GIL - Phase 1 Flashcards
Phases of secretion in the GIT
- Cephalic – thinking/seeing/smelling food (20%, ↑histamine, ↑gastrin)
- Gastric – presence of nutrients + distension (70%, via ACh, histamine and gastrin)
- Intestinal – presence of nutrients + distension (10%, secretin, CCK, GIP, motilin)
Pathophysiology of GORD and treatment (pharmacological and non-pharmacological)
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
Pathophysiology of peptic ulcer disease and treatment
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
Gross anatomy of stomach including blood supply
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
Layers of the gastrointestinal tract
- Mucosa – epithelium, lamina propria, muscularis mucosa
- Submucosa – contains the submucosal nerve plexus
- Muscularis propria – inner circular, outer longitudinal with myenteric nerve plexus between
- Serosa – layer of visceral peritoneum or adventitial fat
Overview of neuronal control of GIT function
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
Major 10 GIT hormones
- Hormone
- Source
- Location
- Stimulus
- Function
Examples of GIT reflexes
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
Phases of vomiting
-
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*
Sequelae of vomiting
Clinical consequences of persistent vomiting include:
- dehydration
- metabolic alkalosis from acid loss
- electrolyte imbalances such as hypochloraemia and compensatory hypokalaemia
- cachexia
Overview of vomiting reflex including receptors involved
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
Overview of GIT embryology
The GIT develops from the mesoderm and endoderm through lateral and craniocaudal folding
development happens within six major regions:
- Stomodeum – primitive oral cavity formed by head curling over thorax
- 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)
- 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
- Midgut – contains vitelline duct (yolk sac), herniates through abdominal wall and grows/rotates in the amniotic cavity before birth
- Hindgut – expansion to form a cloaca which divides into a rectum and a urinary tract
- Proctodeum – forms lower third of anus, invagination of ectoderm
Pharyngeal arches and their corresponding structures
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 5th does not develop)
- (trigeminal) mandible, muscles of mastication and incus/malleus of middle ear
- (facial) stapes of middle ear, styloid process, small part of hyoid bone
- (glossopharyngeal) rest of hyoid bone
- (vagus) thyroid and epiglottic cartilages
- (vagus) all other laryngeal cartilages
Stimuli and process of gastric acid secretion
- CA produces combines waste CO2 and water to form H2CO3 which dissociates
- H+ is pumped into lumen via H+/K+ ATPase
- 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
Outline of NSAID toxicity
NSAIDs – inhibitors of COX, cause damage to stomach lining due to inhibition of prostaglandin synthesis which has a key role in mucus secretion
Description of H. pylori infection and how it is diagnosed
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
Causes of haematemesis
DDx of haematemesis include:
- peptic ulcer disease
- gastric varices
- Mallory-Weiss tears
- recent epistaxis
- stomach or oesophagus malignancies
- gastroenteritis
Phases of swallowing
- Buccal/oral – processing of food in oral cavity, closed soft palate allows air passage
- Pharyngeal – soft palate blocks nasal cavity, epiglottis blocks laryngeal inlet
- Oesophageal – relaxation of UOS and LOS, peristaltic motion down tube
Cells of the stomach mucosa and types of stomach mucosa
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
Australian dietary guidelines
- Achieve + maintain a healthy weight
- Eat from a range of food groups including grains, vegetables, fruits, proteins
- Avoid added salt, alcohol, saturated fats, added sugar
- Encourage breastfeeding of infants
- Ensure that appropriate food hygiene is maintained
Central control of appetite including role of leptin
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
Types of GI motility and use throughout the GIT
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)
Types of mucosa present throughout GIT
Structural GIT pathologies
Types of lactose intolerance
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
Pathophysiology of coeliac disease
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
- Gluten peptides enter the lamina propria by unknown mechanism, suggested mechanisms include transcytosis, tight junction dysfunction and dendritic cell sampling
- Tissue transglutaminase (tTG) deaminates gluten proteins
- Deaminated gluten/gliadin more readily activates an immune response via HLA molecules on dendritic cells (commonly haplotypes DQ2 and DQ8)
- 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
Causes of malabsorption
- Coeliac disease
- Intestinal resection → short gut syndrome
- Gastroenteritis
- Cystic fibrosis/pancreatic insufficiency
- Biliary atresia
Four causes of failure to thrive and some examples
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
Clinical syndromes of gastroenteritis
- Vomiting – upper GIT localisation
- Watery diarrhoea – large volume, moderate frequency, no blood
- Inflammatory diarrhoea – small volume, high frequency, blood present, systemic symptoms
- enterocolitis: small + large, Campylobacter, Salmonella
- colitis: large only, Shigella, E. coli
Major bacterial, viral and protozoan causes of gastroenteritis
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
Four types of diarrhoea
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
Types of lipoproteins
- Density
- Protein %
- Lipid %
- Apoproteins
- Lipids
Overview of lipoprotein transport and examples of inherited disorders
Normal lipoprotein transport
- Lipids absorbed in the GIT are packaged into chylomicrons and release into lymphatic lacteals from which they enter systemic circulation
- TAGS are absorbed into tissues from chylomicrons via the luminal membrane bound enzyme lipoprotein lipase
- Remaining chylomicron remnants are endocytosed in the liver via remnant receptors which recognise ApoE
- The liver synthesises and releases VLDLs these contain TAGs and cholesterol which are absorbed into tissue again by LPL, eventually forming IDLs
- 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:
- 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
- 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
- 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
Process of insulin secretion
- Glucose enters pancreatic B cells via GLUT2 transporters and is trapped as G6P by the enzyme glucokinase
- Metabolism of glucose → production of ATP
- High ATP levels inhibit K+ channels leading to depolarisation of the cell
- Ca2+ influx during depolarisation induces exocytosis of secretory vessels containing insulin and C-peptide
Hormones and cells of the endocrine pancreas
Metabolic effects of insulin and glucagon (including time sequence of insulin)
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
Major types of GLUT transporters
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
Components of the exocrine pancreas
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
Major vitamins (functions + deficiencies)
Description of LFTs
Overview of Jaundice
- Types
- Causes
- Bloods
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
Metabolism of drugs in the liver including alcohol and paracetamol
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
Types of viral hepatitis (route, incubation, acute/chronic, treatment/prevention)
Overview of hepatitis B serology
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
Sequelae of liver damage
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
Four portosystemic anastomoses
- Oesophageal veins
- Rectal veins
- Paraumbilical veins
- colic twigs → renal veins (?)
Description of hepatic lobule and liver microarchitecture
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
Composition of bile
Bile contains: water (98%), bile salts, bilirubin, cholesterol, lecithin, some drugs/hormones
Overview of bile secretion and absorption
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:
- Bile acids are synthesised and conjugated with amino acids to increase water solubility
- Bile from the hepatic (liver) and cystic (gall bladder) ducts drains into the bile duct which enters the duodenum via the hepatopancreatic ampulla
- Once in the intestine, bile acids dissociate and combine with ions to form bile salts which are used to emulsify and absorb fats
Reabsorption:
- Conjugated bile salts cannot be passively reabsorbed however some small intestine bacteria will deconjugate the bile salts allowing for passive absorption
- Active absorption of bile salts occurs in the ileum
- Further bacterial deconjugation and absorption also occurs in the colon
- 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
Gastrointestinal mucosal immunity (physical, chemical, immunological barriers)
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
Pathophysiology of alcoholic liver disease
- Excess alcohol metabolism in the liver creates toxic ROS via the upregulated MEOS system and drains NAD+ levels via the ADH pathway
- Loss of NAD+ disrupts metabolic homeostasis – downregulates beta-oxidation, glycolysis and the TCA cycle while favouring lipogenesis
- Fatty change and hepatocellular damage occur due to TAG deposition, lipid peroxidation, ROS and acetaldehyde
- Activation of stellate cells by various paracrine factors such as TGFβ causes them to differentiate into myofibroblasts which lay down collagen
- Liver fibrosis continues until it progresses to irreversible cirrhosis
Common types of vaccines including pros and cons
Three types of infectious liver pathology including examples
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
Causes of cirrhosis
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
Overview of NAFLD
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)
Causes of acute pancreatitis
I GET SMASHED
Idiopathic
Gallstones
Ethanol
Trauma
Scorpion sting
Mumps/Malignancy
Autoimmune
Steroids
Hypertriglyceridaemia
ERCP
Drugs
Pathophysiology of acute pancreatitis including diagnostic criteria
- 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
- Early activation of pancreatic enzymes causes autodigestion and necrosis
- 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
Common types of hepatic malignancy
- Hepatocellular carcinoma – malignancy originating from hepatocytes, associated with viral hepatitis and cirrhosis
- Cholangiocarcinoma – cancer of the bile duct epithelium which can be intrahepatic or extrahepatic, can result in obstruction of the biliary tree
- Hepatic angiosarcoma – rare but aggressive tumour of endothelium within the liver
Overview of gut microbiome (composition, development, function)
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
Pathophysiology of cholecystitis/cholelithiasis
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
- Gallstones block cystic/bile ducts and cause physical trauma to the gallbladder wall
- Increased lumen pressure causes inflammation and ischaemia
- Opportunistic growth of bacteria results in further inflammation, may lead to perforation
Pathogenesis of colorectal cancer
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
-
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
Common gene mutations for CRC
Presentation of CRC including risk factors
- 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
Examples of hereditary mutations in colon neoplasia
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
Description of TNM and Duke staging
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
Overview of bowel cancer screening in Australia
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
Blood supply of the large intestine
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
Protocol for breaking bad news
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
Pathogenesis of diverticular disease
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
Principles of iron homeostasis
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
Overview of iron deficiency (causes, classification, investigations, treatment)
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
Metrics used in screening tests
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
Examples of different types of colitis that may be found in the large intestine
Types of breast cancer
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
Side effects of breast cancer treatment
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
Overview of somatic and visceral sensation including referred pain
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
Types of inflammatory bowel diseases
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
IBD Vs IBS
Metastatic cascade
- Invasion of the ECM – migration of tumour cells by modifying adhesion molecule expression, ‘inchworm’ movement with adhesion in front but not behind
- Vascular dissemination – intravasation, binding to platelets for circulation and extravasation via rolling/adhesion
- Homing + colonisation – promoting new matrix production and angiogenesis to make new site hospitable, certain molecules necessary for certain sites
Prebiotics vs. Probiotics with examples
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
Three main mechanisms of antibiotics with examples
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
Defecation reflex
- Faeces accumulate in the sigmoid colon then descend into the rectum, activating stretch receptors
- Reflex pathways lead to: contraction of rectum, relaxation of puborectal sling ( straightens anal canal), relaxation of internal anal sphincter
- Voluntary relaxation of external anal sphincter
- Intraabdominal and rectal pressure increase to evacuate the faeces
Causes and treatment of constipation
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)
Definition of Hirschsprung’s disease
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
Which organs are intraperitoneal and retroperitoneal?
Note: Bladder, uterus, fallopian tubes are sub peritoneal
Crohns Vs UC
