1. Chapter 13 Disorders of the Pancreas Lecture 13 The Nature of Disease Pathology for the Health Professions Thomas H. McConnell

2. Overview of Today’s Lecture –Review of normal pancreatic anatomy & physiology –Pancreatitis –Diabetes mellitus –Pancreatic neoplasms Figure from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014 Figure from: Huether & McCance, Understanding Pathology, 5 th ed., Elsevier, 2012 From: Pathophysiology: A Clinical Approach, Braun & Anderson, Lippincott, 2011

3. The exocrine pancreas excretes digestive juice into the intestine. –Protease secreted as inactive enzyme (zymogen) –Lipase and amylase secreted as active enzyme The endocrine pancreas excretes hormones into blood. –Alpha cells: glucagon. Functional opposite of insulin, stimulates liver glycogen >> glucose. Raises blood glucose –Beta cells: insulin. Opens cell membrane to glucose. Lowers blood glucose –Delta cells: somatostatin. Inhibits glycogen formation and insulin secretion. Raises blood glucose –PP cells: pancreatic polypeptide, acts on stomach to stimulate juices and slow intestinal motility Normal Pancreatic Physiology

4. 4 Pancreas Exocrine (digestive) and endocrine (metabolic) functions Completes digestion of proteins that was started in the stomach

5. 5 Pancreatic Juice pancreatic amylase – splits glycogen into disaccharides pancreatic lipases – break down triglycerides pancreatic nucleases – digest nucleic acids bicarbonate ions – make pancreatic juice alkaline (pH = 8) and neutralize acid coming from stomach Pancreatic proteolytic enzymes… 

6. 6 Pancreatic Proteolytic Enzymes Pancreas Proelastase Procarboxypeptidase Chymotrypsinogen TrypsinogenTrypsin Enteropeptidase (Enterokinase) (brush border of sm. intestine) Elastase Carboxypeptidase Chymotrypsin ProteinsDipeptides, tripeptides, amino acids (Proenzymes, Zymogens) Purpose of proteolytic enzymes is continued breakdown of proteins that began in the stomach (Active enzymes)

7. 7 Regulation of Pancreatic Secretions acidic chyme stimulates release of secretin secretin stimulates release of watery pancreatic juice with bicarbonate and phosphate (= buffers; to  pH) CCK and parasympathetic NS stimulate production and secretion of pancreatic enzymes and zymogens

8. Anatomic detail of the pancreas Figure from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014

9. Glucose, glycogen, insulin, and glucagon metabolism Figure from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014 The endocrine function of the pancreas

10. Pancreatitis Extremely serious disease Escape of pancreatic enzymes –Normally very small amount –Stasis increases likelihood that enzymes will cause inflammation Damage parenchyma of pancreas Damage to blood vessels, nerves Damage causes more pancreatic enzymes to be released Can be –Acute : Reversible inflammation of the pancreas –Chronic: Irreversible destruction and scarring

11. Acute Pancreatitis Known associated conditions –Alcohol abuse (67% of cases) –Gallstones (50% of cases) –Unknown etiology (10%) –Other causes Mnemonic phrase: Get Smashed – SG p171) Initial lesions Edema, congestion, acute inflammation Congestion (stasis) causes autodigestion of pancreas May result in hemorrhagic pancreatitis (severe) Complication after resolution –Fibrous walling off of inflammation –Cysts: pseudocysts (no epithelial lining; not true cyst)

12. Pathogenesis of Acute Pancreatitis Figures from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014

13. Chronic Pancreatitis Repeated episodes of subclinical or symptomatic acute pancreatitis Irreversible destruction and scarring Distinctly different clinical syndrome and consequences than acute pancreatitis –Obliteration of pancreas from scar tissue –Duct dilation –Calcification (with Ca soap formation) –Pancreatic duct stones Chronic alcohol abuse – 2/3 of cases Other causes: cystic fibrosis, autoimmune Figure from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014

14. Chronic Pancreatitis Figure from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014

15. The Consequences of Pancreatitis Figure from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014

16. Diabetes Mellitus Disease causing hyperglycemia –Decreased insulin secretion (hyposecretion) –Decreased insulin action (resistance) Worldwide epidemic –350 million people worldwide –25 million in US alone –Over age 65, 27% are diabetic –Leading cause of morbidity and mortality Chronic renal failure Nontraumatic lower limb amputations Adult-onset blindness Major contributor to atherosclerosis

17. Criteria for Diagnosing Diabetes Blood Glucose Level (mg/dl) Euglycemia 1 Pre-diabetes (glucose intolerant) Diabetes Fasting ≤ 100100-125 ≥ 126 OR 3P’s + random ≥ 200 Peak (after OGTT) ≤ 140140-100≥ 200 Hb A1c (%) < 65.7-6.4≥ 6.5 1 Normal fasting blood glucose range: 70 – 110 mg/dl

18. Type 1 Diabetes Mellitus Genetic susceptibility and Environmental factors Immunologically mediated destruction of beta cells –Pancreatic atrophy and specific loss of beta cells; hyperglycemia when 80%-90% cells lost –Macrophages, T- and B-lymphocytes, and natural killer cells are present Manifestations: –Hyperglycemia –Polydipsia –Polyuria –Polyphagia –Weight loss –Fatigue Insulin, amylin, glucagon Figure from: Huether & McCance, Understanding Pathology, 5 th ed., Elsevier, 2012

19. Dysfunction of the Pancreas Type 2 diabetes mellitus –Maturity-onset diabetes of youth (MODY) –Gestational diabetes mellitus (GDM) –Common form of diabetes mellitus type 2 Initial insulin resistance Later loss of beta cells Diagnosis (fasting glucose, postprandial glucose, A1c) Manifestations (non-specific): fatigue, pruritus, recurrent infections, visual changes, or symptoms of neuropathy; often overweight, dyslipidemic, hyperinsulinemic, and hypertensive

20. Diabetes Types I/II Compared Table from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014

21. The Pathogenesis of Type I/II Diabetes Figures from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014

22. Acute Complications of Diabetes Mellitus Hypoglycemia Diabetic ketoacidosis (Type I) Hyperosmolar hyperglycemic non-ketotic syndrome (HHNKS) (Type II) Somogyi effect –Hypoglycemia followed by rebound hyperglycemia –Due to release of epinephrine, GH, corticosteroids –Gluconeogenesis increases blood glucose Dawn phenomenon –Early morning rise in blood glucose –Related to nocturnal release of GH

23. Chronic Complications of Diabetes Mellitus Hyperglycemia and nonenzymatic glycosylation –Normal reversible attachment of glucose becomes irreversible –Blood vessel walls, interstitial tissue, cells Hyperglycemia and the polyol pathway –Insulin independent tissues (kidney, RBC, nerves, etc.) ↑ sorbitol, increasing osmotic pressure in cells Reduction in glutathione (antioxidant) Hyperglycemia and Protein kinase C (PKC) activation –Insulin resistance –Proinflammatory cytokines –Vascular endothelial proliferation Microvascular disease related to diabetes mellitus –Retinopathy –Diabetic nephropathy –Neuropathy Mnemonic: SHAKE (see p. 173 in Study guide)

24. Metabolic Derangements/Complications in Diabetes Figures from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014

25. Diabetic Ketoacidosis Figure from: Huether & McCance, Understanding Pathology, 5 th ed., Elsevier, 2012

26. Treatment & Control of Diabetes Mellitus Three main levels of control –Diet and exercise –Insulin replacement (Type I, Type II if needed) –Oral hypoglycemic drugs Increase insulin secretion and/or production Decrease resistance to insulin Patient education is critically important Food and the glycemic index –Indicator of how fast a food is converted to glucose –Glucose has an index of 100 –All other foods compared to this Hb A1c – useful confirmation of diagnosis

27. Glycemic Index and Glycemic Load Glycemic index - compares the potential of foods containing the same amount of carbohydrate to raise blood glucose. However, the amount of carbohydrate consumed also affects blood glucose levels and insulin responses. Glycemic Load - The glycemic load of a food is calculated by multiplying the glycemic index by the amount of carbohydrate in grams provided by a food and dividing the total by 100 (1). Dietary glycemic load is the sum of the glycemic loads for all foods consumed in the diet. The concept of glycemic load was developed by scientists to simultaneously describe the quality (glycemic index) and quantity of carbohydrate in a meal or diet.(1) From: http://lpi.oregonstate.edu/mic/food- beverages/glycemic-index-glycemic-load From: http://nutritiondata.self.com/topics/glycemic- index

28. Pancreatic Neoplasms Pancreatic neoplasms can be –Cystic or Solid –Benign or Malignant –Endocrine or Exocrine Pancreatic carcinoma is common and lethal Cystic neoplasms are uncommon and usually benign Islet cell tumors are usually benign and functional 95% Exocrine duct adenocarcinoma

29. Pancreatic Carcinoma Figures from: McConnell, The Nature of Disease, 2 nd ed., LWW, 2014