings of type 1 AIP include lymphoplasmacytic infiltrate, storiform fibrosis, and abundant IgG4 cells. IDCP is histologically defined by the presence of granulocytic infiltration of the duct wall (termed a granulocytic epithelial lesion [GEL]) but without IgG4-positive cells. Type 1 AIP is often associated with involvement of other organs in the setting of IgG4-related disease, including bilateral submandibular gland enlargement, characteristic renal lesions, retroperitoneal fibrosis, and stricturing of the suprapancreatic biliary tree. In contrast, IDCP is a pancreas-specific disorder that is associated with inflammatory bowel disease in ~10% of patients. AIP is not a common cause of idiopathic recurrent acute pancreatitis.

Jaundice, weight loss, and new-onset diabetes are the most common presenting symptoms. Elevated serum IgG4 levels are supportive of the diagnosis (elevated in two-thirds of patients with type 1 AIP) but have a low positive predictive value when used in isolation of other clinical findings. CT imaging demonstrates abnormalities in the majority of patients with either diffuse or focal enlargement during active disease, unless the gland is atrophic due to previous disease (Fig. 348-3). The presence of an inflammatory rim, termed a capsule sign, is highly specific (but not sensitive) for AIP. ERCP or MRCP reveals strictures in the bile duct in more than one-third of patients with AIP, including some patients with isolated intrahepatic bile duct strictures (type 1 AIP only), which can mimic primary sclerosing cholangitis, and is referred to as IgG4-related sclerosing cholangitis (previously termed IgG4-associated cholangitis).

The Mayo Clinic HISORt criteria provide a helpful mnemonic to remember the key diagnostic features of this disease, including (1) histology; (2) imaging; (3) serology (elevated serum IgG4 levels); (4) other organ involvement; and (5) response to glucocorticoid therapy. These diagnostic criteria have been harmonized with those from other countries to develop the International Consensus Diagnostic Criteria for AIP, which are the most widely utilized criteria. Glucocorticoids have shown efficacy in alleviating symptoms, decreasing the size of the pancreas, and reversing histopathologic features in patients with AIP. Patients typically 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 per week based on monitoring of clinical parameters. Relief of symptoms, liver biochemistries, and abnormal imaging of the pancreas and bile ducts are followed to assess for treatment response. A poor response to glucocorticoids should raise suspicion of an alternate diagnosis, such as pancreatic cancer. A recent multicenter international study examined >1000 patients with AIP. Clinical remission was achieved in 99% of type 1 AIP and 92% of type 2 AIP patients with steroids. However, disease relapse occurred in 31 and 9% of patients with type 1 and type 2 AIP, respectively. Patients with multiple relapses may be managed with an immunomodulator (e.g., azathioprine, 6-mercaptopurine, or mycophenolate mofetil) or B-cell depletion therapy (e.g., rituximab). The appearance of interval cancers following a diagnosis of AIP is uncommon.

Clinical Features of Chronic Pancreatitis

Patients with chronic pancreatitis primarily seek medical attention due to abdominal pain or symptoms of maldigestion. The abdominal pain may be quite variable in location, severity, and frequency. The pain can be constant or intermittent with 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. There is often a disparity between the reported severity of abdominal pain and the physical findings, which primarily consist of nonfocal abdominal tenderness. Patients with chronic abdominal pain may or may not experience symptoms of maldigestion, such as chronic diarrhea, steatorrhea, and/or weight loss. Fat-soluble vitamin deficiencies are increasingly recognized. Importantly, there is an exceedingly high prevalence of metabolic bone disease in chronic pancreatitis, with ~65% of patients having either osteopenia or osteoporosis. Patients with chronic pancreatitis have impaired quality of life and develop significant morbidity, requiring frequent use of health care resources.

The diagnosis of early or mild chronic pancreatitis can be challenging because there is no accurate biomarker for the disease. In contrast to acute pancreatitis, the serum amylase and lipase levels are usually not strikingly elevated in chronic pancreatitis. Rather, low serum pancreatic enzyme levels are moderately specific for a diagnosis of chronic pancreatitis but have poor sensitivity. Elevation of serum bilirubin and alkaline phosphatase may indicate cholestasis secondary to common bile duct stricture caused by chronic inflammation or fibrosis. The cumulative prevalence of exocrine pancreatic insufficiency is >80%. The presence of overt steatorrhea in a patient with chronic pancreatitis is highly suggestive of this complication. However, in those with milder symptoms, additional testing, such as a random fecal elastase-1 level (on a formed stool specimen) may be needed to confirm the diagnosis of exocrine pancreatic insufficiency. The radiographic evaluation of a patient with suspected chronic pancreatitis usually proceeds from a noninvasive to more invasive approach. Abdominal CT imaging (Fig. 348-4) is the initial modality of choice, followed by MRI, endoscopic ultrasound, and pancreas function testing. In addition to excluding a pseudocyst and pancreatic cancer, CT imaging may show calcifications, dilated pancreatic or biliary 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 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 evolving. 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 specific enough test for detecting early chronic pancreatitis alone (Chap. 347) and may show positive features in patients with diabetes, patients with a history of cigarette smoking, or even in 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. Although alcohol is by far the most common cause of pancreatic calcification, such calcification may also be noted in hereditary pancreatitis, posttraumatic pancreatitis, idiopathic chronic pancreatitis, and tropical pancreatitis.

Complications of Chronic Pancreatitis

There are a number of disease-related complications from chronic pancreatitis in addition to the aforementioned abdominal pain and exocrine pancreatic insufficiency (Table 348-7). The lifetime prevalence of chronic pancreatitis–related diabetes exceeds 80%. Although most patients develop hyperglycemia due to insulin deficiency caused by loss of islet cells, diabetic ketoacidosis and diabetic coma are uncommon. Likewise, end-organ damage (retinopathy, neuropathy, nephropathy) is also uncommon. Nondiabetic retinopathy may be due to vitamin A and/or zinc deficiency. Osteoporosis and osteopenia are increasingly recognized in chronic pancreatitis and likely related to a combination of shared risk factors (e.g., alcohol use, cigarette smoking), vitamin D deficiency, and detrimental effects on the bone from chronic inflammation. 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. 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 chronic calcific pancreatitis, the cumulative risk of pancreatic cancer is 4%. Patients with hereditary PRSS1 or tropical pancreatitis have an increased risk for pancreatic cancer compared to other forms of chronic pancreatitis.

HEREDITARY PANCREATITIS

Hereditary pancreatitis (PRSS1) is a rare form of pancreatitis with early age of onset that is typically associated with familial aggregation of cases. A genome-wide 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 (PRSS1) cause an autosomal dominant form of 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 episodes of acute pancreatitis. Patients frequently develop pancreatic calcification, diabetes mellitus, and steatorrhea; in addition, they have an increased incidence of pancreatic cancer with a cumulative incidence of ~10%. A previous 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 cancer at age 55 years. Abdominal complaints in relatives of patients with hereditary pancreatitis should raise the question of pancreatic disease.

PANCREATIC ENDOCRINE TUMORS

Pancreatic endocrine tumors are discussed in Chap. 84.

OTHER CONDITIONS

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, duodenal 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 duodenojejunostomy 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 minor 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 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 technically challenging and associated with a very high risk of post-ERCP pancreatitis, so patients with pancreatitis and pancreas divisum should likely 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. 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 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 (deceased), Phillip P. Toskes (deceased), Peter A. Banks, and Bechien Wu that were in previous editions of Harrison’s.

FURTHER READING