27a. Maldigestion, Malabsorption CAMTASIA

Question 1

What are common diseases of maldigestion/malabsorption?

What abou hallmark diseases?

Answer 1

_Common: _

Lactose Intolerance

Celiac Dz

Pernicious anemia (B12 def)

Bacterial overgrowth

Hallmark:

Whipple’s Dz

Abetalipoproteinemia

Question 2

What is the definition of digestion?

Definition of absorption?

Answer 2

Digestion: physical and chemical breakdown of food. Includes enzymatic breakdown.

Absorption: movement of nutrients across mucosal cells (enterocytes) to the interstitium, where they enter blood or lymph. Process is either facilitated diffusion or active transport (through apical side, through cytoplasm, then through basolateral membrane)

Question 3

List of where digestive enzymes come from? (may not be exhaustive)

Answer 3

Oral grandular cells

Chief cells in stomach

Pancreatic exocrine cells

Brush border in small intestine

Question 4

Definition of maldigestion?

definition of malabsorption?

Answer 4

• Maldigestion: Failure to break down (hydrolysis) complex nutrients
• Malabsorption: Failure to transport simple nutrients and products of digestion (either not getting particles across brush border/apical surface into enterocyte, or across basolateral surface into interstitium)

Question 5

What basic elements are required in order to absorb and digest carbs and fats?

Answer 5

• intraluminal digestion
• brush border digestion
• transport

Question 6

What basic elements are required to digest fats?

Answer 6

The things that we need to digest carbs and proteins (intraluminal digestion, brush border digestion, transport)

PLUS:

• incorporation into bile salt micelles
• mucosal resynthesis
• packaging into lipoproteins
• Because fats cannot be placed directly into aqueous solution, must be packaged.

Question 7

What are the various types of dietary carbohydrates? Why do we care?

Answer 7

Sugars: mono-, di-, and oligosaccharides, also sugar alcohols/polyols

Polysaccharides: starches from plants (amylose)

Glycogen from animals

Non-starches: dietary fiber

We care because monosaccharides are the only absorbable substrate. Everything else has to be broken down to a monomer to be absorbed.

Question 8

Given that monosaccharides are the only absorbable substrate in the carb category, what does the process of digestion essentially require?

Answer 8

Carb digestion is essentially the process of hydrolyzing polysaccharides to olicosaccharides, to disaccharides, and finally to monosaccharides that we can absorb.

Question 9

What are the 4 steps of carb digestion?

Answer 9

1. Physical denaturation
2. Amylase breakdown
3. Brush Border digestion
4. Carb absorption

Question 10

Describe Step 1 of carb digestion (physical denaturation)

Answer 10

Mechanical breakdown via chewing, antral grinding against a closed pylorus

Result: smaller polysaccharides, increased surface area of the food bolus

Question 11

Describe Step 2 of carb digestion (amylase)

Where does amylase come from?

What conditions does it require to function?

Answer 11

Amylase = enzyme from saliva and pancreas.

Chemical breakdown of starches, enz cleavage into smaller sacharrides.

The 2 amylases are almost identical. Majority of breakdown done in duodenum by pancreatic amylase.

Amylase needs neutral pH and chloride (inactivated by gastric acid- but will still act in the middle of a bolus in the stomach).

Question 12

What pancreatic secretions assist amylase in doing its job?

Answer 12

Once food bolus reaches duodenum, panc secretions are added in response to CCK and secretin.

Pancreatic secretions = bile and bicarb to buffer acid, also chloride. Now amylase can work. (amylase needs neutral pH)

Question 13

Describe Step 3 of carb digestion (Brush border digestion)

What is the result?

What enzymes are involved?

Answer 13

Enzymes are embedded in brush border to further hydrolize carbs into disaccharides

3 enzymes:

• Lactase is specific to lactose
• 2 enzymes (sucrase-isomaltase and maltase-glucoamylase) have dual function. Sucrase hydrolyzes 100% of sucrose. Isomaltase cleaves off 1 glucose at a time from alpha-dextrins (oligopeptides). Maltase hydrolyzes maltose to 2 glucose.

Question 14

What is the limiting step in carb digestion?

(exception to this general rule)?

Answer 14

Limiting step is absorption, not digestion or hydrolysis. Reason: generally they body has a huge reserve of brush border enzymes (disaccharidases)

Exception: Lactase decreases soon after postnatal weaning. Has only part of the efficiency as the others. Susteptible to acquired lactose intol or genetic lactose intol.

Question 15

Describe step 4 of carb digestion (absorption)

Answer 15

At this point, we have broken everything down to only monomers (glucose, galactose, fructose)

-Apical membrane has two proteins/transporters:

GLUT5 for Fructose (Facilitated Diffusion - because fructose is small enough to diffuse across)

SGLT1 for Glucose and Galactose (Active transport - Symport with 2 Na)

Basolateral membrane has one protein/transporter:

GLUT2 (facilitated diffusion of all monomers)

Question 16

Carb absorption across the apical membrane:

what are the transporters? which transporter works with which monomer?

Answer 16

Apical membrane has 2 transporters:

Glucose and galactose are transported by SGLT1 (Na+ dependent active transport; dependent on Na gradient so requires Na/K ATPase at the basolateral membrane) (SGLT1 is a Symporter)

Fructose is transported by GLUT5 (facilitated diffusion) (Fructose Fits through if Facilitated)

Question 17

Carb absorption across the basolateral membrane:

what are the transporters? which transporter works with which monomer?

Answer 17

Only 1 transporter at the basolateral membrane: the GLUT2 transporter. All three monomers diffuse through to interstitium and capillaries

Question 18

Carb digestion: where does most digestion take place?

Answer 18

•Very little in the duodenum

•Peak activity proximal jejunum

• Less in the distal small bowel (ileum)
• None in the colon

Question 19

What happens to carbs that escape absorption in the small intestine and reach the large intestine?

Answer 19

“Colonic Salvage”

carbs are metabolized by intestinal flora to Short Chain Fatty Acids (SCFAs). Increases osmotic load and causes diarrhea.

Can be absorbed by enterocytes in the colon.

Can be a source of calories

Major side effect is gas from fermentation.

Question 20

What things can cause diarrhea due to increased amounts of undigestible carbs?

Answer 20

• Antibiotics will kill off intestinal flora, so less carbs will be metabolized to SCFAs in the large intestine –> not reabsorbed –> osmotic diarrhea
• Ingestion of a lot of polyols (carbs in sugar-free candy) which are undigestible –> diarrhea

Question 21

Protein digestion: major proteins are hydrolyzed to what?

What forms of proteins are absorbable?

What is required for protein absorption?

Answer 21

Major proteins hydrolyzed to oligopeptides and amino acids

Both small polypeptides and amino acids are absorbable (contrast with carbs, where we can only absorb monomers)

Process requires proenzymes to activate enzymes. Impt becasue creating proenzymes can be problematic

Question 22

What is the difference between endopeptidases vs. exopeptidases?

Answer 22

Both cleave bonds between pairs of AAs within a protein

Endopeptidase: enzymes that cleave bonds between specific pairs of AAs within the molecule. Act on interior of molecule first, give more ends for Exos to act.

Exopeptidase: cleaves bonds from one or other end

Question 23

Protein digestion: what are the 4 steps?

Answer 23

1. Mechanical Breakdown (Chewing)
2. Gastric Hydrolysis
3. Trypsin and luminal (premucosal) digestion
4. Absorption to the enterocyte

Question 24

Protein digestion: Step 2 (Gastric hydrolysis)

How much protein hydrolysis is done in the stomach?

What enzymes are involved?

Answer 24

• Minimal protein hydrolysis (10-15%) occurs in the stomach
• Enzyme = gastric pepsinogen (zymogen, activated by acid to pepsin)

–Optimum pH for gastric pepsinogen = approx 2; therefore inactivated by pancreatic secretions in duodenum

-NOT essential for protein digestion (recall people can survive post-gastrectomy)

Question 25

Protein Digestion Step 3 (Trypsin and luminal digestion): What enzymes are involved? What is the process?

Answer 25

- **Trypsin** does most of the protein breakdown in the **duodenum** - Trypsin released as trypsinogen by pancreas - Trypsinogen activated by brush border enterokinase and by self-activation - Trypsin activates 4 other peptidase zymogens from pancreas - Brush border enzymes themselves hydrolyze larger peptides (3-8 AAs)

Question 26

Why don't trypsin and the other pancreatic enzymes digest normal structures in the duodenum?

Answer 26

Once they are in the small int, these enzymes **inactivate rapidly.** Trypsin is responsible for inactivation. (Protective mech that prevents panc enzymes from digesting normal structures.)

Question 27

The passing of the food bolus from the stomach to the duodenum stimulates the secretion of what?

Answer 27

CCK, pancreatic enzymes (??)

Question 28

Protein digestion step 4 (Absorption to the Enterocyte) - What transporters allow protein absorption? - What can occur within the enterocyte cytoplasm? - Is there any other route for absorption?

Answer 28

- For AAs, there are apical membrane transporters. Various transporters have affinity for different AAs (with overlapping affinities) - Larger peptides (di-, tri-, tetra-) can be absorbed intact via carrier molecules - These larger peptides are hydrolized to AAs within the cytoplasm. **There is also a paracellular route for intact peptides!**

Question 29

Summary of Protein assimilation: * Most hydrolysis occurs in duodenum via **trypsin**-activated peptidases and **brush border enzymes** * **Redundant** mechanisms for absorbing both free AA’s and small peptides (both into cytoplasm and paracellular) * **Most absorption is single AA’s;** but also some oligopeptides and whole proteins can be absorbed

Answer 29

Ok.

Question 30

What are the 6 steps of Fat digestion/absorption?

Answer 30

1. Emulsifiation 2. Gastric Hydrolysis 3. Completion of Lipolysis 4. Micelle Formation 5. Absorption 6. Post-processing of dietary fat

Question 31

In general terms, what is the problem with digesting fat? why isn't it as straightforward as digesting carbs and proteins?

Answer 31

Fat is a problem because it is hydrophobic in the aggregate So in addition to being hydrolyzed and absorbed, it ALSO has to be **emulsified** & **packaged** **into lipoproteins** so it can be transported to target tissues.

Question 32

Describe Step 1 of fat digestion (Emulsification)

Answer 32

-Mechanical stuff: mastication, antral grinding and peristalsis in order to turn large amounts of fat into a suspension of fat droplets. (mechanical stuff is impt -- increases surface area of lipids before their enzymatic hydrolysis by lipase). Gut motility provides **mixing**: without this, fat droplets would re-join each other.

Question 33

Fat digestion: What induces the secretion of lipase, bile salts and phospholipids (lecithin)?

Answer 33

With **intake of food**, antral cells in duodenum are induced to produce CCK. CCK causes secr of **lipase**, gallbladder contraction to secrete **bile salts** and phospholipids (**lecithin**) to duodenum. Gut motility prevents re-association of droplets and allows enzymes access to the surface, where they act.

Question 34

Fat digestion: Step 2 (gastric hydrolysis) What % of fat digestion is done by gastric hydrolysis? What enzymes are involved? What stimulates these enzymes? Where do they come from? What is the end product?

Answer 34

-15% of fat digestion **-Gastric lipase**: stimulated by gastrin, released by chief cells Result: TAGs --\> DAGs

Question 35

Fat digestion Step 2 (Gastric Hydrolysis): Qualities of gastric lipase? What environment does it require for action? Can we survive without it?

Answer 35

Made to work in the stomach: **-stable at low pH, inactivated by neutral pH** -Digested by trypsin in duodenum **We can do without gastric lipase** because pancreatic lipase is in great excess.

Question 36

Fat digestion Step 3: (completion of lipolysis) Where does the bulk of lipolysis take place? what enzymes are involved? What conditions do these enzymes require?

Answer 36

Most of lipolysis takes place in **duodenum**. Enzymes: **pancreatic lipase**, hydrolyzes TAG to MAG + FAs. Requires **pancreatic co-lipase, alkaline pH, bile salts** (pancreatic co-lipase anchors lipase to the fat droplet surface, so it's not displaced by bile salts)

Question 37

Fat digestion step 3 (completion of lipolysis) What stimulates the biliary and pancreatic secretions that we need in order to digest fat?

Answer 37

**The presence of fatty acids in the duodenum** stimulates CCK and GIP (gastric inhibitory peptide). **CCK and GIP** then stimulate biliary and pancreatic secretions.

Question 38

Fat digestion Step 4 (Micelle Formation) What's going on?

Answer 38

Big emulsion droplet can't really interact with enterocytes, so bile salts and phospholipids grab MAGs and FAs **(micelles)**, and transport them to the surface of the enterocyte. Basically a way to transport the insoluble stuff and offer it to the enterocytes. The FAs are taken in to the enterocytes by **diffusion**. (different from carbs and proteins which have all those transporters)

Question 39

Fat digestion: What happens to the bile salts once they have delivered their FAs to the enterocytes?

Answer 39

A small amount of bile salts are absorbed along with the FAs but most are **reabsorbed more distally within the ileum**

Question 40

Fat digestion Step 5 (Absorption) What happens once the FAs are within the enterocytes?

Answer 40

FAs etc now **re-form into triacylglycerides (TAGs).** Inside the enterocyte, packaged with apolipoproteins to form **chylomicrons** (which are fat globs surrounded by a protein shell)

Question 41

Fat digestion Step 5 (Absorption) Once chylomicrons are formed within the enterocytes, how do they reach peripheral tissues?

Answer 41

Somehow they get out of the enterocyte (diffusion?) They then go through **lymphatics/thoracic duct** and get to the peripheral tissues directly.

Question 42

Fat digestion step 6 (post-processing of dietary fat) Once chylomicron is at peripheral tissues, how do the TAGs enter cells?

Answer 42

**Lipoprotein Lipase** grabs the chylomicrons as they float past, and extracts and cleaves TAGs. Fats and glycerol are stored in fat cells as TAGs. Chyomicrons return to liver

Question 43

Vitamin B12: in general if someone is B12 deficient, what information does that give us?

Answer 43

Vit B12 comes from meat and dairy, so either their diet is low in these, or there is something wrong with their digestive system Vit B12 absorption is a complex process and vulnerable to disruption therefore it is a "mirror on the soul of the GI system"

Question 44

Vit B12 absorption: What 5 factors does it depend on? Where is it absorbed?

Answer 44

**1. Dietary intake** 2 and 3. B12 is bound to food proteins. **Acid** and **pepsin** hydrolize B12 from the food particles in stomach 4. B12 then bound to R protein which binds to it quite strongly. **Trypsin** needed to cleave R factor from B12. 5. Gastric parietal cells secrete **Intrinsic Factor,** which **binds** Vit B12. Protects it from degradation, **Vit B12 absorbed in the ileum**

Question 45

Causes of Vit B12 malabsorption?

Answer 45

- Decreased Intrinsic Factor secretion (due to pernicious anemia or gastrectomy) - Increased R factor binding (due to pancreatic insufficiency & lack of trypsin) - Increased bacterial B12 uptake (due to bacterial overgrowth) - Decreased Ileal absorption (due to Crohn's, ileal resection)