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Disorders of the Pancreas 30. Ratio: 6.4 nitrogen level >20 mg/dL [7.1 mmol/L] and rising, hematocrit >44%, or elevated serum creatinine level), presence of pleural Peripancreatic Fat effusions and/or infiltrates, and altered mental status. A sys- Edema \ tematic review of 18 multiple-factor scoring systems, includ- ing the Ranson criteria and the Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score, for predict- ing outcome in acute pancreatitis found these systems to have limited clinical value and accuracy. Scoring systems identify severe disease only as it develops, without enough lead time for intervention, and they are too cumbersome for routine use. Elevated hematocrit, elevated blood urea nitrogen levels, and the presence of SIRS are as accurate as complex scoring sys- tems in predicting outcome, and they are easier to use.

30. Ratio: 6.4 nitrogen level >20 mg/dL [7.1 mmol/L] and rising, hematocrit >44%, or elevated serum creatinine level), presence of pleural Peripancreatic Fat effusions and/or infiltrates, and altered mental status. A sys- Edema \ tematic review of 18 multiple-factor scoring systems, includ- ing the Ranson criteria and the Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II score, for predict- ing outcome in acute pancreatitis found these systems to have limited clinical value and accuracy. Scoring systems identify severe disease only as it develops, without enough lead time for intervention, and they are too cumbersome for routine use. Elevated hematocrit, elevated blood urea nitrogen levels, and the presence of SIRS are as accurate as complex scoring sys- tems in predicting outcome, and they are easier to use. Management Mainstays of initial management include fluid resuscitation, pain management, and antiemetics. Early and aggressive fluid resuscitation (250-500 mL/h of intravenous normal saline or lactated Ringer solution) should be given to patients with acute pancreatitis on presentation and is most beneficial in the first 12 to 24 hours. More rapid

Management Mainstays of initial management include fluid resuscitation, pain management, and antiemetics. Early and aggressive fluid resuscitation (250-500 mL/h of intravenous normal saline or lactated Ringer solution) should be given to patients with acute pancreatitis on presentation and is most beneficial in the first 12 to 24 hours. More rapid FIGURE 9. CTscan showing acute pancreatitis with peripancreatic fat stranding fluid resuscitation (boluses) may be needed in patients with and inflammation. The hazy appearance of the mesenteric fat surrounding the severe volume depletion in order to maintain organ perfusion. pancreas in this image is called fat stranding, and the blurring of the margins of the Patients with organ failure or SIRS should be admitted to an pancreas is consistent with peripancreatic edema, features seen with inflammatory ICU or intermediary care setting, with fluid requirements changes of acute pancreatitis. reassessed every 6 hours for the first 24 to 48 hours. Routine use of antibiotics is not warranted in acute pan- over CT because it has a higher sensitivity for detecting gall- creatitis unless there is evidence of extrapancreatic infection, stones, avoids the risks of intravenous contrast material, and is such as ascending cholangitis, bacteremia, urinary tract infec- more cost-effective. Magnetic resonance cholangiopancrea- tion, or pneumonia. Use of prophylactic antibiotics in patients tography may be considered in patients without abnormal with sterile pancreatic necrosis to prevent infected necrosis is findings on ultrasonography when concern remains for con- not recommended. comitant biliary disease. Although less useful for assessing the In mild acute pancreatitis, oral feedings can be started as biliary system, CT may be indicated if the diagnosis is in ques- soon as nausea and vomiting are controlled and clinical symp- tion or clinical symptoms are not improved within the first toms improve. Enteral feeding should begin within 72 hours if 48 hours (especially because abdominal air can limit ultra- oral feeding is not tolerated; it is usually required in patients sonographic visualization of the pancreas). with moderately severe or severe acute pancreatitis. Feeding Aserum alanine aminotransferase level greater than 150 IU/L with a nasojejunal tube has traditionally been preferred, but suggests gallstone pancreatitis. Hyperbilirubinemia should data suggest that nasogastric feedings are probably as effective raise suspicion of biliary obstruction and/or cholangitis. Serum and are easier to administer. Enteral feeding promotes a amylase and lipase levels may be elevated in conditions other healthy gut-mucosal barrier and may prevent translocation of than acute pancreatitis, such as kidney disease, acute appendi- bacteria into inflamed tissues. citis, cholecystitis, intestinal obstruction or ischemia, peptic If a biliary cause of acute pancreatitis is suspected, serial ulcer, or gynecologic disorders. Enzyme levels may be falsely liver chemistry tests and clinical symptoms can show whether low or normal in patients with hypertriglyceridemia-induced the biliary obstruction is ongoing or resolving. Endoscopic pancreatitis because of lipemic-serum interference with labo- retrograde cholangiopancreatography (ERCP) is not indicated ratory assays. Triglyceride levels should be measured in patients in patients with gallstone pancreatitis unless there is persis- without a biliary cause of acute pancreatitis; a triglyceride level tent biochemical evidence of biliary obstruction or choledo- exceeding 1000 mg/dL (11.3 mmol/L) can be considered the cholithiasis is seen on imaging. Patients with cholangitis cause of the acute pancreatitis. should undergo ERCP within 24 hours of admission. Magnetic resonance cholangiopancreatography can be useful when Prognostic Criteria there is persistent elevation of liver chemistries without overt Risk factors for severe disease include age older than 55 years, cholangitis or biliary obstruction. Patients with uncompli- medical comorbidities, BMI greater than 30, presence of SIRS, cated gallstone pancreatitis should be considered for cholecys- signs of hypovolemia on presentation (e.g., serum blood urea tectomy before discharge.

FIGURE 9. CTscan showing acute pancreatitis with peripancreatic fat stranding fluid resuscitation (boluses) may be needed in patients with and inflammation. The hazy appearance of the mesenteric fat surrounding the severe volume depletion in order to maintain organ perfusion. pancreas in this image is called fat stranding, and the blurring of the margins of the Patients with organ failure or SIRS should be admitted to an pancreas is consistent with peripancreatic edema, features seen with inflammatory ICU or intermediary care setting, with fluid requirements changes of acute pancreatitis. reassessed every 6 hours for the first 24 to 48 hours. Routine use of antibiotics is not warranted in acute pan- over CT because it has a higher sensitivity for detecting gall- creatitis unless there is evidence of extrapancreatic infection, stones, avoids the risks of intravenous contrast material, and is such as ascending cholangitis, bacteremia, urinary tract infec- more cost-effective. Magnetic resonance cholangiopancrea- tion, or pneumonia. Use of prophylactic antibiotics in patients tography may be considered in patients without abnormal with sterile pancreatic necrosis to prevent infected necrosis is findings on ultrasonography when concern remains for con- not recommended. comitant biliary disease. Although less useful for assessing the In mild acute pancreatitis, oral feedings can be started as biliary system, CT may be indicated if the diagnosis is in ques- soon as nausea and vomiting are controlled and clinical symp- tion or clinical symptoms are not improved within the first toms improve. Enteral feeding should begin within 72 hours if 48 hours (especially because abdominal air can limit ultra- oral feeding is not tolerated; it is usually required in patients sonographic visualization of the pancreas). with moderately severe or severe acute pancreatitis. Feeding Aserum alanine aminotransferase level greater than 150 IU/L with a nasojejunal tube has traditionally been preferred, but suggests gallstone pancreatitis. Hyperbilirubinemia should data suggest that nasogastric feedings are probably as effective raise suspicion of biliary obstruction and/or cholangitis. Serum and are easier to administer. Enteral feeding promotes a amylase and lipase levels may be elevated in conditions other healthy gut-mucosal barrier and may prevent translocation of than acute pancreatitis, such as kidney disease, acute appendi- bacteria into inflamed tissues. citis, cholecystitis, intestinal obstruction or ischemia, peptic If a biliary cause of acute pancreatitis is suspected, serial ulcer, or gynecologic disorders. Enzyme levels may be falsely liver chemistry tests and clinical symptoms can show whether low or normal in patients with hypertriglyceridemia-induced the biliary obstruction is ongoing or resolving. Endoscopic pancreatitis because of lipemic-serum interference with labo- retrograde cholangiopancreatography (ERCP) is not indicated ratory assays. Triglyceride levels should be measured in patients in patients with gallstone pancreatitis unless there is persis- without a biliary cause of acute pancreatitis; a triglyceride level tent biochemical evidence of biliary obstruction or choledo- exceeding 1000 mg/dL (11.3 mmol/L) can be considered the cholithiasis is seen on imaging. Patients with cholangitis cause of the acute pancreatitis. should undergo ERCP within 24 hours of admission. Magnetic resonance cholangiopancreatography can be useful when Prognostic Criteria there is persistent elevation of liver chemistries without overt Risk factors for severe disease include age older than 55 years, cholangitis or biliary obstruction. Patients with uncompli- medical comorbidities, BMI greater than 30, presence of SIRS, cated gallstone pancreatitis should be considered for cholecys- signs of hypovolemia on presentation (e.g., serum blood urea tectomy before discharge. 20

Disorders of the Pancreas There is no value in rechecking serum amylase and lipase levels after the diagnosis is established. Complications There are two overlapping phases of acute pancreatitis with two peaks in mortality. The early phase is the first week of the disease. In this phase, the body is responding to local pancreatic injury and the cytokine cascade; SIRS and organ failure, especially kidney and respiratory fail- ure, are possible, as is profound hypocalcemia. The late phase occurs after the first week and may persist for weeks to months in patients with moderately severe or severe acute pancreatitis. Significant risk for infection in peri- pancreatic fluid collections and necrotic tissue occurs in the late phase. Proper classification of fluid collections in acute pancrea- titis is important to guide management. In 2012, an interna- tional consensus group updated the Atlanta classification and FIGURE 11. CT scan showing maturation and liquefaction of pancreas necrosis of nearly the entire pancreas over4 weeks’ duration with a well-defined rim or wall definitions of acute pancreatitis and its complications to pro- (arrows), known as walled-off necrosis. mote consistency in diagnosis and management. The group defined four types of fluid collections: 4. Walled-off necrosis (Figure 11) occurs after 4 weeks, when 1. Acute peripancreatic fluid collections occur in edematous the body liquefies the necrosis and contains it within a interstitial pancreatitis (no necrosis) within the first 4 weeks, well-defined wall. are thought to result from rupture of main or side-branch Contrast-enhanced CT may not be able to distinguish solid ducts because of inflammation, are sterile, and usually from liquid content in fluid collections; therefore, necrotic col- resolve spontaneously. lections are frequently misdiagnosed as pancreatic pseudocysts. 2. Pancreatic pseudocysts are acute peripancreatic fluid col- Pancreatic pseudocysts do not require drainage unless they lections that have persisted for longer than 4 weeks, have cause significant symptoms or are infected, regardless of size. developed a well-defined wall, and contain no solid debris Because they contain only fluid, pseudocysts are easily (necrosis). drained under endoscopic or radiographic guidance. Walled- 3. Acute necrotic collections (Figure 10) are areas of necrosis off necrosis is not as amenable to percutaneous or endoscopic in the pancreatic parenchyma and/or peripancreatic tis- drainage because of solid necrotic debris within the cavity and sues within the first 4 weeks of acute pancreatitis. may require surgical debridement. The management of suspected infected necrosis includes initiation of antibiotics (e.g., imipenem-cilastatin, merope-

Complications There are two overlapping phases of acute pancreatitis with two peaks in mortality. The early phase is the first week of the disease. In this phase, the body is responding to local pancreatic injury and the cytokine cascade; SIRS and organ failure, especially kidney and respiratory fail- ure, are possible, as is profound hypocalcemia. The late phase occurs after the first week and may persist for weeks to months in patients with moderately severe or severe acute pancreatitis. Significant risk for infection in peri- pancreatic fluid collections and necrotic tissue occurs in the late phase. Proper classification of fluid collections in acute pancrea- titis is important to guide management. In 2012, an interna- tional consensus group updated the Atlanta classification and FIGURE 11. CT scan showing maturation and liquefaction of pancreas necrosis of nearly the entire pancreas over4 weeks’ duration with a well-defined rim or wall definitions of acute pancreatitis and its complications to pro- (arrows), known as walled-off necrosis. mote consistency in diagnosis and management. The group defined four types of fluid collections: 4. Walled-off necrosis (Figure 11) occurs after 4 weeks, when 1. Acute peripancreatic fluid collections occur in edematous the body liquefies the necrosis and contains it within a interstitial pancreatitis (no necrosis) within the first 4 weeks, well-defined wall. are thought to result from rupture of main or side-branch Contrast-enhanced CT may not be able to distinguish solid ducts because of inflammation, are sterile, and usually from liquid content in fluid collections; therefore, necrotic col- resolve spontaneously. lections are frequently misdiagnosed as pancreatic pseudocysts. 2. Pancreatic pseudocysts are acute peripancreatic fluid col- Pancreatic pseudocysts do not require drainage unless they lections that have persisted for longer than 4 weeks, have cause significant symptoms or are infected, regardless of size. developed a well-defined wall, and contain no solid debris Because they contain only fluid, pseudocysts are easily (necrosis). drained under endoscopic or radiographic guidance. Walled- 3. Acute necrotic collections (Figure 10) are areas of necrosis off necrosis is not as amenable to percutaneous or endoscopic in the pancreatic parenchyma and/or peripancreatic tis- drainage because of solid necrotic debris within the cavity and sues within the first 4 weeks of acute pancreatitis. may require surgical debridement. The management of suspected infected necrosis includes initiation of antibiotics (e.g., imipenem-cilastatin, merope- nem, or ciprofloxacin plus metronidazole), with consideration of fine-needle aspiration with Gram stain and culture under CT guidance. Drainage procedures or debridement should be delayed for at least 4 weeks if possible to allow encapsulation of the necrosis with a fibrous wall.

nem, or ciprofloxacin plus metronidazole), with consideration of fine-needle aspiration with Gram stain and culture under CT guidance. Drainage procedures or debridement should be delayed for at least 4 weeks if possible to allow encapsulation of the necrosis with a fibrous wall. e Biliary disease (gallstones, biliary sludge, or microlithiasis) is the most common cause of acute pancreatitis. e Diagnosis of acute pancreatitis requires two of three cri- teria: (1) acute-onset upper abdominal pain, (2) serum lipase or amylase levels elevated at least three times the upper limit of normal, and (3) characteristic findings on imaging. e Patients with acute pancreatitis should undergo HVC transabdominal ultrasonography rather than CT for FIGURE 10. CTscan showing acute pancreatitis with hypoperfusion of the evaluation of biliary disease. body of the pancreas, as indicated by lack of enhancement following intravenous (Continued) contrast infusion (necrosis) and normal perfusion of the pancreatic tail. 21

Disorders of the Pancreas e Early and aggressive fluid resuscitation should be initiated in patients with acute pancreatitis. e In mild acute pancreatitis, oral feedings can be started as soon as nausea and vomiting are controlled and clinical symptoms are alleviated; enteral feeding should begin within 72 hours if oral feeding is not tolerated. e Pancreatic pseudocysts do not require drainage unless they cause significant symptoms or are infected, regardless of size.

e In mild acute pancreatitis, oral feedings can be started as soon as nausea and vomiting are controlled and clinical symptoms are alleviated; enteral feeding should begin within 72 hours if oral feeding is not tolerated. e Pancreatic pseudocysts do not require drainage unless they cause significant symptoms or are infected, regardless of size. Chronic Pancreatitis Chronic pancreatitis is thought to develop when the inflam- matory response to acute pancreatitis persists and ongoing FIGURE 12. CTscan showing chronic calcific pancreatitis with multiple stones inflammation activates stellate cells, resulting in a fibro- in the main duct and side branches of the pancreas. inflammatory response. This causes distorted tissue architec- ture, loss of normal parenchyma, activation of pancreatic Clinical Presentation and Diagnosis nociceptors, and loss of acinar and islet cell function. Genetic Abdominal pain is the most common presenting symptom of variants affecting inflammatory response, enzyme activation, chronic pancreatitis (seen in 85% of patients), but some and tissue repair are thought to play important roles in the patients have no pain. Pain patterns can vary from constant pathogenesis of chronic pancreatitis. Many genes have been daily pain to intermittent attacks of severe pain. Pancreatic identified as disease modifiers, but the gene-environment enzyme levels may not increase during attacks of pain because interaction is not fully understood. of fibrosis and atrophy of acinar cells and decreased enzyme Alcohol use has long been described as a risk factor for production. Constant daily pain in chronic pancreatitis signifi- chronic pancreatitis, but less than 3% of heavy alcohol users cantly reduces quality of life, with increased use of health care develop pancreatic disease. Patients who consume more resources and disability benefits and time away from employ- than five drinks per day (or 35 drinks per week) seem to be ment. Exocrine or endocrine insufficiency occurs in some more susceptible to chronic pancreatitis. In the largest study patients as a result of significant tissue destruction. of patients with chronic pancreatitis in North America, only Diagnosis of chronic pancreatitis remains challenging 46% had a history of significant alcohol use. The higher because hallmark anatomic features, such as pancreatic calci- prevalence of alcohol-associated pancreatitis among men fications (Figure 12), occur in only 25% of patients, and other could be partially explained by an X chromosome-linked features of atrophy or duct dilation can occur normally with genetic variant, the CLDN2 gene. Tobacco is considered an aging or other disease processes. Imaging with CT or MRI is independent risk factor. Table 15 lists causes of chronic the initial test of choice. In the setting of high clinical suspicion pancreatitis. and negative findings on imaging, endoscopic ultrasonogra- phy and secretin-enhanced magnetic resonance cholangio-

Chronic Pancreatitis Chronic pancreatitis is thought to develop when the inflam- matory response to acute pancreatitis persists and ongoing FIGURE 12. CTscan showing chronic calcific pancreatitis with multiple stones inflammation activates stellate cells, resulting in a fibro- in the main duct and side branches of the pancreas. inflammatory response. This causes distorted tissue architec- ture, loss of normal parenchyma, activation of pancreatic Clinical Presentation and Diagnosis nociceptors, and loss of acinar and islet cell function. Genetic Abdominal pain is the most common presenting symptom of variants affecting inflammatory response, enzyme activation, chronic pancreatitis (seen in 85% of patients), but some and tissue repair are thought to play important roles in the patients have no pain. Pain patterns can vary from constant pathogenesis of chronic pancreatitis. Many genes have been daily pain to intermittent attacks of severe pain. Pancreatic identified as disease modifiers, but the gene-environment enzyme levels may not increase during attacks of pain because interaction is not fully understood. of fibrosis and atrophy of acinar cells and decreased enzyme Alcohol use has long been described as a risk factor for production. Constant daily pain in chronic pancreatitis signifi- chronic pancreatitis, but less than 3% of heavy alcohol users cantly reduces quality of life, with increased use of health care develop pancreatic disease. Patients who consume more resources and disability benefits and time away from employ- than five drinks per day (or 35 drinks per week) seem to be ment. Exocrine or endocrine insufficiency occurs in some more susceptible to chronic pancreatitis. In the largest study patients as a result of significant tissue destruction. of patients with chronic pancreatitis in North America, only Diagnosis of chronic pancreatitis remains challenging 46% had a history of significant alcohol use. The higher because hallmark anatomic features, such as pancreatic calci- prevalence of alcohol-associated pancreatitis among men fications (Figure 12), occur in only 25% of patients, and other could be partially explained by an X chromosome-linked features of atrophy or duct dilation can occur normally with genetic variant, the CLDN2 gene. Tobacco is considered an aging or other disease processes. Imaging with CT or MRI is independent risk factor. Table 15 lists causes of chronic the initial test of choice. In the setting of high clinical suspicion pancreatitis. and negative findings on imaging, endoscopic ultrasonogra- phy and secretin-enhanced magnetic resonance cholangio- TABLE 15. Causes of Chronic Pancreatitis pancreatography may be useful as second- and third-line tests; pancreatic biopsy may rarely be necessary. ERCP is no longer Toxic or metabolic used as a diagnostic tool for chronic pancreatitis. Genetic test- Alcohol, tobacco, hypercalcemia, hypertriglyceridemia, chronic kidney disease ing for cystic fibrosis and familial pancreatitis should be con- sidered in younger patients. Pancreatic exocrine function may Genetic be assessed with fecal elastase testing, which has largely Mutations or polymorphisms of the CFTR, PRSSI, SPINKI, CTRC, replaced fecal fat testing. CASR, CLDN2 genes

TABLE 15. Causes of Chronic Pancreatitis pancreatography may be useful as second- and third-line tests; pancreatic biopsy may rarely be necessary. ERCP is no longer Toxic or metabolic used as a diagnostic tool for chronic pancreatitis. Genetic test- Alcohol, tobacco, hypercalcemia, hypertriglyceridemia, chronic kidney disease ing for cystic fibrosis and familial pancreatitis should be con- sidered in younger patients. Pancreatic exocrine function may Genetic be assessed with fecal elastase testing, which has largely Mutations or polymorphisms of the CFTR, PRSSI, SPINKI, CTRC, replaced fecal fat testing. CASR, CLDN2 genes Recurrent and severe acute pancreatitis Management Vascular disease/ischemia Management focuses on treating symptoms. No effective treat- Obstructive ment exists to reverse or halt disease progression. Patients Pancreatic tumor, intraductal papillary mucinous neoplasm should be counseled to avoid alcohol and tobacco to lessen Posttraumatic (pancreatic duct stricture) attacks of inflammation and pain. Intermittent attacks of Autoimmune (type 1 and type 2) severe acute pain are treated as acute pancreatitis. Possible complications of chronic pancreatitis, including pseudocyst, Idiopathic pancreatic duct stones causing upstream obstruction, and 22

Disorders of the Pancreas malignancy, should be evaluated with imaging (e.g., pancreatic- protocol CT) when a patient’s symptom pattern changes. Endoscopic techniques are first-line therapy for relief of ductal obstruction. Constant daily pain is more challenging to manage; treatment frequently involves medications such as tramadol, serotonin norepinephrine reuptake inhibitors, gabapenti- noids, and opioids. Long-term use of opioids should be avoided because of hyperesthesia and development of tolerance or addiction. Pancreatic enzymes are used to treat steatorrhea but do not effectively treat pain or prevent attacks of pancrea- titis. Two large randomized trials of antioxidants to treat chronic pancreatitis pain showed conflicting results; guide- lines suggest that antioxidants be considered, although it is unclear which antioxidants and doses are appropriate. Nerve blocks and neurolysis procedures are also recommended, although the response rate is low, and pain relief, if achieved, lasts only a few weeks. Surgery offers the best long-term results for chronic FIGURE 13. CTscan showing the homogeneous, hypodense “sausage-shaped" refractory pain management and, depending on anatomy and swelling (arrows) seen in autoimmune pancreatitis. The pancreatic duct is not dilated.

malignancy, should be evaluated with imaging (e.g., pancreatic- protocol CT) when a patient’s symptom pattern changes. Endoscopic techniques are first-line therapy for relief of ductal obstruction. Constant daily pain is more challenging to manage; treatment frequently involves medications such as tramadol, serotonin norepinephrine reuptake inhibitors, gabapenti- noids, and opioids. Long-term use of opioids should be avoided because of hyperesthesia and development of tolerance or addiction. Pancreatic enzymes are used to treat steatorrhea but do not effectively treat pain or prevent attacks of pancrea- titis. Two large randomized trials of antioxidants to treat chronic pancreatitis pain showed conflicting results; guide- lines suggest that antioxidants be considered, although it is unclear which antioxidants and doses are appropriate. Nerve blocks and neurolysis procedures are also recommended, although the response rate is low, and pain relief, if achieved, lasts only a few weeks. Surgery offers the best long-term results for chronic FIGURE 13. CTscan showing the homogeneous, hypodense “sausage-shaped" refractory pain management and, depending on anatomy and swelling (arrows) seen in autoimmune pancreatitis. The pancreatic duct is not dilated. cause, may include lateral pancreaticojejunostomy, duodenal- Pancreatitis endorsed the concept of type 1 and type 2 disease, preserving pancreatic head resection, pancreaticoduodenec- but there is some debate over whether type 2 should be con- tomy, distal pancreatectomy, or even total pancreatectomy sidered an IgG4-related disease. with or without auto-islet-cell transplantation. These proce- For more information on IgG4-related disease, see MKSAP dures improve outcomes in patients at high-volume pancreas 19 Rheumatology. referral centers. Pancreatic endocrine insufficiency may require specialty referral for labile diabetes management. Clinical Presentation and Diagnosis Patients with both types of AIP may present with abdominal e Abdominal pain, which may occur as intermittent attacks pain or obstructive jaundice with or without a mass. In patients or as ongoing daily pain, is the most common symptom presenting with obstructive jaundice or with a mass, pancreatic of chronic pancreatitis. malignancy must be considered. Many patients with malig-

cause, may include lateral pancreaticojejunostomy, duodenal- Pancreatitis endorsed the concept of type 1 and type 2 disease, preserving pancreatic head resection, pancreaticoduodenec- but there is some debate over whether type 2 should be con- tomy, distal pancreatectomy, or even total pancreatectomy sidered an IgG4-related disease. with or without auto-islet-cell transplantation. These proce- For more information on IgG4-related disease, see MKSAP dures improve outcomes in patients at high-volume pancreas 19 Rheumatology. referral centers. Pancreatic endocrine insufficiency may require specialty referral for labile diabetes management. Clinical Presentation and Diagnosis Patients with both types of AIP may present with abdominal e Abdominal pain, which may occur as intermittent attacks pain or obstructive jaundice with or without a mass. In patients or as ongoing daily pain, is the most common symptom presenting with obstructive jaundice or with a mass, pancreatic of chronic pancreatitis. malignancy must be considered. Many patients with malig- HVC e Pancreatic biopsy and endoscopic retrograde cholangio- nancy have a dilated upstream main pancreatic duct. In con- pancreatography are not indicated in the diagnosis of trast, patients with AIP may have a narrowed main pancreatic

cause, may include lateral pancreaticojejunostomy, duodenal- Pancreatitis endorsed the concept of type 1 and type 2 disease, preserving pancreatic head resection, pancreaticoduodenec- but there is some debate over whether type 2 should be con- tomy, distal pancreatectomy, or even total pancreatectomy sidered an IgG4-related disease. with or without auto-islet-cell transplantation. These proce- For more information on IgG4-related disease, see MKSAP dures improve outcomes in patients at high-volume pancreas 19 Rheumatology. referral centers. Pancreatic endocrine insufficiency may require specialty referral for labile diabetes management. Clinical Presentation and Diagnosis Patients with both types of AIP may present with abdominal e Abdominal pain, which may occur as intermittent attacks pain or obstructive jaundice with or without a mass. In patients or as ongoing daily pain, is the most common symptom presenting with obstructive jaundice or with a mass, pancreatic of chronic pancreatitis. malignancy must be considered. Many patients with malig- HVC e Pancreatic biopsy and endoscopic retrograde cholangio- nancy have a dilated upstream main pancreatic duct. In con- pancreatography are not indicated in the diagnosis of trast, patients with AIP may have a narrowed main pancreatic chronic pancreatitis. duct or parenchymal swelling (“sausage-shaped” pancreas [Figure 13]). Endoscopic ultrasonography and biopsy may be e Symptomatic management is the cornerstone of treatment required to differentiate AIP and pancreatic neoplasm. Ten for chronic pancreatitis, including in patients with percent of patients with type 1 AIP may develop chronic pan- refractory pain. creatitis or pancreatic stone formation. e Patients with chronic pancreatitis should be counseled Patients with type 1 AIP have elevated levels of IgG4- to avoid alcohol and tobacco use. positive cells in pancreatic tissue (>10 IgG4-positive cells/hpf), and 60% to 80% of patients have associated sclerosing cholan- gitis, sclerosing sialadenitis, or retroperitoneal fibrosis. Autoimmune Pancreatitis Fulfillment of one or more of the HISORt criteria (diagnostic and IgG4 Disease Histology, suggestive Imaging, Serology with elevated serum

chronic pancreatitis. duct or parenchymal swelling (“sausage-shaped” pancreas [Figure 13]). Endoscopic ultrasonography and biopsy may be e Symptomatic management is the cornerstone of treatment required to differentiate AIP and pancreatic neoplasm. Ten for chronic pancreatitis, including in patients with percent of patients with type 1 AIP may develop chronic pan- refractory pain. creatitis or pancreatic stone formation. e Patients with chronic pancreatitis should be counseled Patients with type 1 AIP have elevated levels of IgG4- to avoid alcohol and tobacco use. positive cells in pancreatic tissue (>10 IgG4-positive cells/hpf), and 60% to 80% of patients have associated sclerosing cholan- gitis, sclerosing sialadenitis, or retroperitoneal fibrosis. Autoimmune Pancreatitis Fulfillment of one or more of the HISORt criteria (diagnostic and IgG4 Disease Histology, suggestive Imaging, Serology with elevated serum Autoimmune pancreatitis (AIP) is a frequent manifestation of IgG4, Other organ involvement, or Response to therapy with IgG4-related disease. Other organs that can be affected include glucocorticoids) can be helpful in the diagnosis of type 1 AIP. the lacrimal and salivary glands, central nervous system, kid- Type 2 AIP has no or few IgG4-positive cells but is charac- neys, thyroid gland, lungs, biliary tract and liver, prostate terized by idiopathic duct-centric neutrophil infiltration, gland, retroperitoneum, and lymph nodes. Storiform fibrosis known as a granulocytic epithelial lesion. Type 2 AIP is a

IgG4-related disease. Other organs that can be affected include glucocorticoids) can be helpful in the diagnosis of type 1 AIP. the lacrimal and salivary glands, central nervous system, kid- Type 2 AIP has no or few IgG4-positive cells but is charac- neys, thyroid gland, lungs, biliary tract and liver, prostate terized by idiopathic duct-centric neutrophil infiltration, gland, retroperitoneum, and lymph nodes. Storiform fibrosis known as a granulocytic epithelial lesion. Type 2 AIP is a and obliterative phlebitis are seen in the pancreas and biliary pancreas-specific disease occasionally associated with inflam- tract. The most common pancreatic manifestation of IgG4- matory bowel disease. related disease is type 1 AIP, with abundant infiltration of IgG4-positive plasma cells and lymphocytes. Type 2 disease is Treatment discussed in Clinical Presentation and Diagnosis. The 2011 Glucocorticoids are effective treatment for types 1 and 2 AIP, International Consensus of Diagnostic Criteria for Autoimmune starting with oral prednisolone at 0.6 to 1.0 mg/kg/d and 23

Disorders of the Pancreas tapered over 2 to 3 months. Response is determined by symp- develop new-onset diabetes mellitus in the 36 months sur- tom relief and imaging features. Failure of clinical symptoms to rounding the diagnosis. Venous thromboembolic events and respond to glucocorticoids suggests an incorrect diagnosis, depression occur at higher rates in patients with pancreatic and other causes should be investigated. Up to 60% of patients adenocarcinoma than in patients with other malignancies. may relapse. Glucocorticoids or immunomodulators, such as 6-mercaptopurine, azathioprine, mycophenolate, or rituxi- Diagnosis mab, may be re-adminstered to treat recurrent AIP. Pancreas-protocol CT uses multiphasic arterial and venous phases with thin cuts (3 mm) through the abdomen to view the primary tumor’s relationship to mesenteric vasculature e Diagnosis of autoimmune pancreatitis requires the and to detect metastatic lesions. Some studies suggest that presence of a narrowed main pancreatic duct and pancreas-protocol MRI may be superior to CT for pancreatic parenchymal swelling (“sausage-shaped” pancreas) on disease. Histopathologic confirmation of pancreatic adenocar- imaging and disease response to glucocorticoids. cinoma is increasingly recommended before initiation of ther- e Type 1 autoimmune pancreatitis is characterized by ele- apy. In patients with potentially resectable disease, endoscopic vated numbers of IgG4-positive cells in pancreatic tissue; ultrasonography-guided fine-needle aspiration biopsy is rec- most patients also have a significant elevation of IgG4 in ommended for histologic confirmation of cancer. It is prefer- serum. able to CT-guided biopsy because of its higher diagnostic yield, e Patients with type 2 autoimmune pancreatitis have normal safety, and lower risk for peritoneal seeding. Patients are con- IgG4-positive cell counts. sidered for primary surgical resection if they have no involve- ment of mesenteric vasculature or metastatic disease and are e Types 1 and 2 autoimmune pancreatitis are treated with healthy enough for major intra-abdominal surgery. glucocorticoids, with a relapse rate of up to 60%. For staging and treatment of pancreatic cancer, see MKSAP 19 Oncology.

tapered over 2 to 3 months. Response is determined by symp- develop new-onset diabetes mellitus in the 36 months sur- tom relief and imaging features. Failure of clinical symptoms to rounding the diagnosis. Venous thromboembolic events and respond to glucocorticoids suggests an incorrect diagnosis, depression occur at higher rates in patients with pancreatic and other causes should be investigated. Up to 60% of patients adenocarcinoma than in patients with other malignancies. may relapse. Glucocorticoids or immunomodulators, such as 6-mercaptopurine, azathioprine, mycophenolate, or rituxi- Diagnosis mab, may be re-adminstered to treat recurrent AIP. Pancreas-protocol CT uses multiphasic arterial and venous phases with thin cuts (3 mm) through the abdomen to view the primary tumor’s relationship to mesenteric vasculature e Diagnosis of autoimmune pancreatitis requires the and to detect metastatic lesions. Some studies suggest that presence of a narrowed main pancreatic duct and pancreas-protocol MRI may be superior to CT for pancreatic parenchymal swelling (“sausage-shaped” pancreas) on disease. Histopathologic confirmation of pancreatic adenocar- imaging and disease response to glucocorticoids. cinoma is increasingly recommended before initiation of ther- e Type 1 autoimmune pancreatitis is characterized by ele- apy. In patients with potentially resectable disease, endoscopic vated numbers of IgG4-positive cells in pancreatic tissue; ultrasonography-guided fine-needle aspiration biopsy is rec- most patients also have a significant elevation of IgG4 in ommended for histologic confirmation of cancer. It is prefer- serum. able to CT-guided biopsy because of its higher diagnostic yield, e Patients with type 2 autoimmune pancreatitis have normal safety, and lower risk for peritoneal seeding. Patients are con- IgG4-positive cell counts. sidered for primary surgical resection if they have no involve- ment of mesenteric vasculature or metastatic disease and are e Types 1 and 2 autoimmune pancreatitis are treated with healthy enough for major intra-abdominal surgery. glucocorticoids, with a relapse rate of up to 60%. For staging and treatment of pancreatic cancer, see MKSAP 19 Oncology. Pancreatic Adenocarcinoma Pancreatic ductal adenocarcinoma has a poor prognosis and e Diagnosis of pancreatic cancer is suggested by abdominal increasing incidence. In 2019, there were approximately pain, weight loss, jaundice, and new-onset diabetes mel- 57,000 cases diagnosed in the United States and 46,000 litus; pancreas-protocol CT or MRI helps support the deaths. It is predicted to become the second leading cause of diagnosis and delineates the extent of disease. cancer-related death in the United States over the next decade, e In patients with potentially resectable disease, endoscopic with an overall 5-year survival rate of 9%. ultrasonography-guided fine-needle aspiration of the pancreas is recommended for histologic confirmation of Epidemiology and Risk Factors cancer. Risk factors for pancreatic cancer include age older than 50 years, smoking history, obesity, chronic pancreatitis, and mucinous cystic lesions of the pancreas. Inherited conditions Cystic Lesions of the Pancreas associated with pancreatic cancer include Peutz-Jeghers syn- Pancreatic cysts are found incidentally in 15% of patients drome, BRCA2 germline mutations, hereditary pancreatitis, undergoing abdominal imaging. The detection of a cystic familial atypical multiple-mole melanoma, Lynch syndrome, lesion in the pancreas causes anxiety in patients and clinicians and familial pancreatic cancer with at least two affected first- and is a growing driver of health care use in the United States. degree relatives. Cystic neoplasms of the pancreas are subcategorized as Clinicians should not screen average-risk individuals mucin-producing and nonmucin-producing cysts (Figure 14). for pancreatic cancer. The American Gastroenterological Mucin-producing cysts, including intraductal papillary muci- Association and the International Cancer of the Pancreas nous neoplasms and mucinous cystic neoplasms, are thought Screening Consortium recommend that clinicians screen to have malignant potential, but many never become malig- select high-risk patients for pancreatic cancer, including those nant. Intraductal papillary mucinous neoplasms are the most with a genetic predisposition to disease. If possible, screening common cystic lesions of the pancreas. Most intraductal papil- should be performed at a center experienced in the diagnosis lary mucinous neoplasms arise from a side branch of the and treatment of pancreatic adenocarcinoma. pancreatic duct and have a low rate of malignant transforma- tion. In contrast, the rate of malignant transformation is as Clinical Presentation high as 65% in intraductal papillary mucinous neoplasms Symptoms of pancreatic adenocarcinoma include abdominal involving the main pancreatic duct (Figure 15). Other worri- pain, back pain, weight loss, and jaundice (if the lesion some features are presence of symptoms (jaundice, pancreati- obstructs the common bile duct). Pancreatic cancer is highly tis), cyst size greater than 3 cm, dilated main pancreatic duct, associated with diabetes mellitus, and two thirds of patients and a solid cyst component.

Pancreatic Adenocarcinoma Pancreatic ductal adenocarcinoma has a poor prognosis and e Diagnosis of pancreatic cancer is suggested by abdominal increasing incidence. In 2019, there were approximately pain, weight loss, jaundice, and new-onset diabetes mel- 57,000 cases diagnosed in the United States and 46,000 litus; pancreas-protocol CT or MRI helps support the deaths. It is predicted to become the second leading cause of diagnosis and delineates the extent of disease. cancer-related death in the United States over the next decade, e In patients with potentially resectable disease, endoscopic with an overall 5-year survival rate of 9%. ultrasonography-guided fine-needle aspiration of the pancreas is recommended for histologic confirmation of Epidemiology and Risk Factors cancer. Risk factors for pancreatic cancer include age older than 50 years, smoking history, obesity, chronic pancreatitis, and mucinous cystic lesions of the pancreas. Inherited conditions Cystic Lesions of the Pancreas associated with pancreatic cancer include Peutz-Jeghers syn- Pancreatic cysts are found incidentally in 15% of patients drome, BRCA2 germline mutations, hereditary pancreatitis, undergoing abdominal imaging. The detection of a cystic familial atypical multiple-mole melanoma, Lynch syndrome, lesion in the pancreas causes anxiety in patients and clinicians and familial pancreatic cancer with at least two affected first- and is a growing driver of health care use in the United States. degree relatives. Cystic neoplasms of the pancreas are subcategorized as Clinicians should not screen average-risk individuals mucin-producing and nonmucin-producing cysts (Figure 14). for pancreatic cancer. The American Gastroenterological Mucin-producing cysts, including intraductal papillary muci- Association and the International Cancer of the Pancreas nous neoplasms and mucinous cystic neoplasms, are thought Screening Consortium recommend that clinicians screen to have malignant potential, but many never become malig- select high-risk patients for pancreatic cancer, including those nant. Intraductal papillary mucinous neoplasms are the most with a genetic predisposition to disease. If possible, screening common cystic lesions of the pancreas. Most intraductal papil- should be performed at a center experienced in the diagnosis lary mucinous neoplasms arise from a side branch of the and treatment of pancreatic adenocarcinoma. pancreatic duct and have a low rate of malignant transforma- tion. In contrast, the rate of malignant transformation is as Clinical Presentation high as 65% in intraductal papillary mucinous neoplasms Symptoms of pancreatic adenocarcinoma include abdominal involving the main pancreatic duct (Figure 15). Other worri- pain, back pain, weight loss, and jaundice (if the lesion some features are presence of symptoms (jaundice, pancreati- obstructs the common bile duct). Pancreatic cancer is highly tis), cyst size greater than 3 cm, dilated main pancreatic duct, associated with diabetes mellitus, and two thirds of patients and a solid cyst component. 24

Disorders of the Pancreas Cystic Neoplasms of the Pancreas \ \ Mucin-producing Non-mucin-producing Y ¥ Intraductal papillary Mucinous cystic neoplasms Serous cystic tumors Solid pseudopapillary mucinous neoplasms Moderate risk for Minimal risk for neoplasms | malignant transformation malignant transformation Moderate to high risk for malignant transformation y Y Main-duct Branch-duct intraductal papillary intraductal papillary mucinous neoplasms mucinous neoplasms High risk for Low to moderate risk for malignant transformation malignant transformation FIGURE 14. Types and malignant potential of cystic neoplasms of the pancreas.

y Y Main-duct Branch-duct intraductal papillary intraductal papillary mucinous neoplasms mucinous neoplasms High risk for Low to moderate risk for malignant transformation malignant transformation FIGURE 14. Types and malignant potential of cystic neoplasms of the pancreas. Non-mucin-producing cysts, such as a serous cystade- Surgical resection of high-risk cysts, including intraductal noma, have no malignant potential and can often be identified papillary mucinous neoplasms involving the main duct, is the by their characteristic imaging features. These cysts require no only treatment option. Multiple guidelines on surveillance of further evaluation unless symptomatic. pancreatic cystic neoplasms have been published, with differ- Mucinous cystic neoplasms are seen almost exclusively in ing recommendations based on target populations, clinical women (more than 98%) and found in the pancreas body or variables (symptomatic or asymptomatic), and initial and tail in 90% of cases; they have a higher malignant potential long-term surveillance recommendations. than intraductal papillary mucinous neoplasm. A thick fibrous capsule with epithelioid cells (similar to ovarian stroma) sur- ¢ Most pancreatic cysts never become malignant; intra- rounds the tumor. Differentiating mucinous cysts from serous ductal papillary mucinous neoplasms involving the main cysts, pseudocysts, and cystic neuroendocrine tumors of the pancreatic duct have the highest risk for malignant trans- pancreas can be challenging because there is no definitive test formation. with high sensitivity and specificity. Endoscopic ultrasonogra- phy with fine-needle aspiration is used for cyst fluid analysis e High-risk cysts are managed with surgical resection. in worrisome lesions; cyst fluid carcinoembryonic antigen levels are frequently elevated in patients with mucinous cysts, whereas cyst amylase levels are often elevated in patients with Other Pancreatic Tumors pseudocysts. Cytology of cyst fluid has a low sensitivity (<60%) Pancreatic Neuroendocrine Tumors and is an unreliable predictor of malignant transformation. Pancreatic neuroendocrine tumors (NETs) are rare, represent- ing 3% of primary pancreatic neoplasms. About 10% to 25% of pancreatic NETs are functional and hypersecrete hormones. Nonfunctional NETs are often discovered incidentally. The liver is the most common site of metastases. Most functional pancre- atic NETs secrete gastrin (gastrinoma) or insulin (insulinoma). Glucagon, vasoactive intestinal peptide, adrenocorticotropic hormone, somatostatin, serotonin, and parathyroid hormone- related hormone levels may be measured as clinically indi- cated. Genetic testing for multiple endocrine neoplasia type 1 is recommended in all young patients with gastrinomas or insu- linomas and in any patient with a family or personal history of other endocrinopathies or multiple pancreatic NETs. Pancreatic FIGURE 15. Magnetic resonance cholangiopancreatogram of a main-duct intraductal papillary mucinous neoplasm of the tail of the pancreas. Cystic dilation NETs may be sporadic or due to hereditary tumor syndromes, of the main pancreatic duct in the tail is seen (arrows). and genetic testing should be considered in these cases.

Non-mucin-producing cysts, such as a serous cystade- Surgical resection of high-risk cysts, including intraductal noma, have no malignant potential and can often be identified papillary mucinous neoplasms involving the main duct, is the by their characteristic imaging features. These cysts require no only treatment option. Multiple guidelines on surveillance of further evaluation unless symptomatic. pancreatic cystic neoplasms have been published, with differ- Mucinous cystic neoplasms are seen almost exclusively in ing recommendations based on target populations, clinical women (more than 98%) and found in the pancreas body or variables (symptomatic or asymptomatic), and initial and tail in 90% of cases; they have a higher malignant potential long-term surveillance recommendations. than intraductal papillary mucinous neoplasm. A thick fibrous capsule with epithelioid cells (similar to ovarian stroma) sur- ¢ Most pancreatic cysts never become malignant; intra- rounds the tumor. Differentiating mucinous cysts from serous ductal papillary mucinous neoplasms involving the main cysts, pseudocysts, and cystic neuroendocrine tumors of the pancreatic duct have the highest risk for malignant trans- pancreas can be challenging because there is no definitive test formation. with high sensitivity and specificity. Endoscopic ultrasonogra- phy with fine-needle aspiration is used for cyst fluid analysis e High-risk cysts are managed with surgical resection. in worrisome lesions; cyst fluid carcinoembryonic antigen levels are frequently elevated in patients with mucinous cysts, whereas cyst amylase levels are often elevated in patients with Other Pancreatic Tumors pseudocysts. Cytology of cyst fluid has a low sensitivity (<60%) Pancreatic Neuroendocrine Tumors and is an unreliable predictor of malignant transformation. Pancreatic neuroendocrine tumors (NETs) are rare, represent- ing 3% of primary pancreatic neoplasms. About 10% to 25% of pancreatic NETs are functional and hypersecrete hormones. Nonfunctional NETs are often discovered incidentally. The liver is the most common site of metastases. Most functional pancre- atic NETs secrete gastrin (gastrinoma) or insulin (insulinoma). Glucagon, vasoactive intestinal peptide, adrenocorticotropic hormone, somatostatin, serotonin, and parathyroid hormone- related hormone levels may be measured as clinically indi- cated. Genetic testing for multiple endocrine neoplasia type 1 is recommended in all young patients with gastrinomas or insu- linomas and in any patient with a family or personal history of other endocrinopathies or multiple pancreatic NETs. Pancreatic FIGURE 15. Magnetic resonance cholangiopancreatogram of a main-duct intraductal papillary mucinous neoplasm of the tail of the pancreas. Cystic dilation NETs may be sporadic or due to hereditary tumor syndromes, of the main pancreatic duct in the tail is seen (arrows). and genetic testing should be considered in these cases. 25