pathology III: pancreas and gall bladder pathology

some study questions for the pathology lectures on the pancreas and gall bladder...

questions
acute pancreatitis...
1. what part of the pancreas is most commonly affected in acute pancreatitis?
2. describe the pancreatic destruction in more severe forms of acute pancreatitis.
3. what are the two most common causes of pancreatitis?
4. what are three general mechanisms for the pathogenesis of acute pancreatitis?
5. what are some morphological features of acute pancreatitis?
6. what is "chicken soup ascites"?
7. what are the lab tests used to diagnose acute pancreatitis?
8. what is a lab result that indicates a poor prognosis in acute pancreatitis?
9. what are the potential complications of acute pancreatitis?

chronic pancreatitis...
10. what is the etiology of chronic pancreatitis?
11. what is the morphology of chronic pancreatitis?
12. what is the basic clinical picture of chronic pancreatitis?

pseudocysts...
13. what are pseudocysts?
14. what are some potential complications of pseudocysts?

pancreatic carcinoma...
15. what is the prognosis of pancreatic carcinoma?
16. what are some risk factors for pancreatic carcinoma?
17. describe a typical patient with pancreatic carcinoma.
18. which pancreatic cells does carcinoma originate with?
19. what part of the pancreas is most affected by carcinoma?
20. what are complications of pancreatic carcinoma specific to body and tail lesions?
21. what is trousseau's syndrome?
22. what is courvosier's sign?
23. carcinoma is more likely to present with jaundice when involving what part of the pancreas?

gallstones...
24. what are some risk factors for gallstone formation?
25. what is the most common type of gallstone and how is it formed?
26. what are three etiological routes that can lead to gallstone formation?
27. what are the top three foods that cause biliary pain?
28. what is the morphology of cholesterol stones?
29. what is the morphology of bile pigment stones?
30. describe the clinical presentation of gallstones.
31. what are some complications of gallstones?

cholecystitis...
32. what is the etiology of acute calculous cholecystitis?
33. what is the clinical presentation of acute calculous cholecystitis?
34. what are some lab markers that are elevated in acute calculous cholecystitis?
35. what is the prognosis or course for acute calculous cholecystitis?
36. acute calculous cholecystitis plus diabetes can lead to what complication?
37. what is acute acalculous cholecystitis generally due to?
38. describe the typical patient who has acalculous cholecystitis.
39. what are complications for acute acalculous cholecystitis?
40. what are Rokitansky-Aschoff sinuses?
41. what is the "porcelain gallbladder" sign?
42. what is the HIDA scan?
43. what is an imaging test useful for discovering gallstones?

answers
1. exocrine pancreas; destruction of acinar cells.
2. fat necrosis and hemorrhage into parenchyma.
3. alcohol consumption
gallstones / sludge
4. duct obstruction, acinar cell injury, defective intracellular transport.
5. necrotic fat cells with debris and calcium
edema, inflammation
chicken soup ascites
pseudocyst
6. brown fluid filled with fat droplets.
7. serum/urinary amylase and lipase elevations.
8. hypocalcemia, which results from precipitation of calcium soaps in fat necrosis.
9. shock
renal failure
ARDS
duodenal obstruction

10. either severe alcoholism or repeated injury from pancreatitis.
11. loss of acinar cells
fibrous deposition
duct obstruction
calcifications
pseudocysts
[loss fiber obstruct calcium cyst] [chan park- lose the fiber, it's blocking your teeth with cysts]
12. chronic abdominal / back pain triggered by alcohol, overeating, drugs
steatorrhea
diabetes
mild jaundice

13. walled off pancreatic secretions from damaged ducts within the interstitial tissues.
14. pain, pancreatic abscess, peritonitis.

15. almost uniformly fatal- 3% 5 year survival rate.
16. smoking
alcohol
diabetes
chronic pancreatitis / cirrhosis
heavy meat / fat consumption
a-napthylamine / benzene exposure
partial gastrectomy
[SAD CHAP]
17. over 50 year old male, black, diabetic.
18. ductal cells.
19. 60% head of the pancreas.
20. impingement of vertebrae, retroperitoneal spaces.
21. migratory thrombophlebitis caused by elaboration of platelet aggregating factors.
22. acute, painless dilation of the gall bladder plus jaundice.
23. head of the pancreas.

24. female, fat, forty, fertile, fair, first nation (native americans)
25. cholesterol, via supersaturation of bile salts in cholesterol.
26. SAD: biliary stasis, decreased bile acid levels, high calorie diet.
27. tomatoes, pork, onions.
28. oval / round, pale yellow.
29. grey-white or black.
30. isolated episodes of severe RUQ pain, after rich meals or at night.
31. empyema
perforation
fistula
cholangitis

32. obstruction via a stone causes biliary stasis, which increases hydrolysis of lecithin to lysolecithin via mucosal phospholipases.
33. RUQ pain
low grade fever
anorexia
tachycardia, diaphoresis, nausea, vomiting
34. alk phos, ALP, GGT.
35. usually self limiting, resolves in 1-7 days.
36. gangrenous cholecystitis.
37. ischemia from surgery, trauma, severe infection, etc.
38. severely ill.
39. perforation and gangrene, as with calculous.
40. outpouchings of the mucosal epithelium through the wall. associated with chronic cholecystitis.
41. radiologic sign that indicates extensive calcifications. associated with chronic cholecystitis.
42. imaging with injection of hydroxy iminodiacetic acid to measure the ejection fraction of the gallbladder, useful in diagnosing gall bladder motility issues.
43. ERCP.

CPD II: stool appearance and pancreatitis

the first part of this lecture focused on the diagnosis of different GI disorders based on stool appearance. ribbon shape might indicate spasm/IBS, uterus malposition or enlargement, compression from a mass. pencil shaped: spasm/IBS and stricture. floating stools: malabsorption, cystic fibrosis. small and hard: dehydration, low fiber, delayed tract time, hypochlorhydria. large and hard: dehydration, hypotonic bowel. difficult to pass: hemorrhoids, anal fissure, dehydration, hypotonic bowel. loose but not watery: mild intestinal irritation and malabsorption. alternating constipation and diarrhea: poor diet, parasites, IBS. offensive stool odor: dysbiosis or food decay. very dark stool: melena, upper GI bleeding. light brown, clay, green, or bright yellow colors: gallbladder issues (obstruction, excess secretion).

the next section in the GI lecture covered pancreatic disorders: acute and chronic pancreatitis. acute pancreatitis causes severe abdominal pain which can feel like a knife stuck in the LUQ and cause extreme limitation of movement and even breathing. it is most commonly caused by heavy alcoholism (pain develops over a few weeks) in men and by biliary tract disease or obstruction (pain develops suddenly) in women. other etiologies might include NSAID use or hypertriglyceridism.

the diagnosis of acute pancreatitis is made through the history/physical and a few useful lab tests. besides the knife like LUQ pain, patients might present with fever, hypoactive bowel sounds, jaundice, dyspnea (because any movement will worsen the pain). additionally, cullens and grey-turner signs might be positive, which indicate retroperitoneal hemorrhage from pancreatic autodigestion. the lab tests most helpful are amylase, lipase, CBC and a chem screen; serum amylase levels are elevated soon after the onset of pain and return back to normal 2-3 days afterwards whereas urine amylase elevates 7-10 afterwards. CBC might show elevated hematocrit and leukocytosis, while a chem screen might show hyperglycemia, hypocalcemia, and elevated bilirubin/AST/ALT. treatment of acute pancreatitis generally involves 100% pancreatic rest and pain management, although 10% of patients will die regardless of treatment. the remaining 90% might recover within 2-3 weeks.

chronic pancreatitis is also caused mainly by long term alcoholism, and can also be idiopathic, or hereditary, or due to hyperlipidemia, protein malnutrition, cystic fibrosis, or biliary obstruction. patients with chronic pancreatitis might remain asymptomatic for 62 months (81 months for alcoholics), then develop severe epigastric/LUQ pain that may radiate to the back in a band like fashion and come in 2-3 hour episodes. the pain might be relieved slightly by lying in the fetal position on the left side, in contrast to acute pancreatitis, the pain of which is generally not relieved by anything.

in contrast to acute pancreatitis, the physical might not be very useful for diagnosis, although fundoscopy might reveal milky white retinal blood vessels from hyperlipidemia, and an abdominal exam might reveal pseuodocysts, which are inflammatory masses. amylase and lipase levels are only slightly elevated- the more useful tests are serum trypsin, calcium, and TG levels, as well as the bentiromide test, which measures the excretion of PABA in the urine (decreased in pancreatic insufficiency). ultrasound, chest xray, and CT all show calcification in 30% of patients. pancreatic function can also be measured via direct tests, or stimulating the pancreas with a secretogogue and measuring pancreatic output in the duodenum or directly via cannulation.

questions
stool diagnosis...
1. what might a ribbon shaped stool indicate?
2. what might a pencil shape stool indicate?
3. what might floating stools indicate?
4. what might stools that are small and hard indicate?
5. what might stools that are large and hard indicate?
6. what might stools that are difficult to pass indicate?
7. what might stools that are loose but not watery indicate?
8. what might be indicated from alternating constipation and diarrhea?
9. what might an offensive stool odor indicate?
10. what might a very dark stool color indicate?
11. what might a light brown or clay stool color indicate?
12. what might a greenish or bright yellow stool color indicate?

acute pancreatitis...
13. what is post prandial exocrine secretion stimulated by?
14. what is acute pancreatitis and what are its hallmark characteristics?
15. what are the common causes of acute pancreatitis in men and women?
16. what is the severity of alcoholism usually associated with acute pancreatitis?
17. what is the relationship between the size of gallstones and the risk of getting acute pancreatitis?
18. besides alcoholism and gallstones, what are some other etiologies for acute pancreatitis?
19. what are the signs and symptoms of acute pancreatitis?
20. what is the difference in the onset of pain for acute pancreatitis caused by alcoholism vs. gallstones?
21. what are the two typical pain patterns presented by patients with acute pancreatitis?
22. what might the pain from acute pancreatitis be alleviated by?
23. what might the pain from acute pancreatitis be worsened by?

acute pancreatitis diagnosis...
24. what are some PE findings that might be found from a patient with acute pancreatitis?
25. what do the cullen's and grey turner signs indicate?
26. what is a potential skin manifestation of acute pancreatitis?
27. which labs would be useful in the diagnosis of acute pancreatitis?
28. what might be found in the serum amylase test?
29. what might be found in the urine amylase test?
30. which amylase test would be ordered if the patient came in immediately after onset of pain vs. a few days after?
31. what is the advantage of the lipase test compared to the amylase test?
32. what does a lipase:amylase ratio of greater than 2 indicate?
33. what might be seen in a CBC of a patient with acute pancreatitis?
34. what might be seen in the chem screen of a patient with acute pancreatitis?
35. what is the imaging technique of choice in diagnosing acute pancreatitis?
36. what is the prognosis for patients with acute pancreatitis?
37. what are the treatment goals for patients recovering from acute pancreatitis?

chronic pancreatitis...
38. what is the mean age of diagnosis for chronic pancreatitis?
39. what is the bimodal age distribution for idiopathic chronic pancreatitis?
40. what are the etiologies for chronic pancreatitis?
41. what is the quality of the pain experienced in chronic pancreatitis?
42. how long do episodes of pain generally last?
43. how long on average might a patient with chronic pancreatitis remain asymptomatic? how does this vary if the patient is an alcoholic?
44. besides the abdominal pain, what are some other symptoms that a patient with chronic pancreatitis might present with?
45. what is the characteristic position that a patient with chronic pancreatitis assumes when undergoing a severe episode?
46. chronic pancreatitis may eventually lead to...

chronic pancreatitis diagnosis...
47. how useful is the PE in the diagnosis of chronic pancreatitis?
48. what might fundoscopy reveal?
49. what might be a finding in the abdomen of a chronic pancreatitis patient?
50. what signs might be present in an advanced case of chronic pancreatitis?
51. what are some lab tests that may aid in the diagnosis of chronic pancreatitis?
52. what is the bentiromide test?
53. at what extent of disease progression of chronic pancreatitis does steatorrhea occur?
54. what are two stool tests that might be helpful in the diagnosis of chronic pancreatitis?
55. what are some pancreatic function tests that can aid in the diagnosis of chronic pancreatitis?
56. what would be shown on an xray and ultrasound of a patient with chronic pancreatitis?
57. what would be shown on a CT scan of a patient with chronic pancreatitis?

answers
1. spasm / IBS, uterus malposition or enlargement, compression from a mass. [ribbon, spasm, IBS, uterus] [the uterus had a ribbon in it that caused it to spasm irritably]
2. spasm / IBS, stricture of colon. [pencil spasm stricture]
3. malabsorption, cystic fibrosis.
4. dehydration, low fiber diet, delayed tract time, hypochlorhydria.
5. dehydration, hypotonic bowel.
6. hemorrhoids, anal fissure, dehydration, hypotonic bowel.
7. mild intestinal irritation and malabsorption.
8. poor dietary habits / food allergies, parasites, IBS, liver/gallbladder irritation / dysfunction. [diet, parasites, IBS]
9. dysbiosis or food decay.
10. melena; upper GI bleeding.
11. lack of bile pigments, liver / gallbladder obstruction.
12. gallbladder problem; excess bile secretions/bile salt.

13. CCK, cephalic stimuli, intestinal stimulation.
14. an acute inflammation of the pancreas associated with edema, swelling, autodigestion, necrosis, hemorrhage.
15. alcohol for men, biliary tract disease for women.
16. greater than 200mL a day for 5-15 years.
17. risk is inversely proportional to size.
18. hypertriglyceridemia, NSAID use, post ERCP.
19. severe LUQ pain that may radiate straight through back.
20. pain from gallstones develops suddenly, whereas pain from alcoholism develops over a few weeks.
21. the feeling of a knife stuck in the left ribcage, and pain in the left scapula that radiates from the front around the side.
22. supine position often alleviates pain.
23. coughing, deep breathing, movement.

24. fever
abdominal tenderness / guarding
hypoactive bowel sounds
jaundice
dyspnea
cullen's sign
grey-turner sign
25. hemorrhage: pancreas is autodigesting and leaking blood into skin.
26. erythematous nodules on extensor surfaces from focal subcutaneous fat necrosis.
27. lipase, amylase, CBC, chem screen.
28. 75% of acute pancreatitis cases have high serum amylase levels which may rise 2-12 hours after onset and remain elevated for 2-3 days.
29. elevated levels 7-10 days after serum amylase returns to normal levels.
30. serum amylase for immediately after onset, urine amylase for a few days afterwards.
31. more specific to the pancreas, and has a longer half life than amylase.
32. alcoholism or gall bladder dysfunction.
33. leukocytosis and elevated hematocrit.
34. hyperglycemia from decreased insulin
hypocalcemia from saponification of peritoneal fat
elevated bilirubin, ALT, AST.
35. abdominal ultrasound.
36. 10% die regardless of treatment, 90% recover within 2 weeks.
37. 100% pancreatic rest and pain management.

38. ~46yo.
39. one peak at 19.2yo, another at 56.2yo.
40. long term alcoholism
idiopathic
hereditary
cystic fibrosis
hyperlipidemia
protein malnutrition
pancreatic obstruction
[that idiot heretic hyped up pancreatic malnutrition]
41. severe, persistent pain often in the mid or LUQ which may radiate in a band to the back.
42. several hours.
43. 62 months, 81 months for alcoholics.
44. diarrhea, weight loss, steatorrhea.
45. lying on left side in the fetal position.
46. type II diabetes.

47. not very useful at all.
48. milky white hue in retinal blood vessels due to hyperlipidemia.
49. pseudocyst- inflammatory mass in abdomen.
50. signs of malnutrition: decreased subcutaneous fat, muscle wasting, sunken supraclavicular fossa.
51. serum amylase and lipase (slightly elevated), serum trypsin, calcium, and TG levels.
52. a test that measures the urinary excretion of PABA, which can indicate pancreatic insufficiency if lowered.
53. when 90% of the pancreas is destroyed.
54. fecal chymotrypsin and elastase.
55. direct tests (sensitive but invasive)
duodenal aspirate tests
pancreatic output tests
56. calcifications found in 30%.
57. calcifications and pseudocysts.

organ systems: glucose regulation

this lecture focused on glucose metabolism: specifically, the interplay of insulin and glucagon secretion and their effect of glucose metabolism and storage in different organs and tissues. the pancreatic islets of langerhans secrete glucagon from alpha cells, insulin from beta cells, and somatostatin from delta cells. glucagon is secreted in response to low blood sugar and has a variety of effects which ultimately serve to raise blood glucose levels. in the liver, glycogenolysis is initiated, freeing glucose units from storage (see the biochem chapter on glycogen for more detail), gluconeogenesis creates glucose from non-carbon precursors such as amino acids. additionally, triacylglyceride stores are converted into fatty acids, which can be cleaved into ketone bodies, which are used as an alternative fuel source. glucagon is released in response to hypoglycemic (low blood sugar) conditions. other mechanisms are in place to raise blood sugar: sympathetic stimulation, cortisol, growth hormone. the symptoms from severe hypoglycemia are caused by these mechanisms; hunger by the hypothalamus and anxiety/tremors/sweating by sympathetic stimulation.

on the other hand, insulin is released in hyperglycemic conditions (high blood sugar) and facilitates uptake of glucose into cells. it accomplishes this by binding to receptors that translocate glucose transport proteins to surface of cell membranes, thereby allowing glucose to enter. there are 5 categories of glucose transport proteins, with different affinities for glucose and found in different locations of the body (see the carb digestion biochem chapter for some more physiology of the GLUT transporters): GLUT1 are found everywhere in the body and also present in placenta. GLUT2 transporters are in the pancreas, liver, kidney, and intestine. GLUT3 transporters are everywhere in the body. GLUT4 transporters are in muscle and adipose tissue and are the only insulin dependent glucose transporters. GLUT5 transporters are in the jejunum.

insulin has a variety of actions on organs and tissues; in the liver it initiates glycogen storage, fatty acid synthesis and subsequent triacylglyceride synthesis. in adipose tissue it stimulates uptake of glucose, triacylglyceride synthesis, and triacylglyceride release (through VLDL's). in muscle it stimulates uptake of glucose and amino acids and promotes glycogen storage from the excess glucose. insulin release is stimulated by a variety of factors- primarily high blood glucose levels, but also via parasympathetic stimulation, amino acids, growth hormone, and various GI hormones. insulin release is inhibited by catecholamines, somatostatin, and glucagon. note: glucagon and insulin reciprocally regulate each other- the release of one inhibits the release of the other. in addition, the release of somatostatin inhibits the release of both insulin and glucagon- preventing "rapid nutrient exhaustion".

diabetes type I is caused by an autoimmune destruction of pancreatic beta cells, resulting in low insulin levels and therefore low glucose metabolism and therefore a shift to ketone body metabolism. this also results in increased glucose levels in the urine, which can cause polyuria (excess urine volume), polydipsia (excess thirst), and polyphagia (excess hunger). type II diabetes is a resistance to insulin that is associated with high visceral fat deposits with high lipolytic activity (releasing fatty acids into the bloodstream) that are resistant to the anti-lipolytic properties of insulin. this can be induced by high free fatty acid, cortisol, or testesterone levels.

questions
glucagon...
1. what are the three types of cells in the pancreatic islets of langerhans and what do they secrete?
2. describe glucagon's effect on the liver.
3. what are the specific processes that occur that release glucose and ketones from the liver?
4. what is glucagon release from alpha cells stimulated by?
5. what is glucagon release from alpha cells inhibited by?
6. how does somatostatin "prevent rapid nutrient exhaustion"?
7. glucagon corrects...
8. what are the other ways that the body corrects for hypoglycemia?
9. what are the symptoms of severe hypoglycemia and what are they caused by?
10. what is reactive hypoglycemia and what is it caused by?

insulin...
11. describe the general function of insulin.
12. how does insulin facilitate the uptake of glucose into cells?
13. where are GLUT1-GLUT5 found?
14. which glucose transporter protein requires insulin?
15. describe insulin's action on muscle.
16. describe insulin's action on the liver.
17. describe insulin's action on adipose tissue.
18. what are some factors that facilitate release of insulin from the pancreas?
19. what are inhibitors of insulin release?

hormonal regulation...
20. describe the "reciprocal regulation" of insulin and glucagon.
21. describe the concept of a "basin of attraction" in regards to glucose regulation.

diabetes...
22. what is IDDM? what is it caused by?
23. what do high glucose levels in urine cause?
24. what is type II diabetes? what is it caused by and what does it result in?

answers
1. alpha cells secrete glucagon, beta cells secrete insulin, delta cells secrete glucagon.
2. increases glucose and ketone production and secretion.
3. glycogenolysis, gluconeogenesis, lipolysis, ketogenesis.
4. amino acids, decreased bloods sugar, CCK, VIP, catecholamines.
5. insulin/glucose, somatostatin.
6. by inhibiting both alpha and beta cell secretion of glucagon and insulin secretion.

7. hypoglycemia.
8. sympathetic stimulation, cortisol, growth hormone.
9. anxiety, tremors, sweating are caused by sympathetic action and hunger is caused by hypothalamus.
10. low blood sugar levels after a meal that results from excess release of insulin triggered by high content of high glycemic index carbohydrates (or insufficient protein).

11. to store metabolic fuels.
12. by binding to receptors which translocate glucose transporter proteins into the cell membrane.
13. GLUT1- ubiquitous, placenta, GLUT2- beta cell, liver, kidney, intestine, GLUT3- ubiquitous, GLUT4- muscle,adipose, GLUT5-jejunum.
14. GLUT4.
15. causes uptake of amino acids and sugar (and therefore promotes glycogen storage).
16. glycogen synthesis, fatty acid synthesis.
17. uptake of glucose and converion into fatty acids and glycerols, triglyceride synthesis, and uptake of fatty acids from blood lipoproteins.
18. high glucose levels, amino acids, parasympathetic stimulation (cephalic phase of pancreatic secretion), growth hormone, cortisol, GI hormones such as gastrin, secretin, CCK, GIP.
19. somatostatin, catecholamines.

20. insulin and glucagon inhibit each other's release from islet cells via paracrine actions.
21. the basin of attraction is the set of homeostatic variables which the body settles into over time; long term changes in hormone levels or autonomic activity can shift this basin of attraction to a new equilibrium point.

22. autoimmune destruction of pancreatic beta cells which results in low levels of insulin, and thus a shift from glucose metabolism to ketone body metabolism.
23. polyuria (excess urine volume), polydipsia (excess thirst), polyphagia (excess hunger)
24. type II diabetes is an insulin resistance that is caused by excess fatty acids, cortisol, or testosterone, which blocks insulin's anti-lipolytic effect on adipose tissue. can not be compensated by excess insulin secretion.

organ systems: carbohydrate and protein digestion, pancreatic secretion

[image courtesy of erica newon zelfand]

this unit focused on pancreatic secretions and their role in carbohydrate and protein digestion in the intestine. each day, the pancreas secretes 1L of pancreatic enzymes, among which are enzymes that break down carbohydrates into monosaccharides, enzymes that break down proteins into peptides, lipases which break down triacylglycerols into fatty acids. these digestive enzymes are secreted by the "acinar" cells of the pancreatic ducts, while water and electrolytes such as bicarbonate are secreted by duct cells (a similar strategy to salivary and gastric secretion). the bicarbonate from duct cells comes from carbonic acid, which is formed in duct cells by carbonic anhydrase. bicarbonate is transported into the duct lumen in exchange for a chloride ion by the CFTR transporter. the acinar cells can be stimulated to produce more secretion either directly by vagal stimulation or by different neuropeptides such as CCK, GRP, SubP, VIP. duct cells are stimulated to increase water and bicarbonate production mainly by secretin (which functions to reduce acidity in the intestine and as such also inhibits gastric secretion and emptying).

as with gastric secretion, pancreatic secretions can be divided into three phases (refer to comparison chart), cephalic, gastric, and intestinal. in the cephalic phase, thoughts or sensation of food causes increase of pancreatic secretion via vagal stimulation. in the gastric phase, gastric distention triggers vagal stimulation of pancreatic secretion. the most important phase for pancreatic secretion is the intestinal phase, where intestinal distention, high acid levels, or other digestive products trigger hormonal release that modify pancreatic secretion. CCK is released from I cells in response to fat and proteins, which stimulates acinar cells to increase enzymatic secretion. secretin is released from S cells in response to acid and fat, which stimulates bicarbonate and water secretion from pancreatic duct cells.

carbohydrate digestion, already initiated with salivary alpha amylase, continues with the secretion of pancreatic alpha amylase into the intestinal lumen. polysaccharides are cleaved into smaller di and tri saccharides, and then further digested by the brush border enzymes (see the biochem chapter for a much more detailed description). different sugars are absorbed into the enterocyte and bloodstream by different transporters: for example, glucose and galactose are absorbed into the enterocyte by SGLT1, a sodium co-transporter, while fructose is facilitatively absorbed by GLUT 5. the pancreas also secretes enzymes that digest proteins, all of which are activated by enterokinase, which activates trypsinogen into trypsin, which activates the other zymogens procarboxypeptidase, chymotrypsinogen, proelastase (see the biochem protein digestion chapter).

an interesting note about the role of tight junctions: most absorption of nutrients occurs through the membrane of the enterocyte, or transcellularly. however, in the case of macromolecules that are too large to be absorbed transcellularly, paracellular transport can occur via modulation of the tight junctions between enterocytes, which can occur reversibly via the molecule zonulin. paracellular transport can also occur in "leaky gut", hyperpermeability of the tight junctions, caused by excess glucose levels, alcohol abuse, NSAID/steroidal use,food allergies, crohn's disease. there is a distinct but underexplored relationship between tight junctino permeability and autoimmune disease; people with dysregulation of tight junction permeability have a higher susceptibility for autoimmune diseases.

questions
1. enzymes digest carbohydrates, fats, proteins by what type of reaction?
2. what is SGLT1 and what does it do?

describe the absorption of these substances from the intestinal lumen into the enterocyte, and from there into the blood stream:
3. glucose
4. lactose
5. fructose
6. glycogen
7. sodium

tight junctions...
8. describe the absorptive pathway from the intestinal lumen to the mucosal capillary.
9. what is a function of tight junctions in intestinal epithelium that is not commonly discussed?
10. what is the relationship of tight junctions and the immune system?
11. what are tight junctions made of?
12. what is "leaky gut" and what are some factors that cause it?
13. what is zonulin and what does it do?
14. what is lactulose and how is related to leaky gut?

pancreas...
15. where is the pancreas?
16. how much liquid does the pancreas secrete per day?
17. what do the acinar and duct cells secrete?
18. what are the electrolytes that are secreted by duct cells?
19. describe the secretion of bicarbonate by duct cells.
20. what are the enzymes that are secreted by the pancreas that digest proteins?
21. how are the protein digestion enzymes activated?
22. what does pancreatic amylase do?
23. what are the pancreatic enzymes that digest lipids?
24. what are the different ways in which pancreatic acinar cells are stimulated?
25. what are the actions of secretin?

pancreatic phases...
26. what are the three phases of pancreatic secretion?
27. describe the cephalic phase of pancreatic secretion.
28. describe the gastric phase of pancreatic secretion.
29. describe the intestinal phase of pancreatic secretion.
30. describe the secretion and actions of CCK.
31. describe the secretion and actions of secretin.
32. how does enzymatic secretion adapt to different dietary compositions?

carbohydrate digestion...
33. what are the approximate proportions of the different types of carbohydrates ingested?
34. pancreatic and salivary amylase digests starch into...
35. how are di and trisaccharides digested into monosaccharides?
36. what are the two ways that glucose and galactose can be transported into the intestinal epithelium?
37. compare the absorption of glucose and fructose.
38. describe the negative feedback that can occur in carbohydrate digestion.
39. how can malfunctioning carbohydrate digestion cause diarrhea?
40. what is the hydrogen breath test?
41. what effect does celiac disease has on the intestinal lining?

protein digestion and absorption...
42. how are proteins digested in the stomach?
43. how are proteins digested in the intestine?
44. how are polypeptides digested and absorbed in the intestine?

pancreatic tests...
45. what is the stool chymotrypsin test?
46. what is the pancreatic elastase test and why might it be more reliable than the stool chymotrypsin test?


answers
1. hydrolysis reactions.
2. it is a sodium / glucose co-transporter, facilitating absorption of glucose, galactose

3. glucose is transported into the enterocyte via SGLT1, then into the blood via GLUT2.
4. lactose is broken down into glucose and galactose via the brush border enzyme lactase, and glucose and galactose are absorbed and transported in the same way as question 3.
5. fructose is transported into enterocytes via GLUT5, and absorbed into blood via GLUT2.
6. glycogen is broken down into oligsaccharides and alpha limit dextrins by alpha amylase, and then broken down further into monosaccharides by brush border enzymes and absorbed the same way as in question 3.
7. sodium is transported along with glucose or galactose via the SGLT1 co-transporter.

8. intestinal lumen -> unstirred layer of fluid -> glycocalxces on microvilli of enterocytes -> cell membranes and cytoplasm -> basement membrane -> capillary
9. tight junctions can facilitate absorption of macromolecules, nutrients that are too big to be absorbed directly into enterocytes.
10. when tight junction regulation of macromolecule absorption is dysregulated, this can sometimes lead to intestinal and extraintestinal autoimmune disorders.
11. occludins, claudin family of proteins, junctional adhesion molecules.
12. hyperpermeability of the intestinal epithelium. caused by alcohol abuse, high sugar intake, food allergies, NSAIDS/steroid drugs, celiac disease and crohn's disease.
13. a molecules that facilitates the permeability of tight junctions and as such is involved in the absorption of fluid and macromolecules across the intestinal barrier, and also protect the intestine from being colonized by microorganisms.
14. a macromolecule that can only be absorbed paracellularly; its presence in the blood as compared to mannose (which is absorbed transcellularly) is a good indicator of leaky gut.

15. the body of the pancreas lies deep to the stomach and the tail extends to the spleen.
16. 1L per day
17. acinar cells secrete enzymes, duct cells secrete water and electrolytes.
18. bicarbonate and sodium.
19. bicarbonate is formed from carbonic acid which is formed by carbonic anhydrase and CO2. H+ is absorbed into blood, and bicarbonate is transported into the lumen by the transmembrane regulator CFTR (cystic fibrosis transmembrane regulator) which exchanges a chloride ion for a bicarbonate ion.
20. trypsinogen, proelastase, chymotrypsinogen, procarboxypeptidase.
21. trypsinogen is activated by the brush border protease enterokinase, forming trypsin, which activates the other enzymes.
22. an endoglucosidase that hydrolyzes carbohydrates into di and tri-saccharides.
23. pancreatic lipase, cholesterol esterase, phospholipase.
24. directly via the vagus nerve, or indirectly via stimulation of the vagus nerve by CCK, VIP, GRP, SubP.
25. stimulates duct cells to release bicarbonate, inhibits gastric secretion and emptying- overall effect is to raise pH.

26. cephalic, gastric, intestinal
27. stimulated by thoughts or sensation of food, vagus nerve stimulates pancreas secretion.
28. gastric distention causes vagal stimulation, which causes pancreas secretion.
29. the most important phase for pancreatic secretion; digestive products or low pH trigger release of hormones that control secretion.
30. CCK is secreted from I cells in the intestinal epithelium in response to proteins or fats. chief among its many effects is to stimulate pancreatic acinar secretion of enzymes.
31. secretin is released from S cells in the intestine in response to acid or fat-- its main effect is to increase water and bicarbonate secretion by pancreatic duct cells, thereby raising the pH of the intestinal lumen. it also decreases gastric motility and emptying.
32. CCK can up or downregulate the protein digesting proteases and the carbohydrate digesting amylases depending on the ratio of protein to carbohydrates in the diet.

33. 50% starch, 20% sucrose, 6% lactose, 1-2% maltose.
34. di and trisaccharides.
35. by the brush border enzymes.
36. transcellularly via the SGLT1 Na+ cotransporter or paracellularly with water with high glucose concentrations (see section on tight junctions)
37. fructose absorption is slower and uses a facilitated transporter rather than a co-transporter. (see question 5)
38. chemo and osmotic receptors sense high glucose levels in the duodenum and jejunum and trigger the vasovagal reflex, which decreases gastric motility and emptying.
39. in the case of lactose intolerance, lactose remains undigested and cause a hyperosmolar intestinal lumen from excess sugar as well as products from bacterial processing of these sugars; causing water to accumulate in the lumen and cause diarrhea.
40. a test which measures amount of hydrogen in breath, which is produced from bacteria that metabolize lactose in the intestine in lactose intolerant people.
41. destroys villi.

42. gastric pepsinogen is secreted and converted to pepsin by the low pH environment of the stomach. it cleaves proteins into smaller polypeptides.
43. in the intestine, proteins are digested by different pancreatic enzymes: trypsin, chymotrypsin, carboxypeptidase, elastase. trypsin activates the other three enzymes, which cleave large polypeptides into small polypeptides.
44. small polypeptides are cleaved further into smaller polypeptides and amino acids, which are then transported into the enterocyte and then absorbed into the blood by carrier proteins.

45. a marker for pancreatic output; normal is >9U/g stool, low is <>200 mcg/g stool, low is <100>
46. another test for pancreatic output, which might be more accurate because elastase is only produced by human pancreatic cells. normal is >200 mcg/g stool, low is <100>

biochem: mark's medical biochem chapter 37- protein digestion

this chapter looked at the digestion, absorption, and transport of proteins. digestion of proteins begins in the stomach, when the zymogen pepsinogen (recall that this is secreted by the parietal cells in the gastric pits) is autocatalytically cleaved to pepsin. pepsin works as an endopeptidase, randomly cleaving peptide bonds within the protein.

in the intestine, protein digestion continues with enzymes secreted from the pancreas, in zymogenic (inactive) form: trypsinogen, chymotrypsinogen, proelastase, procarboxypeptidase. trypsinogen is cleaved first by enteropeptidase into trypsin. trypsin both works to digest proteins directly by cleaving peptide bonds adjacent to carboxyl groups contained by arginine or lysine, and more importantly, it activates the other digestive enzymes.

it converts chymotrypsinogen to chymotrypsin, which then cleaves peptide bonds adjacent to carboxyl groups from acidic or hydrophobic amino acids. it converts proelastase to elastase, which then cleaves peptide bonds in elastin as well as those next to carboxyl groups contained by small chain amino acids such as alanine, glycine, and serine. finally, it activates carboxypeptidase from procarboxypeptidase, which acts an exopeptidase; cleaving amino acids one at a time from the outside edges of the protein fragments created by digestion via the other pancreatic enzymes.

in addition to pancreatic enzymes, the intestinal epithelial cells also contain protein digesting enzymes; these include aminopeptidases, which also act as exopeptidases, and intracellular peptidases, which break down protein fragments that have been absorbed by the enterocytes.

the amino acids produced from degradation of proteins are transported into enterocytes via Na+ cotransporters, similar to the glucose / Na+ cotransporters seen in carbohydrate digestion. these transporters are powered by the low Na+ concentration in the cells which is manufactured by the Na+/K+ pumps. thus amino acids are absorbed via secondary active transport- and then they diffuse out of the serosal side via facilitated transport proteins.

the "intracellular amino acid pool" is a measure of how much amino acid there is at any given moment within a cell. this is a dynamic balance between proteins acquired from the diet vs. the degradation of proteins. the "half life" of a protein refers to the point at which 50% of the protein has been degraded; proteins in muscle cells, digestive enzymes, or hemoglobin, are all examples of proteins which have a short half life and therefore a high "turnover" rate.

a few notes about intracellular protein digestion: cells can digest proteins by the process of "autophagy", in which proteins in extracellular vesicles fuse with lysosomes, which contain proteases which degrade the proteins into amino acids, which then are absorbed into the cytoplasm. another method of protein digestion is through the ubiquitin / proteasome pathway, in which ubiquitin is attached to proteins, "tagging" them for digestion via proteasomes, which are large barrel shaped proteins with multiple internal proteolytic sites.

questions
1. what form are the protein digesting enzymes secreted in?
2. where are parietal and chief cells located and what do they secrete?
3. how is pepsinogen activated?
4. describe the action of pepsin on proteins.
5. what are the zymogens that are secreted by the pancreas into the intestine?
6. describe trypsinogen's role in protein digestion in the intestine.

7. how is trypsinogen activated?
8. how does trypsin directly digest proteins?
9. describe the digestive action of chymotrypsin on proteins.
10. describe the digestive action of elastase on proteins.
11. describe the action of carboxypeptidase on proteins.
12. what is the difference between carboxypeptidase A and B?
13. where are aminopeptidases located and what do they do?
14. what are intracellular peptidases?

15. describe the transport of amino acids from the intestinal lumen into enterocytes.
16. describe the transport of amino acids from the enterocyte to the portal vein.
17. describe the diversity of amino acid transport proteins on the apical side of enterocytes.
18. how do amino acids get transported into cells of peripheral tissues?
19. in what way does transport and absorption of amino acids into peripheral tissues differ from that of carbohydrates?

20. what is the half life of a protein?
21. what are some examples of proteins that undergo extensive synthesis and degradation in the body?
22. how much of the cells lining the intestinal wall are replaced each day?
23. what percentage of proteins that are absorbed from the intestines are excreted?

24. what is autophagy?
25. which enzymes in lysosomes aid in protein digestion?
26. what is the ubiquitin-proteasoms pathway?
27. how does ubiquitin "tag" proteins?
28. what is a proteasome?

answers
1. zymogenic: an inactive, larger form of the enzyme that is activated by proteolytic cleavage once in the digestive tract.
2. in the gastric pits / epithelium of the stomach. parietal cells secrete HCl and chief cells secrete pepsinogen.
3. the acidity in the stomach allows pepsinogen to be cleaved to its active form, pepsin.
4. pepsin acts as an endopeptidase, cleaving peptide bonds at random intervals within the denatured protein.
5. trypsinogen, pepsinogen, proelastase, procarboxypeptidase.
6. trypsin (the activated form of trypsinogen) catalyzes the activation of the other pancreatic enzymes to their active forms, as well as directly aiding in the digestion of proteins.

7. through enteropeptidase.
8. trypsin cleaves peptide bonds adjacent to carboxyl groups that are provided by lysine or arginine.
9. chymotrypsin cleaves peptide bonds next to residues that contain hydrophobic or acidic amino acids.
10. elastase cleaves peptide bonds within elastase as well as bonds next to residues with small side chains (alanine, glycine, serine)
11. carboxypeptidase acts an exopeptidase, removing amino acids one at a time from the carboxyl end, from the smaller peptides resulting from breakdown of the other pancreatic enzymes mentioned above.
12. A preferentially cleaves hydrophobic amino acids while B preferentially cleaves basic amino acids.
13. they are located on the epithelial wall of the intestine and act as exopeptidases, removing one amino acid at a time.
14. the enzymes within cells that break down peptides which are absorbed.

15. a Na+/K+ pump in the enterocyte creates a low concentration of Na+ in the enterocyte. The resulting influx of Na+ is coupled with amino acid transport, this is called secondary active transport.
16. the amino acids in the enterocytes are transported into the portal vein via "facilitated transporters"
17. there are at least 6 such transport proteins which have overlapping specificities for different types of amino acids.
18. mainly through Na+ cotransporters.
19. amino acids are transported into cells mainly by Na+ cotransporters wheras in peripheral tissues carbohydrates are transported by facilitated transporters (recall the GLUT transporters). in the intestine and renal cells the absorption of both amino acids and carbohydrates are Na+ coupled.

20. the point at which 50% of the protein in a cell has been degraded.
21. hemoglobin, muscle proteins, digestive enzymes.
22. roughly 1/4th.
23. roughly 6%.

24. the process by which cells digest proteins using lysosomal enzymes.
25. the cathepin family of proteases.
26. a method of intracellular protein digestion using ubiquitin tagging and degradation via proteosomes.
27. by covalently binding to the epsilon-amino group of lysine residues.
28. a cylindrical 20S protein complex with multiple internal proteolytic sites.