Corso Integrato di Medicina di Laboratorio Insegnamento di Biochimica Clinica Biomarcatori nelle malattie del pancrea

1. Prof M Panteghini - Universit� degli Studi di Milano 2011 1 Corso Integrato di Medicina di Laboratorio Insegnamento di Biochimica ClinicaBiomarcatori nelle malattie del pancreas

2. Pancreatic Secrections Endocrine Insulin & proinsulin (? cells) Glucagon (? cells) Pancreatic polypeptide (F cells) Somatostatin (? cells) Gastric inhibitory polypeptide Secretin, gastrin, bombesin Exocrine (from acinar cells) Amylase, lipase Trypsinogens (1 & 2), chimotrypsinogens (1 & 2) Procarboxypeptidase A and B Proelastase, ribonuclease, deoxyribonuclease Prophospholipase A2

3. Pancreatic Secrections Exocrine (from acinar cells) Amylase, lipase Trypsinogens (1 & 2), chimotrypsinogens (1 & 2) Procarboxypeptidase A and B Proelastase, ribonuclease, deoxyribonuclease Prophospholipase A2

4. Prof M Panteghini - Universit� degli Studi di Milano 2011 4 Fisiopatologia del pancreas esocrino

5. Mechanisms of acute pancreatitis

6. Pathogenic cascade of acute pancreatitis

9. Prof M Panteghini - Universit� degli Studi di Milano 2011 9

10. Prof M Panteghini - Universit� degli Studi di Milano 2011 10 Proposed laboratory tests for diagnosis of acute pancreatitis PANCREATIC LIPASE Pancreatic amylase isoenzyme [Total amylase activity] Pancreatic trypsin-1 (serum) Pancreatic trypsinogen-2 (urine) Pancreatic elastase-1 (serum) Pancreatic phospholipase A2 Pancreatic carboxypeptidase A

11. Prof M Panteghini - Universit� degli Studi di Milano 2011 11 Human amylases Relatively small molecules (54,000 to 62,000 Da). The enzyme is small enough to pass through the glomeruli of the kidneys, and AMY is the only plasma enzyme normally found in urine. AMY is present in a number of organs and tissues.

13. CAUSES OF HYPERAMYLASEMIA Pancreatic disease: Intraabdominal diseases other than pancreatitis: Genitourinary disease: Miscellaneous: Pancreatitis, any cause Pancreatic trauma Biliary tract disease Perforated peptic ulcer Intestinal obstruction Mesenteric infarction Ruptured aortic aneurism Acute appendicitis Peritonitis Gastritis, duodenitis Trauma Ectopic, ruptured tubal pregnancy Salpingitis Ovarian malignancy Renal insufficiency Salivary gland lesions Acute alcoholic abuse Diabetic ketoacidosis Macroamylasemia Septic shock Cardiac surgery Tumors Drugs

14. Prof M Panteghini - Universit� degli Studi di Milano 2011 14

16. CAUSES OF HYPERAMYLASEMIA Pancreatic disease: Intraabdominal diseases other than pancreatitis: Genitourinary disease: Miscellaneous: Pancreatitis, any cause Pancreatic trauma Biliary tract disease Perforated peptic ulcer Intestinal obstruction Mesenteric infarction Ruptured aortic aneurism Acute appendicitis Peritonitis Gastritis, duodenitis Trauma Ectopic, ruptured tubal pregnancy Salpingitis Ovarian malignancy Renal insufficiency Salivary gland lesions Acute alcoholic abuse Diabetic ketoacidosis Macroamylasemia Septic shock Cardiac surgery Tumors Drugs

17. CAUSES OF PANCREATIC HYPERAMYLASEMIA Pancreatic disease: Intraabdominal diseases other than pancreatitis: Renal insufficiency Macroamylasemia Pancreatitis, any cause Pancreatic trauma Biliary tract disease Perforated peptic ulcer Intestinal obstruction Mesenteric infarction Ruptured aortic aneurism Acute appendicitis Peritonitis Gastritis, duodenitis Trauma

20. Prof M Panteghini - Universit� degli Studi di Milano 2011 20 Macroamylasemia These are complexes between ordinary AMY (usually S-type) and IgG or IgA (in 1% of population). These macroamylases cannot be filtered through the glomeruli of the kidneys because of their large size (>MW 200,000) and are thus retained in the plasma. Their presence may increase AMY activity some 2- to 8-fold above the upper reference limit. There is no clinical significance to macroamylasemia.

22. Prof M Panteghini - Universit� degli Studi di Milano 2011 22 Human lipase[triacylglycerol acylhydrolase] Single-chain glycoprotein with a MW of 48,000. LPS is a small enough molecule to be filtered through the glomerulus. It is totally reabsorbed by the renal tubules, and it is not normally detected in urine. LPS concentration in the pancreas is ~9000-fold greater than in other tissues, and the concentration gradient between pancreas and serum is ~20,000-fold.

23. Prof M Panteghini - Universit� degli Studi di Milano 2011 23 Lipase in tissue homogenates

24. Prof M Panteghini - Universit� degli Studi di Milano 2011 24 Lipase has far less tissue distribution than P-AMY and, thus, its elevation in serum is less frequently associated with nonpancreatic disease states

25. Prof M Panteghini - Universit� degli Studi di Milano 2011 25

26. Prof M Panteghini - Universit� degli Studi di Milano 2011 26 Evaluating the clinical efficacy of pancreatic enzymes in the diagnosis of acute pancreatitis <The �clinically relevant� population> Patients admitted to hospital with acute abdominal pain and suspected of having acute pancreatitis

28. Prof M Panteghini - Universit� degli Studi di Milano 2011 28 Pancreatic hyperenzymemia:clinical significance and diagnostic approach

29. Prof M Panteghini - Universit� degli Studi di Milano 2011 29 Clinical efficiency of serum lipase for the diagnosis of acute pancreatitis in patients with acute abdominal pain

30. Prof M Panteghini - Universit� degli Studi di Milano 2011 30 Predictive values of serum lipase for the diagnosis of acute pancreatitis in patients with acute abdominal pain[estimated disease prevalence in Emergency Dept., 10%]

31. CONDITIONS ASSOCIATED WITH AN ELEVATION OF PANCREATIC LIPASE IN SERUM Pancreatic disease: Intraabdominal diseases other than pancreatitis: Renal insufficiency Pancreatitis, any cause Pancreatic trauma Acute cholecystitis Perforated peptic ulcer Intestinal obstruction Peritonitis

32. Prof M Panteghini - Universit� degli Studi di Milano 2011 32 The diagnostic performance of pancreatic enzymes is greatly improved by restricting their use to a population with suspected disease. Lipase measurement is superior to P-AMY in terms of cost and diagnostic performance. It is recommended that lipase replaces P-AMY as initial test for acute pancreatitis; anyway, the obtaining of both serum P-AMY and lipase is not warranted.

33. Prof M Panteghini - Universit� degli Studi di Milano 2011 33 Time course of changes in pancreatic enzymes after ERCP-induced pancreatic injury[an �in vivo� experimental model of pancreatitis] Lipase increases significantly faster (and earlier) than P-AMY The average peak increase of lipase is ~4-times higher than that of P-AMY Lipase returns to normal values somewhat later than P-AMY

34. Prof M Panteghini - Universit� degli Studi di Milano 2011 34 Diagnostic Window of Pancreatic Enzymes in Acute Pancreatitis

35. Prof M Panteghini - Universit� degli Studi di Milano 2011 35 Causes of acute pancreatitis Common causes (?75%) Acute or chronic alcohol abuse Biliary tract diseases (gallstones) Uncommon causes (?25%) Surgery to pancreas or nearby organs Pancreatic tumors � Pancreatic calcification or fibrosis Trauma to abdomen Blockage of pancreatic duct (post-ERCP) Duodenal obstruction � Intra-abdominal inflammation Metabolic disorders (hypertriglyceridemia) Drugs or idiosyncratic reaction Hepatitis of any cause Renal failure of all types

36. Prof M Panteghini - Universit� degli Studi di Milano 2011 36 Diagnostic accuracy of liver enzymes for biliary etiology of acute pancreatitis

37. Prof M Panteghini - Universit� degli Studi di Milano 2011 37 Fisiopatologia del pancreas esocrino

38. Prof M Panteghini - Universit� degli Studi di Milano 2011 38 Determining exocrine pancreatic function Invasive tests of pancreatic function (e.g., the secretin test) are considered the gold standard for determining exocrine pancreatic function. However, very few centers perform direct testing. Elastase-1 measurement in stool is currently the most reliable noninvasive procedure for the diagnosis of pancreatic insufficiency because possible treatment with pancreatic enzyme supplements does not interfere with the test results.

39. Prof M Panteghini - Universit� degli Studi di Milano 2011 39 Fecal Elastase-1

40. Prof M Panteghini - Universit� degli Studi di Milano 2011 40 Fecal chymotrypsin Chymotrypsin measurement in patients with pancreatic insufficiency treated with oral pancreatic enzyme supplements may indicate whether the therapy is adequate or whether increased supplementation is necessary