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Semester 4 PBL Cases 4 - 6 Catch-up ISOC MedEdRamadan Mubarak! Introduction ● Who are we? ● Our mission ● Our team ● Our plan Upcoming MedEd Events April ● Final PBL Catch-up for Cases 7-9 ● CCA Revision Workshops May ● Mock CCA ● PBL Mega Crash Course ● Anatomy Crash Course ● Live MCQ Run-ThroughCase 4 - Colon Cancer Sufian NaseerILOs ● Demonstrate knowledge of the concept of stress in biological and psychological terms ● Demonstrate knowledge of the physiological, psychological and behavioural pathways from stress to illness ● To demonstrate a basic knowledge of the genetic basis of cancer including: sporadic and inherited cancers, predisposition to cancers, chromosomal abnormalities, somatic mutations, oncogenes, tumours suppressor genes, replication error repair genes and DNA repair genes ● To demonstrate an understanding of the ethical and legal frameworks, both supporting and hindering choices, at the end of life ● To demonstrate basic knowledge of the clinical investigation of the lower gastro-intestinal tract ● To demonstrate basic knowledge of the concepts of chemotherapy ● To demonstrate basic knowledge of the laboratory tests used in this case: how they are carried out ● To demonstrate basic knowledge of the laboratory tests used in this case: why they were used ● To demonstrate basic knowledge of the methods of analysing faeces ● To demonstrate knowledge of carcinoma in situ and malignant tumour ● To demonstrate knowledge of the basic concepts of cell proliferation, differentiation and death ● To demonstrate knowledge of the basic concepts of the pathology of cancers: classification, epidemiology, aetiology, spread and clinical effects of tumours ● To demonstrate knowledge of the psychological responses to cancer ● To demonstrate knowledge of the structure and function of the large bowel in water resorption ● To demonstrate knowledge of the structure and function of the large intestine and associated structures including lymph nodes and portal vein ● To demonstrate knowledge of the therapeutic agents used in the case scenario ● To demonstrate understanding of the effect of life style (diet, exercise, alcohol, smoking) on risk of colorectal cancer. ● To demonstrate understanding of the philosophy of palliative care ● To demonstrate understanding of the use of psychological therapy (including brief psychological interventions) and medication in relieving the psychological distress of patientsSmall Intestine ● Segmentations ○ mixing chyme + bile + pancreatic juice + intestinal and pancreatic fluid ○ anterograde and retrograde movement ○ increases contact time with chyme + mucosal surface ● Peristalsis ○ propulsive action ○ occurs when food is present ● Migrating Motor Complex (MMC) - type of peristalsis wave from stomach to ileum ○ in the fasting state ○ every 2 hours and repeats ○ motilin from SI drives MMC ○ ACh can stimulate as well The Colon The colon has 2 main functions: 1. Absorption of water and electrolytes 2. Storage of faecal matter Where does each take place in the colon? Absorption - proximal half Storage - distal halfMixing Movements - Segmentation ● Where? ○ Ascending and transverse colon ● What happens? ○ Faecal matter causes distention -> contraction in the area ■ Circular constrictions in the large intestine - circular muscle contracts ■ Teniae coli (?) contracts - longitudinal muscle contraction ■ Leads to haustra formation - Why? (1) ■ Haustral contractions will carry on in nearby areas ● Role? ○ Absorption of water, electrolytes and complex B vitamins ○ Play a minor role in forward propulsionPropulsive movements - Mass movements ● Where? ○ Mainly in the transverse and descending colon ● What happens? ○ Distention/Irritation/Gastrocolic reflex* -> constrictive ring formation ○ Colon distal to ring loses their haustrations - contracts as a unit ■ Mass movement of faecal material ○ Series of mass movement persist for around 30 minutes ○ 3-5 times a day ● Role? ○ Force mass of faeces into the rectum to allow for defecationRectum ● At most times, the rectum is empty of faeces ● Mass movement of faeces into rectum -> reflex contraction of rectum ● 2 anal sphincters ○ Internal anal sphincter - Circular smooth muscle ○ External anal sphincter - Striated voluntary muscle ■ Which nerve is the external anal sphincter supplied by? ■ Pudendal nerve ● External anal sphincter is usually kept constricted unless the body consciously inhibits constrictionDefecation reflex Intrinsic reflex - Weak on it’s own ● Distention of rectal wall by faeces ● Afferent signals through myenteric plexus - ○ Initiate peristaltic waves from descending colon onwards -> faeces forces to anus ○ Inhibitory signals to relax the internal anal sphincter Extrinsic reflex ● Stretch in sigmoid colon or rectum -> sensory fibres to CNS -> parasympathetic motor fibres (pelvic nerves) to sigmoid colon and rectum ● Intensify peristaltic contractions + relax internal anal sphincter ○ Intrinsic reflex will be converted into a more powerful process ● When you are in the correct place to defecate, pudendal nerve will relax external anal sphincterENS and extrinsic nerves Interstitial Cells of Cajal ● Pacemaker cells of the GI tract ● Create slow waves -> contraction of the smooth muscle Enterochromaffin cells ● Respond to mechanical or chemical stimuli in the GI tract ● Release serotonin (5-HT) -> stimulate sensory nerves via 5-HT3 receptors ● Modulate peristaltic contractions and secretions from smooth muscles based on the hormone released (ACh and Substance P vs NO and VIP) ● 5-HT -> 5-HT3 receptors @ Vomiting centre in Medulla -> VomitingModulation of Slow Waves ● Food stimulates nerve and hormonal activity: ○ Increase or decrease size of the maximum depolarisation. ● Nerves (intrinsic & extrinsic) ○ ACh, Substance P → depolarisation (= increase contraction) ○ NO, VIP→ hyperpolarisation (= ↓ contraction) ○ Noradrenaline →hyperpolarisation (= ↓ contraction) ● Hormones ○ Motilin → depolarisation (= increase contraction) ○ Secretin, G.I.P. → hyperpolarisation (= ↓ contraction) ○ Adrenaline →hyperpolarisation (= ↓ contraction)Opioids and Motility Opioids ● Inhibit relaxation of sphincters which reduces forward propulsion Opioids can be used as antidiarrheal drugs Mu-receptor agonists ● E.g. Loperamide - ● Decreases peristalsis and gastric emptyingLarge Intestine Secretions ● Mucosa of large intestine ○ Crypts of Lieberkuhn ○ Mucous cells - secrete mucus ○ No Villi ● Secretions mainly consist of mucus and bicarbonate ions ● Mucus release is controlled by direct stimulation of epithelial cells ● Electrolyte secretion ○ Chloride + Sodium ions ○ Potassium ionsChloride + Sodium ions ● Occurs in crypts of both SI and LI ● Normally, Chloride channel is not opened ● Requires activation by Ca2+/ Cyclic NucleotidesPotassium ions ● Passive secretion - primary mechanism ● Active secretion - throughout large intestine ● Active absorption - distal aspect of large intestine 1. Aldosterone 2. Intracellular cAMP and Ca2+ (1) Increase activity of both apical K+ channels and basolateral Na-K pumps -> Potassium lostLarge Intestine: Absorption ● Proximal colon = Absorption ● Distal colon = Storage (of faeces) Ion Absorption ● Sodium ● Chloride Bacterial activity in the proximal colon ● Vitamin K is formed ● Amount of Vitamin K in ingested foods is normally insufficient ● What is Vitamin K used for?Sodium Ions ● Active Absorption - Ileum -> Large intestine ● Distal segment of Large Intestine -> via Epithelial Na+ Channels (ENaCs) ○ Blocked by amiloride diuretic ○ Enhanced by Aldosterone ● Increased cAMP + cGMP - reduces NaCl absorption ● Decreased Intracellular Ca2+ - Increases NaCl absorptionChloride Ions ● Passive Cl- absorption ● Cl-HCO3 Exchange ● Parallel Na-H and Cl-HCO3 exchange Water travels down Osmotic gradient created by the NaCl absorptionCancerDefinitions ● Atrophy vs Hypertrophy ● Hyperplasia vs Aplasia ● Metaplasia - change of cell type ● Dysplasia - abnormal version of a cell ● Anaplasia - loss of structural and functional differentiation Cancer = Metaplasia -> Dysplasia -> Anaplasia Cellular replication ● G1 - normal cell functions + cell growth ○ point at which cell is sensitive to proliferative and anti-proliferative signals ● S phase (synthesis phase) - DNA replication ● G2 - Chromosomes condense ready for mitosis ● Mitosis - Stages? ● Prophase – chromosome becomes visible, 2 pairs of centriole separate, and nucleus disintegrates. ● Metaphase – chromatids move to a midline (equator) ● Anaphase – Chromatids are pulled Apart ● Telophase – Chromosomes uncoil, two nuclei formed ● Cytokinesis – Cytoplasmic division.Cell cycle control ● Cyclin Dependant Kinases (CDKs) ○ Activated by Cyclin ○ Control progression through cell cycle ○ Repair/Eliminate damaged cells [apoptosis] ● Cyclin Kinase Inhibitors (CKIs) ○ Inhibit CDKs ○ E.g p21Cancer genes (Proto-)Oncogenes Tumour Suppressor Genes ○ Potential to cause cancer ○ Natural defense ○ Gain of function mechanism ○ Dominant (only need one ○ Loss of function mutated allele to be ○ Recessive (need two activated) mutated alleles to be ○ E.g. B-catenin and KRas inactivated) ○ Two-hit hypothesis ○ E.g. CDKs, p53, APC Loss of TSG is worse than activation of oncogenes!!!Ras Oncogene ● Normally, Ras is bound to GDP and is inactive. ● Upon binding to GTP, it becomes active. ● Once in the active form, Ras can initiate signalling cascades to cause: ○ Inhibition of apoptosis ○ Cell growth ○ Protein synthesisWnt SignallingRb - TSGPathology of Colorectal Cancer Familial Adenomatous Polyposis (FAP) Inherited disease -> predisposes to developing colorectal cancer Many polyps line the surface of colon Individuals inherit one mutated copy of APC. If second copy also mutates = TSG can’t functionHereditary Non-Polyposis Colon Cancer (HNPCC) AKA Lynch Syndrome Inherited diseases - predisposes to Colorectal Cancer and other cancers (ovarian, SI, Urinary tract, skin & brain) Few polyps but progression to Colorectal cancer is fast Due to mutation in mismatch repair gene (TGF-B) -> errors in newly made strands are not repaired -> more likely to acquire mutation leading to cancer● TGF-B is a growth inhibitory factor. ● Mismatch repair mutations cause deletion of AA bases. ● This causes a truncation of the TGF-B receptor gene, meaning that it is no longer synthesised. ● As a result, the cell now becomes unresponsive to anti-proliferative signals (such as that from TGF-B).LEARN THIS!!Colorectal cancer ● Cancer in the colon or rectum ○ Rectum affected the most, followed by the sigmoid colon ● Majority are sporadic Symptoms ● Severe rare familial disease - FAP/HNPCC Right-sided (absorption) ● Usually an adenocarcinoma ● Weight loss ● Anaemia Risk Factors: ● Occult Bleed 1. Diet - high in red meat ● No Bowel Obstruction - 2. Age > 50 Late diagnosis 3. Smoking Left-sided (storage) 4. Family history ● PR Bleed 5. Inherited disease ● Tenesmus 6. Hx of IBD ● ObstructionTNM Staging Tumour (T) Tis - in situ (grown into mucosa) T1 - grown into submucosa T2 - grown into muscular layer T3 - grown into serosa T4 - grown through serosa Node (N) N0 - no nodes involved N1 - 3 nodes involved N2 - 4+ nodes involved Metastasis (M) M0 - no mets M1 - distant metsInvestigations - Ix Lower GI Endoscopy 1. Sigmoidoscopy – the endoscope only reaches to the top of the descending colon 2. Colonoscopy – the endoscope reaches the entire length of the colon to the ileocecal valve During the Endoscopy, biopsies may be taken for tissue analysis Barium Enema A liquid containing barium is placed in the colon via the rectum Applecore sign = Colon cancer Surgery ● Laparoscopic Treatment - Rx ● Right Hemicolectomy ● Left Hemicolectomy ● Anterior resection ● Early - Resection ● Spread to lymph nodes - Chemotherapy ● Metastatic ○ Chemo/Surgery - To ease symptoms Oxaliplatin Fluorouracil (5-FU) Folinic Acid ● Chemotherapy drug ● Stops cell division ● Adjuvant Chemo ● Inhibits DNA ● Side effects= drug synthesis and Nausea, ● Enhances activity of transcription Diarrhoea, 5-FU* ● Side-effect = Vomiting peripheral neuropathyCase 5 - Hepatitis Raiyan AseriCase 5 ILOs 💀 Apply knowledge of the ethical imperative for Confidentiality in the doctor-patient relationship (and its limits) Demonstrate an awareness of hepatitis B and C screening and the public health burden these cause To demonstrate a knowledge of the pathology of the liver in viral hepatitis and in cirrhosis To demonstrate an understanding of the ethical principles involved in patient choice and informed consent and apply this into clinical practice To demonstrate an understanding that patients with compromised liver function can suffer cognitive problems To demonstrate basic knowledge about viral hepatitis including: incidence and prevalence To demonstrate basic knowledge about viral hepatitis including: pathophysiology To demonstrate basic knowledge about viral hepatitis including: treatments To demonstrate basic knowledge of the causes and consequences of jaundice To demonstrate basic knowledge of the laboratory tests used in this case: how they are carried out To demonstrate basic knowledge of the laboratory tests used in this case: why they were used To demonstrate knowledge of how pain is sensed in the abdomen and the anatomical /physiological basis of referred pain To demonstrate knowledge of pharmacokinetics, particularly the role of the liver To demonstrate knowledge of the key features of transmission and prevention of blood borne and sexually transmitted diseases To demonstrate knowledge of the molecular, cellular and physiological processes of the adaptive immune system (humoral and cellular components) To demonstrate knowledge of the molecular, cellular and physiological processes of the innate immune system To demonstrate knowledge of the structure and function of the liver To describe the ethical framework for 'Best Interests' decisionsILOs we’ll be covering today ● Structure and function of the liver ● Pathology of the liver in viral hepatitis and in cirrhosis ● Causes and consequences of jaundice ● Cognitive problems associated with compromised liver function ● Pharmacokinetic role of the liver ● Viral hepatitis including: incidence and prevalence, pathophysiology and treatments ● Laboratory tests used in this case: how they are carried out and why they were used ● Hepatitis B and C screening ● Key features of transmission and prevention of blood borne and STDsSections 1. Liver anatomy 2. Functions of the liver 3. Jaundice & Encephalopathy 4. Pharmacokinetics 5. Liver pathologies 6. Hepatitis1. Liver Anatomy ● Structure ● Microstructure ● Relations ● Ligaments ● Vasculature & InnervationLiver Structure ● Located in right hypochondrium, extends to left hypochondrium ● 4 lobes: large right lobe, smaller left lobe, 2 posterior lobes that arise from the right lobe: ○ Caudate: upper aspect of visceral surface, next to IVC ○ Quadrate: lower aspect of visceral surface, next to gallbladder ● Porta hepatis separates caudate and quadrate - transmits all vessels, nerves and ducts entering/leaving the liverMicrostructure ● The liver has hexagonal lobules ● Each ‘corner’ of the lobule has 3 elements: a portal vein, a hepatic artery, a bile duct - these are called portal triads ● The hepatic arteries and portal veins from each lobule drain into the central vein ● Central veins of all lobules drain into hepatic veinsMicrostructure ● Blood from the hepatic artery and portal vein mix in sinusoids ● The blood drains through fenestrations in the sinusoids, going past Kupffer cells (macrophages) ● They travel past the Space of Disse and get taken up by hepatocytes ● Hepatocytes release albumin and other plasma proteins back into sinusoids and waste products into bile ductsLiver Relations ● Diaphragmatic surface ○ anteroposterior surface, smooth and convex, fits snugly under diaphragm (directly in contact with it) ● Visceral surface ○ Posteroinferior surface, moulded by the shape of surrounding organs making it irregular and flat ○ Lies in contact with the right kidney, right adrenal gland, transverse colon, gallbladder, oesophagus, and stomachLiver Ligaments ● These ligaments are formed by a double layer of peritoneum ● They attach to a number of surrounding structures - check out TeachMeAnatomy for more infoLiver Vasculature & Innervation Vasculature ● Hepatic artery (25%) - supplies the liver with arterial blood ● Hepatic portal vein (75%) - supplies liver with partially deoxygenated blood, carrying blood from the stomach, pancreas, spleen, duodenum ● Venous drainage is achieved through the hepatic veins which open into the IVC Innervation ● Liver parenchyma innervated by the hepatic plexus2. Functions of the Liver2. Functions of the Liver ● Storage ○ Carbohydrates, lipids, vitamins ● Synthesis ○ Plasma proteins, bile ● Metabolism ○ Glucose, amino acids, TAGs, cholesterol, ketone bodies ● Immunity - Kupffer cells → phagocytosis ● Activation of hormones and vitamins ● Excretion ○ Bilirubin, hormones, drugs, toxinsMetabolism Don’t need to learn this! → Well… not all of itMetabolism ● The liver is a metabolic distribution centre ● The portal vein brings blood from the GI tract ● It responds to insulin and glucagon ● It processes carbohydrates, amino acids and lipids based on the physiological conditionCarbohydrate Metabolism ● Regulated by insulin and glucagon ● 2 states: absorptive and fasting ● In an absorptive state: ○ Glycolysis: breakdown of glucose ○ Glycogenesis: glycogenCarbohydrate Metabolism In an absorptive state: ● ↑ Insulin: suppresses HGP ● Glycolysis: glucose breakdown ● Glycogenesis: glycogen synthesis ● Lipogenesis: glucose → Acetyl CoA → TAGs Tissue specific transporters: ● GLUT-2: liver ● GLUT-4: adipose tissue glucose, trapping it inside the livernzyme that phosphorylatesCarbohydrate Metabolism In an fasting state: ● ↑ Glucagon: HGP ● Gluconeogenesis: glucose synthesis ● Glycogenolysis: PKA activates glycogen phosphorylase which breaks down glycogen to glucose ● Lipolysis: TAG hydrolysis → Acetyl CoA → glucose ● Amino acids: deamination, gluconeogenesis ● Ketogenesis: acetoacetate → acetone ○ Fruity, nail varnish breath ○ Ketonemia lowers blood pH (ketoacidosis)Carbohydrate MetabolismLipid Metabolism Synthesis: ● Insulin stimulates lipogenesis Catabolism: ● In hypoglycemic conditions, TAGs are broken down (lipolysis) ● Beta-oxidation of fatty acids produces large amounts of energyAmino Acid Metabolism ● Unlike carbohydrates and TAGs, amino acids have no storage form ● They must be taken up or recycled ● Amino acids are glucogenic so can be used in gluconeogenesis ● Excess amino acids are degraded, and the nitrogen is excreted as ureaBile: Function ● A fluid consisting of water, bile acids/salts, cholesterol, bilirubin, amino acids, ions ● Produced in the liver but stored and concentrated in the gallbladder ● CCK causes bile salt secretion, the bile salts emulsify fats ● 2 main functions: ○ 1. Remove waste products ○ 2. Emulsify fats ● Some components of the bile are reabsorbed ● Waste products are excreted 💩Bile: Synthesis ● Primary bile acids are synthesised in the liver ● They are secreted into the ileum and colon where they are modified by bacteria which makes them secondary bile acids ● Secondary bile acids are conjugated with amino acids making them bile salts ● 50% of the bile salts are stored in concentrated in the gallbladder ● 95% of bile acid/salts are recycled in the enterohepatic circulationBiliary Tree3. Jaundice - What is Bilirubin?? ● Bilirubin is a breakdown product of red blood cells ● Heme → Biliverdin → Bilirubin ● Bilirubin is conjugated with glucuronic acid and the liver secretes it out ● Some bilirubin is converted to urobilinogen by bacteria in the ileum ● Most is converted to stercobilin (brown) in the colon3. Jaundice ● Accumulation of bilirubin in body fluid and tissues ● Causing a yellow appearance of the skin and sclerae ● In liver disease, bilirubin cannot reach the intestine and accumulates in the body ● Unconjugated: haemolysis or failure of liver to conjugate ● Conjugated: cholestasis (blockage) due to strictures, gallstones, tumours, PSC3. Hepatic Encephalopathy ● The liver has a major detoxifying role ● It converts ammonia to urea ● Ammonia is a toxic substance ● A damaged liver will not be able to remove ammonia ● Ammonia (and other neurotoxins) will remain in the blood and cross the BBB ● Confusion → disorientation → delirium → coma → death4. Pharmacokinetic Role of the Liver ● Factors affecting drug metabolism ● ADME ● Distribution and displacement ● Elimination ● Drug induced liver toxicityFactors Affecting Drug Metabolism ● Unmodifiable ○ Age, gender, pregnancy, disease, genetic ● Modifiable ○ Lifestyle, diet, environment, drug-inducedADME - refresherDrug Distribution & Displacement ● Many drugs exist in the bound form ○ e.g., 99% of warfarin is bound to albumin ○ Therefore only 1% of the warfarin is “free” and can have an effect ● In liver disease, there are less plasma protein so there is less drug bound to proteins - so it will be more free ● Bilirubin binds to albumin - displacing warfarin so there will be even more free drugDrug Elimination ● Occurs by two processes ○ 1. Metabolism ○ 2. Excretion ● Drug metabolism is necessary for lipid soluble drugs… WHY? ● If it they aren’t metabolised they would recirculate into systemic circulation ● Drug metabolism is enzyme-mediated, by converting lipid-soluble compounds into water-soluble compounds that can then be excreted ● Cytochrome P450 (CYP450) are family of enzymes involved in drug metabolismDrug Elimination ● Main site of drug metabolism in liver = SER of hepatocytes ● 2 phases ○ 1. Functionalisation - removal of functional groups ○ 2. Conjugation - attaching of makes them pharmacologically inactivatedPolymorphisms ● SNPs can result in structural changes to enzymes that metabolise drugsDrug-induced Liver Toxicity ● Paracetamol is metabolised via 2 different pathways ● In a paracetamol overdose, both pathways become saturated ● Large amounts, more paracetamol is converted to a toxic metabolite ● This toxic metabolite accumulates and results in liver damage5. Liver Pathologies ● Alcoholic liver disease ● Autoimmune hepatitis ● Viral hepatitis ● Liver cirrhosisAlcohol ● 1 unit of alcohol = 10ml or 8g of ethanol ● It takes the liver one hour to metabolise one unit ○ Variation depending on gender, age, alcohol toleranceAlcoholic Liver Disease Stages ● Steatotic (fatty) liver - reversible ● Alcoholic hepatitis - reversible ● Pericellular fibrosis - partially reversible ● Cirrhosis - irreversibleAutoimmune hepatitis ● Production of antibodies that attack the liver ● Resulting in inflammation and ultimately cirrhosis ● May develop after being infected with measles, herpes, or Epstein-Barr virus ● More common in people who already have autoimmune conditions e.g., coeliac, rheumatoid arthritis, Graves’ disease ● Results in same symptoms - ascites, liver failure,Cirrhosis ● Irreversible liver failure ● Fibrosis of the liver tissue - preventing liver from functioning ● Failure of protein synthesis ● Failure of clotting factor production ● Jaundice ● Encephalopathy ● Portal hypertension ● Can result in hepatocellular carcinoma6. Viral Hepatitis Overview ● Hepatitis viruses are immune-mediated ● 5 types: A-EInvestigations ● Bloods - screening + serology ● LFTs ○ Beautiful LFT explanation uploaded onto MedAll ● Liver biopsy - tissue examined under microscope ● Fibroscan - looking for stiffness, fatty change, fibrosisHepatitis A ● Transmission: ○ Fecal-oral ○ Contaminated food/water ● Diagnosis ○ Acute infection: HAV IgM ○ Previous infection/vaccine: HAV IgG ● Prevention ○ Vaccination ○ Improve sanitationHepatitis E ● Transmission: ○ Fecal-oral ○ Contaminated food/water (associated with undercooked pork) ● Diagnosis ○ Acute infection: HAV IgM ○ Previous infection: HAV IgG ● Prevention ○ Vaccine - only in China ○ Sanitation High mortality rate in those with underlying liver disease and in pregnant womenHepatitis B ● Transmission: ○ Blood-borne (IVDU, unsterlie tattooing, shaving, piercing) ○ Sexual (unprotected sex, multiple partners) ○ Mother to baby ● Chronic ○ Linked to maturity of the immune system (age) ● Prevention ○ Highly effective vaccine ● UK prevalence 0.3%Hepatitis B SerologyChronic Hepatitis B Therapies ● Blocking Hep B DNA polymerase ○ Tenofovir ○ Entecavir ○ LIFELONG! ● Interferon ○ Stimulates an immune response to destroy hepatocytesHepatitis D ● Relies on Hep B for replication ● Same transmission as Hep B ○ Simultaneous vs. superinfection ● Chronic ● Diagnosis ○ Acute infection: HDV IgM ○ Previous infection: HDV IgG ● Prevention ○ Hep B vaccine 70% progress to cirrhosisHepatitis C ● Transmission ○ Contact with infected blood (most commonly seen in IVDUs) ○ Sexual transmission - HIV MSM ○ Mother to baby ● Often acquired in childhood due to poor sterilisation procedures ● High chance of infection becoming chronic ● Prevention: ○ No vaccination ○ Safer injection practices, safer sex ● Global prevalence: Parts of Africa (Egypt), Middle East, Pakistan ● UK prevalence: 0.4%Hepatitis C DiagnosisHepatitis C Treatment ● Pegylated Interferon ○ Inhibits viral replication ● Ribavirin ○ Mechanism unclear?? Potentially induces viral mutations ● New drug class: Direct Acting Antivirals (DAAs) ○ Blocks enzymes in Hep C replication ○ Protease inhibitor = ‘previr’ ○ NS5A inhibitor = ‘asvir’ ○ NS5B = ‘buvir’Case 6 - Diabetes hamna.farooq@student.manchester.ac.ukCarbohydrate Metabolism Glycolysis: Breakdown of glucose in the cytoplasm of the tissue, generates intermediates for metabolism Conversion of glucose into Ribose-5p = pentose phosphate pathway Gluconeogenesis: Glycogenesis is attaching a branching enzyme to glucose to allow them all to come together in the liver/ muscle Glycogenolysis: Glycogen -> glucose (Glycogen phosphorylase cleaves glucose and releases 1-glucose-6-phosphate)Glycogen Formation - Highly branched storage form of glucose - Formed when there is excess glucose-6-phosphate - Stored in the skeletal muscle and liver - Is synthesised in the fed state and degraded when in the fasting state - This is a key mechanisms that maintain blood glucose levelsLipid Metabolism & Ketones Any excess carbohydrates/ proteins are converted to fatty acids by the liver and stored as triacylglycerols (TAGs) in adipocytes •TAG → glycerol + FA = lipolysis ß Beta oxidation •Fatty acid + glycerol → TAG = lipogenesis Acetyl CoA à Malonyl CoA is the rate limiting step that requires regulation The liver has a limited ability to converted fatty acids into glucose, so instead creates more ketones Ketone bodies are emergency fuel that the liver produces to preserve glucose during starvation as adipocytes are limited Acteyl CoA à Ketone bodies They can spontaneously disintegrate via ketosis to form acetoneInsulin and GlucagonIn The Fasting State… Blood glucose levels are below normoglycaemic - Glucagon secretion from alpha cells is triggered - Simultaneously, insuli secretion from beta cells in inhibited - Glucagon acts upon the liver to stimulate endogenous glucose productoion from glycogen stores (glycogenolysis)Glucose Release and Glucagon Glucagon is a hormone secreted by alpha cells of the islets of Langerhans when the blood glucose concentration drops - Binds to GLUT1 receptors - Glucose metabolism: Promotes glycogenolysis, increase gluconeogenesis in the liver and inhibits insulin secretion - Lipid metabolism: Glucagon activates lipase which increases the amount of fatty acids High concentrations of amino acids occur in the blood after a protein meal which stimulates the secretion of glucagon- the same effect on insulinIn The Fed State… Blood glucose levels above normoglycaemic - Insulin secretion from beta cells of the islets of langerhans is triggered - Simultaneously, glucagon secretion from alpha cells is inhibited - Insulin acts upon insulin sensitive tissues to increase their uptage of glucose and ‘switches off’ endogenous glucose productionGlucose Uptake and Insulin Insulin binds to its receptor on insulin sensitive tissues The insulin receptor has an intrinsic tyrosine kinase component, which, upon stimulation, triggers a cascade of signalling molecules GLUT4 is then translocated from the intracellular vesicles to the plasma membraneThe Role of the GI Tract in Insulin Secretion… Incretin hormones (GLP-1 and GIP) are released from the enteroendocrine cells of the GI tract as a result of increased nutrient load - GLP-1 is secreted in response to glucose and amino acid load Binds to GLP-1 receptors on the surfaces of cells throughout the body, particularly beta cells of the Islets of Langerhans! Binding triggers: - G protein stimulation, stimulates adenylate cyclase and causes elevation of cAMP Via cAMP, protein kinase A and Epac2 are activated, which are involved in the exocytosis of insulin Somatostatin secreted by delta cells of the pancreas inhibits glucagon and insulin secretion - It also decreases motility of the stomach/ duodenum and decreases secretion and absorption in the GI tractGlucose Transporters Proteins associated with glucose transport into cells: - GLUT (passive) - Glucose binds to GLUT, alters configuration, allows glucose to pass into cell - Elite members of the GLUT club: - GLUT1: brain (insulin INSENSITIVE) - GLUT 2: Kidneys, liver, pancreas (insulin INSENSITIVE) - GLUT4: adipose, striated muscle, heart (insulin SENSITIVE) - Sodium-coupled/linked transporters (SGLTs) - (these are insulin INSENSITIVE!) - High Na+ concentration results in Na+ binding to the SGLT. Na+ travels down its concentration gradient, across the cell membrane anf the energy generated from this transport is used to transport glucose across too - Elite members of the SGLT club: - SGLT1 (encoded by SLC5A1) - SGLT2 (encoded by SLC5A2)Insulin & Metabolism - Pancreatic beta cells secrete insulin, in response to an increased glucose load - - Glucose binds to beta cells via GLUT-2 transporters where glucose is phosphorylated by glucokinase - Glucose is then oxidised to form ATP, which inhibits ATP-sensitive K+ channels of the beta cells - Closure of these channels depolarises the membrane - This allows for an influx of calcium ions that stimulate the release of insulin via exocytosis -The Implications of Insulin In the blood: 1. Binds to receptors at target cells 2. Degraded by enzyme insulinase Once insulin is bound, it has three different effects: 1. The membranes of about 80% body cells markedly increase their uptake of glucose Insulin increases translocation of vesicles containing GLUT4 to the cell membranes, allowing the uptake of glucose 2. The cell membrane becomes more permeable to amino acids, K+ and phosphate ions This causes intracellular processes, like protein synthesis and fat synthesis 3. Slower effects occur over hours/ days due to changes in DNA synthesis This leads to controlled growth of gene expression of the cellDiabetesBlood Glucose Levels Normoglycaemic levels: 4-6 mmol/l Rises by2 mmol/l post-prandial Kidneys secrete 0.3g of glucose per day! Hypoerglycaemic levels: levels above normoglycaemic. Random glucose levels usually abpve 10 mmol/l, sustained Hypoglycaemic levels: levels lower than normoglycaemic, 3mmol/l or lowerDiagnosis of DiabetesWhen should HBA1C NOT be used? In patients with an abnormal red cell lifespan: - Pregnancy - Conditions which reduce RBC survival (haemolytic anaemia, severe blood loss, patients taking antivirals, splenomegaly etc.) - Conditions which increase RBC survival (e.g. splenectomy) - CKD and patients on renal dialysis (this reduces HBA1C) - In iron and B12 deficiency - When taking mediation that may cause hyperglycaemia (e.g. corticosteroids) - If the patient has a rapid onset of diabetes, HBA1C may not be detected until weeeeeks later! So , what test can be used?Specific Investigations for Type 1 DiabetesType 1 Diabetes Mellitus Type 1 diabetes is called insulin-dependent diabetes mellitus (IDDM) This is an autoimmune condition caused by a lack of insulin secretion T1DM generally develops in childhood and is commonly diagnosed before the age of 30 However, the age of onset of type 1 diabetes does have a bi-modal distribution, therefore, there can be a late onset development in adults misdiagnosed as T2DM In T1DM, the cells cannot make enough insulin due to a type 4 hypersensitivity- a cell mediated immune response There are 4 classical symptoms that are presented in diabetes: Polyuria, polydipsia, glycosuria and polyphagiaDiabetic ketoacidosis (DKA) This is the main complication that occurs with type 1 diabetes but can sometimes affect type 2 diabetes Signs and Symptoms: attempt to reduce acidityp and laboured breathing to move CO2 out of the blood in an Hyperkalaemia= The increased concentration of K+ in the blood which is eventually secreted Fruity breath= When the ketone bodies are broken down, the acetone creates a distinct breath smell Nausea, vomiting, abdominal pain and mental status changes Treatment necessitates IV fluids (FIRST), insulin and electrolytesType 2 Diabetes Mellitus T2DM is called non-insulin dependent diabetes mellitus (NIDDM) and is caused by a reduced sensitivity of target tissues to the metabolic effect of insulin resulting in insulin resistanceT2DM Presentation Most patients will present asymptomatically where T2DM is commonly diagnosed based on screening Patients can present fatigue, polyuria, polydipsia and glycosuria; all signs of hyperglycaemia Candida infections of the reproductive organs is common (due to increased glucose secretion in urine) Patients who don’t attend the GP regularly can present with late complications of chronic hyperglycaemiaHyperosmolar Hyperglycaemic State (HHS) This occurs in patients with type 2 diabetes who experience very high blood glucose levels over 40mmol/l, taking weeks to develop Precipitating factors: Acute infections, non-adherence to medications and certain drugs (glucocorticoids/ diuretics) High levels of glucose in the blood creates a hyperosmolar state as water begins to leave the body cells and enter the blood vessels Symptoms= Confusion, generalised seizures, polyuria, polydipsia and N/V Treatment= IV FLUIDS (FIRST), replace electrolytes and IV insulin Recommended prophylactic LMWH (why?)T1DM management insulin therapy is available in several forms following different regimes: Basal-bolus regime → use of rapid or short acting insulin before meals and a long-acting preparation for basal requirements This regime best mimics the pancreas and is the standard approach for newly diagnosed T1DM 1, 2, or 3 injections per day regime → Usually biphasic regime with the use of both short acting and intermediate acting insulin Continuous insulin infusion via pump → Supplies rapid or short acting insulin There needs to be monitoring of blood glucose 4 times a day before meals and bed, with an increase of testing when they are ill, exercise or pregnantManagement in diabetics (T2DM) 1st line= lifestyle changes (for pre-diabetics) 2nd line= Lifestyle + Metformin titrated up as tolerated (start 500mg) Aim for HbA1c of 48 (Add second drug if HbA1c rises to 58) 3rd line= Add sulfonylurea, pioglitazone, DPP-4 or SGLT-2 inhibitor (Based on individual factor and drug tolerance) Aim for HbA1c < 53 4th line= (Triple therapy) Metformin + 2 of the above or metformin + insulin Aim for HbA1c < 53T2DM Medication SummaryQUIZ TIME WIN PRIZES!Prizes 1st - £25 Amazon Gift Card 2nd - £15 Amazon Gift Card 3rd - £10 Amazon Gift CardJoin the Slido! 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