Disorders of the Pancreas

Phases of pancreas secretion

1. cephalic

   • 10% of total pancreas secretion

   • occurs due to sight, smell or taste of food

2. gastric

   • ~20-25% of total pancreas secretion

   • occurs as food enters and distends the stomach

3. intestinal

   • 70-90% of total secretion

   • results when food particles and acidic gastric contents are delivered into the small intestine

   • this stimulates secretin and CCK release from the small bowel enterocytes

     • results in bicarbonate and protein rich pancreas fluid

Bicarbonate secretion

• secretin

  • hormone secreted into the blood stream by duodenal S cells in response to duodenal pH

    • S cells located in the proximal duodenal mucosa

    • secretin released when duodenal pH falls below 4.5

  • binds to the basolateral membrane of the pancreatic duct cells

    • increasing intracellular cAMP and calcium

    • activating cAMP dependent chloride channel CFTR

    • leading to chloride output and bicarbonate rich fluid secretion

  • normal peak bicarbonate concentration is >80 mEq/L

    • used to assess for pancreas function

  • secretin stimulation test

Zymogen protein secretion

• cholecystokinin (CCK)

  • hormone secreted from the enterocytes (Ito cells) of the small intestine into the bloodstream in response to a meal

  • binds to the basolateral membrane of the acinar cells

  • through stimulus secretin coupling events within the pancreatic acinar cell, zymogen granules at the apices of the cells containing inactive proteins are secreted into the pancreas ducts

    • Pathway 1: gastrin-releasing peptide (GRP), CCK, and acetylcholine medicate secretion through increased in intracellular calcium

    • Pathway 2: vasoactive intestinal polypeptide (VIP) and secretin mediate secretion through increased in cAMP

• Trypsinogen

  • secreted into the intestinal lumen and activated to trypsin by enterokinase (enteropeptidase) at the intestinal brush border

• Trypsin

  • activates other proenzymes

• Associated mutations

  • Trypsin inhibitor secreted in low amounts by acinar cells - encoded by SPINK1

  • cationic trypsinogen gene - PRSS1

  • Memory Device - Mario "tryp"ing to save PINK PRinceSS Peach 

• The pancreas has significant reserves such that 90% of the pancreas must be damaged before pancreatic insufficiency (exocrine/endocrine dysfunction) is seen

Digestive Enzymes

• proteases

• amylase

• lipases

• nucleases

Negative Regulation

• Trypsin inhibitor

  • secreted in low amounts by acinar cells 

  • upregulated during inflammation

  • encoded by SPINK1

• Acinar cell proteases degrade trypsin

  • chymotrypsin C

  • trypsin itself

Diagnosis

• Clinical diagnosis requires 2 out of 3 of the follows:

  • typical acute upper abdominal pain

  • elevation of serum amylase and/or lipase at least 3x ULN

  • imaging abnormalities consistent with acute pancreatitis on ultrasound, CT, or MRI

• Revised Atlanta classification (2012) of severity

  • Mild - no organ failure or local complications

  • Moderate - transient organ failure and.or local complications

  • Severe - persistent organ failure >48 hour

    • Rate organ failure using the modified Marshal Scoring System

  • Monitor for organ failure and response to therapy in first 72 hr to determine severity of disease

    • SIRS score at presentation may be useful but APACHE is rarely calculate in practice and more often used in clinical studies

      • with SIRS - 25% mortality

      • without SIRS - no mortality

    • Ranson's criteria is calculated after 48 hr and may be less helpful 

    • BISAP score is calculate within fist 24 hr

      • BUN, impaired mental status, SIRS, age >60, pleural effusion

      • identifies without with increased risk of mortality

      • BUN > 25 mg/dL on admission is associated with a 5 fold increase in risk of organ failure and death 

      • BUN trend with persistent rise associated with poor prognosis due to hemoconcentration 

    • HAPS score predicts mild disease that may not require admission

• Infected necrotizing pancreatitis

  • monitoring for fever, WBC, and CRP after first 48 hr may not be accurate as these may just be related to SIRS rather than true infection

  • Look for elevated procalcitonin, gas on imaging (seen in ~30%), bacteremia, positive gram stain/culture upon sampling necrosis, or clinical deterioration

• Pancreatic duct leak

  • failure to improve after several weeks 

  • large peripancreatic fluid collection 

  • pancreatic ascites

  • assess with MRCP or ERCP to confirm and determine location

• Causes

  • Gallstones - 40%

    • suspect in...

      • women, particularly if pregnant or postpartum

      • age >60

      • AST or ALT > 3x ULN with quick return to normal 

      • Dilated CBD on imaging

  • Alcohol - 30%

    • typically after at least 10 y of heaving drinking

  • Post- ERCP - 5-10%

  • Surgical complication - 5-10%

    • likely due to pancreatic ischemia

    • consider in those undergoing cardiopulmonary bypass

  • Idiopathic - 10-20%

  • Hypertriglyceridemia - 2-5%

    • triglyceride >500 mg/dL

  • Drugs - < 5%

    • Within 1 mo after starting medication

      • azathioprine, mercaptopurine

        • dose independent, idiosyncratic

      • sulfonamides, metronidazole

      • lisinopril, enalapril

      • aminosalicylates

    • After several months of therapy

      • didanosine

      • pentamidine

      • valproic acid

  • Autoimmune - < 1%

  • Infection - < 1%

    • CMV, mumps, EBV

    • Ascaris, Clonorchis

  • Trauma - < 1%

  • Obstruction 

    • Malignancy

      • suspect in those < 40, new diabetes, cholestasis, weight loss, smokers

    • Anatomic abnormalities

      • Pancreas Divisum (PD), seen in 5-10% of the general population - controversial

      • Annular pancreas

      • choledochal cysts

      • periampullary maljunction (> 10 mm)

    • Sphincter of Oddi dysfunction (SOD) - controversial

Risk Factors

• Diabetes

• Obesity

• Smoking

• drugs account for 1-2% of all cases of acute pancreatitis

  • azathioprine is a common culprit

    • usually idiosyncratic

    • hold medication and do not re-challenge (or with related mercaptopurine)

• drugs exacerbating hypertriglyceridemia

  • alcohol, estrogens, thiazides

Signs and symptoms

• abdominal pain, often epigastric radiating to the back

  • improved by leaning forward or brining knees to the chest

• nausea

• vomiting

• rarely may present without abdominal pain and instead with altered mental status and respiratory distress leading to delayed diagnosis

• Splanchnic venous thrombosis

• abdominal compartment syndrome

  • typically in necrotizing dz

  • bladder pressure >20 mmHg

• pleural effusion 

  • posterior disruption of the pancreatic duct (left sided effusion)

• pancreatic ascites

  • anterior disruption of the pancreatic duct

• Hemorrhage 

  • consider pseudoaneurysm, bleed from small vessels in the wall of pseudocysts, gastric variceal bleed relate to splenic vein thrombosis, hemosuccus pancreaticus (bleeding in the main pancreatic duct)

  • assess with CT with early arterial phase

Lab Findings

• elevated serum amylase

  • 80-85% of cases within first 24 hr

  • may be normal in acute alcoholic pancreatitis or pancreatitis due to hypertriglyceridemia (triglyceride >400 mg/mL interferes with the measurement of amylase and partially lipase as well, diluting the serum may help)

  • may also be elevated in cholangitis, GI perforation, ischemia, ruptured ectopic pregnancy, renal failure, salivary gland disease, macroamylasemia (differentiate with amylase isoenzymes)

• elevated serum lipase

  • more sensitive than amylase

    • remains elevated for longer

    • more elevated in acute alcoholic pancreatitis

  • more specific than amylase

    • type of assays is important, some measure pancreatic and nonpancreatic lipase activity

  • May also be elevated in cholangitis, GI perforation, obstruction, ischemia. 

  • May be elevated in acute or chronic renal failure, but typically < 3x ULN

  • may be used without checking amylase

  • In gallstone pancreatitis - AST or ALT > 3x ULN with quick return to normal 

• Should not trend amylase or lipase as this has no prognostic value

• elevated CRP

  • may be a good marking of severity, but peak is often several days after onset 

• pancreatic ascites fluids studies

  • typically exudate with amylase > 1000 U/L

Imaging

• Initial imaging: Transabdominal ultrasound

  • assess for CBD dilation and cholelithiasis

  • reserve CT and MRI for those in whom etiology is unclear or for those with complications from acute pancreatitis

    • CT may be normal in 10-15% with mild disease

• Imaging is not necessary t make the diagnosis of acute pancreatitis if the patient has classic symptoms and an elevated lipase

• CT with contrast

  • needed to show pancreatic hypoperfusion, which is diagnostic of necrosis

  • may require 3-5 d for these findings to become apparent on CT. early CT in admission may underestimate severity if disease

  • perform after initial fluid resuscitation given risk of nephrotoxicity

• CXR

  • pleural effusions (usually left sided) 

    • posterior disruption of the pancreatic duct 

  • ARDS

Treatment

• IV fluids

  • First line: lactated ringer's

    • 20 cc/kg bolus followed by 5-10 cc/kg/hr 

    • repeat bolus at 12 hr into therapy if increase in HCT, BUN, or Cr are seen

      • avoid hemoconcentration which can lead to end-organ damage

    • decreases systemic inflammation in acute pancreatitis

    • decreases blood CRP levels

      • mechanism involves alterations in the GPR81-receptor

• pain control

  • fentanyl and hydromorphone

• Replete calcium slowly

• Replete magnesium

• Nutrition

  • very important component of therapy 

    • low fat, solid oral diet

      • usually can start by ~day 5 in those with moderate or severe disease

        • no difference starting enteral nutrition within 24 hr vs after 72 hr in severe disease

      • may require NG or NJ tube

        • both have been shown to have equal efficacy in randomized trials though some believe there is a physiologic benefit with pancreas rest

  • enteral feeding may decrease septic complications by helping to... 

    • maintain the integrity of the intestinal mucosa

    • reduce bacterial translocation and seeding

    • maintain glycemic control

  • enteral feeding (compared to TPN) reduced infectious complications, multi-organ failure and mortality

  • gastric feeding via nasogastric tube may be as well tolerated as jejunal feeding with similar outcomes

• broad spectrum antibiotics are not recommended prophylactically (no definite benefit to morbidity/mortality) but may be used in those patients with concern for ascending cholangitis or infected pancreatic fluid collections

  • the same is true in acute necrotizing pancreatitis 

  • If using abx, select those that better penetrate the pancreas

    • carbapenems, quinolones, metronidazole, 3rd generation cephaolosporins, pip tazo

• ERCP with biliary sphincterotomy is recommended for cholangitis but is not necessary for all patients with gallstone pancreatitis

• Cholecystectomy should be pursued in nonnecrotizing pancreatitis

  • recurrence >20% if pancreatitis is not performed during index admission

  • in necrotizing disease, wait for local complications to resolve 

• Infected necrotizing pancreatitis

  • up to 25% of all infections occur in the 1st week 

  • no interventions until encapsulation occurs (at least 2 wk)

  • treat with IV abx

    • if fails to improve, consider FNA vs drain with percutaneous catheter with culture to tailor abx

  • initial drainage followed by endoscopic debridement (transgastric or transduodenal) without or without combined percutaneous approach or very large collections (extending deep into the paracolic area) if required is superior to surgical necrosectomy

    • Lumen opposing metal stents vs pigtail catheters

      • fever procedures but more complications including infected necrosis (presents > 1 wk after admission)

• Sterile necrotizing pancreatitis

  • no intervention indicated

• Hypertryglyceridemia

  • typically improves by 2-3 d with IV fluids

  • reduce levels to <500 mg/dL

    • oral fish oil capsules

    • insulin drip

    • plasmapheresis (for levels in thousands)

• Indications for intervention for walled off necrosis (WON) or pseudocyst

  • gastroduodenal or biliary obstruction

  • infected necrosis

  • persistently unwell for many weeks - nausea, abd pain, poor PO, weight loss, failure to thrive

• Pancreatic duct leak

  • ERCP with pancreatic stent placement 

    • surgical resection or internal drainage if unsuccessful

• Bleeding pseudoaneurysm within a pancreatic fluid collection

  • endoscopic drainage is contraindicated

  • treat with VIR angio-embolization

  • emerging EUS-guided coil embolization

• Splanchnic venous thrombosis - anticoagulate 3-6 mo

Diagnosis

• results from interaction of multiple risk factors

• irreversible morphologic changes of the pancreas associated with pain and loss of exocrine and endocrine function

• Etiologies - TIGAR-O

  • toxic-metabolic

  • idiopathic

  • genetic

  • autoimmune

    • evidence of chronicity develops shortly after onset of disease

    • HISOR diagnostic criteria

      • histology, imaging, serology, organ involvement, response to therapy

    • ICDC - international consensus diagnostic criteria

  • recurrent

  • severe acute pancreatitis

  • obstructive

• Stages of disease

  • At risk

  • acute/recurrent

  • early chronic pancreatitis

  • established chronic pancreatitis

  • end-stage chronic pancreatitis

• In mild disease, imaging and lab findings may be conflicting

• Tropical or nutritional chronic pancreatitis

  • India, Indonesia, Africa

  • in the setting of malnutrition, presents in childhood with abd pain, diffuse pancreatic calcifications, malnutrition, diabetes

  • variants in SPINK1 and chymotrypcin C are likely implicated

• Rule out small bowel disease which may yield similar lab findings with steatorrhea resembling pancreatic insufficiency

  • celiac disease - effacement of proximal duodenal mucosa leading to loss of cells secreting CCK and secretin

  • gastro-jejunostomies - dilution of pancreatic enzymes and ineffective mixing with food  

Risk Factors

• Smoking

• Alcohol - 5 drinks/d for 10-15 y

  • less than 5% of heavy drinkers develop chronic pancreatitis

• syndrome often associated with multiple genetic and environmental risk factors

  • genetic variants in CLDN2 (Claudin-2) locus

  • genetic variants in CFTR are strong risk factors for progression, particularly in smokers

  • PRSS1 (serine protease 1) mutations seen in 1% of those with chronic pancreatitis

    • autosomal dominant

    • gain of function mutation

    • constitutive activation of trypsin 

  • CFTR (cystic fibrosis transmembrane conductance regulator) and SPINK1 (serine protease inhibitor Kazal-type 1) mutations seen in 50% 

  • 30% of cases are idiopathic

    • cluster in two age groups - 15-30 and 50-70 yo

    • often with exocrine insufficiency in absence of pain

• prior acute pancreatitis

  • 10% of patients go on to develop chronic pancreatitis

  • 1/3 of those with chronic pancreatitis develop recurrent acute pancreatitis 

Signs and Symptoms

• abdominal pain

  • epigastric, dull, constant, radiating to LUQ

    • often less impressive exam than what is reported

  • continuous (52%), intermittent (20%), absent (28%, often in older patients and idiopathic cases)

  • relieved with leaning forward or lying prone

  • worse with food or EtOH ingestion

  • may be associated with nausea/vomiting

• diabetes

  • occurs in 40% of cases

  • brittle diabetes results form loss of entire islets (insulin, glucagon, and pancreatic polypeptide producing cells) 

• osteoporosis

  • 1 in 4 patients with chronic pancreatitis 

  • likely multifactorial caused by decreased vitamin D levels, enhanced bone reabsorption

• steatorrhea

  • pancreatic exocrine insufficiency

  • occurs when secretion of digestive enzymes reduced to <10%

• fat soluble vitamin deficiencies (A, D, E, K)

• vitamin B12 deficiency

  • requires intrinsic factor to bind to B12 to facilitate absorption in the terminal ileum

  • any interruption of terminal ileal absorptive capacity can lead to B12 deficiency

    • Crohn's disease, ileal resection

  • any condition that leads to decreased parietal cell mass or function can lead to  deficiency due to disrupted intrinsic factor production

    • atrophic gastritis

  • in order for intrinsic factor to bind vitamin B12, B12 must first be released from binding with the R-protein

    • this occurs via pancreatic protease breakdown of the R-protein

    • patients with chronic pancreatitis are not able to break down the R protein as efficiently 

• Splenic vein thrombosis

  • can also be seen after pancreatic surgery

  • can lead to isolated gastric varices (IGV1)

• Complications

  • pseudocyt

  • portosplenic venous thrombosis

  • collaterals

  • arterial pseudoaneurysms

• Increased risk of pancreatic cancer

  • Consider in the case of rising CA 19-9 with worsening abdominal pain, weight loss, diabetes or jaundice

  • EUS guided FNAB has better sensitivity than CT guided FNAB

  • KRAS mutations found on FNA are nonspecific - can present in chronic pancreatitis alone without pancreatic cancer

Lab Findings

• Indirect test of exocrine function

  • low fecal chymotrypsin

  • low fecal elastase <100 mcg

    • can be used while taking pancreatic enzymes

    • not affected by mucosal disease

    • poor sensitivity and specificity

  • low serum trypsinogen

  • high quantitative fecal fat

    • excretion > 7g/24 hr on a diet of 100 g of fat/d

    • also abnormal in mucosal disease-causing malabsorption but values >20-25 g/24 hr suggest pancreatic disease

    • positive qualitative fecal fat (Sudan stain) indicates excretion of 12-15 g/24 hr or more

  • typically less reliable in those with mild disease

  • C13 and C14 triglyceride breath tests are available in Europe but not currently in the US

• Direct test of exocrine function

  • Endoscopic aspiration (over 30-45 min or 1 hr) of duodenal fluid/pancreatic secretions after IV secretin stimulation 

  • normal peak bicarbonate level - 80 mEq/L or more (used as an estimate for exocrine secretion overall)

Imaging Findings

• CT

  • calcifications are better seen in CT than MRI

• AXR

  • calcifications - seen in 20-50% of cases

• MRCP

  • assess for pancreatic and bile duct strictures 

  • apply Cambridge classification grading system for chronic pancreatitis which is typically used for ERCP

  • combined with secretin stimulation may provide additional details of ductal anatomy, size, compliance, secretory function (quantitative estimation of area filled in the duodenum)

• EUS 

  • evaluate ducts and parenchyma

  • identify changes of early chronic pancreatitis difficult to discern on other imaging studies (sensitive but not specific)

Pathology Findings

• atrophied exocrine tissue, replaced with fibrosis

• tan-white, firm pancreas

• chronic inflammation, atrophy of acinar tissue, interlobular fibrosis

• pancreatic duct with alternating strictures and dilations with protein plugs that may be calcified

• proliferation of small ducts

Treatment

• Pain control

  • follow WHO ladder of pain management

    • beware of peripheral and central sensitization leading to neuropathic pain, worsened with narcotic use (opioid-induced hyperalgesia)

  • consider antioxidant preparations

    • 600 mcg selenium, 500 mg ascorbic acid, 900 IU beta-carotene, 270 IU alpha tocopherol, 2 g methionine

  • Endoscopic or operative intervention 

    • consider if narcotics are needed and before onset of central/peripheral sensitization

      • studies suggest surgery results in more durable pain relief without the need for repeat procedures compared to endoscopic therapy

    • Endoscopic

      • extracorporeal shock wave lithotripsy

      • mechanical, electrohydraulic, and laser lithotripsy for ductal stones

      • strictures - balloon dilation with 10 Fr plastic stent or covered metal stent placement for 1 yr

      • for pseudocysts - transmural pigtail drainage with possible transpapillary stenting

      • bile duct entrapment - biliary sphincterotomy with multiple plastic or covered self-expanding stents

      • EUS-guided celiac plexus block

        • not an option for obstructive disease

    • Surgical

      • dilated main pancreatic duct (>6-7 mm) - lateral pancreaticojejunostomy (Peustow) procedure

        • surgical resection/drainage

        • patients with a diffusely dilate main pancreatic duct are the best candidates

        • consider for obstructive disease

        • used in alcoholic pancreatitis with "chain of lakes" appearance of pancreatic duct (strictures and dilations)

        • compared to ERCP, Peustow had improved pain control at 24 months

      • inflammatory mass at the head of the pancreas or disease with nondilated main pancreatic duct

        • head of pancreas resection via modified prancreaticoduodenectomy (Whipple) or duodenum-preserving pancreas head resection (DPPHR) techniques (ex. Frey's, Beger's, Berne, and other procedures)

          • DPPHR has better outcomes then Whipple

          • Frey's (calcifications and fibrotic tissue in the head of the pancreas are cored out followed by lateral pancreaticojejunostomy) has better outcomes than other DPPHR techniques

          • after Whipple 15% develop worsening diabetes

      • disease isolated to the tail of the pancreas

        • distal pancreatectomy

          • 25-30% develop worsening diabetes

      • groove pancreatitis

        • middle aged white male with alcoholism

        • enlarged head, biliary, and/or duodenal strictures

        • inflammatory reaction at the groove between the head of the pancreas and left wall of the duodenum

        • due to inability to rule out malignancy, Whipple is often pursued 

      • "small duct" disease

        • total pancreatectomy with islet autotransplantation (TRIAT)

          • preserves beta cell mass and mitigates diabetic complications

          • up to 92% of patients report relief of pancreatic pain at one year

• CFTR mutation associated disease

  • Ivacaftor and other CFTR potentiators for severe cases associated with cystic fibrosis

    • best for those with mild disease and residual function

• Avoid EtOH and smoking

• Total pancreatectomy with intraportal islet auto transplantation (TPIAT) - performed in limited centers and usually as part of a study protocol

• Pancreatic enzyme replacement

  • Best taken in the middle of the meal or one capsule at the start of the meal and one in the midway through the meal

  • Typical dose 24,000-36,000. Doses above 72,000 are unlikely to be beneficial

  • Unlikely to completely resolve steatorrhea but should improve symptoms and help stabilize weight

  • Specifically for Viokase, an uncoated preparation, always give with PPI to prevent inactivation by gastric acid. All other preparations are coated

    • If steatorrhea is persistent, consider adding a PPI even for coated preparations

• High protein diet - 1.5 g/kg body weight

• Medium-chain triglycerides for those who cannot gain weight despite enzyme replacement

  • does not require intraluminal lipolysis

• Monitor for osteoporosis

Signs and Symptoms

• pleural effusion

  • results from pancreatic duct leak fistulizing into the pleural space (pancreaticopleural fistula)

  • very high amylase (> 1000 U/L)  in pleural effusion

    • confirms pancreatic duct disruption

  • treat with ERCP and pancreatic stent placement 

    • attempt to bridge the pancreatic duct disruption

  • if endoscopic therapy is unsuccessful, surgical options can be considered

• gastric varices without esophageal varices

  • results from obstruction of the splenic vein due to thrombosis

  • definitive treatment is splenectomy

  • banding can be done for gastric varices close to the GEJ (GOV-1)

    • generally not effective of other gastric varices 

Treatment

• acute necrotizing pancreatitis

  • aggressive IVF

  • antibiotics not recommended unless there is evidence of acute cholangitis or infection elsewhere

  • enteral feeding

Diagnosis

• Often due to stones <5mm in diameter blocking the pancreatic duct at the duodenal papilla even transiently

• May also be caused by microlithiasis (<3 mm in diameter) or biliary crystals

  • suspect when ALT is > 3x ULN at diagnosis

  • MRCP and EUS can detect microlithiasis in >90% of cases

Treatment

• Gallstone pancreatitis with clinical deterioration suggestive of ascending cholangitis

  • urgent ERCP

• Mild biliary pancreatitis with no signs of biliary obstruction 

  • interval cholecystectomy as soon as possible once patient improves, ideally during same hospitalization

  • ERCP if not necessary without evidence of biliary obstruction or cholangitis

Diagnosis

• reported to be approx. 3-10% in systematic reviews

• no indication for abdominal imaging if diagnosis is clear based on clinical history and elevated lipase levels

Risk Factors

• female gender

• young age

• difficult cannulation

• repeated pancreatic duct cannulation

• pancreatic sphincterotomy

Prevention

• Prophylactic pancreatic duct stent

  • decreases the risk and severity of post-ERCP pancreatitis

  • presumably prevents pancreatic duct obstruction related to edema from manipulation, allowing pancreatic juices to flow normally into the duodenum

  • NNT 8

• Rectal indomethacin or diclofenac

  • decreases incidence of post-ERCP pancreatitis

  • via an anti-inflammatory pathway

  • oral NSAIDs are NOT used for this purpose

Treatment

• Lactated Ringers

• steroids have NOT been shown to decrease the risk of pancreatitis

Defintion

• also called IgG4 disease

• systemic disease affecting the pancreas, salivary glands, and kidneys

• response to steroids

  • differentiate from pancreatic cancer with a therapeutic trial and repeat imaging

Signs and Symptoms

• mild abdominal pain

• obstructive jaundice

• association with allergic diseases

Risk Factors

• typically presents later in life

Lab Findings

• elevated serum IgG4

  • in about 2/3 of patients

Imaging Findings

• CT or MRCP

  • sausage shaped gland with thin rim of delayed venous enhancement

  • irregular beaded appearance of the pancreatic duct without dilation

  • supra-pancreatic CBD wall enhancement and stricture 

  • Type 1 

    • mass in the head and/or body

    • smooth long strictures in the pancreatic duct

    • retroperitoneal fibrosis

Pathology Findings

• EUS with FNA

  • lymphoplasmacytic infiltrate with positive stains for IgG4 (≥ 20 per HPF) involving the small ducts and venules, sparing the arterioles

  • storiform fibrosis

  • obliterative venophlebitis

Treatment

• corticosteroids

  • responds well but relapse is common

• recurrent disease

  • long term steroid therapy or immunomodulators (azathioprine or mycophenolate) or rituximab (induction and maintenance therapy)

Definition

• idiopathic duct-centric chronic pancreatitis

• mass-like lesion or other focal features on imaging

• unlike type 1 AIP, type 2 involves only the pancreas and recurrence is rare

• diagnosis requires pancreas core biopsy

Signs and Symptoms

• acute pancreatitis

• obstructive jaundice due to pancreatic head mass-like lesion

Risk Factors

• association with IBD

• occurs in younger patients

Imaging Findings

• CT or MRCP

  • sausage shaped gland with thin rim of delayed venous enhancement

  • irregular beaded appearance of the pancreatic duct without dilation

  • supra-pancreatic CBD wall enhancement and stricture

Pathology Findings

• core biopsy showing granulocyte-epithelial lesions (GEL)

• absent or very mildly elevated IgG4 staining

Treatment

• very responsive to glucocorticoids (similar to type 1 AIP)

  • recurrence is rare

• surgical resection not indicated given the high likelihood of response to medical therapy

Definition

• PRSS1 gene mutation

  • cationic trypsinogen gene

  • autosomal dominant gene mutation with incomplete penetrance (80% penetrance)

  • associated with ~40% occurrence of pancreatic cancers by age 60

Signs and Symptoms

• symptoms start in childhood with acute recurrent pancreatitis 

• progresses to chronic pancreatitis, type 1 diabetes and exocrine insufficiency

• incidence of pancreatic cancer is increased to 40% by age 70

• 40-60 fold increased lifetime risk for pancreatic cancer

Treatment

• total pancreatectomy with islet autotransplantation (TPIAT)

  • best for children with recurrent or chronic pancreatitis from PRSS1 gene mutations

  • preserves beta cell mass and mitigates diabetic complications

  • up to 92% of patients report relief of pancreatic pain at one year

• PRSS1 mutation - hereditary pancreatitis

  • autosomal dominant with incomplete penetrance 

  • 40-60 fold increased risk of pancreatic adenocarcinoma 

• BRCA1 mutations - familial pancreas cancer

• SPINK mutations - chronic tropical pancreatitis

• Delta F508 - most common mutation in cystic fibrosis, leads to pancreatic insufficiency in childhood

• Idiopathic chronic pancreatitis

  • Mutations in susceptibility genes

    • PRSS1

    • SPINK1

    • CFTR

      • 10-20% of those with pancreatitis are estimated to have abnormal CFTR or SPINK1 function

    • CTRC

    • CASR

    • CEL

  • Mutations in disease modifying genes 

    • PRSS1-PRSS2 promoter variants

    • CLDN2

    • GGT1

  • these variants are associated with multiple pathologic processes, often linked to...

    • a trypsin activation pathway

    • or an unfolded protein response in the rough endoplasmic reticulum

Definition

• classification of fluid collections in pancreatitis are based on...

  • the duration of the pancreatitis 

    • greater than 4 wks

    • less than 4 wks = acute fluid collection

  • presence or absence of necrosis

    • great than 4 wks + prior acute necrotizing pancreatitis = walled off pancreatic necrosis

• Atlanta Classification categories

  • 1) Acute peripancreatic fluid collection seen in the first 4 wks, non-encapsulated 

  • 2) Pseudocysts that develop after fours weeks, well encapsulated collections 

  • 3) Acute necrotic collection that occurs less than 4 wks from acute pancreatitis episode

  • 4) Walled off necrosis after 4 wks, encapsulated necrosis

Treatment

• Symptomatic (abdominal pain, fever, jaundice, bowel obstruction, or gastric outlet obstruction)

  • requires drainage with a minimally invasive approach (surgical, endoscopic)

Risk Factors

• occurs in ~15% of patients with acute pancreatitis

Treatment

• Asymptomatic

  • follow clinically and with radiological surveillance for improvement/resolution for at least 6 wk

  • often resolve spontaneously

• Pseudocyst drainage

  • Intervention only after a fibrous wall has developed, typically 4-6 wk after acute event

  • Symptomatic

  • rapidly enlarging pseudocyst

  • infected pseudocysts

  • if appropriate, endoscopic drainage with is preferred over surgical drainage (lower cost and shorter hospital stay but similar efficacy and complication/recurrence rate)

    • EUS drainage is superior to endoscopic drainage

    • gastric, duodenal or transpapillary approach

  • Complex fluid collections or suspicion for cystic neoplasm

    • surgical drainage with resection fo part of the cyst wall for histology

• Octreotide to decrease pancreatic secretion

Definition

• serous cystadenoma (glycogen rich adenomas)

  • not premalignant 

  • do not require surveillance

• asymptomatic

• although benign, they can grow in size and cause abdominal pain, jaundice, or weight loss

Risk Factors

• common in females

• usually seen in late 50-60s

Endoscopic Findings

• EUS

  • features of serous cystadenoma

    • central stellate scar or calcification

    • multiple small cysts in a honeycomb appearance

    • these cysts are very vascular and EUS FNA can be bloody

      • leads to low cytology yield

Imaging Findings

• CT and MRI

  • typically small < 5 cm

  • classic microcystic appearance 

  • central fibrous  or stellate scar with calcifications  ("sunburst" appearance)

    • can be seen in 30% of serous cysts

    • considered pathognomonic 

• MRI is preferred to CT to reduce radiation

• MRI is more sensitive to evaluate the PD and delineate the cyst communication with the PD

Pathology Findings

• Aspiration of cyst

  • negative for malignancy

  • low CEA level

  • low amylase

  • low viscosity, no mucin

  • high glycogen level (PAS positive)

  • typically bloody

• cuboidal cells that secrete glycogen 

Treatment

• observation

• management dictated by symptoms associated with cyst enlargement

  • surgery can be considered for symptomatic serous cysts

  • surveillance after resection not required

Surveillance

• ACG 2018 guidelines for incidental 1-2 cm cysts without a solid component, non-dilated PD, <3cm

  • survey with MRI in 1 yr

  • if no change then MRI every 1 yr for a total of 3 yrs

  • if cyst remains stable then MRI every 2-4 yrs

  • if cyst remains stable then lengthening of surveillance interval can be considered

• cystic lesions <3cm can be followed with MRI in 1 yr, then every 2 years for 5 years

• cystic lesions >3cm  or with concerning features (mural nodule, solid component, dilated pancreatic duct) should undergo EUS-FNA to evaluate for a mucinous cystic neoplasm

Definition

• usually solitary located in the body or tail of the pancreas

• do NOT communicate with the pancreatic duct

• moderate risk of malignant transformation

Risk Factors

• almost always occurs in females, often middle aged

Diagnosis

• EUS-FNA

Imaging Findings

• wall "eggshell" calcification

• size >3cm

• mural nodule

• dilated pancreatic duct

• more often in body and tail then in head of pancreas

Pathology Findings

• high CEA from FNA

• variable amylase from FNA

• columnar epithelium surrounded by ovarian-type stroma

Lab Findings

• Serum CEA is NOT helpful for risk stratification in patients with pancreatic cysts

Treatment

• distal pancreatectomy

  • offer resection rather than surveillance to reduce mortality from a pancreatic malignancy

Surveillance

• resected mucinous cystic neoplasms without cancer do not require post-op surveillance

  • large systematic review showed no synchronous lesions or recurrence in absence of invasive cancer

• serum CEA not used for diagnosis or surveillance  

Definition

• rare pancreatic tumor

• makes up <1% of all pancreas cancers

Risk Factors

• often found in the elderly

Signs and Symptoms

• can be associated with...

  • polyarthritis

  • panniculitis

  • subcutaneous nodules

Definition

• Adenocarcinoma derived from ductal epithelium

• Pancreatic mass found in the setting of chronic pancreatitis

  • most likely etiology is adenocarcionma

• five year survival rate of ~8%

  • mostly due to delay in diagnosis

  • small tumors (<3 cm) can be missed on CT and MRI

Risk Factors

• cigarette smoking - most well established environmental risk factor

• Risk increases with age - after 50 yo with peak incidence 65-80 yo

• PRSS1 mutation leading to hereditary pancreatitis

  • 40-60 fold increased risk of developing pancreatic adenocarcinoma (approx 50% chance)

  • encodes cationic trypsinogen

• chronic pancreatitis 

  • nearly 8 fold increased risk of pancreatic cancer

  • need high index of suspicion of alarm symptoms develop

    • weight loss

    • change in frequency or intensity of pain

    • new onset diabetes or hyperglycemia

    • jaundice

• Chemical exposure

  • α-naphthylamine

  • benzidine

• Peutz-Jeghers syndrome

  • 11-36% risk of pancreatic adenocarcinoma in their lifetime

• Lynch Syndrome

  • ~2-18% lifetime risk depending on which mismatch repair gene is mutated

• BRCA-2 carriers

  • ~5% risk of pancreatic cancer

• EtOH use

• Type 2 diabetes

• diet high in red and processed meats

Diagnosis

• EUS-FNA

  • 85% sensitivity

  • high yield for diagnosis of pancreatic malignancy in patients with suspected cancer with a non-diagnostic CT

• Rule out benign etiologies for structure

  • inflammatory stricture from stone passage

  • autoimmune pancreatitis or cholangiopathy

  • primary sclerosing cholangitis

  • chronic pancreatitis

• Boderline resectable

  • short segment vessel contact <180 degree

• Locally advanced unresectable 

  • vessel contact >180 degree

Lab Findings

• CA 19-9

  • not specific and is dependent on tumor size

Treatment

• If radiologically resectable (no lymphadenopathy or vascular invasion)...

  • Treat with pancreaticoduodenectomy (Whipple procedure)

  • ERCP with stent placement to relieve biliary obstruction has NOT been shown to be of benefit in patients with a resectable pancreatic mass

  • surgical outcomes are worse if a stent is placed in the bile duct

  • EUS is sometimes done but in most cases resectable disease should go straight to surgery

• Borderline resectable

  • neoadjuvant chemotherapy then surgical resection 

• if locally advanced (ex. encasing the celiac artery bifurcation, no metastasis)

  • not a surgical candidate for resection

  • treat with neoadjuvant chemotherapy (can be given for 4-6 mo)

    • followed by chemoradiation or SBRT if systemic metastases do not develop

    • if performance status is good and there is disease response to chemotherapy, curative resection can be considered

  • if bilirubin is normal, does not require ERCP

Definition

• can occur anywhere in the pancreas

Risk Factors

• commonly see in young females in their 20-30s

Signs and Symptoms

• abdominal pain

• nausea

Diagnosis

• EUS FNA can have a 75-80% accuracy in diagnosis

Endoscopic Findings

• EUS - lesions can be solid, cystic, or mixed

Imaging Findings

• CT 

  • well encapsulated solid mass with peripheral calcification (in up to 30% of patients)

• MRI

  • well-defined lesion with high and low signal density on T1 and T2 weighted images

  • peripheral calcifications

  • possible debris or solid component within

Pathology Findings

• FNA - cystic fluid 

  • CEA is low

  • amylase is low

  • viscosity is low

• pseudopapillary structures line with cytologically bland cells

Treatment

• Surgical resection

Surveillance

• After surgical resection - MRI every 1y for 5y

Definition

• can often be confused for adenocarcinoma

• does not cause any symptoms of hormonal hypersecretion

Definition

• high potential for malignant transformation

• Risk of high grade dysplasia or invasive carcinoma is >60%

Treatment

• surgical resection if possible for MD-IPMN >1 cm

Diagnosis

• Consider EUS with FNA if...

  • Cyst ≥ 3 cm

  • Cyst enlargement ≥ 5 mm in 2 y or ≥ 3 mm in 1 year

  • enhancing mural nodule < 5mm (consider surgery for ≥ 5mm)

  • pancreatic duct dilation to 5-9 mm

  • abrupt cut off of pancreatic duct with upstreat pancreatic atrophy (suggestive of malignancy)

  • elevated CA 19-9 

Surveillance

• Asymptomatic without concerning features - surveillance interval based on cyst size (Fukuoka guidelines 2017)

  • < 1 cm: CT/MRI in 6 mo then q2 y

  • 1-2 cm: CT/MRI q6 mo for 1 y, then q1 y for 2 y, then q2 y

  • 2-3 cm: EUS in 3-6 mo, then MRI or EUS in 1 y, consider surgery for cysts ≥ 3 cm

  • > 3 cm: EUS or MRI in 3-6 mo, consider surgery

  • Inconclusive EUS/FNA:  EUS or MRI in 3-6 mo, consider surgery

• Consider EUS/FNA, surgery, or more intensive surveillance for cyst enlargement ≥ 5 mm in 2 y or ≥ 3 mm in 1 year

Treatment

• • Resection is indicated for branch-duct IPMN's which are 

    • symptomatic (ex. pancreatitis)

    • associated with obstructive jaundice

    • or main duct involvement (thickened wall, intraductal mucin)

    • have a solid component within the cyst

    • have concerning features on EUS-FNA

  • Post resection surveillance if cancer is found

    • Remnant cysts absent - MRI every 2 years

    • Remnant cysts present - MRI frequency based on size of largest cyst (see above)

  • If no cancer is found, no post resection surveillance is required

Definition

• most common pancreatic endocrine tumor (1-2 per million people/year)

• most are benign, solitary lesions easily found on EUS

Signs and Symptoms

• hypoglycemia

• seizure

Definition

• Zollinger-Ellison Syndrome

• produces massive hyper-secretion of gastric acid

• results in severe peptic ulcer disease and chronic diarrhea

• ~80% of these tumors can be localized to the "gastrinoma triangle" region in the duodenum

Signs and Symptoms

• intermittent abdominal pain

• heartburn

• nausea

• diarrhea

Endoscopic Findings

• esophagitis

• antral erythema

• erosions/ulcerations in the duodenum

Pathology Findings

• Small bowel biopsy - inflammation with mild villous atrophy

• Gastric biopsy - unremarkable

Lab Findings

• Secretin testing with elevated gastrin level

  • helps to differentiate from atrophic gastritis

• negative serology for celiac disease

Definition

• rare neuroendocrine tumor 

• arises from pancreatic alpha-2 cells of the islets

• secretes high levels of glucagon, leading to...

  • insulin resistance

  • diarrhea

  • weight loss

Signs and Symptoms

• Necrolytic migratory erythema

  • rash at the limbs, around the lips and groin/perineum/buttocks

  • crusting, erythematous, vesicular 

  • seen in 70-80% of patients with glucagonoma

  • often the presenting symptom

• diarrhea

Imaging Findings

• solid lesion in the body of the pancreas

Definition

Signs and Symptoms

• significant secretory diarrhea, may result in...

  • dehydration

  • hypokalemia

Definition

• If in the presence of nonspecific symptoms with otherwise unremarkable work up this is a benign condition

• Lipase level < 2x upper limit of normal is not consistent with pancreatitis

Treatment

• Reassurance

• Reveiw possible causatie medications

  • ex. codeine 

Definition

• Due to incomplete rotation of the dorsal and ventral buds

Signs and Symptoms

• Gastric outlet or duodenal obstruction

Risk Factors

• Down's syndrome

Definition

• Congenital

• Komi Classification

• Increased risk of biliary and gallbladder malignancy

  • greater risk in the absence of bile duct dilation

  • though to be due to pancreatic enzyme reflux

Signs and Symptoms

• Asymptomatic

Treatment

• Prophylactic cholecystectomy for all patients