Path 10 Ex 4

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The pancreas Bcells secretes glucose which leads to

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Upregulation of Glut 4 for uptake of glucose in skeletal muscle and adipose tissue
This uptake leads to increased glycogen synthesis, protein synthesis and lipogenesis

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Pancreas Alpha cells secretes

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glucagon which opposes insulin by increasing the blood glucose levels via glycogenolysis and lipolysis

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Acinar cells of the pancreas produce

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the enzymes needed for digestion. Regulation of this secretion involves both neural stimulation mediated by vagal nerves (acetylcholine) and humoral factors

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Function of secretin
Cholecystokinin
both produced in the duodenum

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-– Secretin stimulates water and bicarbonate secretion by duct cells
-cholecystokinin promotes the discharge of digestive proenzymes by acinar cells.

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The majority of the enzymes are synthesized as inactive proenzymes-enzymatically inert - (with the exception of amylase and lipase), however in pancreatitis

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the digestive enzymes are prematurely activated resulting in autodigestion and cytokine response

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Activation of proenzymes requires

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conversion of inactive trypsinogen to active trypsin by duodenal enteropeptidase (enterokinase).

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genetic causes of pancreatitis that are caused by inherited mutations in

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in trypsinogen and SPINK1 genes (serine protease inhibitor )

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– Elevated in serum in acute pancreatitis and therefore useful for laboratory diagnosis

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Enzymes: secreted in active form.
– Amylase and lipase

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– Abnormal fusion of fetal duct systems such that the bulk of pancreatic secretions drain through the minor sphincter instead of through the major papilla of Vater

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• Pancreas divisum. Predisposes patients to chronic pancreatitis.

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• Annular pancreas

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– Abnornal fusion of dorsal and ventral primordial.
– Symptoms of duodenal obstruction.

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– Embryologic remainings in the submucosa or adventitia/serosa of stomach and intestines

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• Ectopic pancreas. – 2% of islet cell tumors arise in ectopic pancreatic tissue

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Abdominal pain is the cardinal manifestation of acute pancreatitis. Its severity varies from mild and uncomfortable to severe and incapacitating. Suspected acute pancreatitis is primarily diagnosed by

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elevated plasma levels of amylase and lipase and the exclusion of other causes of abdominal pain. Hypocalcemia may result from precipitation of calcium soaps in the fat necrosis; if persistent, it is a poor prognostic sign

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Pt with "acute abdomen" with pain that is constant and intense and is often referred to the upper back.

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Full-blown acute pancreatitis is a medical emergency of the first magnitude

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Many of the systemic features of severe acute pancreatitis can be attributed to release of toxic enzymes, cytokines, and other mediators into the circulation and explosive activation of the systemic inflammatory response, resulting in

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leukocytosis,
hemolysis,
DIC
, fluid sequestration,
acute respiratory distress syndrome,
diffuse fat necrosis.
Peripheral vascular collapse and shock with acute renal tubular necrosis may occur

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What causes acute pancreatitis?

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-Pancreatic duct obstruction;
-Primary acinar cell injury;
-Defective intracellular transport of proenzymes within acinar cells
all of which result in the inappropriate activation of enzymes within the pancreas causing proteolysis, lipolysis, and hemorrhage.

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Grossly acute pancreatitis presents with

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(1) microvascular leakage causing edema,
(2) necrosis of fat by lipolytic enzymes,
(3) an acute inflammatory reaction,
(4) proteolytic destruction of pancreatic parenchyma, and
(5) destruction of blood vessels with subsequent interstitial hemorrhage.

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In the western world acute pancreatitis is associated with 2 conditions

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: biliary tract disease (mostly women) or alcoholism mostly men (65% in the United States to 20% in Sweden )

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Hereditary acute pancreatitis characterized by

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recurrent attacks of severe pancreatitis usually beginning in childhood.
• This disorder is caused by germ line (inherited) mutations in the cationic trypsinogen gene (also known as PRSS1). trypsinogen and trypsin become resistant to inactivation, and the abnormally active trypsin activates other digestive proenzymes, resulting in the development of pancreatitis.

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Although most patients with acute pancreatitis recover fully, about 5% die from

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die from shock during the first week of illness. Acute respiratory distress syndrome and acute renal failure are ominous complications.

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what happens if you survive acute pancreatitis

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sequelae may include a sterile pancreatic abscess and a pancreatic pseudocyst. The necrotic debris becomes infected, usually by Gram-negative organisms from the alimentary tract, further complicating the clinical course

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repeated attacks of moderately severe abdominal pain, recurrent attacks of mild pain, or persistent abdominal and back pain

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Chronic pancreatitis. • Attacks may be precipitated by alcohol abuse, overeating (which increases demand on the pancreas), or the use of opiates and other drugs that increase the tone of the sphincter of Oddi.

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The diagnosis of chronic pancreatitis requires a high degree of suspicion.

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• During an attack of abdominal pain, there may be mild fever and mild-to-moderate elevations of serum amylase.
• Gallstone-induced obstruction may be evident as jaundice or elevations in serum levels of alkaline phosphatase.
• A very helpful finding is visualization of calcifications within the pancreas by computed tomography (CT) and ultrasonography.
• Weight loss and hypoalbuminemic edema from malabsorption caused by pancreatic exocrine insufficiency may point toward the disease.

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Chronic pancreatitis complications

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pancreatic exocrine insufficiency and chronic malabsorption may develop, as can diabetes mellitus. In other patients, severe chronic pain may become the dominant problem. Pancreatic pseudocysts develop in about 10% of patients.

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Chronic pancreatitis microscopically and grossly

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characterized by parenchymal fibrosis, reduced number and size of acini with relative sparing of the islets of Langerhans, and variable dilation of the pancreatic ducts. Grossly, the gland is hard, sometimes with extremely dilated ducts and visible calcified concretions

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The proposes hypothesis of chronic pancreatitis pathogenesis involves

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Ductal obstruction by concretions: Alcohol increases protein concentration leading to ductal plugs which calcify and block pancreatic ducts.
Toxic-metabolic: alcohol and metabolites injury acini cells and cause parenchymal fibrosis
Oxidative stress: caused by alcohol leads to oxidation of acinar cells membrane and upregulation of transcription factors that recruite lymphocytes leading to acinar cell necrosis and fibrosis.
Necrosis-fibrosis

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Diabetes type 1 is due to

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-autoantibodies against insulin
-Manifests in childhood:
-Associated with HLA-DR3 and HLA-DR4

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Hyperglycemia is exacerbated in DM1 because of

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unopposed glucagon which leads to gluconeogenesis, glycogenolysis and lypolysis.

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DM1 presentation

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Polyuria, Polydipsia, glycosuria.

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The most common type of diabetes

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End organ insulin resistance leading to hyperglycemia. Arises in middle aged, obese adults

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Why is obesity linked to dm2?

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Obesity leads to decreased numbers of insulin receptors. Beta cells reveal amyloid deposition in the islets

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DM2 risk for hyperosmolar non ketotic coma arises when

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Glucose is greater than 500 mg/dL which causes life threatening diuresis with hypotension and coma. No ketones present

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Pancreatic endocrine neoplasm associated with MEN 1 along with parathryoid hyperplasia and pituitary adenomas

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Tumors of islet cells.

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• Most common of pancreatic endocrine neoplasms

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β-cell tumors (Insulinomas) • Characteristic clinical triad:
– episodic hypoglycemia with blood glucose below 50 mg/dL, mental status change, precipitated by fasting or exercise relieved of symptoms by glucose administration

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Zollinger-Ellison syndrome (Gastrinoma)

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Present as treatment resistant ulcers. Ulcers can be multiple and extend into the jejunum. Hypergastrinemia from a pancreatic (or duodenal tumor) stimulates extreme gastric acid secretion, which in turn causes peptic ulceration

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Somatostatinomas:

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achlorhydia (gastrin inhibition) and cholelithiasis with steatorrhea (cholecystokinin inhibition)

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Vipomas

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secrete extensive vasoactive intestinal peptide leading to watery diarrhea, hypokalemia and achlorhydria.

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• Unequivocal criteria for malignancy in Pancreatic Endocrine Neoplasms include

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– Metastases to regional lymph nodes or distant organs (including the liver),
– Vascular invasion, and
– Gross invasion of adjacent viscera
• In general, tumors less than 2 cm in diameter tend to behave in an indolent manner
• The functional status of the tumor might have some import on prognosis, as approximately 90% of insulinomas are benign, while 60% to 90% of other functioning and nonfunctioning pancreatic endocrine neoplasms tend to be malignant.

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origin.
• Carcinomas involving the head of pancreas manifest somewhat earlier, due to

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obstruction of the common bile duct. However, by the time jaundice appears, the tumor is usually unresectable. The location of this tumor in the head of the pancreas is responsible for severe obstructive jaundice.

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Head of the pancreas carcinoma is detected by

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-conjugated hyperbilirubinemia with a marked elevation of alkaline phosphatase and gamma-glutamyl transpeptidase.
– The absence of urobilinogen in urine indicates nearly complete obstruction of bile flow into the gut.

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Pancreatic Intraepithelial Neoplasia are often found in

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pancreatic parenchyma adjacent to infiltrating carcinomas. The genetic alterations identified in PanINs are similar to those present in invasive cancers.

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Pancreatic Intraepithelial Neoplasia show dramatic telomere shortening. A critical shortening of telomere length in PanINs may predispose these lesions to

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to accumulate progressive chromosomal abnormalities and to develop invasive carcinoma

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Molecular Alterations in Invasive Pancreatic Adenocarcinoma. Most common:

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K-ras, p16 >p53, SMAD4>Other

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Clinical Features of Pancreatic Adenocarcinoma

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Carcinomas of the pancreas generally remain silent until their extension impinges on some other structure.
• Pain is usually the first symptom, but by the time pain appears, these cancers are usually beyond cure.
• Obstructive jaundice is associated with most cases of carcinoma of the head of the pancreas, but it rarely draws attention to the invasive cancer soon enough.
• Weight loss, anorexia, and generalized malaise and weakness tend to be signs of advanced disease.
• Migratory thrombophlebitis, known as the Trousseau sign, occurs in about 10% of patients and is attributable to the elaboration of platelet-aggregating factors and procoagulants from the tumor or its necrotic products.

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• Early detection of pancreatic cancer?

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– Although the K-RAS oncogene is mutated in 90% of pancreatic cancers, the utility of screening tests for K-RAS mutations remains unproven.
– Serum levels of many enzymes and antigens (e.g., carcinoembryonic antigen [CEA] and CA19-9 antigen) have been found to be elevated, but these markers are not specific nor are they sensitive enough to be used as screening tests.

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What is the role of endoscopic ultrasonography and CT in detecting pancreatic cancer?

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have proved of great value in diagnosis and the performance of percutaneous needle biopsy. Both of these techniques, while useful in establishing a diagnosis, are not useful as screening tests.