PANCREAS JR. BASIC SCIENCE

ANATOMY & PHYSIOLOGY

ANATOMY: -Retroperitoneal -Regions: *Head: Adjacent to C-loop and posterior to transverse mesocolon, anterior to vena cava, right renal artery, and renal veins. CBD transverses the pancreatic head and joins the main pancreatic duct at the ampulla of Vater *Neck: Anterior to portal vein *Uncinate process: Wraps around portal vein and ends posteriorly in the space between the SMA and SMV *Body & Tail: Anterior to splenic artery and vein. Located in floor of lesser sac posterior to stomach. Covered by gastrocolic omentum.

Embryology: -The pancreas forms from two diverticulae of the endodermal lining of the foregut in a region which later becomes the duodenum. -The dorsal pancreatic bud passes anterior to the portal vein (forms head,neck, body, & tail). -The ventral pancreatic bud is smaller and rotates around behind the duodenum (forms caudate part of the head & the uncinate process. -Both buds then usually fuse (~8 weeks). -Ducts develop in both buds and fuse. -Pancreatic duct is usually 2-3 mm in diameter.

-Duct of Wirsung starts at the tail and extends to the head -Duct of Wirsung starts at the tail and extends to the head. It terminates at the papilla of Vater. It is derived from the ventral pancreatic bud. -Duct of Santorini (accessory pancreatic duct) drains a small upper portion of the pancreatic head and terminates in the duodenum as a small accessory papilla. It is derived from the dorsal pancreatic bud.

PANCREAS DIVISUM: -In 10% of patients, the ducts of Wirsung and Santorini fail to fuse. -Most of the pancreas is then drained through the duct of Santorini and the minor papilla. -In some of these patients, the minor papilla is unable to handle the volume of pancreatic juices produced by the gland, resulting in a relative outflow obstruction. -Can result in pancreatitis. -Treatment: Sphincteroplasty of minor papilla.

SPHINCTER OF ODDI: -The main pancreatic duct joins with the common bile duct and empties into the ampulla of vater in the second portion of the duodenum. -Muscle fibers around the ampulla form the Sphincter of Oddi. -Contraction and relaxation of the Sphincter of Oddi are regulated by hormones and neuronal control.

ARTERIAL SUPPLY: -Celiac axis gives off common hepatic, which gives rise to GDA, which becomes superior pancreaticoduodenal artery as it passes behind the 1st portion of the duodenum. This branches into the anterior and posterior superior pancreaticoduodenal arteries. -The SMA gives off the inferior pancreaticoduodenal artery as it passes behind the neck of the pancreas. This divides into the anterior and posterior inferior pancreaticoduodenal arteries. The superior and inferior pancreaticoduodenal arteries join together to form an arcade of blood vessels supplying the pancreatic parenchyma and duodenum. The dorsal, great, and pancreatic arteries form connections between the splenic artery and the inferior pancreaticoduodenal artery.

-Venous drainage tends to follow arterial supply. -Lymphatic drainage is diffuse and widespread. Lymphatics connect with the lymph nodes draining the jejunum and transverse mesocolon. There are also lymph nodes adjacent to the head of the pancreas as well as the hilum of the spleen. ***The extensive lymphatics explain why pancreatic cancer often presents with positive lymph nodes and a high incidence of recurrence after resection.***

NEURAL CONTROL OF PANCREATIC SECRETIONS: -Parasympathetics: Stimulate secretion of endocrine & exocrine pancreas. -Sympathetics: Inhibit secreation. -Rich supply of afferent sensory fibers, which are responsible for intense pain associated with pancreatitis and pancreatic cancer.

EXOCRINE PANCREAS: -Secretes 500-800cc/day -Acinar cells contain zymogen granules, which fuse with the membrane and secrete a variety of enzymes into a ductal system -These enzymes are responsible for digestion of food.

ENZYMES: *Amylase: Only pancreatic enzyme secreted in its active form Hydrolyzes starch and glycogen *Gastric hydrolysis of proteins causes peptides to enter the small intestine and release cholecystokinin and secretin, which stimulate the pancreas to release enzymes and bicarbonate. Cl- secretion is inversely related to bicarbonate secretion. *The enzymes are secreted as proenzymes, which are then activated by enterokinase, located in the small intestine. This explains why autodigestion of the pancreas does not occur.

ENDOCRINE PANCREAS: * ~1 million islets of Langerhans (spherical collections of cells scattered throughout the pancreatic parenchyma) * Contain a variety of cells, which secrete a variety of hormones into the bloodstream

Hormone Islet Cell Functions IAPP = islet amyloid polypeptide. Table 32-2 Pancreatic Islet Peptide Products Hormone Islet Cell Functions Insulin    (beta cell) Decreased gluconeogenesis, glycogenolysis, fatty acid breakdown and ketogenesis   Increased glycogenesis, protein synthesis Glucagon    (alpha cell) Opposite effects of insulin; increased hepatic glycogenolysis and gluconeogenesis Somatostatin     (delta cell) Inhibits gastrointestinal secretion Inhibits secretion and action of all gastrointestinal endocrine peptides Inhibits cell growth Pancreatic polypeptide PP (PP cell) Inhibits pancreatic exocrine secretion and secretion of insulin Facilitates hepatic effect of insulin Amylin (IAPP) Counterregulates insulin secretion and function Pancreastatin Decreases insulin and somatostatin release Increases glucagon release Decreases pancreatic exocrine secretion

ACUTE PANCREATITIS

ACUTE PANCREATITIS: *Inflammation of the pancreas with little or no fibrosis of the gland *Due to: Alcohol Biliary tract disease Vasculitis Hyperlipidemia Pancreatic duct obstruction Heredity Neoplasms Hypercalcemia Pancreas divisum Trauma Ampullary and duodenal lesions Surgical Infections ERCP Venom (scorpion) Ischemia Drugs (thiazides, lasix, estrogens, Hypoperfusion azathioprine, methyldopa, 6-MP, etc) Embolic Idiopathic

BILIARY TRACT DISEASE: Colocalization Theory:

ALCOHOL: -Pancreatitis may occur after a single use, but more often occurs in patients who have used 100-150g/day of alcohol >2 years. (10-15%) -Can be recurrent after continued alcohol abuse. -Mechanism: *Ethanol causes sphincter of Oddi spasm. (Blockage) *Ethanol is a metabolic toxin to pancreatic acinar cells, which interferes with enzyme synthesis and secretion. *Get initial secretory increase followed by inhibition. Enzymes and calcium precipitate within the pancreatic duct, resulting in multiple obstructions. *Ethanol increases ductal permeability. Enzymes leak out into surrounding tissue. *Ethanol transiently decreases pancreatic blood flow, causing focal ischemia.

Pathophysiology of acute pancreatitis: ***Ultimate severity of pancreatitis depends on the extent of the systemic inflammatory response and cytokines that play a role in activation and migration of inflammatory cells.***

DIAGNOSIS: *Diagnosis of exclusion—Rule out perforated peptic ulcer, gangrenous small bowel obstruction, and cholecystitis. (Require immediate intervention) -Abdominal pain (usually epigastric), usually after a meal. -”Knifing” or “boring” pain through to the back—relieved by leaning forward. -Nausea and vomiting, with continued retching after stomach is emptied. Vomiting does not relieve the pain. -Tachycardia, tachypnea, hypotension, fever -Voluntary/Involuntary guarding -Decreased or absent bowel sounds -Abdomen may be distended with intraperitoneal fluid -Blood from necrotizing pancreatitis dissects through soft tissues and causes a bluish discoloration around the umbilicus (Cullen’s sign) or flanks (Gray Turner sign)

Pancreatic-specific amylase: -More specific for pancreatitis (88-93%) Serum amylase: -usually increases immediately with onset of pancreatitis & peaks within a few hours (However, may be normal in pancreatitis) -remains elevated 3-5 days -no correlation between magnitude of elevation & severity of pancreatitis -can also be elevated with SBO, perforated duodenal ulcer, other intra-abdominal inflammatory conditions Urine amylase: -may be more sensitive than serum amylase in detection of pancreatitis (lipids may interfere with measurement of serum amylase) -levels remain elevated for several days longer than serum amylase Pancreatic-specific amylase: -More specific for pancreatitis (88-93%) Serum lipase: -Remains elevated longer than serum amylase.

Imaging: *CT: uniform enhancement of pancreas *Ultrasound

APACHE II score: (acute physiology & chronic health evalutation) RANSEN’S CRITERIA Criteria for acute pancreatitis not due to gallstones  At admission During the initial 48 h   Age >55 y   Hematocrit fall >10 points   WBC >16,000/mm3     BUN elevation >5 mg/dL   Blood glucose >200 mg/dL   Serum calcium <8 mg/dL   Serum LDH >350 IU/L   Arterial PO2 <60 mm Hg     Serum AST >250 U/dL   Base deficit >4 mEq/L       Estimated fluid sequestration >6L Criteria for acute gallstone pancreatitis    Age >70 y   WBC >18,000/mm3     BUN elevation >2 mg/dL   Blood glucose >220 mg/dL   Serum LDH >400 IU/L   Base deficit >5 mEq/L   Estimated fluid sequestration >4L Prognosis: <2: Mortality-0 3-5: Mortality 10-20% >7: Mortality >50% *Only useful for 1st 48h APACHE II score: (acute physiology & chronic health evalutation) -uses vital signs, labs, age, and chronic health status of patient - >8 is severe

TREATMENT: *Mild pancreatitis: (no systemic complications, low Ranson’s & Apache II score) -IVF resuscitation/maintenance -Pain management (avoid morphine due to Sphicter of Oddi contraction) -Supportive (rest the pancreas) -NPO -NGT -H2 blockers *No abx unless suspect infection -Slow feeding after pain subsides, amylase decreases, patient feels hungry

Severe Pancreatitis: (Ranson’s >7, Apache II Severe Pancreatitis: (Ranson’s >7, Apache II >8, systemic symptoms) -ICU & Supportive Care -TPN vs jejunal feeds -If necrotizing: Flagyl, Imipenim, 3rd gen cephalosporin, Diflucan prophylaxis -If necrotizing & septic: Consider necrosectomy

Biliary Pancreatitis: -Treatment controversial -Cholecystectomy once pancreatitis improves before discharge home -If patient still has pancreatitis, but CBD is obstructed, ERCP with sphincterotomy & stone extraction is indicated -Routine ERCP is not indicated due to risk of post-ERCP pancreatitis

CHRONIC PANCREATITIS

-Pain: Midepigastric RUQ or LUQ Penetrating through to the back Steady & boring (not colicky) Often exacerbated by eating & drinking -Pain causes patient to lay still -Nausea/Vomiting -Anorexia, malabsorption, weight loss -Diarrhea/Steatorrhea due to pancreatic exocrine dysfunction -Diabetes due to pancreatic endocrine insufficiency

CHRONIC PANCREATITIS: Incurable, chronic, inflammatory condition -Associated with ETOH in 70% of cases Multiple hit theory: Multiple episodes of acute pancreatitis cause inflammatory changes that result in chronic inflammation & scarring

Chronic Calcific Pancreatitis Chronic Obstructive Pancreatitis Chronic Inflammatory Pancreatitis Chronic Autoimmune Pancreatitis Asymptomatic Pancreatic Fibrosis Alcohol Pancreatic tumors Unknown Associated with autoimmune disorders (e.g., primary sclerosing cholangitis) Chronic alcoholic Hereditary Ductal stricture   Endemic in asymptomatic residents in tropical climates Tropical Gallstone- or trauma-induced pancreas divisum Hyperlipidemia Sjögren's syndrome Hypercalcemia Primary biliary cirrhosis Drug-induced Idiopathic

Histology: Induration, nodular scarring, fibrosis, mononuclear cell infiltrates, patchy areas of necrosis, reduced islet size and number (Sheets of fibrosis & loss of acinar tissue) (Mononuclear cell infiltrate)

***Mostly a clinical diagnosis!*** I. Measurement of pancreatic products in blood   A. Enzymes   B. Pancreatic polypeptide II. Measurement of pancreatic exocrine secretion   A. Direct measurements     1. Enzymes     2. Bicarbonate   B. Indirect measurement     1. Bentiromide test     2. Schilling test     3. Fecal fat, chymotrypsin, or elastase concentration     4. [14C]-olein absorption   III. Imaging techniques   A. Plain film radiography of abdomen   B. Ultrasonography   C. Computed tomography   D. Endoscopic retrograde cholangiopancreatography   E. Magnetic resonance cholangiopancreatography   F. Endoscopic ultrasonography Tests for Chronic Pancreatitis: ***Mostly a clinical diagnosis!***

Dilated pancreatic duct with intraductal stones & parenchymal calcification EUS, MRCP, ERCP, transabdominal US

Treatment: -Analgesics, celiac plexus block -Cessation of ETOH -Oral enzyme therapy -Selective use of antisecretory therapy (Octreotide) -Some benefit from ERCP with sphincterotoy/stenting (proximal panc duct stenosis) -Surgery

TRANSDUODENAL SPHINCTEROPLASTY: -Incision of the ampullary, bile duct, & pancreatic duct sphincters -Suture apposition of mucosal edges of the incision -Used for obstruction & inflammation isolated to this region

Puestow: (Lateral pancreaticojejunostomy) -Permits extensive drainage of the pancreatic duct -Drainage procedure for “chain of lakes” (segmental narrowings & dilations of the duct) -Good for pancreatic duct >6mm

Distal pancreatectomy: -Good for inflammatory changes isolated to body & tail -Good for patients without ductal dilation -Leaves pancreas behind– high rate of recurrence

Whipple (Pancreaticoduodenectomy):

Beger: (Duodenum sparing pancreatic head resection)

Frey Procedure: Resection of the pancreatic head with longitudinal pancreaticojejunostomy (provides complete decompression of the entire ductal system)

Islet Cell Autotransplantation: -Used to prevent diabetes in pancreatic resection -Need 2-3 million islet cells -Islets are infused into the portal venous system for intrahepatic grafting -Limited by ability to harvest enough islet cells from a sclerotic gland

Complications of chronic pancreatitis: -Pseudocyst: Chronic collection of pancreatic fluid surrounded by a nonepithelialized wall of granulation tissue & fibrosis

-Acute pseudocyst (acute fluid collection): Usually due to pancreatic duct leak with extravasation of pancreatic juice. -Wall of granulation tissue without fibrosis forms around the fluid collection after 3-4 weeks & seals it -50% resolve spontaneously (usually those <6cm)

Treatment: If asymptomatic: expectant -If symptomatic or enlarging: ERCP with stent, cystenterostomy (endoscopically, laparoscopically, or open) -Infected: aspirate/drain ***ANY PSEUDOCYST WITHOUT PRECEEDING ACUTE PANCREATITIS NEEDS INVESTIGATION TO DETERMINE THE ETIOLOGY***

Pancreatic abscess: Pseudocysts that become secondarily infected -Can lead to venous thrombosis, pseudoaneurysms, or hemorrhage

Other complications: -Splenic/portal vein thrombosis (can get gastric varices). Tx: splenectomy -Pancreatic ascites/effusion. Tx: octreotide, bowel rest, TPN -Pancreatic-enteric fistula -Inflammatory mass in head of pancreas

NEOPLASMS OF THE ENDOCRINE PANCREAS

INSULINOMA: -Most common type of islet cell tumor -Arise from pancreatic beta cells -Most common cause of fasting hypoglycemia in adults -83-92% are single, 8-17% are multiple (MEN) -84% benign, 16% malignant (metastatic) -90% sporadic, 10% associated with MEN I -Physiology: Tumor secretes excessive insulin Results in hypoglycemia The brain reacts with initial excitation (convulsion) Eventually results in neurologic depression (coma)

Signs/Symptoms (often due to the release of epinephrine as a response to hypoglycemia) Loss of consciousness Tremor Confusion Hunger Weakness/Fatigue Positive Babinski sign Deep coma Paresthesias Sweating Irritability Drowsiness/stupor Transient hemiplegia Lightheadedness Abdominal pain Visual disturbances Palpitations Amnesia Clonic convulsions Headache ***It is not possible to differentiate benign from malignant lesions based on symptoms. ***It is not possible to correlate the size of the tumor with the extent of symptoms.

Check insulin to glucose ratio while patient is having symptoms. Diagnosis: Check insulin to glucose ratio while patient is having symptoms. -Low glucose, but elevated insulin Check C-Peptide levels (to rule out exogenous insulin) -elevated 3. Check Urine sulfonylureas

Preoperative localization: CT and EUS -100% of insulinomas are located in the pancreas. -Most tumors are <1cm -Best localization test is intraoperative ultrasound.

Treatment: RESECTION -1/3 found in head and uncinate process, 1/3 found in body, 1/3 found in tail -Enucleation is usually best for tumors of the head and body -Spleen sparing distal pancreatectomy is usually best for lesions in the very distal pancreas.

-Lymph node dissection is not necessary -For malignant (metastatic) insulinoma, perform appropriate pancreatic resection and liver resection. -Radiofrequency ablation can be used to address unresectable lesions in the liver. -Post-op: -Often get rebound hyperglycemia (~160-200) for 24-48h. Glucose should return to normal after that. -Insulin supplementation is usually not required. -Medical tx: Diazoxide or octreotide

GASTRINOMA: (Zollinger-Ellison Syndrome) -Most common islet cell tumor in MEN I syndrome -May be sporadic (75%) or familial (as in MEN I syndrome) (25%) -Autosomal dominant inheritance -Often is metastatic at time of diagnosis

Symptoms: Abdominal pain Ulcerations in the upper GI tract Diarrhea GERD Suspect… Recurrent ulcer after medical or surgical treatment Postbulbar ulcer Family history of ulcer disease Ulcer with diarrhea Prolonged undiagnosed diarrhea MEN I in family Nongastrinoma pancreatic endocrine tumors Prominent gastric rugal folds on UGI

DIAGNOSIS: -Fasting serum gastrin level >200pg/ml -Levels >1000 with hyperacidity and ulcer disease are pathognomonic for gastrinoma

Differentiate between Gastrinoma, G-cell hyperplasia, G-cell hyperfunction, etc. -SECRETIN TEST: (normally, secretin inhibits gastrin release) -Draw baseline gastrin level -Give 2units/kg of secretin IV -Collect gastrin levels at 5 minute intervals for 30min -Increase in gastrin level by >200pg/ml indicates gastrinoma -MEAL TEST: -Measure serum gastrin response to a standard meal -Should see little change in gastrinoma patients -Should be increased in patients with antral G-cell hyperplasia *Once gastrinoma is diagnosed, next step is to treat with H2-blockers or PPI’s

Localize: -CT abdomen/pelvis -Somatostatin receptor scintigraphy study (Octreotide Scan) -MRI -EUS *Most are located within the Gastrinoma Triangle (Passaro’s Triangle) (Junction of cystic duct to common bile duct, third portion of duodenum, neck of pancreas)

Treatment: -Complete resection: -Enucleation in head of pancreas -Full thickness excision of duodenal lesions -Full lymph node dissection -Resection or radiofrequency ablation of liver mets -Use intraoperative ultrasound to help locate tumor -Whipple if unable to find tumor Retropancreatic, Transverse mesocolic, Sybpyloric, Hepatic, Celiac lymph nodes

-For metastatic disease (usually to liver or bone) -Radiation therapy -Chemotherapy (Streptozocin and 5-fluorouracil or etoposide and cisplatinum) -Somatostatin analogs

GLUCAGONOMA: -Produced by alpha cells of pancreatic islets -Produce excessive glucagon *SYMPTOMS: Diabetes Necrolytic migratory erythema (skin rash) Tendency to develop DVTs Stomatitis Glossitis Cheilosis Hypoaminoacidemia

DIAGNOSIS: -Elevated fasting plasma level of glucagon ->1000pg/ml is diagnostic -150-1000pg/ml is suggestive -Could biopsy skin lesions

LOCALIZATION: -Always located within the pancreas -Usually large at presentation -CT scan -Somatostatin receptor scintigraphy -Intraoperative ultrasound **Usually are malignant and may have lymph node and liver mets

TREATMENT: -Complete resection: -Resect primary disease, regional lymph nodes, and metastatic sites -If can’t completely resect…debulk -Octreotide can be useful in controlling symptoms in incurable disease

VIPoma: (Verner-Morrison Syndrome) -Tumors mostly located in body/tail of pancreas and occasionally in duodenum -SYMPTOMS: Watery secretory diarrhea that persists even during fasting Hypokalemia (due to fecal loss of large amounts of potassium) Achlorhydria (because inhibits gastric acid secretion) Lethargy, muscle weakness, & nausea (due to hypokalemia) Metabolic acidosis (due to loss of bicarb in stool) Hyperglycemia Hypercalcemia Cutaneous flushing

Diagnosis: -Rule out other causes of diarrhea -Elevated plasma VIP in the presence of diarrhea (usually >3L/day) and does not resolve when patient fasts Localization: -Generally, VIPomas are large tumors -CT scan -Ultrasound (EUS) - Somatostatin receptor scintigraphy

Treatment: -Compete resection -Resection of appropriate portion of pancreas, lymph node dissection, resection of any metastatic disease -Cholecystectomy , regardless of disease stage, to facilitate later treatment with a somatostatin analog (can case gallstones) -Octreotide can be used to control diarrhea in unresectable disease

SOMATOSTATINOMA: -Rare neuroendocrine tumors of D-cell origin -Secrete excessive amounts of somatostatin -Symptoms: (Pancreatic somatostatinoma) Mild diabetes (inhibits insulin and glucagon) Cholelithiasis (inhibits cholecystokinin with dec. gallbladder contractility) Diarrhea (inhibits pancreatic enzyme and bicarb secretion that leads to impaired intestinal absorption of lipids) *Duodenal somatostatinomas usually have symptoms due to local mass effect rather than the actions of the hormones.

-Most are found within the pancreas (head), although there have been -Most are found within the pancreas (head), although there have been reports of somatostatinomas elsewhere (duodenum and jejunum). -Diagnosis: Serum somatostatin levels >100pg/ml (may reach as high as 10ng/ml) -Difficult to diagnose due to nonspecific symptoms, and often there are liver metastasis upon diagnosis. TREATMENT: -Treat hyperglycemia and malnutrition -Localization studies -Resection and debulking -Cholecystectomy due to cholelithiasis due to hypersomatostatinemia.

NEOPLASMS OF THE EXOCRINE PANCREAS

-Worst prognosis of all cancers (5% 5yr survival) -Risk factors: ->60yrs old -African American -Women -Relative with pancreatic ca. (2-3X inc risk) -Smoking (doubles risk) -Diet high in fat & low in fiber & veggies -Diabetes -Chronic pancreatitis -k-ras mutation

DIAGNOSIS: - “Painless jaundice” (but, pain is often 1st sx) -US -CT -CA 19-9 -EUS when suspect malignancy, but can’t see on CT scan or when need biopsy -Diagnostic laparoscopy when suspect resectable

Treatment: -Resection vs palliation -Chemotherapy, radiation -Stenting, biliary-enteric bypass *Highly individual*

INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM -Arises from pancreatic ducts -Mucin production causes cystic dilation of the ducts -Atrophic pancreatic parenchyma due to duct obstruction ->70yrs old, chronic pancreatitis due to duct obstruction, pancreatic insufficiency -Tx: Resection (malignancy determined by invasion) -50% 10 year survival

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