GI and Liver Flashcards
How is swallowing initiated?
Initiated when pressure receptors in the walls of the pharynx are stimulated by food or drink, forced into the rear of the mouth by the tongue
What is the innervation of the nasopharynx, oropharynx, and laryngopharyx?
- Nasopharynx: Maxillary nerve (V2 (second branch of trigeminal nerve (V))
- Oropharynx: Glossopharyngeal nerve (IX)
- Laryngopharynx: Vagus nerve (X)
What is step 1 of the process of swallowing?
Voluntary:
- Food is compressed against the roof of the mouth and pushed towards the oropharynx by the action of the tongue
- The buccinator & supra hyoid muscles manipulate food during chewing. They also elevate the hyoid bone and flatten the floor of the mouth
What is step 2 of the process of swallowing?
Involuntary:
- The nasopharynx is closed off by the soft palate via the action of the muscles of
the palate which tense & elevate it - helping to form the bolus of food
- The pharynx is also shortened & widened (using longitudinal muscles) by the
elevation of the hyoid bone via the actions of the muscles of the floor of the palate
which depress (lower) the mandible if the hyoid bone is fixed or elevate (raise) the
hyoid bone & larynx if the mandibles is fixed - Impulses from the swallowing centre inhibit respiration, raise the larynx (as
mentioned above) and close the glottis (the area around the vocal cords and the space
between them) - keeping food from entering the trachea - As the tongue forces the food farther back into the pharynx the food tilts the epiglottis
backward to cover the closed glottis - this prevents aspiration of food - a
dangerous situation where food travels down the trachea and can cause choking or
regurgitated stomach contents are allowed into the lungs causing damage
What is step 3 of swallowing?
Involuntary:
- Pharyngeal constrictor muscles - 3 overlapping muscles that form the posterior & lateral sides of the pharynx - innervated by vagus (X). They contract sequentially from above down to drive the bolus into the oesophagus
- Depression of the hyoid bone and pharynx is carried out by the infra hyoid muscle of the neck - they fix the hyoid bone enabling the opening of the mouth.
What is the fourth and final step of swallowing?
The next stage of swallowing occurs in the oesophagus:
- Skeletal muscle surrounds the upper third of the oesophagus
- Smooth muscle surround the lower two-thirds of the oesophagus
- The luminal pressure in the pharynx at the opening to the oesophagus is equal to the atmospheric pressure and the pressure at the opposite end of the oesophagus in the stomach is slightly greater than atmospheric pressure. Thus these pressure differences tend to force both air from above and gastric contents from below into the oesophagus - however this does not occur due to the presence of sphincter muscles at both ends of the oesophagus.
- A ring of skeletal muscle surround the oesophagus just below the pharynx - called the upper
oesophageal sphincter
- A ring of smooth muscle surround the oesophagus in the last portion of the oesophagus - called the lower oesophageal sphincter
- Before food can enter the oesophagus the upper oesophageal sphincter relaxes - immediately after the food has passed through the sphincter closes, the glottis opens and breathing resumes
- Once in the oesophagus, the food moves towards the stomach by a progressive wave of muscle contractions that proceed along the oesophagus, compressing the lumen and forcing the food ahead - these are peristaltic waves
- One oesophageal peristaltic wave takes 9 seconds to reach the stomach
- The lower oesophageal sphincter opens and remains relaxed throughout the process of swallowing, allowing the arriving food to enter the stomach
Explain the gag reflex?
• The reflex elevation of the pharynx - often followed by vomiting cause by irritation
of the oropharynx - the back of the tongue
• Reflex arc between the glossopharyngeal (IX) and the vagus (X) nerves
What are the functions and features of saliva?
Functions:
- Lubricant for mastication
- Maintaining oral pH: needs to be maintained at about pH 7.4 (slightly alkaline) this is
achieved by the bicarbonate/carbonate buffer system for the rapid neutralisation of
acid
- Release digestive enzyme - salivary alpha amylase is released from the parotid gland for starch digestion
Features:
• Daily secretion = 800 -1500ml in adults
• pH ranges from 6.2 to 7.4
Serous secretion = alpha amylase for starch
digestion
• Mucous secretion = mucins for lubrication of
mucosal surfaces
What are the three main salivary glands and what percentage of salivary flow do they contribute?
Submandibular gland, Parotid gland, Sublingual Gland.
They contribute 80% of salivary flow
What are minor salivary glands?
Minor salivary glands contribute to 20% of salivary flow - they are found in the submucosa or the oral mucosa of the lips, cheeks, hard & soft plate and the tongue
Which glands have mucous secretions and which have serous secretions?
Parotid: Serous
Submandibular: Mucous and Serous
Sublingual: Mucous and Serous (mainly mucous)
Minor glands: Predominantly mucous (but some are serous)
What are the Factors affecting the composition & amount of saliva produced?
Flow Rate Circadian Rhythm (Sleep Cycle) Type and Size of Gland Duration and type of stimulus that causes saliva to be produced Diet Drugs Age Gender Time of Day
Defences of the oral cavity are provided by?
The Mucosa: Physical barrier
Salivary glands: Saliva washes away food particles
which bacteria or viruses may use as metabolic support
Palatine tonsils: act as the “surveillance system” for the immune system
Salivary glands are surrounded by lymphatic system(linked to thoracic duct and
blood): which contains a broad range of functional immune cells
Which glands are continously active and which require stimulation?
Submandibular: Continuously Active (Unstimulated components of the salivary system are dominated by submandibular components)
Sublingual: Continuously Active
Parotid: Requires stimulation to become main source of saliva
Minor Glands: Continuously Active
What is the structure of salivary glands?
Composed of two morphologically and distinct epithelial tissues:
Acinar Cells
(functional unit of a salivary gland)
There are two types of acini:
- Serous acinus:
- Dark staining nucleus
- Nucleus in basal third
- Small central duct
- Secrete: water & alpha amylase
- Found mainly in the parotid gland - Mucous acinus:
- Pale staining “foamy”
- Nucleus at base
- Large central duct
- Secrete: mucous (water & glycoproteins)
- Found in submandibular & sublingual glands
Ducts (surrounded by acinar cells)
collect to form the large cut entering the mouth. Equipped with channels and transporters in the apical and basolateral membranes enabling transport of fluid and electrolytes
- Intralobular ducts are divided into intercalated & striated
- Intercalated:
• Short narrow
duct segments with cuboidal cells that
connect acini to larger striated ducts - Striated:
• Striated like a thick lawn
• Major site for reabsorption of NaCl
• Appear striated at basal end
• Basal membrane is highly folded into microvilli (giving the duct its striated appearance) for active transport of HCO3 against concentration gradient, the
microvilli are filed with mitochondria for energy to facilitate the active transport
The epithelium of the ducts reabsorbs water so final saliva is hypotonic (has less water in it so have a higher concentration of solutes (K+ & HCO3-)
What is the Structure and location, Structures passing through, and Innervation of the Parotid gland?
Structure and location: Superficial triangular outline between: - Zygomatic arch - Sternocleidomastoid - Ramus of mandible •Parotid duct: -Also called Stenson’s duct - crosses masseter muscle and pierces through the buccinator muscle where it enters the oral cavity near the second upper molar - Can be palpated a fingers breadth below the zygomatic arch
Structures passing through:
- External carotid artery
- Retromandibular vein
- Facial nerve (VII - exits skull through the
stylomastoid foramen) - supplies the muscles of facial expression
- Thus the parotid capsule is very tough
• The parotid glands are entirely made up of serous acini with ducts interspersed
Innervation:
- Sympathetic sensory innervation (inhibits/minimises secretion) is provided by the auriculo-temporal nerve which is a branch of the mandibular nerve (V3 - this
division of the trigeminal nerve exits the skull through the foramen ovale)
- Parasympathetic innervation is supplied by glossopharyngeal nerve (IX) - stimulates secretion
• Horizontally it has a triangular outline with the apex on the carotid sheath
What is the Structure and location and Innervation of the submandibular gland?
Structure and location:
Two lobes separated by mylohyoid muscle - larger superficial lobe and a smaller
deep lobe in the floor of the mouth
• The submandibular duct (Whartons duct) begins in the superficial lobe, wraps around the free posterior border of the mylohyoid, then runs along the floor of the mouth and empties into the oral cavity at the sublingual papillae - located more posteriorly than the sublingual gland
Innervation:
Parasympathetic innervation is supplied by the chorda tympani branch of the facial nerve (VII)
- Sympathetic innervation is supplied via the lingual nerve which is derived from the facial nerve (VII)
What is the Structure and location and Innervation of the sublingual gland?
Structure and location:
located more anteriorly than the submandibular glands
Located in the floor of the mouth between mylohyoid muscles and oral mucosa of
floor of mouth
• Very close to the submandibular gland
• Saliva is transmitted via the submandibular/
whartons duct as well or small ducts that pierce oral
mucosa floor of mouth
• Much smaller than submandibular - but size is variable
Innervation:
- Similar to submandibular gland
- Parasympathetic innervation is supplied by the chorda tympani branch of the
facial nerve (VII)
- Sympathetic innervation is supplied via the lingual nerve which is derived from the facial nerve (VII)
What is the Structure and location and Innervation of the minor salivary glands?
Structure and location:
Concentrated in the; buccal labial, palatal & lingual regions
• Also found at; superior pole of tonsils (Weber’s glands), tonsillar pillars & at the base
of the tongue (von Ebner’s glands - underlying circumvallate papillae)
• All minor salivary glands are mucous EXCEPT for the serous glands of von Ebner
• They lack a branching network of draining ducts so each salivary unit has its own simple duct
Innervation:
• PARASYMPATHETIC = stimulates salivary secretion
• SYMPATHETIC = inhibits salivary secretion (but some baseline secretion)
What is Xerostomia?
Dry Mouth, classified by If salivary output falls to
less than 50% of normal flow
What are the causes of xerostomia?
• medication and irradiation for head and neck cancers
• Obstruction:
- Saliva contains calcium & phosphate ions that can from salivary calculi (stones)
- Most common in submandibular gland (80% incidence) - they block the duct at the
bend around the round mylohyoid or at exit at the sublingual papillae
• Inflammation:
- Caused by infection secondary to obstruction
- Infections caused by; mumps (viral infection) - results in fever, malaise, swelling of the glands
• Degeneration:
- Complication of radiotherapy to head and neck for cancer treatment
- May be a consequence of cystic fibrosis or Sjorgren’s syndrome (autoimmune
condition where immune cells attack glands resulting in little or no saliva produced -
affects mainly women)
What are the consequences of xerostomia?
• Low lubrication - oral function becomes difficult
• Low natural oral hygiene -poor pH control =accumulation of plaque =dental caries or increases
incidence of opportunistic infections especially fungal
e.g candida - thrush
What is the name for an oral cancer?
Squamous cancer, Squamous tumours respond well to radiotherapy and chemotherapy
What epithelium is present in salivary glands?
Secretory Glandular epithelium
What are the is the foregut?
Foregut starts from the mouth to the common
bile duct
- Blood supply: Celiac artery
- Components: • Pharynx • Oesophagus • Stomach • Proximal half of duodenum and the derivative (liver, biliary apparatus & the pancreas)
What is the midgut?
Midgut starts from the common bile duct to
2/3rds of the transverse colon
- Blood supply: Superior mesenteric artery
- Components: • Distal half of the duodenum • Jejunum • Ileum • Caecum • Appendix • Ascending colon • Right 2/3rds of the transverse colon
What is the hindgut?
Hindgut starts from 2/3rds of the transverse colon
to the anal canal
- Blood supply: Inferior mesenteric artery
- Components: • Left 1/3 of the transverse colon • Descending colon • Sigmoid colon • Rectum • Anal canal
What is step 1 of the GI embyronic folding?
Folding occurs in two planes, the horizontal & medial
Planes
Folding occurs in two planes due to the differing rates of growth of the embryonic
structures
- Folding in the horizontal plane results in the formation of the two lateral body folds
What is step 2 of the GI embryonic folding?
Folding in the medial plane results in the formation of the cranial & caudal folds
- Folding in both planes takes place simultaneously
What is step 3 of the GI embryonic folding?
The endoderm is mainly responsible for the development of the GI tract
- As embryonic folding continues, the endoderm moves towards the midline and
fuses - incorporating the dorsal part of the yolk sac to form the primitive gut tube
- The primitive gut is derived from the endoderm and the visceral mesoderm
What is step 4 of the GI embryonic folding?
The foregut is on the cranial end of the embryo and is temporarily closed by the oropharyngeal membrane which at the end of the 4th week of development ruptures to form the mouth
- The midgut lies between the fore and hindgut and remains connected to the yolk sac until the 5th week of development
- As embryonic folding continues, the connection to the yolk sac narrows into a stalk called the vitelline duct
- The hindgut lies at the caudal end of the embryo, it is temporarily closed by the cloacal membrane, which
during the 7th week of development, ruptures to form the anus
What GI structures are formed from the endoderm?
- Epithelial lining of digestive tract
- Hepatocytes of the liver
- Endocrine and exocrine cells of the pancreas
What GI structures are formed from the visceral mesoderm?
- Muscle, connective tissue & peritoneal components of the wall of the gut
- Connective tissue for the glands
- The primitive gut tube, differentiates into three distinct parts; the foregut, midgut &
hindgut
Describe the development of the pharyngeal arches?
Part of the foregut
Extends from the oropharyngeal membrane to the respiratory diverticulum
In the 4th & 5th week of fetal life, the pharyngeal arches develop:
• There are five arches; 1,2,3,4 & 6 (there is no 5th in humans - sort of combines into
the 4th)
• They contribute greatly to the external appearance of the embryo.
• Formed of masses of mesenchymal tissue (connective tissue derived from
mesoderm) which are invaded by cranial neural crest cells.
Each pharyngeal arch is covered externally by endoderm (forming the pharyngeal
clefts)
- Each pharyngeal arch is covered internally by ectoderm (forming the pharyngeal
pouches)
Each arch has its own; nerve supply, arterial supply & venous supply
• Each arch gives rise to various structure of the pharynx & larynx
What is the innervation, the muscles and bone of the 1st pharyngeal arch?
Innervation: Mandibular nerve (V3 - i.e third branch of trigeminal (V)
Muscles: mastication, tensor tympani, digastric, myolohyoid
Bone:maxilla, mandible, incus, malleus
What is the innervation, the muscles and bone of the 2nd pharyngeal arch?
Innervation: Facial nerve (VII)
Muscles: facial expression, stapedius, stylohyoid
Bone: stapes, styloid and lesser horn of hyoid cartilage
What is the innervation, the muscles and bone of the 3rd pharyngeal arch?
Innervation: Glossopharyngeal nerve (IX)
Muscles: stylopharyngeus of the pharynx
Bone: body & greater horn of hyoid cartilage
What is the innervation, the muscles and bone of the 4th pharyngeal arch?
Innervation: Superior laryngeal nerve of Vagus nerve (X)
Muscles: Cricothyroid
Bone: thyroid cartilage & epiglottic cartilage
What is the innervation, the muscles, and bone of the 6th pharyngeal arch?
Innervation: Recurrent laryngeal nerve of Vagus nerve (X)
Muscles: All muscles of the larynx except the cricothyroid
Bone: cricoid cartilage, arytenoid cartilages, corniculate & cuneiform cartilage
What is the process of the development of the oesophagus?
Step 1: At the 4th week, at the end of the pharynx and the beginning of the oesophagus, at
the ventral wall of the foregut - respiratory diverticulum (lung buds) appear
Step 2: The trancheoesophageal septum develops and separates the respiratory diverticulum from the dorsal part of the foregut - in this way the foregut is divided
into the ventral respiratory primordium & the dorsal oesophagus
Step 3: Initially the oesophagus is short but it lengthens rapidly with the descent of the heart and lungs
What are mesenteries?
Parts of the gut tube are suspended from the dorsal & ventral body walls by mesenteries
Mesenteries are double layers or peritoneum that surround an organ and connect
it to the body wall, such an organ is called intraperitoneal
When an organ is sitting directly on the posterior abdominal wall and covered by peritoneum on its anterior surface only, it is known as a retroperitoneal organ
Ligaments: are double layers of peritoneum which pass from one organ to another or from one organ to the body wall
Mesenteries & ligaments provide pathways for blood vessels, lymphatics & nerves
to go to and come from the abdominal viscera
By the 5th week the lower part of the foregut, midgut & major part of the hindgut are suspended from the posterior abdominal wall by DORSAL MESENTERY - which extends from the lower part of the oesophagus to the cloacal region
What is the vental mesentery?
Present only in the region of the foregut - terminal part of the oesophagus, the stomach and the upper part of the duodenum
Thus the foregut has both ventral & dorsal mesenteries
is derived from the septum transversum
Its free lower margin contains; the hepatic artery, portal vein and bile duct
The liver develop IN the ventral mesentery and divides IT into the lesser omentum & the falciform ligament
What is the first step of stomach development?
Appears as a fusiform (spiral-shaped) dilation in the foregut in the 4th week
•Its appearance and position changes greatly as a result of the different rate of growth in various
regions of its wall
•The developing stomach is attached to the body walls by the dorsal & ventral mesenteries
•The left & right vagus nerves flank the left and right side of the developing stomach respectively
•The dorsal wall of the stomach grows faster than the ventral wall, this differential growth
forms the greater & lesser curvatures of the stomach
What is the second step of stomach development?
During the 7th week, the stomach rotates 90 degrees CLOCKWISE about a longitudinal axis - this rotate
produces a space behind the stomach called the lesser sac
The greater curvature (on the embryonic dorsal side) now faces the left of the body & the lesser curvature (on the embryonic ventral side) faces the right
• The left vagus is now on the anterior side of the stomach and the right vagus is located on the posterior side - thus they are now
called the anterior & posterior vagal trunks
What is the third step of stomach development?
In the 8th week the stomach and duodenum ROTATE about a ventrodorsal axis, pulling the end of the stomach upwards, they
pull the duodenum into a C-shape
•These rotations result in the thinning of the dorsal mesentery, which now hangs from the greater
curvature of the stomach - it is now called the greater omentum
•The ventral mesentery is now attached to the developing liver and has formed the lesser
omentum
•The development of the omen and the rotations of foregut structures produce distinct spaces of
the peritoneal cavity
•The space posterior to the stomach is called the lesser sac
•The space anterior to the stomach is called the greater sac
•The greater and lesser sacs communicate via a small opening (located near the hilum of the liver) called the epiploic foramen
What is the fourth step of stomach development?
During the foetal period, the anterior & posterior folds of the greater omentum FUSE to form one THICK sheet formed from 4 layers of peritoneum
What are the functions of the stomach?
Store and mix food Dissolve and continue digestion Regulate emptying into the duodenum Kill microbes Secrete protease Secrete intrinsic factor Activate proteases Lubrication Mucosal Protection
What are the key cell types and what are their functions?
Mucous Cells: produce mucous, at entrance to gland
G Cells: Produce Gastrin
Parietal Cells: produce gastric acid and intrinsic factor
D Cells: Release somatostatin
Chief Cells: Secrete pepsinogen
Enterochromaffin-like (ECL) cell: releases histamine
What are the features of gastric acid secretion?
Occurs from parietal cells
Hydrochloric acid: very strong, pH 2, [H+] > 150mM, approximately 2 litres/day
Energy Dependent
Neurohormonal regulation
H20 in the parietal cell breaks down into Oh- and H+
What is the process of gastric acid secretion?
1: The origin of the H+ ions is CO2
2: CO2 & H2O from respiration are converted into bicarbonate (H2CO3) via the enzyme carbonic anhydrase
3: H2CO3 rapidly disassociates into HCO3- and H+
4: The H+ ions produced can then react with the OH- ions from the breakdown of H2O to regenerate H2O
5: The H+ ions from the break down of H2O are then pumped into the stomach lumen via H+/K+ ATPase pumps in the luminal membrane of parietal cells, they pump 1 K+ ion into the parietal cell for every 1 H+ ion they pump out into the stomach (so as to ensure there is no change in polarity of the cell) - these pumps require ATP to function
6: The K+ ions pumped in can then diffuse back out into the stomach via K+ channels on
the plasma membrane of parietal cells
7: The HCO3- from the breakdown of H2CO3 is secreted into the capillary for the
exchange of Cl- ions
8:Cl- ions can then enter the stomach by diffusing through Cl- channels in the plasma
membrane of the parietal cell
9:Then in the stomach, the H+ ions and Cl- ions can react to form HCl
10:Removal of the end products of this reaction enhance the forward rate of reaction -
in this way production and secretion of H+ are coupled
11: Increased acid secretion stimulated by the factors mentioned in section on regulating gastric acid secretion, results from the migration of H+/K+ - ATPase protein in the membranes of intracellular vesicles in the parietal cell to the plasma membrane by fusion of these vesicles with the membrane thereby increasing the number of pump protein in the plasma
membrane meaning more H+ can be pumped in = more acid
What is the process of the Cephalic Phase (during a meal) of regulating gastric acid secretion?
• Parasympathetic nervous system
• Initiated by the sight, smell, taste of food and chewing
• Acetyl choline is released
• ACh acts indirectly on parietal cells, triggering the release of GASTRIN (from G
cells in the pyloric antrum of stomach) & HISTAMINE (from enterochromaffin-like
(ECL) cells)
• Both gastrin & histamine increase the number of H+/K+-ATPase pumps on the
plasma membrane of the parietal cell
• Net effect = increased acid production
What is the process of the gastric phase (after the meal) of turning on gastric acid secretion?
• Initiated by; gastric distension from the volume of ingested material & the presence
of peptides and amino acids (released by the digestion of luminal proteins)
• Gastrin is released which acts directly on parietal cells
• Gastrin also triggers the release of histamine which also acts directly on the parietal cells
• Both gastrin & histamine increase the number of H+/K+-ATPase pumps on the
plasma membrane of the parietal cell
• Net effect = increased acid production
• NOTE: it can be deduced that histamine is really important since it mediates the effects of gastrin and acetylcholine - thus can be a good therapeutic target for e.g. acid overproduction etc.
- Protein in the stomach:
• Direct stimulus for gastrin release (as seen above)
• Proteins of foods in the lumen, act as a buffer thereby reducing the amount of H+ ions = increase in pH : resulting in the decreased secretion of somatostatin (see below) which results in more parietal cell activity resulting in more acid production
What is the process of the gastric phase (after the meal) of turning off gastric acid secretion?
• Low luminal pH (high [H+]) directly inhibits gastrin secretion thereby indirectly
inhibiting histamine release
• Low pH also stimulates SOMATOSTATIN release which inhibits parietal cell activity
- Intestinal phase - in the duodenum:
• Initiated by; duodenal distension, low pH, hypertonic solutions, the presence of amino acids & fatty acids
• These all trigger the release of a locally produced chemical messengers called
enterogastrones such as SECRETIN (inhibits gastrin release & promotes somatostatin release) & CHOLECYSTOKININ (CKK)
• They also trigger short & long neural pathways which reduce ACh release
• Net effect = reduced acid secretion
What is the summary of the molecules involved in gastric acid secretion?
Regulation of gastric acid secretion is controlled by the brain, stomach &
duodenum
• 1 parasympathetic neurotransmitter -ACh (+)
• 1 hormone - gastrin (+)
• 2 paracrine (produced in stomach) -histamine (+) & somatostatin (-)
• 2 key enterogastrones - secretin (-) & CCK (-)
What is a peptic ulcer?
An ulcer is a breach in a mucosal surface
What are the causes of peptic ulcers?
Helicobacter pylori infection - most common
Drugs - NSAIDS e.g. aspirin and ibuprofen
Chemical irritants: alcohol, bile salts (secreted into duodenum but can reflux into
stomach and wash way protective mucous lining)
Explain how Helicobacter Pylori infection leads to peptic ulcer formation and explain the treatment?
Explanation:
• Lives in gastric mucus
• Secretes urease, splitting urea into CO2 and ammonia
• Ammonia + H+ = ammonium
• Ammonium is toxic to gastric mucosa resulting in less mucous produced
• Secreted proteases, phospholipase & vacuolating cytotoxin A can then begin
attacking the gastric epithelium further reducing mucous production
• Results in an inflammatory response and less mucosal defence
Treatment:
eradicate organism using triple therapy; proton pump inhibitor (inhibits pump pumping H+ ions into stomach lumen thereby increasing gastric pH making
conditions inhospitable for helicobacter pylori) & antibiotics (clarithromycin, amoxicillin, tetracycline & metronidazole)
Explain how NSAIDs may lead to peptic ulcer formation and explain the treatment?
Explanation:
NSAIDS - non-steroidal anti-inflammatory drugs
• Mucous secretion is stimulated by prostaglandins (in inflamed tissue, prostaglandin
triggers inflammatory response thus inhibition = less inflammation)
• Cyclo-oxygenase 1 is needed for prostaglandin synthesis
• NSAIDS inhibit cylclo-oxygenase 1
• Thus reduced mucosal defence
Treatment:
use prostaglandin analogues (mimic effect of prostaglandins) e.g.
misoprostol and reduce acid secretion
Explain how chemical irritants may lead to peptic ulcer formation?
Duodenal-gastric reflux causes bile to enter stomach, alkaline bile strips away
gastric mucous layer of stomach resulting in reduced mucosal defence
- Gastrinoma - rare tumours of parietal cells = excessive gastrin release = increase in gastric acid = increased attack on gastric mucosa = ulcer
List and explain the synthetic ways to regulate gastric acid secretion?
Proton Pump Inhibitor: inhibit pumps pumping H+ into stomach lumen, they only
block pumps NOT the activators e.g. gastrin, examples include; omeprazole, lansoprazole & esomeprazole (all have varied side effects)
H2 receptor agonist: block receptors for histamine thereby reducing acid
secretion, examples include; cimetidine & ranitidine
What is the process of protease secretion?
1: Chief cells produce pepsinogen
2:Pepsin is secreted as an inactive zymogen (pepsinogen) - it is stored this way to
prevent it digesting the chief cells and the rest of the body
3: Pepsinogen is mediated by input from the enteric nervous system via neurotransmitter ACh
(parasympathetic)
4: Secretion parallels HCl secretion
5: When pepsinogen is released into the stomach lumen, the low pH (generated by HCL) of the stomach activates a rapid autocatalytic process
in which pepsin is produce from pepsinogen ((Most efficient conversion when pH < 2)
6: Once some pepsin is produced, it can be used to produce more since it can aid in
the cleavage of pepsinogen - positive feedback
7:HCO3- released in the duodenum irreversibly inactivates pepsin
What is the role of pepsin in protein digestion?
Not essential - protein digestion can occur if the stomach is removed, HOWEVER if
removed then no vitamin B-12 absorption can occur in the small intestine since the
stomach parietal cells produce intrinsic factor - essential for vitamin B-12
absorption in the small intestine
Accelerates protein digestion
Normally accounts for 20% of total protein digestion
Breaks down collagen in meat thereby helping shred meat resulting in smaller pieces with greater surface area for digestion
What is gastric motility?
- Empty stomach has volume of around 50ml
- When eating it can accommodate roughly 1.5L with little increase in luminal
pressure - It does this by the smooth muscles in the body & fundus receptive relaxation
What is receptive relaxation?
Mediated by parasympathetic nervous system acting on the enteric nerve plexuses with coordination provided by afferent input from the stomach via the vagus nerve and by the swallowing centre in the brain
Nitric oxide and serotonin released by the enteric nerves mediate relaxation
Acetyl choline activates parietal & chief cells & initiates receptive relaxation
What is the process of peristalsis?
1
1: As in the oesophagus the stomach produces peristaltic waves in response to the arriving food
2: Each wave begins in the body of the stomach producing a ripple as it proceeds towards the antrum
3: The initial contraction in the body is too weak to produce much mixing of luminal contents with acid and pepsin
4: There are more powerful contractions in the antrum which enables better mixing of the luminal contents
5: The pyloric sphincter (a ring of smooth muscle and connective tissue between the atrium and duodenum) closes as peristaltic waves reach it
6:This contraction, every time a wave reaches it means little chyme (smooth, somewhat orange coloured liquid = the end result of stomach digestion and peristalsis) enters the duodenum
It also means that the antral contents are forced back towards the body meaning there is more mixing and thus digestion
- The frequency of peristaltic waves are determined by pacemaker cells (INTERSTITIAL CELLS OF CAJAL) in the muscular propria (longitudinal smooth
muscle layer) and is constant (3 every minute)
- Pacemaker cells undergo slow depolarisation-repolarisation cycles
- The depolarisation waves are transmitted through gap junctions to adjacent smooth muscle cells
- These cells do not cause significant contraction in the empty stomach
The strength of the peristaltic contraction varies
• Excitatory neurotransmitters and hormones further depolarise membranes
• Action potentials are generated when the threshold is reached
• The interstitial cells of cajal are active all the time, but the action potential threshold for muscle contraction can be altered by the enteric nervous system
What is the effect of gastrin secretion on the strength of contraction?
Increases the strength
What is the effect of gastric distension (mediated by mechanoreceptors) on the strength of contraction?
Increases the strength
What is the effect of Duodenal distension, Increase in duodenal fat, Increase in duodenal osmolarity, Decrease in duodenal pH,Increase in sympathetic nervous system stimulation, Decrease in parasympathetic nervous system stimulation on the strength of contraction?
Decreases the strength
What is the result of overfilling of the duodenum?
The capacity of the stomach is greater than that of the duodenum, the overfilling of the duodenum by a hypertonic solution results in dumping syndrome; vomiting, bloating, cramps, diarrhoea, dizziness, fatigue, weakness, sweating & electrolyte
Imbalances
What are the natural mechanisms to delay gastric emptying?
- As gastric contents enter duodenum, duodenal pH falls
- Gastric emptying is regulated by the same things that regulates parietal & chief cells
What is gastroparesis?
Delayed gastric emptying
What are the causes and symptoms of gastroparesis?
Causes:
- Idiopathic (cause unknown)
- Autonomic neuropathies e.g. diabetes mellitus
- Abdominal surgery
- Parkinsons disease
- Multiple sclerosis
- Scleroderma (connective tissue disorder)
- Amyloidosis
- Female gender (more common in women)
Drugs can cause gastroparesis: - H2 receptor antagonists
- Proton pump inhibitors
- Opiod analgesics
- Diphenhydramine (Benadryl)
- Beta-adrenergic receptor agonists
- Calcium channel blockers
- Levodopa (Parkinson’s drug)
Symptoms:
• Gastroparesis can cause matter in the stomach to rot and smell and become a similar
appearance to faeces
- Nausea
- Early satiety (feeling full early)
- Vomiting undigested food
- GORD (gastro-oesophageal reflux disease - can be caused by; PREGNANCY,
HIATUS HERNIA (when stomach goes above oesophagus), OBESITY & SMOKING)
- NOTE: a sedentary lifestyle does not increase the risk of acid reflux
- Abdominal pain/bloating
- Anorexia (loss of appetite)
How much water enters the small intestine per day?
Approx 8000ml
What percentage of water is reabsorbed in the small intestine?
Approx 80%
Of the remaining water that passes to the large intestine, what percentage is reabsorbed? What happens to the remaining water?
Approx 98%, the final 2% is excreted in the stool as about 200ml
Which part of the small intestine absorbs the most water?
Jejunum
Why are such small amounts of water absorbed in the stomach?
Small amounts of water are reabsorbed in the stomach, but the stomach has a much smaller surface area available for diffusion and lacks the solute-absorbing
mechanisms that create the osmotic-gradient necessary for absorbing water
Describe the mechanism of the absorption of the water in the small intestine?
- The epithelial membranes of the small intestine are very permeable to water, and net water diffusion occur across the epithelium whenever a water concentration
difference is established by the active absorption of solutes - Na+ accounts for most of the actively transported solutes because it constitutes the
most abundant solute in chyme - it is actively transported from the lumen in the
cell membranes of the ileum & jejunum - Luminal membrane transport is variably coupled glucose, amino acids or other
substances
Describe the mechanism of the absorption of the water in the colon?
- The contents are iso-osmotic (concentration in lumen of colon = that of blood) in the
colon so Na+ is actively pumped from the lumen and water follows - Potassium reabsorption: In general K+ reabsorption is by passive diffusion, the
net movement begin determined by the potential difference between the lumen and
intestinal capillaries. Note: Diarrhoea can result in severe hypokalaemia (loss of K+) - Chloride reabsorption: Cl- is actively reabsorbed in exchange for bicarbonate -
resulting in the intestinal contents becoming more alkaline
Describe the absorptive state?
- During which ingested nutrients enter the blood from the GI tract
- During this state, some of the ingested nutrients provide the energy requirements of the body and the remainder is added to the body’s energy stores to be called upon during the next postabsorptive state
Describe the postabsorptive state?
- During which the GI tract is empty of nutrients and the body’s own stores must supply energy
Where are vitamin B and C absorbed and what is the process?
absorbed by diffusion or mediated transport in the JEJUNUM
Where is Vitamin B12 absorbed and what is the process?
vitamin B-12, which is a very large and charged vitamin. To be absorbed B-12 must first bind to the protein intrinsic factor (secreted by
parietal cells of the stomach) - intrinsic factor whit bound B-12 then binds to specific sites on the epithelial cells in the LOWER PORTION OF THE ILEUM
where vitamin B-12 is absorbed via endocytosis.
• Vitamin B-12 is needed for erythrocyte formation and a deficient in B-12 can lead to pernicious
anaemia and is usually caused due to a deficiency in intrinsic factor
How long will the energy stores of glycogen, lipid, and tissue protein last?
Glycogen: 12 hours
Lipids: sufficient to last 3 months
Tissue Protein: Only becomes significant in times of prolonged starvation
What fuel can be used by the brain?
Glucose, ketone bodies
What fuel can be used by muscle?
glucose, ketone bodies (in starvation), triacyglycerol & branched-chain amino acids
What fuel can be used by the liver?
amino acids, fatty acids (including short chain acids), glucose & alcohol.
NOTE: ketone bodies are not used by the liver, although they are produced here
they are then sent to extrahepatic tissue to buy used there, the liver cannot use ketone bodies for fuel due to the fact they do not have the enzyme thiolase
What fuel can be used by the kidney?
glucose & ketone bodies (cortex), only glucose (medulla)
What fuel can be used by the small intestine?
ketone bodies (mainly in starvation), glutamine (amino acid)
What fuel can be used by the large intestine?
short-chain fatty acids, glutamine
What is the Basal Metabolic Rate?
Minimum amount of energy required to keep the body alive
• Usually measured by O2 consumption in a person who is awake, restful and faster
for 12 hours
• BMR decrease with age
• Measure in kcal expended/hr/m2
Equations used across the UK:
• Harris Benedict Equations (1919)
• Schofield Equations (1985)
• Henry equations (2005)
Rough estimate: ~1kcal/kg body mass/hour
What are the conditions essential for measuring BMR?
What must be stated if these conditions are not met?
Post-absorptive (12 hour fast) Lying still at physical and mental rest Thermo-neutral environment (27 – 29oC) No tea/coffee/nicotine/alcohol in previous 12 hours No heavy physical activity previous day Establish steady-state (~ 30 minutes)
If any of the above conditions are not met, we may refer to Resting Energy Expenditure (REE) or Resting Metabolic rate (RMR)
What factors cause BMR to decrease?
Age- Increasing
Gender- Females have lower rate
Dieting/Starvation
Hypothyroidism
Decreased Muscle mass
What factors cause BMR to increase?
Increasing Body Weight
Fever/infection/chronic disease
Low ambient temperature
Hyperthyroidism
What is the storage, function, source, and effect of deficiency of Vitamin A?
Storage:
Fat Soluble
Store in ito cells in the space of Disse of the liver
Functions: • Cellular growth & differentiation • Process of vision (retinal pigments) • Healthy skin • Reproduction • Embryonic development • Maintenance of bodies mucus membranes • Used in lymphocyte production - immune system
Sources: • Liver • Dairy products • Oily fish • Margarine
Deficiency: • Night blindness • Xerophthalmia (eye fails to produce tears) • Growth retardation • Keratinisation of epithelia • Impaired hearing, taste & smell • Increased susceptibility to infection
What is the storage, function, source, and effect of deficiency of Vitamin C?
Storage:
Water Soluble
Function:
• Synthesis of; collagen, neurotransmitters & carnitine (used in beta-oxidation)
• Antioxidant ability - can donate electrons to radical O2 compounds
• Absorption of non-haem (plant based) iron
Source: • Citrus fruits • Green leafy vegetables • Potatoes • Kidney
Deficiency:
• Initial signs are non-specific
• Weakness
• Bleeding gums
• Hyperkeratosis (thickening of outer layer of skin)
• 50 - 100 days without Vitamin C = signs of scurvy
What is the storage, function, source, and effect of deficiency of B Vitamins?
Storage:
Water soluble
Function:
Important in cell metabolism & energy production
- Main one is B-12 For absorption, intrinsic factor is required which is produced by the parietal cells of
the stomach
Source:
found in fish, poultry, meat & eggs
Deficiency:
Deficiency results in less erythrocyte formation - pernicious anaemia
- B-12 is absorbed in the terminal ileum
What is the storage, function, source, and effect of deficiency of Vitamin D?
Storage:
Fat Soluble
Function:
- Vitamin D3 (cholecalciferol) is formed by the action of ultra-violet (UV) radiation from sunlight on a cholesterol derivative in the skin
- Vitamin D2 is derived from plants
- Both these are collectively referred to as Vitamin D
- Its metabolised by the addition of hydroxyl groups, first in the liver and then in certain kidney cells, the end result of these changes is 1,25-dihydroxyvitamin D
(1,25-(OH)2D) - the active hormonal form of vitamin D
- Functions of 1,25-(OH)2D:
• Its major action is to stimulate intestinal absorption of Ca 2+ and phosphate
Source:
Sunlight and plants
Deficiency:
• Major consequence is decreased intestinal Ca2+ absorption resulting in a
decreased plasma Ca2+
• This decrease in detected via a plasma membrane Ca2+ receptor in the
parathyroid glands (embedded in the posterior surface of the thyroid gland)
• Resulting in the parathyroid glands releasing PARATHYROID HORMONE (PTH)
which exerts multiple actions that increase extracellular Ca2+ concentration:
1. It directly increases the resorption of BONE by osteoclasts, which causes
Ca2+ & phosphate ions to move from bone into the extracellular fluid - this
can lead to a decrease in bone mass - osteoporosis (higher incidence of
bone fractures etc.)
2. It directly stimulates the formation of 1,25-dihydroxyvitamin D which then
increases intestinal absorption of Ca2+ & phosphate ions, thus the effect of
PTH on the intestines is indirect
3. It directly increases Ca2+ reabsorption in the kidneys, thereby decreasing
urinary Ca2+ excretion
4. It directly decreases the reabsorption of phosphate ions in the kidneys
thereby increasing its excretion in the urine - this keeps plasma phosphate
ions from increasing when PTH causes an increased release of both Ca2+ &
phosphate ions from the bone and an increased production of 1,25-
dihydroxyvitamin D leading to calcium & phosphate ion absorption in the
intestine
Liver storage prevent deficiency for 3-4 months
What is the storage, function, sources, and effect of deficiency of vitamin E?
Storage:
Fat Soluble
Function:
Main function is as an antioxidant
Source:
plant oils – such as rapeseed (vegetable oil), sunflower, soya, corn and olive oil.
nuts and seeds.
wheatgerm – found in cereals and cereal product
Deficiency:
Vitamin E deficiency can cause nerve and muscle damage that results in loss of feeling in the arms and legs, loss of body movement control, muscle weakness, and vision problems. Another sign of deficiency is a weakened immune system
What is storage, function, source, and effect of deficiency of Vitamin K?
Storage:
Fat Soluble
Function:
Main function is that is is essential for the production of clotting factors (10,9,7 & 2) in the liver
Source:
green leafy vegetables – such as broccoli and spinach. vegetable oils. cereal grains.
Deficiency:
Vitamin K deficiency results from extremely inadequate intake, fat malabsorption, or use of coumarin anticoagulants. Deficiency is particularly common among breastfed infants. It impairs clotting.
What is malabsorption?
The inadequate absorption of nutrients from the intestines
• Failure to absorb certain vitamins, minerals, carbohydrate, proteins or fats
• Chiefly caused by disease of the small bowel
What is Giardiasis?
infection which causes the villi to atrophy thus reducing absorption capacity
What is Coeliac Disease and how can it lead to malabsorption?
- Abdominal distension
- Muscle atrophy
- Occurs in genetically disposed individuals
- Auto-immune condition whereby gluten is partially degraded triggering an
immune response whereby the system attacks the villi & microvilli resulting in a loss of intestinal brush border surface area resulting in decreased absorption of many nutrients - Can prevent the absorption of vitamin D which ultimately results in the decrease in
calcium absorption in the GI tract - resulting is osteoporosis
How does cystic fibrosis lead to malabsorption?
- Caused by an autosomal recessive mutation in an epithelial channel called the cystic fibrosis transmembrane conductance regulator (CFTR). This results in problems with salt & water movement across cell membranes, which leads to thickened secretions & a high incidence of lung infection. The airways secrete a watery fluid upon which mucus can ride freely, in CF suffers the production of this fluid is impaired causing the mucous layer to become thick & dehydrated thereby obstructing the airways
- The exocrine portion of the pancreas secretes HCO3- and a number of digestive enzymes e.g. lipase, colipase & alpha amylase (see further up) into the ducts that converge into the pancreatic duct which joins the common bile duct from the liver
before it enters the duodenum at the duodenal papillae. - The enzymes are secreted by gland cells at the pancreatic end of the duct system
whereas HCO3- is secreted by the epithelial cells lining the ducts. - The pancreatic duct cells secrete HCO3- (produced from CO2 & H2O using carbonic anhydrase) into the duct lumen via an apical membrane Cl-/HCO3-
exchanger, while the H+ produced (from the dissociation of H2CO3) is exchanged for extracellular Na+ on the basolateral side of the cell. - The H+ enters the pancreatic capillaries to eventually meet up in portal vein blood
with the HCO3- produced by the stomach during the generation of luminal H+. - The energy for secretion of HCO3- is provided by Na+/K+ - ATPase pumps on the
basolateral membrane. - Cl- normally does not accumulate within the cell because these ions are recycled into the lumen through the CFTR.
- Via a paracellular route, Na+ & H20 move into the ducts due to the electrochemical
gradient established by chloride movement through the CFTR. - However in cystic fibrosis, the CFTR is faulty meaning Cl- will build up in the gland cells thereby preventing the movement of HCO3- into the duct this means
that less HCO3- enters the small intestine, its secreted to act as a buffer to raise the pH in the small intestine, since the contents have just been thought the low pH
stomach - at low pH the digestive enzymes of the pancreas are not active - HCO3- is used as a buffer to increase intestinal pH so that the digestive enzyme can be active. - Thus less HCO3- in the small intestine will result in a decrease in digestion and thus absorption
- Furthermore the lack of normal water movement leads to a thickening of pancreatic secretions - resulting in the clogging of the pancreatic ducts and thus enzymes and HCO3- cannot be released resulting in a decrease in digestion and thus absorption. Furthermore the digestive enzymes begin clogged in the duct can result in pancreatic damage resulting in the pancreas eventually not being able to
produce digestive enzymes - Thus CF suffered are given pancreatic enzyme replacements to aid their digestion
and thus absorption
What is BMI, how is worked out, and what are the relevant values?
- Body Mass Index
- BMI = Weigh (Kg)/ Height2 (m)
- BMI > 30 = obese
- BMI < 18.5 = underweight
- BMI > 25 = overweight
- 18.5 < BMI < 25 = normal
What is MUST?
‘MUST’ is a five-step screening tool to identify adults, who are malnourished, at risk of malnutrition (undernutrition), or obese. It also includes management guidelines which can be used to develop a care plan. It is for use in hospitals, community and other care settings and can be used by all care workers
What are the steps of MUST?
1: Measure height and weight to get a BMI score using chart provided. If unable to obtain height and weight, use the alternative procedures shown in this guide.
2: Note percentage unplanned weight loss and score using tables provided.
3: Establish acute disease effect and score.
4: Add scores from steps 1, 2 and 3 together to obtain overall risk of malnutrition.
5: Use management guidelines and/or local policy to develop care plan
Define malnutrition?
A state of nutrition with a deficiency, excess or imbalance of energy, protein or other nutrients,
causing measurable adverse effects. Adverse effects are on tissue/body form (shape, size, composition), body function and clinical outcome.
What is the process of starvation?
Overnight fast:
- ↓insulin
- Glycogenolysis
- The brain requires about 150 g of glucose a day.
- After an overnight fast the liver only has about 80g glycogen.
- During a longer period of fasting/starvation, glucose must be formed from non-carbohydrate sources - gluconeogenesis
2-4 days:
• ↓insulin • ↑cortisol Gluconeogenesis uses ○ Lactate ○ Amino acids □ Muscle □ Intestine □ Skin ○ Glycerol □ Fat breakdown
over 4 days:
○ Liver → ketones from fatty acids,
○ Brain adapts to using ketones,
○ ↓BMR = accommodation.
What is the average daily intake of lipid?
70-100 per day most in the form of triglycerides (glycerol with three fatty acids attached)
Which are the three most important fatty acids we absorb and which one is most abundant?
Palmitic Acid (Most Abundant)
Stearic Acid
Oleic Acid
What are triglycerides?
A glycerol molecule with 3 fatty acids attached
What are the first processes of fat digestion?
- Triglyceride digestion occurs to a limited extent in the mouth & stomach but it predominantly occurs in the small intestine.
- The major digestive enzyme is lipase (synthesised in the PANCREAS) which catalyses the splitting of bonds linking fatty acids to the 1st & 3rd carbon atoms of glycerol, producing two free fatty acids & a monoglyceride as products: Triglyceride —> Monoglyceride + 2 Fatty acids , under the action of lipase
- The lipids in ingested food are insoluble in water so aggregate into large lipid droplets in the upper portion of the stomach
How are the large lipid droplets converted into smaller droplets and what are the two parts of this process?
These lipid droplets are then converted into very small droplets (1mm in diameter) via the process of emulsification
The two steps are:
1. Mechanical Disruption of the large droplets into smaller droplets
- An emulsifying agent
Describe the mechanical disruption of the large droplets into smaller droplets?
provided by the motility of the GI tract, in the lower portion of the stomach & in the small intestine, which grinds & mixes the luminal contents
Describe the process the action of the emulsifying agent?
provided by the phospholipids in food and by bile salts secreted in bile:
• Phospholipids are amphipathic (both hydrophilic & phobic) molecules(containing polar or ionised groups on one end of the molecule and non-polar groups on the other) consisting of 2 non polar fatty acid chains attached to glycerol with a charged phosphate group on one end
- Bile salts are formed from cholesterol in the liver and are also amphipathic
- The non-polar portion of the phospholipids and bile salts associate with the non polar interior of the lipid droplet - leaving the polar portions exposed at the water surface - here they repel other lipid droplets that are similarly coated with these emulsifying agents thereby prevents their reaggregation into larger fat droplets
- The coating of the lipid droplets with these emulsifying agents however, impairs the accessibility of the droplet for lipase
- To overcome this issue, the pancreas secretes a protein called colipase which binds to the lipid droplet surface as well as binding to lipase - thereby holding it onto the surface of the lipid droplet
- These small droplets are further converted into smaller droplets, under the further action of bile salts, called micelles (4-7 nm in diameter) - these consist of bile salts with fat soluble vitamins (A,D,E,K) and cholesterol , fatty acids, monoglycerides & phospholipids all clustered together with their polar ends facing outwards and their non-polar ends facing inwards
- Despite the fact that fatty acids and monoglycerides have an extremely low solubility in water, some do exist in solution and are able to diffuse across the lipid portion of the luminal plasma membranes of the epithelial cells of the small intestine
- The micelles are in equilibrium with these free fatty acids and monoglycerides meaning the micelles are continuously breaking down & reforming - as the concentration of free lipids decreases since they are diffusing through the epithelial cells more lipids are released into solution by the breakdown of the micelles
- NOTE: it is not the micelle which is absorbed but instead the individual lipid molecules released from the micelle, thus micelles can be regarded as holding stations for lipids
What happens after the emulsification of the large lipid droplets into small lipid droplets?
Step 1: Once in the small intestine the fatty acids and monoglycerides are re-synthesised into triglycerides in the smooth endoplasmic reticulum where the enzymes for triglyceride synthesis are located. This process decreases the cytosolic concentration of free fatty acids and monoglycerides and thus maintains a diffusion gradient for these molecules into the cell from the intestinal lumen. The resynthesises fat aggregates into small droplets coated by proteins that perform an emulsifying function similar to that of bile salts
Step 2: - The fat droplets then pinch off the endoplasmic reticulum in vesicles where they are then processed through the golgi apparatus where they are modified into CHYLOMICRONS, they then bud off the golgi in vesicles which then fuse with the plasma membrane and enter the interstitial fluid via exocytosis
Step 3: - Chylomicrons contain not only triglycerides but other lipids such as phospholipids, cholesterol & FAT-SOLUBLE VITAMINS which have been absorbed in the same process as the fatty acids
- The chylomicrons then enter the lacteals - lymphatic vessels in the intestinal villi rather than into the blood capillaries - this is due to the fact that chylomicrons cannot enter the capillaries due to the basement membrane at the outer surface of the capillaries providing a barrier to diffusion - The lacteals have large pores between their endothelial cells which enable the chylomicrons to pass through
Step 4: - The lymph from the small intestines eventually empties into the systematic veins
Step 5: • Once absorbed:
- Once the chylomicrons (containing triglycerides, phospholipids, cholesterol & fat soluble vitamins) have entered the circulation the processing of the triglycerides in chylomicrons in blood plasma is similar to that for VLDL’s produced by the liver - The fatty acids of plasma chylomicrons are released, mainly within adipose-tissue capillaries by the action of endothelial lipoprotein lipase (since it hydrolyses the triglyceride)
Step 6: - The released fatty acids then diffuse into adipocytes and combine with alpha-glycerol phosphate (produced from dihydroxyacetone phosphate in glycolysis),synthesised in the adipocytes from glucose metabolites to form triglycerides
Why is Glucose ESSENTIAL for triglyceride synthesis in adipocytes?
due to the fact that adipocytes do not have the enzyme required for phosphorylation of glycerol to alpha glycerol, so glycerol can only be produced by reducing dihydroxyacetone phosphate (from glycolysis) and NOT from glycerol or any other fat metabolites
In contrast to alpha glycerol there are 3 main sources of fatty acids for triglyceride synthesis, what are they?
- Glucose that enters adipose tissue and is broken down to provide building blocks for the synthesis of fatty acids
- Glucose that is used in the liver to form VLDL triglycerides, which are transported in the blood and taken up by adipocytes
- Ingested triglycerides transported in the blood in chylomicrons and taken up by adipocytes
• 2 & 3 require lipoprotein lipase to release the fatty acids from the circulating triglycerides
Through which pathway are fat soluble vitamins absorbed?
Fat-soluble vitamins such as vitamin A,D,E & K follow the pathway for fat absorption mentioned in fat digestion but in the ILEUM
Where does the digestion of proteins occur?
Mainly in the duodenum
How much protein does a healthy adult require per day to supply essential amino acids and replace
the nitrogen contained in amino acids that are converted to urea?
A healthy adult only requires 40 to 50g of protein a day to supply essential amino acids and replace
the nitrogen contained in amino acids that are converted to urea
How many amino acids found in proteins do humans use?
20
How many essential amino acids are there and what does essential mean?
9 are essential - we cannot manufacture them
What are the 9 essential amino acids?
histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine
Do enzymes exist as optical isomers?
Enzymes exist as optical isomers, HOWEVER only the L-forms are found in the proteins we utilise
What are zwitterions and why do amino acids form them?
a zwitterion, also called an inner salt, is a molecule that contains an equal number of positively- and negatively-charged functional groups. With amino acids, for example, in solution a chemical equilibrium will be established between the “parent” molecule and the zwitterionoptical isomers HOWEVER only the L-forms are found in the proteins we utilise
What is the basic building block of a protein?
The basic building block of a protein is the peptide bond - CONH (HN-C=O)
What is step 1 of the process of protein digestion and what are the relevant enzymes and zymogens?
Process:
- Begins in the stomach where the enzyme pepsin (chief cells release pepsinogen which is rapidly activated by the low luminal pH) cleaves some of the peptide linkages - forming peptide fragments
- Pepsins hydrolyses the bonds between an aromatic amino acid (tyrosine or phenylalanine) and a second amino acid
- The optimum pH for pepsins is around pH 1.6 - 3.2 thus action is terminated on exit from the stomach
- The pH in the duodenal cap is around pH 2 - 4
- The pH in the rest of the duodenum is around pH 6.5
Enzyme:
Pepsin
Zymogens:
- Pepsinogen I - found only in the HCl secreting region (mainly the body) of the stomach
- Pepsinogen II - found in the pyloric region
What is step 2 of the process of protein digestion and what are the relevant enzymes?
Process:
- In the small intestine these smaller peptides are further fragmented by enzymes produced in the pancreas
enzymes produced in the pancreas which can be divided into:
- Endopeptidases: trypsin, chymotrypsin & elastase
- Exopeptidase’s: carboxyl dipeptidases and the amino peptidases of the brush border (microvilli border)
What is step 3 of the process of protein digestion and are there relevant enzymes?
- Some di & tripeptides are absorbed and finally broken down by intracellular peptidases meaning final digestion of peptides occurs in three locations;
- the intestinal lumen
- the brush border
- within the cell
No enzymes
Where does digestion and absorption of carbohydrate occur?
In the duodenum
What is a monosaccharide?
single sugars e.g. glucose, fructose & galactose
What is an oligosaccharide?
several sugar molecules:
- Lactose - forms beta linkages since OH groups lies above the plane of the molecule thus it requires its own enzyme to be broken down, can’t use the same one as sucrose since it has alpha linkages. People who are lactose-intolerant do not have sufficient amounts of beta enzymes
- Sucrose (most common disaccharide)
- Both are disaccharides - the important dietary ones
What is a polysaccharide?
many sugar containing molecules e.g. starch & glycogen
• Sugar molecules also exist as optical isomers - only the D-isomers are utilised in metabolism
• Glycogen - the principal dietary polysaccharide from animal sources, polymer of glucose molecules which are joined by alpha 1-4 glycosidic linkages and some chain branching by alpha 1-6 glycosidic linkages
• Starch - majority alpha 1-4 glycosidic linkages with some chain branching by alpha 1-6 linkages but LESS THAN IN GLYCOGEN
• Cellulose - only beta 1-4 glycosidic linkages
What is the process of carbohydrate digestion?
Step 1 Starch is first degraded by ptyalin - the alpha amylase of saliva in the mouth only a small fraction of starch digestion occurs here
- The optimal pH for this is pH 6.7 and activity is terminated by gastric acidity of the stomach
Step 2 Once in the small intestine (responsible for 95% of starch digestion), pancreatic alpha amylase catalyses alpha 1-4 linkages
- But NOT the alpha 1-6 linkage, the alpha 1-4 linkages next to branch points or the terminal alpha 1-4 linkages
Step 3 Thus the end products of this digestion are:
• the disaccharide maltose
• the trisaccharide maltotriose
• larger polymers of glucose with alpha 1-4 linkages
• branched polymers consisting of around 8 units called the alpha-limit dextrins
Step 4 These are further digested by the oligosaccharidases located at the outer portion of the membrane of the microvilli (the brush-border):
• maltase
• lactase
• sucrase
• alpha-limit dextrinase
- They are broken down into monosaccharide - glucose, galactose & fructose
What is the process of the absorption of hexose and pentose sugars (glucose as an example)?
- Hexoses & pentoses are rapidly absorbed across the intestinal mucosa, these then enter the capillaries which drain to the HEPATIC PORTAL VEIN
- Glucose and Na+ SHARE the SAME TRANSPORTER - sodium-glucose cotransporter (SGLT) thus a high Na+ concentration at the mucosal surface facilitates glucose absorption
What is the process of the absorption of galactose?
Galactose, a glucose isomer, is transported from the lumen by the SGLT
What is the process of the absorption of Fructose?
Fructose utilises a different carrier and its absorption is independent of luminal Na+ since it is absorbed by facilitated diffusion via a glucose transporter (GLUT)
What 2 step process happens after absorption of monosaccharides?
Step 1 These monosaccharides then leave the epithelial cells and enter the interstitial fluid by way of facilitated diffusion via GLUT proteins in the basolateral membranes of the epithelial cells
Step 2 From there, the monosaccharide diffuse into the blood through capillary pores
Most ingested carbohydrates are digested & absorbed within the first 20% of the small intestine - i.e duodenum
What is the post-absorption of monosaccharides process?
Step 1 After entering the hepatic portal vein and thus the liver, the liver then converts these carbohydrates into glucose
Step 2 Skeletal muscle make up the majority of the body and so is the major consumer of glucose, even at rest
- Skeletal muscle not only catabolises (breaks it down into smaller units) glucose in the absorptive phase but also converts some of the glucose to the polysaccharide glycogen, which is then stored in the muscle for future use - During the absorptive state there is a net uptake of glucose by the liver
Step 3 The LIVER also converts glucose into glycogen to be used at some point in the future
- The LIVER can also convert the glucose into alpha-glycerol phosphate ( by reducing dihydroxyacetone phosphate via glycolysis) and fatty acids which are then used to synthesise triglycerides - NOTE: this process of converting glucose into alpha-glycerol phosphate (via glycolysis) and fatty acids also occurs in adipose-tissue cells (adipocytes) which can then be used to synthesise triglycerides which can be then stored in the adipocytes
What is the process of lipoprotein formation?
Step 1 Most of the fat synthesised from glucose in the liver is packaged along with specific proteins into molecular aggregates of lipids and proteins known as lipoproteins
Step 2 These aggregates are secreted by hepatocytes and enter the blood
- They are called very-low-density lipoproteins (VLDL’s) since they contain more fat than protein and fat is less dense than protein
- The synthesis of VLDL’s in hepatocytes occurs by a similar process as that of chylomicrons by intestinal mucosa cells (see above)
Due to their large size, VLDL’s in the blood do not readily penetrate capillary walls, instead, their triglycerides are hydrolysed mainly to monoglycerides (i.e glycerol linked to one fatty acid) and fatty acids by the enzyme lipoprotein lipase
- Lipoprotein lipase is located on the on the blood-facing surface of capillary endothelial cells, especially those in adipose tissue
- In adipose-tissue capillaries the fatty acids generated by the action of lipoprotein lipase diffuse from the capillaries into the adipocytes - there they combine with alpha- glycerol phosphate, supplied by glucose metabolites to form triglycerides once again. As a result, most of the fatty acids in VLDL triglycerides originally synthesised from glucose in the liver end up being stored in triglyceride in adipose tissue
- Some of the monoglycerides produced by the break down of triglycerides by lipoprotein lipase in the blood in adipose-tissue capillaries are also taken up by adipocytes where enzymes can then reattach fatty acids to the two available carbon atoms of the monoglyceride and thereby form a triglyceride
- Some of the monoglycerides travel via the blood to the liver to be metabolised
What is iron essential for use in?
haemoglobin, myoglobin & bone marrow
What are sources of iron?
meat, liver, shell fish, egg yolk, beans, nuts and cereals
Where does the homeostastic control of iron balance occur?
The homeostatic control of iron balance resides primarily in the intestinal
epithelium, in the DUODENUM - which actively absorbs IRON from ingested foods
Normally only a small fraction of ingested iron is absorbed - however, this fraction is increased or decreased in a negative feedback manner depending on the state of the bodies iron balance
• Only about 10% of ingested iron is absorbed into the blood each day
What is the process of iron balance homeostasis?
Step One:
Iron ions are actively transported into the duodenal intestinal epithelial cells - once here some iron ions are incorporated into FERRITIN (protein-iron complex) that acts as an intracellular store for iron
Step Two:
Most of the iron bound to ferritin in the intestinal epithelial cells is released back into the intestinal lumen when the cells at the tips of the villi disintegrate, and the iron is then excreted in the faeces
When Iron stores are satisfied:
Iron absorption depends on the body’s iron content. When the body’s stores are enough, the increased concentration of free iron in the plasma and intestinal
epithelial cells leads to an increased transcription of the gene encoding for ferritin and thus an increased synthesis of ferritin protein. This results in an increased
binding of Fe in the intestinal epithelial cells and a reduction in the amount of iron released into the blood
When iron stores are low:
When body stores are low (e.g. after blood loss), the production of intestinal ferritin decreases resulting in a decrease in the amount of iron bound to ferritin thus increasing the unbound iron released into the blood
Step Four:
The absorbed iron that does not bind to ferritin is released into the blood where it is
able to circulate around the body bound to the plasma protein TRANSFERRIN
• Transferrin transports iron in the blood plasma to the bone marrow to be incorporated into new erythrocytes
Step Five:
Once iron has entered the blood, the body has very little means of excreting it meaning it accumulates in tissues, most of the iron is stored in the LIVER in liver
ferritin within KUPFFER CELLS (reticulo-endothelial macrophages)
How is iron stored and what are the percentages?
Haemoglobin: 50%
Haem containing proteins (mainly cytochromes): 25%
Liver ferritin: 25%
What proteins are produced by the liver?
The liver is a major producer of proteins
• It produces plasma proteins, clotting factors & complement factors
What are the two main plasma proteins?
Albumin and Globulins
What is the function of albumin and what are issues that can arise?
Functions:
- Binding & transport of large, hydrophobic compounds such as bilirubin, fatty
acids, hormones & drugs (NSAIDS & warfarin)
Maintenance of colloid osmotic pressure
Issues that arise:
• When there is liver failure there is a reduction in albumin resulting in less
albumin in the blood (hypoalbuminaemia). This in turn will mean there will
be a decreases in capillary oncotic pressure, since there will be less of a
difference in the concentration of water between plasma and interstitial fluid
resulting in the accumulation of water in the interstitial fluid, resulting inoedema.
Hypoalbuminaemia = Oedema
• Albumin can also decrease due to conditions:
- Nephrotic syndrome: where there is an increased glomerular
permeability which allows proteins to filter through the basement
membrane meaning the loss of up to several grams of protein a day
can occur
- Haemorrhage
- Gut loss: a rare syndrome in which the wall of the gut is unusually
permeable to large molecules resulting in albumin loss
- Burns: Extensive tissue damage with damage to capillaries can cause
loss of protein through the walls of the capillaries
What is the process of maintenance of colloid osmotic pressure by albumin?
overall:
Colloid osmotic pressure is the effective osmotic pressure across blood
vessel walls which are permeable to electrolytes but NOT large molecules. It
is almost entirely due to plasma proteins
1: Albumin maintains osmotic pressure due to the fact that it presence in the plasma means that the water concentration of the blood plasma is slightly
lower than that of the interstitial fluid meaning there is a net flow of water OUT OF the interstitial fluid INTO the blood plasma
2:
• Opposing forces act to move fluid across the capillary wall, there are 4, these are known as Starling Forces:
1. Capillary hydrostatic pressure (favouring fluid movement out of the capillary)
2. Interstitial hydrostatic pressure (favouring fluid movement into the capillary
3. Osmotic force due to plasma protein concentration (favouring fluid movement into the capillary)
4. Osmotic force due to intestinal fluid protein concentration (favouring fluid movement out of the capillary
3:
At the arterial ends of the capillaries the hydrostatic pressure from the capillary is 38 mmHg which is greater than that from the interstitial fluid
(which is virtually zero since there is very little fluid in the interstitial spaces since it quickly picked up by the lymphatics etc.) and the interstitial fluid
protein concentration is 3mmHg and the osmotic pressure due to plasma proteins 28mmHg thus net outward pressure EXCEEDS the net inward
pressure resulting in bulk filtration of fluid OUT OF the capillaries
• However, at the venous end, the only difference in Starling forces is the capillary hydrostatic pressure which has decreased from 35 to around 15mmHg due to the resistance encountered as blood flow through the capillary wall. The other three forces are virtually the same as above so the net inward pressure EXCEEDS the net outward pressure so bulk
absorption of fluid INTO the capillaries occurs
What are the functions of globulin?
Antibody functions (most are gamma-globulins NOT MADE IN LIVER, but some
are alpha/beta globulins which ARE MADE IN LIVER)
• Blood transport of:
- Lipids by lipoproteins
- Iron by transferrin
- Copper by caeruloplasmin
What clotting factors are produced by the liver and what are the functions?
Produces ALL clotting factors EXCEPT; calcium (IV) & von Willebrand factor (VIII)
- The liver also produces bile salts which are essential for vitamin K absorption (fat soluble). Vitamin K is essential for the synthesis of numerous clotting factors 10,9,7,2 (1972)
What are complement factors?
Plays an important role in the immune response to pathogens, its a plasma protein which sticks to pathogens, that is recognised by neutrophils, essentially help mark pathogens to kill
What is protein turnover?
Protein turnover refers to the continuous degradation and re-synthesis of all cellular proteins
The rate of protein turnover is very variable and reflects usage/demand, when does it increase?
Increase is seen when tissues are undergoing structural re-arrangement e.g. when tissue is damaged due to trauma, uterine tissue during pregnancy in
skeletal muscle during starvation - gluconeogenesis. In starvation the skeletal muscle is degraded and the liberated amino acids are used in gluconeogenesis
It also increases due to severe burns since there attempts at re-modelling the skin, its complicated by the fact that significant amounts of protein can be lost
in the exudate from the damaged tissue
What are the two primary methods of protein breakdown?
Lysosomal and Ubiquitin-Proteasome Pathway
Describe lysosomal protein breakdown?
- Carried out in the reticulo-endothelial system of the liver
- This is comprised of the sinusoidal endothelial cells, Kupffer cells & pit cells
- Sinusoidal endothelial cells remove soluble proteins and fragments from the blood
through the fenestrations known as sieve plates on their luminal surface - they are important for removing; fibrin, fibrin degradation products, collagen & IgG
complexes. Once in the liver these proteins are then fused into lysosomes containing lysozyme which are hydrolytic enzymes that break down the protein into
amino acids - Kupffer cells are the livers resident macrophages and perform a similar function except there phagocytose particulate matter thereby packaging them in to
phagosomes in the cell which contain hydrolytic enzymes which will break down the protein into amino acids
Describe the Ubiquitin-proteasome pathway?
occurs in cytoplasm of cells
- Degradation is a selective process
- Rapidly degraded proteins include those that are defective because of incorrect amino acid sequences or because of damage to normal function (denatured)
- Different proteins degrade at different rates, in part, this depends on the structure of the protein - a denatured (unfolded) protein is more readily digested than a protein with an intact conformation
- Proteins can be targeted for degradation by the attachment of a small peptide called ubiquitin to the protein. This peptide directs the protein to a protein complex called a proteasome - “the cellular executioner”, which unfolds the protein and breaks it
down into small peptides
Explain the concept of amino acid degradation and catabolism and explain what is produced?
these reaction occur in the hepatocytes of the liver:
• Any amino acids that are not required as building blocks for protein synthesis must undergo degradation (degraded to specific compounds)
• Catabolism is the break down of complex substances to simpler ones accompanied by the release of energy
• Amino acids contain nitrogen atoms (in their amino group) in addition to carbon, hydrogen and oxygen atoms
• Amino acid catabolism requires the alpha amino group (nitrogen containing) to be removed
What is produced:
Nitrogen - which is incorporated in other compounds or excreted
- Carbon skeleton - which can then be metabolised and used in the Kreb’s
Cycle
What is the process of oxidative deamination?
- Results in the liberation of an amino group as free ammonia (NH3)
- Glutamate is the only amino acid that undergoes rapid oxidative deamination
- Amino acid gives rise to a molecule of ammonia (NH3) and is replaced by an oxygen atom from water to form a alpha-keto acid e.g. alpha-ketoglutarate
- Reaction results in the formation of an alpha-keto acid (e.g alpha-ketoglutarate) & ammonia
- The alpha-keto acid can then be used in the Kreb’s cycle for use in glucose production - GLUCONEOGENESIS - essentially reversing Krebs + glycolysis to Start
-The co-enzyme involved is NAD+ (forwards reaction)/NADPH (backwards
reaction) - The enzyme which catalyses the reaction is glutamate dehydrogenase
- NOTE: the ammonium (NH4+) produced quickly disassociates to form ammonia
(NH3) which can then be converted to urea, via the urea cycle since it is very
toxic - The process is readily reversible and is dependent on concentrations of;
glutamate, alpha-ketoglutarate & ammonia - if the amino acid at the start is
glutamate - the most abundant amino acid in the body - Since this is a reversible reaction, when there is EXCESS ammonia (NH3+) it can
easily cross the blood-brain barrier and then react with alpha-ketoglutarate (thereby meaning there will be a decrease in ATP - DANGEROUS in the brain) - After a protein rich meal, the glutamate concentration will be high, oxidative deamination will degrade the amino acid glutamate resulting in ammonia formation
What is the process of transamination?
- Transfer of an alpha-amino group from amino acid to a keto-acid to form an alpha-keto-acid
If the amino acid alanine is transaminated then the amino group from it is transferred to the keto-acid called alpha-ketoglutarate and results in the formation
of pyruvate (for use in the Kreb’s cycle for use in GLUCONEOGENESIS) and glutamate (amino acid, which can then be oxidatively deaminated) - The enzyme involved for this reaction is called aminotransferase, they are found in the cytosol of the mitochondria throughout the body and particularly in the kidneys & liver. If alanine is being transaminated then the enzyme used is known as alanine aminotransferase (ALT)
- Each aminotransferase is specific to one or a few amino group donors
- This reaction is readily reversible, degradation will occur after a protein-rich meal and amino acid synthesis will occur depending on dietary supply and cellular demand
Do transamination and oxidative deamination occur separately?
No, they occur in unison
What are the brief features and roles of bile?
Secreted in the liver by hepatocytes more or
less continuously
Stored & CONCENTRATED in the gall bladder
since some NaCl & water are absorbed into the
Blood
Used to emulsify fats
Also serves as an excretory pathway for most
steroid hormones, many drugs as well some
toxins metabolised by the liver
What are the six main components of bile?
Bile salts, HCO3-, Cholesterol, Bile pigment, Lecithin (A phospholipid), and trace metals
Describe bile salts?
Bile salts are manufactured and secreted by hepatocytes
Bile salts, cholesterol & lecithin are aggregated into mixed micelles and MAINTAIN this aggregation in the gall bladder even when concentrated. The main reason for this is that bile salts are powerful detergents which they need to be for their fat emulsification function (derived due to the fact that bile salts are anionic (negative)). However they are also capable of damaging cell membranes and so they are separated in micelles to reduce damage until they are required
The most important digestive components are the bile salts
Which cells secrete Lecithan?
Hepatocytes
Descibe HCO3- as a component of bile?
HCO3- helps neutralise the acids in the duodenum
Secreted by epithelial cells lining the bile ducts
Secretion of the HCO3- rich solution by the bile ducts, just like the secretion by the pancreas, is stimulated by secretin in response to the presence of acid in the duodenum
Which cells secrete cholesterol and bile pigment?
Hepatocytes
What is the anatomical relation of the gall bladder and the liver?
The gall bladder, lies at the junction of the right-mid-clavicular line & costal margin
• The livers connection with the GI tract is via the portal vein which collects blood from the superior mesenteric vein (which in turn is effectively the venous drainage of both the small and large intestines). The functional unit of the liver is the hepatic lobule (formed by hepatic plates stacked on top of each other)
Describe the hepatic lobule structure?
Hepatic lobules are hexagonal in cross-section with a portal triad at each corner • The portal triad consists of: - A hepatic portal vein - Hepatic artery - Bile duct
Running up the centre of the lobule is the central vein which eventually becomes the hepatic vein
Substances absorbed from the small intestine wind up in the hepatic sinusoid (type of blood vessel (with fenestrated, discontinuous endothelium) where oxygen-rich blood from the hepatic artery and nutrient rich blood from the portal vein is found, hepatocytes are separated from the sinusoids by the space of disse) either to reach the vena cava via the central vein or are taken up by the hepatocytes in which they can be modified
• The hepatic lobules are wedge-like arrangements of hepatocytes around 1 to 2 cells deep which are surrounded by sinusoids (containing mixed portal/hepatic artery blood)
The liver is unique in that the majority of its blood supply comes from a vein - the portal vein - which is responsible for 80% of the supply with the remaining 20% supplied by the hepatic artery
• When the branches of artery and vein leave the portal triad they join and blood is mixed as it enters the sinusoids It flows through the centre and exits via the central vein
The formed bile heads in the opposite direction to the blood
The sinusoids are lined with a continuous layer of specialised endothelial cells interspersed with Kupffer cells (the resident macrophage population)
On the undersurface there are cells called stellate cells which are responsible for producing the extracellular matrix in the space of disse
Between adjacent hepatocytes are bile canaliculi - these are not true vessels (they do not have specialised walls) but are like a groove running along the side of the hepatocytes, they are bound together by tight junctions, gap junctions & desmosomes which cross both cell membranes. Actin filaments are found in the areas around the canaliculi and serve to pump the formed bile toward the bile ducts
What is the bile pathway to the GI tract?
The bile ducts in the the hepatic lobules
drawing either into the left or right hepatic
ducts which in turn join to form the common
hepatic duct
The cystic duct joins the common hepatic duct,
allowing bile to collect in the gall bladder
After the cystic duct had joined the common
hepatic duct, the duct becomes the common
bile duct
The pancreatic duct then joins the common bile
duct at a point known as the ampulla of vater
These two ducts then enter the duodenum at
the major duodenal papilla (2nd part duodenum)
A sphincter around the two ducts, to regulate the entry of bile into the duodenum is
called the sphincter of Oddi
Describe bile storage?
The gallbladder receives its bile from the common hepatic duct which is formed by the the left and right hepatic ducts
The hepatic bile enters the gallbladder via the cystic duct and is stored & concentrated here - hepatic bile is relatively dilute and is then concentrated in the
gallbladder
Bile remains here until the gallbladder contracts under the action of cholecystokin (CCK) - CCK is released due to amino + fatty acids in duodenum
What is strange about the vasculature of the gallbladder?
The vasculature of the gallbladder is strange in that it the cystic artery supplied oxygenated blood to the gallbladder but it has no venous drainage. The
gallbladder is stuck to the liver bed & blood drains from the gallbladder directly into the liver with no identifiable venous pathway
Describe enteropathic circulation?
During the digestion of a fatty meal, most of
the bile salts entering the intestinal tract via
the bile are absorbed by specific Na+-
coupled transporters in the jejunum and
terminal ileum (largest amounts absorbed
here)
The absorbed bile salts are returned via the
portal vein to the liver, where there are once
again secreted into the bile
Uptake of bile salts from the portal blood into
hepatocytes is driven by secondary active
transport coupled to Na+
Are any bile salts lost from the enteropathic circulation?
A small amount (5%) of the bile salts escape this recycling and is lost in faeces, but the liver synthesises new bile salts from cholesterol to replace it
Describe the relationship between cholesterol and bile?
Bile is synthesised from cholesterol
The liver also secretes cholesterol extracted from the blood into the bile
Bile secretion, followed by excretion of cholesterol in the faeces, is one of the mechanisms for maintaining cholesterol homeostasis in the blood
Cholesterol is insoluble in water, and it solubility in bile is achieved by its incorporation into micelles (whereas in blood, cholesterol is incorporated into lipoproteins)
What is the process of bile secretion from the gall bladder?
1: Although bile secretion is greatest during & just after a meal, the liver is always
secreting some bile
Surrounding the common bile duct at the ampulla of vater is a ring of smooth muscle known as the sphincter of Oddi. When this sphincter is closed, the dilute bile secreted by the liver is shunted into the gallbladder - here the bile is concentrated as some of the NaCl & water is absorbed into the blood
2: The bile duct system is a low pressure system
So when the gallbladder fills with bile it must exhibit adaptive relaxation - which is where the size increases but the pressure doesn’t (opposite of what happens when you blow up a balloon)
3: Shortly after the beginning of a fatty meal, the hormone cholecystokinin (CCK) is released in response to the presence of fat in the duodenum
4: CCK causes the gallbladder to contract & the sphincter of Oddi to relax resulting in the flow of bile down the cystic duct through the common bile duct and into the duodenum where it mixes with the food in the duodenum & lipid digestion occurs
What are bile pigments?
Bile pigments are substances formed from the haem portion of haemoglobin when old/damaged erythrocytes are broken down in the spleen and liver
- The predominant bile pigment is bilirubin, which is extracted from the blood by the hepatocytes and actively secreted into bile
- Bilirubin is yellow and contributes to the colour of bile
- When erythrocytes are old/damaged they are broken down by macrophages (which are phagocytic)
- This occurs mainly in the spleen & bone marrow but can also occur in the kupffer cells (resident macrophages) of the liver
What is the process of bilirubin metabolism?
1: Red blood cell/erythrocytes is ingested into macrophage
2: Haemoglobin is broken down into; haem & globin
3: Globin (a protein) is broken down into amino acids which can then be used to generate new erythrocytes in the bone marrow
4: Haem is further broken down, under the action of the enzyme hemoxygenase into biliverdin and Fe2+ & CO
5: The Fe2+ bound to the iron transporter transferrin is then shuttled to the bone marrow, to be incorporated into new erythrocytes
6: Biliverdin in reduced under the action of biliverdin reductase into unconjugated bilirubin
7: Unconjugated bilirubin is toxic and must be excreted, it is lipid soluble and thus insoluble in the blood
8: Unconjugated bilirubin is bound to albumin and then transported to the liver
9: Here it undergoes glucuronidation (essentially the addition of a glucuronic acid - in order to make it soluble to be excreted, similar to xenobiotic
metabolism) under the action of the enzyme UDP Glucuronyl Transferase which converts it into conjugated bilirubin
10: The conjugated bilirubin is then able to be dissolved in bile and can then travel down the right & left hepatic ducts, into the common hepatic duct,
into the cystic duct to store in the gallbladder, but also into the common bile duct where it can then enter the duodenum
11: The conjugated bilirubin travels to the small intestine until it reaches the ileum or the beginning of the large intestine where under the action of
intestinal bacteria it is reduced through a hydrolysis reaction (a glucuronic acid group is removed) forming urobilinogen
12: Urobilinogen is lipid soluble, around 10% is reabsorbed into the blood and bound to albumin and transported back to the liver - urobilinogen oxidised to urobilin
13: Here it is either re-cycled into bile or transported into the kidneys where it is excreted in urine - responsible for the yellowish colour of urine
14: The remaining 90% of urobilinogen is oxidised by a different type of intestinal bacteria to form stercobilin
15: Stercobilin is then excreted into the faeces - responsible for its brownish colour
What are the three main types of jaundice?
- Pre-hepatic
- Hepatic/intra-hepatic
- Post-hepatic/obstructive
What is jaundice?
A yellow discolouration of the skin caused by a high serum bilirubin level (detectable clinically when bilirubin is above 50micromol/L
What is the mechanism, the symptoms, and the causes of pre-hepatic jaundice?
Mechanism:
• Increased breakdown of erythrocytes resulting in increased levels of
unconjugated bilirubin
• Causes an increased serum unconjugated bilirubin without excess bilirubin
in the urine
Symptoms:
• Sufferers will have a raised serum unconjugated bilirubin - stools brown & urine
normal
• Yellow skin
• Enlarged spleen (due to excess breakdown)
Causes:
malaria, sickle cell anaemia, thalassaemia, physiological jaundice of the newborn (caused by the excess breakdown of foetal
haemoglobin since its no longer required, meaning that there is an increase in
unconjugated bilirubin and the liver cannot conjugate it fast enough since its not
developed properly yet resulting in jaundice)
What is the mechanism, the symptoms, and the causes of hepatic/intra-hepatic jaundice?
Mechanism:
• Result of hepatocellular swelling e.g. in parenchymal liver disease or
abnormalities at a cellular level or the result of infection or exposure to a harmful
substance
• Impaired cellular uptake, defective conjugation or abnormal secretion of bilirubin
by the hepatocytes
• The is liver is damaged so is unable to metabolise the unconjugated bilirubin
resulting in a buildup in serum unconjugated bilirubin
• Damage could also mean that conjugated bilirubin is unable to be secreted
resulting in a raised serum conjugated bilirubin as well
Symptoms: • Increased conjugated AND unconjugated bilirubin • Decreased urobilinogen • Urine will be dark • Stools can be pale or normal • Enlargement of the spleen • Yellow skin
Causes:
• Caused by; viral hepatitis, drugs, alcohol hepatitis, cirrhosis & jaundice of
the newborn
What is the mechanism, symptoms, and causes of post-hepatic/obstructive jaundice?
Mechanisms:
• Occurs when the biliary system is damaged, inflamed or obstructed
Symptoms: • Elevated serum conjugated bilirubin • Dark urine • Pale stools • Normal levels of unconjugated bilirubin • Decreased urobilinogen • No enlargement of the spleen • Yellow skin
Causes:
gallstones, pancreatic cancer, gallbladder cancer, bile duct cancer,
pancreatitis (acute or chronic)
• NOTE: The reason that cancer or inflammation of the pancreas can cause
jaundice is because the head of the pancreas is situated in the duodenal loop
which is near the common bile duct thus any inflammation or cancer of the
pancreas can eventually cause obstruction to the duct resulting in jaundice
• FURTHER NOTE: With acute pancreatitis pain will radiate from the BACK
• FURTHER FURTHER NOTE: In gilbert syndrome (where there is shortage of
UDP glycerol transferase, meaning only small amounts of conjugation occur)
there will be a normal conjugated bilirubin level but a raised unconjugated
bilirubin level
What are gall stones?
Bile not only contains bile salts, but also cholesterol & phospholipids which are water-insoluble and are maintained in a soluble form in the bile as
Micelles
When the concentration of cholesterol in bile becomes high in relation to the concentrations of phospholipid & bile salts, the cholesterol will crystallise out of solution forming gall stones
How are gall stones formed and what problems do they cause?
When the concentration of cholesterol in bile becomes high in relation to the concentrations of phospholipid & bile salts, the cholesterol will crystallise out of solution forming gall stones
If the stone is small it may be able to pass freely through the common bile duct into the intestine with no complications
If its larger the stone may become lodges in the opening of the gallbladder causing painful contractile spasms of the smooth muscle
If its larger the stone may become lodges in the opening of the gallbladder causing painful contractile spasms of the smooth muscle
The problem becomes more serious if the stones become lodged in the common bile duct thereby preventing the bile from entering the intestines
A significant decrease in bile can decrease fat digestion & absorption
This can result in an impaired absorption of fat-soluble vitamins A,DK & E resulting in clotting problems (Vit K) or calcium malabsorption (Vit D)
- The fat that is not absorbed will enter the large intestine and appear in the faeces (steatorrhea)
Also the bacteria in the large intestine convert some of this fat into fatty acid derivatives that alter salt & water movements leading to a net flow of fluid into the large intestine - resulting in diarrhoea & fluid & nutrient loss
If a gall stone becomes lodged at a point that prevents both bile & pancreatic secretions from entering the intestine then this will result in failure to both neutralise acid & adequately digest most organic nutrients not just fat - this can result in severe nutritional deficiencies
What are xenobiotics?
Foreign chemical substance not normally found or produced in the body which cannot be used for energy requirements
Can be absorbed across lungs, skin or ingested
Drugs are xenobiotics
Excreted in bile, urine, sweat and breath
What are the characteristics of pharmacologically active substances?
Lipophilic: to be able to pass through plasma membranes to reach metabolising enzymes
Non-ionised at pH 7.4
Bound to plasma proteins to be transported in
blood
What is a microsome?
a small particle consisting of a piece of endoplasmic reticulum to which ribosomes are attached, so microsomal enzymes - are just enzymes which can be
found in these microsomes
Describe microsomal enzymes and give examples?
mainly involved in Phase I reactions, but can do phase 2
- Located on smooth endoplasmic reticulum
- Mostly found in liver hepatocytes but can be found in the kidneys & lungs too
• Examples; Cytochrome P450 (CYPs), Flavin monooxygenase (FMOs) & UDP
glucoronosyltransferase (UGT) - PHASE 2 REACTION
- Phase I reactions: biotransform substances (transformed one chemical to another)
- Phase II reactions: glucuronidation (the addition of glucuronic acid to a substance)
- Activity can be induced or inhibited by; drugs, food, age, bacteria & alcohol
- Involved in oxidative,reductive & hydrolytic reactions
Describe non-microsomal enzymes and give examples?
Involved mainly Phase II reactions:
• Located in the cytoplasm & mitochondria of hepatocytes in the liver but also in
other tissue too
• Non-Specific so can be involved in both Phase I & Phase II reactions
• Involved in all conjugation reactions except GLUCURONIDATION
• Non-inducible
• Examples; protein oxidases, esterases, amidases, conjugases (transferase),
alcohol dehydrogenase, aldehyde dehydrogenase
Additional examples: • Alcohol dehydrogenase • Aldehyde dehydrogenase • Reduction • Hydrolysis
Describe drug metabolism?
Most drugs are excreted by the kidneys but lipophilic drugs are not effectively removed as they are passively absorbed due to the fact they can diffuse through cell membranes easily
The aim of drug metabolism is to make the drugs more polar so they cannot get across membranes and thus are easily excreted
This mostly occurs in the liver
Via 2 mechanisms - Phase I & Phase II reactions which are used sequentially and mostly occur in the liver where the enzymes are located
What is the aim of phase I reactions?
Aim is to make the drug more hydrophilic so that it can be excreted by the kidneys- it does this by adding a hydroxyl group to the drug
What is/are the basic mechanism/s of phase I reactions?
They introduce or expose hydroxyl (-OH) groups or other reactive sites that can be used for conjugation reactions (the Phase II reactions)
Non-Synthetic catabolic (chemical decomposition of complex substances by the body to form simpler ones, accompanied by the release of energy) reactions; oxidation, reduction & hydrolysis
Introduces reactive group to drug - attack point for conjugation
Hydrophilic molecules usually do not reach the metabolising enzymes since they are
excreted easily
Known as ‘functionalisation”:
- Introduces reactive group to drug
- Includes adding or exposing; -OH,-SH,-NH2,-COOH
- The product of the reaction is usually more reactive
- There is a small increase in HYDROPHILICITY
• Mainly occur in the liver
• Mainly catalysed by cytochrome P450 enzymes
• Drug has to get into the cell - so needs to be more lipophilic
Describe phase I Oxidation reactions?
Oxidation:
- Hydroxylation (add -OH)
- Dealkylation (remove -CH side chains)
- Deamination (remove -NH)
- Hydrogen removal
What is phase I reduction?
Reduction: Add hydrogen (saturate unsaturated bonds)
What is phase I hydrolysis?
Hydrolysis: Split amide (peptide bond (between a carboxyl (COOH) & amino (NH) group) O=C-NH) & ester (the H from a COOH (carboxylic acid) is replaced by some sort of hydrocarbon) bonds
What is the phase I reaction CYP450 enzyme?
- Cytochrome P450 reductase:
• The enzyme required to transfer electrons from NADPH to CY P450
• Contains flavoprotein which in turn consists of; Flavin adenine dinucleotide (FAD) &
flavin mononucelotide (FMN)
• FAD - accepts electrons from NADPH
• FMN - electron donor to CYPs
Overall reaction:
• NADPH + H+ + O2 + RH —> NADP+ + H2O + R-OH
• REMEMBER: - Non-microsomal enzymes:
• Alcohol dehydrogenase
• Aldehyde dehydrogenase
• Reduction
• Hydrolysis - Phase I reactions can:
• Inactivate drugs
• Further activate drug
• Activate drug from pro-drug (inactive form of drug)
• Make a drug into a reactive intermediate (could be carcinogenic or toxic)
What is the aim of phase II reactions?
Significantly increases hydrophilicity for renal excretion
- Most Phase II reactions involve non-microsomal enzymes which are mostly found in the cytoplasm or mitochondria of HEPATOCYTES
What is/are the mechanism/s of phase II reactions?
Occurs mainly in the liver but can occur in other tissues like the lungs & kidneys
Synthetic anabolic (the synthesis of complex molecules such as proteins & fats, from
simpler ones) reactions:
- Glucuronidation (donor compound is UDPGA)
- Sulfation
- Glutathione conjugation
- Amino acid conjugation
- Acetylation (donor compound is Acetyl CoA)
- Methylation (donor compound is S-adenodyl methionine)
- Water conjugation
• Known as “conjugation reaction”:
- Attachment of substituent groups (endogenous (from the body) molecules)
- Usually inactive products
- Catalysed by transferases
Describe Phase II Glucuronidation?
GLUCURONIDATION REACTION:
- Essentially adding a glucuronic acid group (glucuronide) to the drug to make it
more hydrophilic
- Enzyme: Glucuronosyltransferase (Uridine 5’-diphospho-glucuronosyltransferase) (UGT) - microsomal enzyme, used in Phase II reactions, catalyses reaction
- Uridine diphospho-glucuronic acid (UDPGA) - essentially a co-enzyme/donor compound required to conjugate glucuronic acid,
- Substances arising from this process are known as glucuronides
- Process forms covalent bonds
What are Cytochrome P450 enzymes?
Type of microsomal enzyme
Involved in Phase I reactions
Uses heme group (Fe2+) to oxidise substances
Products of P450 enzymes are more water soluble
- Cytochrome P450 enzymes are a large family of enzymes with the prefix CYP -
these family members are known as isoforms/isozymes- 1st number = the family the enzyme belongs to
- Letter= indicates subfamily
- 2nd number= individual genes involved
- Important P450 isozymes: CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 2E1 &
CYP 3A4
Describe the metabolism of aspirin?
Description of drug:
- Analgesic (pain relief)
- NSAID
- Antiplatelet
- Pro-drug
- Irreversibly inhibits cyclooxygenase (COX)
Phase I metabolism:
- Since its a pro-drug it is activated upon metabolism
- Hydrolysis reaction
- Aspirin + H20 —> Salcylic acid + Ethanoic acid
Phase II metabolism:
- Conjugated with glycine or glucuronic acid Elimination (usually polar drug, excreted unchanged)
- Forms a range of ionised (thus won’t be passively absorbed so can be excreted by the kidneys and excreted in the urine) metabolite
Describe the metabolism of paracetamol?
Description of drug:
Phase I metabolism:
No phase I metabolism
Phase II metabolism:
- Predominantly metabolised via a Phase II reaction - conjugated with glucuronic
acid & sulphate
Toxicity:
- If stores of glucuronic acid and sulphate are running low
- Paracetamol will undergo Phase I metabolism via oxidation to produce toxic
NAPQI
- This is removed by conjugation with glutathione
- In overdoses stores of glutathione can run low resulting in toxicity
- Treated with N-Acetyl Cysteine
Describe alcohol metabolism?
- Ethanol — (ADH)—> Acetaldehyde — (ALDH)—> Acetate —> CO2 + H2O
- ADH - Alcohol Dehydrogenase
- ALDH - Aldehyde Dehydrogenase
- Operates at different speeds in different people
- Acetaldehyde is CARCINOGENIC, indications of high levels include; facial flushing, rapid heartbeat & nausea
What is nitrogen balance?
A measure of the equilibrium of protein turnover
• People can be defined as healthy if their nitrogen balance is in equilibrium
What is a positive nitrogen balance and what causes it?
i.e net gain in amino acids
Anabolic
-
Positive nitrogen balance [ANABOLIC]: nitrogen intake > nitrogen loss
- Pregnancy is the most common cause of a positive nitrogen balance
- The recommended daily intake of amino acids to remain in nitrogen balance is 0.8g/kg bodyweight (in normal man and women), 1.3g/kg bodyweight (in
pregnant women) & 2.4g/kg bodyweight (in first few months of live)
What is a negative nitrogen balance and what causes it?
net loss in amino acids
Catabolic
If any of the essential amino acids (i.e. those the body cannot synthesise of which
there are nine) are missing from our diet a negative nitrogen balance (loss greater
than gain) results
Negative nitrogen balance [CATABOLIC]: nitrogen intake < nitrogen loss
- Malnutrition is the most common cause
- Multiple trauma or extensive trauma where there is a lot of tissue damage can
result in a negative nitrogen balance
What is the process of the glucose alanine cycle?
1: In muscles there are aminotransferases such as alanine aminotransferase (ALT) that utilise pyruvate (produced from glycolysis) as an alpha-keto acid for
transamination. This produces alanine as the amino acid product and alpha-ketoglutarate as the alpha keto acid product which can then be used in the Kreb’s cycle to produce glucose via gluconeogenesis (essentially reverse transamination of alanine)
2:
Excess alanine is released into the bloodstream and transported into the liver
3:
Once in the liver, the alanine is converted back to pyruvate by transamination
(reverse reaction of that below)
4:
The pyruvate can be used as a source of carbons for glucose production via gluconeogenesis
5:
The pyruvate can be used as a source of carbons for glucose production via gluconeogenesis
6:
The glucose then enters the blood and can be used in the muscles which in turn can produce pyruvate via glycolysis which can then be used again to remove excess ammonia (NH3) - this is the glucose-alanine cycle
7:
The glutamate produced can then be converted to ammonium (NH4+) via oxidative deamination producing ammonium (NH4+) which then rapidly disassociates into ammonia (NH3) which in turn can be converted to urea via the urea cycle
What is the process of the urea cycle?
1:
Arginine either from the diet or protein breakdown, is cleaved by arginase generating urea & ornithine
2: Then ammonia (NH3) and CO2 is built on the ornithine to form citrulline
3:
Another molecule of ammonia (NH3) is then added to citrulline to regenerate arginine and enable the cycle to go around again
The reactions of one turn of the urea cycle consume?
- 3 ATP equivalents
- 4 high energy nucleotides (PO4-)
• Urea is the ONLY compound generated by the cycle, all the other components are
Recycled
What is the result of deficiencies of any enzymes involved in the urea cycle?
Deficiencies of ANY of the enzymes involved is associated with higher levels of
ammonia in the blood, ABSENCE of them is NOT COMPATIBLE WITH LIFE
How are high levels of ammonia associated with neurotoxicity?
1:
Ammonia is able to cross the blood brain barrier VERY easily
2:
Once inside it is converted to glutamate under the action of the glutamate dehydrogenase enzyme
3:
This means there is a depletion in alpha-ketoglutarate
4:
As alpha-ketoglutarate falls so does oxaloacetate ultimately resulting in the Kreb’s cycle coming to a halt
5:
This results in IRREPARABLE CELL DAMAGE & neural cell DEATH
This is the reason why ammonia is neurotoxic
What are the key features and facts about the pancreas?
completely RETROPERITONEAL apart from Tail
The tail of the pancreas is attached to the spleen and is intraperitoneal
The body can be crushed against the vertebral bodies during trauma
The head of the pancreas is closely related to the common bile duct meaning a carcinoma or inflammation of the head of the pancreas can block the bile duct resulting in post-hepatic/obstructive jaundice
The uncinate process comes from the ventral bud (the rest of the pancreas comes from the
dorsal bud) the superior mesenteric vein & artery are entrapped between the head and uncinate process
The pancreas develops as two separate outgrowths - the ventral & dorsal pancreas and during development of the embryo the ventral bud rotates around and fuses with the dorsal pancreas - in effect becoming the head of the pancreas
The pancreas receives its main blood supply from the coeliac trunk which arises directly from the aorta and divides at the coeliac axis to form the gastric arteries, the hepatic artery & the splenic artery
The superior mesenteric artery which runs “through” the head for the simple reason that it
is enveloped during the rotation when the dorsal and ventral pancreas fuse, provides some supply to the head of the pancreas
Venous drainage is achieved mainly by the splenic vein which then joins the superior mesenteric vein to form the portal vein
NOTE: the superior gastroduodenal artery runs in close proximity to the duodenum, so a duodenal ulcer can eventually erode into the gasproduodenal artery resulting in haemorrhage and haematemesis (vomiting of blood)
What does the exocrine pancreas secrete?
HCO3- (Bicarbonate) and digestive enzymes
Describe the HCO3- secretion by the exocrine pancreas?
• Secreted by epithelial cells lining the ducts known as duct cells
• In order to protect the duodenal mucosa from gastric acid
• It also buffers the material entering the duodenum to a pH suitable for enzyme action
• The release of the gastrointestinal hormone SECRETIN (produced in the small intestine) in response to the presence of acid in the duodenum stimulates the secretion of HCO3- from both the pancreas & liver & also potentiates the action of the hormone CCK (which stimulates enzyme secretion)
• NOTE: Secretin also inhibits acid secretion and gastric motility in the stomach
• The pancreatic duct cells secretes HCO3- into the duct lumen via an apical membrane Cl-/HCO3- exchanger:
- Formed by H+ which was pumped out of the duct cell in exchange for Na+ via a Na+/H+ exchanger
- Which then reacted with HCO3- in the blood resulting in the formation of carbonic acid (H2CO3) which then rapidly dissociates to H20 & CO2
- CO2 then enters the duct cell via diffusion where, under the action of the enzyme carbonic anhydrase reacts with the H2O in the duct cell to produce carbonic acid which then dissociates to form H+ and HCO3-, the H+ can then be pumped out again via the Na+/H+ exchanger)
• While the H+ prodcued is exchanged for extracellular Na+ on the basolateral side of the cell
• The H+ enters the pancreatic capillaries to eventually meet up in the portal vein blood with the HCO3- produced by the stomach during the generation of luminal H+
• The energy for secretion of HCO3- is provided by Na+/K+ -ATPase pumps on the basolateral membrane
• The Cl- normally does not accumulate within the cell because these ions are recycled into the lumen via the CFTR channel (Cystic Fibrosis Transmembrane Conductance Regulator)
• Via a paracellular route (moving through spaces between the cells e.g. tight junction) Na+ & H2O
move into the ducts due to the electrochemical gradient established by chloride movement through the CFTR
Describe the secretion of the digestive enzymes by the exocrine pancreas?
• The enzymes secreted are either active or precursors (secreted in inactive form
(zymogens) similar to pepsinogen)
• They enzymes are secreted by gland cells at the pancreatic end of the duct system
• The release of gastrointestinal hormone CCK (produced in the small intestine) in response to the presence of amino acids & fatty acids in the small intestine stimulates the secretion of digestive enzymes and also potentiates the actions of SECRETIN (which stimulates bicarbonate secretion from the pancreas & liver)
• NOTE: CCK also stimulates the contraction of the gall bladder and relaxes the sphincter of Oddi
• The enzymes the pancreas secretes digest triglycerides (fat) to fatty acids & monoglycerides,
polysaccharides to sugar, proteins to amino acids & nuclei acids to nucleotides
• Active:
- Alpha-amylase: Converts starch —> maltose
(glucose disaccharide)
- Lipase: Converts triglycerides —> monoglyceride & fatty acids
• Pre-cursors:
- Like pepsinogen, the secretion of zymogens protects pancreatic cells from autodigestion
- A key step in this activation is mediated by ENTEROKINASE which is embedded
in the luminal plasma membranes of the intestinal epithelial cells
- Enterokinase is a proteolytic enzyme that splits off a peptide from pancreatic
trypsinogen forming the active enzyme TRYPSIN
- Trypsin is another proteolytic enzyme which in turn goes on to active other
pancreatic zymogens once activated by splitting off peptide fragments e.g. in
the case of chymotrypsinogen which is activated into the enzyme
CHYMOTRYPSIN
- Both trypsin & chymotrypsin are enzymes used to break peptide bonds in
proteins to form peptide fragments i.e. they digest ingested proteins
What are the features of pancreatic secretion?
Secretions arise from the acinar tissue of the pancreas
The secretions are secreted into ducts which converge into the pancreatic duct which in
turn joins the common bile duct just before it enters the duodenum at the ampulla of Vater
The sphincter of Oddi is a separate bundle of circular muscle which regulates flow into the duodenum and may serve also to prevent mixing of bile & pancreatic juice within the pancreatic duct
Reflux of bile down the pancreatic duct will result in acute inflammation because of its detergent properties
The accessory pancreatic duct usually emerges above the ampulla of Vater
What are the types of cells of the Islets of Langerhans and what are their functions?
Alpha Cells: Produce glucagon
Beta Cells: Produce insulin and amylin
Delta Cells/ D Cells: Produce somatostatin
PP Cells: Produce pancreatic polypeptide
How is pancreatic secretion inhibited?
SOMATOSTATIN produced by the D cells in the pancreatic islets/ islets of Langerhans is a
powerful inhibitor of pancreatic exocrine secretion
Describe autoimmune damage to the islets and langerhans? What are the different types?
Autoimmune destruction of the islets of langerhans results in diabetes mellitus i.e. normal diabetes
Type 1: Pancreas failure to produce enough insulin
Type 2: Cells fail to respond to insulin properly
What stimuli is most important for pancreatic exocrine secretion?
most of the pancreatic exocrine secretions are controlled by stimuli arising from the intestinal phase of digestion
What is the cephalic phase of pancreatic secretion?
Initiated by the sensory experience of seeing & eating food and primarily involves parasympathetic vagus nerve stimulation of acinar cells to produce
digestive enzymes
What is the gastric phase of pancreatic secretion?
Initiated by the presence of food within the stomach and also primarily involves parasympathetic vagus nerve stimulation of acinar cells to produce digestive
enzymes
What happens after the gastric phase of pancreatic secretion?
By the end of the cephalic & gastric phases, the pancreatic ducts are filled with inactive digestive zymogens ready for release into the intestinal lumen along with bicarbonate via the sphincter of Oddi
When amino acids + fatty acids are present in the duodenum then CCK is
released and the gallbladder contracts inducing enzyme secretion
What is the primitive gut?
Made from the endoderm (epithelial lining, hepatocytes of liver & endocrine and exocrine cells of pancreas) and visceral mesoderm (muscle & connective tissue)
What are the structures of the foregut?
- Oral pharyngeal membrane —> liver bud
- Coeliac artery
- Oesophagus
- Stomach
- Liver
- Biliary apparatus
- 1/2 of duodenum
What are the structures of the midgut?
- Liver bud —> 2/3rds traverse colon
- Superior mesenteric artery
- Distal 1/2 of duodenum
- Jejunum
- Ileum
- Appendix
- Ascending colon
- Right 2/3rds of transverse colon
What are the structures of the hindgut?
- 2/3rds transverse colon —> cloacal membrane
- Inferior mesenteric artery
- Left 1/3rd of transverse colon
- Sigmoid colon
- Rectum
- Anal canal
What is the hepatic diverticulum?
- A cellular expansion of the foregut which gives rise to the parenchyma (functional part) of the liver
- Appears in the middle of the 3rd week as an outgrowth of the endodermal
epithelium at the distal end of the foregut (duodenum) - The liver bud contains rapidly proliferating cells that penetrate the septum transversum (thick mass formed in the embryo that gives rise to parts of the thoracic
diaphragm & ventral mesentery) - The bile duct forms when the connection between the liver diverticulum and the foregut narrows
- A small ventral outgrowth develops from the bile duct which gives rise to the gallbladder & cystic duct
- Further growth of the liver bud allow the epithelial liver cords to intermingle with the umbilical & vitelline veins, forming the hepatic sinusoids
- Liver cords differentiate into hepatocytes (liver parenchyma) and form the lining of the biliary ducts
• In the sixth week the mesoderm of the ventral mesentery gives rise to haematopoietic cells, Kipper cells & connective tissue cells
• NOTE: haematopoiesis is an important function of the liver at this stage since it acts as the “bone marrow” in the production of white blood cells & red blood cells
• At the 10th week, the liver weight is about 10% of the total body weight - this is due to the presence of large numbers of sinusoids and involvement of the liver in
haematopoietic function
• At birth, the liver weighs about 5% of the weight due to the existence of small numbers of haematopoietic islands in the liver, and its haematopoietic function is
greatly reduced
• Hepatic cells start production of bile at the age of the 12th week
• The haematopoietic function subsides during the last 2 months of intrauterine life
What events happen in the liver after birth?
The left umbilical vein obliterates to form the LIGAMENTUM TERES
The ductus venosus undergoes fibrosis leaving a remnant called the
LIGAMENTUM VENOSUS
What is a mesentery?
A mesentery is a fold of tissue that attaches the organs to the body wall
What is meant by intraperitoneal?
Double layer of peritoneum that completely surrounds the organ
What is meant by retroperitoneal?
The organ is only covered by the peritoneum on its anterior side
Describe the ventral and dorsal mesentery?
ventral occurs only in the foregut
ventral Derived from the septum transversum
(also gives rise to the thoracic diaphragm)
Foregut has dorsal & ventral mesenteries
Midgut & hindgut only have a dorsal mesentery
The liver divides the ventral mesentery since it grows so rapidly
The liver gives rise to the falciform ligament to the anterior abdominal wall
(free edge contains the umbilical vein which becomes the ligament teres/
round ligament after birth
The liver also gives rise to the lesser omentum to the ventral borders of the stomach & duodenum (free edge contains the hepatic artery, portal vein & bile duct
The bare areas of the liver are those NOT covered by
ventral mesentery
What are the two stages of lesser omentum formation?
1:
- 1st it rotates 90 degrees along a longitudinal axis (left now becomes anterior)
2:
2nd it rotates around the anterior posterior axis - the
pyloric region of the stomach moves right and up an the cardiac region of the stomach moves left & down
what two types of glands exist in the pancreas?
- Exocrine - secretes digestive enzymes & bicarbonate into the duodenum
- Endocrine - consists of the islets of langerhans, which secrete hormones into the bloodstream.
Describe the process of pancreas development?
1:
Develops from the endodermal lining of the duodenum as dorsal & ventral buds
- The dorsal bud is in the dorsal mesentery
- The ventral bud is in the ventral mesentery - close to the bile duct
2:
When the duodenum rotates and becomes C-shaped, the ventral bud and the entrance to the common bile duct in the duodenum are shifted dorsally
3:
The ventral bud comes to lie immediately below & behind the dorsal bud, finally the
parenchyma & duct systems of both buds fuse together
- The ventral pancreatic bud forms the uncinate process and inferior part of the head of the pancreas
- The dorsal bud forms the remaining part of the pancreas
How does the pancreatic duct develop?
The main pancreatic duct is formed by the union of the ventral pancreatic duct with the distal part of the duct of dorsal bud
What are the features of the pancreatic duct?
The main pancreatic duct along with the common bile duct enter the ampulla of vater which enters the wall of the duodenum at the site of the major duodenal
papilla
The accessory pancreatic duct when present (10%) drains the lower part of the head & uncinate process, it opens into the duodenum at the minor papilla, 3cm proximal to the opening of the main duct
Describe the development of the islets of langerhans?
1:
Develop from the parenchyma of the pancreas at the third month of fetal life
2:
Insulin secretion begins at the fifth month
3:
Pancreatic connective tissue develops from the visceral surrounding mesoderm
Describe the absorptive state in glucose regulation?
Absorptive State:
- Ingested nutrients are absorbed from the GI tract into the blood
- A proportion of nutrients are catabolised and used
- The remainder are converted and stored for future use
- During the absorptive state:
• Glucose is used to generate ATP
• Amino acids are converted to proteins
• Glycerol & fatty acids are converted to lipids
• Glucose is converted to glycogen
Describe the post-absorptive state in glucose regulation?
- Nutrients are no longer absorbed from the GI tract
- Nutrient stores MUST supply the energy requirements of the body
• Glucose regulation in the post-absorptive state: - Glucose is no longer being absorbed from the GI tract
- Yet it is essential to maintain the plasma glucose concentration due to the
fact that the CNS is always using it for fuel
In the post-absorptive what are the 3 main sources of glucose?
- Glycogenolysis
- Lipolysis
- Protein
Describe glycogenolysis?
- The hydrolysis of glycogen to monomers of glucose-6-phosphate
- Occurs in the liver & skeletal muscles
- In the liver; glucose-6-phosphate is enzymatically converted to glucose which
then enters the blood - Hepatic glycogenolysis begins within seconds of an appropriate stimulus, such
as sympathetic nervous system activation. Consequently it is the first line of
defence in maintaining the plasma glucose concentration within a homeostatic
range - The amount of glucose available from the liver can only supply the bodies
requirements for only several hours before hepatic glycogen stores are nearly
Depleted
Also occurs in skeletal muscles, which contains the same amount of glycogen
as the liver - HOWEVER unlike the liver, skeletal muscle does not possess the enzyme
necessary to from glucose from the glucose-6-phosphate formed during
glycogenolysis, thus muscle glycogen is not a source of blood glucose - Instead, the glucose-6-phosphate undergoes glycolysis within muscle to yield
ATP, pyruvate & lactate - The ATP & pyruvate are used directly by the muscle cell
- However, some of the lactate enters the blood and circulates to the liver and is
converted into glucose which can then leave the liver cells to enter the blood - Thus, muscle glycogen contributes to blood glucose indirectly by way of the
livers processing of lactate
Describe lipolysis?
- The catabolism of triglycerides in adipose tissue via the hydrolysis of
triglycerides to produce glycerol and fatty acids - Glycerol and fatty acids enter the blood via diffusion
- The glycerol enters the liver which in turn enzymatically converts it through a
series of steps into glucose
Describe the conversion of protein to glucose?
- A few hours into the post-absorptive state, protein becomes another source of
blood glucose - Large quantities of protein in muscle and tissues can be catabolised without
significant cellular malfunction - There are limits however, and continued protein loss during a prolonged fast
ultimately means disruption of cell function, sickness and eventually death - The proteins supply amino acids, which enter the blood and are taken up by the
liver where they can be converted via the alpha-keto acid pathway to glucose,
which can then be released into the blood
• The synthesis of glucose from such precursors as amino acids and glycerol is
known as gluconeogenesis
• Thus glycogenesis is the process of generating new molecules of glucose from non-
carbohydrate precursors
6 MOLECULES OF ATP ARE CONSUMED PER MOLECULE OF GLUCOSE FORMED
Where is fat stored in the body?
Most of the bodies fat is stored in adipocytes which form tissues called adipose tissues
• Some is stored in hepatocytes
What are triglycerides?
- Triglycerides (TGs or TAGs) consist of 3 fatty acids bound to a glycerol molecule
- It accounts for 78% of energy stored in the body
- Proteins account for 21% and carbohydrates account for 1%
- 95% of dietary lipids are triglycerides, the rest consist of phospholipids, free fatty acids (FFAs), cholesterol and fat soluble vitamins
What are lipids?
- They are esters of fatty acids and certain alcohol compounds
- They have several functions;
• Energy reserves
• Structural part of cell membrane
• Hormone metabolism
What are lipoproteins?
- They are used to transport cholesterol in the blood
- HDL - formed in the liver:
• Remove excess cholesterol from blood and tissue
• They then deliver this cholesterol to the liver which secretes it into the bile
or converts it into bile salts
• Referred to as “good” cholesterol, since it removes cholesterol from plasma
What are Low Density Lipoproteins?
Formed in the plasma
• The main cholesterol carriers and they deliver cholesterol to cells throughout the body
• LDLs bind to plasma membrane receptors specific for a protein component
of the LDLs and are then taken up by the cells via endocytosis
• LDL cholesterol is said to be “bad” due to the fact that high plasma concentrations can be associated with increased deposition of cholesterol in arterial walls and a higher incidence of heart attacks
• However, LDL is essential in supplying cells with the cholesterol they require to synthesise cell membranes and for steroid hormone production in the gonads and adrenal glands + aldosterone + cortisol
What are very low density lipoproteins?
VLDL - synthesised in hepatocytes - carries triglycerides from glucose in liver to adipocytes
What are the features of fatty acid catabolism?
Under resting conditions approximately half the energy used by muscle, liver and the kidneys is derived from the catabolism of fatty acids
Most cells store some degree of fat, but most of the body’s fat is stored in adipocytes
almost the entire cytoplasm of each adipocyte is filled with a single large fat droplet
Clusters of adipocytes form adipose tissue, most which is in deposits underlying the skin or surrounding internal organs
The function of adipocytes is to synthesise and store triglycerides during periods of food uptake and the, when food is not being absorbed from the small intestine, to release fatty acids and glycerol into the blood for uptake & use by other cells in order to provide the energy required for ATP formation
What is the process of fatty acid catabolism?
1: Molecule of coenzyme A link to the carboxyl at the end of a fatty acid
2: This step is followed by the breakdown of ATP —> AMP + 2Pi
3: The coenzyme A derivative of fatty acid then proceeds through beta-oxidation reactions
4: A molecule of acetyl coenzyme A is split off from the fatty acid and two pairs of hydrogen atoms are transferred to coenzymes (one pair to FAD and the
other pair to NAD+)
5: The hydrogen atoms from the coenzymes then enter the oxidative phosphorylation pathway to form ATP
6: Another coenzyme A attaches to the fatty acid and the cycle is repeated
7: Each passage through this sequence shortens the fatty acid chain by two carbons atoms until all the carbon atoms have transferred to coenzyme A molecules
8: These molecules then lead to the production of CO2 & ATP via the Kreb’s cycle & oxidative phosphorylation
What are the enzymes of hepatic metabolism of lipids and what are their roles?
Lipoprotein lipase:
Hydrolyses triglycerides in lipoproteins (chylomicrons & VLDLs)
into 2 free fatty acids & 1 glycerol molecule
Hepatic lipase:
- Expressed in the liver and adrenal glands
- Converts IDL (intermediate density lipoprotein) into LDL thereby packaging it with more triglycerides to be released in the body
