GI 🤮 Flashcards
(211 cards)
1
Q
What are the functions of the stomach?
A
Store and mix food
Dissolve and continue digestion
Regulate emptying into duodenum
Kill microbes
Secrete (inactivated) proteases
Secrete intrinsic factor
Activate proteases
Lubrication
Mucosal protection
2
Q
What is the purpose of intrinsic factor?
A
Binds to vitamin b-12 and allows it to be absorbed in the ileum
3
Q
Key cell types in the stomach
A
Mucous cells
Parietal cells
Chief cells
Enteroendocrine cells- produce hormones e.g gastrin
4
Q
Describe gastric acid secretion in the stomach
A
Hydrochloric acid
Approx 2 litres/day
[H+] >150mM -> need to pump them against the conc. gradient
Parietal cells
Energy dependent
Neurohumoral regulation- part controlled by brain and part by glands near stomach
5
Q
What happens in parietal cells to produce stomach acid?
A
In parietal cells-
-water splits into OH- and H+
-K+ ions into the cell against conc. gradient
-H+ ions out of cell against conc. gradient
-Both processes need ATP
-
6
Q
Describe the cephalic phase of switching on gastric acid secretion
A
Parasympathetic nervous system
Sight, smell, taste of food, and chewing
Acetylcholine release
ACh acts directly on parietal cells
ACh triggers release of gastrin and histamine
Net effect = increased acid production
7
Q
Describe the gastric phase of turning on gastric acid secretion
A
Gastric distension, presence of peptides and amino acids
Gastrin release
Gastrin acts directly on parietal cells
Gastrin triggers release of histamine
Net effect = increased acid production
8
Q
What is the function of histamine in the gastric phase?
A
Histamine acts directly on parietal cells
Acts directly but also mediates effects of gastrin and acetylcholine
9
Q
Describe the protein in the stomach during switching on gastric acid secretion
A
Direct stimulus for gastrin release
Proteins in the lumen act as a buffer, mopping up H+ ions, causing pH to rise:
decreased secretion of somatostatin
more parietal cell activity (lack of inhibition)
10
Q
Describe the gastric phase of turning off gastric acid secretion
A
Low luminal pH (high [H+])
Directly inhibits gastrin secretion
Indirectly inhibits histamine release (via gastrin)
Stimulates somatostatin release which inhibits parietal cell activity
Negative feedback loop
11
Q
What things in the duodenum stimulate the switching off of gastric acid secretion?
A
Duodenal distension- usually not distended
Low luminal pH
Hypertonic luminal contents
Presence of amino acids and fatty acids
Trigger release of enterogastrones:
Secretin (inhibits gastrin release, promotes somatostatin release)
Cholecystokinin (CCK)
And short and long neural pathways, reducing ACh release
12
Q
Outline the duodenal phase of switching off gastric acid secretion
A
Trigger release of enterogastrones:
Secretin (inhibits gastrin release, promotes somatostatin release)
Cholecystokinin (CCK)
And short and long neural pathways, reducing ACh release
13
Q
Which signalling molecules turn on gastric acid secretion?
A
Gastrin- hormone
Acetylcholine- neurotransmitter
Histamine- paracrine factors
14
Q
Which paracrine factors turns gastric acid production off?
A
Somatostatin
15
Q
Define and list the causes of peptic ulcers
A
Definition:
An ulcer is a breach in a mucosal surface
Causes:
Helicobacter pylori infection
Drugs – NSAIDS
Chemical irritants – alcohol, bile salts, ? Dietary factors
Gastrinoma
16
Q
How does the gastric mucosa defend itself?
A
Alkaline mucus (bicarbonate rich- forms a barrier)
Tight junctions between epithelial cells
Replacement of damaged cells
Feedback loops
17
Q
How does Helicobacter pylori cause peptic ulcers?
A
Lives in the gastric mucus
Secretes urease, splitting urea into CO2 + ammonia
Ammonia + H+ = Ammonium
Ammonium, secreted proteases, phospholipases and vacuolating cytotoxin A damage gastric epithelium
Inflammatory response
Reduced mucosal defence
18
Q
How do NSAIDs cause peptic ulcers?
A
Non-steroidal anti-inflammatory drugs
Mucus secretion is stimulated by prostaglandins
Cyclo-oxygenase 1 needed for prostaglandin synthesis
NSAIDs inhibit cyclo-oxygenase 1
Reduced mucosal defence
19
Q
How do bile salts cause peptic ulcers?
A
Duodeno-gastric reflux
Regurgitated bile strips away mucus layer
Reduced mucosal defence
20
Q
How to treat peptic ulcer disease caused by H-pylori?
A
Eradicate the organism!
Triple therapy: 1 proton pump inhibitor
2 antibiotics
clarithromycin
amoxicillin
tetracycline
metronidazole
21
Q
How to treat peptic ulcer disease caused by NSAIDs?
A
Prostaglandin analogues – misoprostol
Reduce acid secretion
22
Q
What are some proton pump inhibitors?
A
Omeprazole
Lansoprazole
Esomeprazole
23
Q
What are some H2 receptor antagonists?
A
Cimetidine, Ranitidine
24
Q
Describe protease secretion
A
Chief cells produce pepsinogen
Synthesised in inactive form (zymogen)
Pepsinogen mediated by input from enteric nervous system (ACh)
Secretion parallels HCl secretion
Luminal activation
25
Describe protease activation
Conversion of pepsinogen to pepsin is pH dependent
Most efficient when pH <2
Positive feedback loop (Pepsin also catalyses the reaction)
Pepsin only active at low pH. Irreversible inactivation in small intestine by HCO3-
26
Role of pepsin in protein digestion
Not essential (protein digestion can occur if the stomach is removed)
Accelerates protein digestion
Normally accounts for ~20% of total protein digestion
Breaks down collagen in meat – helps shred meat into smaller pieces with greater surface area for digestion
27
What are the stomach volumes?
Empty stomach has volume of ~50mL
When eating, can accommodate ~1.5L with little increase in luminal pressure
28
What is receptive relaxation?
The smooth muscles of the stomach relax when stimulated by the presence of food
29
What mediates and coordinated receptive relaxation?
Mediated by parasympathetic nervous system acting on enteric nerve plexuses
Coordination – afferent input via Vagus nerve
Nitric oxide and serotonin released by enteric nerves mediate relaxation
30
Describe the mechanism of peristalsis in the stomach
Peristaltic waves begin in gastric body
Weak contraction in body (little mixing) towards the pylorus
More powerful contraction in gastric antrum
Pylorus closes as peristaltic wave reaches it
Little chyme enters duodenum
Antral contents forced back towards body (mixing)
31
Describe the basic electrical rhythm of the stomach
Frequency of peristaltic waves determined by pacemaker cells in muscularis propria and is constant (3/minute)
Pacemaker cells (interstitial cells of cajal) undergo slow depolarisation-repolarisation cycles
Depolarisation waves transmitted through gap junctions to adjacent smooth muscle cells
Do not cause significant contraction in empty stomach
32
Describe the varying strength of peristaltic contractions
Excitatory neurotransmitters and hormones further depolarise membranes
Action potentials generated when threshold reached
33
How is the strength of peristaltic contractions increased?
Gastrin
Gastric distension (medicated by mechanoreceptors)
34
How is the strength of peristaltic contractions decreased?
Duodenal distension
Increased Duodenal luminal fat
Increased Duodenal osmolarity
Decreased Duodenal luminal pH
Increased Sympathetic NS action
Decreased Parasympathetic NS action
35
Describe gastric emptying
Capacity of stomach > capacity of duodenum
Overfilling of duodenum by a hypertonic solution causes dumping syndrome:
Vomiting, bloating, cramps, diarrhoea, dizziness, fatigue
Weakness, sweating, dizziness
36
Describe the response of the duodenum to gastric emptying
After duodenum takes in material from the stomach
increased Secretion of enterogastrones
Stimulates neural receptors
Both lead to gastric emptying
37
Pathway of glucose in the body
Intestine-> blood-> liver -> brain, muscle, RBC, adipocytes
38
Describe glucose in the liver
insulin stimulates it to take up glucose
Then converted into glycogen or acetyl CoA
From acetyl CoA you can either make ATP from the krebs cycle or converted into triglycerides and then into VLDL
39
Glucose in the muscle
Insulin promotes uptake and it is converted to glycogen
40
Glucose in the brain
Needs constant supply of glucose from the blood
Converts to ATP via Krebs cycle
41
Glucose in RBCS
Need constant supply of glucose
Converts it to lactate and pyruvate as no mitochondria
42
Glucose in Adipocytes
Uptake stimulated by insulin
Converts to ATP and Triglycerides
43
Amino acids
Absorbed by intestines
In cells converted to protein, other compounds e.g peptide hormones
Can also be used in the krebs cycle
44
Triglycerides
Absorbed by intestines
Combined with protein
Forms Chylomicrons
Carried in the lymphatic system
45
Main storage of energy
Triglycerides in adipose tissue
Glycogen in liver & muscle
46
Describe the release of glucose in a short fast
Glycogen broken down into glucose
Stimulated by glucagon
Glycogenolysis
47
Describe the release of glucose in a longer fast
Not glycogen
AAs, lactate and glycerol broken down in liver and uses it to create glucose
Gluconeogenesis
48
Describe the action of fats during fasting
Glucagon stimulates triglycerides to break down into glycerol and fatty acids
gycerol-> glucose
Fatty acids either used by kidneys and muscle or broken down into ketones
Lipolysis
49
Describe the release of energy in prolonged fasting
Decreased use of ketones in muscles
Fatty acids converted to ketones in the liver (ketogenesis) which can supply the brain rather than glucose so glucose is available for RBCs
Decreased gluconeogenesis
50
What substances can be measured to check metabolism?
Glucose, Ketones, Insulin, lactate, Triglycerides
51
Hormones that regulate fuel metabolism
Growth Hormone
Somatostatin
Cortisol- adrenals, stress
Adrenaline+ Noradrenaline- fight or flight
Thyroxine
Insulin + glucagon-> glucose regulation
52
Is insulin anabolic or catabolic and what does it do?
Anabolic
Glycogen storage
Fat storage
Protein synthesis
53
Is glucagon anabolic or catabolic and what does it do?
Catabolic
Glycogenolysis
Gluconeogenesis
Ketogenesis
54
What are DIT and BMR
DIT-energy to break down food
BMR- basic amount of energy we need to survive
55
What are the factors contributing to obesity?
Genetics
Environment
Energy dysregulation
56
What is leptin?
Produced by fat cells and acts on the brain
In normal weight
supresses appetite
In obesity
High leptin levels
Leptin resistance
57
What is ghrelin?
Released by stomach cells and stimulates the brain to relax the stomach
Increases before meals
Stimulates appetite
58
What functions does the liver perform?
-Carbohydrate metabolism
-Fat metabolism
-Protein metabolism
-Hormone metabolism
-Toxin/Drug metabolism and excretion
-Storage
-Bilirubin metabolism and excretion
59
Where is iron used?
Haemoglobin in RBCs
Myoglobin in muscles
60
61
What is ferritin?
Large spherical protein consisting of 24 noncovalently linked subunits
Subunits form a shell surrounding a central core.
Core contains up to 5000 atoms of iron.
Ferritin found in the cytoplasm of cells but can also be found in the serum.
Concentration of ferritin is directly proportional to the total iron stores in the body
62
Excess iron storage disorders
Hereditary haemochromatosis
Haemolytic anaemia
Sideroblastic anaemia
Multiple blood transfusions
Iron replacement therapy
63
Examples of non-iron iron overload ferritin excess
Liver disease
Some malignancies
Significant tissue destruction
Acute phase response:
-Inflammation
-Infection
-Autoimmune disorders
64
Describe ferritin deficiency
The only known cause of a low ferritin is iron deficiency.
This can result in anaemia.
Ferritin less than 20 µg/L indicates depletion
Ferritin less than 12 µg/L suggests a complete absence of stored iron.
65
Describe the importance of vitamins in the diet
Usually vitamins are provided in the diet.
Characteristic disorders when someone is vitamin deficient
Recommended daily allowance (RDA)
Adequate intake (AI) where no evidence to determine RDA
Vitamins act as:
Gene activators
Free-radical scavengers
Coenzymes or cofactors in metabolic reactions
Excessive vitamin ingestion can result in toxicity.
66
What are the difference between water soluble and fat soluble vitamins?
Water- BC
Fat- ADEK
Water soluble vitamins pass more readily through the body, therefore, require more regular intake than fat soluble vitamins
67
Describe the types of vitamin A in the body
Retinols- Vertebrates ingest retinal directly from meat or produce retinal from carotenes: liver cereals, eggs, dairy
Carotenoids- Tomato, spinach, carrots
68
What is vitamin A functions?
Vision:
Used to form rhodopsin in the rod cells in the retina.
Reproduction:
Spermatogenesis in male
Prevention of foetal resorption of female
Growth
Stabilisation of cellular membranes
69
Describe vitamin A deficiency
Rare in affluent countries as vitamin A levels drop only when liver stores are severely depleted.
Deficiency may occur due to fat malabsorption
Clinical Features:
Night blindness
Xeropthalmia
Blindness
70
Describe vitamin A excess
Acute:
Abdominal pain, nausea and vomiting
Severe headaches, dizziness, sluggishness and irritability
Desquamation of the skin
Chronic:
-Joint and bone pain
-Hair loss, dryness of the lips
-Anorexia
-Weight loss and hepatomegaly
Carotenemia:
-Reversible yellowing of the skin
-Does not cause toxicity
71
Describe Vitamin D functions
Increased intestinal absorption of calcium
Resorption and formation of bone
Reduced renal excretion of calcium
72
Describe vitamin D deficiency
Demineralisation of bone:
Rickets in children
Osteomalacia in adults
73
How vitamin D
Sunlight converts 7-Dehydrocholesterol to vitamin D3 (cholecalciferol)
This is combined with dietary vitamin D3 and D2 to form 25-hydroxyvitamin D3 in the liver
Then this is converted to 1,25-dihydroxyvitamin D3 in the kidney
74
Describe vitamin E in the body
Stored in:
Non-adipose cells such as liver and plasma – labile and fixed pool
Adipose cells – fixed pool
Important antioxidant
Vitamin E requirements:
4 mg/day in men
3 mg/day in women
75
Describe vitamin E deficiency
Deficiency
Caused by:
Fat malabsorption (e.g. cystic fibrosis)
Premature infants
Rare congenital defects in fat metabolism e.g. abetalipoproteinaemia.
Clinical manifestations:
Haemolytic anaemia
Myopathy
Retinopathy
Ataxia
Neuropathy
Vitamin E excess is relatively safe in excess
76
Describe vitamin K sources and uptake
Vitamin K is rapidly taken up by the liver but then is transferred to very low-density lipoproteins and low density lipoproteins which carry it into the plasma.
Sources:
Vitamin K1 (phylloquinone)
Synthesized by plants and present in food
Vitamin K2 (menaquinone)
Synthesized in humans by intestinal bacteria
Synthetic vitamin K’s:
K3 (menadione)
K4 (menadiol)
77
What are vitamin K functions?
Vitamin K is responsible for the activation of some blood clotting factors.
Necessary for liver synthesis of plasma clotting factors II, VII, IX and X.
Can be assessed by measuring prothrombin time.
78
Describe vitamin K deficiency
Haemorrhagic disease of the newborn:
Vitamin K injection given to newborn babies
Rare in adults, unless on warfarin.
79
Describe excess vitamin K
K1 is relatively safe
Synthetic forms are more toxic
Can result in oxidative damage, red cell fragility and formation of methaemoglobin.
80
Describe vitamin C sources and functions
Found in:
Fresh fruit and vegetables
Adults need 40 mg/day
Functions:
Collagen synthesis
Antioxidant
Iron absorption
81
Describe vitamin C deficiency
Scurvy
Easy bruising and bleeding
Teeth and gum disease
Hair loss
Treatment with vitamin C improves symptoms quickly
Joint pain gone within 48 hours
Full recovery within two weeks
82
Describe vitamin C excess
Doses > 1g/day can cause GI side effects
No evidence that increased vitamin C reduces the incidence or duration of colds.
83
Describe vitamin B12 (Cobalamins)
Two active forms:
Methylcobalamin
5-deoxyadenosylcobalamin
Released from food by acid and enzymes in the stomach
Binds to R protein to protect it from stomach acid
Released from R proteins by pancreatic polypeptide.
Intrinsic factor (IF) produced by the stomach needed for absorption.
IF-B12 complex absorbed in the terminal ileum.
B12 is stored in the liver.
84
Describe vitamin B12 deficiency
Causes:
Pernicious anaemia – autoimmune destruction of IF-producing cells in stomach.
Malabsorption – lack of stomach acid, pancreatic disease, small bowel disease.
Veganism
Symptoms:
Macrocytic anaemia
Peripheral neuropathy in prolonged deficiency
85
What is folate and what is it used for?
Folate is found in may foods fortified with folic acid.
Individuals have higher requirements in pregnancy.
Functions as a coenzyme in methylation reactions, DNA synthesis, synthesis of methionine from homocysteine.
86
Describe folate deficiency causes and symptoms
Causes:
Malabsorption
Drugs that interfere with folic acid metabolism (anticonvulsants, methotrexate)
Disease states that increase cell turnover (e.g. leukaemia, haemolytic anaemia, psoriasis)
Symptoms:
High homocysteine levels
Macrocytic anaemia
Foetal development abnormalities (neural tube defects)
87
Intrinsic pathway activated by contact.
Extrinsic pathway activated by FVII coming in contact with tissue factor.
Initiates a cascade which ultimately results in fibrin clot formation.
88
What are the clotting factors produced in the liver?
Produced in the liver
I (Fibrinogen)
II (Prothrombin)
IV
V
VI
VII
89
How can clotting factors be measured and what does prolonged PT show?
The performance of the clotting pathways can be measured using:
Prothrombin time (PT) (extrinsic pathway)
International normalised ratio (INR)
Activated partial thromboplastin time (aPTT) (intrinsic pathway)
A prolonged PT may indicate a deficiency in the synthetic capacity of the liver.
Prolonged PT is not specific for liver disease:
DIC
Severe GI bleeding
Some drugs
Vitamin K deficiency
90
What are xenobiotics?
Xenobiotics are foreign substances that don’t have nutritional value. Xenobiotic compounds are mostly in the diet, but we also breathe in potential toxins, and importantly the body treats medications as xenobiotics.
These unwanted compounds need to be changed into a safer form by detoxification.
91
What are the 2 main types of xenobiotic transformation reactions
Phase 1 and Phase 2, usually make the compounds non-toxic and water-soluble.
92
What does phase I of biotransformation do
Functionalisation- non synthethic
Add or expose functional groups- -OH, -SH, -NH2, -COOH
93
What does phase II of biotransformation reactions do?
Conjugation- Biosynthetic
Conjugation with endogenous molecules: glucuronic acid, sulphate, glutathione
Covakent bonds formed
94
Are glucuronides polar?
Glucuronides are polar (hydrophilic) as the glucuronyl group has a number of hydroxyl groups which make the molecule polar and facilitate excretion in the urine.
95
What detoxidication happens in the liver
* inactivation and facilitated elimination of drugs and other xenobiotics
* active metabolites formed, with similar or occasionally enhanced activity
* activation of pro-drugs
* toxification of less toxic xenobiotics
96
Where in the liver does the detoxification take place?
Most biotransformation in the liver occurs in the endoplasmic reticulum, specifically smooth endoplasmic reticulum.
97
Describe cytochrome P450 enzymes genotypes
Cytochrome-P450 enzymes are encoded by a superfamily of more than 50 different genes in humans.
98
What features do all P450 enzymes have in common?
They are present in the smooth Endoplasmic Reticulum (hence called “microsomal” enzymes).
They all oxidise the substrate and reduce oxygen
They have a cytochrome reductase subunit which uses NADPH,
They are inducible – enzyme activity may be increased by certain drugs, some dietary components, and some environmental toxins eg smoking,
They generate a reactive free radical compound.
99
How can cytochrome P450 be used?
As well as enzyme induction by medication, these enzymes can be induced by some dietary components, and some environmental toxins such as smoking.
100
2 most common cytochrome P450 enzymes
Induction: one drug can induce numerous cytochrome isoenzymes.
Genetics: Note genetic variation especially in CYP2D6
101
Describe some drug interactions with cytochrome P450
One of the commonest mechanisms of drug interactions is via cytochrome P450.
Cytochrome P450 enzymes are inducible, which may accelerate the breakdown of some medications;
- Example; phenytoin and rifampicin can result in enzyme induction with accelerated breakdown of a wide variety of medications (accelerated breakdown);
Cytochrome P450 enzymes can be inhibited by various drugs and foodstuffs (usually takes effect quicker than induction);
- inhibition can result in increased blood concentrations of certain medications (less breakdown).
102
How is cytochrome P450 inhibited?
An example of enzyme inhibition that is sometimes in the popular press is inhibition of a cytochrome P450 by compounds in dietary components such as grapefruit juice.
A lot of medications are metabolised in Phase I by CYP3A4.
Most statins are metabolised by CYP3A4.
By inhibiting metabolism of simvastatin and atorvastatin, grapefruit juice causes increased blood levels with increased risk of side-effects.
103
How does smoking link to clozapine?
Changes in smoking behaviour can significantly alter clozapine metabolism.
The clozapine dose may need to be increased if someone on clozapine takes up smoking.
Clozapine levels increase after cessation of smoking, which means a dose reduction of 30-50% may be required to avoid drug toxicity.
104
Describe some conversions from active and inactive drugs to active or inactive metabolites
Active Drug to Inactive Metabolite
Phenobarbital Glucuronides etc
Active Drug to Active Metabolite
Codeine Morphine
Diazepam oxazepamInactive Drug to Active Metabolite
Clopidogrel Active drug
Active Drug to Reactive Intermediate
Benzo[a]pyrene Reactive metabolite
(carcinogenic)
Paracetamol NAPQI (toxic)
105
Describe the inactivation of xenobiotic
An illustration is Phenobarbital which is a barbiturate derivative with both sedative and anti-epileptic activity, metabolised in classic Phase I & Phase II reactions,
Phenobarbital is relatively lipophilic; drug distributes into fat tissue.
The amount that remains in the plasma is mostly bound to plasma proteins.
only a small fraction of the drug is found freely dissolved in the blood plasma,
Elimination of the unmodified drug is thus very slow, and most of the drug is excreted after enzymatic conjugation.
106
Describe the conversion of active drug to active metabolites in opiates
Codeine is a morphine molecule with one hydroxyl group replaced by a methyl group which makes the compound less susceptible to first-pass metabolism (in gut mucosa and liver).
Codeine is active, and is de-methylated in the liver to morphine which is also active.
107
Describe active drug to active metabolites
Diazepam is demethylated in the liver (a phase-1 reaction) to nordiazepam (an active metabolite).
Nordiazepam is hydroxylated (also a phase-1 reaction) to oxazepam.
Oxazepam is also an active metabolite, and can be prescribed as a shorter-acting sedative. Oxazepam is metabolised by conjugation (phase-2) and excreted without any phase-1 step.
108
Describe the pro-drug to active drug pathway
An inactive drug or pro-drug may be converted in the liver to an active agent.
For example Loratadine, a non-sedating antihistamine, is the prodrug of desloratadine, which is largely responsible for the antihistaminergic effects of the parent compound.
Similarly clopidogrel is a pro-drug. Conversion to the active form varies with variations in CYP activity, including genetic variations.
109
How to tell if it is small or large intestine on an x-ray?
Plicae circularis on small bowel Lines go all the way across
Haustral folds on large intestine- lines don't go all the way across
110
Functions of the colon
Absorption of water and electrolytes (osmosis)
Excretion of waste (motility)
Production of vitamins/regulation of immune system (microbiome)
111
Describe redundant colon and the conditions it causes
Constipation
twisting of the bowel
112
Describe the layers of the colonic wall from inside to outside
Mucosa
Muscularis mucosae
Submucosa
Muscularis propria
Subserosa
Serosa
113
Describe the colonic mucosa
Single layer columnar epithelium
Goblet cells- secrete mucin that lubricates the bowel
Lamina Propria - Inflammatory cells- helps maintain immunological homeostasis
114
Describe the muscularis propria
Inner circular muscle (CM) – mass movement by peristalsis- contain cells of cajal which regulates the contraction of the bowel
Auerbach Nerve Plexus- myenteric plexus
Longitudinal muscle (LM) – segmental motility- creates haustra
115
Describe the nerve supply to the colon and rectum
Enteric Nervous System- little brain
Intrinsic -
Myenteric Plexus
Submucosal Plexus
Extrinsic -
Parasympathetic- anoreactal control- non-conscious control
Sympathetic- conscious control
116
Parasympathetic defecation reflex
stretching which stimulates stretch receptors
info to the brain which sends a message via pelvic nerve so they
117
Describe the rectum
temporary storage for stool
can store lots with little increase of pressure
118
internal anal sphyncter
119
External anal sphyncter
ring
conscious control
120
Describe the puborectalis
at rest creates 90 degree angle
121
What are the four phases of defecation?
1. Basal
2. Pre-expulsive
3. Expulsive
4. Termination
122
Describe the basal phase
Colon – segmental contractions (mixing)
Rectum - motor complexes (to keep rectum empty)
“braking mechanism”
Anal Sphincter - tonic contraction
Puborectalis - contracted (90o anorectal angle)
123
Describe the pre-expulsive phase in the colon
Colon – high amplitude propagating contractions
Mass movement of stool ~8 times day
Gastro-colic reflex
124
Describe the pre-expulsive phase in the rectum
Rectum –
Fills causing distension
Rectal compliance (adaptive relaxation)
125
Describe the pre-expulsive phase in the anal sphincter and puborectalis
Anal Sphincter –
EAS maintains contraction
Reflex relaxation of IAS (RAIR) – for stool sampling
Puborectalis – remains contracted
126
Describe the expulsive phase
Rectum contracts
IAS, EAS and PR relaxes
Valsalva manoeuvre/posture
aid emptying
127
Describe the termination phase
Traction loss causes sudden contraction of EAS (“closing reflex”)
Valsalva ceases
Change in posture (to standing)
128
What are some causes of constipation?
Consistency of stool
Bowel motility
Physical blockage to the bowel
Pelvic floor disorders
129
Describe a colonic transit study
130
Defecating postogram
To test for anatomical anomalies
barium paste inserted into anus and then x-rayed
131
Anorectal manometry
Probe inserted- allows us to assess pressure
at rest and during
132
Describe causes of faecal incontinence
Consistency of stool or frequency of movements
Diseased bowel mucosa
Reduced rectal capacity
Pelvic floor disorder
133
Describe the endo-anal ultrasound
looking for circular anal sphynters
134
What is an amino acid?
It is the building block of protein. All human proteins can be formed from chains formed of 20 different amino acids.
There are more than 20 amino acids. Some have a role in human health, such as homocysteine, but are not actually incorporated into human proteins.
135
Where do we get protein from
Dietary protein (0.75g/kg/day)
136
Where are aas in the body?
METABOLIC PRECURSORS
(Glycolysis and TCA cycle intermediates, Acetyl CoA)
Freee aa pool
Proteins (around 10kg)
137
Where is nitrogen lost?
Renal excret
138
add in cards
139
Describe aa metabolism
140
How is dietary protein absorbed
Dietary protein --- pepsin and HCl in stomach----> denatured protein------
141
What are essential amino acids?
Need to have it in your diet and can't synthesis it
e.g phenylalanine and valine
142
Conditionally essential meaning
Can synthesise them but needs an essential amino acid to make them
143
What are non-essential amino acids?
Can synthesise them de novo
144
Some important hepatic proteins
ALBUMIN
Coagulation Factors
IGF-1
C-Reactive Protein
Carrier proteins (eg caeruloplasmin)
Apolipoproteins (for lipoproteins
145
slide 15
146
How can aas be used in the TCA cycle?
Some aas are
147
Degradative pathway length from aas to
PKU
148
Describe transamination
149
Transamination of alanine
Alanine + alpha Ketoglutarate -> pyruvate + glutamate
150
no storage of amino acids so take it from bodily protein
151
Describe protein degradation
Faulty/aging/obsolete proteins
Signal transduction
Flexible system to meet protein/energy requirements of environment
Main means:
1. PROTEASOME (ubiquitin-dependent)
2. LYSOSOME
152
What is ubiquitin (the mark of death)
Small protein
Carboxyl group forms isopeptide bond with multiple Lysine residues
Three enzymes involved:
E1 Ubiquitin-activating enzyme
E2 Ubiquitin-conjugating enzyme
E3 Ubiquitin-protein ligase
Formation of ubiquitin chains (stronger signal, esp if >4)
153
Describe the proteosome
caps- interact with ubiquitin
Proteasome
154
What is the N-terminal rule?
N-terminal residues determine protein half-life
PEST Sequences (proline, glutamate, serine, threonine)
Cyclin Destruction Box
some are stabilising N- terminal residues e.g alanine and glycine
Some are destabilising N- terminal residues e.g lysine and arginine
155
Describe lysosomal
Proteolytic enzymes within lysosome separated from cytosolic components
156
What is macroautophagy?
non-selective
ER derived autophagisomes engulf cytosolic proteins/aggregates organelles. Lysosome fuses with this to initiate proteolysis.
157
What is microautophagy?
non-selective
Invaginations of lysosomal membrane engulf proteins/organelles.
158
What is chaperone-mediated autophagy?
selective
Chaperone protein hsc70, in cytosol and intralysosomal, accompany specific cytosolic proteins in response to stressors (fasting/ oxidative stress etc).
159
What is endocytosis/ phagocytosis of?
Extracellular substances.
160
What is cystinosis
Genetic condition
Autosomal recessive
1 in 200,000
Defect in transporter leads to cystine accumulation in tissue lysosomes
Eye and kidney problems
Crystalisation occurs
161
What does Alanine do in amino acid catabolism?
Glucose-alanine cycle transports nitrogen from amino acid breakdown from the tissues to the liver, whilst recycling a carbon backbone that can be converted to glucose for energy.
162
What does cortisol do in amino acid catabolism?
+ Proteolysis
- Protein synthesis
+ Gluconeogenesis
163
What does glutamine do in amino acid catabolism?
Glutamine is formed from BCAA degradation in the tissues. In the fasting state, it is an important metabolic fuel for the kidney and gut, and provides ammonia to buffer proton diuresis in metabolic acidosis states.
164
What is the role of glucagon in amino acid catabolism?
+ Glycogenolysis
+ Gluconeogenesis
+ Amino Acid degradation
+ Ureagenesis
+ Entry of Amino Acids to Liver
165
Describe the role of branched chain aas in amino acid catabolism
Isoleucine/Valine/Leucine. Major amino acids that can be oxidised in tissues other than the liver, especially skeletal muscle.-
166
What are the major proteins synthesised in the liver?
Most plasma proteins (except for immunoglobulins) including:
Albumin
CRP
Hormone binding globulins
Apolipoproteins
Other transport proteins
Caeruloplasmin
Ferritin
All factors in the complement cascade
Parts of the following pathways:
Inhibitors of clotting
Fibrinolysis
Inhibitors of fibrinolysis
Complement
167
Describe albumin
~Properties:
66 kDalton protein
Negatively charged
10-15g produced by the liver per day
Functions:
Plasma oncotic pressure
Carrier protein:
Hormones
Vitamins
Electrolytes (Ca2+, Mg2+, etc)
Drugs
168
What are some causes of hypoalbuminaemia?
Inflammation
Liver disease
Renal disease
Burns/trauma
Sepsis
Malnutrition
169
What are some consequences of hypoalbuminaemia?
Oedema
Effusions
Carrier protein – may need to adjust for this
170
What are some albumin calculations?
Exudates vs Transudates
Adjusting for electrolytes – esp Ca2+
Adjusting for hormone levels – eg free testosterone
Renal disease
171
What are some of the key features of the clotting cascade?
Made in liver: Fibrinogen, Prothrombin, Factors V, VII, IX, X, XI, XII, XIII, Protein C, Protein S
Vitamin K: Essential factor to the hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII, IX and X
(see slide 9 of protein synthesis and urea cycle lecture)
172
What is the link between chronic liver disease and bleeding?
Reduced synthesis of clotting factors
Hepatic dysfunction
Vitamin K deficiency/malabsorption
Reduced synthesis of inhibitors
Production of abnormal/dysfunctional proteins
Enhanced fibrolytic activity
Reduced clearance of activators of fibrinolysis
Reduced production of inhibitors
Reduced hepatic clearance of clotting factors
Disseminated intravascular coagulation
Multifactorial – includes endotoxaemia
Platelet abnormalities
Number
Function
Development of varices!
173
What are some core clinical problems of the urea cycle?
15 – Confusion/delirium
16 – Loss of consciousness/coma
23 – Seizure
32 – Deterioration of intellect
34 – Learning difficulty
Most because of toxicity
174
What is the significance of NH4+?
It is a product of amino acid breakdown
can either be used again in amino acids or excreted
175
Describe the glucose-alanine cycle
176
Describe the Krebs bicycle
A
177
What are the 2 ways that ammonia enters the urea cycle?
178
How does ammonia lead to neurotoxicity?
lead to brain swelling and damage
179
180
What are some key features of OTC?
Late onset, very variable:
male, 16th birthday, vomiting, encephalopathy, diagnosed, died.
male, 17, Scout camp, drowsy, vomiting, swollen brain, died.
female, 51, protein avoidance, P2+1, ops, 6 admissions 2002-3.
Triad: encephalopathy, resp. alkalosis, hyperammonaemia
Plasma ammonia
181
Describe treatment of urea cycle disorders
Avoidance of catabolism, glucose polymers when unwell
Induction of anabolism – give dextrose 10% 2ml/kg/hr -> insulin!
Low dietary protein, arginine, benzoate, phenylbutyrate
Haemofiltration
Liver transplantation, umbilical vein hepatocyte transfusion
Gene therapy: NIH NGVL UPenn trial stopped after death (adenovirus E1 E4 del., fever, multi-organ failure)
182
Give an overview of GI function
Take relatively large solids and digest them into smaller molecules that can be absorbed as nutrients, while still serving as a barrier to toxins, bacteria, parasites, etc.
183
Give an overview of the functional anatomy of the GI system
GI system is a hollow organ, a tube through the body.
The lumen is “outside” the body’s tissues, but its environment is tightly controlled by the body.
Specialized organs for secretion of enzymes & bile.
Epithelial cells line the entire GI tract and serve as the primary barrier.
Structure maximizes surface area for secretion and absorption (folds, villi, and crypts).
184
Describe the daily fluid balance
185
Where does absorption and secretion in the small intestine occur?
Net absorbtion- top of villi
Net secretion- Crypts of villi
186
Describe the movement of H2O and electrolytes in the small intestine
Water moves down an osmotic gradient
Electrolytes move down electrochemical gradients
To move against concentration gradients requires energy
Energy is supplied by sodium gradients (generated by the sodium pump) and by proton gradients
187
How do we absorb water
Sodium moves from gut into cell then out into the lumen then water follows
Can also go through gap junctions between cells
188
Describe the mechanism of intestinal secretion
Chloride ions enter the crypt epithelial cell by cotransport with sodium and potassium; sodium is pumped back out via sodium pumps, and potassium is exported via a number of channels.
Activation of adenylyl cyclase by a number of so-called secretagogues leads to generation of cyclic AMP.
Elevated intracellular concentrations of cAMP in crypt cells activate the CFTR, resulting in secretion of chloride ions into the lumen.
Accumulation of negatively-charged chloride anions in the crypt creates an electric potential that attracts sodium, pulling it into the lumen, apparently across tight junctions - the net result is secretion of NaCl.
Secretion of NaCl into the crypt creates an osmotic gradient across the tight junction and water is drawn into the lumen.
189
Factors affecting absorption
number and structure of enterocytes
Blood and lymph flows
Nutrient intake
GI motility- hormonal and neural
190
Factors influencing secretion
Irritants
Bile
Bacterial toxins
191
What does coeliac disease and what do they present with?
Damage to villi
Low iron, B12, calcium, lethargy, osteoporosis
192
Describe cholera
Vibrio cholerae can survive in the water without a host for a long enough time to be ingested by its next host.
Cholera is transmitted by either contaminated food or water. Source of contamination is typically other cholera sufferers when their untreated diarrheal discharge is in waterways, groundwater, or drinking water supplies. It rarely spreads from person to person.
Major sources:
In developed world: seafood is typically the cause
In developing world: it is often water
193
How does cholera induce diarrhoea?
Cholera toxin released from bacteria in infected intestine
Binds to Intestinal cells
Stimulates adenylate cyclase to produce cAMP
Dramatic efflux of ions and water
Watery Diarrhoea
194
Describe oral rehydration
Water passively follows the osmotic gradient
SGLT1- sodium glucose co-transporter which moves Na and glucose from the luminal membrane into the enterocyte
195
Definition of digestion and absorption
Breakdown of large, complex organic molecules that can be used by the body.
Mechanical (eg. chewing, churning of food)
Chemical (eg. enzymes)
196
Digestion of carbohydrates
Salivary amylase then pancreatic amylase breaks down larger glucose polymers
Then the disaccharides (maltase, sucrase and lactase) break them down into monomers
Enterocytes absorb glucose and galactose through an Na-dependent secondary active transport process, while fructose is absorbed by facilitated transport.
197
Describe the digestion and absorption of proteins
Process starts in the stomach with pepsin the continues with trypsin ect in the small intestine
198
Describe the digestion of fats
Fat and water separate- enzymes are in water and can't get to the fat
Bile (an emulsifier) arrives, bile has an affinity for both fat and water and can therefore bring the fat into the water
After emulsification, the fat is mixed in the water solution do the fat-digesting enzymes have access to it
199
Digestive enzymes in the salivary gland and what they target
39
200
Digestive enzymes in the stomach and what they target
201
Digestive enzymes in the pancreas and what they target
202
Digestive enzymes in the intestine and what they target
203
What stimulates the pancreas to work?
CCk release when you consume food
vagus nerve
204
What are some symptoms of pancreatic failure?
Maldigestion symptoms- e.g steatorrhea, weight loss, diahorrea, abdominal pain, bloating
205
Impact of PEI
malnutrition- maldigestion/malabsorption
206
Causes of PEI- Parenchymal diseases
Chronic pancreatitis
Acute pancreatitis
Cystic fibrosis
Pancreatic cancers
autoimmune pancreatitis
207
Extra-pancreatic diseases
Coealic disease
208
Outline H1 histamine receptors
Location: Throughout the body, specifically in smooth muscles, vascular endothelial cells, heart and CNS
Type of receptor: G-protein coupled linked to intercellular Gq. which activates phospholipase C
Effect: Mediate an increase in vascular permeability of inflammation induced by histamine
Diseases: Allergies, nausea, sleep disorders
209
Outline H2 histamine receptors
Location: Mainly gastric parietal cells, low level can be found in vascular smooth muscle, mast cells, neutrophils, CNS, heart and uterus
Type of receptor: G-protein coupled linked to intercellular Gs
Effect: Increases the release of gastric acid
Diseases: stomach ulcers
210
Outline the H3 histamine receptor
Location: Found mostly presynaptically in the CNS, with a high level in the thalamus, caudate nucleus & cortex, also a low level in small intestine, testis & prostate
Type of receptor: G-protein coupled possibly linked to intercellular Gi
Effect: Neural presynaptic receptor may function to release histamine
211
Outline H4 histamine receptors
Location: They were discovered in 2000. They are widely expressed in component of the immune systems such as the spleen thymus and leukocytes
Type of receptor: Unknown (most likely also G-protein coupled)
Effect: Unknown
