Disorders of the Pancreas

Introduction

Acute pancreatitis: acute inflammation which subsides without leaving permanent damage to the gland

Chronic pancreatitis: repeated acute injury to the pancreas resulting in irreversible damage

Secretory Functions of Pancreas

Endocrine – Islet of Langerhans Þ hormones (Somatostatin, Glucagon, Insulin, etc) Þ Portal Vein

Exocrine – Acinar cells Þ Digestive enzymes, NaCl, H₂0; Ductal cells Þ HCO₃^-, H₂0 Þ duodenum

Digestive enzymes include proteolytic, amyolytic, lipolytic enzymes, nuclease and others Þ secreted as zymogens

Enterokinase from enterocytes activate Trypsin which in turn activates the other enzymes

regulated hormonally (CCK - activates enzyme secretion; Secretin - activates HCO₃ secretion) and neurally (ACh - activates HCO₃ and enzyme secretion)

Why doesn’t pancreas digest itself?

enzymes are synthesized as inactive zymogens

enzymes are segregated within membrane bound compartments

pancreas contains intracellular trypsin inhibitor Þ inactivates any trace of trypsin mistakenly activated within pancreas

the activating enzyme (enterokinase) is geographically separated from the pancreas

Acute Pancreatitis (reversible)

When the factors for protecting the pancreas no longer work Þ pancreas "auto digests" itself Þ acute pancreatitis

Pathogenesis (theories)

reflux of duodenal contents (which contain activated trypsin)Þ activation of zymogens within pancreas Þ pancreatitis

bile reflux/common channel Þ choledocholithiasis (common bile duct stone) Þ obstruction at level of ampulla of Vater Þ intraductal pressures within pancreas rise Þ activation of pancreatic zymogens

obstruction/secretion theory Þ obstruction at Sphincter of Oddi by spasm or tumor, or elsewhere along ductÞ prevention of normal outflow of enzyme rich fluid Þ pancreatic ductal hypertension Þ autoactivation of enzymes

autoactivation theory Þ occurs at acinar level, not in the interstitium Þ there is fusion of enzymes and lysosomal hydrolases (called crinophagy) Þ activation of trypsinogen Þ activation of other zymogens Þ auto-digestion

suggested model for alcoholic pancreatitis Þ alcohol induces increased conc of total pancreatic juice protein and decreased conc of trypsin inhibitor (cholinergically mediated)

Etiology: ethanol, gallstones (biliary tract disease), foreign bodies obstructing Ampulla of Vater, Idiopathic; many others

In the US, 90% of all cases of pancreatitis are secondary to either alcohol, cholelithiasis or are considered idiopathic

Clinical Presentation

local effects

once trypsinogen is activated, autodigestion begins with activation of other proenzymes

lipases Þ TG Þ FAs Þ Fat necrosis (sequesters calcium Þ hypocalcemia)

elastase Þ Elastin Þ degraded elastin Þ increased vascular fragility and hemorrhage

trypsin/chymotrypsin Þ Protein Þ degraded protein Þ cell necrosis (acinar, vascular)

Activated enzymes destroy pancreatic tissue Þ edema, hemorrhage, inflammation Þ can impact adjacent organs

Patients complain of mid-epigastric boring pain that radiates thru the mid-back Þ as inflammation spreads, peritoneal surface becomes irritated Þ paralysis of intestinal motility Þ ileus Þ nausea and vomiting

systemic effects

Phospholipase can damage cell membranes (cell death), surfactant (pulmonary dysfunction – ARDS), and lead to production of prostaglandins and leukotrienes (clotting disorders)

Trypsin activates plasma kallikrein Þ formation of bradykinin Þ Ý capillary permeability and cause vasodilation

Also forms thrombin (clot formation) and plasmin (clot lysis) Þ consumptive coagulopathy (DIC) can occur

Elastase destroys elastin in blood vessels so blood vessels are destroyed

Diagnostic tests

Amylase (most common)

40% of serum amylase comes from pancreas; 60% from salivary glands Þ cleared by the kidney

with inflammation, obstruction or trauma to pancreatic duct Þ serum amylase elevates

numerous situations cause false positives Þ macroamyasemia, renal insufficiency, bowel obstruction, etc

macroamylasemia (aggregates of amylase with Ig) Þ can’t be filtered by kidney Þ elevation of serum amylase

Lipase (most common back up test)

Will be elevated in acute pancreatitis in 87% of patients; more specific for pancreatits (but less sensitive)

Treatment - "putting the pancreas at rest" Þ remove all stimulation from the inflamed pancreas

Pathology

Hemorrhagic pancreatitis Þ inflammation pulls acini apart Þ hemorrhage, necrosis Þ metabolic dysfunction Þ death

Fat necrosis Þ lipases destroy pancreas -more enzymes released Þ Ca salt deposits Þ FA bind Ca Þ hypocalcemia

Pancreatic necrosis Þ need debridement

Pseudocyst – cyst without an epithelial tissue lining Þ lined with granulation tissue

Chronic Pancreatitis (irreversible)

obstructive pancreatitis Þ obstruction of the ducts by tumors or strictures that possibly may be related to trauma

chronic calcifying pancreatitis Þ represents more than 95% of chronic pancreatitis

Pathogenesis:

majority of cases of chronic calcifying pancreatitis are associated with alcoholism Þ Ý pancreatic juice protein concentration Þ intraductal protein precipitates occur (plugs are formed of fibrillar protein called lithostathine H2) Þ protein precipitates become calcified Þ obstruction of pancreatic secretion outflow Þ ducts atrophy and replaced with connective tissue and scar formation

in alcoholics, lithostathine S (stabilizes calcium) and citrate (lith S chelator) are reduced Þ Ca salts are produced

Calcifications also occur with malnutrition, hypercalcemia, and hereditary pancreatitis

Etiology:

Alcohol Þ associated with 95% of all chronic pancreatitis

Hereditary pancreatitis Þ autosomal dominant disease with variable penetrance Þ calcified chronic pancreatitis

Cystic Fibrosis Þ thick secretions lead to obstruction of pancreatic ducts (clubbing and rectal prolapse common)

Traumatic pancreatitis Þ disruption of pancreatic ducts secondary to duct trauma fibrosis with stricturing of the ducts

Idiopathic (20 to 30% of cases)

Inflammatory pancreatitis Þ seen in elderly Þ diffuse fibrosis and inflammatory infiltration by mononuclear cells

Clinical presentation:

near continuous abdominal pain (may be related to pancreatic ductal hypertension, perineural scaring or fibrosis)

Acinar destruction occurs Þ pancreatic insufficiency Þ malabsorption (B₁₂)

Due to reserve capacity of pancreas, significant protein and fat malabsorption is not seen until >90% of secretory capacity of pancreas is lost

Weight loss is an obvious consequence Þ due to malabsorption and decreased food intake due to abdominal pain

fibrosis Þ calcification and destruction of Islets of langerhans Þ >70% of patients will have overt diabetes mellitus

Diagnositc Tests:

Radiologic tests Þ imaging (look for calcification); ERCP (altered ductal anatomy) Þ enlarged pancreatic duct and secondary branches; fecal fat (decreased fat digestion) Þ Steatorrhea

Pancreatic function tests Þ Secretin test (altered HCO₃ secretion); Lundh test meal Þ tests enzyme secretion; Bentiromide test (most often used); Blood (glucose) Þ endocrine damage

Treatment Þ centers around pain control and treatment of malabsorption; certain complications (common bile duct compression, pseudocysts) require either surgical and/or endoscopic therapy

Pathology:

Obstruction of the main duct; Alcoholics Þ secrete protein into main duct Þ calcification Þ dilation of the duct; Lobules die Þ fibrosis Þ steatorrhea; Will not find fat necrosis and hypocalcemia; Acini die off due to obstruction; Islets die off due to fibrosis Þ leads to diabetes; Neural inflammation

Pancreatic Cancer

Neoplasms

Benign or malignant tumors show evidence of endocrine cell differentiation (Relatively uncommon <1 per 100,000)

Majority are functional (ie they actively secrete hormones)

Types – insulinoma, gastrinoma (ZE syndrome) Þ persent with ulcers, glucagonoma, somatostatinoma

Serous cystadenomas – benign – rare, occur ~68 yo, gross anatomy Þ large, well circumscribed

Mucin – secreting cystic neoplasms Þ malignant potential

Carcinoma of the Exocrine Pancreas

Incidence ~9 to 10 cases per 100,000; Disease of industrialized western country; M:F Þ 2:1; Rare before 45 yo; Risk Ý with age; Smoking is greatest risk factor (other risk factors Þ diet, diabetes mellitus, familial clustering, occupation)

Head of pancreas is most common site – why? Largest part of organ

Presentation – pain (due to perineural invasion), weight loss, obstructive jaundice; thrombosis in some instances

Histology: ductal adenocarcinoma – most common

Metastases – most common in lymph nodes, liver, peritoneum; cures are rare;

Desmoplasia – tumor produces a fibrous response

Overall 5 year survival rate Þ 5%

Adenocarcinoma is highly lethal

cures are rare but only possible with resection

preoperative evaluation Þ CT, ERCP, laproscopy – hard to differentiate pancreatitis from carcinoma with ERCP

cystic lesions – differentiate pseudocyst from all others

all mucinous cysts potentially malignant

most neoplastic cysts should be resected

Surgical Treatment

Procedure (loop of resection or palliative Whipple) Þ 7 to 8 hour procedure:

try to put finger between pancreas and posterior vasculature (ie portal vein) Þ if possible Þ can perform surgery

cut duodenum out of peritoneum

disconnect blood supply Þ gastroduodenal artery Þ superior (ant/post) pancreaticoduodenal; inferior (ant/post) PD

disconnect stomach, bile duct, head form body of gland, duodenum from jejunum, and stomach from duodenum

reconnect jejunum to pancreas, bile duct to jejunum, and stomach to jejunum

Biliary/Gastric bypass (do not remove tumor) vs Palliative Whipple (resection)

1 year survival rate Þ B/G bypass (22%); resection (44%)

2 year survival rate Þ B/G bypass (2%); resection (24%)

thus, is some benefit to getting the tumor out