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Gastrointestinal System Flashcards

1
Q

Describe the signals regulating appetite/food intake in the mouth

A

FED STATE
- Anorexigenic signals like ghrelin
- Send nerve impulses to the ventromedial nucleus in the hypothalamus
- Increase appetite

FASTED STATE
- Orexigenic signals like gastrin
- Send nerve impulses to the ventromedial nucleus in the hypothalamus
- Decrease appetite

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2
Q

Explain the importance of saliva

A
  • Lubricate food
  • Contains digestive salivary amylase
  • Dilution and buffering of digested food
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3
Q

Describe the anatomical structure of the salivary gland

A

3 types of salivary glands: parotid, sublingual, submandibular

Salivary glands consist of glandular secretory tissues (aka the parenchyma) and the supportive connective tissue (the stroma)

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4
Q

Describe the histological features of salivary glands

A
  • Parenchyma consists of acinar cells and ductal cells
  • Stroma consists of mesoepithelial cells
  • Intercalated ducts within each gland + striated ducts in parotid and submandibular glands → collecting ducts → main duct at hilum to drain secretions
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5
Q

Name the benign and malignant tumours that can be found in the salivary gland

A

BENIGN
1. Pleomorphic adenoma (50%)
2. Warthin tumour (5-10%)

MALIGNANT
1. Mucoepidemoid carcinoma (15%)
2. Adenocarcinoma (10%)
3. Adenoid cystic carcinoma (5%)
4. Acinic cell carcinoma (5%)
5. Low grade non-Hodgkin B cell lymphoma (of extranodal MALT type)

**PW MAAA

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6
Q

Which salivary gland is most affected by tumours?

A

Parotid (75%) > submandibular > sublingual

Dual gland pathology → Warthin tumour

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7
Q

What are the unique characteristics of pleomorphic carcinoma?

A
  • Average: 40 years old
  • Rarely have malignant transformation
  • Uncapsulated → prone to recurrence → avoid enucleation/surgical removal of organ
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8
Q

Describe the gross features of pleomorphic carcinoma

A
  1. Painless, slow-growing mass in front or below the ear (parotid gland)
  2. Lobulated, uncapsulated
  3. Knobbly mass with solid, firm, translucent chondroid (cartilagenous) cut surface
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9
Q

Describe the microscopic features of pleomorphic carcinoma

A
  1. Ducts, squamous metaplasia
  2. Myoepithelial components
  3. Chondromyxoid components
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10
Q

Describe the gross features of Warthin tumour

A
  1. Encapsulated, well circumscribed mass
  2. Soft, pale grey
  3. Milky secretions
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11
Q

Describe the micrological features of Warthin tumour

A
  1. Dense lymphoid stroma with germinal centres
  2. Double layer of epithelium cells
  3. Cystic changes
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12
Q

What is the rule of thumb for salivary gland neoplasms?

A

Likelihood of malignancy is inversely proportional to size of gland → parotid gland usually benign tumour, submandibular or sublingual gland usually malignant tumour

But overall it’s mostly benign for salivary gland (60%)

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13
Q

Define sialadenitis

A

Inflammation of salivary glands

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14
Q

What are the causes of sialadenitis?

A

Trauma

Infection
- Viral = mumps virus → unilateral/bilateral enlargement of salivary glands
- Bacteria = S. aureus, Viridans strep (sialadenitis secondary to sialolithiasis)

Autoimmune = SJOGREN SYNDROME
- Destruction of salivary and lacrimal glands by immune cells → difficulty swallowing → increased risk of dental caries + oral candidiasis

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15
Q

Where does sialadenitis most commonly occur?

A

Mumps-causing → parotid gland

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16
Q

Define sialolithiasis

A

Calculi/stones in the salivary duct → obstruction

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17
Q

What are the risk factors of sialolithiasis?

A

Smoking
Dehydration
Trauma
Gum disease

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18
Q

Where does sialolithiasis most commonly occur?

A

Submandibular glands

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19
Q

Explain the importance of chewing

A
  • Mixes food with saliva for lubrication
  • Decrease size of food particles mechanically
  • Mixes food with digestive amylase enzymes for increased starch digestion
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20
Q

Describe the process of mastication

A

MASTICATION = chewing reflex

  1. Mechanoreceptors detect bolus compressing mouth lining
  2. Sensory neurons relay this information to brain stem
  3. Reflex dropping of jaw (involuntary)
  4. Muscle stretch
  5. Reflex bound contractions
  6. Voluntary control can override involuntary control anytime
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21
Q

Describe the process of deglutition

A

DEGLUTITION = swallowing reflex

ORAL PHASE
1. Tongue moves upwards and backwards, forcing bolus towards pharynx
2. Somatosensory receptors detect food bolus and send involuntary reflex in medulla

PHARYNGEAL PHASE
3. Soft palate pulled upwards by levator veli palatini muscle → prevent food from entering nasopharynx
4. Epiglottis covers surface of larynx → prevent food from entering trachea
5. Upper oesophageal sphincter relaxes to allow passage of food from pharynx to oesophagus
6. Peristaltic wave is initiated in the pharynx by food intake

OESOPHAGEAL PHASE
7. Lower oesophageal sphincter contracts → prevent food reflux back into pharynx
8. Primary peristaltic wave continues and travels down oesophagus
9. if food not completely cleared, secondary peristaltic wave initiated by distention of oesophagus by local mesenteric and vagovagal reflex

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22
Q

Describe the muscles involved in deglutition

A
  1. Levator veli palatini: elevation of soft palate
  2. Tensor veli palatini: push bolus backwards towards oesophagus from pharynx
  3. Palatoglossus: push bolus backwards towards oesophagus from pharynx
  4. Palatopharyngeus: elevation of pharynx and closure of nasopharynx by soft palate
  5. Musculus uvulae: elevation of uvula in soft palate
  6. pharyngeal constrictor muscles (three paired muscles): push bolus downwards towards oesophagus after pharynx receives it
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23
Q

Describe the sensory innervation of the oral cavity

A
  1. Vagus nerve (CN10) → levator veni palatini, musculus uvulae, 3 pharyngeal constrictor muscles, palatopharyngeus, palatoglossus, laryngopharynx
  2. Medial pterygoid branch of mandibular nerve (CNV3) → tensor veni palatini
  3. Maxillary nerve (CNV2) → nasopharynx
  4. Glossopharyngeal nerve (CN9) → oropharynx
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24
Q

Name the sphincters in the oral cavity

A

Upper oesophageal sphincter and lower oesophageal sphincter

Upper oesophageal sphincter is not an anatomical sphincter but a physiological one; lower oesophageal sphincter is an anatomical sphincter

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25
Q

Describe the role of sphincters in the oral cavity with reference to pressure in the oesophagus

A

Intraoesophageal pressure = intrathoracic pressure; intrathoracic pressure < intraabdominal pressure

Upper oesophageal sphincter prevents air from entering upper oesphagus

Lower oesophageal sphincter prevents acidic gastric contents from entering lower oesophagus

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26
Q

Describe the tone of lower oesophageal sphincters

A

INCREASED TONE = INCREASED CONTRACTILITY

Transient regulators
- Gastric distention → increased tone to prevent gastric contents from reflux into oesophagus
- Belching → decreased tone to allow gastric contents to enter oesophagus

Parasympathetic regulators → increase tone
- Cholinergic agonists
- Gastrin

Sympathetic regulators → decrease tone
- Beta adrenergic agonist
- CCK
- Nicotine, coffee, tea

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27
Q

What are some pathological events that can affect the oesophagus?

A
  1. Congenital abnormalities
  2. Motor dysfunction (functional or physical obstruction)
  3. Oesophageal varices
  4. Oesophagitis
  5. Neoplasm
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28
Q

What are the congenital abnormalities associated with the oesophagus?

A
  1. Oesophageal atresia
  2. Oesophageal agenesis/absence
  3. Diaphragmatic/hiatus hernia
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29
Q

Define diaphragmatic/hiatus hernia and its complications

A

An abnormality where the diaphragm is incompletely formed → abdominal viscera (part of stomach) herniate into thoracic cavity

Most commonly on left side where heart is

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30
Q

What are the complications of diaphragmatic hernia?

A
  1. Disruption of LES → GERD, Barrett’s
  2. Symptoms of GERD → haematemesis, dysphagia, strictures etc
  3. Compression of lung → pulmonary hypoplasia
  4. Gastric dysplasia/ adenocarcinoma
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31
Q

Define oesophageal atresia

A

Absence/narrowed oesophageal lumen near the bifurcation of the trachea

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32
Q

Oesophageal atresia is usually associated with

A

Tracheoesophageal fistula = abnormal connection between trachea and oesophagus

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33
Q

What are the complications of oesophageal atresia?

A

Aspiration of fluids/food into lungs → aspiration pneumonia, suffocation, respiratory distress, difficulty feeding (regurgitation)

Requires prompt surgical repair

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34
Q

Name the common functional disorders of the oesophagus that affects its motility

A
  1. Achalasia
  2. Nutcracker oesophagus
  3. Corkscrew oesophagus/ diffuse oesophageal spasm
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35
Q

What are the common symptoms of these oesophageal motility disorders?

A
  1. Heart burn
  2. Dysphagia (swallowing difficulties)
  3. Frequent choking and coughing
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36
Q

Define achalasia

A

Aperistalsis + increased sphincter tone of lower oesophagus + incomplete lower oesophageal sphincter relaxation

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37
Q

Name the primary and secondary causes of achalasia

A

PRIMARY CAUSES
- Idiopathic
- Degenerative changes

SECONDARY CHANGES
- Chagas disease → parasitic invasion of nerve plexus of oesophagus → destruction of ganglion cells of myenteric plexus
- Diabetic autonomic neuropathy
- Polio/surgery → lesions of dorsal motor nuclei

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38
Q

How is achalasia treated?

A
  1. Myotomy → incision of muscles of the lower oesophageal sphincter to improve relaxation
  2. Pneumatic balloon dilation → stretch lower oesophageal sphincter
  3. Botox injection → paralysis of muscle fibres → decrease lower oesophageal sphincter pressure → improved oesophageal emptying
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39
Q

Name the various diseases that lead to physical oesophageal obstruction

A
  1. Oesophageal stenosis
  2. Oesophageal mucosal webs
  3. Oesophageal rings/Schatzi rings
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40
Q

Describe the pathogenesis of oesophageal stenosis

A
  1. Congenital
  2. Chronic GERD
  3. Chemical/radiation-induced oesophagitis

Fibrous thickening of submucosa

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41
Q

Describe the pathogenesis of oesophageal mucosal webs

A

Idiopathic, but associated with GERD and chronic host-vs-graft disease

Ledge-like, semi-circumferential protrusions of mucosa in the upper oesophagus

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42
Q

Describe the pathogenesis of oesophageal rings

A

Similar to mucosa webs but circumferential and thicker, including submucosa

In some cases, hypertrophic muscularis propria

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43
Q

Name the oesophageal lacerations and their pathogenesis

A
  1. Mallory-Weiss tears
    - Longitudinal, superficial tears near gastroesophageal junction → upper GI bleed → haematemesis
    - Associated with severe retching/vomiting secondary to acute alcohol intoxication
  2. Boerhaave syndrome
    - Sharp increase in intraluminal pressure → transmural tearing → distal oesophagus rupture → severe mediastinitis (severe chest pain, tachypnea, shock)
    - Requires surgery
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44
Q

Define oesophageal varices

A

Extremely dilated submucosal tortuous veins in the lower third of the oesophagus

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45
Q

Explain how oesophageal varices arise and its complications

A

Liver cirrhosis → portal hypertension → increase portal venous pressure → induce formation of collateral channels for PORTAL SYSTEMIC ANASTOMOSIS → collateral veins direct blood flow from portal vein → dilated tortuous vessels

Rupture of varices → upper GI bleeding → haematemesis + melena

High risk of mortality (15-20%)

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46
Q

Name the causes of oesophagitis and their pathogenesis

A
  1. Mucosal injury (e.g. lacerations, ulcerations)
  2. Chemical irritants (e.g. alcohol, too hot liquids) → damage mucosa
  3. Infections (e.g. HSV, CMV, candida)
  4. Iatrogenic injury (e.g. chemo/radiation, graft-vs-host disease)
  5. Eosinophilic oesophagitis
  6. GERD (most common)
  7. Drugs (tetracyclines, bisphosphonates, NSAIDs, warfarin)
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47
Q

Explain the pathogenesis of GERD

A

Gastroesophageal Reflux Disease (GERD) aka reflux oesophagitis

  1. Decreased LES tone/increased abdominal pressure/delayed gastric emptying (TRANSIENT LES RELAXATION)
  2. Reflux of acidic gastric contents into lower oesophagus
  3. Squamous epithelial cells secrete inflammatory cytokines in response to acids and bile salts (not direct damage)
  4. Inflammation
  5. Damage to mucosa
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48
Q

What are the risk factors for GERD?

A
  • Old age
  • High BMI
  • Smoking
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49
Q

What are the symptoms of GERD?

A
  • Heart burn
  • Acid regurgitation
  • Sore throat, cough
  • Dysphagia
  • Stricture
  • Peptic ulceration
  • Haematemesis
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50
Q

What are the complications of chronic GERD?

A

BARRETT’s OESOPHAGUS → distal oesophageal mucosa changes from squamous to columnar (same as intestines) → intestinal metaplasia

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51
Q

Describe the key features of Barrett’s

A
  1. Red velvety look on distal oesophagus extending upwards from gastroesophageal junction
  2. Dysplasia → adenocarcinoma (increases risk by 40x)
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52
Q

What are the criterias for diagnosis of Barrett’s?

A
  1. Endoscopy → columnar epithelium above gastroesophageal junction
  2. Histology → intestinal metaplasia (Goblet cells)
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53
Q

Describe the possible mucosal changes in the oral cavity

A

LEUKOPLAKIA = thick, white mucous plaque formation on tongue and mouth lining that CANNOT be scraped off

ERYTHROPLAKIA = thin, friable, atrophic mucosa → underlying vascular structures less hidden → red, velvety area

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54
Q

What are the causes and risk factors of leukoplakia?

A

Idiopathic
It is a clinical syndrome, not a particular disease

More common in older men
Associated with alcohol, substance abuse and chronic friction

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55
Q

Where in the oral cavity can you find leukoplakia?

A
  • Buccal mucosa (most common)
  • Floor of mouth
  • Ventral tongue
  • Palate
  • Gingiva
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56
Q

Describe the histological features of leukoplakia

A

Keratinisation
Mild/severe dysplasia depending on stage of progression

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57
Q

What are the differentials for leukoplakia?

A
  1. Candidiasis (but can be scraped off)
  2. Lichen planus = chronic recurrent rash due to inflammation of skin and mucous membranes (in immunocompromised)
  3. Irritation
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58
Q

Where in the oral cavity can you find erythroplakia?

A

Thin squamous mucosal sites: lateral-ventral tongue, floor of mouth, palatine arch etc

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59
Q

Describe the histological features of erythroplakia

A

Epithelial dysplasia > 50%
Absence of keratinisation

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60
Q

Why is knowing these mucosal changes important?

A

5-25% of ERYTHROPLAKIA are premalignant
- Higher risk of malignant transformation than leukoplakia
- Spectrum of changes ranges from hyperkeratosis to dysplasia to even carcinoma

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61
Q

What are the main types of diseases that affect the oral cavity?

A
  1. Inflammation
  2. Neoplasms
  3. Oral ulcers
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62
Q

Name the causes of mouth ulcers

A

Infection
- Oral candidiasis
- Herpes simplex virus 1/2
- HFMD

Trauma
- Ill-fitting dentures
- Lip-biting

Autoimmune
- Lichen planus
- Pemphis vulgaris = autoantibodies to dermosomal proteins
- Erythema multiforme = hypersensitivity reaction leading to “bull’s-eye spots” with blistering in the middle
- SLE = extensive vacuolation
- Inflammatory bowel disease

Iatrogenic
- Cytotoxic chemotherapy

Idiopathic aka Aphthous ulcers

Nutritional deficiency in B12 and folate

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63
Q

Explain the features of oral candidiasis

A

Candida albicans in mouth flora (30-40% of population) affects immunocompromised

Adherent, whitish, curd-like plaque that can be scraped off to reveal underlying glandular erythematous surface

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64
Q

Explain the features of Herpes Simplex Virus causing mouth ulcers

A
  • Extremely common, HSV 1>2
  • Forms cold sores/fever blisters
  • Small vesicles containing clear fluid
  • Asymptomatic → persist in dormant state in inactivated ganglia → subsequent activation due to lowered immunity
  • More severe vesicles with lymphadenopathy in immunocompromised
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65
Q

What is the key defining feature of Lichen planus?

A

Wickham’s striae: reticular, lacy web-like, white threads that are slightly raised in the inner cheeks

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66
Q

Explain the pathophysiology of Aphthous ulcers aka canker sores

A
  • Superficial erosion
  • Grey white exudate + erythematous rim
  • Resolves within 2 weeks
  • Common, usually small (<5mm)
  • Most common in first 2 decades of life
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67
Q

Describe the histological features of the oral cavity

A

Squamous epithelium-lined mucosa

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68
Q

Name the malignancies of oral cavity

A

Squamous cell carcinoma (95%)
Squamous cell papilloma (most common benign epithelial neoplasm)

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69
Q

Name some risk factors of SCC in the oral cavity

A
  • Elderly male (90% male, 50-70 years)
  • Tobacco
  • Alcohol
  • Betel nut chewing
  • Chronic irritation
  • Actinic damage (sun)
  • HPV (especially type 16)
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70
Q

Where is SCC most commonly seen?

A

Lower lips > tongue (anterior 2/3, lateral border) > floor of mouth > cheek > palate

Usually at areas with a lot of saliva and thin non-keratinised squamous epithelium

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71
Q

Describe the macroscopic and microscopic features of SCC

A

MACROSCOPIC APPEARANCE
- Masses with necrosis
- Ulcers
- Induration/thickening → suggest infiltration
- Rolled borders for skin lesions → suggest invasive growth into surrounding tissues

MICROSCOPIC APPEARANCE
- Keratinisation
- Infiltrative stromal invasion
- Nuclear atypia
- Abundant eosinophilic cytoplasm

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72
Q

What is the epidemiology of HPV-related SCC

A

Patients are younger, predominantly Caucasians and of higher SES than HPV-negative SCC

Oral sexual contact is a major risk factor but not alcohol or tobacco

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73
Q

Where is HPV-related SCC most commonly seen?

A

Oropharynx, specifically tonsils, base of tongue and adenoids
Posterior pharyngeal wall

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74
Q

Distinguish between HPV-related and classic SCC

A

Classic SCC is keratinising and mostly differentiated

HPV SCC is non/minimally keratinising

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75
Q

Where is SCC most likely to spread first?

A

Local infiltration
Metastasis to neck lymph nodes

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76
Q

What is SCC usually associated with?

A

Leukoplakia → hyperplasia → dysplasia → carcinoma in-situ → invasive carcinoma
Erythroplakia

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77
Q

Describe the macroscopic and microscopic features of squamous cell papilloma

A

MACROSCOPIC APPEARANCE
- Warty
- Cauliflower-like lesions
- Exophytic/projections from outer surface → visible, palpable mass/lump

MICROSCOPIC APPEARANCE
- Papillary projects of delicate fibrovascular cores
- Surfaced by mature squamous epithelium (unaffected)

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78
Q

How to treat squamous cell papilloma

A

Local excision

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79
Q

Describe the histological features of the oesophagus

A

Squamous epithelium-lined mucosa

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80
Q

Name the common malignancies affecting the oesophagus

A

MALIGNANT
1. Squamous cell carcinoma
2. Adenocarcinoma

BENIGN
1. Leiomyoma

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81
Q

Name some risk factors of SCC in the oesophagus

A
  • Elderly male
  • China/Africa
  • Alcohol
  • Smoking
  • Achalasia
  • Radiation (5-10 years prior)
  • Frequent consumption of hot beverages
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82
Q

Where can SCC in the oesophagus spread to?

A

Local infiltration → mediastinum

Lymph node metastasis → upper 1/3 to cervical group, middle 1/3 to mediastinal group, lower 1/3 to gastric and celiac group

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83
Q

What are the key features of adenocarcinoma in the oesophagus?

A
  • Lower 1/3 of oesophagus
  • Associated with Barrett’s
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84
Q

Name the functions of the stomach in gastric motility

A
  1. Proximal stomach relaxes/expands → reservoir to accommodate food
  2. Distal stomach contracts/churns/undergoes tituration → decrease bolus size and mix with gastric secretions
  3. Antroduodenal unit empties gastric contents → propel chyme to duodenum
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85
Q

Discuss the receptive relaxation of the stomach

A
  1. Mechanoreceptors in the proximal stomach detect distention of stomach
  2. Sensory neurons relay info to brain stem
  3. Vagus nerve via vagovagal reflex
  4. Release of vasoactive intestinal peptide (VIP)
  5. Reflex relaxation of smooth muscle wall of proximal stomach
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86
Q

What eliminates receptive relaxation?

A

VAGOTOMY

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87
Q

Describe the process of tituration/gastric churning

A
  1. Interstitial cells of Cajal produce undulating action potentials
  2. Contractions in distal/caudad stomach further break food down into smaller pieces and mix with gastric juices
  3. PROPULSIONS of bolus towards pylorus
  4. Pyloric antrum grinds and churns trapped material
  5. RETROPULSION of bolus back into stomach for further digestion
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88
Q

What are the layers of the gut wall?

A
  1. Epithelium (outermost)
  2. Lamina propria
  3. Muscularis mucosa
  4. Submucosa
  5. Muscularis propria/externa (longitudinal on outside and circular on inside)
  6. Serous/adventitia (innermost)

MUCOSA = epithelium + lamina propria + muscularis mucosa

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89
Q

In relation to the layers of the GIT, explain where the interstitial cells of Cajal are located

A

Interstitial cells of Cajal are located within the submucosa and muscularis propria layer

Submucosa layer: submucosal plexus
Muscularis propria layer: myenteric plexus (between circular and longitudinal muscles)

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90
Q

What is the basal frequency of slow waves produced by interstitial cells of Cajal at the diff organs and the significance?

A

Stomach: 3-5/minute → allows sufficient time for digestion

Duodenum: 11-12/minute, Ileum: 8-9/minute → faster transit and greater contractile activity than stomach

Colon: 3-4/minute → segmentation and mixing of colonic contents + propulsive movement for defecation

All in all, help to coordinate and regulate smooth muscle contractions in the GIT

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91
Q

Describe the regulation of gastric churning

A

PARASYMPATHETIC
- Increased gastrin/motilin secretion
- Increased frequency of action potentials and force of contraction
- Increased gastric churning

SYMPATHETIC
- Increased gastrin-inhibitory peptide (GIP) and secretin secretion
- Decreased frequency of action potentials and force of contraction
- Decreased gastric churning

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92
Q

Name the constituents of gastric secretions and the cells that secrete them

A
  1. Gastrin secreted by G cells in duodenum/antrum
  2. Gastric lipase secreted by chief/peptic cells
  3. Pepsinogen secreted by chief/peptic cells
  4. Intrinsic factor secreted by parietal cells
  5. HCl secreted by parietal cells
  6. Mucus secreted by mucous neck/goblet cells
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93
Q

Describe the stimuli and roles of gastrin

A

STIMULI
- Distention of stomach
- Vagal stimulation
- Small peptides and aa

EFFECTS (“digest full meal”)
- Stimulate H+ secretion by parietal cells
- Stimulate pepsinogen secretion by chief cells
- Increase smooth muscle contraction → increase gastric motility + gastric emptying
- Increase gastric mucosal growth
- Stimulate pancreatic secretions

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94
Q

Classify the types of glands in the stomach based on their key features

A
  1. Oxyntic/gastric/fundic glands
    - Parietal, mucous neck cells and chief cells found here
  2. Pyloric glands
    - Deeper gastric pit
    - Scattered parietal cells
    - Mucous cells and G cells found here
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95
Q

Describe the activation of pepsinogen and its role

A

Autocatalytic conversion from pepsinogen to pepsin due to acidic pH of stomach

Pepsin digests proteins into amino acids and oligopeptides (but insignificant as pancreatic and brush border enzymes alone can fully digest proteins)

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96
Q

Describe the digestion of lipids in the stomach

A
  • Bile acid not present so lipid droplets emulsified by dietary proteins
  • Lingual and gastric lipase hydrolyse ~20-30% of TG to monoacylglycerol and free FAs
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97
Q

What are the phases of gastric acid secretion

A

CEPHALIC PHASE (30%)
GASTRIC PHASE (60%)
INTESTINAL PHASE (10%)

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98
Q

Detail the mechanism by which gastric acid HCl is secreted in parietal cells

A
  1. Signals cause vesicle compartments containing H+-K+ ATPase proton pumps to insert those pumps on luminal surface of cell
  2. Carbonic anhydrase catalyses conversion of H2O and CO2 into H2CO3 which dissociates into H+ and HCO3-
  3. H+-K+ ATPase actively pumps H+ from parietal cell out into apical lumen
  4. HCO3- diffuses from gastric parietal cell into bloodstream
  5. HCO3–Cl- antiporter couples this diffusion to the transport of Cl- into parietal cell
  6. Cl- diffuses out of parietal cell into apical lumen
99
Q

Describe the phenomenon of alkaline tide

A

Post-prandial, blood in gastric veins draining the stomach will be alkaline due to diffusion of HCO3- from parietal cells into the bloodstream during gastric acid secretion

100
Q

Discuss the upregulation of gastric acid secretion at the cephalic phase

A

Stimuli: smell, taste, anticipation of food

VAGOVAGAL REFLEX
1. Acetylcholine released from vagus nerve
2. Bind directly to muscarinic receptors on parietal cells
3. Activate phospholipase C
4. Liberate IP3 and glycerol from phospholipids
5. IP3 increase intracellular Ca2+
6. Activate protein kinases
7. Stimulate H+ secretion by parietal cells

GASTRIN-RELEASING PEPTIDE (GRP) → increase gastrin secretion by G cells in antrum

ACETYLCHOLINE → increase histamine secretion by enterochromaffin-like cells

101
Q

Describe the role of acetylcholine

A

Released by cholinergic neurons of GI mucosa
1. Contracts smooth muscles in wall → increase GI motility
2. Relaxation of sphincters
3. Increase salivary/gastric/pancreatic secretions

102
Q

Describe the role of GRP

A

Neuropeptide released from enteric neurons
1. Stimulate gastrin release
2. Stimulate pancreatic secretions
3. Increase gastric motility
4. Stimulate appetite

103
Q

Discuss the upregulation of gastric acid secretion at the gastric and intestinal phases

A

Stimuli: stomach distention, small peptides and aa, vagus stimulation

HISTAMINE
1. Histamine secreted by enterochromaffin-like cells (ECL)
2. Histamine diffuse via paracrine mechanism to parietal cells
3. Bind to H2 receptors on parietal cells
4. Activate adenylyl cyclase, increasing cAMP production
5. Activate protein kinase A
6. Stimulate H+ secretion by parietal cells

GASTRIN
1. Bind to CCK-B receptors on parietal cells → stimulate H+ secretion
2. Bind to enterochromaffin-like cells (ECL) → increase histamine secretion → stimulate H+ secretion

104
Q

Discuss the downregulation of gastric acid secretion in the gastric and intestinal phases

A

SOMATOSTATIN
1. D cells detect decreased pH and secrete somatostatin
2. Somatostatin bind to ECL cells to inhibit histamine release
3. Somatostatin bind to gastrin cells to inhibit gastric release
4. Somatostatin directly bind to parietal cells and inhibit H+ secretion

PROSTAGLANDINS
1. PGE2 bind to EP receptors on parietal cells
2. Inhibit the production of cAMP
3. Inactivate protein kinase A
4. Inhibit H+ secretion by parietal cells

VASOACTIVE INTESTINAL PEPTIDE
1. Chemoreceptors detect decreased pH
2. Vasoactive intestinal peptide released by vagal nerve
3. Bind to G cells and inhibit gastrin production
4. Inhibit H+ secretion by parietal cells

105
Q

What are the characteristics of paracrines?

A
  1. Act locally
  2. Site of secretion near site of action
  3. Pass thru short distances with capillaries or through interstitium
106
Q

Describe the role of somatostatin

A

Paracrines secreted by delta (D) cells of GI mucosa + hypothalamus + beta cells of pancreas
1. Inhibit secretion of gastrointestinal hormones
2. Inhibit H+ secretion by parietal cells
3. Inhibit gastric emptying

107
Q

Describe the role of PGE2

A

GRIME

  1. Gastric epithelium defence
  2. Regulate mucous + HCO3- production
  3. Inhibit H+ secretion by parietal cells
  4. Mucosal blood flow increase
  5. Epithelial restitution
108
Q

Describe the process of gastric emptying

A
  1. Pyloric antrum undergoes peristaltic contractions → pump chyme into duodenum
  2. Pyloric sphincter remains contracted but not closed → regulate flow of chyme and size of food particles
109
Q

Discuss the upregulation of gastric emptying

A

GASTRIN
1. Distention of stomach, increased gastric volume
2. Increase gastrin secretion by G cells
3. Gastrin stimulates antral smooth muscle contraction
4. Increased gastric emptying

PARASYMPATHETIC → vagal stimulation → increase gastrin secretion by G cell

110
Q

Discuss the downregulation of gastric emptying

A
  1. CHOLECYSTOKININ (CCK)
  2. SECRETIN
  3. SOMATOSTATIN
  4. VIP
  5. GASTRIN-INHIBITORY PEPTIDE/GLUCOSE-DEPENDENT INSULINOTROPIC PEPTIDE
  6. SYMPATHETIC
111
Q

Describe the role of CCK

A

Hormone secreted by I cells in duodenum and jejunum
1. Contract sphincter of Oddi and relax gallbladder → inhibit gastric emptying and increase bile secretion into small intestine
2. Stimulate pancreatic secretions by acinar cells
3. Increase intestinal peristalsis
4. Potentiate effect of secretin (minor)

112
Q

Describe the role of GIP

A

Hormone secreted by I cells in duodenum and jejunum

STIMULI
Oral glucose, fatty acids, amino acids (only one that responds to all 3 nutrients)

EFFECTS
1. Stimulate insulin and inhibit glucagon secretion by beta cells
2. Decrease gastric motility
3. Inhibit H+ secretion by parietal cells
4. Inhibit gastric emptying

113
Q

Describe the role of VIP

A

Neuropeptide released from vagal nerves
1. Reflex relaxation of smooth muscle wall of proximal stomach
2. Stimulate H2O and electrolyte secretion → forms intestinal fluid, maintains electrolyte balance
3. Stimulate HCO3- secretion by ductal cells in pancreas
4. Inhibit gastrin production

114
Q

How long does gastric emptying take and how is this significant?

A

Gastric emptying takes 3 hours approximately → ensures adequate time for digestion by stomach + neutralisation of acidic chyme in the duodenum + absorption at small intestine

115
Q

What are the various protection mechanisms against gastric autodigestion?

A
  1. Mucous secretion: acid and pepsin-containing fluid
  2. Bicarbonate secretion: create neutralisation zone at the interface between gastric lumen and mucosal barrier
  3. Epithelial barrier with intercellular tight junctions: provide barrier to prevent back diffusion of H+ and digestive enzymes into lamina propria
  4. Mucosal blood flow: provides O2, HCO3- and nutrients to epithelial cells, remove back-diffused acid
116
Q

What is the unstirred layer?

A

Alkaline rich layer in the gastric mucosa with slow inward diffusion of H+ and slow outward diffusion of HCO3-

H+ can still diffuse to gastric lumen as it is secreted in aq form

117
Q

Describe the regulation of mucosal layer

A

Mechanical stimulation/ACh/gastrin → increase mucous secretion

Ca2+/cholinergic agonists → increase HCO3- secretion

Prostaglandins → increase mucous and HCO3- secretion

118
Q

Give examples of diseases relating to the stomach

A

CONGENITAL
1. Diaphragmatic hernia
2. Congenital pyloric stenosis

ACQUIRED
1. Gastropathy (general)
2. Peptic ulcer disease
3. Acute gastritis
4. Chronic gastritis
5. Neoplasms

119
Q

What are the diseases associated with H. pylori?

A
  1. Chronic gastritis
  2. Peptic ulcer disease
  3. Gastric carcinoma
  4. Gastric lymphoma (MALT)
120
Q

Where is H. pylori located in the stomach?

A

H. pylori is in most of our normal flora
The common site of H. pylori infection is before the pylorus → antrum (90%)

121
Q

Gastropathies vs acute gastritis?

A

Acute gastritis indicate inflammation of the gastric mucosa → neutrophils are present

Gastropathy denotes a gastric mucosal disorder with minimal to no inflammation → inflammatory cells are rare/absent

122
Q

What are the possible etiologies of gastropathies/acute gastritis?

A
  1. Reactive/chemical: alcohols, NSAIDs, cigarettes
  2. Chemotherapy/radiation
  3. Vascular: portal hypertension
  4. Localised ischaemia → stress-induced mucosal injury
  5. Uremia: inhibition of HCO3- transporter by NH4+ ions
123
Q

Define peptic ulcer disease

A

Peptic ulcer disease refers to chronic mucosal ulceration affecting duodenum/stomach

124
Q

Name the main etiologies of PUD

A
  • H.pylori
  • NSAIDs + corticosteroids
  • Smoking
  • COPD (somehow)
  • Alcoholic cirrhosis
  • Zollinger-Ellison syndrome
  • Psychological stress
125
Q

Which location is the peptic ulcer most likely to be in?

A

Proximal duodenum (75%)
Stomach (20%)

126
Q

What are the other areas that peptic ulcers could be in and the respective causes?

A
  • Lower esophagus → GERD
  • Stoma of gastroenterostomy
  • Merkel diverticulum (gastric mucosa in the diverticulum)
  • Distal duodenum/jejunum → Zollinger Elison syndrome
127
Q

Define Zollinger-Ellison syndrome

A

A rare condition in which one or more tumours aka GASTRINOMAS form in your pancreas or duodenum → secrete large amounts of the hormone gastrin → stimulate excessive H+ production by parietal cells

128
Q

Describe the pathogenesis of PUD

A

PUD in antrum/duodenum
1. Excessive acid-pepsin secretion
2. Decreased duodenal HCO3- secretion
3. Impaired mucosal defence

PUD in gastric body/fundus
1. H pylori-induced/autoimmune chronic gastritis
2. Mucosal atrophy
3. Motility defects, mucosal ischaemia, inflammation
4. Impaired mucosal defence
*acid secretion actually decreases

129
Q

Detail the mechanisms of H. pylori contributing to peptic ulceration

A

H. PYLORI SECRETIONS
- Urease to protect itself from acidic environment → urease generates free ammonia from endogenous urea →
- Protease → breaks down glycoprotein in gastric mucus
- Phospholipase → damages epithelial cells

  • Neutrophils from inflammation cause damage
  • Inflammatory cells recruited by other antigens → chronic inflammation → more susceptible to acid injury
  • Bacterial platelet activating factor → thrombotic occlusion to capillaries → decreased blood flow
  • Damaged mucosa → leakage of nutrients → sustaining the bacteria
130
Q

Describe the clinical features of PUD

A
  1. Epigastric burning/aching pain
  2. Pain tends to occur 1-3 hrs after meals during the day & worse at night (increased parasympathetic outflow)
  3. Pain relieved by alkali/food
  4. Nausea, vomiting, bloating, belching, weight loss
  5. Iron deficiency anaemia
  6. Haemorrhage, perforation
131
Q

Describe the macroscopic appearance of peptic ulcers

A
  1. Breach in mucosa → sharply punched out defect with smooth and clean base
  2. Penetrates muscularis mucosae and deeper
  3. Mucosal margin may overhang the base slightly
  4. Variable depth
  5. Scarring and puckering of wall
132
Q

Describe the microscopic appearance of peptic ulcers

A
  1. Surface zone of fibrinopurulent exudate
  2. Acidophilic layer of necrotic tissue
  3. Zone of granulation tissue
  4. Zone of dense scar tissue
  5. Interruption of muscularis propria
  6. Proximation of muscularis propria and mucosa
  7. Endarteritis obliterans = obliteration of vessel lumen
133
Q

What are the fates of peptic ulcers?

A

May perforate or heal (likely)
May be recurrent

134
Q

Define acute gastritis

A

Acute mucosal inflammation, transient in nature

135
Q

Describe the pathogenesis of acute gastritis

A

IMPAIRED PROTECTIVE MECHANISMS
1. Disruption of adherent mucus layer
2. Decreased HCO3- buffer production
3. Reduced blood flow

INCREASED INSULTS
4. Direct damage to epithelium
5. Increased acid secretion
6. Regurgitation of bile acids

136
Q

What are the symptoms and complications of acute gastritis?

A
  • Epigastric pain
  • Indigestion
  • Nausea and vomiting
  • Congestion → bleeding → petechial haemorrhages
137
Q

Define chronic gastritis

A

Chronic mucosal inflammation leading to mucosal atrophy and intestinal metaplasia

138
Q

Name the etiologies of chronic gastritis

A
  1. H. pylori infection (most common)
  2. Autoimmune gastritis (<10%)
139
Q

Describe the pathogenesis of chronic gastritis from acute gastritis

A
  1. Prolonged inflammation
  2. Mucosal atrophy
  3. Intestinal metaplasia
  4. Mucosal cells become dysplastic
  5. Development of gastric carcinoma/ lymphoma
140
Q

Describe the histological features of H. pylori associated chronic gastritis

A
  1. Active inflammation: neutrophil infiltrate, lymphocytes, plasma cells, lymphoid aggregates
  2. Regenerative changes: mitosis in epithelium, loss of mucous vacuoles
  3. Atrophy: loss in glandular structure and specialised cells
  4. Intestinal metaplasia
  5. Hyperplasia
  6. Dysplasia → carcinoma in-situ → Frank invasive carcinoma
141
Q

Define autoimmune gastritis

A

A type of chronic gastritis where there is autoimmunity against the stomach parietal cells and intrinsic factor

142
Q

Describe the key features of autoimmune gastritis

A
  1. Defective gastric acid secretion → hypochlorhydria (less Cl-)
  2. Endocrine cell hyperplasia →
  3. Disabled ileal vit B12 absorption → megaloblastic anaemia
  4. More alkaline pH → chief cell destruction → reduced serum pepsinogen
143
Q

Describe the morphological features of autoimmune gastritis

A
  • Diffuse gastritis (lymphocytes, macrophages, plasma cells) of oxyntic/parietal mucosa in the body and fundus
  • Extensive intestinal metaplasia and pseudopyloric metaplasia
  • Severe gastric body-fundal atrophy
144
Q

Which location does autoimmune gastritis usually affect?

A

Body and fundus of stomach (not antrum)

145
Q

How to diagnose autoimmune gastritis?

A
  • Antibodies to gastric parietal cells and intrinsic factors detected in serum and gastric secretions
  • Affect body and fundus of stomach
  • Usually associated with other AI conditions like Hashimoto thyroiditis, DM, Graves
146
Q

What are the sequelae of autoimmune gastritis?

A
  1. Vit B12 deficiency → pernicious anaemia
  2. Adenocarcinoma
  3. Carcinoid tumour
147
Q

Define a polyp

A

Small, painless non-cancerous growth on the epithelium

(*BUT certain benign polyps are pre-cancerous)

148
Q

Classify the 5 forms of polyps by their developmental causes

A
  1. Neoplastic
  2. Hyperplastic/inflammatory
  3. Hamartomatous/developmental
  4. Mesenchymal
  5. Miscellaneous
149
Q

Which type of polyp has a higher risk of malignancy?

A

Adenomatous carcinomas that come from NEOPLASTIC polyps

150
Q

Name the 2 forms of GIT polyps

A
  1. Pedunculated
  2. Sessile (no stalk)
151
Q

Which type of polyp has a higher risk of malignancy?

A

Sessile; it is deeper and hence more likely to have submucosal invasion

152
Q

How are each type of polyp removed surgically?

A

Pedunculated: looping a snare → cauterise the stalk of the polyp

Sessile: inject saline into submucosa → elevate polyp → assist looping of a snare → cauterise the polyp directly (no stalk)

153
Q

Define fundic gland polyps and fundic gland polyposis

A

Fundic gland polyps are common benign polyps of the fundus and body of the stomach

Fundic gland polyposis is a medical syndrome where the fundus and body of the stomach develop many polyps

154
Q

Classify the 2 types of stomach fundic gland polyps

A
  1. Sporadic: proton pump inhibitors
  2. Familial: in patients with familial adenomatous polyposis (FAP) and attenuated variants (AFAP)
155
Q

What are stomach fundic gland polyps commonly associated with?

A

Reduced acidity → stimulates gastrin release hypergastrinemia → oxyntic gland hyperplasia

156
Q

Describe the microscopic features of fundic gland polyps

A
  1. Dilated glands/microcysts lined by oxyntic epithelium
  2. Increased smooth muscle bundles in lamina propria
  3. No proliferation of foveolar epithelium
  4. Shorted foveola (the pits in the surface epithelium of the gastric mucosa)
157
Q

Name the factors that determine if an adenomatous polyp will develop into cancer

A
  1. Degree of dysplasia (grading)
  2. Size of polyp (bigger = higher risk)
  3. Type of polyp (villous = higher risk)
  4. Sessile vs pedunculated (sessile = higher risk)
158
Q

Define familial adenomatous polyposis and its mode of inheritance

A
  • An AUTOSOMAL DOMINANT disease characterised by hundreds to thousands of adenomas throughout the colorectum
  • 80-100% gene penetrance
  • Gene of concern is APC, a tumour-suppressor gene → inactivating mutations like deletions
  • > 90% develop into cancer by age 50 if untreated by total colectomy
159
Q

What are stomach hyperplastic polyps and what are they often preceded by?

A

Chronic erosive gastritis → hyperplastic polyps form as regenerative response to injury

Surface erosions may cause bleeding

Patients usually in their 50-60s

160
Q

Describe the microscopic features of stomach hyperplastic polyps

A
  1. Elongated, tortuous, dilated gastric foveolae with pyloric/fundic glands
  2. Lamina propria has inflammatory cells
  3. Scattered smooth muscle bundles
  4. Oedema
  5. Patchy necrosis
  6. Surface mucosa may show regenerative changes due to ulceration
161
Q

How might hamartomatous polyps be found?

A

Hamartomatous polyps are often found by chance, occurring in syndromes like
1. Peutz-Jegher syndrome
2. Juvenile Polyposis syndrome

Mutated genes → excessive cell growth and division

162
Q

What is the clinical presentation of hamartomatous polyps?

A

Increased pigmentation around lips, genitalia, buccal mucosa feet and hands

163
Q

What are the chances of hamartomatous polyps developing into malignancy and how is it diagnosed?

A

Very low chance of malignancy

Diagnosis of the syndrome is normally at age 9 and when there is intussusception (one segment of intestine invaginating into another segment causing blockage of lumen)

164
Q

Define gastrointestinal stromal tumours (GIST)

A

Most frequent sarcoma of gastrointestinal tract, made up of spindle cells and most commonly in the stomach or small intestine

The tumors are thought to grow from interstitial cells of Cajal (ICCs) or precursors to these cells

165
Q

What is the gene of concern in GIST?

A

KIT/ PDGFRA

166
Q

What is the main marker used for diagnosis of GIST?

A

Immunohistochemistry → CD117/ CD34/ DOG1

167
Q

Define gastric adenocarcinoma

A

Malignant neoplasm showing GI epithelial glandular differentiation

CARCINOMA = malignant + epithelial
ADENO = glandular

168
Q

Classify the subtypes of gastric adenocarcinoma and how they arise

A

LAUREN CLASSIFICATION

  1. Intestinal subtype (53%): arise from complete-type intestinal metaplasia
    - Pattern of genetic alterations resembles colonic carcinoma
  2. Diffuse (aka linitis plastica/leather bottle appearance) (33%): arise directly from gastric foveolar epithelium
  3. Unclassified (14%)
169
Q

How to test for linitis plastica?

A

Pump air into the stomach, inelastic stomachs would denote “leather bottle appearance”

170
Q

Why is gastric adenocarcinoma one of the leading causes of cancer deaths worldwide?

A
  • Tendency for late clinical presentation → asymptomatic until late stage and non-specific symptoms
  • Poor response to conventional chemotherapy
  • Average age of diagnosis is 7th decade of life
171
Q

What are the non-specific symptoms of gastric adenocarcinoma?

A
  • Weight loss
  • Abdominal pain
  • Anorexia
  • Vomiting
  • Altered bowel habits
  • Dysphagia
  • Anaemic symptoms
  • Haemorrhage
172
Q

What are the 3 types of histological growth patterns for gastric adenomas and which is the most likely to become malignant?

A
  1. Tubular (invaginations)
  2. Tubulovillous
  3. Villous (projections) → more likely to become maligant

TUBULAR ADENOMA → loss of goblet cells
VILLOUS ADENOMA → loss of tubules

173
Q

What are the risk factors for gastric adenocarcinoma?

A
  • Asians
  • 60 ish
174
Q

What are the histological features of gastric adenocarcinoma?

A

INTESTINAL SUBTYPE
1. Well-formed glands lined by cuboidal to columnar epithelial cells
2. Goblet cells
3. Well differentiated

DIFFUSE SUBTYPE
1. Individual/poorly formed nest of cells growing in infiltrative patterns
2. Signet ring cells: distended with mucin, pushing nucleus to the edge
3. Poorly differentiated

175
Q

Which subtype of gastric adenocarcinoma has better prognosis

A

Intestinal type

176
Q

Outline the adenoma-carcinoma genetic change sequence

A

Transforms benign adenomas into malignant carcinomas

  1. Loss of APC TSG
  2. DNA hypomethylation
  3. KRAS activation
  4. Loss of 18q
  5. Loss of p53
  6. PRL3 amplification
177
Q

Where is gastric carcinoma most likely to occur?

A

Pylorus and antrum > cardia (start of stomach, descended from oesophagus) > lesser curvature > greater curvature

178
Q

Explain the invasive spread of gastric carcinomas

A

Local:
- Oesophagus (proximal carcinomas)
- Duodenum (distal carcinomas)
- Omentum/peritoneum
- Colon, pancreas, spleen

Distal:
- Lung and liver
- Widespread seeding of peritoneum
- Adrenal gland, spleen, ovary

179
Q

Describe the growth patterns of gastric carcinomas

A
  1. Exophytic: protrusion of tumour mass into lumen (BULGE OUT)
  2. FLAT/depressed: no obvious tumour mass in mucosa
  3. Excavated: shallow/deeply erosive crater (BULGE IN)
180
Q

Describe the clinical manifestations of gastric carcinoma

A
  1. Metastasis to supraclavicular/Virchow’s node (lymph node in the left supraclavicular fossa that takes its supply from lymph vessels in the abdominal cavity)
  2. Troisier’s sign = hard and enlarged Virchow’s node
  3. Trousseau’s sign of malignancy = migratory thrombophlebitis
181
Q

Explain how Trousseau’s sign arises

A

Cancer cells form procoagulant factors → multiple venous thrombosis formation at different and changing sites

182
Q

Explain when the best prognostic improvement for gastric carcinoma happens

A

Surgical resection of cancer at low stage (95% survival)

Everyone >50 should get per-rectal exam + colonoscopy if possible

183
Q

How is early gastric cancer defined?

A

Invasive gastric cancer that invades no more deeply than submucosa

IRRESPECTIVE OF LYMPH NODE METASTASIS

184
Q

Hence, the most important prognostic factor is

A

DEPTH OF INVASION

185
Q

What are the differences between peptic ulcer and gastric cancer?

A

CHRONIC PEPTIC ULCER
1. Round to oval, sharply demarcated and punched out
2. Flat ulcer edge, level with remaining stomach
3. Base is smooth and clean, though haemorrhagic
4. Mucosal margin may overhang base slightly
5. Variable depth
6. Scarring and puckering of wall, but straight and vertical edges

CANCER
1. Irregular borders/demarcation
2. Not oval, can be any shape
3. Not punched out or well demarcated due to uncontrolled growth

186
Q

Describe the structure of the pancreas

A

EXOCRINE

187
Q

Name the constituents of pancreatic secretions and the cells that produce them

A

EXOCRINE PART
- Mucin secreted by goblet cells
- HCO3- rich pancreatic juice by ductal cells
- Cl- by acinar cells
- Pancreatic enzymes (pancreatic alpha-amylase, lipase, nuclease, proteases, peptidases) by acinar cells

ENDOCRINE PART
- Insulin/glucagon by beta/alpha cells of islet of Langerhans
- Somatostatin by delta (D) cells
- Pancreatic polypeptides by islet of Langerhans

188
Q

What is the role of mucin?

A

Mucin is a large molecule with carbohydrate side chains
It is resistant to digestion → protect and lubricate epithelium lining

189
Q

What is the role of the respective pancreatic enzymes?

A

Pancreatic alpha-amylase digests polysaccharides (except cellulose) into maltose/isomaltose

Pancreatic lipase digests esters to fatty acid + monoacylglycerol

Pancreatic nuclease digests nucleic acids into nucleotides

Pancreatic proteases digest proteins into polypeptides

Pancreatic peptidases activate pancreatic proteases (e.g. enterokinase)

190
Q

If the esters are water soluble, what else is required for digestion other than lipase?

A

BILE SALTS

191
Q

Describe the autoprotective mechanisms that protect the pancreas from its own secretions

A
  1. Secretion of active digestive enzymes as zymogens
  2. Secretion of pancreatic trypsin inhibitor
  3. Compartmentalisation of zymogens and protease inhibitors in vesicles
  4. Condensation of secretory proteins at low pH
192
Q

Outline the activation of zymogens in the intestine

A
  1. Enterokinase (brush border enzyme secreted by acinar cells of the pancreas) convert trypsinogen to trypsin
  2. Trypsin converts chymotrypsinogen to chymotrypsin
  3. Trypsin converts proelastase to elastase
  4. Trypsin converts procarboxypeptidase to carboxypeptidase
193
Q

Detail the mechanism of pancreatic juice secretion in ductal cells

A
  1. Rough endoplasmic reticulum of acinar cells synthesises pancreatic enzymes
  2. Sent to Golgi complex to be packaged
  3. Secreted as condensing vacuoles concentrated in zymogen granules
  4. Zymogen granules store enzymes until stimulus triggers their secretion
  5. Ductal cells produce HCO3- isotonic secretion
  6. Carbonic anhydrase converts CO2 and H2O to H2CO3, which dissociates into H+ and HCO3-
  7. Cl-/HCO3- antiporter on apical surface secretes HCO3- into intestinal lumen
194
Q

Name the phases of pancreatic juice secretion

A

CEPHALIC PHASE (25%)
GASTRIC PHASE (10-20%)
INTESTINAL PHASE (50-80%)

195
Q

Describe the regulation of pancreatic secretions in the cephalic and gastric phase

A

ACETYLCHOLINE
1. Acetylcholine released from vagus nerve
2. Bind directly to muscarinic receptors on ductal cells
3. Activate phospholipase C
4. Liberate IP3 and glycerol from phospholipids
5. IP3 increase intracellular Ca2+
6. Activate protein kinases
7. Stimulate HCO3- secretion by ductal cells

196
Q

Describe the regulation of pancreatic secretions in the intestinal phase

A

SECRETIN
1. Acidic pH detected by S cells in duodenum and upper jejunum which secrete more secretin
2. Secretin binds to secretin receptors on ductal cells of the pancreas
3. Activate adenylyl cyclase, increasing cAMP production
4. Activate protein kinase A
5. Stimulate HCO3- secretion by ductal cells

VASOACTIVE INTESTINAL PEPTIDE
1. VIP released from vagus nerve
2. VIP binds to VIP receptor type 1 and type 2 on ductal cells of the pancreas
3. Activate adenylyl cyclase, increasing cAMP production
4. Activate protein kinase A
5. Stimulate HCO3- secretion by ductal cells

197
Q

Describe the role of secretin

A

Hormone produced by S cells of duodenum

STIMULI: acidic pH of chyme, fatty acids

EFFECTS:
- Stimulate HCO3- secretion by ductal cells
- Inhibit gastrin
- Inhibit H+ secretion by parietal cells
- Decrease intestinal peristalsis
- Inhibit gastric emptying

198
Q

What are the general abnormalities that can happen to the pancreas?

A
  1. Congenital
  2. Pancreatitis (acute and chronic)
  3. Neoplasms
199
Q

Describe the embryological development of pancreas, including notable structures

A
  1. Fusion of dorsal and ventral outpouchings (primordia) of the foregut
  2. Dorsal primordium: body, tail, superior/anterior aspects of head, accessory duct of Santorini
  3. Ventral primordium: posterior/inferior aspects of head, drains through main pancreatic duct (of Wirsung) into papilla of Vater
  4. Main pancreatic duct (of Wirsung) joins the common bile duct just proximal to the papilla of Vater
  5. Accessory pancreatic duct (of Santorini) drains into duodenum through separate minor papilla
200
Q

Name the congenital abnormalities of the pancreas and how they arise

A
  1. Pancreatic division (most common) → dorsal and ventral pancreatic primordia does not fuse → common bile duct and main pancreatic duct enter separately
  2. Annular pancreas → band-like ring encircling duodenum
  3. Ectopic pancreas (pancreatic tissue located outside its usual anatomical location) → stomach, duodenum, jejunum, Merkel’s diverticulum, ileum
  4. Agenesis → homozygous germline mutation involving PDX1 gene
201
Q

What are pancreatic pseudocysts and how do they arise?

A

Fluid-filled sacs surrounded by fibrous/granulation tissue that develop in or around the pancreas

Acute or chronic pancreatitis → damage to pancreatic ductal/acinar cells → leakage of inflammatory fluid, tissue debris and pancreatic enzymes into surrounding tissues

202
Q

Define acute pancreatitis

A

Reversible pancreatic parenchymal injury associated with inflammation

203
Q

What are the main causes of acute pancreatitis?

A

Biliary tract disease & long term alcohol abuse (80% of AP in western countries)

204
Q

Classify the types of acute pancreatitis according to severity

A
  1. Acute interstitial pancreatitis (least severe)
  2. Acute necrotising pancreatitis
  3. Acute haemorrhagic pancreatitis (most severe)
  4. Full-blown acute pancreatitis (MEDICAL EMERGENCY!)
205
Q

Outline the pathogenesis and initiating events of acute pancreatitis

A

Basically has to do with abnormal autoprotective functions of the pancreas

  1. Inappropriate release and activation of pancreatic enzymes → destroy pancreatic tissue + elicit acute inflammatory reaction
  2. Duct obstruction → raises intrapancreatic ductal pressure → accumulates enzyme rich fluid in the pancreatic secretions
    - Alcohol can also make the secretions thicker
  3. Acinar cell injury → release of intracellular proenzymes and lysosomal hydrolases
  4. Defective intracellular transport → proenzymes delivered to lysosome
206
Q

What is the link between alcohol consumption and acute pancreatitis?

A
  1. Transient increase in contraction of Sphincter of Oddi
  2. Chronic alcohol ingestion → secretion of protein-rich pancreatic fluid → deposition of inspissated protein plugs + obstruction of small pancreatic ducts
  3. Direct toxic effects on acinar cells → oxidative stress
207
Q

What are the clinical features of acute pancreatitis?

A
  1. Constant, intense abdominal pain
  2. May be referred to the upper back/left shoulder
  3. Nausea, vomiting, loss of appetite
208
Q

What are the histological features of acute pancreatitis?

A
  1. Microvascular leak and oedema
  2. Fat necrosis with saponification
  3. Acute inflammation
  4. Destruction of ALL pancreatic parenchyma
  5. Destruction of blood vessels
  6. Interstitial haemorrhage
209
Q

What are the complications of acute pancreatitis?

A

Release of toxic enzymes, cytokines and mediators into circulation → explosive activation of systemic inflammatory response (SIRS)

  1. Endothelial injury + increased vascular permeability → shock, Acute Respiratory Distress Syndrome (ARDS)
  2. Hypotension and hypovolemia → systemic organ failure (e.g. acute renal failure)
  3. Activation of coagulation cascade → DIC
  4. Sterile pancreatic “abscess” (can become infected 40-60% of the time)
  5. Pancreatic pseudocysts
210
Q

What gives the definite diagnosis for acute pancreatitis?

A
  1. Increased serum amylase (1st 24hrs) and lipase (72-96hrs)
  2. Precipitation of calcium soaps in necrotic fat → hypocalcaemia
  3. Leukocytosis, DIC
  4. GLYCOSURIA (10%)
  5. Jaundice (if gallstones present)
211
Q

Which is the worst prognostic feature of acute haemorrhagic pancreatitis?

A

Hypocalcaemia

212
Q

How is acute pancreatitis managed?

A

Supportive, monitoring for complications

213
Q

Define chronic pancreatitis

A

Prolonged inflammation of the pancreas associated with irreversible destruction of exocrine parenchyma and fibrosis

In the late stages there is destruction of the endocrine parenchyma

214
Q

What are the main causes of chronic gastritis?

A
  1. Long term alcohol abuse (middle-aged men)
  2. Long standing pancreatic duct obstruction (calculi, inflammation, neoplasm)
  3. Autoimmune
  4. Hereditary pancreatitis (up to 25%)
215
Q

Describe the pathogenesis of chronic gastritis from acute pancreatitis

A
  1. Repeated episodes of acute pancreatitis
  2. Fibrogenic factors predominate
  3. TGF-beta and PDGF induce activation and proliferation of PERIACINAR MYOFIBROBLASTS/ PANCREATIC STELLATE cells
  4. Collagen deposition and fibroblasts
216
Q

What are the clinical features of chronic pancreatitis?

A
  1. Abdominal pain (recurrent/persistent)
    - Can be precipitated by alcohol abuse, overeating, use of opiates or drugs that close sphincter of Oddi
  2. Asymptomatic until pancreatic insufficiency
  3. Exocrine insufficiency → chronic malabsorption → VIT ADEK deficiency
  4. Endocrine insufficiency → diabetes mellitus type 1 develops
  5. Pancreatic pseudocysts
217
Q

What are the characteristics of autoimmune pancreatitis?

A
  • Distinct form associated with IgG4+ plasma cells
  • Mimics pancreatic carcinoma
  • Responds to steroid therapy
218
Q

What are the histological features of chronic pancreatitis?

A
  1. Variable dilation of pancreatic ducts with protein plugs/calcified concretions (especially with alcohol)
  2. FIBROSIS
  3. ATROPHY and dropout of acini, relative SPARING OF ISLETS (exocrine > endocrine)
  4. Ductocentric inflammation (especially if autoimmune)
  5. Pseudocysts
219
Q

What gives the definite diagnosis for chronic pancreatitis?

A

Pancreatic calcifications on CT

220
Q

Explain how these pancreatic calcifications arise

A

SAPONIFICATION = fatty acids combine with Ca2+ ions to form insoluble complexes

  1. Severe inflammation or injury
  2. Extensive necrosis of pancreatic tissue
  3. Enzymes released, causing damage to adipose tissues within and around pancreas
  4. Release of free fatty acids from TG stored in adipocytes
  5. Fatty acids combine with Ca2+ in bloodstream
221
Q

Classify the benign pancreatic masses into 2 general types

A
  1. Cystic (congenital, pseudocysts) → can be benign, pre-malignant or malignant
  2. Solid (autoimmune pancreatitis, ductal adenocarcinoma, pancreatic neuroendocrine tumours) → usually malignant
222
Q

Distinguish between congenital and pseudocysts

A

PSEUDOCYSTS (75%)
- Localised (usually solitary) collection of haemorrhagic material rich in pancreatic enzymes without epithelial lining
- Follows acute pancreatitis (esp if superimposed on chronic pancreatitis/trauma)
- Resolves spontaneously
- Secondary infection/compression → perforation into adj structures

CONGENITAL
- Unilocular, thin-walled, contain serous fluid
- Follows anomalous development of pancreatic ducts
- Thin fibrous wall lined by single layer of variably attenuated uniform cuboidal epithelium (can be flattened)
- Sporadic/inherited (ADPKD, VHL etc)

223
Q

Are cystic neoplasms common in the pancreas?

A

No, only 5% of total

224
Q

Describe the diagnosis of pancreatic masses

A

Solid pancreatic lesions → EUS-FNA CYTOLOGY (ENDOSCOPIC US GUIDED FINE NEEDLE ASPIRATION)

Cystic pancreatic lesions → cyst fluid analysis (incl biochemical and molecular components like amylase, CEA, KRAS mutation)

225
Q

What are the most common pancreatic solid neoplasms?

A
  1. Invasive ductal adenocarcinoma
  2. Pancreatic neuroendocrine tumour
226
Q

What are the characteristics and risk factors of ductal adenocarcinoma?

A
  • Very aggressive → high mortality rate
  • Susceptible age group: 60-80

RISK FACTORS
- Smoking
- High fat content
- Chronic pancreatitis
- Diabetes mellitus
- Genetic dispositions (BRCA2, CDKN2A)

227
Q

What are the precursors of ductal adenocarcinoma?

A
  1. Premalignant neoplasms (cystic neoplasms)
  2. Non-invasive small duct lesions → pancreatic intraepithelial neoplasia (PanIN)
228
Q

Describe the genetic basis of ductal adenocarcinoma

A

Multiple genes somatically mutated/ epigenetically silenced

While there is a general temporal seq, more mutations > specific order of mutations

Most frequently mutated are
- KRAS (oncogene)
- CDKN2A, TP53 and SMAD4 (TSG)

229
Q

What are the clinical features of ductal adenocarcinoma?

A
  • Asymptomatic
  • Pain
  • Large bile duct obstruction (very common) → obstructive jaundice (HOP disease)
  • Systemic symptoms (advanced disease - LOW, LOA, lethargy)
  • Migratory thrombophlebitis/Trousseau’s sign (10%)
230
Q

Describe the gross appearance of ductal adenocarcinoma

A
  1. Large pale firm mass with infiltrative border
  2. Adenocarcinoma with desmoplasia
  3. Perineural (loves nerves) and lymphatic involvement (PNI and LPI are important in all hepatic/ pancreatic neoplasms)
231
Q

Describe the histological appearance of ductal adenocarcinoma

A
  1. Clusters
  2. Nuclear polymorphism
232
Q

Where is ductal adenocarcinoma most likely located?

A

Head (60%)
Body (15%)
Tail (5%)
Entire gland (20%)

233
Q

How is ductal adenocarcinoma diagnosed?

A
  • Markers: Serum CEA (carcinoembryonic antigen), CA19-9 will increase (though not sensitive/specific)
  • Non-invasive: imaging
  • Invasive: EUS-FNAC/core biopsy
234
Q

What are the key characteristics of pancreatic neuroendocrine tumours (PanNET)?

A
  • Uncommon compared to pancreatic exocrine tumours (ductal adenocarcinoma)
  • Either functional (clinical syndrome) or non-functional
  • Can be single or multiple
235
Q

What are the genetic alterations associated with PanNET?

A

SPORADIC (>90%
Recurrent somatic alterations in 3 major genes/ pathways:
1. MEN1
2. Loss of function in TSG
3. Inactivation of ATRX and DAXX genes

SYNDROMIC/FAMILIAL (<10%)
1. Multiple endocrine neoplasia type 1 (MEN1)
2. Von Hippel-Lindau disease (VHL)
3. Neurofibromatosis type 1 (NF1)
4. Tuberous sclerosis (TSC1 or TSC2)

236
Q

How do we predict the biological behaviour of PanNET?

A
  • Difficult to predict based on light microscopy
  • Depends on tumour size and grade
  • All have malignant potential even if low-grade
237
Q

Describe the histological features of PanNET

A
  1. Solid pale masses +/- cystic change
  2. Nests, islands and trabeculae of small round cells with “SALT AND PEPPER” CHROMATIN
  3. Highly vascular
  4. Immunohistological stain for neuroendocrine and secretory products
  5. US image of neurosecretory granules in cytoplasm
238
Q

Name the Islet of Langerhans neoplasms and their associated symptoms
(i) Insulinoma
(ii) Glucagonoma
(iii) Somatostatinoma
(iv) PP-secreting endocrine tumour
(v) VIPoma
(vi) Carcinoid tumour
(vii) Gastrinoma

A

(i) INSULINOMA (beta cell tumour, most common)
- WHIPPLE’s TRIAD = hypoglycemia episodes + CNS manifestations relating to fasting (confusion etc) + symptom relief with glucose administration

(ii) GLUCAGONOMA (alpha cell tumour)
- Mild diabetes mellitus
- Necrolytic migratory skin erythema
- Anaemia

(iii) SOMATOSTATINOMA (delta cell tumour)
- Inhibit gallbladder contraction and secretion
- Diabetes mellitus
- Cholelithiasis
- Steatorrhoea
- Hypochlorhydria

(iv) PP-SECRETING ENDOCRINE TUMOUR
- Asymptomatic

(v) VIPOMA (D1 cell tumour)
- WDHA syndrome = watery diarrhoea + hypokalaemia + achlorhydria

(vi) CARCINOID TUMOUR (ECL tumour)
- Carcinoid syndrome

(vii) GASTRINOMA (G cell tumour)
- Zollinger-Ellison syndrome

239
Q

Define carcinoid tumours

A

Slow growing neuroendocrine tumours (NET) that originate from the cells of the neuroendocrine system

240
Q

How do we predict the behaviour of carcinoid tumours?

A
  • They resemble ow grade cancers but might infrequently spread to other parts of the body
  • Clinical course is variable
  • No reliable pathological marker to predict tumour behaviour
241
Q

Describe the pathogenesis of carcinoid syndrome

A

Over-production of many substances/ amines (e.g. serotonin) → released into the systemic circulation (bypass inactivated by the liver for primary GIT carcinoids)

Only 10% of carcinoid patients will reach carcinoid syndrome

242
Q

Name the symptoms of carcinoid syndrome

A
  • Flushing
  • Diarrhoea/increased bowel movements
  • Bronchoconstriction
  • Right sided cardiac valve disease
  • Abdominal cramping
  • Peripheral oedema
243
Q
A

Y1 (14 decks)

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