GI Flashcards
What are the major functions of the GI tract
Ingestion: occurs when materials enter digestive tract via the mouth
Mechanical processing: crushing, shearing, wetting, softening; makes materials easier to propel along digestive tract
Digestion: the chemical breakdown of food into small organic fragments for absorption by digestive epithelium
Secretion: the release of water, acids, enzymes, buffers and salts by epithelium of digestive tract or by glandular organs
Absorption: movement across digestive epithelium into interstitial fluid of digestive tract
Excretion: removal of indigestible material and waste products from bodily fluids
What is peristalsis
Smooth muscle contraction
Co-ordinated to move bolus forwards
Need relaxation of sphincters
What does the stomach do
Storage vessel
Churns food
Produces acid to start breakdown of food
What are the functions of the pancreas
Exocrine secretions aid digestion: discharged into intestine via pancreatic duct; Amylase, Lipase and trypsin; need alkaline medium for efficiency; produces bicarbonate
Endocrine secretion regulate carbohydrate metabolism: glucagon, insulin, gastrin, somatostatin
What is the function of the liver
Synthesis of bile
Helps to digest fats
Detoxification of blood from the GI tract
Metabolism of carbohydrates, proteins, fats
Manufacture proteins (clotting factors)
Storage of carbohydrates and fat-soluble vitamins
What are the functions of the small and large intestine
Large: water absorption (can survive without
Small: Major role in absorption (cannot survive without)
What are the stages of liver disease
Fatty liver -> liver fibrosis -> cirrhosis
What are the EAR, LRNI, RNI and safe intake in the guidelines for nutritional requirements
EAR: estimated average requirement, half the population usually need more and half less
LRNI: lower reference nutrient intake, sufficient for the few people who have low needs but not meeting the needs of 97.5% of population
RNI: reference nutrient intake, sufficient for about 97.5% of the population
Safe: Sufficient for almost everyone but not so large as to cause undesirable effects
What does energy expenditure depend on
Basic metabolic rate
Amount and intensity of physical activity
What are the essential amino acids
9 amino acids that cannot be synthesised by humans and must be obtained from diet
Methionine Valine Histidine Leucine Phenylalanine Tryptophan Isoleucine Lysine Threonine
Many Very Happy Little Pigs Try Iced Lemon Tea
What are the different types of fats and where are they found
Saturated: no double bond, found in meat and dairy
Monounsaturated: one double bond, found in olive and peanut oil
Polyunsaturated: more than 1 double bond, corn and sunflower oil
Trans: trans double bonds, cakes, biscuits and pastry
What are the different types of carbohydrates and where are they found
Polysaccharides: mainly starch
Disaccharides: mainly sucrose
Monosaccharide: mainly glucose and fructose
Non-starch polysaccharide: dietary fibre
What is a vitamin
Organic compounds required for normal metabolic function, which cannot be synthesised by the body
What are minerals
A naturally occurring inorganic compound
What are the key minerals needed by the body
Iron Zinc Calcium Magnesium Iodine Fluoride Phosphate Sodium Potassium
Why may nutritional deficiencies arise
Inadequate intake:
Food availability
Food choices
Problems with eating
Inadequate absorption:
Problems with fat absorption affects fat soluble vitamins
Pernicious anaemia
Excess loss/increased requirements:
Iron deficiency anaemia
Folic acid deficiency
What is malnutrition
Inadequate or excess intake of protein, energy, and micronutrients scubas vitamins and minerals
What are current nutritional guidelines
Starchy foods ~40% of energy intake At least 5 portions of fruit and veg per day Moderate amounts of protein-rich foods Moderate amounts of milk and dairy Less saturated fat, salt and sugar
What are current vitamin guidelines
Children should take vitamin A, D and C supplements
Pregnant women should take folic acid daily until week 12
What is the GI tract
Also called digestive tract or alimentary canal
Muscular tube lined by epithelium
Extends from oral cavity to anus, passing through pharynx, oesophagus, stomach, small and large intestines
About 8-9 meters long: Pharynx, oesophagus and stomach ~1m
Small bowel ~6m
Large bowel ~1.5m
What is the peritoneum
Parietal: Lines the abdominal cavity
Visceral: covers organs
Forms mesenteries, which suspend the organs, support them and keep them from tangling
Secretes peritoneal fluid, which provides lubrication and permits organs to move against each other without friction
What parts of the GI tract are supplied by each of the 3 unpaired arteries of the Aorta
Coeliac trunk: Foregut
Superior mesenteric artery: mid gut
Inferior mesenteric artery: hind gut
What is epithelia
Layers of polarised cells covering internal or external surfaces
What are glands
Structures the produce secretions
What is the Net flux
Net flux (Jnet) = absorptive flux (Jabs)- secretory flux (Jsec) Difference between the absorption and sectarian of molecules into and from the blood stream
What are the layers of the abdominal wall
Skin
Subcutaneous tissue (fat)
Muscle layers
Peritoneum
What are the three pairs of the muscles of the abdominal wall
External oblique
Internal oblique
Transversus abdominus
What is the line alba
A thick cartilaginous tendon which connects the abdominal wall muscles in the midline
What is an aponeurosis
A flat tendons sheet
What is the rectus abdominis
Long strap muscles which are divided into six muscle bays with small tendon interfaces between
Form the six pack
What are the function the abdominal muscles
Support for vertebrae
Protection
Aids with deification
What is the rectus sheeth
Aponeurosis formed from the layers of abdominal wall muscle
Fibrous compartment containing rectus abdominis, epigastric arteries and tips of thoracoabdominal nerves
How does the rectus sheeth above the umbilicus compare to that below
Above:
Anterior: external oblique aponeurosis, anterior layer of internal oblique aponeurosis
Posterior: Posterior layer of internal oblique aponeurosis, transversus abdominis and peritoneum
Below:
Anterior: external oblique aponeurosis, internal oblique aponeurosis, transversus abdominis
Posterior: peritoneum
What is the inguinal region
An area of the abdominal call that extends from the anterior superior ilia spine (ASIS) to the pubic tubercle
The inguinal can is found here
What is in the inguinal canal
Spermatic cord in the male and the round ligament in the female
What teeth are in our mouths
Central incisors Lateral incisors Cuspid 1st Premolar 2nd Premolar 1st molar 2nd molar 3rd molar
What are the functions of the muscles of mastication (chewing)
Close the jaw Slide or rock lower jaw from side to side Chewing involves mandibular: Elevation and depression Protraction and retraction Medial and lateral movement
What do the tongue and cheeks do
Move food across teeth
What are the functions of saliva
Lubrication of mouth and food and cleaning: serous fluid mucus Facilitation of taste Protection against acid and bacteria: antibacterial enzymes bicarbonate calciumions Digestion: salivary amylase lingual lipase
How is saliva production regulated
Almost entirely due to neural control Both parasympathetic (watery) and sympathetic (mucoid) activity increase secretion Parasympathetic controlled by salivary centre in the brain stem, driven by: local stimuli (test and touch in mouth) Central stimuli (smell and sight of food) Learned reflex (think of Pavlov's dogs
What are the major salivary glands
Parotid gland
Tongue
Sublingual gland
Submandibular gland
What are the characteristics of the parotid gland
Largest salivary gland
Predominantly serous secretion
About 25% of salivary volume
Main source of salivary amylase and proline-rich proteins
Parasympathetic supply via CN IX
Sympathetic supply from superior cervical ganglion
What are the characteristics of the submandibular gland
Mixed serous and mucous secretion
About 70% of salivary volume
Main source of lysozyme and lactoperoxidase
Parasympathetic supply via CN VII
Sympathetic supply from superior cervical ganglion
What are the characteristics of the sublingual gland
Predominantly mucous secretion About 5 % of salivary volume Main source of lingual lipase Parasympathetic supply via CN VII Sympathetic supply from superior cervical ganglion
What problems will patients with Sjogren’s syndrome present with, what is this syndrome and how is it treated
An autoimmune condition in which salivary and lacrimal glands are damaged
Dry eyes Dry mouth Difficulty speaking and swallowing Sever dental disease Other autoimmune issues
Artificial tears Acid sweets Drink water Careful dental care May need steroids or immunosuppressants
What is Ptyalin
An a- Amylase
Can cut at a-1,4 sites of carbohydrates
pH optimum is about 7 and denatured at pH 4
What is lingual lipase
initial digestion of triglycerides
Cleave the outer fatty acids off triglycerides, leaving diacyl glycerol
pH optimum is ~4 so stable in the stomach but denatured by pancreatic proteases
Works together with gastric lipase
What are the different types of papillae on the tongue
Foliate
Circumvaliate
Fungiform
What are the two types of taste sensors and what are the sensing
Specialised epithelial cells
Ion-channel based sensor: salty and sour
GPCR-based sensor: sweet and bitter
What are odour receptors
Nerve cells
What is the cephalic phase
A combination of stimuli
Mediated by parasympathetic nervous system:
Salivary secretion via facial and glossopharyngeal nerves
Control of GI motility and secretion via vagus
Vagus also carries afferent fibres which contribute- feedback system
What are the roles and secretions of the LES and cardia region of the stomach
Mucos HCO3- Prevention of reflux Entry of food Regulation of belching
What are the roles and secretions of the fundus and body region of the stomach
H+ Intrinsic factor Mucus HCO3- Pepsinogens Lipase
Reservoir
Tonic force during emptying
What are the roles and secretions of the Antrum and pylorus region of the stomach
Mucus
HCO3-
Mixing
Grinding
Sieving
Regulation of emptying
How is gastric emptying controlled
Particles larger than 1-2 mm cannot pass pyloric sphincter
Duodenum senses delivery of acid, amino acids and lipids, and so secretes hormone which decrease gastric motility and emptying
Enteric nervous system
What is gastrin
Peptide hormone release from G cells of stomach and duodenum into the bloodstream
Two forms:
G17: main form secreted from Antrum
G34: main form secreted from duodenum
Main actions on the stomach are to stimulate acid secretion and promote mucosal growth
What is gastrin release stimulated by
Lumenal proteins/amino acids
Parasympathetic input, mediated by gastrin releasing peptide from interneurons
What is gastrin release inhibited by
Lumenal (H+) negative feedback
What is pepsin
Family of proteases, secreted from the chief and mucus cells in response to ACh, [H+]
Secreted as pro hormones (pepsinogens)
Cleave spontaneously at low pH (
What is gastric lipase
Initial digestion of triglycerides
Cleave the outer fatty acids off triglycerides, leaving diacyl glycerol
pH optimum is ~4
Stable in the stomach but denatured by pancreatic proteases
Works together with lingual lipase
What causes vomiting
Centrally controlled: area postrema = chemoreceptor trigger zone
Vagal afferents in response to irritants in or around the bowel
Psychogenic: pain, revulsion
Motion sickness
Drugs or toxins with a direct effect
Pregnancy
What are the three parts of the primitive gut tube
Foregut: mouth to 1st half of duodenum
Midgut: 2nd half of duodenum to 2/3 along transverse colon
Hindgut: distal 1/3 transverse colon to superior 2/3 rectum
What are intraperitoneal organs vs retroperitoneal organs
Organs enclosed in a mesentery are intraperitoneal
Organs that are not surrounded by peritoneum are retroperitoneal
Where are the dorsal and ventral mesenteries
Dorsal: from lower oesophagus to cloaca
Ventral: from lower oesophagus to 1st part of duodenum
What is formed by the ventral mesentery
Lesser momentum and falciform ligament (umbilical vein)
What happens to the vitelline arteries
Give rise to the 3 arteries which supply the GI tract by undergoing remodelling, losing their connection to the yolk sac in order to supply the GI tract
How is the definitive gut lumen formed
In week 6, proliferation of the endoderm derived epithelial lining occludes the gut tube
Apoptosis occurs over the following 2 weeks to create vacuoles (racanlisation)
During the process the epithelial lining further differentiates
What can happen as a result of abnormal recanalization
Can cause duplication of the GI tract
Incomplete recanalosation can cause stenosis (narrowing) or atresia (blockage) of the gut tube
What happens with the oesophagus in embryological terms
Forms in week 4
Caudal to the lung bud
Has endodermal epithelial lining and smooth muscle layer from visceral mesoderm
Some skeletal muscle derived from the paraxial mesoderm
Initially very shirt with the stomach located in the future thorax
Extens rapidly in weeks 4-7 as stomach descend to abdomen
How does the stomach develop
Appears in week 4 as a dilation of the foregut
Is suspended in the abdomen by the dorsal and ventral mesenteries
Differential growth in week 5 forms the greater curvature
In weeks 7-8 the stomach rotates around 2 axes
How does the stomach rotate
90* clockwise rotation around the craniocaudal axis causes the lesser curvature to move from ventral position to right while greater curvature moves from dorsal to left
Vagus nerves are initially on left and right sides but rotate also such that the left vagus nerve becomes anterior and right vagus nerve becomes dorsal
Also some rotation around the ventrodorsal axis so that the GC faces slightly caudally and the LC slightly cranially
How are the lesser and greater peritoneal sacs formed
Lesser: As the stomach rotates around the craniocaudal axis, it creates a space behind it
Greater: the remaining peritoneal cavity
What is the epiploic foramen
the narrow opening that connects the greater and lesser sacs
What is congenital pyloric stenosis
Narrowing of the pyloric sphincter caused by hypertrophy of smooth muscle
Restricts gastric emptying and so can lead to dilation of the stomach
How is the duodenum formed
Has to origins, 0.5 foregut, 0.5 midgut
Boundary is distal to the entrance of the common bile duct
It elongated in week 4 resulting in a ventrally projecting C-shape
This is dragged to the right by the rotating stomach
Dorsal mesentery attached to the duodenum degenerates so that the majority of it lies against the posterior abdominal wall
What are the characteristics of the small intestine
Villi and microvilli amplify the surface area available for interaction with food
Crypts secrete bicarbonate-rich fluid
Brush border enzymes
What are brush border enzymes
Integral membrane proteins
On surfaces of intestinal microvilli
Break down materials in contact with the brush border
How are carbohydrates digested
Soluble amylases only break internal a1,4 bonds
Remaining short chain carbs are broken down by specific enzymes on the brush border
Glucose and galactose actively absorbed by SGLT1
Fructose passively absorbed by GLUT5 transporter
What are endopeptidases vs exopeptidase and what are some examples
Endopeptidases cut within protein chain: trypsin, chymotrypsin, elastase
Cut at the last peptide bond: carboxypeptidases
How is fat digested
Bile salts break up lipid droplets increasing surface area
Pancreatic lipase cleaves off outer fatty acids
Once broken down, form a complex with bile salts, solubilising them allowing to diffuse close to brush border delivering contents to the membrane
How are vitamins absorbed
Fat-soluble (ADEK): absorbed with lipids
Water-soluble: require special transport proteins, usually Na+ linked
Vitamin B12: absorbed when bound to intrinsic factor
Where does most digestion and absorption happen
In the small bowel
What is the colon important for
Electrolyte balance and final water reabsorption
What does the small bowel secrete and where does it receive secretions from
Alkaline fluid into the lumen and hormones into the blood
Liver and pancreas
What is the ampulla of Vater
The little prominence where the common duct enters the duodenum
Where is bile stored and where does it secrete to and what stops this secretion
The bile produced by the liver and the secretions from the pancreas enter the duodenum via a common duct
The sphincter of Oddi can close this of and relaxes in response to CCK-PZ
When the sphincter is closed the bile is stored in the gall bladder
What is secretin
Peptide hormone secreted by S cells of the small intestine
Stimulated mainly by acid in the small intestine
Main effect is to stimulate bicarbonate secretion by ductal cells in the pancreas and liver
Trophic effect on the pancreas
Modest inhibition of gastric acid production
What is CCK
Peptide hormone secreted by I cells of of the small intestine
Release stimulated mainly by lipids and peptides in the small intestine
CCK-A receptors for CCK
CCK-B receptors for gastrin
Two effects: stimulate pancreatic secretion
stimulate gallbladder emptying
What does bile contain
A complex mixture of components
Phospholipids and cholesterol
Pigments from the breakdown of haemoglobin
Inorganic ions: cations> antions, due to negative charge of bile acids
Bicarbonate
Salt
Water
What are the different types of pancreatic enzymes secreted in an alkaline fluid
Proteases (trypsinogen) Pancreatic a-amylase Pancreatic lipases (nonspecific esterase) Nucleases (DNA, RNA) Monitor peptides
What are the boundaries of the abdominal cavity
Superior: thoracic diaphragm
Inferior: continuous witch pelvic cavity
Anterior and lateral: abdominal muscles
Posterior: lumbar vertebrae
What is parietal peritoneum
Layer of peritoneum lining the abdominal wall, pelvic and inferior surface diaphragm
What is the visceral peritoneum
Layer of peritoneum the specifically covers a viscus organ , the parietal and visceral layers of peritoneum are continuous just like the pleura
What are the greater and lesser sac
Greater: main peritoneal cavity which is subdivided into supracolic and infracolic
compartments
Lesser: Recezz of peritoneal cavity between stomach and posterior abdominal wall
The two are linked by the epiglottic foramen
How is the midgut formed
Week 5 midgut and associated dorsal mesentery undergo rapid elongation form the primary intestinal loop, containing cranial and caudal limbs, which communicates with the yolk sac through the vitelline duct
What do the cranial and caudal limbs form
Cranial: distal duodenum, jejunum and proximal ileum
Caudal: distal ileum, caecum, appendix, ascending colon and proximal 2/3 transverse colon
Why does the primary intestinal loop herniate into the umbilical cord in week 6 and what happens while herniation is happening
There is not enough room in the abdomen due to elongation of the midgut and growth of the liver
The midgut rotates 90* anti-clockwise bringing the cranial limb to the right and the caudal limb to the left
Jejunal loops form
What happens to the midgut in week 10
The midgut returns to the abdomen and rotates a further 180* anti-clockwise, bringing the proximal jejunal loops to the left and the caecum lies inferior to the liver, forming a wormlike diverticulum called the vermiform appendix
The vitilline duct is obliterated during this
What has happened to the midgut by week 11
It has returned to the abdomen and undergone 270* anti-clockwise rotation in total
What is the result of the descent of the caecum
Caecum descends from below the liver to right iliac fossa pilling the ascending and transverse colon into place resulting in the final arrangement of the midgut
What is Meckel’s diverticulum and what is the role of 2s in relation to it
A remnant of the vitilline duct that created an out pocketing of the ideal wall
Usually asymptomatic but may contain ectopic pancreatic or gastric tissue causing inflammation, ulceration and bleeding
Affects 2% population 2 times more common in males 2 feet from ileocaecal junction 2 inches long Symptomatic in 2% of cases
What is omphalocele
Failure of midgut to return to abdomen in week 10
Associated with an increased risk of mortality and other malformations
Diagnosed prenatally by ultrasound
Varies in size depending on contents
What is the result of non-rotation of the midgut
Gut undergoes initial 90* anti-clockwise rotation but fails to rotate a further 180* when gut is retracted
Results in small intestine on the right side and large intestine on the left
Usually asymptomatic
What is reversed rotation of the midgut
Initial 90* anti-clockwise rotation occurs normally but the gut rotates 180* clockwise upon retraction, thereby entering abdomen in correct order but duodenum lies ventral to transverse colon
What is volvulus of the midgut
Twisting due to abnormal rotation causing parts that would normally be retroperitoneal to remain suspended by the dorsal mesentery and can cause acute obstruction of the bowel and bilious vomiting and may constrict arterial supply to the gut causing schema and infarction
How is the hindgut formed
The distal end of the handout enters the dorsal part of the cloaca- anorectal canal.
Ventral part of the cloaca (urogenital sinus) will form the bladder, pelvic urethra, penile urethra (males) and caudal part of vagina (females)
During weeks 4-6 a layer of mesoderm extends caudally to separate the urogenital sinus and anorectal canal (urorectal septum)
What happens in week 7 th the cloacal membrane and the urorectal septum
It ruptures to create the anal opening and ventral opening for the urogenital sinus
Urorectal septum lies between them and forms the perineal body
How is the anal canal formed
The upper 2/3 is derived from endoderm (hind gut) and the lower 1/3 is derived from ectoderm (proctodeum) which become continuous when the cloacal membrane degenerates
The pectinate line in adults marks the junction between endoderm and ectoderm derivatives
Each area has different epithelial linings, lymphatic drainage and blood supply
What are congenital recourethral and rectovaginal fistulas
Uncommon
Caused by abnormal cloaca, e.g. too small or failure of urorectal septum to extend caudally
Opening of handgun is shifted ventrally to the urethra in males and the vagina in females
what is an imperforate anus
Failure od anal membrane to degenerate
Usually requires immediate surgery to allow defection of faeces
What are the 2 enteric plexi
Myenteric plexus: between the circular and longitudinal muscle layers co-ordinated muscle contraction
Submucosal plexus between circular muscle and mucosa and regulates secretion
What is Hirschprung disease
Failure of neural crest cells to migrate to migrate to bowel
Absence of enteric ganglia leads to bowel obstruction due to lack of peristalsis causing dilation of the aganglionic part of the bowel
Genetic condition commonly associated with trisomy 21
Treated by removing the affected bowel
What are the parts of the large intestine
Cecum -> ascending colon -> transverse colon -> descending colon -> sigmoid colon -> rectum
How does the ileoceacal valve work
Flutter valve acts one way
Periodic relaxation allows flow to pass through
Opens due to ideal distention and closes due to cecal distention
How is the motility in the colon
Designed not to move contents along
Slow contractions of circular muscle squeeze contents back and forth
Occasional organised into peristaltic wave- mass movement
How is motility coordinated and regulated
Controlled mostly intrinsically by enteric nervous system and some parasympathetic control
Enteroendocrine and neurocrine influences from cells releasing 5-HT and peptide YY
Gastocolic and orthocolic reflexes can trigger mass movements
What causes a release of peptide YY and what happens as a result
Ileal break which is the presence of undigested lipid in distal ileum and proximal colon releases peptide YY, slowing gastric emptying and small bowel peristalsis
How does digestion work in the colon
Done by bacteria digesting:
Fibre -> short chain fatty acids
Urea and amino acids -> ammonia
Bilirubin -> urobilinogen and stercobilins
Cystein and methionine -> hydrogen suphide
Primary bile acids ->secondary bile acids
Conjugated bile acids -> unconcjugated bile acids
Fermentation releases about 1l of nitrogen, hydrogen and CO2
What types of muscle make up the anal sphincter
Intern anal sphincter: smooth muscle
External anal sphincter: skeletal muscle
What happens in the rectum and anus
As faeces enter the rectum, pressure rises triggering reflex relaxation of internal anal sphincter and urge to defaecate
A small amount enters the anus to allow anal sampling
External anal sphincter contracts
How does defection happen
Sitting to squatting increases the rectosigmoid angle facilitating passage of faeces
relaxation of puborectalis muscle also increase the angle
Relaxation of EAS and pelvic floor muscles open the way
Rectal peristalsis, sometime triggering colonic mass movement, provides the motive force
What does the colon secrete and absorb
Secretes: Potassium and bicarbonate
Absorbs: salt and water
What are the general principles of immune response
Multilayer defense Network of pathogen recognition Effective inter-cellular communication Multiple mechanisms of pathogen clearance Adaptive réponses to changing pathogen Self-regulation Limitation of host damage
What are pattern recognition receptors
Inclusive term for antigen recognition receptors in innate system
2 groups
Cell surface, transmembrane and intracellular receptors
Fluid-phase soluble molecules
What are the roles of the GI tract mucosal surface
Separates the external environment from the internal sterile environment and therefore represent the first line of defence
Encounters:
Harmless antigens (food)
Commensal bacterial flora
Pathogenic organisms which have developed effective methods for colonisation and invasion
This requires:
Ignorance/ tolerance (harmless encounters)
Robust protective immune response (potentially harmful encounters)
What does the gut immune system comprise of
Innate:
Commensal bacterial flora
Epithelial barrier
Biochemical factors produced by epithelial cells
Specific:
Lymphoid tissue associated with mucosal surfaces
What are the benefits of commensal bacterial flora
Resistance to colonisation by pathogens Stimulate local immunity\Oral tolerance Nutrition Epithelial cell turnover Intestinal motility
What are some hazards of gut microflora
It is a reservoir of pathogens so can cause:
Disease of GI tract: IBS, Ulcers (H.pylori)
Extraintestinal disease: septicaemia
Autoimmunity: reactive arthritis
Allergy
What is the epithelial barrier of the gut immune system
Prevents penetration by microorganisms
Intestinal mucosal barrier is a single cell layer
Self-renewing system undergoing continuous renewal from stem cells located near the base of the crypts of Lieberkhun
What can the stem cells in the epithelial barrier differentiate into and what do these cells do
Enterocytes: mechanical action creates current to remove microbes that are poorly adhered and produces antimicrobial peptides and proteins
Goblet cells: produce mucins to provis mucus layers that resist microbial access
Enteroendocrine cells
Paneth cells
What happens at Peyer’s patches in a specific immune response
Initiation of immune responses
M-cells: specialised enterocytes adapted to antigen uptake
Pass antigens to professional APCs (dendritic cells)
Dendritic cells present antigens to t and B cells which then become activated
B-cells migrate to mesenteric lymph nodes
Differentiated plasma cells migrate to tissues
Plasma cells secrete IgA
What are intraepithelial lymphocytes
Found between intestinal epithelial cells Large granular lymphocytes Mostly CD8+ (cytotoxic T-cells) Produce IL-2, IFN-y, CCL5 Function: epithelial homeostasis mucosal barrier function reactivity with stress-induced epithelial cell antigens
What are Lamina Propria Lymphocytes
Found in loose connective tissue, the lamina propria, the lies under the epithelium
Mostly CD4+ (helper T-cells)
What are the helper T-cells
Th1: cell-mediated responses (intracellular pathogens)
Th2: antibody-mediated responses (allergens, parasites
Th17: cell-mediated responses (mucosal pathogens, IBS)
What are B-cells
Synthesised by plasma cells in lamina propria
Transported across epithelium
Secreted in colostrum, maternal milk, saliva and tears
Prevents attachment of bacteria or toxins to epithelia
Protects against infectious agent
Wha does IgA do in the gut and how does it exist
Binds to mucus layer on top of epithelial cells to form a barrier that neutralises pathogens before they reach the underlying cells
Exists as two isotopes:
IgA1: found inserumand made by bone marrow B-cells
IgA2: made by B-cells in the mucosa
IgA2: IgA1 ratio in the gut is 3:2
What are the properties of secretory IgA
Relatively resistant to proteolysis Neutralises viruses and toxins Enhances non-specific defence mechanisms Inhibits: Bacterial adhesion Macromolecule absorption Inflammatory effect of other immunoglobins
What is metabolism
All the chemical reactions in the body
What is anabolism
The reactions the synthesise new (larger) molecules from smaller precursors
These need energy
What is catabolism
The reactions the break down larger molecules into smaller ones
These release energy
What are the phases of metabolism
Absorptive: dealing with a meal
Post-absorptive: maintaining homeostasis between meals
Fasting: dealing with the challenge of longer periods without food
Intense exercise: responding to dramatic increases in demand
What are the time scales of matabolism
Acute: minute to minute regulation of plasma glucose
Longer term: maintenance of adequate stores, turnover of proteins and cells, growth, reproduction
What is AMP
A marker od low-energy state and regulates a number of metabolic enzymes allosterically
How is excess glucose stored and then released
As polymers, mainly glycogen, in liver and muscle which provides a rapid but relatively short-lived store
Liver can release glucose derived from glycogen into the circulation
What happens to excess fats
Provide a dense energy store
Takes longer to re-release the energy
Many tissues use fatty acids as their main source of energy
The liver can convert fatty acids into ketone bodies during starvation
What happens to excess protein
Not ideal as a source of energy ad mainly stored a s functional proteins
Liver can convert amino acid to glucose by gluconeogenesis
Muscle cells contain a lot of protein, and can be converted to alanine and glutamic which can be exported for gluconeogenesis
How do erythrocytes use metabolism
Lack mitochondria so unable to carry out aerobic metabolism but has low metabolic demand
Positive: job is to carry oxygen not use it up
Negative: must get all energy from anaerobic metabolism which is inefficient
How does the brain use metabolism
Has mitochondria and has high metabolic demand
Blood-brain barrier limits what foodstuffs can cross
Brain depends on a fairly steady plasma glucose concentration which if lower than 3mM can be fatal
During fasting ketone bodies are used
How do Adipocytes use metabolism
Insulin-sensitive uptake of glucose and glucagon-sensitive release of FFA and glycerol
During periods of high glucose, convert glucose to triglyceride
As glucose levels fall, metabolise triglyceride to release FFA and glycerol
How does the liver use metabolism
First place for food stuffs absorbed from the gut
Insulin sensitive uptake, and glucagon-sensitive release of glucose
During high glucose, converts to glycogen
During low glucose, metabolises glycogen to release glucose
What is used in gluconeogenesis
Lactate
Glycerol
Amino acids
How do cardiac muscles use metabolism
Highly aerobic: up to 40% mitochondria and abundant in myoglobin
Main energy source is fatty acids but can also use lactate or ketone bodies
Glucose uptake is insulin-sensitive
How do skeletal muscle types use metabolism
Type 1:
Highly aerobic
Adapted to prolonged, relatively modest, activity
Main energy source is fatty acids
Type 2a:
Intermediate between 1 and 2b
contain some mitochondria and myoglobin
Maintain aerobic as much as possible
Phosphocreatine and glycogen are good energy stores
Adrenaline or insulin allow glucose uptake
At low exercise levels, fatty acids are main energy source
Release amino acids for gluconeogenesis during fastin
Type 2b
Fast-teitch muscle: explosive performance but quickly fatigued
Few mitochondria and little or no myoglobin
Phosphocreatine provides rapid replenishment of ATP, but only for a few seconds
Rely mainly on anaerobic glycolysis, with glucose from glycogen store
Adrenalin or insulin allow glucose uptake
Why is plasma glucose not just kept high
Osmotic effects
Glucose lost in urine, wasting energy and causing polyuria
Glycation of proteins and later cross-linking:
microvascular and microvascular disease
peripheral neuropathy
low grade inflammatory effects
What are the possible fates of sugars after absorption
Metabolism to produce energy
Conversion to glycogen for storage
Synthesis of other cellular components
Conversion to fat for storage
How is glucose metabolised anaerobically
Glycolysis in absence of oxygen
Takes place incytosol of all cells
2 phases:
Preparative phase: Glucose
-> fructose 1,6 bisphosphate (requires ATP)
Generating phase: fructose 1,6 bisphosphate -> (2) pyruvate (generates ATP and NADH)
Pyruvate -> lactate
2 molecules of ATP are generated per molecule of glucose
NAD+ is regenerated from NADH
How is glucose metabolised aerobically
NADH is used to generate further 3-5 molecules of ATP via oxidative phosphorylation
Aerobic glycolysis generated 5-7 molecules of ATP per glucose molecule
Complete oxidation of glucose via the Krebs cycle yields 30-32 ATP
How is excess glucose stored
As glycogen mainly found in the liver and skeletal muscle
Glycogen has a branched structure with a-1,4 linkages and a-1,6 branch points
How is glucose converted to fatty acids and triacylglycerol for energy storage
Glucose -> fatty acids -> triacylglycerols
Fatty acid synthesis occurs in the cell cytosol of:
mainly the liver
adipose tissue
breast tissue during lactation
Triacylglycerol synthesis:
Addition of 3 fatty acids to a molecule of glycerol-3-phosphate
Occurs in endoplasmic reticulum
In adipose tissue: stored in cytosol
In liver: packaged to form VLDL -> secreted into blood and transported to:
adipose tissue for storage
other peripheral tissues for use as energy store
What is the importance of metabolic control
At least 1/3 of all serious health problems are consequences of metabolic disorders
Maintaining blood glucose at ~5mM is crucial for survival
Brain relies on glucose for ATP synthesis:
Below 3mM: confusion, coma, death
Above 8mM long term vascular damage occurs through protein glycation
How is glycogen synthesised
Conversion of glucose-6-phosphate to glucose-1-phosphate Synthesis of UDP-glucose Needs a primer Chain elongation Insertion of branch points
Key control enzyme:
glycogen synthase
How is glycogen broken-down by glycogenolysis
Glycogen phosphorylase removes glucose units
Additional enzymes required to remove branches
Glucose-1-phosphate converted to glucose-6-phosphate enters glycolysis
How does insulin influence glycolysis
Increases expression of genes which code for enzymes of glycolysis
Decrease expression of genes which code for enzymes of gluconeogenesis
How does glucagon influence glycolysis
Regulates the level of fructose 2,6 bsphosphate which activates glycolysis and inhibits gluconeogenesis
This occurs via phosphorylation of a protein which catalyses synthesis and degradation of fructose 2,6 bisphosphate
When phosphorylated:
Glucagon high
Enzyme degrades F 2,6 BP
Glycolysis decreases
When dephosphorylated:
Glucagon low
Enzyme synthesises F 2,6 BP
Glycolysis increases
Describe some roles of lipids other than their role in energy production
Incorporation into cell membranes: particularly phospholipids and cholesterol
Essential fatty acids are precursors for prostaglandins, leukotrienes and thromboxanes
Describe how lipids are transported in the blood
Chulomicrons are formed in the intestinal epithelial cells, released into the lymph, enter circulation via thoracic duct into subclavian vein
Describe the oxidation of fatty acids to acetyl CoA and the control of this pathway
fatty acid activated to fatty acetyl CoA in cytosol
B oxidation takes place in mitochondria:
spiral process
each turn releases 1 acetyl CoA and produces NADH and FADH2 which are oxidised by the electron transport chain
acetyl CoA then enters the Krebs cycle
Overall reaction produces 108 tap from each molecule of fatty acetyl CoA
Long chain fatty acids require carnitine for transport which is inhibited by malonyl CoA, which prevents the synthesis and degradation fatty acids and is formed by acetyl CoA carboxylase
Explain what ketone bodies are and how they are formed
Ketone bodies are formed from excess acetyl CoA
Synthesis occurs in the mitochondria of liver cells under conditions where the body relies on fatty acid oxidation for energy: fasting and uncontrolled diabetes
Ketone are released into the blood and are oxidised to produce energy in peripheral tissues including brain tissue
But ketoacidosis is a life-threatening condition
Outline the synthesis of cholesterol and the control of this pathway
Acetyl CoA to melvalonate (C6) -> melvalonate to phosphorylated isoprene units (C5) (activation) -> polymerise 6 isoprene units to form a C30 chain (squalene) -> cyclisation to form ring structure (lanosterol) then cholesterol
First stage controls rate of synthesis by adjusting the activity or amount of HMG CoA reductase
High cholesterol levels inhibit further synthesis
Insulin increases synthesis by signalling energy availability
Occurs in the cytosol and smooth endoplasmic reticulum
What common diseases are the result of excess lipids
Coronary heart disease: elevated cholesterol levels
Alzheimer’s disease: raised cholesterol
Steatohepatitis: can lead to cirrhosis and hepatic carcinoma
What is cholesterol needed for
Bile salts Membranes Vitamin D Steroid hormones: androgens (testosterone) oestrogen progestogens (progesterone) mineralocorticoids (aldosterone) glucocorticoids (cortisol)
How does fat arrive at peripheral tissue
In chylomicrons or VLDL: released by lipoprotein lipase
or
From adipose tissue:
triacylglycerols broken down by hormone sensitive lipase
fatty acids release into blood
transported to tissues bound to albumin
What results form high LDL and HDL levels
High LDL: increased risk of atherosclerosis
High HDL: decreased risk of atherosclerosis
What is atherosclerosis
Damage to endothelial cells allows LDL access to suboptimal space
LDL become oxidised and are internalised by macrophages to make foam cells
Accumulation of foam cells create bulge in vessel wall called an atherosclerotic plaque
Fibrous collagen cap is formed
Plaque may restrict blood flow, in coronary arteries this causes angina
Strokes and heart attack occur when plaques rupture and thrombosis follows
What are the different parts of the liver and the structures associated with it
Liver body Hepatic vein Hepatic artery Hepatic portal vein Common bile duct Stomach Cystic duct Gallbladder
What are the input and output blood supply of the liver
Input: Portal vein (75%) Hepatic artery (25%)
Output:
Hepatic vein into inferior vena cava
What are the cell types of the liver and what do they do
Hepatocytes: 60% of live cells, carry out most of metabolic functions
Endothelial cells: lining of sinusoids, contain fenestrations so don’t form a barrier against small molecules
Kupffer cells: located within sinusoidal lining, macrophages, phagocytose bacteria, old erythrocytes, protect liver from gut derived bacteria
Pit cells: natural killer cells, help protect liver from viruses/ tumour cells
Hepatic stellate cells: lipid-filled cells, primary state of vitamin A storage, also control turnover of connective tissue, synthesise collagen and regulate contractility of sinusoids
What are the functions of the liver
The factory:
receive raw materials, manufacture new goods, recycle, deliver and store
Waste management:
treat hazardous material, dispose of internal waste
What is a prodrug
An inactive or less active compound which is metabolised by the liver to produce the therapeutically active form into the body
What happens to amino acids
Protein synthesis Synthesis of nitrogen containing metabolites Energy (ATP) Fatty acids, ketone bodies Glucose, glycogen
How is ammonia disposed of
It is converted to urea for excretion by the kidneys
3 steps:
transamination: transfer of amino group from amino acid to a-ketoglutarate forming glutamate (all tissues)
deamination: release of ammonia from glutamate (in liver)
urea synthesis: urea cycle (in liver)
What is the urea cycle
Inside mitochondria:
Carbamoyl phosphate formed from ammonia and bicarbonate (control step)
Carbamoyl group transferred to ornithine to form citrulline
In the cytosol:
Second Amin group added from aspartate
Arginine formed
Urea released
What do glycogenic and ketogenic mean
Glucogenic: can be degraded to glucose precursors
Ketogenic: can be degraded to precursors of fatty acids and ketone bodies
What is the turnover of of ATP
~ 75 kg/day
What is the structure of mitochondria
Outer:
smooth and freely permeable to molecules under 5000 Da
no ionic or electrical gradients
Inner:
folded into christae
permeable to a small number of molecule only via specific transporters
a very good electrical insulator, capable of maintaining large ionic and electrical gradients
contains more protein than lipid- respiratory enzymes, transporter proteins
What is the matrix of the mitochondria
contains wide range of enzymes for: Krebs cycle, fatty acid oxidation, urea cycle
High concentrations of substrates, cofactors and ions
Contains mitochondrial DNA, RNA and ribosomes though few mitochondrial protein are coded on mitochondrial DNA
What is the inter membrane space of the mitochondria
Has metabolite and ion concentrations similar to cytosol
contains cytochrome C
What is the turnover of of ATP
~ 75 kg/day
What is the structure of mitochondria
Outer:
smooth and freely permeable to molecules under 5000 Da
no ionic or electrical gradients
Inner:
folded into christae
permeable to a small number of molecule only via specific transporters
a very good electrical insulator, capable of maintaining large ionic and electrical gradients
contains more protein than lipid- respiratory enzymes, transporter proteins
What is the matrix of the mitochondria
contains wide range of enzymes for: Krebs cycle, fatty acid oxidation, urea cycle
High concentrations of substrates, cofactors and ions
Contains mitochondrial DNA, RNA and ribosomes though few mitochondrial protein are coded on mitochondrial DNA
What is the inter membrane space of the mitochondria
Has metabolite and ion concentrations similar to cytosol
contains cytochrome C
What is the function of antiporters
Antiporter in the inner mitochondrial membrane allows transport of ADP into the mitochondria and ATP out to other areas of the cell
This is aided by phosphate
How is the Krebs cycle controlled
Entry of pyruvate is controlled by need for energy and availability of Acetyl CoA from fat oxidation
Control of cycle by need for energy as monitored mainly by ATP:ADP and NADH:NAD+ ratios
How is the Krebs cycle used in other metabolic pathways
Amino acid carbon skeletons feed into the Krebs cycle
A number of anabolic pathways use Krebs cycle intermediates as binding blocks
What is the ATP synthesis step
Oxidative phosphorylation is made up of two tightly coupled processes
Electron transport: the energy of the electrons in NADH/FADH2 is used to create a proton gradient across the inner mitochondrial membrane- OXIDATION
ATP synthesis: the energy from the proton gradient is used to phosphorylate ADP to synthesise ATP- PHOSPHORYLATION
What is the function of antiporters
Antiporter in the inner mitochondrial membrane allows transport of ADP into the mitochondria and ATP out to other areas of the cell
This is aided by phosphate
What do the out pocketings of the foregut give rise to
Liver
Gallbladder
Pancreas
How do the liver and gallbladder develop
In week 3, the liver appears as an out pocketing of the future duodenum- hepatic diverticulum
This contains rapidly proliferating cells that penetrate the septum transversum
The connections between the hepatic diverticulum and duodenum narrows to form the bile duct
A ventral outgrowth of the bile duct forms the gallbladder and cystic duct
Endodermal cells differentiate into hepatocytes of liver
Haemotopoietic, Kupffer cells and connective tissue are derived from mesoderm of the septum transversum
Liver continues to rapidly expand and becomes too large to be contained within the septum transversum so protrudes into the ventral mesentery, dividing the mesentery into 2 parts:
Falciform ligament
Lesser omentum
Why is the liver so large in utero and why does this change after birth
In utero liver is important in haematopoiesis
After birth haematopoiesis shifts to the bone marrow
How does the spleen develop
Derived from the mesoderm and appears in week 5 as a mesenchymal condensation in the dorsal mesentery
Rotation of stomach brings the spleen to left side
The dorsal mesentery between the stomach and the spleen is the gastosplenic ligament and the dorsal mesentery between the spleen and kidney is the spleorenal ligament
What do the ventral and dorsal buds of the developing pancreas form
Dorsal: head, body and tail of pancreas
Ventral: uncinate process
How are the ducts of the pancreas formed an
Main pancreatic duct: distal portion of dorsal pancreatic duct and all of the ventral pancreatic duct
Accessory pancreatic duct: proximal portion of the dorsal pancreatic duct
What is an annular pancreas
The ventral pancreatic duct is bilobed and one lobe migrates ventral to the duodenum and the other dorsally to surround the duodenum, resulting in compression of the duodenum causing gastrointestinal obstruction
What do Beta cells secrete and why
Insulin in response to glucose
What is secreted by alpha cells and what does it do
Glucagon and antagonises the effects of insulin
What are the effects of insulin and glucagon on muscle
Insulin:
Glycogen, triglyceride and protein synthesis increase
Glucagon:
Proteolysis: releasing AA for gluconeogenesis
What are the functions of glucocorticoids
Inhibit insulin responses and enhance SNS responses (sending glucose to brain and other organs to use fat)
In liver, promotes gluconeogenesis and glucose release
In fat, lipolysis
In muscle, protein breakdown for gluconeogensis
What is secreted by alpha cells and what does it do
Glucagon and antagonises the effects of insulin
What are the results of excess and deficient growth hormone levels in children and adults
Children:
Excess: leads to gigantism
Deficiency: leads to dwarfism
Adults:
Excess: leads to acromegaly where bones are excessively thick and other tissues overgrow
Deficiency: no obvious disease but replacement increases body mass, decreases fat and increases vigour
What are the functions of glucocorticoids
Inhibit insulin responses and enhance SNS responses (sending glucose to brain and other organs to use fat)
In liver, promotes gluconeogenesis and glucose release
In fat, lipolysis
In muscle, protein breakdown for gluconeogensis
What is ghrelin
28 amino acid peptide produced from neuroendocrine cells in the stomach
Released when stomach is empty
Appetite inducing agent
Present as neuropeptide in the brain
What are anorexigens
suppress hunger Examples: CCK Insulin FLP-1 Peptide YY Oxyntomodulin Somatostatin
What are the results of extreme starvation
Wasting of muscle
Muscle fatigue and reduced exercise capacity
Diminished respiratory capacity
Slowed heart rate and decreased contractility
Loss of heat-generating capacity
Apathy
Death from respiratory or cardiac failure or infection
How is BMI calculated
BMI = (weight in kg) / (Height in meters)squared
