Digestive system

• Anterior opening (lips, oral fissure), posterior opening (oropharyngeal isthmus)

• Lateral - cheeks

• Roof - Hard palate (anteriorly) and soft palate (posteriorly, and it extends inferolaterally to form palatoglossal and palatopharyngeal arches)

• Floor - tongue and other soft tissues (mylohyoid muscle and geniohyoid muscles)

• Between teeth and cheeks - oral vestibule

Three major salivary glands - Parotid (largest) CNIX, submandibular CNVII and sublingual CNVII glands

• Salivary glands opens into oral cavity

  • Opening of submandibular and sublingual - Sublingual caruncle (under tongue)

  • Opening of parotid - parotid papilla (stensen’s duct), located in upper second molar

• Secrete saliva - mix of ions, water, mucus and enzymes

• Its an extraoral gland

• lies antero-inferior to the ear

• superficial to the masseter muscle

• superior to the angle of mandible

• Submandibular glands are located inferior to the mandible

• Sublingual glands are located inferior to the tongue

• Stimulated directly by parasympathetic input

• Sympathetic nerves reduce it by causing vasoconstriction of blood vessels that supply tha glands

Muscles of the tongue can be grouped into intrinsic and extrinsic

• Intrinsic muscles are confied to the tongue. Runs longitudinal (superior / inferior), transverse or vertical to change the shape of the tongue by lengthening, shortening, curling and flattening. > allow precise movements required for speech, eating and swallowing.

• There are four extrinsic muscles - Genioglossus, Hypoglossus, styloglossus and palatoglossus > helps protrude, retract, depress and elevate the tongue

• Intrinsic muscles are supplied by CN XII (hypoglossal nerve)

• Extrinsic Genioglossus, hypoglossus and styloglossus are supplied by CN XII but the palatoglossus is supplied by CN X (vagus)

• Functions: taste, speech, manipulate food for chewing

• V -shaped terminal sulcus separates into anterior 2/3 and posterior 1/3.

• Terminal sulcus: forms the inferior margin of the oropharyngeal isthmus

• Apex of terminal sulcus: foramen cecum (the middle of cross in bottom pic) its the point of attachement of thyroglossal duct and is formed during embryological development of thyroid gland

• Tongue is supplied by lingual artery - branch of external carotid artery

• Tongue is drained by dorsal lingual and deep lingual veins > internal jugular vein in the neck

• extends inferolaterally to form palatoglossal and palatopharyngeal arches.

• The arches lie anterior and posterior to the palatine tonsil

• B/L they form oropharyngeal isthmus

1. Nasopharynx - posterior to the nasal cavity

2. Oropharynx - posterior to the oral cavity

3. Laryngeopharynx (posterior to the larynx)

then it continues distally as oesophagus

• Superior - primarily consits of skeletal muscle (controls swallowing)

• middle - mix of smooth and skeletal muscle

• inferior constrictors - entirely smooth muscles = involuntary = controlled by autonomic nervous system

• Muscles of tongue manipulate food to form bolus > swallowed

• When the bolus touches the soft palate, swallowing reflex initiated

• Blous pass through oropharyngeal isthmus into oropharynx (lies anterior between C1-C6)

• Oesophagus is a muscular tube, begins in the neck at the lower border of C6

• Descends through superior and posterior mediastinum of the thorax

• Enters abdominal cavity by piercing the diaphragm at the oesophageal hiatus (level of T10)

• Inferior to the diaphragm, it opens into stomach at the cardiac orifice.

• Stomach is J-shaped hollow organ

• Extends from the cardiac orifice to the duodenum distally

• Occupies the left hypochondriac, epigastric and umbilical region of the abdomen.

Stomach is divided into multiple portions:

• Cardia (gastro-oesophageal junction)

• Fundus (adjacent to cardia)

• Body (largest portion of stomach)

• Antrum (between body and pylorus)

• Pylorus (where stomach and duodenum meets) with pyloric sphincter

Other features:

• Greater curvature

• Lesser curvature

• Cardiac Notch

• Angular incisure - common site for gastric ulcers and early cancerous changes (endoscopy site)

Stomach receives blood from celiac artery which supplies left and right gastric arteries.

• celiac truck (located under diaphragm) has 3 branches:

  • left gastric artery - curves to left > lesser curvature

  • Splenic artery - runs posterior to stomach > spleen then divides into upper short gastric artery (supplies fundus) and left gastroepiploic artey (supplies greater curvature)

  • Common hepatic artery - into 2 branch: gastro duodenal artery (goes down to join R gastroepiploic artery) and proper hepatic artery

• They connect the stomach to other organs in the abdominal cavity

• GO hangs down (anteriorly) from the greater curvature of the stomach covering the intestine. Provides protection and insulation to abdominal organds.

  • Also contains immune cells to help fight infection

• LO connects lesser curvature of the stomach to the liver (posteriorly). Serves as a support structure for the stomach and liver

• Space is called Lesser sac / omental bursa

• Prone to pancreatitis (behind the stomach) or gastric ulcer rupture .

Penetrates Buccinator muscle of the cheek opposite crown of 2nd upper molar tooth

The clinical importance of these are in swallowing (swollen objects likley to lodge) and manipulation of instruments during endoscopy.

The epiglottis is a flap of connective tissue made of elastic cartilage, it is present in the posterior floor of the oral cavity to close the trachea during swallowing to prevent food entry into the larynx and trachea

• Foregut - Celiac trunk

  • distal oesophagus, stomach, 1st/2nd part duodenum, spleen, liver

• Midgut - Superior mesenteric artery

  • jejunum, ileum, ascending colon and proximal 2/3 of transverse colon

• Hindgut - inferior mesenteric artery

  • distal 1/3 of transverse colon, descending, sigmod colon and anus

Liver - largest gland, produces bile, stores glycogen and does detoxification of ingested contents .

Four lobes - Right, left, caudate and quadrate lobes

Attachments - Falciform (red), Round (blue), Coronary (green) and triangular ligament (yellow)

Porta hepatis - hepatic hilum

• Common bile duct (leaving)

• Proper hepatic artery (enters)

• Hepatic portal vein (enters)

  
  

• Stores bile produced by liver

• 3 parts - neck, body and fundus

• Supplied by cystic artery - branch of right hepatic artery

• Cholelithiasis = gall stones formed withing GB from precipitated bile components

• Parts - uncinate process (behind superior mesenteric vessel), head (adjacent to 2nd part of duodenum), neck, body and tail

• Exocrine - Production of pancreatic juice > into duodenum

• Endocrine - insulin by Islet of langerhans > blood

The common bile duct (desends from GB) joins main pancreatic duct at the opening into the duodenum called hepatopancreatic ampulla

• The palate, upper teeth, and upper parts of the cavity are innervated by the maxillary nerve branch of trigeminal (V2)

• The lower parts, including teeth and oral part of tongue are innervated by the mandibular nerve (V3)

• Taste from the oral part of the tongue (anterior 2/3s) is carried by branches of the facial nerve (VII)

• Parasympathetic fibres to the glands are also carried by the facial nerve

The anterior 2/3rds (oral portion):

• General sensation is supplied by the mandibular nerve (V3) via the lingual nerve

• Special sensation (taste) is supplied by the facial nerve (VII) via chorda tympani

The posterior 1/3rd of the tongue (pharyngeal) has both general and special sensation supplied via the glossopharyngeal nerve (IX)

Mastication by teeth - tear and grind food to increase SA

Bolus formation by the tongue - also has sensory and speech role

Enzymatic digestion and lubrication by saliva.

Salivary amylase.

Parotid, submandibular, and sublingual glands. - responsible for producing saliva.

• Functions of the saliva - Protection, buffering (neutralise the acidic contents), maintain tooth integrity, tissue repair, digestion, taste and antimicrobial activity

Normal saliva production varies between 0.5 to 1.5L. Saliva is hypotonic and alkaline.

The rate of secretion reduces during sleep and inc when eating.

Structure consits of series of ducts that end in either spherical or tubular secretory acini.

• The serous Acinar cells produce water and enzyme, the mucous acinar cells produce mucous = both leads to saliva.

• The duct cells dilute the secretions allowing them to flow

Duct cells dilute and modify the initial acinar secretion.

Parasympathetic nervous system.

• IgA Ab - binds to pathogenic Ag

• Lactoferrin - peptide protein that binds iron in antimicrobial action

• Lysozymes - enzyme that attack bacterial cell wall

• Bicarbs, PO4 and proteins - maintains pH between 6-7.5

• Alkaline nature - protects from bacterial acid and acid reflux

• Contains glucose, urea, cortisol, sex hormones and blood group substances helps with screening

IgA - binds pathogenic antigens

It is supersaturated with calcium hydroxyapatite, preventing dental demineralisation.

• The salivary epidermal growth factor enhances the speed of oral mucosal healing and protects oesophageal mucosa.

Reduced saliva production causing dry mouth.

• Associated with numerous medications

• Can also be caused by Sjogren’s syndrome, mumps (parotitis) and RT

• Reduced lubrication (difficulty chewing and swallowing)

• low amylase (impaired oral carb digestion)

• low bicarb can affect buffering

• increased oral microbial dysbiosis (caries / oral infection)

• Can cause dysphagia due to poor bolus formation > inefficient oesophageal transit > increase friction

• Reduced antibicrobial activity

Excessive salivation.

• Can be due to excess production and stimulation or due to decreased clearance (swallowing)

• Common in those with neurodegenerative disorder

To transport the food bolus from the pharynx to the stomach.

• Starts with upper OS and ends with lower OS

Striated muscle.

• under control of central control system from the brainstem

• This is the swallowing reflex (primary peristalsis)

Smooth muscle.

• controlled by the nerve plexus in the oesophagus

• Responsible for secondary peristalsis

Swallow-initiated contractions controlled by the brainstem.

(Proximal oesophagus involved, has striated muscles)

Distension-induced contractions controlled by the enteric nervous system.

(Involves distal oesophagus, has smooth muscles)

To prevent aspiration / regurgitation back into airways and excess air entry into the gastrointestinal tract.

• high pressure area located between pharynx and upper oesophagus

To prevent reflux of gastric contents into the oesophagus and allow passage of food into stomach.

• High pressure zone at the end of the oesophagus

1. Oral preparatory - bolus undergoes mastication in the mouth

2. oral phase - bolus reaches the pharynx and swallowing begins

3. pharyngeal - Once swallowing iniated, the glottis is shut by the movement of epiglottis, breathing stops and the upper OS is relaxed to allow passage of food

4. oesophageal phase - bolus travel down the oesophageal body, this triggers relaxation of lower OS

Chronic symptoms or mucosal damage due to abnormal reflux of gastric acid into the oesophagus.

• Associated with over relaxation of the lower OS

Treatment:

• Conservative - weight loss, avoid food / alcohol close to bedtime

• Medical - PPI (decrease acid), histamine blockers, antacids in increase pH, alginates (gaviscon or rennie)

• Surgical - anti-reflux (fundoplication), repair of hernia, vagotomy to decrease acid production.

• Obesity - an increased intra-abdominal pressure and hormonal changes can contribute to the relaxation of the LOS

• Hiatus Herniae - sliding or rolling hernias.

• Pregnancy - same reasons as obesity, intrabdominal pressure and oestrogen and progesterone can relax the LOS

• Zollinger-Ellison syndrome - cancer of G cells in the stomach (gastrinomas). These cells produce Gastrin which in turn causes oversecretion of stomach acid. These gastrinomas can be found in many places e.g. pancreas or duodenal wall

Oesophagitis, stricture, Barrett’s metaplasia and oesophageal adenocarcinoma

Inflammation with erosion or ulceration of the oesophageal mucosa.

Chronic acid irritation leads to scarring and narrowing of the oesophagus.

• can present as dysphagia or food impaction

Replacement of normal stratified squamous epithelium with columnar epithelium in the distal oesophagus.

• Prolonged and continuous acid exposure causes this metaplasia change

• Columnar epithelium is resistant to stomach acid

• Increases risk of oesophageal cancer

• Seen as change in texture and colour of the tissue - Normal squamous epithelium is pale and glossy > salmon coloured with velvety texture in metaplasia.

• Dx by cytosponge

• Rx with PPI, endoscopic eradication (heat by laser /radiofrequency / argon plasma coagulation / cold cryotherapy or photodynamic therapy)

Increased risk of oesophageal adenocarcinoma.

Low absolute cancer risk, high cost, and limited effectiveness of surveillance.

• Sliding hernia (80%) - GOJ, abdominal part of the oesphagus and the cardia of the stomach slides upwards through the diapragmatic hiatus into the thorax

• Rolling hernia - upward movement of gastric fundus, causing it to lie alongside a normally positioned GOJ.

• Squamous cell carcinomas are significantly decreasing. Adenocarcinomas are significantly increasing

• Adenocarcinomas are cancers that start in mucus-producing glandular cells

Incidence of adenocarcinomas of the distal oesophagus and GOJ increase rapidly due to Barrett's metaplasia as more genetic defects become acquired

Failure of relaxation of the lower oesophageal sphincter due to loss of the myenteric plexus.

Dysphagia to solid and regurgitation, chest discomfort and halitosis

Bird’s beak appearance towards the oesophageal sphincter on barium swallow.

Heller’s myotomy or botulinum toxin injection at LOS.

A chronic immune-mediated inflammatory condition of the oesophagus. Characterised by trachealisation of the oesophagus.

• causes dysphagia and reflux

Trachealisation with concentric oesophageal rings throughout the entire length of the oesophagus.

Oesophageal biopsy showing increased eosinophil counts.

To measure oesophageal high pressure zones (upper OS and Lower OS) and motility.

The degree of lower oesophageal sphincter relaxation.

• Oesophageal monometry probe is inserted through the nose > oesophagus > down the lower OS.

• Pressure sensors on the catheter measures the pressure produced by contraction and relaxation of oesophageal muscles.

• Patient then swallows 5ml water to initiate upper OS opening. Tracing produced allows observation of the pressure changes during peristalsis as well as degree of relaxation of the lower OS. this is IRP

The stomach has 3 major regions

• The fundus - upper region

• Main body - corpus

• Antrum - lower region

  • Has thickened muscular walls that grind the food bolus before it enters the duodenum

• The folds are called rugae on the inner surface of the stomach.

• These flatten out as the stomach fills and expands.

• The purpose of the rugae is to increase surface area and stretch out to increase stomach volume when the stomach is full.

• Mucosa - Inner lining, consists of simple columnar epithelium, lamina propria, muscularis mucosae and gastric glands (pits)

• Submucosa

• Muscularis externa - contains circular (inner) and longitudinal (outer) muscles. On the cardiac/LOS end there is extra layer called oblique muscles. These muscles aid distension of stomach and storage of food.

• Serosa - connective tissue

• The external surfae of the stomach is lined by peritoneum

• Reservoir - passes only small amounts of the food bolus into the small intestine at a time. It stores food not yet passing into the intestine

• Mixing/Churning - the food bolus is mixed and churned by secreting and mixing it with gastric juices

• Acid production (digestion + protection) - involved in both chemical digestion of the food bolus and protection against microorganisms

• simple columnar epithelial cells characterized by their goblet-like shape, which is due to the accumulation of mucus granules in their apical portion

• Known as ‘mucous neck cells’ - secrete mucus along with alkali bicarbonate ions (HCO3) which protects the lining of the stomach

• Present in both the corpus (body) and antrum

• Parietal (aka oxyntic) cells - these secrete gastric acid (HCl), which helps break down food and kill harmful bacteria.

• Also secrete intrinsic factor which is essential in vitamin B12 absorption

• Present in the corpus (body) only

• D cells - involved in the secretion of somatostatin which inhibits acid secretion by inhibiting gastrin release, these cells are mainly located in the antrum, some in the corpus

• G cells - stimulate release of gastrin, which stimulates acid secretion. Located in antrum, some in corpus

• ECL cells - these stimulate release of histamines which are also involved in stimulating acid secretion, these cells are present in both the corpus and antrum

Acid release is mediated by H+/K+ pump located in apical (lumen side) membrane of parietal cells. This is an ATP-driven pump. Process as follows:

• CO2 from blood plasma diffuse into parietal cells

• CO2 then combines with water to form carbonic acid (H2CO3). This reaction is catalysed by carbonic anhydrase.

• The carbonic acid dissociates into H+ and HCO3- ions (it is a weak acid)

• The HCO3- are transported into the blood, down a concentration gradient, in exchange for Cl- ions via an antiporter on the basolateral membrane

• H+ and Cl- ions are then transported from the parietal cell into the lumen of the stomach, against their concentration gradients. H+ via the H+/K+ pump and Cl- a chloride channel

• This cause pH of 1-3 in stomach —> activates pepsin (protease enyzyme) and microbial activity.

• Carbonic acid (CO2 + H2O) dissociates into H+ and HCO3

• H+ (proton) get pumped into stomach lumen by parietal cells.

• HCO3 get transported into blood. Since it is ‘basic’ we expect an increase in pH of the blood post meal > alkaline.

• However, this doesn’t happen - As stomach empties its contents into duodenum, the cells senses acid > secretin from S cells > triggers pancreas to release bicarb alkaline rich fluid to neutralise the contents in duodenum.

  • So in the pacreas, the HCO3 goes into the lumen, while H+ goes into the blood (the opposite of what happens in the stomach).

  • ‘Acid tide’ - These two opposing effects neuralises and prevents blood getting too alkaline post prandial.

• Gastrectomy = removal of stomach partly or fully

• This leads to loss of carbonic anhydrase in the stomach = lack of H+ into lumen + lack of HCO3 into the blood

• Carbonic anhydrase is present in the pancreas —> H+ into blood and HCO3 into duodenum.

  • We therefore expect these pt’s blood to be acidic > CO2 build up > hyperventilation.

• However, this doesn’t happen - This is because, usually, the duodenum triggers pancrease to produce HCO3 into the lumen (H+ into blood) to neutralise the acid contents from the stomach.

  • In patients with gastrectomy, there is loss of acid production by stomach > no need for duodenum to trigger neutralisation = no H+ into blood to cause acidity.

By controlling the activity of H+/K+ pump. Can be done directly or indirectly. Parietal cells, G cells, D cells, ECL cells (last 3 are ‘supplementary cells’) are all involved in regulation of acid secretion.

• Vagus nerve innervates all cell types (M3/Ach)

• Parietal cell can be stimulated to produce acid by both protein kinase A and C

  • Direct stimulation features Ach, histamine and gastrin. Indirect features Ach and gastrin mediated histamine release by ECL cells.

• Histamine from ECL cells promotes acid secretion

• Gastrin promotes acid secretion from parietal cell

• Somatostatin halts acid secretion

Vagus Nerve

• Innervates parietal cells. When stimulated, the post ganglionic fibres release Ach onto parietal cell plasma membrane.

• Ach binds to M3 receptors on the cell > increased activity of H+/K+ pump > increased acid release

Histamine stimulation

• Histamine is produced and released by ECL cells found in same gastric pit as parietal cells. Can be due to vagus (Ach binding to M3 receptor on ECL) / gastrin binding.

• Histamine binds to H2 receptors on parietal cell > promotes H+ release.

Gastrin stimulation

• Gastrin is produced by G cells of antrum + duodenum.

• Due to vagus stimulation or presence of peptone (AA) in stomacl.

• It is a weak CCK (cholecystokinin) agonist, acts on CCK-B receptors on parietal cell > H+ release

• Involves release of histamine by ECL cells due to binding of Ach from vagus nerve or gastrin from G cells.

  • Histamine > H+ relese by parietal cells

Somatostatin inhibit H+ release by parietal cells. It is released by D cells of the antrum. It inhibits by:

• Binding to receptors on parietal cells, reducing H+/K+ pump activity

• Binding to receptors on ECL cells, inhibiting histamine release

• Binding to receptors on G cells, inhibiting gastrin release

D cells can be inhibited by Ach from vagus nerve.

Somatostatin release is inhibited when the luminal acid is neutralised.

Distension of stomach causes Ach release by vagus nerve. Ach:

1. Direct stimulation of Parietal cell —> Increases H+

2. Direct stimulation of ECL cells —> increases histamine

3. D cells —> inhibit somatostatin release

G and D cells are subject to vagal stimulation.

1. G cells —> increases gastrin release using GRP (gastrin releasing peptide) rather than Ach. > triggers parietal cell to release acid directly, and also indirectly via ECL cells.

2. D cells —> Ach binds and inhibits somatosatin release

• Negative = High luminal H+ stimulates D cells to release somatostain > reduce acid secreretion

• Positive = Products of protein digestion (peptones) stimulates G cells to release gastrin > stimulates acid secretion.

Secretin

• Released by duodenal S-cells.

• Stimulated by presence of fat and acid in duodenum

• Inhibits acid secretion by inhibiting antral gastrin release and promotes somatostain release

CCK

• Released by duodenal I-cells

• Stimulated by fat in duodenum (stimulates pancreatic enzyme release)

• Binds to CCK receptors on D cells to stimulate release of somatostain > inhibits H+

• When stomach empties its contents to the duodenum, the acid can destroy the epithelium lining the duodenum

• Low pH can destroy the digestive enzymes in the duodenum.

• Bile and bile salts which emulsify fats also doesn’t work at lower pH.

• So when gastric emptying occurs, the cells in the duodenum senses the acid > stimulates pancrease to release secretin > inhibits antral gastrin > inhibits acid secretion.

  • Secretin also promotes somatostain release

• Proton pump inhibitors (PPI) - e.g. Omeprazole, Esomeprazole, Lansoprazole

• Histamine receptor antagonists - e.g. Ranitidine, Famotidine, Cimetidine, Zantac

• Antacid medications - e.g. Gaviscon and pepto-bismol

Basal

• Follows circadian rhythm, no external stimuli

• Highest in the evening and lowest in the morning

Cephalic

• Food smell, sight and taste sends sensory signal to medulla oblongata > triggers parasympathetic stimulation of vagus nerve > HCl and pepsin release by corpus (directly by parietal cells) and gastrin release by antrum (indirect) > stimulates corpus to release more acid.

  • Also release histamine (indirect) and inhibit somatostain release

• 30% acid produced before food enters stomach.

Gastric phase

• 50-60% of total acid, activated by stomach distension by food> Medulla > prasympathetic vagus stimulation > acid by various mechanisms.

• Antral G cells release > gastrin due to peptones in antrum

Intestinal

• Partially digested peptides (peptones) in the duodenum > gastrin by duodenal G cells > 5-10% of acid secretion.

• Pensinogens are proteolytic pro-enzymes (inactive) produced by chief cells in response to Ach.

• Converted to Pepsin (active enzyme) spontaneously at pH <5 (most active at pH <3).

  • Pepsis is an endopeptidase which initiates protein digestion.

• Irreversibly inactivated at pH 8

• Pepsin is the major agressive agen responsible for oesophageal and laryngeal tissue damage during acid reflux

• Mucosal layer traps local HCO3 to neutralise and maintain pH 7

• Epithelial and endothelial cells in stomach produce prostaglandins - it maintains mucosal diffusion barrier.

• Fibre (Roughage) in the food stimulates mucous protection.

• Prostaglandins stimulate mucous and HCO3 secretion by mucous cells in stomach. IT also inhibit acid secretion.

• NSAIDs inhibit prostaglandins > increase acid > prone to ulcers

• Discontinuation in the inner lining of the GI tract due to gastric acid or pepsin.

• Damage extends to muscularis propria layer of the gastric epithelium.

• Can be gastric ulcer or duodenal ulcer

  • Gastric ulcer causes epigastric pain 15-30 mins after eating, whereas duodenal uncler pain tends to occur 2-3 hrs after a meal.

H.pylori

• Bacteria that induces acid production > damage to mucosal barrier > peptic ulceration.

• Responsible for 90% duodenal ulcer and 70-90% gastric ulcers

• Wide spectrum of virulence factors > adhere to and inflame gastric mucosa > increased acid production > damage

• In the corpus - H.pylori damages parietal cells > decrease acid secretion > gastric atrophy (ulcer)

• In the antrum - its main target > D cell damage > increase acid production.

• H.pylori > hypochlorhydria pH >4 (low stomach acid level) > reduce iron absorption due to impaired reduction of Fe3+ to Fe2+

• Fe3+ must be reduced to fe2+ to enable absorption by enterocytes.

Diagnosis

• Urea breath test —> H.pylori releases urease enzyme which breaks down urea into NH3, CO2 and H2O.

  • During test, patient ingest tablet or liquid containing carbon-isotope labelled urea. H.pylori breaks this urea down and produced CO2 which is labelled.

  • Pt exhales the CO2 which is measured

• CLOtest —> Biopsy of mucosal tissue in the antrum taken via endoscopy.

  • Placed into a medium containing urea and an indicator such as phenol red. The urease enzyme produced by H. pylori hydrolyzes urea to ammonia, which raises the pH of the medium, and changes the color of the specimen from yellow (NEGATIVE) to red (POSITIVE).

• Stool antigen test —> Stool sample added to chemicals + colour developer. Blue colour = H.pylori antigen +ve

Treatment

• Tripple therapy - PPI with 2 Abx (amoxicillin, clarithromycin and metronidazole)

Note: Urease neutralises acid and ammonia cause mucosal injury

• Its an autoimmune condition which causes atrophic gastritis. Auto-Ab caused parietal cell destruction

• Parietal cells produce intrinsic factors which are essential for absorption of vitamin B12

• B12 is important for erythrocyte production. Deficiency can cause megablastic anaemia.

  • Large immature RBC

• Digestion of nutrients, fat, protein, carbohydrates

• Provides appropriate environment for enzymatic digestion in the small bowel

• Important in regulating fed and fasted states using insulin and glucagon etc.

Exocrine and endocrine components.

• The endocrine tissue secretes hormones such as insulin and glucagon

• Exocrine tissue secretes pancreatic juice - containing digestive enzymes and bicarbonate-rich fluid.

• Pancreas is divided to lobules (Acinar + islet of Langerhans) that drains into ducts

• Acinus > intercalated duct > Intralobular ducts > interlobular ducts > main pancreatic duct which connects the gland into lumen of the GI tract

• Major pancreatic duct merges with common bile duct to form ampulla of vater.

  • If gallstones blocks the duct distally > pancreatitis

• Muscular wall around it thickens to form sphinchter of Oddi - regulates ductal flowand prevent reflux

• Duct empties secretions into descending part of duodenum at major duodenal papilla

  • point where foregut transition to midgut, celiac trunk no longer supplies the gut and superior mesenteric artery takes over.

To regulate pancreatic and bile duct flow and prevent reflux.

Into the descending part of the duodenum at the major duodenal papilla.

They resides within pacnreatic lobules. Each unit composed of:

Acinus cells and an intercalated duct.

• under microscope, the acinar cells have lots of mitochondria and RER (essential for large amount of protein synthesis) - these secretory cells produce zymogens > ducts

1. Acinar cells —> produce proteins (zymogens - inactive)

2. Duct cells —> transport electrolytes (HCO3) to neutralise pH

3. Centroacinar cells —> located at junction of acinar and ductal cells

4. Goblet cells —> produce mucus (mucin) important for hydration, immunological function.

• Specialised / polarised for production of large quantity of proteins.

• Produce Zymogens (inactive enzyme precursors), digestive enzymes, and isotonic fluid.

• Note: Acinus = cluster of acinar cells

Rough endoplasmic reticulum. > secretory granules > exocytosis at apical pole

To secrete bicarbonate-rich fluid that alkalinises acid content in the duodenum and it hydrates acinar secretions.

• contain specific membrane transporters and an abundance of mitochondria to provide energy for active transport of electrolytes

Secretin.

• released by S cells of duodenum due to acidity > triggers pancreas to secrete bicarb rich fluid.

• Produce mucous (in the form of mucin, which when hydrated forms mucous) - important for lubrication, hydration, mechanical protection of surface epithelial cells

• The mucous also has an immunologic role, the binding of pathogens and interacting with immune competent cells, ultimately preventing pancreatic infections

When unstimulated - they secrete low levels of digestive proteins via constitutive secretory pathway.

Two routes to stimulation:

1. CCK and Ach (muscarinic receptors)- located on the basolateral membrane.

   • Both activates PKC + Ca2+ release

   • Signal > CCK/muscarinic Ach receptor > Gq > PLC > DAG / IPC > PKC activation (DAG) and Ca2+ ion release (IP3) > enzyme secretion from acinar cells.

2. VIP and secretin - Both binds to their receptors > Gs > activates adenyl cyclase > increased cAMP and PKA activation

Gs protein pathway increasing cAMP and activating PKA.

Their prime role is to secrete HCO3 rich fluid that alkalanise and hydrates the secretions of acinar cell. Done via:

1. Cl-/HCO3 exchanger —> Cl- into duct cell, exchanged with HCO3 into the duct lumen

2. Carbonic anhydrase —> in the cytoplasm it catalyses the formation of HCO3 from CO2 and OH-

3. Secretin, a potent stimulus for HCO3 (Gs pathway) induces CFTR channel and Na-HCO3 co-transporter

   • Secretin via Gs > adenylyl cyckase > high cAMP > activates PKA > opening of CFTR channels > Cl- diffuse into lumen.

   • This Cl- then re-enters the cell via Cl-HCO3 exchanger > HCO3 secreted into the lumen. = Cl- recycling.

4. Ach (Gq pathway) —> increased Ca2+ > activates Ca2+ dependent PKC in duct cells

Via the Cl⁻/HCO₃⁻ exchanger.

• Cl- into the duct cell, HCO3 into the duct lumen

Chloride exits through CFTR into the lumen and re-enters via the Cl⁻/HCO₃⁻ exchanger to allow continued bicarbonate secretion.

• CFTR (cystic fibrosis transmembrane conductance regulator) is a cAMP activated Cl- channel present on apical membrane of pancreatic duct cell

• When open, it allows Cl- to diffuse from cytoplasm > lumen.

• Then the Cl- cycle back into the cell via Cl-/HCO3 exchanger to allow secretion of HCO3 into the lumen.

• CF results from mutation affecting CFTR > premature degradation > loss of CFTR expression at the plasma membrane. > impaired Cl- levels

• This disrupt the apical transport process of the duct cell > decreased HCO3 + water secretion > thick protein rich secretion > ductal obstruction / pancreatic tissue destruction

  • Low HCO3 > low pH > disrupts the digestive enzyme

• Leads to pancreatic enzyme deficiency > maldigestion, diabetes and steatorrhoea.

• Product of acinar, duct and goblet cells > pancreatic juice serection rich in protein and alkaline

• Pancrease is highest protein synthesis and secretory organ in the body ~1.5L a day containing 5-15g protein

• Secretes over 20 proteins - either inactive zymogens (e.g trypsinogen,chymotrypsinogen, proelastase, procarboxypeptidase A, procarboxypeptidase B ) or active digestive enzymes (e.g Lipase and co-lipase).

• Rate of secretion depends on fed or fasted state

  • tightly linked with biliary and gastric secretion + instestinal motility

  • Levels low in fasted state, increase 15-20 x more in fed state.

    
    

It stimulates acinar cells to increase enzyme (zymogens) secretion. Also stimulates gall baldder to contract > bile

• CCK is released from I cells of the duodenum in response to fatty meal (lipids)

• Also stimulated by CCK-releasing factor e.g. LCRF (luminal CCK releasing factor) - these are endogenously produced and secreted into gut lumen > stimulates CCK

  • In fasting state, LCRF are degraded by digestive enzmyes > no CCK

Somatostatin.

• Produced by D cells of the islets of Langerhans.

• Inhibits release of CCK and secretin > inhibits pancreatic secretion

The intestinal phase.

1. Cephalic —> stimulated by sight, taste and smell > 25% secretion. Mediated by Ach > Ach receptor stimulation on acinar cell. (no involvement of CCK or secretin

2. Gastric —> 10-20% secretion, caused by presence of food:

   • Luminal peptides / AA > G cells on antrum > release of hormone gastrin > CCK receptors on acinar cell (gastrin is weak CCK agonist)

   • Gastric distension > stimulates neural pathway > low levels of pancreatic secretion via vagovagal gastropancreatic reflex

3. Intestinal —> 50-80%. Chyme entering duodenum stimulates pancreatic secretion by 3 ways:

   1. Acid > S cells of duodenum > secretin > pancreatic duct cells > HCO3 and fluid

   2. Lipids > I cells of duodenum > CCK > acinar cells > digestive enzymes

   3. Lipids > activates vagovagal enteropancreatic reflexes > acinar cells

The cephalic phase.

1. By storing enzymes as inactive zymogens in the secretory granules and activating them only in the small intestine.

   • Zymogens get activated only after coming in contact with small instetine brush border enzyme enterokinase (enteropeptidase).

   • This converts trypsinogen to trypsin which initiates conversion of all other zymogens to active form

2. The secretory granule is impermeable to proteins - zymogens and digestive enzymes kept seperated from intracellular environment

3. Enzyme inhibitors (pancreatic trypsin inhibitor) are co-packed in the granule

4. Condesation of zymogens, low pH and ionic conditions within secretory pathway further limits enzyme activity

When these mechanisms fails > pancreatitis

Enterokinase. - a small bowel brush border enzyme

GET SMASHED.

• Gall stones

• Ethanol

• Trauma

• Steroids

• Mumps

• Autoimmune (SLE, Sjogrens syndrome)

• Scorpion sting

• Hypercalcaemia, hypertriglyceridaemia, hypothermia

• ERCP

• Drugs (paracetamol, cisplatin, erythromycin)

Characteristic abdominal pain

• Epigastric pain, radiating to the back. A/W N&V

serum amylase or lipase ≥3 times normal

CT findings consistent with pancreatitis.

1. Premature enzyme activation of zymogens in acinar cells > activation of other enzymes.

2. intra-pancreatic inflammation - autodigestion of pancreas > inflammatory or endothelial cells

3. systemic inflammation - extrapancreatic inflammation such as sepsis / multi organ failure

Premature activation of trypsin within acinar cells.

• Can be due to hyperstimulation > inhibition of acinar secretion > maturation in the cell. Possible mechanisms:

• Ca2+ signalling disruption / trypepsinogen cleavage / decreased pancreatic trypsin inhibitor SPINK-1

• 80% its mild so Rx is supportive - IV fluids, fluid balance, analgesia, NBM

• In severe cases - USS ? gallstones / CT if unwell after 48hrs.

• May require ERCP (therapeutic endoscopic retrograde cholangiopancreatography) to Rx gallstones (removal), narrowing or blocked pancreatic or bile duct, leaks in bile duct and pesudocysts

  • Endoscopy > duodenum > common duct ?visible stones which can be removed to relieve obstruction

Acute: Removal of gallstones and relief of duct obstruction.

Chronic alcohol abuse.

• Inflammation of the pancreas that get worse with time > permanent damage to pancras.

• Other causes - Hereditary disorders of the pancreas, Cystic fibrosis, Hypercalcemia and Hyperlipidaemia

• May require admission: analgesia, IV fluids, nutritional support, synthetic pancreatic enzymes

• Diet plan - low fat, small frequent meals

• ERCP for complications associated with chronic panreatitis - to enlarge duct opening, to drain pseudocysts, to insert stent to keep patent pancreatic or bile duct

• synthetic pancreatic enzyme CREON

  
  

Diabetes and pancreatic calcification.

• The tissue hardens from deposits of insoluble calcium salts

• Destruction of pancreatic tissue > DM

Defective CFTR reduces bicarbonate and water secretion, leading to thick secretions, duct obstruction, and pancreatic destruction.

Upper digestive tract

• Oral cavity (mouth)

• Pharynx

• Oesophagus

Lower digestive tract

• Stomach

• Small intestine (duodenum, jejunum

and ileum)

• Large intestine (cecum and colon)

Smooth muscles (involuntary) - most regions of the GIT

• Can be Phasic (rapid contraction/relaxation) or Tonic (Sustained contraction)

Skeletal muscle (voluntary) - in pharynx, top 3rd of oesophagus and external anal sphincter.

GI mortility involves co-ordinated contractions and relaxations of GIT that moves contents from mouth to anus. 3 main patterns of mortility:

• Peristalsis, segmentation, and tonic contraction.

GIT has 2 types of contractions:

1. Phasic contractions are rapid, rhythmic and short-lasting. Occurs in body of oesophagus, stomach antrum, small and large intestines

2. Tonic contractions are sustained and maintain tension. Occurs in sphinters and upper stomach

Oesophagus, stomach antrum, small intestine, and large intestine.

Sphincters and upper stomach.

1. Enteric nervous system (intrinsic)

   • myenteric and submucosal plexus

2. ANS (extrinsic)

   • Vagaus nerve (parasympathetic) supplies most of the GIT but the distal part is innervated by pelvic nerves (S1-S3)

Myenteric plexus and submucosal plexus.

• The enteric nervous system is made up of myenteric plexus and submucosal plexus.

• The sensory neuron communicates with an interneuron, which communicates with a motor neuron > motor action

Activation of the myenteric plexus:

increases tonic contraction, increases intensity and rate of rhythmic contractions, and increases velocity of conduction

Regulates secretion and absorption.

• Activation of submucosal plexus > increased secretory activity and modulates intestinal absorption

Enteric sensory neurones: intrinsic primary afferent neurone

• Mechanoreceptors - Stretch in muscle cells activates a reflex contractile response. Mainly myenteric plexus

• Chemoreceptors - presence of substances e.g. fats, peptides that activate the enteric nervous system. Mainly submucosal plexus

The vagovagal reflex.

• Filling of the stomach is aided by relaxation of the smooth muscle in the fundus.

• Relaxation in the fundus is regulated by the vago-vagal reflex (receptive relaxation).

• If vagal innervation is interrupted then intra-gastric pressure increases as the stomach fills up.

Relaxation of the stomach fundus to accommodate food without increasing pressure.

• stomach has an ability to store food, involves contraction and relaxation of the smooth muscles of the stomach wall. This process is known as gastric accomodation

• Empty stomach vol is ~50ml (because walls are highly folded to Rugae which flattens), during swallowing, the smooth muscles in the fundus relaxes.

• Stomach vol increase to 1.5L with small increase in pressure

Intragastric pressure increases as the stomach fills.

• relaxation of the fundus is regulated by vago-vagal reflex termed ‘receptive relaxation’ - if vagal innervation is interrupted (vagotomy), intra-gastric pressure increases as you start to eat

• 
  

Propulsion, grinding, and retropulsion.

Backward movement of large particles from the antrum to the body of the stomach for further grinding.

• There is a rapid flow of liquids with suspended small particles

• There is a delayed flow of large particles towards the pylorus

• Liquids with small particles pass through the pylorus and leave the stomach. Particles have to be smaller than 2mm

• Large particles remain in the bulge of the antrum and are subject to grinding. This is the bolus

Retropulsion of large particles (>2mm) and clearing of the terminal antrum.

• Gastric emptying is the process by which the contents of the stomach are discharged into the duodenum.

• Primarily regulated by autonomic nervous system (vagus nerve) and GI hormones.

• Controlled by pyloric sphincter —> prevents regurgitation of duodenal contents into stomach.

  • Innervation by vagus = relaxation

  • Innervation by sympathetic = constriction

• Gastric mucosa are highly resistance to acid but can be damaged by bile if regurgitates from the duodenum

It causes constriction of the pyloric sphincter.

It causes relaxation of the pyloric sphincter.

1. Cephalic phase (inhibitory phase)

   • Initiated by thought, sight, smell, taste of food

   • Vagus nerve stimulates gastric acid and pepsinogen secretion

   • gastric motility and gastric emptying reduced

2. Gastric phase (excitatory phase)

   • Initiated by chemical presence of food in the stomach + prepsence of food (distension)

   • Regulated by myogenic reflex (stretching of smooth muscles)

3. Intestinal phase (inhibitory phase)

   • low pH in duodenum > secretin secretion

   • Fat > CCK secretion

   • AA > increase gastrin secretion

   • Carbs > GIP (gastrin inhibiting peptide) secretion

   • All these reduce gastric motility. The ileo-gastric reflex initiated by mechanoreceptors in the duodenum > reduced gastric motility.

Gastric phase of the gastric emptying is an excitatory phase. the stomach empties at a rate proportional to its volume. This is due to 3 mechanism:

• Myogenic reflex (stretching of smooth muscle stimulates contraction)

• Pressure receptor activation (due to distension of the stomach wall, leading to increased motility via the vagus nerve and local nerve plexuses)

• Gastrin release - in response to peptones

Disorder due to delayed gastric emptying without mechanical obstruction of the stomach. - pathogenesis unclear

• The symptoms are: postprandial fullness, nausea, vomiting, bloating, upper abdominal pain

• Treatment: dietary changes (several smaller meals per day), pro-motility agents

Diabetes mellitus.

Duodenum and jejunum

• Mixing - of chyme from the stomach with pancreatic, liver and intestinal secretions

• Propulsion - of food along the GIT

• Release -  of chyme into the colon

Fed (absorptive) state: initated by chemical and pressure stimuli from food bolus in the GIT

• Segmentation = Rings of circular muscles contract (some relax) moving food in both directions. Purpose of this is to mix food

• Peristalsis = Involves both longitudinal and circular muscles which contracts and relax (alternates) in a continuous wave pattern along the tract > rhythmically pushes bolus along the tract. Purpose is to propel chyme towards colon.

Fasted state: Small bowel is relatively dormant

• But still exhibits synchronised, rhythmic changes in both electrical and motor activity, termed the migrating motor complex (MMC).

• Involves sequential contraction of adjacent segments of small intestine.

Alternating contractions of circular muscle that mix chyme by moving it in both directions.

To propel chyme toward the colon.

• function of small intestine - mixing stomach content with digestive enzymes, propulsion and release of chyme into colon

A cyclic pattern of motility occurring during fasting that sweeps through the small intestine. Ocurs at intervals of 90-120 mins and consits of 4 phases:

1. A prolonged quiescent period

2. Period of increasing action-potential frequency and contractility

3. Period of peak electrical and mechanical activity that lasts a few minutes

4. Period of declining activity that merges into the next quiescent period

   
   

   Usually starts in the stomach, travels to distal ileum. Feeding terminates MMCs and start the fed motor phase (segmentation and peristalsis)

   
   

ENS, hormones and extrinsic innervation all impact MMC and transition to fed state. Major determinant of MMC pattern is hormone ‘motilin’.

Motilin - a 22 amino-acid peptide that is synthesised in the duodenal mucosa and released just before phase 3 of MMC cycle

The role of MMC is to:

• propel particles >2mm from the stomach into duodenum,

• To clear residual food (undigested food, desquamated cells, intestinal / pancreatic secretions) from s. intestine

• Stop colonic bacteria migrating into terminal ileum.

It has no villi. Functions:

• Absorb large quantities of fluid and electrolytes

• Absorb short chain fatty acids (products of carbohydrate fermentation)

• Regulate release of faecal material

• Store/reservoir (distal colon)

• Provides environment for synthesis of vitamin B complex and K-beneficial bacteria

• Secretes mucus and ions (K+, Cl-, HCO3-)

  
  

• The proximal colon is the site of absorption and bacterial fermentation. (transverse colon, ascending colon and cecum)

• The distal colon is a reservoir/ storage. (descending colon and sigmoid colon)

Rhythmic phasic contractions and giant migrating contractions.

Rhythmic phasic contractions (RPC):

• Segmented (haustra) contrations mainly for churning / absorption

• Short duration RPC (3secs) - do not propagate along the colon.

• Long duration RPC (12-20 sec) - propagate over short distance, aids in absorption of fluid, solidify contents

Giant migrating contractions:

• Large amplitude contractions which propagate very rapidly in distal directions over large distance. > mass peristalsis of colonic contents.

• Occurs randomly, 2-10x day, as a result of pelvic parasympathetic nerves.

It inhibits colonic motility.

Proximal is supplied by vagus nerve, distal is by pelvic nerve

Pelvic splanchnic nerves (S2–S4).

• Promotes Giant migrating contractions

Congenital absence of enteric nervous system neurons in the distal colon causing failure of peristalsis.

• The aganglionic, aperistaltic bowel segment effectively prevents the propulsion of the fecal stream, resulting in in megacolon) above the point where the nerves are missing and hypertrophy of the normal proximal colon (compensatory mechanism).

It increases colonic motility.

Distension of the rectum.

Important in regulation of colon motility - Peristalsis and distension of one part of the GIT influences activity in another part of GIT.

Downstream reflexes (excitatory to prepare for food)

• Gastro-ileal reflex - Motility in the stomach leads to increased motility in the ileum, as well as relaxation of ileo-cecal sphincter

• Gastro-colic reflex - Motility in the stomach leads to increased motility in the colon *

• Duodeno-colic reflex - High tension in the duodenum leads to increased motility of the colon

Upstream reflexes (inhibitory):

• Ileo-gastric reflex - Distension of the ileum decreases gastric motility.

• Intestino-intestinal reflex - Over-distension of part of the small intestine leads to relaxation of the rest of the small intestine

Involves internal and external anal sphincters which controls defection.

• Faeces in the sigmoid colon and rectum > distension > initiates stretch reflex

• Stretch receptors are activated > parasympathetic nervous system > motor fibers

• Internal anal sphincter (made of involuntary smooth muscles) are activated by PNS —> relaxation > faeces moves to anal canal.

• External anal sphincter (voluntary skeletal muscles) innervated by somatic nervous system. Remains constricted to prevent defecation

• CNS signals external sphincter to voluntarily relax > defecation.

Skeletal muscle.

Right (quadrate, and caudate lobes) and left lobe.

• Largest solid organ, located in RUQ

• Composed of 2 main lobes (R+L) separated by Falciform ligament

The porta hepatis - H-shaped fissure through which structures leave or enter the liver.

Common hepatic duct (right anterior)

Hepatic artery proper (left anterior)

Portal vein (posterior)

Liver is covered by visceral peritoneum like the other intraperitoneal organs. Visceral peritoneum is absent in:

1. Bare area (where is likes adjacent to diaphragm)

2. Fossa of GB (where it attaches to liver)

3. At the porta hepatis

4. At the groove for inferio vena cava.

Lies in a shallow fossa between the right lobe and quadrate lobe on the inferior surface.

Eight segments - based on its blood supply and bile drainage.

• Each segment of the liver has an independent supply system which is important for its vascular inflow, outflow and biliary drainage

• In patient with cancer, one or more of this segments can be removed and the liver would regenerate.

The acinus and the lobule.

• Liver subdivided into 8 segments,within each segment the tissue can be dividedinto lobules or acinus

• These are composed to hepatocytes, sinusoidal channels, inlet/exit blood vessels and bile canaliculi

The liver receives blood via 2 vessels (dual supply):

• Hepatic Portal vein - carrying venous blood from the foregut, midgut and hindgut (75%)

  • Drains via splenic, superior mesenteric and inferior mesenteric veins.

• Hepatic artery - carrying arterial blood (25%)

Blood enters the lobules, mixes in the sinusoids (capillary bed) and drains via hepatic veins into the IVC near the right atrium.

Blood comes in through the central portal tract > sinusoids > central vein

A branch of the portal vein, hepatic artery, and bile duct.

Into the central vein.

From hepatocytes through canaliculi toward the bile duct in the portal triad.

Zone I.

Zone III.

Hepatocytes - main functional cell

Biliary epithelium - bile secretion/transport

Endothelium - lines hepatic vasculature

Kupffer cells - hepatic macrophages

Stellate cells - lipocytes

Polarised polyhedral epithelial cells (20-30uM).

• Hepatocytes makes up 60-65% of liver - main functional cell of the liver (get scarred when diseased)

• Polarised = different ends of the cells are functionally different (blood supply above and blow to secrete or extract)

• There are tight juctions between them to ensure the bile stays within the canaliculus (on lateral cell wall)

• Have low mitotic index

• Carry out metabolic functions

• Don’t have basement membrane but held in by ECM rich in collagen + proteins + proteoglycans

• They form the collecting vessels to collect canalicular bile - Involves in transport and secretion of hepatic bile

• Histology: polarised cuboidal or columnar epithelial cell

• Made of simple squamous epithelial cells which lines the hepatic vasculature

• Protect the liver parenchyma from blood cells, bacteria, virus and filter fluid

• Functions:

  • anti-thrombogenic surface, regulates coagulation / leukocyte traffic, selective uptake of solutes and partciles and scavenging of waste products (in the capillaries)

Kupffer cells.

• Located within the sinusoids and makes up 80% of all macrophages in the body

• Functions:

  • Phagocytosis, receptor mediated endocytosis

  • Regulation of microcirculation

  • Removal of endotoxins

  • Produce cytokines, present antigen and stimulate immune response

Stellate cell (ito cells)

• Also known as lipocytes, non-hepatocyte cells in the liver

• Star shaped, branches and sit between endothelium and hepatocyte

• Function - perisinusoidal fat / retinoid (vit A) storing cell

• Can transform to fibroblast-like morphology in disease (forms connective tissue > fibrosis of liver)

• Carbohydrate and fat metabolism

• Protein metabolism

• Storage of vitamins and minerals

Cholesterol is an essential component of cell membranes. It is also an important component for production of bile acids, steroid hormones and vitamin D.

• Hepatocytes covert acetyl-coA > HMG-coA > mevalonate > series of reactions to produce cholesterol.

• This reaction is catalysed by HMG-coA reductase

HMG-CoA reductase - catalyses the conversion of acetyl-coA into cholesterol.

Phase 1 - oxidation by ctochrome P450 emzymes

Phase 2 - Metabolism (conjugation reactions) to make is lipid or water soluble

• Liver is responsible for modifying drugs into more water soluble products which are excreted in bile / urine.

• Liver converts drug > hydrophilic substances to inactivate or enhance excretion. This is done via phase 1 and phase 2 metabolism

Cytochrome P450.

Albumin (50% of all plasma protein)

Fibronectin and components of coagulation cascade

Transferrin

Alpha-1 antitrypsin

Hepcidin and plasminogen.

• Protection against pathogens arriving in the blood

• Phagocytosis of old or dying cells

• Innate immune functions

• Induction of tolerance

Hepatocytes produce around 500ml bile a day, some stored in the gallbladder - released into the intestine on demand

• Involved in emulsification of fat in the intestine

• fat soluble vitamin uptake (A,D,E,K)

• Excretion of substance which cant be done by kidney (cholesterol and bilirubin)

• ALT is an enzyme in the liver that converts proteins into energy for the liver cells.

• AST is an enzyme that helps the body break down amino acids

When liver is damaged, both AST and ALT get released into blood and level increase.

AP (alkaline phosphatase) and gGT are also released

Other - albumin will be low, autoAb (autoimmune hepatitis), viral markers, tumour markers, metabolic indicators.

Cholecystokinin (CCK).

Around 2 mg/dL.

• Bilirubin is a product of haemoglobin catablism from RBC, plus breakdown of myoglobin, cytochrome and peroxidase enzyme.

• It is required to form bile (get recycled 6-8x day)

Macrophages engulf old red blood cells and extract the haem groups from them.

The haem group is then converted into biliverdin through oxidation, which is then reduced to form unconjugated bilirubin

1. RBC > Haem > Biliverdin (oxidation) > unconjugated bilirubin

2. Carried by albumin (hydrophobic) and transported to hepatocytes in the liver

3. In the liver, it is conjugated with glucuronic acid by UDP glucoronyltransferase —> soluble

4. Conjugated bilirubin excreted through bile ducts into the guts. Occurs via gallbladder which is stimulated by release of CCK by duodenal I cells in reponse to fat

5. In the colon, its converted to urobilinogen by bacterial or epithelial β-glucuronidase enzymes

   • Most urobilinogen is oxidised by bacteria into stercobilin and excreted in faeces

   • 20% get reabsorbed into blood > liver

6. Some urobilinogen is re-used to produce bile, rest transported to kidney

7. In the kidney, it is oxidised to urobilin and excreted in urine

No.

UDP-glucuronyl transferase.

Brown colour of faeces.

Excretion of conjugated bilirubin as urobilin in urine.

1. Pre-hepatic = not related to liver

2. Intrahepatic / hepatic = liver disorders

3. post hepatic/ extra hepatic = cause is after the liver

• Haemolysis - increased unconjugated bilirubin with normal AST/ALT, ALP and gGT. Sickle cell anaemia or

  • Gilbert’s syndrome - Mutation in bilirubin UDP-gluccuronyltransferase 1 gene > low enzyme level > rised unconjugated bilirubin. No Rx required, Sx appears during fasting, dehydration, illness

  • Sickle cell - abnormal Hb > haemolysis > high bilirubin, low Hb. Rx RBC transfusion to reduce HbS

• Neonatal jaundince - common, affects 90% of babies (high risk if born prematurely).

  • Cause - delay in bilirium clearance from RBC breakdown. Rx phototherapy

Unconjugated.

Jaundice due to liver injury - failure of cellular mechanism of excretion of conjugated bilirunin.

Bloods —> High total bilirubin (conjugated + unconjugated), high AST/ALT (2-20x), mild inc ALP + gGT.

Symptoms —> dark urine, pale stool

Causes —> liver injury, acute hepatitis (viral, alcohol, autoimmune or toxic), chronic hepatitis and cirrhosis

• Viral hepatitis - Hep A to E selectively infect hepatocytes > strong immune response > severe hepatitis. Immune system kills infected hepatocytes > cholestasis (reduced bile flow from liver) as bilirubin is not excreted into biliary system. Conj + unconj > circulation. pt not always jaundiced.

• Liver injury - causes cholestasis or interruption of bile flow. Due to cancer, bile duct destruction (autoimmune or drugs) or cholestasis 2ndary to pregnancy or drug toxicity.

AST and ALT (2-20x)

Bloods —> increased conj bilirubin, mod high AST/ALT (x5) and raised ALP/gGT (x3)

Causes —> Gallstones, ductal disease (cancer or inflammation), compression of ducts (lymph node, pancreatic ca)

• Gallstones - mostly asymptomatic, women>men, caused by imbalance in chemical constituents of bile. If the stone goes to bile duct, cause obstruction, jaundice and cholangitis (inflammation of bile duct tract).

• Ca pancreas - Growth > obstruction of bottom of common bile duct > painless jaundice + weight loss.

ALP and GGT.

Viral hepatitis, alcohol, and metabolic syndrome/obesity.

• These factors then act to cause: acute hepatitis → Chronic hepatitis → Liver fibrosis → Liver Cirrhosis → May lead to lead to liver cancer

Portal hypertension - an excess fibrosis > increase in BP in vessels that drain into liver from intestine and kidneys.

This leads to:

• Renal failure

• Varices (enlarged vein) in oesophagus

• Splenomegaly (enlarged spleen)

• Ascites (fluid collecting in peritoneal cavity)

Obesity and metabolic syndrome.

• Liver steatosis = excess accumulation of fat in the liver.

• Alcohol and obesity are risk factors for liver disease as they can cause liver steatosis.

• In the absense of excess alcohol, this is referred to as Non-alcoholic fatty liver disease

Steatohepatitis, Fibrosis, cirrhosis, and hepatocellular carcinoma.

Stellate (Ito) cells.

Oral cavity:

• Mostly non-keratinised stratified squamous epithelia

• 3 types of oral mucosa;

  • Lining (lips, cheeks, soft palate)

  • Masticatory (hard palate, gingiva)

  • Specialised (dorsum of the tongue) - taste bud

• Some keratinisation occurs in some parts to protect it

• Keratinisation can also be sign of damage to mucosa

Hard palate mucosa = partly kertinised

sof palate = inferiorly non-keratinised contains elastic lamina. Superiorly has respiratory epithelia (ciliated pseudostratified) - faces nasal surface.

Small intestine is exclusively responbile for absorption of dietary nutrients.

There are 3 levels of increasing surface area:

• Macroscopic folds of Kerckring (plicae circulares)

• Villi, which are surrounded by the openings of glandular structures called crypts of Lieberkühn, or crypts

• Microvilli on the apical surface of the epithelial cells and crypts

Approximately 6.5 litres.

• large intestine re-absorbs 1.9L

Sodium (Na⁺) and chloride (Cl⁻).

• NA+, CL- and HCO3- are transported into lateral intracellular spaces

• This results in high NaCl near apical end of intracellular space > hypertonic

• This causes osmotic flow of water from the lumen via tight junctions into the intracellular space.

Both paracellular and transcellular.

Na+ is absorbed along the entire length of the intestine. There are 4 different transport routes of entry depending on where we are in the gut

• Na/Glucose transport or Na/Amino acid transport

• Na-H exchanger

• Parallel Na-H and Cl-HCO3 exchange

• Epithelial Na+ channels

SGLT1.

• Occurs in fed state

• Na+ is transported into epithelial cell from the lumen via SGLT1 pritein along with glucose (symport)

  • This is down the Na conc but against glu cons

• Na+ is actively transported out the epithelial cell via Na/K ATPase > blood

Na⁺/K⁺ ATPase.

Fed state.

Na⁺/H⁺ exchanger.

• Sodium is actively transported out the epithelial cell via Na/K ATPase, into the blood

• Sodium diffuses into the epithelial cell from the lumen via an antiporter protein, and H+ leaves the cell into the lumen

• Absorption will be linked with pH, more likely to occur in intestine, not stomach, think about proton gradient

Parallel Na⁺/H⁺ and Cl⁻/HCO₃⁻ exchangers (closely linked).

This is the mode of sodium absorption that is affected by secondary messengers

• H+ and HCO3- leave the epithelial cell whereas Na+ and Cl- enter the epithelial cell through their respective antiporter proteins (Na/H and Cl/HCO3 exchangers)

• This process is regulated by cAMP and cGMP as well as intracellular Ca2+. An increase in either one of these reduces NaCl absorption.

• Reduction in NaCl absorption also affects water absorption, this results in a secretory diarrhoea

• This is the primary method of sodium absorption in the fasted state (between meals)

  • Occurs in the ileum and throughout large intestine. Not affected by luminal glucose or pH.

cAMP, cGMP, and intracellular Ca²⁺.

• Enterotoxins induce secretory diarrhoea by elevating cAMP and inhibiting NaCl absorption

Epithelial sodium channel (ENaC).

• Na+ entry occurs via apical membrane via ENaC that are highly sepecific for Na+

• Na+ in epithelium > blood via Na/K ATPase

• Na+ from lumen > epithelial cells down conc gradient via ENaC

  • This makes Na+ absorption in the distal colon highly efficient as it allows Na+ to be absorbed against large conc gradient

Aldosterone (mineralocorticoid) - increases Na+ by:

1. Increase the opening of apical Na+ channels

2. Inserts pre-formed Na+ channels from sub-apical epithelial vesicle poor into the apical membrane

3. Increase synthesis of apical Na+ channel and Na/K pumps

• Absorptagogues promote absorption

• Secretagogues promote secretion (diarrhoea)

Angiotensin and aldosterone. (other e.g. somatostatin, enkephalins and noradrenaline)

• Dehydration and low BP > stimulation of RAAS axis > aldosterone and angiotensine release

• They regulate Na+ homeostasis by stimulating Na+ absorption

• Angiotensin - Enchances small intestine electroneutral NaCl absorption by upregulating apical membrane Na-H+ exchange

• Aldosterone - Stimulates colon Na+ absorption via ENaC

• Bacterial enterotoxins (Cholera, C.diff, E.coli)

• Hormones and neurotransmitters (ACh, VIP)

• Products of cells of the immune system (histamine)

• Laxatives (bile acids)

Vibrio cholerae.

• Transmission occurs through ingesting contaminated food or water

• cholera patient produce ~20L watery stool per day

• Releases Cholera toxin (enterotoxin) > fatal diarrhoea (lead to shock in 2 - 12hrs)

• Enterotoxin induce intracellular conc of cAMP > Cl and K+ secretion + inhibition of electroneutral NaCl absorption

• The 2nd messenger do not alter the nutrient-coupled Na+ absorption (Na/Glu), giving oral dioralyte with Na+ and glu is effective Rx.

cAMP.

• increases Cl and K secretion, inhibits NaCl absorption

Because Na⁺/glucose cotransport remains functional, allowing sodium and water absorption.

• Dioralyte contains Sodium chloride 350mg, Potassium chloride 300mg, Sodium citrate 580mg, Pre-cooked rice powder 6g

  
  

• Bulk laxatives - Increase fibre when taken with water

• Stool softeners - allow water to enter the stool more readily

• Lubricant agents - Lubricate the stool surface

• Osmotic laxatives - Hypertonic increase in stool water

• Stimulant laxatives - Increase peristalsis

• Prokinetic laxatives - Increase peristalsis

Duodenum.

• Ca2+ load in small intestine is both dietary source and digestive secretions.

• Small intestine absorbs ~500mg/day of Ca2+ and secretes ~325mg/day so net uptake = 175mg/day

Calcium is absorbed by both active and passive transport

• Passive transport - absorption of Ca2+ that occurs throughout the whole small intestine, via the paracellular pathway, which is not under the control of vitamin D receptors

• Active transport - active, trans-cellular uptake of Ca2+ occurs only in the epithelial cells of the duodenum and is under the control of vitamin D receptors.

Vitamin D deficiency > hypocalcaemia > soft bones > bowed legs.

Rx - increase dietary Ca+ and vitamin D intake, sunlight exposure, oily fish.

Haem iron.

• Dietary iron comes from 2 different sources - inorganic and haem food groups.

• Haem is more bioavailable - iron is readily present in haem foods such as meat, chicken and fish.

• only <10% of the consumed iron is absorbed (equal amounts of rion absorption from haem and inorganic food)

• Iron from destroyed erythrocytes also recycled by the body

• Iron can be stored in liver, spleen and bone marrow

DMT1.

• Iron absorption primarily occurs in small intestine via action of reductase enzyme on the apical surface of enterocytes.

• The enzyme reduces Fe3+ into Fe2+ > get transported into enterocytes via DMT1 transporter protein located inside the enterocytes.

• Fe2+ stored by bound to ferritin or transported into blood via ferroportin followed by oxidation to ferric rion (Fe3+) by hephaestin.

Ferroportin.

• In the blood stream, ferric iron is bound to transferrin and delivered to target cells

• At target cells, it binds to transferrin receptors > triggers receptor mediated endocytosis

• Fe3+ is reduced to Fe2+ within endosomes by reductase enzyme, then transported into cytoplasm via DMT1

• In the cytoplasm, Fe2+ is utilised by mitochondria to produce cytochrome enzymes or stored bound to ferritin.

• Unused Fe2+ can be released from cell via ferroportin prn.

Hepcidin.

• Liver, spleen and bone marrow are major stores of iron

• absorption must be tightly regulated as per body iron level

• Hepcidin is a hormone produced in the liver, it tightly regulates iron metabolism

  • High iron levels > hepcidin release by liver > binds to ferroportin > internalisation and degradation of ferroportin > reduces cellular iron transport > lowers iron level.

  • Low iron leve > suppresion of hepcidin by liver

Ferroportin is internalised and degraded > reduced iron level

Interleukin-6 (IL-6).

• Inflammation / infection > high hepcidin levels due to IL-6 which induce hepcidin production.

  • This inhibits cellular iron absorption in small intestine and efflux of iron stored in macrophages. Bacteria needs iron to proliferate so iron is locked away.

High.

• Infection / inflammation causes high hepcidin which lowers iron levels

• Prolonged hepcidin activation in inflammation > anaemia of chronic disease > limited bacterial iron acquisition + reactive O2 species formation.

• Anaemia of chronic disease is different from iron deficiency anaemia (former locks away abdundant iron stores, later is due to iron deficiency)

• So hepcidin levels are gold standard to differentiate between IDA and ACD

Low.

Levels of Haemoglobin below 13 g/dL in men over 15 years, below 12 g/dL in non-pregnant women over 15 years, and below 11 g/dL in pregnant women

Hereditary disease characterised by improper dietary iron metabolism due to either:

• Inability to produce hepcidin

• Mutated, non-functional hepcidin

• Insensitivity of ferroportin to hepcidin

This results in the accumulation of iron in body tissues.

Eventually cause organ damage, most notably in the liver and pancreas. Pancreatic end organ damage can cause diabetes mellitus, in the liver it can cause liver failure

Rx - Phlebotomy to remove excess iron

Occurs through fenton reactions and reactive oxygen species.

These mediates oxidative stress, cellular damage and eventually cellular death by apoptotic signalling. Organs involved are:

Gastrointestinal blood loss.

• IDA has prevalence of 2-5% in men and postmenopasal women in developed world.

  • Menstrual blood loss is common cause of IDA in pre-menopausal women

  • GI blood loss common cause in men / post-menopausal women

Anti–tissue transglutaminase antibodies. (+ small bowel biopsy)

• Autoimmune disorder of small bowel > immune reaction to gliadin (gluten protein found in wheat, barley and rye)

• Gluten sensitive enteropathy = exposure to gliadin > enzyme tissue transglutaminase modifies it > cross reaction with bowel tissue by immune system > inflammation > villous atrophy

• Sx - IDA, diarrhoea, weight loss, stunted growth in children, fatigue.

• Rx - life-long gluten free diet

Villous atrophy.