GIL - Phase 1 Flashcards

Question

**Types of lactose intolerance**

Answer 1

**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

Answer 2

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

Answer 3

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

Answer 4

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

Answer 5

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*

Answer 6

_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*

Answer 7

_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

Answer 8

***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

Answer 9

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

Answer 10

**_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

Answer 11

**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

Answer 12

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

Answer 13

**_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

Answer 14

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

Answer 15

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

Answer 16

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

Answer 17

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

Answer 18

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 ![]()

Answer 19

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

Answer 20

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

Answer 21

**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

Answer 22

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

Answer 23

_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

Answer 24

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

Answer 25

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)

Answer 26

**I GET SMASHED** Idiopathic Gallstones Ethanol Trauma Scorpion sting Mumps/Malignancy Autoimmune Steroids Hypertriglyceridaemia ERCP Drugs

Answer 27

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

Answer 28

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

Answer 29

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

Answer 30

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

Answer 31

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

Answer 32

* 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

Answer 33

_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

Answer 34

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

Answer 35

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

Answer 36

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

Answer 37

**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

Answer 38

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

Answer 39

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

Answer 40

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

Answer 41

*_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

Answer 42

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

Answer 43

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

Answer 44

_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*

Answer 45

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

Answer 46

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

Answer 47

**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

Answer 48

_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

Answer 49

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

Answer 50

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)

Answer 51

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

Answer 52

Note: Bladder, uterus, fallopian tubes are sub peritoneal