Case 3 Flashcards
1
Q
By which pathway does secretion take place in the pancreas, starting form acinus and ending at pancreatic duct.
A
Acinus –> intercalated duct –> intralobular duct –> interlobular duct –> main pancreatic duct
2
Q
Function of trypsin
A
splits whole and partially digested proteins into peptides of various sizes but not into amino acids
Most abundant proteolytic enzyme
3
Q
Function of chymotrypsin
A
splits whole and partially digested proteins into peptides of various sizes but not into amino acids
4
Q
Function of carboxypolypeptidase
A
splits peptides into individual amino acids, thus completing the digestion of some proteins
5
Q
What are the inactive forms of pancreatic proteolytic digestive enzymes called?
A
Zymogen
6
Q
What activates trypsinogen?
A
ENTEROKINASE enzyme (secreted by intestinal mucosa when chyme comes in contact) Also autocatalytically activated by TRYPSIN, previously formed from secreted trypsinogen.
7
Q
What activates chymotrypsinogen?
A
Activated by trypsin to form chymotrypsin
8
Q
What activates Procarboxypolypeptidase ?
A
Activated by trypsin to form carboxypolypeptidase.
9
Q
when do the zymogens become active?
A
after they’ve been secreted into the intestinal tract
10
Q
what products are formed by the digestion of carbs by pancreatic amylase?
A
mostly disaccharides and few trisaccharides
11
Q
what are the three pancreatic fat digestive enzymes and their function?
A
- Pancreatic Lipase – this hydrolyses neutral fat into fatty acids and monoglycerides.
- Cholesterol Esterase – this causes hydrolysis of cholesterol esters.
- Phospholipase – this splits fatty acids from phospholipids.
12
Q
apart from proteolytic digestion, what other function does proteases serve in the body?
A
Proteases help keep the intestine free of parasites such as bacteria, yeast and protozoa.
13
Q
What kind of effects will be caused by the shortage of proteases?
A
- Allergies or the formation of toxic substances due to incomplete digestion of proteins.
- Increased risk for intestinal infections.
14
Q
What can a shortage of amylases cause?
A
Diarrhoea due to the effects of undigested starch in the colon.
15
Q
What can a shortage of lipases cause?
A
- Lack of needed fats and fat-soluble vitamins.
* Diarrhoea and/or fatty stools.
16
Q
Function of trypsin inhibitor
A
secreted by the same cells that secrete proteolytic enzymes .
Secretion of trypsin inhibitor prevents digestion of the pancreas itself, as it prevents the activation of trypsin.
17
Q
Acute pancreatitis
A
- When pancreas is severely damaged or a duct becomes blocked, lots of pancreatic secretion become pooled in damaged areas.
- effect of trypsin inhibitor is often overwhelmed
- pancreatic secretions rapidly become activated, thus causing digestion of the pancreas.
18
Q
Which cells in the pancreas secrete the digestive enzymes?
A
Pancreatic acini
19
Q
Which cells in the pancreas secrete HCO3- and water?
A
Duct cells
20
Q
The mechanism of secretion of sodium carbonate solution by ductal cells in the pancreas
A
- Carbon dioxide diffuses into the ductal cell from the blood:
• carbonic anhydrase catalyses its reaction with water to form carbonic acid (H2CO3).
• The carbonic acid in turn dissociates into bicarbonate ions and hydrogen ions (HCO3- and H+).
o Some HCO3- ions also enter the cell directly across the basolateral membrane via an Na/HCO3 cotransporter.
• Then the bicarbonate ions are actively transported into the lumen via a Cl-HCO3 exchanger. - Na+/H+ echanger on the blood border of the cell.
• supplies the Na+ that are transported through the luminal border into the pancreatic duct lumen to provide electrical neutrality for the secreted bicarbonate ions. - The overall movement of sodium and bicarbonate ions from the blood into the duct lumen creates an osmotic pressure gradient that causes osmosis of water also into the pancreatic duct, thus forming an almost completely isosmotic bicarbonate solution.
- Some sodium ions (Na+) enter the lumen through the tight junctions due to the negative voltage of the lumen.
21
Q
Which 3 basic stimuli cause pancreatic secretion? how do they do it?
A
- ACh (M3 receptors) - from vagus nerve and ENS.
- Cholecystokinin (CCK) - in response to proteoses and peptones (products of partial protein digestion) and long-chain fatty acids in the chyme.
- Secretin - in resonse to highly acid food in duodenum
ACh and CCK stimulate acinar cells to secrete large amounts of pancreatic digestive enzymes.
Secretin stimulates ductal cells to secrete large amounts of water solution of sodium bicarbonate.
22
Q
what is the mechanism within the acinar cell that cause secretion of digestive enzymes?
A
- ACh and CCK both activate Gαq, which stimulates PLC, which ultimately leads to the activation of PKC and the release of Ca2+.
- Elevated [Ca2+]i also activates calmodulin (CaM), which can activate protein kinases (PK) and phosphatases (PP).
- Finally, VIP and secretin both activate Gαs, which stimulates adenylyl cyclase (AC), leading to the production of cAMP and the activation of PKA.
23
Q
The duct cells have receptors for particular hormones that stimulate HCO3- secretion. Which are these hormones?
A
Secretin and GRP
24
Q
The duct cells have receptors for particular molecules that inhibit HCO3- secretion. Which are these molecules?
A
Substance P
25
What happens during the cephalic phase of pancreatic secretion?
• sight, taste, or smell of food stimulates pancreatic acinar cells, through the vagus nerve and M3 receptors (acetylcholine), to release digestive enzymes
• However, only a small amount of the secretion flows (due to small amounts of water and electrolytes being secreted)
(25% secretion)
26
What happens during the gastric phase of pancreatic secretion?
• The presence of food in the stomach stimulates pancreatic secretions – primarily from the acinar cells – through two routes:
1. Distention of the stomach activates a vagovagal reflex.
2. Protein digestion products (peptones) stimulate G-cells in the antrum of the stomach to release gastrin, which is a poor agonist of the CCKA receptors on acinar cells.
(10-20% secretion)
27
What happens during the intestinal phase of pancreatic secretion?
• Protein and lipid breakdown products stimulate a vagovagal reflex that stimulates primarily the acinar cells
• S-cells secrete secetin
• I-cells secrete CCK
(50-80% secretion)
28
Sodium bicarbonate causes neutralisation of HCl in the duodenum.
What is the equation?
HCl +NaHCO3 --> NaCl +H2CO3
29
Which receptors do CCK bind to?
CCKA receptors
30
Which enzymes are present in the enterocytes lining the villi of the small intestine that break down disaccharides into monosaccharides?
1. Lactase
2. Sucrase
3. Maltase
4. α-dextrinase
31
function of lactase enzyme
Lactose --> galactose + glucose
32
function of sucrase
sucrose --> fructose + glucose
33
Function of maltase
Maltose --> glucose + glucose
34
function of α-dextrinase
small glucose polymers --> multiple molecules of glucose
35
Which are the two main peptidase enzymes that breakdown large polypeptides into tripeptides and dipeptides and a few into amino acids?
1. Aminopolypeptidase
2. Dipeptidases
breakdown products of polypeptides are transported into enterocytes which contain more specific peptidases.
36
Which enzymes in the saliva do about 10% of fat digestion?
lingual lipase from lingual glnads
37
what is emulsification and how does it happen?
it is the first step in fat digestion.
1. It begins by agitation in the stomach to mix the fat with the products of stomach digestion.
2. Then, most of the emulsification occurs in the duodenum under the influence of bile.
Bile contains BILE SALTS and LECITHIN. The fat-soluble portions of these liver secretions dissolve in the surface layer of the fat globules, with the polar portions projecting.
The polar projections are soluble in the surrounding watery fluids, which greatly decreases the interfacial tension of the fat and makes it soluble.
The emulsification process increases the surface area of the fat globules for the action of enzymes to follow. Lipase enzymes are water-soluble compounds and can attack the fat globules only on their surfaces.
38
Which is the main enzyme that further breaks down fat globules?
And what products are formed?
Pacreatic lipase
Triglycerides --> free fatty acids + 2-monoglycerides
39
How are micelles formed?
* The hydrolysis of triglycerides results in accumulation of monoglycerides and free fatty acids in the vicinity of digesting fats, which block further digestion.
* Bile salts help prevent this by forming a micelle around the fatty acids and monoglycerides. this happens because of the hydrophilic and hydrophobic nature of bile salts.
* Micelles also help transport the monoglycerides and free fatty acids to the brush borders of the intestinal epithelial cells. There monoglycerides and free fatty acids are absorbed into blood, while bile salts are released back into the chyme to be recycled.
40
the longer the chain of the fatty acid,
the greater the pancreatic secretion.
41
which substances are absorbed by simple diffusion?
most lipids
42
which substances are absorbed by endocytosis?
vitamin B12 + intrinsic factor
43
which substances are absorbed by carrier-mediated transport?
amino acids, sugars and possibly lipids
44
which substances are absorbed in the mouth, oesophagus and stomach?
very limited diffusion
| stomach - some alcohol
45
which substances are absorbed in the duodenum and jejunum
major site of nutrient and ion absorption
46
which substances are absorbed in the ileum
vitamin B12 and bile salts
47
which substances are absorbed in the colon
some Na+ and H2O (+short chain fatty acids)
48
which substances are absorbed in the rectum
limited diffusion
49
lipids are absorbed into lacteals and carried to the blood system
...
50
another name for pilcae circulares
folds of kerckring
51
What ions are absobed in the small intestine?
net amounts of water, Na+, Cl-, and K+.
52
What ions are secreted in the small intestine?
HCO3-
53
what cells did the absorption and secretion?
Absorptive function in villous cells
| secretory processes in crypt cells
54
Glucose absorption is dependent on ____ absorption.
Na+ ion
55
How is glucose absorbed into the blood?
1. Active transport of sodium ions through the basolateral membranes of the intestinal epithelial cells into the blood ==> depletes Na+ from the cells
2. This causes absorption of sodium ions from the intestinal lumen across the apical membrane of the epithelial cells by a process of facilitated diffusion.
2Na+ ions bind to a sodium-glucose transporter protein.
This causes absorption of glucose.
Once inside the epithelial cell, other transport proteins (e.g. GLUT1) and enzymes cause facilitated diffusion of the glucose through the cell’s basolateral membrane into blood
56
Galactose absorption
same way as glucose
57
Fructose absorption
by facilitated diffusion via GLUT4, no sodium cotransport.
inside the enterocyte, fructose is converted to glucose and is transported the same way as glucose out of the cell and into the blood.
58
absorption of fats
after the monoglycerides and fatty acids diffuse immediately out of the micelles and into the interior of the epithelial cells and bile salts get recycled,
fatty acids and monoglycerides are taken up by ER of the epithelial cell. mainly used to form new triglycerides that are subsequently released in the form of chylomicrons.
• These chylomicrons are exocytosed through the base of the epithelial cell, and are transported in the lymphatic system to the liver.
59
whihc fatty acids are directly diffused into the portal blood?
some short and medium-chain fatty acids because they're more water-soluble
60
absorption of proteins
* Most proteins, after digestion, are absorbed through the luminal membranes of the intestinal epithelial cells in the form of dipeptides, tripeptides, and a few free amino acids
* The energy for most of this transport is supplied by a sodium co-transport mechanism in the same way that sodium co-transport of glucose occurs
* A few amino acids are absorbed via facilitated diffusion similar to fructose
61
sodium absorption in the small intestine
Na+ are actively transported from inside the epithelial cells through the basal and side walls of these cells into paracellular spaces. occurs due to Na+/K+ ATPase pump mainly.
62
how does aldosterone increase Na+ absorption?
dehydration stimulates the release of aldosterone from the cortices of adrenal glands.
• Within 1 to 3 hours this aldosterone causes increased activation of the enzyme and transport mechanisms for all aspects of sodium absorption by the intestinal epithelium
• And the increased sodium absorption in turn causes secondary increases in absorption of chloride ions, water (thereby overcoming the dehydration),
63
active absorption of bicarbonate ions into blood. how does this happen?
o When sodium ions are absorbed, some H+ ions are secreted into the lumen of the gut in exchange.
o These H+ ions combine with HCO3- to form H2CO3, which then dissociates to form water and carbon dioxide.
water remains as part of the chyme in the intestines,
CO2 is readily absorbed into the blood and subsequently expired through the lungs
64
1 unit of alcohol = ____ pure ethanol
10ml or 8g
65
recommended safe limits of alcohol for men and women
14-21 units/week for women
| 21-28 units/week for men
66
why do women have a lower recommended safe limit of alcohol?
because they have low amounts of alcohol dehydrogenase enzyme that breaks down some alcohol in the stomach
67
where does majority of alcohol metabolism occur?
Liver
68
Alcohol is converted to acetaldehyde and excreted by conversion to __(a)__ in __(b)__ cycle.
(a) carbon dioxide
| (b) citric acid cycle.
69
which enzyme metabolises alcohol in the liver?
cytochrome p4502E1
70
what is the average rate of metabolism of alcohol
1 unit/hr
71
at low levels, alcohol has protective effect against ___
atheromas
72
Are Acute fatty change (early), Alcoholic hepatitis and hepatic fibrosis reversible?
Yes (to an extent)
73
what is mallory's hyaline
globular red hyaline material within hepatocytes resulting from chronic alcoholism related hepatocyte injury.
74
Which cells in the liver become activated in hepatic fibrosis?
hepatic stellate (Ito) cells that are fucultative myofibroblasts
75
What is the proposed minimum unit price of alcohol
45p per unit
76
which blood tests can be used to identify heavy drinkers
o Gamma glutamyl transferase (GGT)
| o Mean corpuscular volume (MCV)
77
any other screening tools to identify heavy drinkers
CAGE and AUDIT questions
78
CAGE questionnaire
1. Have you ever felt you should CUT down on your drinking?
2. Have people ANNOYED you by criticizing your drinking?
3. Have you ever felt bad or GUILTY about your drinking?
4. Have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (EYE opener)?
•A total score of 2 or greater is considered clinically significant.
79
AUDIT
| Alcohol Use Disorders Identification Test
* Score >8 is 95% sensitive and 85% specific for harmful drinking
* Better at detecting harmful drinking
80
Definition of addict
someone who ‘has no control over their behaviour’, ‘lacks moral fibre’, ‘uses a maladaptive coping mechanism’, ‘has an addictive behaviour’
81
Definition of addiction
a need for a drug’, ‘the use of a substance that is psychologically and physiologically addictive’, ‘showing tolerance and withdrawal’
82
Definition of dependency
showing psychological and physiological withdrawal
83
Moral model (Criminal Justice model) of addiction
* Addicts are “weak” and can overcome a compulsion to use with willpower.
* Drug abusers choose to use drugs.
* Drug abusers are anti‐social and should be punished.
* Drugs are evil.
84
Biomedical model of addiction
• Neurotransmitter imbalance.
• Disease Model:
Agent: drug
Vector: dealers
Host: addict
• Need to “stamp out” the disease by eliminating drugs.
• Drug antagonist medications: Welbutrin; naltrexone; antabuse
85
Social model of addiciton
• Drug use is a learned behaviour:
Classical conditioning: associative behaviour
Operant conditioning: either positively reinforced by the presence of a positive event, or negatively reinforced by the absence or removal of a negative event
Observational learning/ modelling: behaviours are learnt by observing significant others carrying them out (e.g. parents drinking).
Cognitive factors: factors such as self-image, problem-solving behaviour, coping mechanisms.
• People use drugs because drug use is modelled by others.
• Peer pressure.
• Environmental effects lead to drug use (advertising, etc).
• Drug use is a maladaptive relationship negotiation strategy.
86
relationship between alcohol and dopamine and addiction
* Alcohol inhibits the inhibition that GABA interneurones have on dopamine neurones.
* So now dopamine interneurones become dis-inhibited, hence why there is an increase in dopamine release.
* extra dopamine in the brain – the dopamine receptors upregulate.
* So when you are presented with the stimulus of alcohol, your response is dampened.
* Therefore, you have to drink more to maintain the state of reward sensation and so you become addicted.
87
Main causes of acute pancreatitis
| mnemonic
```
I GET SMASHED
I: Idiopathic (20%)
G: Gallstones (50%)
E: Ethanol (25%)
T: Trauma
S: Steroids
M: Mumps
A: Autoimmune
S: Scorpion venom
H: Hyperlipidaemia
E: ERCP
D: Drugs
```
88
Clinical presentation of acute pancreatitis
Severe abdominal pain that radiates to the back
Nausea and vomiting
Rapid development of shock
Greatly elevated serum amylase
89
Main causes of chronic pancreatitis
```
chronic alcohol abuse
autoimmune pancreatitis
Cystic fibrosis
hyperlipidaemia
Idiopathic
```
90
Clinical presentation of chronic pancreatitis
Intermittent severe upper abdominal and back pain
Weight loss
Exocrine tissue replaced by fibrosis
Leads to pancreatic malabsorption (steatorrhoea and reduced vitamins A, D, E, K)
Relative preservation of endocrine tissue
91
Diagnosis of CP
• Currently:
Faecal elastase test – a stable proteolytic enzyme that can be picked up in the faeces. It indicates severe pancreatitis.
Endoscopic ultrasound – not so good as there is a lot of bowel gas to go through when imaging the pancreas. However, it is a good way to look at the texture of the pancreas. It is useful, as it allows us to drain cysts, and dilate structures if needed.
CT/MRI – cross section imaging
• Possible:
Urine collection and test for PABA (para-amino Benzoic Acid)
Direct hormonal stimulation
• Historical:
Faecal fat analysis after a three day sample.
92
risk factors of CP
* Tobacco smoke
* Alcohol
* Diabetes
93
Pathogenesis of chronic pancreatitis and alcohol
* Alcohol increases production of viscous secretions.
* Alcohol increases the protein secretions (enzymes) from the acinar cells of the pancreas.
* Alcohol reduces the secretion of bicarbonate ions and water from duct cells.
* The enzymes accumulate in the acini (plugging of the pancreatic duct) and begin to digest the pancreas itself.
94
Tobacco and alcohol relationship with CP
Tobacco smoke and alcohol metabolism -->
pancreatic oxidative stress (alcohol dehydrogenase)-->
Cytochrome P450 non-oxidative pathway -->
reactive oxygen species -->
cell damage
95
In Cp, lipase levels fall before amylase and protease, causing
causing fat malabsorption and steatorhhea (7g faecal fat/100g diet)
96
Pain in CP
* Dilation of the pancreatic ducts can occur as a result of blockage (e.g. gallstones) or from the viscous secretions (e.g. alcohol) -pressure pains
* Reduced bicarbonate secretion can cause pain elsewhere (e.g. stomach – gastritis) because of the lack of neutralization of stomach acid.
97
pancreatin
a mixture of several digestive enzymes, include amylase, lipase and protease (trypsin)
98
complications of CP
1. pseudocysts - localised fluid collection due to chronic inflammation, fluid can be drained
2. Bleeding - variceal (splenic vein thrombosis), psuedocyst, pseudoaneurysm
3. Obstruction - bile duct and duodenal
4. pancreatic cancer - 20% increased risk in those with CP, poor prognosis
99
pancreatic vs gastric dysfunction
stomach disorders usually lead to excess acid secretion, so drugs that act on acids, e.g. antacids and PPIs will only be effective in gastric dysfunction.
In both cases, there is pain:
pancreatitis - pain referred to back
gastritis - pain localised to epigastrium
analgesics and NSAIDs - little effect in visceral pain but efficient for somatic pain
100
main symptoms of malnutrition/malabsorption
Steatorrhea
Excessive flatus – because intestinal bacteria usually only receive fibre. But due to indigestion and malabsorption, there is more food (mainly fats) available for the intestinal bacteria
Diarrhea - rarely a feature of gastroduodenal disease, except coeliac disease. It is a symptom of pancreatitis.
Excessive weight loss with a normal diet.
101
Endoscopic Retrograde Cholangiopancretography (ERCP)
involves injecting a dye into the pancreatic duct.
In pancreatitis, there will be (1) clubbing of the side branches of the main pancreatic duct (2) the main pancreatic duct is dilated (1.5x normal diameter).
RISKY!
