GI Histopathology and Visceral Afferents Flashcards
What is the difference between haematoxylin and Eosin stains?
Haematoxylin
- Purple-blue basic stain
- Stains acidic macromolecules , ie DNA, RNA- nuclei
Eosin
- Pink acidic stain
- Stains basic macromolecules, ie cytoplasm of cells, collagen
Special stains
Perodic acid Schiff (PAS) +/- diastase- stains glycogen
Alcian blue- mucin
Masson’s trichrome- collagen etc
Perl’s- stains iron
Immunohistochemistry
Modern technique for staining
First described by Coons in 1941
Relies on Antigen (Ag)- Antibody (Ab) link
Used to label specific antigens
- indirect method, primary antibody targets antigen of interest and secondary antibody attaches to this- enzyme attaches to secondary antibody converts substrate into coloured product (diaminobenzidine- brown)
- direct where enzyme or fluorescent molecule attached directly to antibody but indirect means multiple secondary antibodies attach to primary = amplification
Primarily diagnostic use
Increasingly used to guide therapy
Epithelium structure
- Closely packed cells, with little to no extracellular material
- Form membranes or glands
- Epithelium separated from connective tissue by basement membrane
- Squamous, columnar, cuboidal cells
Epithelium functions
Protection : skin
Secretion/ excretion
Epithelium types
Simple (one cell layer)
Stratified ( more than one cell layer)
Pseudo-stratified
What tissue is this?
Simple epithelium
lots of pin cytoplasm because of lots of mitochondria
What tissue is this?
Stratified epithelium
What tissue is this?
Transitional epithelium (urothelium)
Has ability to stretch and maintain a tight barrier to prevent urine leaving the bladder
Connective tissue structure
Composed of
- Extracellular matrix
- A few cells
- Provides structural and metabolic support
Extracellular matrix
- Fibres (collagen , elastin)
- Amorphous ground substance (gel like matrix)
- Extracellular fluid
Connective tissue cell types
Fibroblasts
Adipocytes
Macrophages
Lymphoid cells ( plasma cells, leucocytes)
What tissue is this?
Label diagram
Connective tissue
What type of tissue is adipose tissue?
Connective tissue
What type of tissue is this?
Adipose tissue
What type of tissue is cartilage?
Connective tissue
What tissue is this?
Cartilage
What cartilage type:
articulates bone surfaces?
is in the ear?
is in intervertebral discs?
Hyaline cartilage articulates bone surfaces
Elastic cartilage in ear
Fibrocartilage in intervertebral discs
What cells produce cartilage?
Chondrocytes (found in lacunae)
What are the bone cells that sit in lacunae in the bone matrix?
Osteocytes
Bone composition
Protein matrix containing collagen
Mineral substances - calcium hydroxyapatite laid down on matrix giving it calcified supportive structure
Osteoclasts also present to reabsorb bone
Where does haematopoiesis occur?
Bone marrow
Skeletal muscle
Attached to skeleton
Long cylindrical fibres with an eccentric nuclei
Striated
Smooth muscle
Present in hollow viscous organs
Shorter cells with centrally placed nucleus
No striations
Cardiac muscle
Striated
Centrally located nucleus
Identify which muscle type each one is
Nervous tissue: CNS vs PNS
CNS: Neurons Supporting cells Oligodendroglia, astrocytes Schwann cells, microglia
PNS:
Bundles of parallel elongated fibres
Wavy, zig zag configuration
What tissue is this?
Nervous tissue
What tissue is this?
Histopathology
Microscopic examination of cells and tissue to study disease
The gold standard diagnostic technique
Metaplasia
Transformation of one differentiated cell type to another differentiated cell type
Dysplasia
An abnormality of development
Epithelial dysplasia- loss of maturation
Structure of wall of GI tract
Structure of the wall of GI tract
What lines normal oesophagus?
Pale pink squamous mucosal lining
Squamous mucosa structure
What is the deepest layer of normal oesophagus lined with?
Basal cells (single layer) including stem cells
Features of normal oesophageal squamous epithelium
Causes of impaired oesophageal sphincter control in GORD/reflux oesophagitis?
Hiatus hernia Obesity/pregnancy Gastric distension by food/gas Stress Alcohol and tobacco/drugs
What does acid gastric contents damage?
Unprotected squamous mucosa
Acidic damage to unprotected squamous mucosa causes what?
infiltration of the damaged surface epithelium by neutrophil polymorphs and eosinophils
basal cell hyperplasia as epithelium proliferates to replace damaged cells
What does reddened patches on lower oesophagus mean?
Inflammation, secondary to reflux of acidic gastric contents
What happens to basal cells in GORD/reflux oesophagitis?
Hyperplasia
Complications of GORD
Peptic ulceration, i.e. acid-induced benign ulceration
Replacement of squamous mucosa by glandular mucosa.
Columnar metaplasia = Barrett’s oesophagus
Development of dysplasia in Barrett’s oesophagus
Development of adenocarcinoma in Barrett’s oesophagus
What happens to mucosa in an ulcer?
Complete break in mucosa, discontinuation in mucosa. Inflammatory slough with fibrin on surface
Base of ulcer formed from granulation tissue consist of early fibrosis with proliferation of new capillaries (later forms fibrosis or scar tissue)
What problems can arise from a healing peptic ulcer?
As peptic ulcer heals scar tissue can form leading to peptic stricture in oesophagus
Barrett’s oesophagus
Complication of GORD
The squamous mucosa undergoes metaplasia from the normal squamous epithelium to columnar epithelium (glandular type epithelium)
(acid reflux causes metaplasia)
Metaplasia and reversability
Metaplasia is the reversible replacement of one mature type of epithelium by another in response to adverse circumstances.
Columnar cell metaplasia in oesophagus = Barrett’s oesophagus
2º v(secondary) to GORD/reflux oesophagitis
Mucus barrier of columnar epithelium protects against acid
Metaplasia is reversible if the stimulus is removed.
What replaces squamous epithelium in Barrett’s oesophagus?
Metaplastic columnar epithelium
What does Barrett’s metaplasia consist of?
Barrett’s metaplasia is often a mixture of non-specialised gastric-type mucosa and intestinal metaplasia
Intestinal metaplasia with goblet cells
Dysplasia
Premalignant change within the epithelium
Characterised by:
Impaired cell differentiation : disorganised, often failing to mature towards surface
Atypical nuclear features, eg pleomorphism
Increased numbers of mitoses
Dysplasia in Barrett’s oesophagus
Dysplasia in Barrett’s oesophagus: surface epithelium shows multilayering of nuclei, with hyperchromatism, pleomorphism and increased mitoses
Non-dysplastic metaplastic columnar mucosa in Barrett’s oesophagus
How does carcinoma of oesophagus present in Barrett’s oesophagus?
Carcinoma of oesophagus presents with dysphagia due to luminal narrowing and infiltration of the wall, inhibiting peristalsis
What are the 2 types of adenocarcinoma of oesophagus?
Intestinal type formed by irregular glands
Diffuse type (signet ring carcinoma)
Normal squamous vs dysplasia squamous
Normal squamous mucosa shows orderly maturation from the basal layer to the surface.
Squamous epithelial dysplasia in the oesophagus. Disordered maturation and increased mitotic figures.
Where does squamous cell carcinoma typically occur?
Mid or upper oesophagus
Where does adenocarcinoma of oesophagus typically occur?
lower oesophagus and GOJ (gastroesophageal junction)
What mucosa is on the surface of the body and fundus?
Specialised gastric mucosa
Mucous neck cells secrete a blanket of mucus over the surface which protects it from digestion by enzymes and acid.
2 types of specialised body-type gastric mucosa
Parietal cells (pink-staining) secrete gastric acid
Chief cells (purple-staining) secrete pepsinogen, which is activated by acid in the lumen of the stomach to form the active protease enzyme pepsin.
What cells are found on the antrum and pylorus?
Non-specialised gastric mucosa
Glands formed by mucus producing cells
Protective mechanisms in stomach
MUCUS BLANKET continually secreted by mucus neck cells
BICARBONATE BUFFER LAYER secreted by epithelial cells in gastric neck/isthmus
What can interfere with the mucus blanket?
Drugs, alcohol and H. pylori infection
Mucus blanket relies on intact mucin neck cells for production so any inflammatory stimulus will interfere
What can interfere with bicarbonate buffer layer?
Bicarbonate (HCO3-) secretion is stimulated by prostaglandins, produced from arachidonic acid by COX pathway, inhibited by NSAIDs
How does pepsin form?
Pepsin forms from pepsinogen in acid-rich environment
What do parietal cells and chief cells secrete?
Parietal: acid
Chief: pepsinogen, not activated until pH is low
Gastritis pathology
Infiltration by acute inflammatory cells like neutrophils and chronic inflammatory cells like plasma cells and lymphocytes
2 main causes of gastritis
NSAIDs and H. pylori
What is a consequence of gastritis?
Gastric peptic ulcer in stomach
Duodenal peptic ulcer in duodenum
Peptic-type ulceration is due to acid.Seen in oesophagus, stomach and duodenum
Complications of peptic ulcers in stomach or duodenum
Intestinal-type adenocarcinoma vs ulcerated adenocarcinoma
Intestinal-type adenocarcinomas usually present as ulcers or polypoid tumours.
Ulcerated adenocarcinoma has a ‘rolled’ everted edge, unlike the overhanging edge of benign peptic ulcer
Gastric peptic ulcer vs ulcerated gastric adenocarcinoma
Gastric peptic ulcer:
surface has granulation tissue with inflammatory slough, NO epithelial cells in submucosa
Adenocarcinoma:
nests of irregular glands invading from mucosa into submucosa and into muscularis propia
Gastric peptic ulcer vs ulcerated gastric adenocarcinoma
Gastric peptic ulcer:
surface has granulation tissue with inflammatory slough, NO epithelial cells in submucosa
Adenocarcinoma:
nests of irregular glands invading from mucosa into submucosa and into muscularis propia
Diffuse (signet-ring cell) type adenocarcinoma presentation in stomach
Stomach often shrunken, thickened and non-distensile; patient may present with early satiety.
Somatic pain
musculoskeletal (joint pain, myofascial pain), cutaneous; often well localized
Visceral pain
hollow organs and smooth muscle; usually referred
Neuropathic
pain initiated or caused by a primary lesion or disease in the somatosensory nervous system.
Hollow and solid organs
Not all internal organs sensitive to pain e.g. liver, lungs, kidneys – no nociceptors
Stretching of hollow viscera such as gall bladder, ureters, colon can cause excruciating pain
no close relationship between severity of damage and severity of pain
Extrinsic sensory neurones work with what other cells?
Immune cells in gut wall
Interstitial cells of Cajal
Pacemaker cells
Sensations from the gut
Oesophageal distension Gastric distension – fullness Nutrient density in stomach/duodenum Nausea-toxins or excess nutrients Movement of gas Pain Awareness of rectal content Urgency
Visceral afferent pathways in the GI tract
Vagal afferents
Thoracolumbar (splanchnic) afferents (pain)
Pelvic afferents (gut)
Enteric afferents - viscerofugal neurons
How many different types of sensory neurones give rise to sensation from the gut?
Serosal/Muscular/Mesenteric
– distension/contraction – mechanoreceptors
Mucosal – entero-endocrine mediators
Musculo-mucosal Vascular afferents (serosal)
What is the location of the sensory neurons of the gut?
Intra-ganglionic – low threshold mechanoreceptors primarily in vagal and pelvic pathways (longitudinal muscle)
Intramuscular afferents – mechanosensitive (muscular propria)
Mucosal afferents – mucosal distortion and entero-endocrine cell mediators (vagal and spinal) (mucosa)
Muscular-mucosal – mucosal stroking and distension/contraction – in vagal and pelvic pathways (submucosa)
Vascular afferents – on extramural and intramural blood vessels – mechano-nociceptors – splanchnic and pelvic pathways (submucosa to longitudinal muscle)
Entero-viscerofugal – interneurons with mechanosensitivity (LM)
Visceral pain in clinical practice- pain caused by:
‘structural’ conditions?
‘functional’ conditions?
Pain caused by ‘structural’ conditions
- Inflammatory e.g. acid-peptic disease,
- Neoplastic
Pain caused by ‘functional’ conditions
- Irritable bowel syndrome (include bloating)
- Functional dyspepsia (include nausea)
Stimuli for visceral pain
Hollow organ distension Traction Ischaemia Acid/Irritant chemicals Inflammation Electrical stimulation ‘pinching’ does not cause pain except when hyperalgesic
Somatic abdominal pain features
‘Painful rib’ syndrome
Spinal pain
Pain from abdominal wall or inguinal ligaments
Constant, can be sharp and momentary with movement or straining
Well localised
Unaffected by food, defaecation
Affected by position, movement, straining
Localised Tenderness, reproduces pain
Subluxation of costal cartiledge tips causing impingement of the intercostal nerves
Example of visceral pain becoming somatic
Acute appendicitis:
- In early phase visceral intestinal pain – central abdominal, colicky
- With onset of inflammation of parietal peritoneum, somatic pain localised to RIF
- Worse with movement and straining
- Tenderness at McBurney’s point
Treatment of visceral pain
- Treat disease e.g. peptic ulcer
- Anti-spasmodics e.g. for irritable bowel syndrome
- For visceral hypersensitivity use tricyclics
e. g. Amitryptiline - Used in sub-anti-depressant doses
- Start at low dose e.g. 10 mg nocte and step up
- Main problem is sedation – take at 6 pm
Hyper vigilance and pain
Mild pain can become difficult to bear when patients are worried about it – leads to anxiety, panic etc
Pain may not be noticed when engaged in other activities e.g. Watching TV
‘Painful rib’ syndrome – continuous pain day and night. Many patients cope with it much better once they understand it is not serious. Analogous to rheumatism
Achalasia
An oesophageal motility disorder causing dysphagia
Degeneration of ganglion in myenteric plexus in oesophageal wall leading to motility disorder:
- Aperistalsis
- Incomplete lower sphincter relaxation
- Treat by myotomy, pneumatic dilatation or botulinum toxin injection
Gastro-oesophageal reflux
Incompetent lower oesophageal sphincter, but resting pressure may be normal
Gastric acid secretion usually within normal limits
Oesophagitis seen at endoscopy but normal appearances in non-erosive gastro-oesophageal reflux
Ambulatory lower oesophageal pH monitoring
Oesophageal exposure to acid causes…
Hypersensitivity
(hyperalgesia aka primary, local OR allodynia aka to non painful stimuli OR, secondary hyperalgesia aka generalised)
Hyperalgesia
an increased sensitivity to feeling pain eg overuse of opiods ie exaggerated response
Allodynia
things that don’t normally cause pain eg very sensitive to touch/temperature
Secondary hyperalgesia
generalized response not just at the area of injury
Ion channels in the oesophagus
- Transient Receptor Potential Vanilloid-1 (TRPV-1)
- Acid-Sensing Ion Channel (ASIC)
Acid excites primary sensory neurons by activating TRPV1 and ASIC – leads to release of pro-inflammatory mediators and neurogenic inflammation
Sensitive to mechanical, electrical and thermal stimuli
Erosive reflux disease vs NERD
Erosive- mucosal damage
NERD- no mucosal damage
What organs does Gi tract share neural pathways with?
Lungs and trachea
Using pH testing on a patient with GORD the result is abnormal what is the likely diagnosis?
NERD
Posiitve result- abnormal acid exposure
What would pH result be if a patient with GORD had functional heartburn?
Normal pH test
May have symptoms associated with pH changes- hypersensitive oesophagus or just functional heartburn
Gastric motility and secretion
Fundus – accommodates
Antrum – grinding effect
Food boluses converted into chyme
Greasy and rich food delays gastric emptying
Stomach secretes acid and pepsin
Vagus, gastrin (secreted by G cells) and acetylcholine promotes acid secretion
Proton pump - final common pathway for acid secretion
Delayed gastric emptying
Often occurs in dysmotility type dyspepsia, sometimes associated with nausea, vomiting and weight loss
Severe gastric emptying delay in gastro-paresis, often diabetic, sometimes post-infective
Pro-kinetic drugs: domperidone, metoclopramide also helps nausea and vomiting
Isotope gastric emptying study
IBS demographics
10-15% of the population 30% consult a physician Greater anxiety, lower quality of life Female preponderance No excess mortality Rome and Manning Criteria
Rome IV criteria
Recurrent abdominal pain, on average, at least 1 day/week in the last 3 months, associated with two or more of the following criteria:
Related to defecation
Associated with a change in frequency of stool
Associated with a change in form (appearance) of stool
Disorders of gut-brain interaction Related to: - Motility disturbance - Visceral hypersensitivity - Altered mucosal and immune function - Altered gut microbiota - Altered CNS processing
IBS and abnormal perception of normal stimuli
Distension in IBS -> abnormal sensory response, pain, urgency, feeling unwell
normal sensory stimulus giving rise to different sensation
increases with increasing distension (higher pressure = more sensitive to discomfort)
Importance of physician-patient interaction
IBS phenotypes
IBS with constipation >25% hard stools, <25% loose stools
IBS mixed - both hard and loose stools
IBS with diarrhoea >25% loose stools, <25% hard stools
Constipation
Many possible causes: low fibre diet, medications such as opiates, hypercalcaemia, hypothyroidism
Chronic constipation not a symptom of colon cancer
Does not produce toxins, ill health or increase risk of colon cancer
Functional types: colonic inertia – slow transit (can assess by marker studies), pelvic floor dys-synergia: pelvic muscles do not relax with defaecation
Management similar for both types of constipation
Constipation demographics
More common in lower socioeconomic class
Less fibre and less exercise
F:M – 2.2:1
Constipation demographics
More common in lower socioeconomic class
Less fibre and less exercise
F:M – 2.2:1
Beneficial diet for constipation
Diet:
Meta-analyses
- Bran – less effect if constipated
- Ispaghula
RCTs
- Prunes (sorbitol)
- Kiwifruit
- Vegetable and wholegrain powder
- Fruit and fibre to porridge
What is the most effective osmotic laxative?
Macrogol (polyethylene glycol) more effective and better tolerated than lactulose
Macrogol
- Proven efficacy in long term treatment
- Improved stool frequency
- Improved pain
- Less need for other laxatives
SE – diarrhoea, bloating
First line laxatives for:
Osmotic?
Stimulant?
Stool softeners?
Osmotic:
- Macrogol
- Avoid lactulose
Stimulant
- Sodium picosulphate
- Bisacodyl
- Senna
Stool softeners
- Sodium docusate
SE – osmotic – bloating
SE – stimulant - cramps
Individualised diet for patients with IBS
Regular, small meals Fat reduction Caffeine Reduce lactose and fructose Reduce gas-producing foods Modify soluble/insoluble fibre Reduce wheat Low FODMAP diet (reduces bifidobacteria)
What do we know about bifidobacteria in relation to helping IBS patients?
Gas related symptoms
Inverse relationship between pain and bifidobacteria
Sites of abdominal pain- what organs are implicated in: Chest Upper Mid Lower Back pain?
- Chest - oesophagus
- Upper- oesophagus, stomach, duodenum, pancreas, gallbladder, colon
- Mid – Small intestine
- Lower – Colon, gynaecological
Radiation to back with severe pain, biliary pain, pancreatic pain, spinal pain
Visceral vs non-visceral pain
Visceral pain lasts minutes/hours, intense can come and go
Non visceral pain well localised, lasts for seconds or constant
Exacerbated by movement, coughing, straining
Nerve pains- shooting and needle-like, sharp
Musculoskeletal- spinal, painful rib syndrome, pain over ligaments, bones and joints
Character and severity of upper abdominal pain:
Acid peptic pain?
Intestinal pain?
Biliary colic?
Acid peptic: burning or dull (mild or moderately severe)
Intestinal/colonic: colicky (extremely severe, bad or worse than labour pains)
Biliary/pancreatic pain: constant or colicky (extremely severe)
Associated symptoms with oesophageal pain
heartburn, regurgitation, dysphagia, odynophagia
Associated symptoms with gastric pain
early satiety, post-prandial fullness, nausea
Associated symptoms with biliary pain
dark urine, pale stools, jaundice
Associated symptoms with colonic pain
diarrhoea, constipation, distension
Causes of upper abdominal pain
- gastro-oesophageal reflux
- functional dyspepsia
- gastric ulcer/duodenal ulcer
- ca stomach/oesophagus/pancreas/liver
- cholelithiasis
- acute or chronic pancreatitis
- irritable bowel
- Non-visceral pain: musculo-skeletal, neuralgic, cardiac
- More than one cause of pain
Exacerbating/aggravating factors in: Oesophagitis Gastro-oesophageal reflux Peptic ulcer IBS
- Oesophagitis – exacerbated by swallowing
- Gastro-oesophageal reflux - exacerbated by food, drink, lying down, bending over, relieved by antacids, milk, sitting up
- Peptic ulcer – nocturnal, worse on hunger, improved by food and antacids
- Irritable bowel syndrome – pain gives an urge to defaecate, relieved by defaecation, distension
Investigations for abdominal pain
• ‘Test and treat’ for Helicobacter (if no alarm
symptoms)
• Blood count, ESR, LFTs, amylase
• Plain X ray, urgent CT, if acute abdomen
suspected
• Ultrasound
• CT
• Upper endoscopy
• Colonoscopy- not normally indicated for
abdominal pain
• Lower oesophageal pH study
In primary care, dyspepsia is defined as:
- recurrent epigastric pain, heartburn or acid regurgitation, with or without bloating, nausea or vomiting
- Also… postprandial fullness, early satiation and heartburn…
- GORD and dyspepsia symptoms often overlap
- Lower quality of life than pts with DM/CHF1
Initial presentation of dyspepsia
- Differential Diagnosis – cardiac and biliary disease
- FBC
- Medication review – calcium antagonists, nitrates, theophyllines, bisphosphonates, corticosteroids and NSAID’s
- Offer H. pylori ‘test and treat’ to people with dyspepsia.
What to do if initial therapy for dyspeptic patient doesn’t work?
• H.Pylori Eradication
– 83% had Symptoms (Sx) at 12 mths
– 34% incurred further costs
• PPI Therapy (proton pump inhibitor)
– 84.5% had Sx at 12mths
– 33% incurred further costs
What are the predictors of a positive response to a 4 week trial of PPI?
• Fewer days of Sx during the 1st week of treatment • Age>40 • Symptoms > 3 mths • High Score for heartburn at baseline • Low Score for Epigastric Pain, bloating, diarrhoea at baseline • Low impairment of vitality at baseline
CASE:
• 46 year old man, 6 week history of ‘indigestion’
• FBC, LFT’s, ECG normal
• Medication review – calcium antagonists, nitrates, theophyllines, bisphosphonates, corticosteroids and NSAID’s – none taken
• H. pylori Stool Ag - negative
Persistent symptoms
• Would you send him for an OGD?
• What are the indications for a TWR OGD (2 week rule GI endoscopy)?
CT
If expect a cancer, investigation done much more rapidly eg TWR- doesn’t seem to be the case here
Patient is under 5 so not seen as urgent to do this
When would you want to perform URGENT direct access upper GI endoscopy TWR?
dysphagia
or aged 55 and over with WEIGHT LOSS and any of the following:
• upper abdominal pain
• reflux
• dyspepsia
(weight loss may be an indication of cancer- urgent)
Reflux oesophagitis grades
A - 1 or more mucosal breaks no longer than 5mm, does not extend between tops of 2 mucosal folds
B - 1 or more mucosal breaks more than 5mm long, does not extend between tops of 2 mucosal folds
C - 1 or more mucosal breaks continuous between tops of 2 or more mucosal folds, involves less than 75% of circumference
D - 1 or more mucosal break involving 75% at least of oesophageal circumference
Duration of treatment for someone with severe oesophagitis (Grade C/D)?
8-12 weeks
PPI works best over 8 week period
Healing lasts up to 12 weeks
While being taken, when are PPIs more effective?
Better acid suppression when taken BEFORE a meal
If patient is still symptomatic after PPI therapy, what is added in?
Add in PPI BID (twice daily) and H2 receptor antagonist
Improves gastric acid control and decreases nocturnal acid breakthrough (bc taken morning and night)
What do do if patient has refractory reflux symptoms?
• Step 1 check adherence
• Step 2 confirm diagnosis
– Does the patent really have GORD?
do endoscopy if necessary
What % of patients with PPI refractory
reflux symptoms (heartburn and
regurgitation) do not have GORD?
– 50%
When is surgery considered for GORD?
If PPIs not tolerated (cause diarrhoea, headaches, dizziness, tiredness) or patient has concerns about long term use of tablets
Montreal classification of GORD
Alarm symptoms in patients with dyspepsia
- Anorexia
- Weight loss
- Persistent vomiting
- Anaemia
- Haematemesis and melaena
- Abdominal mass
Treatment of GORD
• Lifestyle
– Wt loss, elevation of head of bed, smoking, meal times, (CBT, psychological therapies in dyspepsia)
• Medical
– Antacids, alginates, H2RA,PPI, prokinetics
• Surgical
– Fundoplication
• New endoscopic and surgical techniques
Management of gastro-oesophageal reflux disease (GORD)
• Lifestyle and postural measures:
- Avoid alcohol, smoking, greasy food, caffeine,
weight reduction
- Small meals, eat and drink separately
- No food or drink for 3 hours before going to bed
- Elevate the head of the bed
- Pharmacological treatment - PPI
- (Endoscopic treatment)
- Fundoplication
Grade A/B vs Grade C/D treatment
Non-erosive, Grade A and B – treat
symptomatically
Grade C and D – probably need long-
term treatment
When it does heal some patients will habe Barrett’s oesophagus- 0.5% annual risk of adenocarcinoma, endoscopy to look for dysplasia
Laproscopic nissen fundoplication
• Most common procedure • Under general anaesthetic • Upper portion of stomach is wrapped around distal oesophagus • Common side effects include: – dysphagia – belching – bloating – flatulence
Stretta procedure
Augment oesophageal sphincter and increase barrier function of lower sphincter
LINX procedure
Metallic bead wrapped around lower sphincter to augment barrier function
Peptic ulcer
- Gastric or duodenal
- Most cases due to H pylori infection or aspirin/NSAIDs
- ‘No acid, no ulcer’: reduction in gastric acid heals ulcers
- Can be uncomplicated, Bleeding or perforated
- Gastric ulcer can be malignant: need follow-up to healing, but not duodenal ulcer won’t be
Why do gastric ulcers need follow up?
They can be malignant (cancerous), unlike duodenal ulcers
Gastric vs duodenal ulcer effects on patient sleep and meals
Treatment of peptic ulcer
- Treat Underlying Cause: H pylori infection or aspirin/NSAIDs
- Acid Suppression – PPI
- Gastric ulcer to be followed up to healing, not necessary for duodenal ulcer
- Check for Helicobacter eradication if history of complications
- Bleeding ulcer – maintain haemodynamic stability, endoscopic treatment
- Perforated ulcer - surgery
What abdominal pain is H pylori infection associated with?
- H pylori infection associated with peptic ulcer which can be cured by antibiotic treatment
- Most patients with H pylori infection do not have ulcer, only gastritis. Some have dyspepsia.
- Dyspepsia cured by treatment of H pylori infection in <10% of patients with functional dyspepsia and H pylori.
Barrett’s BSG guidelines 2014
BO occurs in patients with longstanding reflux symptoms (perhaps >10 years) But screening for BO not routinely justified
Only consider if ≥3 risk factors: • Males • Obese individuals • those aged >50 • Caucasian • FH of Barrett’s or oesophageal ca, • Smoking
What in OGD would guide management of Barrett’s oesophagus?
Length of lining of oesophagus
Prague classification:
Circumference length = C number
Maximum length = M number
image: C3M5
Surveillance intervals BSG guidelines 2014 for Barrett’s oesophagus- how often to survey the patients?
Take into account two endoscopic factors:
presence/absence of Intestinal Metaplasia and length of segment:
• Without intestinal metaplasia and <3cm –
single repeat endoscopy in 3-5 years
• With intestinal metaplasia:
<3 cm - 3-5 yearly
>3 cm – every 2-3 years
• Patient co-morbidity and preference
Where are pre-ganglionic parasympathetic fibres found?
Brainstem cranial nerves
Sacral S2-S4
What are the parasympathetic pre ganglionic nerves in the brainstem?
3- oculomotor
7- facial
9- glossopharyngeal
10- vagus
Length of parasympathetic pre ganglia?
LONG
Length of parasympathetic post-ganglionic fibres?
SHORT (close to end organs)
What neurotransmitter is released at parasympathetic post ganglionic fibres (at the end organ)?
Acetylcholine at muscarinic receptors
What neurotransmitter is released at parasympathetic pre ganglionic fibres?
Acetylcholine at nicotinic receptors
In the heart, stimulation of vagus nerve releases what neurotransmitter acting at what receptor?
Acetylcholine
at M2 receptors
Where are M2 receptors found?
SA node
AV node
In the heart what happens when the vagus nerve is stimulated?
Stimulation of vagus nerve releases Ach which acts at M2 receptors
↓ Pacemaker potential frequency at SA node leading to in heart rate
↓ Electrical conduction through atria-ventricular node
to balance ↓ heart rate to contraction
Using : CO = HR x SV
Stimulation of vagus nerve (↓ HR) will DECREASE CARDIAC OUTPUT
Parasympathetic nerves in the heart do NOT…
do not innervate ventricles, most blood vessels -> do not affect contractility (SV) or TPR
What is the exception to parasympathetic not innervating blood vessels?
Exception : male genitalia, where release of NO (not Ach) causes dilatation of vessels to cause erection
How does stimulation of Mus receptors produces reduction in HR?
Pacemaker cells have hyperpolarised Na channel (If) -> hyperpolarisation, then repolarisation influx of Na depolarises membrane and strikes up another AP
Parasympathetic stimulates M2 receptors = activation of GPCRs (Gi class)
Gi causes inhibition of Adenylate cyclase → decreased conversion of ATP to cAMP → less cAMP = ↓ If current = ↓ pacemaker potentials in SA node → reduced HR
How do drugs increase heart rate?
Drugs that inhibit Mus receptors can increase HR by inhibiting parasympathetic action
Mus antagonist, e.g. Atropine used to HR following sinus bradycardia after MI
Caution
Tachycardia - potential side effect of Mus antagonists given for other reasons
Muscarinic agonists
Mus agonists, e.g. Bethanechol, used to treat urinary incontinence
may induce bradycardia
What do parasympathetic nerves regulate in the eye?
Pupil diameter
Intra-ocular pressure
Accommodation (focusing)
How do parasympathetic nerves regulate pupil diameter
Stimulation of M3 receptors lead to constriction of the circular smooth muscle of the iris (constrictor pupillae), constrict of the pupil (miosis)
How do parasympathetic nerves regulate intra-ocular pressure?
Constriction of the pupil (M3) has a secondary action on opening the canal of Schlemm at the side of the pupil
Drains aqueous humour from eye, reducing pressure within the eye
Action of muscarinic agonists vs antagonists on parasympathetic nerves in eye
Mus agonist, e.g. Pilocarpine - lowers intraocular pressure in glaucoma
Mus antagonists – dilate pupil to examine retina
Eye drops have less systemic side effects
Distance vision mechanism
Ciliary muscle relaxed
Suspensory ligaments taut - pulls lens
Long thin lens
Little refraction to focus
How do parasympathetic nerves control accommodation of the eye?
CLOSE VISION: stimulates parasympathetic nerves
Stimulation of oculomotor nerve (3) → Ach release → acts on M3 receptors → contracts smooth muscle cells →
Ciliary muscle contracted causes
Ciliary bodies moving inwards/forwards so
Suspensory ligaments relaxed
Bulged lens shape →
Increased refraction to focus
How can drugs affect accommodation of the eye?
Both Muscarinic agonists and antagonists can cause blurred vision
Bladder voiding involves interactions with…
Parasympathetic, sympathetic, motor and sensory afferent nerves
Brainstem micturition centre
Coordinates bladder reflex to cause voiding
Where are pre ganglionic sympathetic nerves found?
Lumbar region of spinal cord
SNS in bladder voiding
Pre ganglionic SNS fibres get info from micturition centre -> send info via pre and post ganglionic fibres to bladder and innervate:
- Muscle wall (detrusor muscle - smooth muscle cells)
- Internal sphincter
Release Noradrenaline to act on B2 receptors on detrusor muscle to cause relaxation, expanding bladder enabling bladder to fill more
NA also at A1 receptors at internal sphincter constricting smooth muscle to ‘close the tap’ so no leaky bladder
PNS in bladder voiding
Parasympathetic pre ganglionic fibres in Sacral region of spinal cord - receive info from micturition centre and send info via pre and post ganglionic fibres to detrusor muscle of bladder
→ Release Ach acting on M3 receptors of smooth muscle cells in bladder wall → contraction
Increases pressure and helps eject urine from bladder
Motor nerves in bladder voiding
Motor nerves travel to smooth muscle cells of external sphincter of bladder, act at nicotinic receptors to contract (hold) or relax (void)
Motor nerves travel from sacral region of spinal cord
Mechano-sensitive afferent fibres and bladder voiding
Sensory nerves (mechanoreceptors) found in wall of smooth muscle of bladder wall, sense when bladder is full
Stimulated when bladder is full → send info to micturition centre that bladder is full
Process of bladder voiding through innervation
When bladder full- SNS innervation = relaxation of wall + contraction of internal sphincter
Stimulates sensory nerves = send info to micturition centre to switch off SNS, turn on PNS → M3 receptors in bladder wall contract
So internal sphincter opens bc SNS gone and detrusor muscle wall contracts = increased pressure and tap open so able to void
Motor system allows external sphincter to relax in order to void
Muscarinic activist effect on detrusor muscle
Mus agonists, e.g. Bethanechol – urinary incontinence due to detrusor neuropathy
Helps bladder to void in cases where PNS innervation may not be able to work (incontinence bc without contraction of detrusor muscle person can’t void)
Muscarinic antagonist effect on detrusor muscle
Mus antagonists, e.g. oxybutynin – urinary incontinence due to over activity bladder
Overactive bladder, too much stimulation so bladder doesn’t fill properly and always wants to void so block M3 receptors to slow down this frequency
What PNS nerve innervates GI tract?
Vagus nerve
What receptors do parasympathetic nerves act on in the GI tract?
M3 receptors
Parasympathetic innervation of GI tract
Stimulation of vagus nerve releases Ach which acts on M3 receptors
↓
Contraction of circular and longitudinal smooth muscle in GI tract
↓
Increased motility
Vagus also contains afferent (sensory) fibres – peristaltic reflex control
GI tract secretions: Salivary gland innervation
Salivary glands- VII (facial) & IX (glossopharyngeal)
Stimulate acinar cells
↑ Amylase / mucins
GI tract secretions: Gastric glands
Gastric glands - X (vagus)
Stimulate parietal cells
↑ Gastric acid
GI tract secretions: Pancreatic glands
Pancreatic glands - X (vagus)
Stimulate acinar + islet cells
↑ Pancreatic secretions, e.g. insulin
Side effects of Muscarinic antagonists that treat GI tract
Mus antagonists, e.g. Hyoscine (Buscopan) – treat IBS-like symptoms
May cause tachycardia, blurred vision etc
Stimulation of what receptors contracts bronchi m=smooth muscle cells?
Stimulation of M3 receptors contracts bronchi smooth muscle cells causing bronchoconstriction
Parasympathetic innervation
Why are ipratropium and tiotropium used as bronchodilators?
Stimulation of M3 receptors contracts bronchi smooth muscle cells causing bronchoconstriction- need to reduce this aka reduce M3 stimulation to increase airflow
Thus,
anti-muscarinic drugs are used as bronchodilators, e.g.
Ipratropium
Tiotropium
Used in COPD (chronic obstructive pulmonary disease)
Need to increase airway flow
Problems with muscarinic antagonists in patients with bladder outflow problems?
In patients with bladder outflow problems and glaucoma
Mus antagonist will reduce urine outflow, increase intraocular pressure
Conditions also associated with elderly (as is COPD)
These are potential contraindications
How does stimulation of M3 receptors lead to contraction of smooth muscle cells?
IN SM CELL:
Ach binds to M3 M3 is GPCR → Gq pathway stimulated → activates phospholipase C = PIP2 broken down into DAG + IP3 → IP3 water soluble so moves to cytoplasm → binds to IP3R on sarcoplasmic reticulum → opens ligand gated calcium channels (IP3 MEDIATED CALCIUM RELEASE) = rise of calcium in cell
(meanwhile DAG → activates protein kinase C → acts on ion channels to increase membrane excitability = depolarisation)
Depolarisation = activation of voltage gated calcium channels → calcium enters cell
= rise in calcium in cell
So now rise in calcium → Calcium calmodulin → myosin light chain kinase → myosin light chain- phosphorylated → actin-myosin interactions = contraction
PNS innervation of male genitalia
Specialised sacral parasympathetic ‘vasodilator’ nerves
innervate erectile tissue
Stimulation of these nerves release nitric oxide (NO) NOT Ach
Remember this is an exception to the normal rule
NO is a lipophilic, membrane-permeable gas
NO causes relaxation of vascular smooth muscle cells
composing the corpus cavernosum
Corpus cavernosum dilates and fills with blood
Produces and maintains erection
Sildenafil (viagra)
Sildenafil (Viagra) - erectile-dysfunction, prevents breakdown of the actions of NO – increasing it vasodilator effects
Stimulation of parasympathetic nerves leads to a reduction in heart rate. What best describes the receptor subtype involved?
M2 receptor
A new anti-histamine drug is being designed to treat hay fever. Clinical trials indicate that the drug produces side effects of blurred vision, constipation, and tachycardia. What most likely describes the off target actions of this drug?
Muscarinic antagonist
remember M2 receptors in heart slow down HR
