GIL - Phase 1

Question 1

Phases of secretion in the GIT

Answer 1

1. Cephalic – thinking/seeing/smelling food (20%, ↑histamine, ↑gastrin)
2. Gastric – presence of nutrients + distension (70%, via ACh, histamine and gastrin)
3. Intestinal – presence of nutrients + distension (10%, secretin, CCK, GIP, motilin)

Question 2

Pathophysiology of GORD and treatment (pharmacological and non-pharmacological)

Answer 2

regurgitation of gastric contents due to incompetence of the LOS:

• physical cause: ↑ abdominal pressure, pregnancy, hiatus hernia
• transient relaxation: neuromuscular disease, alcohol, coffee, irritation from reflux

non-pharmacological: avoiding acidic/spicy foods, large meals and lying down after eating

pharmacological: proton pump inhibitors, antacids/alginates

Question 3

Pathophysiology of peptic ulcer disease and treatment

Answer 3

Caused by an imbalance between acid secretion and mucosal protective mechanisms leading to breach of the mucosal lining

• H. pylori infection, colonises mucosa and secretes NH3 and degradative enzymes
• Chronic use of NSAIDs, inhibit COX ↓ prostaglandin synthesis ↓ mucus secretion
• Zollinger-Ellison syndrome, gastrin secreting tumour ↑ HCl synthesis

Question 4

Gross anatomy of stomach including blood supply

Answer 4

Gross anatomy:

four parts: cardia, fundus, body, antrum

two curvatures: lesser, greater

two surfaces: anterior/posterior

Arterial supply:

lesser curvature – left gastric (coeliac), right gastric (common hepatic)

greater curvature – left gastro-omental (splenic), right gastro-omental (gastroduodenal)

fundus – short gastric arteries (splenic)

pylorus – gastroduodenal (common hepatic)

Venous drainage:

gastric arteries → portal vein

left gastro-omental → splenic → portal vein

right gastro-omental → superior mesenteric → portal vein

Question 5

Layers of the gastrointestinal tract

Answer 5

1. Mucosa – epithelium, lamina propria, muscularis mucosa
2. Submucosa – contains the submucosal nerve plexus
3. Muscularis propria – inner circular, outer longitudinal with myenteric nerve plexus between
4. Serosa – layer of visceral peritoneum or adventitial fat

Question 6

Overview of neuronal control of GIT function

Answer 6

Extrinsic control

SNS: ganglia in sympathetic chain via splanchnic nerves

PNS: ganglia in myenteric and submucosal plexes

Intrinsic control

enteric nervous system, organised into myenteric and submucosal plexes, controls gastrointestinal function by integrating local reflexes with extrinsic nerve signals

Question 7

Major 10 GIT hormones

• Hormone
• Source
• Location
• Stimulus
• Function

Answer 7

Question 8

Examples of GIT reflexes

Answer 8

Gastrocolic – stretch in the stomach promotes an increase in small + large intestine motility

Enterogastric – presence of acid in the duodenum inhibits gastric motility and secretion

Gastroileal – opening of the ileocaecal valve stimulates urge to defecate

Question 9

Phases of vomiting

Answer 9

1. Pre-ejection – movement of stomach contents into the oesophagus
   * retroperistalsis coordinated by PNS

2. Retching – rhythmic action of ICs, diaphragm and abdominal muscles against closed glottis

• motor neurons coordinate muscle contraction

3. Ejection – intense abdominal contraction and relaxation of UOS

• motor neurons coordinate muscle contraction
• SNS response also involved in causing associated tachycardia and diaphoresis*

Question 10

Sequelae of vomiting

Answer 10

Clinical consequences of persistent vomiting include:

• dehydration
• metabolic alkalosis from acid loss
• electrolyte imbalances such as hypochloraemia and compensatory hypokalaemia
• cachexia

Question 11

Overview of vomiting reflex including receptors involved

Answer 11

The vomiting reflex is coordinated in the emetic centre in the medulla which receives inputs from several different pathways:

• higher brain centres – special sensory input, memory, fear, dread, anticipation
• inner ear → vestibulocochlear nerve → cerebellum
• other triggers are detected by the chemoreceptor trigger zone and NTS via sympathetic, vagal and cranial nerve afferents including:
  
  • blood borne irritants/emetics
  • irritation/infection/drugs within the GIT
  • gag reflex from pharyngeal stimulation

Question 12

Overview of GIT embryology

Answer 12

The GIT develops from the mesoderm and endoderm through lateral and craniocaudal folding

development happens within six major regions:

1. Stomodeum – primitive oral cavity formed by head curling over thorax
2. Pharyngeal gut – forms five arches containing arteries, nerves and cartilage which develop into the major structures of the lower head and neck (mandible, hyoid, larynx)
3. Foregut – develops a number of key structures

• oesophagus: respiratory bud forms lungs + trachea
• stomach: dilation/rotation arranges duodenum and jejunum into final position
• liver: grows between layers of ventral mesentery
• pancreas: develops from dorsal bud and a ventral bud which migrates with the biliary ducts to form a single structure

4. Midgut – contains vitelline duct (yolk sac), herniates through abdominal wall and grows/rotates in the amniotic cavity before birth
5. Hindgut – expansion to form a cloaca which divides into a rectum and a urinary tract
6. Proctodeum – forms lower third of anus, invagination of ectoderm

Question 13

Pharyngeal arches and their corresponding structures

Answer 13

each contains a cranial nerve, artery, vein and cartilage which can remain as cartilage or become a bony structure, they are labelled 1, 2, 3, 4 and 6 (the 5^th does not develop)

1. (trigeminal) mandible, muscles of mastication and incus/malleus of middle ear
2. (facial) stapes of middle ear, styloid process, small part of hyoid bone
3. (glossopharyngeal) rest of hyoid bone
4. (vagus) thyroid and epiglottic cartilages
5. (vagus) all other laryngeal cartilages

Question 14

Stimuli and process of gastric acid secretion

Answer 14

1. CA produces combines waste CO2 and water to form H2CO3 which dissociates
2. H+ is pumped into lumen via H+/K+ ATPase
3. HCO3- is exchanged into blood for Cl- which flows down gradient into lumen to form HCl

Major stimuli for gastric acid secretion:

• ACh from vagus → M3 receptors (Gαq)
• gastrin from G cells → gastrin receptor (Gαq)
• histamine from ECL cells (↑ by gastrin) → H2 receptors (Gαs)

Negative regulation from somatostatin and prostaglandins via Gαi

Question 15

Outline of NSAID toxicity

Answer 15

NSAIDs – inhibitors of COX, cause damage to stomach lining due to inhibition of prostaglandin synthesis which has a key role in mucus secretion

Question 16

Description of H. pylori infection and how it is diagnosed

Answer 16

H. pylori is able to survive within the stomach due to presence of the enzyme urease which converts urea to CO2 and NH3 → generates alkaline cloud that protects from acidity

• ammonia and various bacterial enzymes cause damage to mucosal lining
• colonisation leads to an inflammatory response which can exacerbate damage

Urease breath test – involves taking a pill containing C13-labeled urea, if H. pylori are present the urea will be converted and C13-labeled CO2 can be detected in the breath

Question 17

Causes of haematemesis

Answer 17

DDx of haematemesis include:

• peptic ulcer disease
• gastric varices
• Mallory-Weiss tears
• recent epistaxis
• stomach or oesophagus malignancies
• gastroenteritis

Question 18

Phases of swallowing

Answer 18

1. Buccal/oral – processing of food in oral cavity, closed soft palate allows air passage
2. Pharyngeal – soft palate blocks nasal cavity, epiglottis blocks laryngeal inlet
3. Oesophageal – relaxation of UOS and LOS, peristaltic motion down tube

Question 19

Cells of the stomach mucosa and types of stomach mucosa

Answer 19

Major cell types found within the gastric glands include:

• columnar epithelial cells (enterocytes)
• goblet cells: mucus secreting
• parietal cells: secrete HCl and IF
• chief cells: secrete pepsinogen
• enteroendocrine cells including G and ECL cells

There are two types of stomach mucosa with varying distribution of these cells:

Oxyntic – in the fundus and body, primarily parietal and chief cells

Antral – in antrum and pylorus, goblet and endocrine cells

Question 20

Australian dietary guidelines

Answer 20

1. Achieve + maintain a healthy weight
2. Eat from a range of food groups including grains, vegetables, fruits, proteins
3. Avoid added salt, alcohol, saturated fats, added sugar
4. Encourage breastfeeding of infants
5. Ensure that appropriate food hygiene is maintained

Question 21

Central control of appetite including role of leptin

Answer 21

Central appetite control occurs within the arcuate nucleus of the hypothalamus which contains groups of orexigenic (hunger) and anorexigenic (satiety) neurons which can be upregulated or downregulated with projections to feeding centres, hormonal axes etc.

• Negative energy balance: ↑ ghrelin
• Positive energy balance: ↑ leptin, insulin, CCK, GLP-1

Question 22

Types of GI motility and use throughout the GIT

Answer 22

Peristalsis = wave of contraction and relaxation to propel along a tube (O, S, SI)

Segmentation = discrete rings of contraction to separate and mix food/enzymes (S, SI, LI)

Migrating motor complexes = intense, prolonged peristaltic wave to clear contents (LI)

Question 23

Types of mucosa present throughout GIT

Answer 23

Question 24

Structural GIT pathologies

Answer 24

Question 25

Types of lactose intolerance

Answer 25

Primary – due to low lactase activity, normal decline occurs with age

Secondary – due to underlying disease such as GE, IBD

Congenital – genetic deficiency in lactase

Question 26

Pathophysiology of coeliac disease

Answer 26

Coeliac disease is an autoimmune reaction to the peptide antigens found in gluten which are highly resistant to protease digestion and persist in the intestinal lumen

1. Gluten peptides enter the lamina propria by unknown mechanism, suggested mechanisms include transcytosis, tight junction dysfunction and dendritic cell sampling
2. Tissue transglutaminase (tTG) deaminates gluten proteins
3. Deaminated gluten/gliadin more readily activates an immune response via HLA molecules on dendritic cells (commonly haplotypes DQ2 and DQ8)
4. Immune activation and inflammatory response lead to

• TH1 response – immune infiltrate, villous atrophy, crypt hyperplasia
• TH2 response – B cell activation and Ab generation against tTG/gliadin/endomysium

Results in malabsorption and various clinical manifestations including failure to thrive, anaemia, bloating, diarrhoea, steatorrhea

Question 27

Causes of malabsorption

Answer 27

• Coeliac disease
• Intestinal resection → short gut syndrome
• Gastroenteritis
• Cystic fibrosis/pancreatic insufficiency
• Biliary atresia

Question 28

Four causes of failure to thrive and some examples

Answer 28

Inadequate intake – access to food, feeding/swallowing problems, social issues

Increased expenditure – chronic infection or chronic illness

Inefficient use of calories – malabsorption disorders (e.g. coeliac), metabolic diseases

Excessive loss of nutrients – severe vomiting and diarrhoea

Question 29

Clinical syndromes of gastroenteritis

Answer 29

1. Vomiting – upper GIT localisation
2. Watery diarrhoea – large volume, moderate frequency, no blood
3. Inflammatory diarrhoea – small volume, high frequency, blood present, systemic symptoms

• enterocolitis: small + large, Campylobacter, Salmonella
• colitis: large only, Shigella, E. coli

Question 30

Major bacterial, viral and protozoan causes of gastroenteritis

Answer 30

Bacteria: Campylobacter jejuni, Salmonella enterica, Shigella, Clostridium difficile, Vibrio cholera, Escherichia coli (ETEC, EHEC, EPEC, EIEC)

Viruses: rotavirus, norovirus

Protozoans: Giardia spp., Cryptosporidium spp., Entamoeba histolytica

Question 31

Four types of diarrhoea

Answer 31

Osmotic – substances in the lumen induce fluid secretion to maintain osmolality

Secretory – substances that physiologically induce fluid/electrolyte secretion e.g. toxins, drugs, hormones from endocrine tumours

Inflammatory – mucosal injury due to inflammation e.g. coeliac disease, IBD

Dysmotility – bowel hypermotility or rapid gastric emptying

Question 32

Types of lipoproteins

• Density
• Protein %
• Lipid %
• Apoproteins
• Lipids

Answer 32

Question 33

Overview of lipoprotein transport and examples of inherited disorders

Answer 33

Normal lipoprotein transport

1. Lipids absorbed in the GIT are packaged into chylomicrons and release into lymphatic lacteals from which they enter systemic circulation
2. TAGS are absorbed into tissues from chylomicrons via the luminal membrane bound enzyme lipoprotein lipase
3. Remaining chylomicron remnants are endocytosed in the liver via remnant receptors which recognise ApoE
4. The liver synthesises and releases VLDLs these contain TAGs and cholesterol which are absorbed into tissue again by LPL, eventually forming IDLs
5. IDLs can be endocytosed into the liver via LDL-R or further absorption of TAGs can be carried out by hepatic lipase to create circulating LDLs which are taken up by LDL-R expressing tissues

Reverse cholesterol transport:

1. Nascent HDLs are released from the liver and absorb excess cholesterol from the periphery via ABC A1 receptor, this cholesterol is converted to cholesterol esters by LCAT
2. The enzyme CETP mediates an interaction between HDLs and IDLs in which HDL CEs are exchanged for IDL TAGs which regulates the overall proportion of each in circulation
3. HDLs are endocytosed via scavenger receptors in the liver and steroidogenic organs

Examples of genetic dyslipidaemia diseases associated with mutations in the proteins involved in this process include:

• Familial combined hyperlipidaemia,
• Familial hypercholesterolaemia, and
• Familial hypertriglyceridaemia

with some of these associated with increased CVD risk

Question 34

Process of insulin secretion

Answer 34

1. Glucose enters pancreatic B cells via GLUT2 transporters and is trapped as G6P by the enzyme glucokinase
2. Metabolism of glucose → production of ATP
3. High ATP levels inhibit K+ channels leading to depolarisation of the cell
4. Ca2+ influx during depolarisation induces exocytosis of secretory vessels containing insulin and C-peptide

Question 35

Hormones and cells of the endocrine pancreas

Answer 35

Question 36

Metabolic effects of insulin and glucagon (including time sequence of insulin)

Answer 36

Insulin

Acts via the insulin receptor, a membrane bound tyrosine kinase which activates PI3K and MAPK signalling pathways to promote anabolic metabolism

• early effects – skeletal muscle, upregulates GLUT4 expression to take up glucose
• intermediate effects – modulation of enzyme activity via PI3K ↑ glycogenesis, glycolysis
• late effects – trophic effects, promotes tissue growth via MAPK

Glucagon

Primarily targets the liver as well as adipose tissue where it promotes catabolism by influencing enzyme activity

• liver – ↑ gluconeogenesis, glycogenolysis
• adipose – ↑ lipolysis

Question 37

Major types of GLUT transporters

Answer 37

GLUT 1: foetal tissues, RBCs, blood brain barrier

GLUT 2: bidirectional transporter in kidneys, liver, pancreatic B cells and basement membrane of small intestine epithelium

GLUT 3: found in neurons and the placenta

GLUT 4: insulin regulated transporter in adipose and skeletal muscle

GLUT 5: fructose transporter on luminal side of enterocytes

Question 38

Components of the exocrine pancreas

Answer 38

Secretory acinar cells – produce digestive enzymes in the form of inactive zymogen granules which are secreted by exocytosis

Duct epithelial cells – columnar epithelium lines the ducts and secrete bicarbonate and water to dilute and alkalise the pancreatic juice

Question 39

Major vitamins (functions + deficiencies)

Answer 39

Question 40

Description of LFTs

Answer 40

Question 41

Overview of Jaundice

• Types
• Causes
• Bloods

Answer 41

Prehepatic

Due to excessive haemolysis that overwhelms liver bilirubin metabolism which is otherwise functioning normally

e.g. physiological jaundice of the newborn, haemolytic disease of the newborn, sickle cell disease, thalassemia

Cholestatic – intrahepatic

damage to hepatocytes results in release of bilirubin into circulation

e.g. viral hepatitis, cirrhosis/AUD, parasitic liver infection, HCC, drug toxicity

Cholestatic – obstructive

Obstruction of the biliary system causes stasis, inflammation and damage that results in release of conjugated bilirubin into the blood

e.g. gallstones, iatrogenic injury, pancreatic head cancer, cholangiocarcinoma

Question 42

Metabolism of drugs in the liver including alcohol and paracetamol

Answer 42

Hepatic drug metabolism typically occurs in two stages:

note: some drugs will only be processed through phase 1 or phase 2, most do both in order

Phase 1 reactions – chemical reactions including oxidation, reduction and hydrolysis which typically converts the drug into an inactive or less active metabolite

• possible for the metabolite to be the active form (prodrug → drug)
• oxidation is the most common pathway, largely carried out by the cytochrome P450 enzyme system

Phase 2 reactions – conjugation of the phase 1 metabolites to other molecules to form conjugates which are more water soluble and able to be excreted, molecules include glucuronic acid, acetyl groups and sulfate groups

Initial phase 1 alcohol metabolism occurs through two different pathways which produce acetaldehyde, a toxin that can be further degraded into acetate by ALDH

• alcohol dehydrogenase, major pathway
• MEOS system (cytochrome P450), upregulated in chronic AUD

Most paracetamol is immediately conjugated to glucuronic acid or sulfate however a small amount is first converted to a toxic metabolite NAPQI before glucuronidation, this is an issue in paracetamol overdose where there is insufficient glucuronic acid to clear NAPQI

Question 43

Types of viral hepatitis (route, incubation, acute/chronic, treatment/prevention)

Answer 43

Question 44

Overview of hepatitis B serology

Answer 44

HBV DNA – detected by PCR, indicates viral load

HBsAg – indicates acute infection or very recent vaccination

HBsAb – patient has either been previously infected or vaccinated

HBcAb – distinguishes that viral infection has previously occurred (not vaccination), screening for IgM vs. IgG determines time sequence

HBeAg – indicates active viral replication and infectivity

Question 45

Sequelae of liver damage

Answer 45

Some of the potential complications of liver disease include:

• Hepatic encephalopathy: neurological damage that occurs due to excess circulating NH3 from impaired liver nitrogen metabolism, results in excess brain glutamate and glutamine which causes astrocyte swelling and damage
• Portal hypertension: due to impaired flow of blood through the liver, leads to formation of varices and haemorrhage
• Hepatorenal syndrome: renal failure associated with advanced liver disease thought to be associated with changes in blood vessel tone
• Ascites: combination of portal hypertension and hypoalbuminaemia
• Bleeding/haemorrhage: thrombocytopaenia due to splenomegaly as well as reduction in synthesis of clotting factors

Question 46

Four portosystemic anastomoses

Answer 46

• Oesophageal veins
• Rectal veins
• Paraumbilical veins
• colic twigs → renal veins (?)

Question 47

Description of hepatic lobule and liver microarchitecture

Answer 47

The hepatic acinus consists of double layer sheets of hepatocytes with fenestrated endothelial sinusoids in which blood from the portal vein and hepatic artery combine and drain through to a central vein

• Hepatocyte – major functional cells of the liver
• Kupffer cell – resident macrophages of the liver
• Stellate cell – found in the perisinusoidal space of Disse, involved in liver fibrosis and scarification in response to damage as well as vitamin A storage
• Bile canaliculi – between hepatocytes drain bile into the bile duct system

Question 48

Composition of bile

Answer 48

Bile contains: water (98%), bile salts, bilirubin, cholesterol, lecithin, some drugs/hormones

Question 49

Overview of bile secretion and absorption

Answer 49

The components of bile are synthesised and release from liver hepatocytes into the bile canaliculi which drain into the hepatic bile duct

• bile duct epithelium adds bicarbonate, water and alkaline phosphatase
• storage between meals in the gall bladder which absorbs water to concentrate the bile, released from gall bladder in response to CCK and vagal stimulation

Synthesis + secretion:

1. Bile acids are synthesised and conjugated with amino acids to increase water solubility
2. Bile from the hepatic (liver) and cystic (gall bladder) ducts drains into the bile duct which enters the duodenum via the hepatopancreatic ampulla
3. Once in the intestine, bile acids dissociate and combine with ions to form bile salts which are used to emulsify and absorb fats

Reabsorption:

1. Conjugated bile salts cannot be passively reabsorbed however some small intestine bacteria will deconjugate the bile salts allowing for passive absorption
2. Active absorption of bile salts occurs in the ileum
3. Further bacterial deconjugation and absorption also occurs in the colon
4. Bile salts that are not absorbed are lost in the faeces

Reabsorbed bile salts circulate back to the liver via the portal circulation, this is the basis of the enterohepatic circulation which is a key pathway for processing of a number of drugs and hormones e.g. oestrogen, oral contraceptive, morphine

Question 50

Gastrointestinal mucosal immunity (physical, chemical, immunological barriers)

Answer 50

Physical – microvilli, tight junctions, glycocalyx

Chemical – gastric acid, secretion of antimicrobial peptides e.g. defensins, calprotectins

Immunological –

• Peyer’s patches: MALT containing DCs, lymphocytes, macrophages
• intraepithelial lymphocytes
• M cells sample the lumen above Peyer’s patches by transcytosis
• T-Regs key cells involved in suppressing immune overactivation by IL-10 secretion

Question 51

Pathophysiology of alcoholic liver disease

Answer 51

1. Excess alcohol metabolism in the liver creates toxic ROS via the upregulated MEOS system and drains NAD+ levels via the ADH pathway
2. Loss of NAD+ disrupts metabolic homeostasis – downregulates beta-oxidation, glycolysis and the TCA cycle while favouring lipogenesis
3. Fatty change and hepatocellular damage occur due to TAG deposition, lipid peroxidation, ROS and acetaldehyde
4. Activation of stellate cells by various paracrine factors such as TGFβ causes them to differentiate into myofibroblasts which lay down collagen
5. Liver fibrosis continues until it progresses to irreversible cirrhosis

Question 52

Common types of vaccines including pros and cons

Answer 52

Question 53

Three types of infectious liver pathology including examples

Answer 53

Hepatocellular damage – viral hepatitis e.g. HAV, HBV, HCV

Bile obstructing – Fasciola hepatica, Clonorchis, Opisthorchis, Schistosomiasis

Space occupying lesions – hydatid disease due to Echinococcus granulosus, amoebic and pyogenic liver abscesses

Question 54

Causes of cirrhosis

Answer 54

Cirrhosis is a common end-stage of any chronic liver disease including chronic viral hepatitis, AUD, NAFLD, haemochromatosis, primary biliary cholangitis, biliary obstruction such as atresia or CF

Question 55

Overview of NAFLD

Answer 55

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in developed countries, it is diagnosed based on fatty change of the liver in absence of chronic alcohol abuse

• aetiology is unclear but is associated with features of the metabolic syndrome
• excessive accumulation of triglyceride in the liver leads to damage and oxidative injury which may include NASH (inflammatory form of NAFLD)

Question 56

Causes of acute pancreatitis

Answer 56

I GET SMASHED

Idiopathic

Gallstones
Ethanol
Trauma

Scorpion sting
Mumps/Malignancy
Autoimmune
Steroids
Hypertriglyceridaemia
ERCP
Drugs

Question 57

Pathophysiology of acute pancreatitis including diagnostic criteria

Answer 57

1. Acute injury to pancreatic acinar cells occurs via any of the various causes of acute pancreatitis – often involving changes in calcium homeostasis or ductal hypertension
2. Early activation of pancreatic enzymes causes autodigestion and necrosis
3. Tissue death results in a massive inflammatory response which causes more damage and spreads systemically

Diagnostic criteria – require at least two of the following

• Elevated serum lipase, greater than triple normal upper limit
• Abdominal pain consistent with acute pancreatitis
• Characteristic imaging findings

Question 58

Common types of hepatic malignancy

Answer 58

1. Hepatocellular carcinoma – malignancy originating from hepatocytes, associated with viral hepatitis and cirrhosis
2. Cholangiocarcinoma – cancer of the bile duct epithelium which can be intrahepatic or extrahepatic, can result in obstruction of the biliary tree
3. Hepatic angiosarcoma – rare but aggressive tumour of endothelium within the liver

Question 59

Overview of gut microbiome (composition, development, function)

Answer 59

The gut microbiome is first inoculated during birth and breastfeeding but develops over time with a strong influence from diet

• Nose/mouth: S. aureus, S. pneumoniae, C. albicans
• Small intestine: Streptococcus, Enterococcus, Bacteroides, Lactobacillus
• Large intestine: Bifidobacterium, Lactobacillus, Bacteroides, Clostridium, Eubacterium

Functions of the microbiome include:

• Digestion of complex polysaccharides
• Metabolism of bile salts and bilirubin
• Development of the gut immune system
• Competitive inhibition of pathogen overgrowth

Question 60

Pathophysiology of cholecystitis/cholelithiasis

Answer 60

Gallstones can form in the gallbladder due to a number of factors including excess cholesterol in bile, presence of protein nucleation points and bile stasis, these are typically asymptomatic unless they obstruct a duct

Acute cholecystitis is inflammation of the gall bladder which is almost always caused by cholelithiasis

1. Gallstones block cystic/bile ducts and cause physical trauma to the gallbladder wall
2. Increased lumen pressure causes inflammation and ischaemia
3. Opportunistic growth of bacteria results in further inflammation, may lead to perforation

Question 61

Pathogenesis of colorectal cancer

Answer 61

The development of colorectal cancer characteristically occurs through a stepwise process of genetic mutations within cells of the intestinal epithelium that allow them to develop the hallmarks of cancer.

There is a broad range of different mutations that have been associated with this process, these can be grouped under one of three potential pathways of carcinogenesis although there is often overlap between them, each of these pathways increases the instability of the genome and therefore increases the rate of mutation compared to baseline

1. Chromosomal instability – most common pathway, involves imbalances in normal chromosome segregation as well as telomeres and DNA repair machinery
   e. g. APC, p53, DCC, K-Ras, B-Raf, C-Myc
   * 2. Microsatellite instability* – due to changes in microsatellites or short tandem repeats present in the genome, typically associated with mutations in mismatch repair enzymes such as MSH/MLH
   * 3. Aberrant methylation* – abnormal patterns in the epigenetic methylation of the genome (usually hypermethylation) can lead to carcinogenesis through silencing of key genes

Progressive accumulation of these mutations allows for development of a benign adenoma (polyp) and eventually a malignant cancer which invades the colon wall and metastasises to distant organs via lymphatic and haematogenous routes

Question 62

Common gene mutations for CRC

Answer 62

Question 63

Presentation of CRC including risk factors

Answer 63

• Ascending colon: less likely to be obstructive, occult blood
• Transverse colon: obstruction more likely, constipation, abdominal pain, distension
• Descending/sigmoid colon: obstruction leads to alternating pattern of constipation/diarrhoea
• Rectum: diarrhoea, frank bleeding on the outside of the stool

Risk factors:

M – obesity, low fibre diet, sedentary lifestyle, high consumption of red/processed meats

NM – genetics, FHx, increased age, male sex, IBD

Question 64

Examples of hereditary mutations in colon neoplasia

Answer 64

Familial adenomatous polyposis (FAP) = hereditary mutation in the APC gene which leads to the development of thousands of adenomas within the colon which all have the potential to develop into CRC

Lynch Syndrome = hereditary condition that arises due to inherited mutations that impair the DNA mismatch repair system, associated with high risk of CRC as well as other cancers including endometrial, ovarian, brain, skin

Question 65

Description of TNM and Duke staging

Answer 65

T1-4: size and extent of primary tumour

N0-3: extent of spread to local lymph nodes

M0-1: distant metastasis

Once a cancer has been assessed and given a complete TNM score e.g. T3N1M0, this score can be used to classify the cancer as stage I-IV with categorisation depending on the cancer type

Duke staging for CRC only:

A: invasion of mucosa only

B: invasion of cancer through bowel wall including muscularis externa

C: involvement of local lymph nodes

D: distant metastases

Question 66

Overview of bowel cancer screening in Australia

Answer 66

NBSCP = National Bowel Cancer Screening Program

• Free screening program offered to Australians every two years from age 50-74
• Uses iFOBT test to determine presence of occult faecal blood, may occur due to CRC, haemorrhoids, gastroenteritis, diverticulitis, PUD etc.
• High sensitivity, low specificity
• Positive results are followed up with a colonoscopy to investigate

Question 67

Blood supply of the large intestine

Answer 67

The colon is supplied by the marginal artery which travels around the entire length forming anastomoses with various branches from the SMA and IMA

Superior mesenteric artery

• ileocolic artery: terminal ileum and ileocaecal junction
• right colic artery: ascending colon
• middle colic artery: first 2/3 of transverse colon

Inferior mesenteric artery

• left colic artery: supplies 1/3 of transverse colon and descending colon
• sigmoid artery: sigmoid colon
• superior rectal artery: upper part of the rectum

The middle and inferior rectal arteries arise from branches of the internal iliac artery

Question 68

Protocol for breaking bad news

Answer 68

SPIKES

Setting – arranging for privacy, being prepared with as much information as possible

Perception – asking and understanding for the patient’s perspective

Invitation – ask the patient the extent of what they would like to know

Knowledge – provide information in small, easy to understand pieces

Emotion/Empathy – recognise and empathise with the patient’s emotions

Strategy – establish a clear plan of action

Question 69

Pathogenesis of diverticular disease

Answer 69

Diverticulosis = formation of diverticula in the colon wall

• mechanism thought to be increased intraluminal pressure due to longer transit time with a low fibre diet
• outpouchings of mucosa + submucosa through the muscle layer, forms at weak points where vasa recta penetrate between taeniae coli
• most commonly in the sigmoid but also left in Western countries, right in Asia

note: true diverticula contain all layers of the wall e.g. Meckel’s, those in GIT diverticulosis are false diverticula as they only contain mucosa and submucosa

Diverticulitis = inflammation of diverticula due to obstruction, bacterial overgrowth or ischaemia, can result in bowel perforation, adhesions, abscesses and fistulae

Question 70

Principles of iron homeostasis

Answer 70

Small amounts of dietary iron are absorbed in the duodenum with haem (animal) and non-haem (plant) iron being absorbed through different transporters

• haem iron via HCP1
• non-haem iron via DMT1

There are two possibilities for absorbed iron:

• storage in enterocytes before being lost by epithelial sloughing
• transport into the blood via ferroportin, this is negatively regulated by high iron stores via secretion of the hormone hepcidin

Iron is transported in the blood bound to a protein called transferring which carries it to iron storing tissues such as the liver and macrophages in the form of ferritin or haemosiderin

Question 71

Overview of iron deficiency (causes, classification, investigations, treatment)

Answer 71

Iron deficiency can be classified as either

• Absolute – three major causes
  
  • decreased iron intake
  • increased iron loss e.g. GI bleeding, haemorrhage, blood donation
  • increased iron requirements e.g. pregnancy
• Functional – due to an issue of utilisation e.g. excess hepcidin secretion

Investigations include:

• FBC – ↓ Hb, ↓ reticulocyte count unless acute active bleeding due to marrow response
• blood smear – hypochromic microcytic, may be normal if combined with a macrocytic anaemia
• iron studies – ↓ ferritin (useful), ↓ serum iron, ↑ transferrin (TIBC), ↓ transferrin saturation

First line of treatment for iron deficiency is oral iron supplementation e.g. Ferro-grad C, other routes include intramuscular iron, intravenous iron or blood transfusion

Question 72

Metrics used in screening tests

Answer 72

Sensitivity = ability to correctly identify those with the disease

Specificity = ability to correctly identify those without the disease

Positive predictive value = probability that people with positive results truly have the disease

Negative predictive value = probability that people with negative results truly don’t have it

Question 73

Examples of different types of colitis that may be found in the large intestine

Answer 73

Question 74

Types of breast cancer

Answer 74

Structural/histological classification: ductal, lobular, papillary, medullary, mucinous etc.

Molecular classification: (based on expression of certain markers)

• hormone receptors – oestrogen and progesterone
• HER2 – growth signalling receptor
• Ki-67 – marker for proliferation

Question 75

Side effects of breast cancer treatment

Answer 75

Common side effects of breast cancer surgeries such as lumpectomy, BCS or mastectomy include:

• scarring, pain and decreased range of motion in chest muscles
• lymphoedema due to damage to lymphatic system
• support issues as a result of asymmetry
• donor site issues if skin flaps used
• sleep disturbances

Question 76

Overview of somatic and visceral sensation including referred pain

Answer 76

Somatosensation

Direct pathways from dermatomes back to the CNS via somatic nerves which arise from spinal nerve plexes (e.g. intercostal nerves, sciatic, femoral, ulnar, iliohypogastric), separate pathways carry fine touch/proprioception and pain/temperature

Visceral sensation

Two types of visceral afferents travel along different pathways

• ‘reflexive’ information e.g. stretch, pressure, rate travels back along PNS pathways via cranial nerves or pelvic splanchnic nerves
• visceral pain follows SNS pathways back to T1-L2 spinal cord levels, typically felt as referred pain due to interneurons with other pain pathways within the same segments

note: visceral pain below the pelvic pain line follows the PNS back to the sacral spinal cord

Question 77

Types of inflammatory bowel diseases

Answer 77

IBD describes a group of GIT disorders associated with a dysregulated mucosal immune response, with genetic, environmental and immune factors leading to an inappropriate response against the gut microbiome that results in inflammatory damage

Crohn’s disease

• patchy distribution anywhere along the GIT, typically around the ileum and caecum
• transmural inflammation, can lead to complications such as fistula, perforation
• granuloma, cobblestone appearance with deep longitudinal ulceration

ulcerative colitis

• continuous distribution extending from rectum proximally, can be a pancolitis
• inflammation of the mucosa and submucosa only
• ulceration, contact bleeding and friable tissue

Indeterminate colitis is a classification used when the pathology does not definitively match either of the other two categories

Question 78

IBD Vs IBS

Answer 78

Question 79

Metastatic cascade

Answer 79

1. Invasion of the ECM – migration of tumour cells by modifying adhesion molecule expression, ‘inchworm’ movement with adhesion in front but not behind
2. Vascular dissemination – intravasation, binding to platelets for circulation and extravasation via rolling/adhesion
3. Homing + colonisation – promoting new matrix production and angiogenesis to make new site hospitable, certain molecules necessary for certain sites

Question 80

Prebiotics vs. Probiotics with examples

Answer 80

Prebiotics = food ingredients that are not broken down by human digestive enzymes and therefore act as energy sources to selectively stimulate the growth of certain bacteria

• resistant starches and fibres
• fructans
• galacto-oligosaccharides

Probiotics = dietary supplements that contain live bacteria used to colonise the GIT with favourable microbes

• Inner Health Plus – Lactobacillus acidophilus, Bifidobacterium lactis
• Yakult – Lactobacillus casei Shirota
• fermented foods such as yoghurt, kimchi, sauerkraut

Symbiotic therapy uses a combination of both prebiotics and probiotics

Question 81

Three main mechanisms of antibiotics with examples

Answer 81

Cell wall synthesis – preventing development of the bacterial cell wall

• β-lactams inhibit cross linking of peptidoglycan e.g. penicillin, cephalosporin, carbapenems
• glycopeptides prevent incorporation of peptidoglycan subunits e.g. vancomycin

Folic acid metabolism – inhibition of enzymes involved in de novo synthesis of folic acid which is necessary for bacterial growth and replication e.g. sulfonamides, trimethoprim

Protein synthesis – inhibition of protein synthesis by interfering with normal ribosomal function

• aminoglycosides block the 30S ribosomal subunit e.g. streptomycin
• tetracyclines interfere with the attachment of tRNA to the 30S subunit e.g. doxycycline
• amphenicols block the 50S ribosomal subunit e.g. chloramphenicol
• macrolides block the 50S ribosomal subunit e.g. clarithromycin

Question 82

Defecation reflex

Answer 82

1. Faeces accumulate in the sigmoid colon then descend into the rectum, activating stretch receptors
2. Reflex pathways lead to: contraction of rectum, relaxation of puborectal sling ( straightens anal canal), relaxation of internal anal sphincter
3. Voluntary relaxation of external anal sphincter
4. Intraabdominal and rectal pressure increase to evacuate the faeces

Question 83

Causes and treatment of constipation

Answer 83

Unsatisfactory defecation characterised by infrequent stools, difficult passage or a combination of the two

• primary: disordered regulation of the gut
• secondary: metabolic changes, drugs, neurological disorders, behavioural problems

Treatment is by addressing the underlying cause and uses of laxatives in severe cases, these include osmotic (increase fluid) or stimulatory (increase colonic activity)

Question 84

Definition of Hirschsprung’s disease

Answer 84

Hirschsprung’s disease = aganglionic megacolon, congenital GIT defect in which neural crest cell migration is impaired and a segment of the colon does not develop enteric ganglia leading to failure of relaxation

Question 85

Which organs are intraperitoneal and retroperitoneal?

Answer 85

Note: Bladder, uterus, fallopian tubes are sub peritoneal

Question 86

Crohns Vs UC

Answer 86