tbl 3 physiology: small intestine and pancreas

Question 1

_________ are transverse folds of mucosa with sub-mucosal connective tissue that extend half to two thirds around the circumference of the lumen and slows movement of chyme for optimal digestion and increases surface area for optimal absorption

Answer 1

Circular folds of Kerckring

Question 2

The small intestine is a hollow cylinder about 6 meters or 18 feet long. Its lumen is lined by columnar epithelium. Circular and longitudinal muscles form the muscular layers sandwiching the plexi. Neural and endocrine elements are also present. The surface area of the small intestine is amplified at three levels:
1) Macroscopic circular folds of Kerckring,
2) Villi and _____________,
3) ___________.
The area of the apical plasma membrane in the small intestine equals 200 m2.

Answer 2

Crypts of Lieberkuhn; Microvilli

Question 3

Villi and Crypts of Lieberkuhn: These are finger-like projections surrounded by the openings of glandular structures called Crypts of Lieberkuhn. The cells of the villi are primarily responsible for __________, whereas crypt cells primarily participate in _______.

Answer 3

nutrient and electrolyte absorption; secretion

Question 4

Progenitor cells are located near the base of the crypt. They differentiate into ________ and _______, and some migrate along the crypt-villi axis and eventually differentiate into the __________________ after undergoing substantial changes in its morphology and function. They then slough off into the intestinal lumen. The overall period from the initiation of cell proliferation to sloughing is approximately 48-96 hours.

Answer 4

goblet cells and Paneth cells; enterocyte absorptive cell

Question 5

Goblet cells are glandular simple columnar epithelial cells that secrete _______, which dissolves in water to form mucus.

Paneth cells are identified microscopically by their location just below the _____________ in the crypts and by the large _______________ granules that occupy most of their cytoplasm. When exposed to bacteria, they release antibacterial compounds, primarily the peptides ________ (a.k.a. cryptdins).

Answer 5

mucin; progenitor cells; eosinophilic refractile; defensins

Question 6

Enteric endocrine cells
• _____ (duodenum & jejunum) secrete cholecystokinin
• ____ (duodenum & jejunum) secrete gastric inhibitory peptide
• S cells (duodenum & jejunum) secrete secretin in response to duodenal H+.
• M cells secrete _________
• _______ secrete peptide YY (PYY)

Answer 6

I cells; K cells; motilin; L cells

Question 7

Extrinsic Innervation
1. Parasympathetic: The _______________ provides parasympathetic control of the esophagus, stomach, small intestine and the ascending colon, while the Pelvic nerve innervates the remainder of the colon and rectum. Pre-ganglionic fibers synapse with the intrinsic nervous system in the __________________ and ________________. The fibers are cholinergic (secrete acetylcholine) and peptidergic (secrete VIP [vasoactive intestinal polypeptide), motilin, enkephalins, substance P).

2. Sympathetic: Pre-ganglionic fibers project into the celiac ganglia (CG), the superior mesenteric ganglia (SMG) and the inferior mesenteric ganglia (IMG), Fibers from CG innervate the esophagus, stomach, entire small intestine and the ascending colon; fibers from the SMG provide sympathetic control of the ______________; fibers from the IMG control the ___________________.

Answer 7

Vagus nerve (Cranial nerve X); submucosal plexus (Meissner’s plexus); Myenteric plexus (Auerbach’s plexus)

transverse colon; descending colon and rectum

Question 8

Intrinsic innervation (enteric nervous system) can direct all functions of the gastrointestinal tract, even in the absence of extrinsic innervation. Ganglia in the submucosal plexus and myenteric plexus control the contractile, secretory and endocrine functions of the GI tract. These ganglia receive inputs from the _________, which modulate their activity. These ganglia also receive sensory information directly from mechanoreceptors and chemoreceptors in the _________ and send information directly to smooth muscle, endocrine and secretory cells.

Information is relayed between ganglia in the two plexi by ____________ . A large number of neurocrines have been identified in the enteric nervous system.

Answer 8

extrinsic nervous system; mucosa;

inter-neurons;

Question 9

Acetylcholine from cholinergic neurons cause __________ of smooth muscle in the intestinal wall, _________ of sphincters, ______ pancreatic secretion

Answer 9

contraction; relaxation; enhance

Question 10

Norepinephrine from adrenergic neurons cause _________ of smooth muscle in the intestinal wall and _________ of sphincters.

Answer 10

relaxation; contraction

Question 11

Vasoactive intestinal peptide from neurons of mucosa and smooth muscle cause _____ of smooth muscle in the intestinal wall and ________ intestinal and pancreatic secretion.

Answer 11

relaxation; enhance

Question 12

Enkephalins (opiates) from neurons of mucosa and smooth muscle cause ________ of smooth muscle in the intestinal wall and ______ intestinal secretion.

Answer 12

contraction; suppress

Question 13

Neuropeptide Y from neurons of mucosa and smooth muscle cause ________ of smooth muscle in the intestinal wall and _____ intestinal secretion.

Answer 13

relaxation; suppress

Question 14

Substance P co-secreted with ACh from cholinergic neurons causes _______ of smooth muscle

Answer 14

contraction

Question 15

Segmentation Contractions are ring-like contractions of circular smooth muscle that appear at regular intervals. The intestine becomes compartmentalized into several short segments. The contractions disappear after a few seconds, only to reappear as another set of contractions. The purpose of segmental contractions is to move the chyme back and forth and increase its exposure to the mucosal surface.

Step 1: A bolus of chyme in the intestinal lumen causes ______________
Step 2: This section of the small intestine contracts, splitting the chyme and sending it in both ________ directions.
Step 3: This section of the intestine ________, allowing the chyme that was split to merge together again.

Answer 15

localized distention; orad and caudad; relaxes

Question 16

Peristaltic Contractions
• Designed to propel chyme.
• Contraction occurs behind bolus of food and smooth muscle relaxes in front of bolus.
• Neurotransmitters for contraction: ACh (Vagus).
• Neurotransmitters for relaxation: ___________________

Peristaltic contractions propel chyme along the small intestine towards the large intestine.
Step 1: A bolus of chyme causes distention of the intestinal wall.
Step 2: Muscle ___________ occurs at a point orad (proximal or behind) to the bolus. Simultaneously, the portion of intestine that is caudad (distal, in front of) to the bolus __________.
Step 3: Chyme is propelled in the caudad direction. A wave of peristaltic contractions moves the chyme down the small intestine.

Answer 16

VIP and nitric oxide (Vagus).

contraction; relaxes

Question 17

Motor functions in between meals

Migrating motor complexes
• During inter-digestive periods (between meals), residual food in the small intestine is cleared by Migrating Motor Complexes.
• Migrating motor complexes are periodic waves of contractions during fasting or between meals. MMCs immediately stop with ingestion of food.
• Basal electrical rhythm, the electrical activity underlying MMCs, originates in pacemaker cells (Interstitial cells of Cajal), which lie near the _____________. When there are no MMCs, the basal electrical rhythm consists of rhythmic oscillation of the resting membrane potential.

MMCs occur in a cyclical pattern, each cycle lasting 90 min. It occurs in three phases. During ____________ of MMCs, secretion of bile and pancreatic juices is increased to help clear the small intestine of luminal contents in preparation for the next meal. _____________________ terminate the MMC in the upper small intestine. Vagal inputs also regulate the MMC.

Answer 17

Myenteric (Auerbach) plexus; phase II and phase III; Gastrin and cholecystokinin

Question 18

Exocrine Pancreas - General organization

Exocrine pancreas (90% of pancreas)
• Resembles bunch of grapes (similar to salivary gland).
• A single acinus is connected to an ___________ and these lead into interlobular ducts, and from there into the ________________.
• ___________ secrete pancreatic enzymes for digestion of proteins, lipids and carbohydrates
• ___________ release aqueous secretion high in bicarbonate (HCO3-) to neutralize acidic chyme.
• Intralobular Ductal cells release aqueous secretion high in bicarbonate (HCO3-) to neutralize acidic chyme.

The main pancreatic duct of Wirsung joins with the common bile duct and opens into the duodenum at the ____________. The accessory pancreatic duct of Santorini, when present, opens into the duodenum proximal to the duct of Wirsung.

Answer 18

intercalated duct; main pancreatic duct of Wirsung

Pancreatic acinar cells; Centroacinar cells;

Ampulla of Vater

Question 19

Pancreatic juice is the major source of digestive enzymes that digest all components of the food proteins, carbohydrates, fats and nucleic acids. The volume of pancreatic juice secreted per day is estimated to be 1-1.5 L. It is highly alkaline pH (8.4) due to its high HCO3- concentration, which is 2-5 times higher than that of plasma. It neutralizes gastric HCl in the chyme that enters the duodenum.

1. _________ secrete the initial pancreatic secretion, which contains the inactive digestive enzymes (zymogens) and water and NaCl.
2. _________ modify the initial pancreatic secretion, primarily by transporting bicarbonate into the lumen.
3. Comparison with salivary gland - two critical differences: (1) The salivary duct is impermeable to water and hence water is not absorbed and remains
   in the lumen while solutes (e.g. sodium) are absorbed. In contrast, the pancreatic duct is freely permeable to water. (2) Final saliva is hypotonic because solutes are absorbed without water. Final pancreatic secretion is _______.

Answer 19

Acinar cells; Ductal cells; isotonic

Question 20

Steps in pancreatic secretion

1. Initial pancreatic secretion containing enzymatic component: Acinar cells secrete pancreatic amylase and pancreatic lipase as active enzymes, whereas ____________ are secreted in inactive forms (zymogens) and converted into active enzymes in the ___________. The enzymes are stored in granules until a stimulus (parasympathetic activity or CCK) triggers their secretion.
2. Ductal cells modify the initial pancreatic secretion. ___________ produce the initial aqueous secretion, which is isotonic and contains Na+, K+, Cl- and HCO3-. In the presence of __________, CO2 and H2O combine to form H2CO3 (carbonic acid). H2CO3 dissociates into H+ and HCO3-. The HCO3 - is secreted into the pancreatic juice by the anion exchanger (_____________ exchanger) on the apical surface of the ductal cell. The H+ is transported into the blood by the Na+-H+ exchanger on the basolateral membrane. The Na+ that comes into the ductal cell in exchange for H+ is pumped out by Na+-K+-ATPase. The result is net secretion of HCO3 - and net absorption of H+.

Answer 20

pancreatic proteases; duodenum;

Centroacinar cells; carbonic anhydrase;

Cl-/HCO3-

Question 21

Secretin induces bicarbonate–rich pancreatic secretion

• Secretin, a hormone, induces pancreatic secretion.
• As the flow rate increases, bicarbonate ________ while chloride _______. This is due to bicarbonate chloride exchange via the anion exchanger at the luminal surface of the ductal cell.
• Sodium and potassium do not change

Flow rates effect of composition of pancreatic juice. As the flow rate increases, the Na+ and K+ concentration in pancreatic juice remain constant. However, HCO3- concentration in pancreatic juice increases with increasing flow rate while Cl concentration correspondingly drops.

Answer 21

increases; decreases;

Question 22

[Control of pancreatic secretion]

Cholecystokinin triggers enzyme secretion
•Secreted by ______ in response to small peptides, amino acids, and fatty acids in duodenal lumen. CCK stimulates a pancreatic secretion rich in enzymes.
• Acts on pancreatic ___________ to increase enzymatic secretion. Involves calcium-signaling.
•Potentiates effect of ______ on ductal cells to stimulate HCO3- secretion.

Answer 22

I cells; acinar cells; secretin

Question 23

[control of pancreatic secretion]
Secretin triggers bicarbonate secretion
• Secreted by S cells in response to H+ in _________.
• Acts on pancreatic ductal cells to increase HCO3- secretion. ________ pathway involved. Acetylcholine and cholecystokinin potentiate this effect.

Answer 23

duodenal lumen; Cyclic AMP

Question 24

Acetylcholine from vagal nerve fibers binds to __________ receptors on acinar cells and potentiates the CCK effect via a vago-vagal reflex.

• Released in response to H+, __________, amino acids, and fatty acids in duodenum.
• Stimulates enzyme secretion by acinar cells and potentiates effect of ________ on HCO3- secretion.

Answer 24

M3 muscarinic; small peptides; secretin

Question 25

The three phases of Pancreatic Secretion

Like gastric secretion, pancreatic secretion is divided into cephalic, gastric and intestinal phases, the last being the most important. During the cephalic and gastric phases, the pancreas produces a small secretion rich in enzymes. During the intestinal phase, both _____ and __________secretions are stimulated

Deficiency of pancreatic enzymes: When secretion of pancreatic enzymes falls below 10% of normal, impairment of fat and protein digestion occurs, which leads to_________ (presence of excess fat in feces; bulky & difficulty-to-flush stool; pale; oily; foul-smelling), deficiency of fatsoluble vitamins and weight loss. Treatment is with pancreatic enzyme supplements, . Pancreatic insufficiency leading to deficiency of pancreatic enzymes can be due to cystic fibrosis, chronic pancreatitis, ____________.

Answer 25

enzymatic and aqueous;

steatorrhea; post-pancreatic resection

Question 26

[Carbohydrate digestion]

1. MOUTH: ____________ begins the digestion, and its activity continues in the stomach until acid penetrates the bolus. It is NOT an essential enzyme for carbohydrate digestion.
2. PANCREAS: Pancreatic α-amylase is a required enzyme for carbohydrate digestion. Pancreatic amylase is secreted as an active enzyme. It digests the interior _____________ in starch, yielding three disaccharides, __________________________.
   • Elevated serum pancreatic amylase is a diagnostic marker for acute pancreatitis. Acute pancreatitis occurs as a consequence of premature activation of zymogen granules, releasing proteases which digest the pancreas and surrounding tissue.
3. SMALL INTESTINE: The splitting of tri-saccharides, disaccharides, oligosaccharides occurs on the brush border (apical membrane of enterocytes).
   • α-dextrinase cleaves α1,4 bonds, producing glucose.
   • Lactase hydrolyzes lactose into ______ and ______.

Deficiency of lactase causes lactose intolerance (discussed below).
• Sucrase splits sucrose into ____________________.
• Maltase splits maltose and maltotriose to form 2 and 3 glucose units, respectively.
• Trehalase splits trehalose into glucose.

Answer 26

Salivary α-amylase; 1,4-glycosidic bonds; α-limit dextrin, maltose, and maltotriose

glucose& galactose; glucose and fructose

Question 27

[Absorption of Carbohydrates]

Monosaccharide end products (glucose, galactose and fructose) are readily absorbed from the small intestine, mainly in the jejunum. Disaccharides in the diet (sucrose, lactose and trehalose) are NOT absorbed.

Effect of sodium on glucose and galactose absorption across the apical membrane

• Sodium is co-transported with glucose or galactose across the apical membrane of enterocytes by the transporter ________ against an electrochemical gradient. A high concentration of sodium in the lumen increases glucose and galactose absorption, while a low concentration inhibits absorption of these two monosaccharides. The Na+ gradient is set up on the basolateral side by Na/K ATPase.
• Fructose is transported across both the apical and basolateral membranes by ____________. In the apical membrane, the fructose-specific transporter is called ________, and in the basolateral membrane, fructose is transported by GLUT 2. Fructose absorption is not affected by sodium, since it is absorbed by facilitated diffusion separately by Glut5. Fructose cannot be absorbed against an electrochemical gradient (in contrast to glucose and galactose).
• Oral rehydration: In diarrheas, oral rehydration involves the use of a glucose and sodium containing solution counters because glucose and sodium are reabsorbed together via SGLT1 . GLUT-2 located on the basolateral (serous) side of enterocytes is responsible for the absorption of all three monosaccharides.

Answer 27

SGLT1; facilitated diffusion; GLUT5

Question 28

Lactase deficiency results in inability to digest lactose
• Lactose, a disaccharide, is nonabsorbable.
• Human milk contains around 200 mmol/L of lactose, which is normally digested to _______________ by lactase prior to absorption. If lactase is missing from the brush border, lactose remains undigested in the lumen of the intestine. Lactose causes the retention of water in the intestinal lumen and causes osmotic diarrhea.

Unhydrolysed lactose enters the colon, where bacterial fermentation produces volatile ____________, hydrogen and carbon dioxide. The higher hydrogen secretion is the basis for the hydrogen breath test.
• The enzyme is deficient in up to 90% of adult Africans, Asians and South Americans, but only 5% of northern Europeans.

• Primary Lactase deficiency: jejunal morphology normal.
• Secondary Lactase deficiency occurs as a consequence of disorders which damage the jejunal mucosa, e.g. coeliac disease and viral gastroenteritis.

Answer 28

glucose and galactose;

short-chain fatty acids;

Question 29

[Protein Digestion]

1. STOMACH: _____ begins the digestion of protein in the acid medium of the stomach; however, it is NOT an essential enzyme.
2. PANCREAS: Digestion continues with the pancreatic proteases (trypsin, chymotrypsin, elastase and carboxypeptidase A and B), which are essential enzymes. All these pancreatic enzymes are secreted as inactive proenzymes (zymogens) and are activated ONLY in the intestinal lumen. _____ is almost totally responsible for their secretion following a meal.
   • Step 1: __________ is the master switch. It converts trypsinogen to its active form, trypsin. Trypsin autocatalyses the remaining trypsinogen to form more trypsin.
   • Step 2: Trypsin activates the other zymogens to their active forms (chymotrypsin, elastase, carboxypeptidase A & B).
   • Step 3: Pancreatic proteases hydrolyze dietary protein to amino acids, dipeptides, tripeptides, and larger peptides called oligopeptides.
   • Pancreatic secretory trypsin inhibitor (PSTI) (also known as _______________ cleaves and inactivates any trypsin that gets activated in the pancreas. A mutation of the trypsin inhibitor affects the inactivating cleavage of trypsin activated in the pancreas. This leads to a disease called pancreatitis.
3. SMALL INTESTINE:
   • Step 4: Dipeptidases and amino-peptidases, enzymes produced by ___________, cleave peptides into amino acids. The main end products are amino acids (40%) and peptides (dipeptides, tripeptides) (60%).

Answer 29

Pepsin; CCK;
Intestinal enterokinase;
serine protease inhibitor Kazal type I or SPINK1);
brush border cells

Question 30

[Protein absorption]
Most absorption takes place in the ______.

Apical (Luminal) Membrane
•L-Amino acids are transported by secondary active transport via a sodium-amino acid cotransporter. Pumping out of sodium by Na-K-ATPase on the basolateral membrane creates the driving force. Four transporters are present in the small intestine, one each for neutral, basic, acidic and ______ amino acids.
• Hartnup disease is a genetic disorder caused by a defect in the transporter for ____________ (e.g. L-phenylalanine).
• Cystinuria is a genetic disorder in which the transporter for the dibasic amino acids cystine, lysine, arginine, and ______ is absent in both the small intestine and the kidney.
•Small di- and tri-peptides are absorbed together with H+. A ___________ in the luminal membrane powers this process. Once inside the cell, most of the di- and tripeptides are hydrolysed to amino acids by cytosolic peptidases.

Basolateral Membrane
•___________ of amino acids into the blood stream. Separate mechanisms for absorption of neutral, basic, acidic and imino amino acids.
•Remaining di- and tri-peptides are absorbed unchanged.

Answer 30

jejunum; imino; aromatic amino acids; ornithine; Na-H antiporter;

Facilitated diffusion

Question 31

[Fat digestion]

1. STOMACH: Fatty materials are _______ to decrease particle size and increase surface area.
2. GALL BLADDER: Bile micelles emulsify the fat making it easier for them to be digested.
3. PANCREAS: pancreatic lipases digest fat. Micelles and pancreatic lipases are required for triglyceride digestion. The major end products are __________ and fatty acids. CCK is almost totally responsible for their secretion following a meal.

Answer 31

pulverized; 2-monoglycerides

Question 32

[Fat digestion]

Step 1. Luminal phase: Fatty acids cause CCK release from the duodenum and upper jejunum. CCK stimulates release of pancreatic enzymes. CCK also stimulates gallbladder contraction and promotes _________ relaxation, resulting in bile flow into the small bowel. The bile salts promote the formation of micelles that disperse fats at the molecular level, and make them accessible to __________ for rapid hydrolysis. Micelles contain detergents (bile salts, phospholipid) on the outside and absorbable fats (fatty acids, monoglycerides, lysolecithin/lysophosphatidylcholine, cholesterol, fat soluble-vitamins) at the core.

Step 2. Digestion by pancreatic lipase: Most fat digestion begins in the duodenum. Pancreatic lipase is secreted as an active enzyme. In contrast, procolipase is inactive and is converted to active colipase by _______. Pancreatic lipase in the presence of colipase cleaves long chain triglycerides, yielding fatty acids and monoglycerides. These are solubilized by interacting with bile salts and phospholipids to form micelles. Once hydrolyzed, the products are dispersed for ease of absorption.

Step-3. Absorption. Micelles diffuse to the brush border of the enterocytes. Lipids are released and enter the cell.

Step-4. Enterohepatic Circulation: Bile salts remain in the small intestinal lumen and are actively transported from the __________ into the portal circulation and returned to the liver.

Step 5: Re-esterification: Within the enterocyte, fatty acids are re-esterified to form triglycerides. Triglycerides combine with _____________, fat-soluble vitamins, phospholipids and apoproteins to form chylomicrons.

Step 6: Transport: Chylomicrons leave the enterocytes by exocytosis, enter __________ lymphatics, pass into the thoracic duct, and eventually reach the systemic circulation. Chylomicrons have a shell made of phospholipids, free cholesterol and various apoproteins
(ApoA, ApoB, ApoC, ApoE). Please review the biochemistry of lipoproteins.

Answer 32

sphincter of Oddi; pancreatic lipases; trypsin

terminal ileum;

cholesterol ester;

mesenteric

Question 33

Bile salts inhibit pancreatic lipase. ______ displaces bile salts and allows pancreatic lipase to digest triglycerides.

Elevated serum pancreatic lipase is a diagnostic marker for __________.

Congenital pancreatic lipase deficiency is a rare, form of exocrine pancreatic failure. All reported patients presented with oily/greasy stools from infancy or early childhood and the absence of discernible pancreatic disease.

Colipase is a co-enzyme required for optimal activity of pancreatic lipase. It is secreted by the pancreas in an inactive form, procolipase, which is activated in the intestinal lumen by trypsin. Its function is to prevent the inhibitory effect of bile salts on the lipase-catalyzed intra-duodenal hydrolysis of _____________.

Answer 33

Colipase ; acute pancreatitis ; dietary long-chain triglycerides

Question 34

[Absorption of lipids]
Step 1: Formation of mixed micelles. Bile salts are on the exterior of the micelle because they are amphipathic and can interact with the aqueous environment. Cholesterol (Chol), _______, ________, free fatty acids (FFA) are in the core of the micelle.

Step 2: Micelles diffuse to ___________ membrane of epithelial cells. At the apical membrane, lipids are released from the micelle and diffuse into the cell. The bile salts are left in the intestinal lumen to be reabsorbed in the ileum.

Step 3: The free fatty acids, cholesterols, and phospholipids re-esterify inside the cell.

Step 4: Re-esterified lipids are packaged into chylomicrons.

Step 5: Chylomicrons are packed in secretory vesicles on Golgi apparatus. Exocytosis of chylomicrons into lymphatic capillaries –> _______________ –> bloodstream.

Answer 34

monoglycerides (MG); lysolecithin (LysoPL);

apical (brush-border);

thoracic duct

Question 35

Absorption of fat-soluble vitamins (A, D, E, K)

• Most absorption in upper small intestine, particularly _________.
• Carried in micelles.
• Absorption as with other fats.

Vitamin A deficiency (more in clinical section)
• Night blindness: difficult or impossible to see in relatively low light.
• _________: eye fails to make tears. If untreated can result in corneal ulceration and blindness.
• __________: cornea becomes opaque.

Vitamin D deficiency
• Rickets, a childhood disease characterized by impeded growth and deformity of the long bones, softening or thinning of the skull (craniotabes) , bowed legs, and rachitic rosary (prominent knobs of bone at the costochondral joints).
• __________, a bone-thinning disorder that occurs exclusively in adults and is characterized
by proximal muscle weakness and bone fragility.
• Osteoporosis, a condition characterized by reduced bone mineral density and increased bone fragility.
• ___________ is a risk factor for depression.

Vitamin K
- hemorrhagic disease,, prolonged coagulation, bleeding.

Answer 35

jejunum; Xerophthalmia; Keratomalacia

Osteomalacia; Hypovitaminosis D

Question 36

Absorption of water-soluble vitamins (B, C, Folate)

1. __________ in upper small intestine for vitamin B1, B2, B3, B5, B6, biotin, C.
2. ____________ in proximal small intestine.

Deficiency of

• B1 (Thiamine) –> ___________
• B2 (Riboflavin) Glossitis, angular stomatitis, __________ (3Ds: Dermatitis, Diarrhea, Dementia)
• B6 (Pyridoxine)–> Peripheral neuropathy especially in patients taking __________ (isoniazid)
• Folate –> __________ anemia, neural tube defects, C Scurvy

Answer 36

Na+-dependent co-transport; Folate-Hydroxyl co-transporter

Beri-Beri; Niacin Pellagra; anti-TB drugs; Megaloblastic

Question 37

Beriberi (Thiamine deficiency) (more in clinical section)
• Dry beriberi specially affects the peripheral nervous system. _________, a primarily neurological thiamine-deficiency related condition.
• Wet beriberi specially affects the _________ and other bodily systems.
• Infantile beriberi affects the babies of malnourished mothers.
• Gastrointestinal beriberi affects the digestive system and other bodily systems.

Answer 37

Wernicke’s encephalopathy; cardiovascular system

Question 38

_________ deficiency results in painful red tongue with sore throat, chapped and fissured lips (cheilosis), and inflammation of the corners of the mouth (angular stomatitis). There can be oily scaly skin rashes on the skin.

Answer 38

B2 (Riboflavin)

Question 39

Pellagra (Niacin deficiency)
• Primary pellagra is due to a diet that does not contain enough niacin and __________.
• Secondary pellagra is due to a poor ability to use the niacin within the diet, because of alcoholism, long-term diarrhea, and a number of medications such as the anti-TB drug _______.
• Symptoms: ___________ (broad ”collar rash” called ”Casal Collar”; sensitivity to sunlight) diarrhea, dementia (and death).

Answer 39

tryptophan; isoniazid; Dermatitis

Question 40

Absorption of Vitamin B12: Vitamin B12 cannot be synthesized in the body and must be supplied in the diet principally from meat and dairy products. Pure vegetarians who do not take dairy products can become vitamin B12 deficient.

1. In food: Vitamin B12 in food is complexed to proteins. Normally gastric acid and enzyme secretion is required for the release of vitamin B12 from food. _______ (reduced gastric acid) can impair the release of vitamin B12 from food.
2. R-Binder (a.k.a. ________) is a protein made by the salivary gland. It travels down to the stomach where it binds the released vitamin B12, stabilizing it and preventing its breakdown in the low pH environment of the stomach.
3. Intrinsic factor: Intrinsic factor is a protein made by the parietal cells of the stomach. On entering the duodenum, the pancreatic secretions raise the pH in the gut lumen. The vitB12- R-binder complex is digested and vitamin B12 is released. Free vitamin B12 binds intrinsic factor in the upper small intestine. Binding is optimal at pH 8.
4. Terminal ileum: The vitB12-IF complex is resistant to ___________ and travels to the distal ileum where the complex binds specific receptors on the mucosa. The complex is then taken into the mucosal cell.
5. Transcobalamin II and vitamin B12: Inside the ileal epithelial cell, Vitamin B12 dissociates from IF and is transported to the plasma where it binds to another protein, transcobalamin II, which is produced by the liver. The transcobalamin-vitamin B12 complex is transported in the blood stream (portal circulation) to the liver and from there to other tissues for utilization. Excess vitamin B12 can also be transported in the blood by a second protein called __________.
6. Stores: The store of vitamin B12 (5 mg or 5000 μg) is relatively large compared to the daily requirement (2-5 μg). If no vitamin B12 is taken in the diet, it would take nearly 1000 days to deplete the store, that is nearly three years. Levels of vitamin B12 falls during pregnancy. In the last trimester 5-10% of women may have levels below 100 ng/L (normal range is __________).

Answer 40

Hypochlorhydria; haptocorrin; proteolytic digestion; transcobalamin I; 200-900 ng/L

Question 41

Calcium absorption: The small intestine absorbs calcium by two mechanisms.
1. Passive, _________ (between cells) absorption of calcium occurs throughout the intestine. It is the predominant route of absorption, and is NOT under vitamin D control.
2. Vitamin D-dependent active uptake takes place through enterocytes in the small intestine.
• Active Ca2+ absorption requires biologically active Vitamin D (1,25-dihydroxycholecalciferol). Calcium enters the enterocyte via the ___________ in the apical membrane.
• Inside the cell, the calcium is buffered by proteins such as _________, whose synthesis is induced by vitamin D.
• Some calcium is taken up by organelles.
• Calcium is extruded from the basolateral membrane via a calcium pump (plasma membrane Ca²⁺ transporting ATPase1 or PMCa1b) and a _____________.

Answer 41

paracellular; TRPV-5/6 channel; calbindin-D; sodium-calcium exchanger (NCX1)

Question 42

[Iron absorption]

• 1-2 mg Iron is absorbed in the intestine, mainly in the duodenum.
• Loss of iron from body daily: 1-2 mg /day
• Blood: Iron is bound to a serum protein called _________. The iron-Tf complex travels to tissues.

Bone Marrow: Tf binds to Tf receptors on _________ in the BM. The Tf-iron complex is endocytosed. Tf delivers iron to the mitochondria where heme is synthesized.

Storage tissues: Excess iron is stored in the liver and spleen. The Iron complexes with _________ to form ferritin (storage iron). When iron levels fall, iron is released from ferritin into the blood. Total store of iron = ~1 g. A second storage protein is ________, but it does not release iron easily.

Modifiers of iron absorption:
• Ascorbic acid (vitamin C) and citrates increase iron absorption.
• Antacids, some antibiotics (ciprofloxacin, tetracycline), _________ (e.g. from bran) and tannins decrease iron absorption.

Answer 42

transferrin (Tf); erythroblasts; apoferritin; hemosiderin; phytates

Question 43

Iron Absorption: Iron is absorbed from all parts of the small intestine, but primarily in the ________.

Step-1: On the apical or luminal side of the enterocyte (intestinal epithelium), __________ reduces ferric to ferrous. Ferrous is taken into the cell through a transporter protein called __________. Heme-containing iron is taken up through the _____________.

Step-2: Some iron is stored in the enterocyte complexed to a protein called apoferritin to form
ferritin. The bulk is transferred across the basal side of the enterocyte via a transporter called _______.

Step-3: The ferrous is oxidized to ferric by _________. The ferric is bound to transferrin and transferred into the blood stream.

Step 4: __________ produced by the liver inhibits iron absorption by blocking ferroportin and ensures that excessive iron is not absorbed or released into the blood stream.

___________ is a hormone produced by erythroblasts in the bone marrow in response to erythropoietin (EPO) produced by the kidney. Erythroferrone suppresses hepcidin production by the liver and thereby removes hepcidin’s inhibitory effect on ferroportin. Thus, more iron is absorbed (e.g. in iron deficiency anemia).

Administering iron to patients with iron deficiency:
• Ferrous is administered rather than ferric because it gets absorbed better.
• Do not give __________ or ciprofloxacin or tetracycline to patients receiving iron.

Answer 43

duodenum; Ferri-reductase; DMT1 (divalent metal transporter 1); heme receptor HCP1

ferroportin; ferroxidase; Hepcidin

Erythroferrone; antacids

Question 44

Fluid delivered to small intestine = 8.5 liters/day (food & water + saliva + Gastric + Pancreatic + Bile = 7.5 L + 1 L made by the small intestine).

Fluid (1 L) secreted by small intestine is called _____________. It is an isotonic bicarbonate rich
fluid secreted daily by the Crypts of Leiberkuhn. Most of the enzymes in this secretion come from desquamated mucosal cells. The mucous secreted comes from enterocytes and goblet cells. The secretion of succus entericus is stimulated by _____.

Fluid absorbed in the small intestine = 6.5 liters/day
Water: H2O is absorbed passively paracellularly (between cells) to balance the absorption of ions. Water absorption is passive and occurs as the direct result of active sodium absorption. Most water and electrolytes are absorbed in the small intestine, mainly in the jejunum. Fluid delivered to the colon = 2 liters / day
Fluid absorbed in the colon (mainly in the proximal colon) = 1.9 liters / day Fluid in feces = 0.1 L/day

Answer 44

succus entericus; VIP

Question 45

In the jejunum there is net absorption of Na+ and HCO3-. Electroneutral: Na+ absorption balanced by HCO3- & Cl- absorption.
Apical surface: Na+ enters by four mechanisms.
• Coupled to glucose or galactose via _____
• Na-amino acid transporters (Na-AA transporter)
• Na-H exchanger
• ___________________________.
• Chloride comes into the cell via chloride channels. Chloride can also passively flow between cells.

Basolateral surface:
• Na+ pumped into interstitial fluid by Na-K-ATPase.
• HCO3- goes through a bicarbonate transporter into the interstitial fluid.
• Chloride leaves the cell through chloride channels.
• K+ that comes into the cell via Na-K-ATPase leaves the cell via potassium channels.

Cholera: In epithelial cells, cholera toxin (from Vibrio cholera) causes adenylyl cyclase to be in a perpetual state of activation, resulting in the continuous formation of cAMP. The cAMP activates protein kinase and phosphorylates various membrane transport proteins, resulting in the active transport of electrolytes into the intestinal lumen. Water follows passively, causing life threatening diarrhea.

Answer 45

SGLT1; Amiloride-sensitive sodium channel (called ENaC)

Question 46

Ileum: Net absorption of Na+ and Cl- . Electroneutral: Na+ absorption balanced by Cl- absorption. Net secretion of HCO3-.

Ileum contains the same mechanism as the jejunum plus a ________________ in the apical membrane and a ___________ in the basolateral membrane. The result of the combined Na-H exchange and the chloride-bicarbonate exchange is a net movement of NaCl into the ileal cell, and net secretion of bicarbonate into the lumen. In contrast, in the jejunum, there is net absorption of HCO3-.

1. Apical surface: Na+ enters by four mechanisms.
   (1) Coupled to glucose or galactose via SGLT1.
   (2) Na-amino acid transporters (Na-AA transporter),
   (3) Na-H exchanger,
   (4) An amiloride-sensitive sodium channel (called ENaC). HCO3- is secreted in exchange for Cl absorption via the anion exchanger.
2. Basolateral surface: Na+ pumped into interstitial fluid by Na-K-ATPase. Chloride leaves the cell through chloride channels. K+ that comes into the cell via Na-K-ATPase leaves the cell via potassium channels.

Answer 46

bicarbonate-chloride exchanger; chloride channel

Question 47

The GI mucosal immune system consists of three major compartments: epithelium, lamina propria and gut-associated lymphoid tissue.

Epithelium
• Intra-epithelial lymphocytes reside within the epithelium layer. They are unconventional _________ and γδ T cells.
• Dendritic cells project dendrites into the epithelium to uptake antigens. They then migrate to the lamina propria, secondary lymphoid tissue and draining lymph nodes, where they prime naive T cells.
• ___________ located in the epithelium of Peyer’s patches, pass antigens to DCs, macrophages and other APCs.

Lamina Propria contains T cells, B cells, dendritic cells and _________.

Answer 47

CD8αα+ αβ T cells; Microfold (M)-cells; macrophages

Question 48

What does CD4+ Th1 secrete?

Answer 48

IFN-g

Question 49

what does Th2 secrete?

Answer 49

Il4, Il-13

Question 50

What does Th-17 secrete?

Answer 50

Il17, Il-22

Question 51

What does Treg secrete?

Answer 51

Il-10 TGFb

Question 52

Gut associated lymphoid tissues
• Peyer’s patches are oval or round lymphoid follicles in the submucosa that extend into the mucosa. Humans contain about 100 Peyer’s patches, roughly half in the distal ileum. B cells are found in the follicle’s germinal center. T cells are found between follicles. Peyer’s patches are covered by a relatively porous follicle associated epithelium containing fewer _____________ (less mucous covering). The epithelium also contains specialized microfold (M) cells that take up and transport antigens from the intestinal lumen to the Peyer’s patch.
• Fat-associated lymphoid tissue obtains antigen by lymphatic drainage directly from the intestine and from the peritoneal cavity.
• __________ are located at the base of crypts, start recruiting T cells soon after birth and develop into isolated lymphoid follicles.
• Isolated lymphoid follicles when mature contain mainly B cells in germinal centers that serve as inductive sites for antigen-specific _____ responses. They also contain interspersed T cells and dendritic cells. The epithelium adjacent to mature ILF shows characteristics of a follicle associated epithelium containing M cells that allow for direct uptake of antigens from the intestinal lumen.
• _____________-formation starts during embryogenesis and are among the first lymph nodes to develop. Antigen-immune interactions that occur in the GI tract travel to the mesenteric lymph node and from there to the rest of the body.

Answer 52

mucous secreting goblet cells; Cryptopatches; IgA; Mesenteric lymph node

Question 53

Celiac disease is an immunologically mediated inflammatory disorder of the small bowel occurring in genetically susceptible individuals and resulting from intolerance to __________ and similar proteins found in rye, barley and, to a lesser extent, oats. It can result in malabsorption and responds to a gluten-free diet. The condition occurs world-wide but is more common in northern Europe.

Pathogenesis: The precise mechanism of mucosal damage is unclear but immunological responses to gluten play a key role. Gluten peptides are thought to be taken up by M cells and transferred into the Peyer’s patches. Tissue _____________ deamidates the gluten peptides. These are processed by antigen presenting cells and presented to T cells eliciting a TH1 autoreactive response. Autoantibodies (________ (especially IgA) and anti-endomysial antibodies) also develop. The intestinal mucosa is damaged reducing the surface area for nutrient absorption.

Clinical features: In infants presenting symptoms include diarrhea, malabsorption, failure to thrive. In older children and adult presenting symptoms include delayed growth, diarrhea, malabsorption, tiredness, weight loss, oral ulceration, folate deficiency, iron deficiency anemia.

Investigations: Endoscopic small intestine biopsy. Autoantibodies = Serum antigliadin (especially IgA) and _____________; test for iron deficiency anemia, or folate deficiency anemia.

Management: avoid gluten-containing foods. Correct anemias.

Answer 53

wheat gluten; transglutaminase; antigliadin; anti-endomysial antibodies

Question 54

Diarrhoea: condition in which feaces are discharged from the bowels frequently and in a liquid form. Stool weight (i.e. H2O content) that exceeds 200g in 24 h.

• Acute Diarrhea < 4weeks, usually due to infectious organisms or toxins, usually self-limited.
• Chronic Diarrhea: When diarrhea lasts more than 4 weeks it is considered chronic.

Many types of diarrhea:
• Osmotic - e.g. _______________
• Secretory – e.g. _________
• Inflammatory – e.g. ____________
• Infectious – e.g. Amebiasis, Shigella dysentery
• Decreased absorption surface – e.g. bowel resection
• Dysmotility syndromes – e.g. irritable bowel syndrome

Treatment is symptomatic

Answer 54

Lactose intolerance; Cholera; Ulcerative colitis

Question 55

Symptom therapy for diarrhoea

1. Intra-luminal agents

Hydroscopic agents:
• Kaopectate: Binds water avidly and may also bind ___________. Used for mild diarrhea.
• Magnesium-Aluminum disilicate (Diasorb): Binds water avidly and may also bind enterotoxins. Used for mild diarrhea.

Bile salt-binding resins:
• ___________, Colestipol: Binds bile acids and bacterial toxins. In Crohn’s disease affecting the terminal ileum, or when the terminal ileum is resected, the enterohepatic circulation of bile salts is impaired resulting in bile salts- induced diarrhea.

Bismuth
• PeptoBismol (Bismuth subsalicylate): __________, anti-inflammatory & antimicrobial (H. pylori) effects. Used to treat traveler’s diarrhoea.

Answer 55

enterotoxins; Cholestyramine; Anti-secretory

Question 56

Symptom therapy for diarrhoea

2. Anti-motility and anti-secretory agents

μ-opioid receptor agonists
• _________: well tolerated, lacks abuse potential; overdose can cause CNS depression and paralytic ileus, particularly in children. Over-the-counter distribution!
• __________: significant abuse potential; overdose can cause constipation, megacolon.

α2-adrenergic receptor agonists
• Clonidine: Stimulate absorption. Inhibit secretion. Used to treat ______________.

3. Analogue of ___________
   • Octreotide Inhibits gastrin, acid, insulin, pancreatic secretion and gall bladder contraction.
   Used to treat secretory diarrhoeas due to hormone-secreting tumors of the pancreas and GI tract; Diarrhoea due to Dumping syndrome; Chemotherapy- induced diarrhoea & HIVassociated diarrhea.

Answer 56

Loperamide; Diphenoxylate; opioid-induced diarrhoea

somatostatin

Question 57

Deficiency of pancreatic enzymes: When secretion of pancreatic enzymes falls below 10% of normal, impairment of fat and protein digestion occurs, which leads to steatorrhea (presence of excess fat in feces; bulky & difficulty-to-flush stool; pale; oily; foul-smelling), deficiency of fatsoluble vitamins and weight loss. Pancreatic insufficiency leading to deficiency of pancreatic enzymes can be due to cystic fibrosis, _________, post-pancreatic resection (more details in clinical section). Treatment is with pancreatic enzyme supplements.

Pancrelipase: Enriched preparation of porcine-derived pancreatic enzymes including _____________. Rapidly inactivated by gastric acid, so administered as enteric coated tablets, or encapsulated forms containing _________________ (eg. Creon) or microtablets (eg. Pancreaze).

Non-enteric coated preparations (eg. Viokase) have to be administered with a _____________________.

• Pancreatin: alcohol-derived extract of hog pancreas with relatively less concentrations of lipase and proteases. Not commonly used. Less effective than pancrelipase.

Answer 57

chronic pancreatitis;

amylase, lipase and proteases;

acid-resistant microspheres;

proton-pump inhibitor