Pathophysiology Flashcards

Question

Inflammation

Answer 1

* A pathophysiological mechanism of host defence against harmful stimuli * Tissue injury and infection leads to release of PAMPs and DAMPs * Host immune cells (via pattern recognition receptors) recognise these which elicits a signalling cascade resulting in the release of pro-inflammatory cytokines (TNFa, IL-1, IL-6, IL-8), chemokines (ICAM-1, VCAM-1) and nitric oxide * Fever * PMNs become activated and migrate to site of injury; release of mediators by PMNs at site of infection = responsible for cardinal signs of local inflammation: warmth and erythema due to local vasodilation and hyperaemia, and protein-rich oedema due to increased microvascular permeability * Neutrophils are phagocytic cells defending against pathogens; mechanisms of defence include engulfing and destroying offending microorganism, secretion of antimicrobial peptides & release of neutrophil extracellula rtraps which aid in pathogenesis clearance but may also promote inflammation and tissue damage in sepsis; crucial role in DIC and intravascular thrombosis * This process is highly regulated by a mixture of pre-inflammatory and anti-inflammatory mediators secreted by macrophages; if mediators balance each other out and infectious insult is overcome, homestasis will be restored --\> end result = tissue repair and healing

Answer 2

Exaggerated systemic response to allergen, characterised by vasodilation, vascular permeability, smooth muscle spasm and cellular infiltrate An example of type 1 hypersensitivity Driven by IgE binding to allergen and activating mast cells and basophils, with release of primary mediators (histamine, bradykinin, prostaglandins) and secondary mediators (leukotrienes).

Answer 3

Acquired consumptive coagulopathy characterised by microvascular thrombosis leading to organ dysfunction. Exposure of blood to procoagulant susbtances (TF) leads to widespread coagulation and tissue ischaemia. Depletion of clotting factors leads to bleeding. Diagnosis includes - Low plt - Low fibrinogen - Increased PT and APTT - Increased D-Dimer - Schistocytes (haemolysed red cells)

Answer 4

* Monocryl * 50% at 1 week * Absorbed in 3 months * Vicryl (Polyglactin) * 75% strength at 2 weeks, 50% at 3 weeks * Absorbed in 3 months * PDS * 70% at 2 weeks, 50% at 4 weeks * Absorbed at 6-8 months * Maxon * 80% at 2 weeks, 60% at 4 weeks * Absorbed by 6 months * (combines prolonged strength of PDS and good handling and knotting of Vicryl) * Chromic gut: * loses strength in 10-14 days * digested by 2-3 months

Answer 5

* A state of organ/systemic hypoperfusion, with resultant cellular hypoxia, cellular death and dysfunction of organs * 3 broad phases: * Compensated * Decompensated/reversible * Irreversible * Multiple aetiologies, broadly classified as: * Obstructive * Distributive * Hypovolaemic * Cardiogenic * Common pathophysiology is cellular hypoxia due to inadequate oxygen delivery. This leads to: * Cell membrane ion pump dysfunction * Intracellular oedema * Leakage of cellular contents * Inadequate regulation of cellular pH * This progresses on the systemic level leading to: * Acidosis * Lactataemia * Endothelial dysfunction * Inflammation * This is compounded by neurohumoral mechanisms to defend central end-organ perfusion at the expense of peripheral perfusion. * Sympathetic activation and vasoconstriction * Renin-angiotensin-aldosterone system

Answer 6

* Progressive organ dysfunction in acutely ill pt - is at severe end of severity of illness spectrum of both infectious (sepsis, septic shock) and non-infectious conditions (eg SIRS from pancreatitis) * Defined as an alteration in 2 or more organs' function such that homeostasis cannot be maintained * May be primary (due to inciting tissue injury) or secondary (due to host response) * A hypometabolic, immunosuppressed state with clinical and biochemical evidence of decreased function of the body's organ systems No universially accepted criteria for individual organ dysfunction in MODS, but the organ-specific parameters used in SOFA are commonly used to diagnose MODS • CNS - GCS • Cardiovascular – hypotension, inotrope requirement • Coagulation - platelets • Renal - creatinine • Respiratory - paO2/FiO2 • Liver – bili All scored from 0 - 4

Answer 7

* A dysregulated host inflammatory response to an injury or infection * A combination of humoral and cellular immune responses, cytokine release, and activation of the complement pathway; thought to be associated with an imbalance between the pro-inflammatory and anti-inflammatory cascades * Injury leads to production of **proinflammatory cytokines (IL-1, IL-6, IL-8, TNFa, IFN-y)** * These cytokines spill over into the circulation in order to amplify the inflammatory response and lead to recruitment of macrophages, lymphocytes and platelets to the area * Usually there's homeostasis that occurs with a **compensatory anti-inflammatory response mediated by IL-4 and IL-10** - inhibit production of the inflammatory cytokines * But if no homeostasis then a significant systemic reaction occurs - leads to activation of various different cascades - release of further cytokines, prostaglandins, activation of leukotriene and complement pathways, fever, sympathetic stimulation, RAS activation, vasoactive compound release, as well as alteration in coagulation leading to end-organ microthrombosis * Consequent endothelial damage and vascular permeability leads to organ dysfunction

Answer 8

* endothelial injury (from pro-inflammatory substances in bloodstream e.g. LDL and glycated Hb, haemodynamic forces, toxins & infectious agents) --\> decreased NO production and increased permeability, and increased expression of leukocyte adhesion molecules which increases adherence of macrophages & other leukocytes * permeability of endothelium allows entry of leukocytes & lipoproteins to subendothelial space * plaque formation: * **fatty streaks** (focal thickening of intima w accumulation of foam cells which are lipid-laden macrophages) * **deposition of layers of matrix** (ECM) around layered macrophages, T cells, SMCs * lesions become a well defined **lipid core with a fibrous cap** which begins to compromise arterial lumen and protrude into it (foam cells at centre of developing atheroma become necrotic & form a central lipid core; shoulder regions contain SMCs, macrophages and other leukocytes) * **vasa vasorum** from nearby adventitia in-grows to supply the lesion, weakening the walls & causing remodelling * **fibrous plaque** (smooth muscle hypertrophy, collagen formation and consolidation of deep lipid core - may have relatively thin surface, vulnerable to rupture) * **intra-plaque haemorrhage** (plaque neovascularisation results in spontaneous haemorrhage and subsequent rupture with thrombo-embolism) * coronary, carotid & aortoiliac lesions tend to occur at branch points, however obstructive SFA plaque tends to develop in distal portion of vessel (generally straight w few branches - but anatomic compression by adductor tendons at adductor hiatus which limits compensatory arterial dilation to growing plaque) - Inciting events include proinflammatory substances in the vasculature, including glycated Hb and LDLs, and shear forces from turbulent blood flow (eg at junctions) - Endothelial injury leads to accumulation of lipid-laden macrophages. - Platelet aggregation, fibroblast and smooth muscle activation leads to a raised lesion with a fibrous cap, calcification, lipid-rich necrotic core and intimal smooth muscle hypertrophy

Answer 9

Mucosal breakdown leads to extrusion and intravasation of intestinal gas, with contribution from translocation of gas-forming bacteria

Answer 10

I: 0-15% (\<750mL) II: 15-30% (750-1500mL) III: 30-40% (1500-2000mL) IV: \>40% (\>2000mL)

Answer 11

JC A series of proteins involved in the innate immune response to antigen. These exist in the serum as precursor molecules - stimuli including antigen-antibody binding, direct microbe binding or mannose-binding lectin. Common result is activation of C3, C5 and formation of the membrane attack complex. Actions are: - Formation of membrane attack complex (via the classical pathway) - Opsonisation for phagocytosis (via the alternative pathway) - Inflammation, attracting macrophages and leucocytes (via the Lectin pathway)

Answer 12

Formation of free radicals leads to DNA damage Tumour cells lack DNA repair mechanisms and so are destroyed, whereas normal cells can repair DNA and recover

Answer 13

Acute effects due to: • GI epithelium has a high proliferation rate -\> susceptible to injury from radiation & chemo • Loss of mucosal stem cells in Crypts of Lieberkuhn either directly or as a result of microvascular damage, so decreased cellular reserves for intestinal villi • Consequent mucosal denudation with associated intestinal inflammation, oedema, shortened villi and decreased absorptive area Occur within hours of irradiation. Should repopulate within days and symptoms should resolve within 2 weeks ``` Late effects (\>3 months) are due to: • Progressive obliterative vasculitis of the blood vessels within the bowel wall and submucosal fibrosis -\> eventually vascular thrombosis, vascular insufficiency & chronic intestinal ischaemia • Mucosal ulcerations can occur -\> perforation, fistulas or abscess formation • As ulcers heal, can be fibrosis w narrowing of intestinal lumen & stricture formation/obstruction • Stasis can --\> SB bacterial overgrowth • These chronic changes can impair absorption of fats, carbs, proteins, bile salts & vit B12 -\> loss of water, electrolytes & proteins in SB - Lactase degradation can be impaired --\> increased bacterial fermentation & associated flatulence, abdominal distension & diarrhoea - Bile salt resorption may be impaired --\> increased amounts of conjugated bile salts in colon --\> bile salts then deconjugated by bacteria --\> intraluminal water retention w resultant diarrhoea ``` NB large intestine generally believed to be less radiosensitive than SB; when radiation injury does involve colon, pts can develop a pancolitis that mimics inflammatory bowel disease

Answer 14

Dilated ectactic submucosal vessels thought to be due to obstruction of smaller vessels in submucosa

Answer 15

A hydatid liver cyst is caused by an infection with Echinococcus granulosus most commonly, and rarely Echinococcus multilocularis parasite. E granulosus resides as an adult tapeworm in the SB of the definitive host (the dog). Humans are an accidental host and ingest the eggs of the E. granulosus through faecal route. Eggs then release larvae in the GI tract due to an interaction with bile salts and trypsin. Larvae then penetrate into wall of jejunum and are transported via portal circulation to liver, or via lymphatics to lung, where these larvae develop into hydatid cysts. Cysts then enlarge asexually, producing protoscolices which are contained in brood capsules, as well as daughter cysts, which fill the cysts. When the organ containing the cysts are ingested by the definitive host (dog), the protoscolices evaginate and the scolices attach to the intestine of the dog and develop into adult tapeworms which completes the life cycle. Usually intermediate host is the sheep; we are accidental hosts.

Answer 16

V: splenic vein thrombosis, haemangiosarcoma, portal hypertension I: malaria, HIV, abscess, TB T: rupture/pseudocyst A: ITP, AHA, Sarcoid, SLE, Felty’s syndrome M: lysosomal storage disease, amyloidosis I: hypersplenism N: lymphoma, leukaemia, secondary deposit, myelofibrosis C: spherocytosis, elliptocytosis D: cyst

Answer 17

* an inflammatory injury to the lung endothelium and epithelium * leads to increase in lung vascular and epithelial permeability, and the passage of protein-rich oedema fluid into the airspaces * lung injury is caused by neutrophil- and platelet-dependent damage to the endothelial and epithelial barriers * resolution of ARDS is delayed because the lung epithelial barrier injury prevents removal of the alveolar oedema fluid and deprives the lung of surfactant * initial injury can be compounded by ventilator-associated lung injury * criteria: * lung injury of actue onset * bilateral opacities on chest imaging not explained by other pulmonary pathology * respiratory failure not explained by heart failure or volume overload * decreased arterial PaO2/FiO2 ratio * mild ARDS: 201-300 * Moderate ARDS: 101-200 * Severe ARDS: ≤100 * high mortality * many survivors develop chronic lung disease, with the damaged lung healing by fibrosis

Answer 18

* Lethal triad = hypothermia, acidosis, coagulopathy * Trying to avoid these, as well as treating them * Lethal diamond = add hypocalcaemia * Independently assoc w high risk of mortality outside of its effects on coagulopathy alone * Acidosis * Effects * Reduces contractility & CO * Vasodilation & worsening hypotension * Impaired metabolic function & coagulation * Vasopressor & other catecholamines don’t work as well * BD of ≥6 is strongly assoc w * Need for MT & mortality * ICU days * ARDS & MODS * Pts tend to have elevated BD BEFORE their BP drops to classic ‘hypotension’ levels * Hypothermia * Develops at some point in up to 57% of trauma pts * Independently assoc w 3x odds of death when adjusted for age, ISS, mechanism, BP * In ISS \<25: * Temp \>34 = 7% morality * \<34C = 40% * \<32C = 100% * effects * metabolism: shivering -\> oxygen consumption (increases proportion of anaerobic metabolism & therefore lactic acid production) -\> _acidosis_ * CNS: confusion -\> coma * Cardiac: vasoconstriction; and AF -\> VF -\> cardiac arrest * Resp: RR, bronchospasm; and decreased resp drive -\> apnoea * GI: motility decreased * Blood cells: platelet dysfunction; coagulation enzymes impaired -\> _coagulopathy_ * Renal: cold diuresis * Coagulopathy * All above relate to coagulopathy, ultimately the most important aspect * Non-surgical bleeding difficult to control * Documented linear relationship with mortality * Many different types of coagulopathy; trauma-induced coagulopathy is different to other types * Combination of tissue injury -\> endothelial glycocalyx injury * Significant role for protein C as well * Risk is that there is a proportion of these pts who are already coagulopathic and we don’t want to worsen things by giving them resuscitation-induced-coagulopathy * Hypocalcaemia * Decreases liver’s ability to metabolise citrate -\> more calcium being bound & less available in the blood

Answer 19

* Lethal triad = hypothermia, acidosis, coagulopathy * Trying to avoid these, as well as treating them * Lethal diamond = add hypocalcaemia * Independently assoc w high risk of mortality outside of its effects on coagulopathy alone * Acidosis * Effects * Reduces contractility & CO * Vasodilation & worsening hypotension * Impaired metabolic function & coagulation * Vasopressor & other catecholamines don’t work as well * BD of ≥6 is strongly assoc w * Need for MT & mortality * ICU days * ARDS & MODS * Pts tend to have elevated BD BEFRORE their BP drops to classic ‘hypotension’ levels * Hypothermia * Develops at some point in up to 57% of trauma pts * Independently assoc w 3x odds of death when adjusted for age, ISS, mechanism, BP * In ISS \<25: * Temp \>34 = 7% morality * \<34C = 40% * \<32C = 100% * effects * metabolism: shivering à oxygen consumption (increases proportion of anaerobic metabolism & therefore lactic acid production) à _acidosis_ * CNS: confusion à coma * Cardiac: vasoconstriction; and AF à VF à cardiac arrest * Resp: RR, bronchospasm; and ¯resp drive à apnoea * GI: motility ¯ * Blood cells: platelet dysfunction; coagulation enzymes impaired à _coagulopathy_ * Renal: cold diuresis * Coagulopathy * All above relate to coagulopathy, ultimately the most important aspect * Non-surgical bleeding difficult to control * Documented linear relationship with mortality * Many different types of coagulopathy; trauma-induced coagulopathy is different to other types * Combination of tissue injury à endothelial glycocalyx injury * Significant role for protein C as well * Risk is that there is a proportion of these pts who are already coagulopathic and we don’t want to worsen things by giving them resuscitation-induced-coagulopathy * Hypocalcaemia * Decreases liver’s ability to metabolise citrate à more calcium being bound & less available in the blood * Damage control resus = a systematic group of concepts of resuscitation that are utilized in an attempt to reduce ongoing blood loss and minimize the exacerbating underlying metabolic processes until definitive haemorrhage control can be achieved * 3 main tenets to it: * permissive hypotension * haemostatic resuscitation (how we should resuscitate pts to minimize the effects of worsening the acute coagulopathy) * early haemorrhage control/DCS * involves: * rapid diagnosis – trying to identify the group early that are going to benefit most from these interventions * limit crystalloids * early 1:1:1 transfusion strategy * permissive hypotension * rapid anatomic control * antifibrinolytics * DCR doesn’t stop when get to theatre, and also DCS is part of DCR * Permissive hypotension * Allow SBP/MAP to fall low enough to minimize bleeding, but high enough to maintain vital tissue perfusion (cardiac & neurological) * Avoiding disruption of the clot formed * Low BP is not the target, it is a compromise – don’t TRY to reduce BP * Haemorrhage control is the goal (not hypotension) * Remains controversial & not completely widely accepted * Animal studies * Variable interpretation of meaning & use * Prolonged retrieval times * Use in those w brain & spinal cord injuries * Appropriate targets for that individual? Some peoples version of hypotension might be normal for them, but other people who are relatively normotensive that might be quite low for them * Primarily applicable to penetrating trauma * If using in blunt trauma would have to be clear that dealing with a specific group of people that have a short time to likely definitive surgical/radiological intervention so risk/benefit ratio would mean that permissive hypotension likely ok * Targets differ: ?European guidelines (guidelines differ) * Target MAP of 50-60mmHg in pts w/o TBI/SCI * Target 80-90mmHg in pts w confirmed or suspected TBI/SCI * Some recommendations go further and say if a pt has a palpable radial pulse in the pre-hospital setting that’s enough; or alternatively if mentating * Haemostatic resuscitation – 3 main concepts * Minimize the use of crystalloids * Balanced blood product transfusion * Management of acute coagulopathy of trauma * IV fluids * Minimize the amount of all non-blood product or oxygen carrying capacity fluids * Excessive use of crystalloids been shown to worsen outcomes in trauma * As little as 500mL * How? * Hyperchloraemic acidosis which tends to worsen their coagulation profile * Dilution of remaining coagulation factors * What if you don’t have blood available? * Ideal fluid of choice unclear, but likely not 0.9% NaCl * ATLS has reduced their recommended initial 2L to 1L * Doesn’t stop after leave ED – intraop important too

Answer 20

* spore forming, anaerobic, gram +ve bacteria * faecal oral transmission * in setting of disrupted colonic microbiome from antibiotic use which causes proliferation of c diff * pathogenic mechanism: * cytotoxin A: damages mucosa, villous tips * cytotoxin B: endocytosis and induces apoptosis of epithelial cells * leads to inflammatory response and SIRS * forms pseudomembrane: fibrin, dead neutrophils, bacteria, mucous

Answer 21

* ACS is a sustained intra-abdominal pressure of \>20mmHg, associated with new organ dysfunction * affects multiple organ system * GI issues due to direct pressure on the bowel as well as reduced splanchnic blood flow --\> tissue hypoxia, can lead to mesenteric thrombosis and bowel wall ischaemia, predisposes to translocation of bacteria * renal impairment due to direct compression of renal parenchyma and renal vein leading to increased renal vascular resistance, decreased renal blood flow and decreased urinary output * cardiovascular compromise * compression of IVC and portal vein reduces venous return --\> hypotension and reduced stroke volume * increased intrathoracic pressure due to elevated diaphragm can cause compression of pericardium and decreased LV end-diastolic volume * hypotension worsens the renal impairment and activates RAAS leading to arterial constriction * respiratory compromise * reduced compliance of diaphragm against increased pressure within abdomen * increases airway pressures and causes decreased tidal volumes * can cause compressive atelectasis and VQ mismatch --\> resultant hypoxia and acidosis * increased intracranial pressure - impaired venous return causes increased ICP and decreased cerebral perfusion - can cause worsening cognitive impairment and delirium * hepatic impairment * decreased portal blood flow --\> decreased mitochondrial function in liver and decreased lactate clearance * reduced blood flow to abdominal wall - impaired healing * SIRS * increased risk of DVT due to decreased venous return from lower limbs

Answer 22

* there are a number of different contributing mechanisms that predispose patients to these * **arterial issues** * **microvascular disease** - hyperglycaemia causes vasoconstriction, inflammation and thrombosis; reduced endothelial NO, increased ROS, 'advanced glycation endproducts' all cause thickened capillaries; contributes to nerve issues * **macrovascular disease** * these lead to ischaemia, contribute to ulceration and secondary infection, and reduce ability of foot to heal from infection/repetitive trauma b/c can't increase blood supply needed to heal * **nerve issues** * **sensory neuropathy** due to disease of vasa nevorum from microvascular disease and hyperglycaemia * loss of protective pain sensation and proprioception * repetitive microtrauma to joints & pressure points on skin b/c not sensing and moving the foot like they normally would --\> damage * **autonomic neuropathy** - warm, dry foot * denervation of sweat glands leads to dry skin & cracks * opens AV shunts whihc increase blood flow to limb but shunts blood away from skin capillaries --\> functional local skin ischaemia * **motor neuropathy** * atrophy of intrinsic muscles --\> guttering, altered foot shape, clawed toes & prominent MT heads --\> change in weight distribution & eventual dislocation of MTP heads --\> increased foot pressures & subsequent ulceration * diabetes commonest cause of Charcot foot * **visual impairment** - contributes to trauma and ulceration * **tissue effects of hyperglycaemia** * chronic hyperglycaemia --\> glycosylation of proteins and collagen bundles become thickened & cross-linked --\> alters mechanics of walking, high plantar pressures * impaired chemotaxis & phagocytosis (leukocyte dysfunction due to chronic glycosylation of neutrophils) * ideal bacterial substrate * i.e. leads to higher risk of infection and difficulty dealing w infection when it does occur

Answer 23

* Virchow's triad * endothelial injury due to e.g. * surgery * trauma * lines, venepuncture * hypercoagulability, e.g. * malignancy * thrombophilia syndromes * nephrotic syndrome * pregnancy and post-partum * trauma incl surgery * venous stasis due to e.g. * immobility * prolonged surgery * varicose veins * venous hypertension * venous obstruction

Answer 24

* goitre = enlarged thyroid gland * diffuse if evenly enlarged * multinodular = enlarged, diffusely heterogeneous thyroid gland comprised of multiple nodules of varying sizes * iodine deficiency = most common cause of goitre worldwide * primary from low iodine intake * secondary from diet (goitrogens eg brassica family or excess fluoride/calcium) or drugs (iodine, lithium, amiodarone) * in places where significant iodine deficiency doesn't exist, multinodular goitre, chronic autoimmune (Hashimoto's) thyroiditis and Graves' disease more common * in iodine deficiency or chronic autoimmune thyroiditis, increase in TSH secretion = predominant cause of goitre * most patients with sporadic nontoxic multinodular goitres have normal serum TSH concs; goitre prob caused by several growth factors (incl TSH) that act over time on thyroid follicular cells that have different synthetic and growth potentials * often fhx of goitre, suggesting that genetic factors may also play a role * result = diffuse and later multinodular thyroid enlargement; nodularity occurs due to haemorrhage and scarring and involution of the gland, leading to irregular nodularity * some nodules eventually become autonomous due to activating mutations in TSH receptor or G proteins within the thyroid follicular cells, and others may undergo cystic degeneration * in Graves': TSH receptor antibodies (TRAb) stimulate the TSH receptor to cause thyroid growth and excessive hormonal secretion * 2 stages in development of MNG which may be separated by long period of time eg decades * early stimulus for generalised thyroid hyperplasia = iodine deficiency/goitrogens/genetic predisposition * second stage = due to focal somatic mutations * although most mutations result in enlarged colloid follicles, focal hyperplasia, hypertrophy, adenoma or even carcinoma can all contribute to the MNG * over time these nodules undergo haemorrhage, cystic degeneration, necrosis +/- fibrosis and calcification

Answer 25

* A severe thyrotoxic state which may be precipitated by illness or a procedure in an un or undertreated patient * characterised by severe tachycardia, hypo or hypertension, fever, confusion, vomiting and adrenergic overstimulation to the point of mania and coma with potential for arrhythmias and cardiovascular collapse * treatment is with * rapid fluid replacement * cooling * high dose PTU * beta blockers * iodine solution * steroids * cardiac monitoring * in life-threatening situations, plasmaphoresis or plasma exchange may be effective in reducing T4 & T3 levels

Answer 26

* fibroblastic proliferation and collagen deposition in the palmar fascia * leads to contracture and the development of nodules and cords in the palmar fascia

Answer 27

**Acute phase:** Insufficient substrate (glucose) delivery and insufficient oxygen delivery Local anaerobic metabolism leads to lactic acidosis Failure of ATP pumps: cellular damage with K+ release, cytokine release, and oedema due to increased membrane permeability Oedema further impairs oxygen delivery, bacterial infections may be superimposed, especially in the context of pre-existing disease Compartment syndrome is caused when local compartmental pressure becomes greater than perfusion pressure. **Reperfusion phase:** Generation of oxygen free radicals; attach to FAs in the phospholipid membrane and cause mechanical and functional derangements Revascularisation results in sudden venous return of blood with anaerobic metabolitse, low pH and high K conc Reperfusion of large mass of ischaemic tissue --\> systemic inflammatory response; may lead to multiple organ dysfunction & failure (hypotension and arrythmias), K+ may cause arrhythmias Renal function may be furhter impaired by myoglobinuria (helped by maintaining good diuresis) Revasc of ischaemic muscle can lead to considerable swelling within fascial compartments of legs --\> increased compartment pressures causing venous compression, worsening oedema & if not treated promptly, permanent neurological insult. Pts at highest risk of this = prolonged ischaemia or ischaemia from embolic source.

Answer 28

* early dumping syndrome up to 50% after RYGB * rapid onset usu within 15mins * result of rapid emptying of food into SB & bc of hyperosmolality of food, rapid fluid shifts from plasma into bowel occur --\> hypotension & SNS response * colicky abdo pain, diarrhoea, nausea, tachycardia * avoid foods high in simple sugar content & replace w diet consisting of high-fibre, complex carb & protein rich foods; also small frequent meals & separate solids from liquid intake by 30mins * usu self-limiting and resolves within 7-12wks * late dumping syndrome/reactive hypoglycaemia 1-2% * usu 1-3hrs after ingestion of carb-rich meal, typically months to yrs after surgery * neuroglycopenic sx (dizziness, fatigue, diaphoresis, weakness) assoc w low serum glucose levels; exact aetiology uncertain but prob includes combo of late dumping, beta cell hyperfunction and exaggerated incretin response * same dietary modification as above

Answer 29

A progressive, obliterative fibrosis (same as radiation enteritis) of the intra and extrahepatic biliary tree, causing strictures, secondary cholangitis and progressive liver failure

Answer 30

Many causes; all associated with gradual and incremental loss of liver cell mass and function, due to chronic or repeated cell injury and attempts at repair. There's a fibrosis and scarring process associated with this regeneration and repair, that leads to the clinical condition of cirrhosis, with a typically small, shrunken, irregular liver and an increased risk of HCC development. Cycles of necrosis, fibrous scarring & regeneration --\> distortion of microcirculation of liver & disturbances to liver cell perfusion (hepatocellular injury and necrosis) --\> fibroblast activity --\> collagen deposition (esp in space of Disse) --\> loss of fenestrations in sinusoidal endothelial cells --\> Cirrhosis ETOH --\> hepatic steatosis --\> alcoholic hepatitis --\> cirrhosis on biopsy: hepatocellular necrosis, PMN infiltration, presence of Mallory bodies * lactic acidosis & hypoglycaemia bc of impaired Cori cycle * build up of ammonia bc of impaired nitrogen homeostasis * immune function compromised as liver's phagocytic and synthetic capacity impaired * portal hypertension +/- varices * ascites * coagulopathy/thrombocytopaenia * hepatic encephalopathy * hepatorenal syndrome (vasoactive changes in arterial circulation --\> decreased GFR) * bacterial infection & hepatic encephalopathy = leading causes of death * HCC

Answer 31

Entamoeba histolytica (parasite). Faecal oral spread; humans ingest cysts orally and then trophocytes are released and multiply in the colon (espec caecum) - which causes diarrhoea in ~30% - then these trophocytes reach liver by portal venous and lymphatic circulation or sometimes by direct extension through colon wall --\> peritoneum --\> liver capsule.

Answer 32

A combination of two things; 1. **An increase in the vascular resistance to portal flow** - _due to an architectural distortion in the liver_ (increased passive resistance secondary to fibrosis and regenerative nodules) _and also an imbalance in the endogenous vasoconstrictors_ which are increased (norepinephrine, endothelin etc) _& vasodilator_ nitric oxide which is decreased - increases hepatic vascular tone through contraction of myofibroblasts/activated stellate cells/vascular smooth muscle cells of intrahpeatic veins. 2. **An increase in portal blood flow** due to _progressive splanchnic arteriolar vasodilation/splanchnic hyperaemia_ (most of the medications for portal HTN are aimed at reducing this increased splanchnic blood flow)

Answer 33

* increase in portal venous pressure causing splanchnic vasodilatation which alters the capillary pressures and permeability --\> fluid leakage into peritoneal space * also increased lymphatic pressure leading to transudation and leakage of lfuid from lymphatic system * low plasma protein from reduced production of proteins in liver --\> reduced osmotic pressure of plasma --\> less fluid removed from extravascular sites and more fluid leaking from blood vessels * also increased sodium and water retention in chronic liver failure due to reduced circulating plasma volumes and pooling of blood in splanchnic system --\> messaging to kidneys to activate JGA --\> increased aldosterone and ADH levels via activation of RAAS

Answer 34

biliary obstruction causes cholestasis and increased pressure in biliary system --\> leads to infection and cholangiovenous reflux, causing translocation of bacteria from the biliary system into the venous system --\> systemic sepsis

Answer 35

* a benign inflammatory disease characterised by irreversible fibrosis and atrophy of pancreatic parenchyma secondary to repeated injury resulting in altered structure and function, both endocrine and exocrine * aetiology * most common is chronic alcohol abuse * **T**oxin + metabolites - alcohol, smoking, Tg, Ca, medications * **I**diopathic * **G**enetic - SPINK1, PRSS1, CF * **A**utoimmune - IgG4 * **R**ecurrent and severe: post-necrotic severe AP * **O**bstructive - SOD, divisum * multiple theories for pathogenesis; no one really knows; does seem to be common pathway of an initial insult with injury which is often recurrent, followed by an attempt at healing through fibrosis & regeneration * 2 hit hypothesis: * pre-existing acute pancreatitis risk factor that initiates first acute hit of pancreatitis * abnormal repsonse to that pancreatitis --\> chronic inflammation & progression to chronic pancreatitis * this fits with necrosis-fibrosis pathway theory which is that multiple episodes of acute pancreatitis -\> duct distortion & altered pancreatic secretions that over time lead to loss of panc parenchyma & fibrosis * toxic metabolite hypothesis: * alcohol, tobacco & other environmental factors damage acinar cells which results in their chronic destruction * several products of alcohol metabolism eg fatty acid ethyl esters & ROS cause fragility of intraacinar organelles, such as zymogen granules & lysosomes, which -\> abnormal panc enzyme activation inside acinar cells * acetaldehyde, another alcohol metabolite, causes direct acinar injury * NB alcohol also directly activates pancreatic stellate cells which produce fibrosis * ductal blockade theory * protein plugs that form in panc ducts, diffuse fibrosis, increased viscosity of panc juice, stone formation, calcification --\> increased ductal pressure --\> acinar cell autodigestion & inflammation --\> chronic pancreatitis * thought that alcohol also works through this pathway bc reduces bicarb & water secretions in ductal secretions making it thicker & more likely to clog ductal system * oxidative stress theory * oxidative stress causes free radical generation within acinar cells -\> membrane lipid oxidation & activation of inflammatory pathways -\> fibrosis * exocrine failure due to * loss of acinar cells * fibrosis and strictures within ductal system from chronic scarring that stop the flow of any panc juices that may be required * leads to steatorrhoea & requirement for replacement panc enzymes * ≥90% of gland needs to be dysfunctional before steatorrheoa, diarrhoea & other sx of malabsorption * endocrine function * islet cells initially preserved but over time get progressive atrophy -\> endocrine dysfunction * chronic pain related to chronic pancreatitis; number of mechanisms (intra and extra-pancreatic) * increased pressure within ductal system/parenchyma due to obstructive-type pathophysiologies --\> pain * inflammatory involvement of intra-panc nerve fibres - neuro-immune reaction - inflammatory cells infiltrate round the nerves * increase in number of nerve fibres in fibrotic panc tissue * increased amounts of neurotransmitters in afferent panc nerves * aberrant CNS perception of pain * other complications: * biliary stricture where distal aspect of CBD passes through panc head * duo stenosis & GOO due to fibrosis & scarring here * pseudocysts espec in setting of disruption of panc duct * false aneurysms of visceral vessels can form leading to bleeding which may be acute presentation * portal & splenic vein occlusion due to chronic inflammation --\> extrahepatic portal HTN that can present as haematemesis & melaena * pancreatic ascites * pancreatic fistula * risk factor for pancreatic ductal adenocarcinoma

Answer 36

* Immune thrombocytopenic pupura * Auto-antibodies against the membrane glycoproteins on the platelets that labels the platelets for destruction in the spleen * Treatment * medical: observation, steroids or immunoglobulins, or cytotoxic agents (eg rituximab) * indications for surgery: resistant to medical treatment, incomplete responder, severe drop in platelets \<10 for 6 weeks, pregnancy if plt \<30 and not responding to treatment * 80% cured, 15% partial, 5% failure (accessory spleen or rupture)

Answer 37

* bile (with bilirubin and bile salts) unable to be secreted into intestine * --\> decreased fat absorption as usually bile salts help to emulsify fat within the SB, aiding its absorption * and --\> stools pale bc it is usu the bile pigments that, when converted to urobilinogben by bacterial enzymes in intestine, gives stool its characteristic colour * increased serum conjugated bilirubin --\> excreted in urine (dark) * excess bilirubin deposited in skin & sclera (bili \>42 to have scleral icterus; \>85 for cutaneous jaundice) * increased bile salts in circulation --\> pruritis * decreased absorption of fat-soluble vitamins (ADEK) * prolonged INR due to decreased vit K (fat soluble vitamin) * increased ALP - an enzyme present in bile duct epithelium & in the canalicular membrane of hepatocytes (and similar enzyme in bone & placenta) * increased GGT * NB cholestyramien is an anion exhcange resin; binds bile salts in intestinal lumen, preventing their reabsorption - relieves itch

Answer 38

A reversible neuro-psychiatric syndrome, with multiple causes. Aetiology is multifactorial; predisposing/exacerbating factors include portosystemic shunts (spontaneously and surgically or radiologically created), constipation & GI haemorrhage (with resultant increase in absorption of nitrogenous products). Characterised by cerebral oedema, increased ICP with risk of brain herniation and death. Range of factors may contribute including raised ammonia, glutamine and lactate. Ammonia has a range of effects on brain function, affecting neurotransmission as well as impairing mitochondrial function and key cellular transport systems. Brain glutamine conc increase may influence development of hepatic encephalopathy through toxic metabolites, modulation of hepatic blood flow or by amplifying toxic effects of ammonia. Lactate can result in significant swelling of astrocytes.

Answer 39

* as for many other cancers, a sequential pathway has been observed in the development of PDAC from pancreatic intraepithelial neoplasia (PanIN) to invasive ca; pancreatic carcinogenesis comprises histologically distinct precursor lesions * preneoplastic lesions usu asymptomatic and small in size (usu \<5mm), so radiographically occult & more commonly found at time of resection * precursor lesions include pancreatic intraepithelial neoplasia (PanIN) - most common, seen in 82% of neoplastic pancreases * normal -\> PanIN-IA -\> PanIN-IB -\> PanIN-2 -\> PanIN-3 * most common 4 genes that play a role in pathogenesis of PDAC (driver mutations) are: * K-ras - commonest, \>95% panc ca, thought to be the initiating event in tumourigenesis * CDKN2A - occurs early in development of PDAC * P53 and SMAD4 - occur later * IPMN and MCN are also considered precursor lesions Aetiology of pancreatic cancer: * modifiable risk factors: obesity, T2DM, smoking, also dietary fat, meat, heavy ETOH, occupational exposures * non-modifiable: age, male * inherited risk factors (5-10% of all pancreatic cancer) * pts w known genetic syndromes are responsible for 20% of all hereditary cases of pancreatic ca; term familial pancreatic cancer applies to remaining 80% of pts w an inherited genetic predispositino but who don't' have an identifiable genetic syndrome * Peutz Jeghers (STK11, 35% increased risk), Lynch (8.6x increased risk), APC, BRCA2, PALB2, ATM, FAMMM (CDKN2A - 17% increased risk) * genes assoc w hereditary pancreatitis (pts w hereditary panc have \>50x increased risk panc ca (PRSS1, SPINK1, CFTR) * first degree relatives w panc ca have at least 2x increased risk * mucinous pancreaitc lesions: IPMNs, MCNs

Answer 40

* usually D3 is protected by a fat pand and lymphatic tissue surrounding the SMA (which passes over D3) * when there is marked or rapid weight loss, this fat pad is lost, causing acute angulation of the SMA at its origin from the aorta, and causing compression of D3, leading to duodenal obstruction and GOO-type picture

Answer 41

* caused by atherosclerotic disease of the vessels feeding the GI tract (CA, SMA, IMA) * these patients develop chronic abdominal pain and symptoms caused by a gradual decrease in blood frow to the intestines, with symptoms most prevalent after eating due to increased blood flow required for digestion * because there is an abundant mesenteric blood supply, and atherosclerosis often progresses slowly, pts may develop a number of collateral pathways and therefore not present until they develop quite advanced atherosclerotic disease

Answer 42

* may be occlusive or non-occlusive (low flow state), thrombotic or embolic, venous or arterial * initially mucosal ischaemia - visceral pain but no clinical signs * as injury progresses, there is epithelial separation at basement membrane --\> capillary damage and increased mucosal permeability/loss of mucosal integrity --\> bacterial translocation, development of pneumatosis intestinalis --\> eventual gangrene and perforation * if reperfusion is established, pts may also suffer from reperfusion injury with infiltration of oxygen free radicals leading to an inflammatory infiltrate into the bowel, and also the release of lactate and potassium-rich blood into systemic circulation --\> may lead to a systemic response

Answer 43

* acquired pulsion diverticuli often found at the mesenteric border of the SB * mucosa and submucosa only * thought to be due to a motor dysfunction of the smooth muscle or of the myenteric plexus --\> disordered contractility, increased intra-luminal pressure, herniation of mucosa

Answer 44

* protected against by continued luminal flow by peristalsis, the acidity of gastric contents entering the small bowel, local effects of immunoglobulins and prevention of reflux of colonic contents by the presence of the ileocaecal valve * if any of these mechanisms are overcome, can get overgrowth of bacteria in SB, which leads to: * deconjugation of bile salts --\> these are reabsorbed in jejunum so that fats and fat soluble vitamins aren't absorbed well * unabsorbed fatty acids enter colon --\> lead to diarrhoea from increased net secretion of water and electrolytes from osmosis * hypocalcaemia bc calcium gets bound to these free unabsorbed fatty acids and secreted * oxalate renal stones - bc calcium is being bound to these FFAs, it can't bind to oxalate and help w excretion of oxalate from body as usual - so oxalate gets absorbed and screted by kidneys, leading to precipitation and oxalate stones * anaerobic bacteria in SB also bind vitB12 --\> malabsorption of vit B12 and macrocytic anaemia * bacteria can also catabolise carbs and proteins --\> contribute to malabsorption and weight loss * bloating, constipation, diarrhoea and pain bc bacteria ferment unabsorbed carbs --\> hydrogen and methane gas

Answer 45

* normally, midgut herniates out of abdo cavity ~5wth wk of embryonic development, as the embryonic coelom can't accommodate the rapidly expanding GI tract; as a result, the primary intestine loop buckles into the area of the yolk stalk, which will be the future umbilicus; the axis of this loop is the developing SMA * as the primary intestinal loop buckles out of the abdomen, it begins the normal rotation of the bowel by twisting 90 degrees anticlockwise * this initial rotation is driven by two factors: * the proximal bowel ('pre-arterial' or 'DJ loop') grows faster than the distal bowel ('post-arterial' or caecocolic loop), and * the rapid growth of the liver * primary loop continues to grow, then returns to abdomen by 10th week; with return to abdomen there is an additional 180 degrees counterclockwise rotation --\> overall effect = bowel rotates 270 degrees counterclockwise from original primary loop * DJ segment returns first & rotates beneath and to right of SMA to fix to left of midline at ligament of Treitz, at level of L1 vertebral body * caecocolic segment also rotates counterclockwise around SMA to rest in final position in RLQ * by week 12, this process of intestinal rotation is complete & colon becomes fixed to retroperitoneum * normal rotation & fixation --\> wide-based mesentery that extends from ligament of Treitz in LUQ to ICV in RLQ, and prevents rotation around SMA * complete non-rotation of midgut * occurs when neither DJ nor caecocolic limb undergoes correct rotation * SB located on right of abdomen & colon on left * nonrotation not as dangerous as malrotation bc in general, base of mesentery is wider than in malrotation and risk of volvulus is less (pts have effective anatomy of those who have had Ladd procedure) * normal relationship of superior mesenteric vessels is reversed/altered (vein is to right of artery) * malrotation occurs when DJ limb doesn't rotate but caecocolic limb does rotate normally and fix (though usually partial rotation of 90 degrees rather than 100) --\> caecum ends up in mid-upper abdomen and is fixated to right lateral abdominal wall by bands of peritoneum (Ladd's bands) that extend from colon across anterior duodenum; can cause extrinsic compression & obstruction of duo * can also have normal rotation of DJ limb w nonrotation of caecocolic segment, or other rare anomalies of rotation * anatomic features of malrotation can lead to volvulus from narrow mesentery base (may be complete or incomplete/intermittent), or duodenal obstruction from Ladd bands or associated duodenal atresia or stenosis * 60% of children w intestinal malrotation have an associated anomaly; congenital diaphragmatic hernia, congenital heart disease & omphalocele are common; also gastroschisis, certain types of intestinal atresias, oesophageal atresia, biliary atresia, Meckel's, complex anorectal malformations, Cornelia de Lange syndrome

Answer 46

Results from incomplete closure of the omphalomesenteric, or vitelline duct, which connects the midgut to the yolk sac in the fetus, and normally undergoes obliteration at approx 8th week of gestation. Persistence of this duct beyond fetal development may result in a variety of anatomical patterns, including omphalomesenteric cysts, omphalomesenteric fistulae that drain through the umbilicus, and fibrous bands from the diverticulum to the umbilicus. Most common form is a diverticulum w/o additional attachment = Meckel's diverticulum. Embryological origin of the ectopic tissue within the walls of the diverticulum in 60% of cases is not known. A remnant of the left vitelline artery can persist to form a mesodiverticular band, which connects the Meckel's to the ileal mesentery (and can cause obstruction). Most common presentations are bleeding (from ulceration of small bowel due to acid secretion by ectopic gastric mucosa within the diverticulum), obstruction (from a band adhesion - mesodiverticular band or fibrous band to abdo wall, or volvulus around a fibrotic band attached to abdominal wall, or intussusception) and diverticulitis

Answer 47

Encompasses a number of different conditions - peripheral sensory neuropathy, peripheral arterial disease, ulceration, infection including osteomyelitis, and charcot neuro-osteoarthropathy 1. Arterial issues * microvascular disease * at the arteriolar/small un-named vessel level - contributes to nerve issues * hyperglycaemia causes vasoconstriction, inflammation & thrombosis * decreased endothelial NO, increased ROS, 'advanced glycation endproducts' all contribute * macrovascular disease * occurs in up to 30% diabetics * diabetes often part of the metabolic syndrome that drives macrovascular disease * diabetics often get disease in smaller/below knee vessels & often diffuse/widespread rather than focal stenosis like smokers get * leads to ischaemia, contributes to ulceration & secondary infections & decreases ability of foot to heal from infection/repetitive trauma 2. Nerve issues * sensory neuropathy * disease of vasa nevorum from microvascular disease & hyperglycaemia also directly damages nerves --\> loss of protective pain sensation & proprioception * insensate foot more prone to trauma & burns and pt may be unaware * repetitive microtrauma to joints & pressure points on skin bc not sensing and moving the foot like normal * autonomic neuropathy * denervation of sweat glands --\> dry skin & cracks * opens arteriovenous shunts which appears to increase bloof flow to limb with easily bounding pulses, but consequences of shunting blood away from skin capillaries --\> functional local skin ischaemia (warm, dry foot) * motor neuropathy * atrophy of intrinsic muscles --\> guttering, altered foot shape, clawed toes & prominent MT heads --\> increased foot pressures with subsequent ulceration * Charcot foot been reported in most sensory neuropathies but diabetes now commonest cause; can be triggered by trauma to or infection of the foot * visual impairment * contributes to trauma & ulceration 3. Tissue effects of hyperglycaemia * chronic hyperglycaemia --\> glycoslyation of proteins & collagen bundles become thickened & cross-linked --\> alters mechanics of walking, high plantar pressures * impaired phagocytosis and chemotaxis (leukocyte dysfunction) due to chronic glycosylation of neutrophils * ideal bacterial substrate * i.e. lead to higher risk of infection & difficulting in dealing with infection when it does occur 4. NB also assoc w ESRF and development of foot ulcers increases exponentially in first year after starting dialysis - ?related to decreased transcutaneous presure of O2 during/after HD, also variation in peripheral oedema & therefore shoes rubbing

Answer 48

* venous system returns deoxygenated blood from capillary beds to right atrium via low-pressure, high-volume venous channels * flow towards heart maintained by unidirectional valves throughout predominantly the peripheral venous system, and muscle pumps located in the calf and foot which compress the gastroc & soleus sinuses and propel blood towards heart * retrograde flow (away from heart) = venous incompetence or reflux; usually due to damage to venous valves - the main pathogenetic factor underlying chronic venous insufficiency * _chronic venous insufficiency causes sustained venous hypertension in the legs_ * contributors to chronic venous hypertension * superficial venous reflux secondary to valve incompetence = most common * deep venous reflux * venous outflow obstruction (post-thrombotic (thickening/scarring), non-thrombotic or extrinsic compression) * calf muscle pump failure (usu due to ankle stiffness or poor calf muscle bulk) * dependency * obesity * venous hypertension initiates a sequence of anatomic, physiologic and histologic changes leading to venous dilation, skin changes or skin ulceration * chronic venous hypertension leads to oedema and leakage of macromolecules in the blood into the superficial tissues * leakage of white cells --\> inflammation and tissue damage * fibrinogen --\> fibrous cuff around the vessels; reduces ability for oxygen to cross to the skin, leading to local ischaemia * red cells --\> taken up by macrophages --\> leads to haemosiderin deposition * all of these together cause the clinical picture of hyperpigmentation/haemosiderosis, lipodermatosclerosis and venous eczema which eventually leads to ulceration * commonest cause = superficial venous reflux secondary to valve incompetence * other factors contributing include * deep venous reflux * venous outflow obstruction (post-thrombotic (thickening/scarring), non-thrombotic or extrinsic compression) * calf muscle pump failure (usu due to ankle stiffness or poor calf muscle bulk) * dependency * obesity * in many cases, espec after venous thrombosis, obstruction & reflux coexistent resulting in severe CVI

Answer 49

* an autoimmune disease with an abnormal T cell mediated and humoral response to the ingestion of gliadin, a component of gluten * this essential leads to mucosal damage; can be seen as * atrophy of mucosal folds --\> loss of brush border enzymes * loss of stimulation for pancreatic and bile secretion * protein loss due to exudation of proteins across an abnormal mucosa * in long term may lead to longstanding disease e.g. intestinal lymphoma, if pts aren't on a diet that excludes gliadin

Answer 50

* there are a number of both structural and functional changes to the SB that increase its absorptive capacity * structural * SB lengthens and dilates * muscle wall becomes thicker (muscular hypertrophy) * villi increase in size and number * functional * slowing of peristalsis to increase transit time and absorption * increase/upregulation of the enzymes at the brush border to improve absorption of the SB * increased absorptive capacity of the epithelial cells * ileum is better at adapting than jejunum * hypersecretory phase 1-2mo * adaptation phase 3-12mo * stabilisation phase - max adaptation will take up to 1-2yrs

Answer 51

* main function of TI over other parts of bowel is its ability to absorb bile salts and vit B12 * reduced absorption of vit B12 --\> macrocytic anaemia * reduced absorption of bile salts in TI --\> reduction of enterohepatic circulation of bile salts and therefore a decreased pool of bile salts to be excreted * because there are reduced bile salts to be excreted, there is reduced absorption of fat and fat soluble vitamins * vit D important for bone health and vit K for clotting * increased bile salts entering colon --\> watery diarrhoea as they stimulate colonic fluid secretion * can also get steatorrhoea due to fat malabsorption * bc fat is reaching colon, get oxalate renal stones bc FFAs bind to calcium, calcium is excreted (and get hypocalcaemia), and that calcum would usually be bound to oxalate which is instead reabsorbed into the circulation and secreted in the kidneys --\> precipitates out as oxalate stones

Answer 52

* Not entirely clear; though to be a complex interaction between the gut, brain, endocrine system and fat stores, with both genetic and environmental factors * A multifactorial process, probably contributed to by genetic predisposition, environmental factors, socioculture factors, hormonal, metabolic, behavioural and physiological factors * Obesity leads to accumulation of adipose tissue which is metabolically and hormonally active * These adipocytes secrete adipocyte-derived peptides such as leptins and cytokines, which are collectively called adipokines * These adipokines contribute to a state of chronic, low grade inflammation, which in turn interferes with many physiological cellular processes such as insulin signaling  leads to the metabolic derangements often seen in obesity e.g. T2DM * Ie essentially pts have a pro-inflammatory state, metabolic dysfunction and endothelial dysfunction which all contribute to the pathophysiological sequelae of obesity

Answer 53

* Restrictive component due to small stomach/pouch created * Malabsorptive – some procedure e.g. bypass procedure – will bypass some of the absorbative length of the bowel, leading to malabsorption of nutrients and calories * Hormonal and neural signaling * decreased hunger signals  reduced food intake * increased number of cells that secrete post-prandial satiety gut peptides – eg GLP-1 and GLP-2 * also vagal signaling is changed post bariatric surgery – may play a role in satiation, reduction of signaling of grhelin, and reduction in meal sizes and altered food preferences

Answer 54

Sweating, erythema or warmth over parotid bed area whilst eating - thought to be due to parasympathetic nerve fibres from auriculotemporal nerve re-anastomosing with sweat glands after parotidectomy. Reported incidence up to 63% but may be much higher when objectively treated w electrogustatory or starch-iodine testing

Answer 55

* a synergistic soft tissue infection * infection usually begins via a break in the muco-cutaneous barrier; usually the skin (or in Fourniers can be urethral or GI mucosa) * bacteria, aided by pathogenic factors e.g. hyaluronidase, lipase, collagenase (many sp.), streptokinase and M-proteins (GAS) and alpha-toxin (clostridial sp.) spread throughout the layers of the skin / along the relatively hypoxic fascial planes in the case of nec fasc * local inflammatory changes also promotes microvascular occlusion which facilitates further spread of infection * can also lead to a systemic inflammatory response syndrome with shock and MODS * oedema due to vessel damage and leaking of fluid as a result of the inflammatory response, that leads to increasing pressure in compartments and spaces, further impairing tissue perfusion * types of nec fasc: * type 1 - polymicrobial infection - synergistic infection with both aerobes and anaerobes * type 2 - monomicrobial infection - group A haemolytic strep most common * type 3 - marine (vibrio) or fresh water (aeromonas) * type 4 - rare fungal infections, usu assoc w trauma or severe immunocompromise * in traumatic gas gangrene from C perfringens, alpha toxin is largely responsible for both the widespread tissue necrosis and the characteristic absence of a tissue inflammatory response (PMNs notably absent from infected tissues in contrast to soft tissue infections caused by orgs like staph aureus) * associated shock may be attributable to both direct and indirect effects of alpha and theta toxins from the C perfringens; alpha toxin directly suppresses myocardial contractivlity & may contribute to profound hypotension; theta toxin reduces systemic vascular resistance (pts w gram neg sepsis compensate for hypotension by markedly increasing cardiac output, but this adaptive mechanism may not be possible in setting of shock due to C perfringens given the negative inotropic effect of alpha toxin

Answer 56

* main hypothesis (pretty well accepted) = Correa hypothesis - multistep process * theory that there's a pathway of transformation from normal mucosa --\> gastritis --\> chronic atrophic gastritis --\> metaplasia --\> dysplasia --\> cancer * recently been expanded w stepwise molecular alterations * a few of the risk factors for gastric cancer have a pathway that leads to either gastritis or atrophic gastritis * e.g. H pylori causes chronic gastritis & eventually loss of gastric glands and replacement of normal mucosa by intestinal metaplasia, which then predisposes to malignant transformation * one particular strain - CAG-A positive H pylori strain - has higher assoc w gastric ca - this strain more common in countries like Japan * inflammation of gastric mucosa can also be due to * chemical agents (NSAIDs, alcohol, bile reflux) * or the consequence of an autoimmune process (eg pernicious anaemia with parietal cell autoantibodies) * chronic inflammation can either result in the shrinkage or complete disappearance of typical gastric glands followed by replacement fibrosis of the lamina propria or the replacement of the native glands by metaplastic glands (i.e. intestinal and/or pseudopyloric metaplasia); under both conditions there is 'atrophy' (loss of normal glands), but only presence of metaplastic glands is considered a condition with increased risk of carcinoma development * genetic changes thought to occur during this pathway * association between overexpression of COX2 and cyclin D2 * p53 mutations (Li Fraumeni syndrome) increases risk * gastric cancer been found to have MSI (where Lynch syndrome fits in) * can have alteration in transcription factors (eg CDX1 and CDX2) * chronic gastric ulcer * typically located at edge of atrophic mucosa * if chronic gastric ulcer detected on endoscopy, should be considered malignant until histo has proven otherwise * pts w gastric ulcer have increased risk for gastric carcinoma as a gastric ulcer and gastric carcinoma have same risk factors * overall \<1% of gastric carcinoma develop in pre-existing peptic ulcers * NB chronic atrophic gastritis not in itself pre-malignant, but intestinal metaplasia is associated with increased risk of carcinoma development; for both should eradicate H pylori, treat with PPI and repeat gastroscopy and mapping biopsies in 3yrs * gastric dysplasia is the same as intra-epithelial neoplasia, usu would see at endoscopy espec if HGD lesion - w flat or depressed or polypoid growth pattern * low grade has 23% risk of adenocarcinoma at 10mo-4yrs (eradicate H pylori, treat w PPI, ensure good mapping biopsies and if any visible lesions these are biopsied +/- resected so you know no high grade component, repeat gastroscopy within 12mo) * high grade has 60-80% risk of adenocarcinoma over 1-5yrs; carcinoma in situ - manage as gastric cancer

Answer 57

* factors contributing to normal anal continence: * contraction of pubirectalis & external sphincter * maintenance of angle between rectum and anal cana w abdominal pressure flattening the lower anterior rectal wall over the upper end of the canal * prsence of mucosal cushions in the canal * internal sphincter, though assisting closure, can only maintain continence if no distension (which causes relaxation of the sphincter) * rectum can accommodate itself to receive a certain amount of colonic content wo any significant increase in pressure * when increasing rectal pressure causes faeces to enter upper anal canal, the ext sphincter contracts & causes the contents to return back into rectum * feeling of distension is conveyed within the spinal cord by gracile tracts * defaecation allowed to occur by release of cortical inhibition that developed during childhood training * pathways in spinal cord probably run with the lateral corticospinal fibres (like those for control of micturition) * abdominal pressure is increased, puborectalis relaxes and the anorectal angle straightens with the relaxation of the ext sphincter and contraction of the lower colon and rectum (via its parasympathetic supply) * incontinence will follow * damage to ext sphincter e.g. in obstetrics & perineal operations * some cases may be due to pudendal nerve entrapment * in cerebral or spinal cord lesions, may be loss of cortical control

Answer 58

* increase in counter-regulatory hormones - cortisol, adrenaline, glucagon and inflammatory cytokines * increase in daily energy requirements * increase in nitrogen requirements * insulin resistance and glucose intolerance * preferential oxidation of lipids * increased gluconeogenesis and protein catabolism * loss of adaptive ketogenesis * fluid retention and hypoalbuminaemia * these all lead to * impaired immune function * delayed wound healing * impaired cardiac and respiratory function * atrophy of smooth and skeletal muscle * increase in post-op morbidity and mortality

Answer 59

* glucagon levels rise, which increases the conversion of glycogen to glucose in liver * Cori cycle activated to use muscle glycogen; these stores are broken down by glycogenolysis - leads to lactate, which goes to liver where it's converted to glucose * after 24hrs, glycogen stores used up; instead body uses amino acids which are broken down in liver, fat is oxidised turning it into glucose and FAs; those FAs are converted into ketones in liver which can be used by CNS as a fuel * also reduction in resting energy expenditure by decreased deiodination of T4 to T3

Answer 60

* a constellation of biochemical abnormalities that occurs when normal intake is resumed after a period of starvation * characterised by low levels of phosphate, potassium, magnesium and sodium * **can lead to cardiac arrhythmias, congestive heart failure, peripheral oedema, muscle weakness, muscle rhabdomyolysis, seizures, haemolysis, respiratory insufficiency** * hypophosphatemia is the hallmark of the syndrome and predominant cause of refeeding syndrome * pathogenesis of hypophosphataemia begins when stores of phosphate are depleted during episodes of starvation (though serum levels may be normal) * reintroduction of carbohydrates causes release of insulin which triggers cellular uptake of phosphate (and potassium and magnesium) and a decrease in serum phosphorous evels * insulin also causes cells to produce a variety of molecules that require phosphate (eg ATP) which further depletes stores of phosphate * subsequent lack of phosphorylated intermediates causes tissue hypoxia, myocardial dysfunction, respiratory failure due to inability of diaphragm to contract, haemolysis, rhabdomyolysis and seizures * risk of refeeding directly related to amount of weight loss during current episode and rapidity of weight restoration process * management of complications of refeeding syndrome may include reducing rate of nutritional support and always involves proactively screening for and correcting hypophosphataemia, hypokalaemia and hypomagnesaemia * malnourished patient may be thiamine deficient at baseline; with refeeding, intracelluar uptake of electorlytes leads to increased utilisation of thiamine, and Wernicke encephalopathy may occur - encephalopathy, oculomotor dysfunction, gait ataxia; give 100mg thiamine at least 30min before starting nutritional replenishment and continue BD for 7-10 days

Answer 61

* due to infection with clostridium tetani, an anaerobe which lives in the soil and guts of mammals * produces tetanus toxin which travels to CNS by retrograde axonal transport * irreversibly binds to receptors at the site and prevents the presynaptic release of inhibitory neurotransmitters eg GABA and glycine, which usually relax muscles by blocking the release of acetylcholine * so there's a lack of inhibitory signals to motor neurons, leading to the constant release of acetylcholine to muscle fibres, leading to irreversible contraction and spasm of the muscles, leading to spastic paralysis * clinical presentation = stiff neck, sardonic smile, board-like rigid abdomen, periods of upper airway obstruction and dysphagia * also autonomic overactivity with irritability, restlessness, sweating and tachycardia * tetanic spasms - clenching of fists, arching of back, flexing and abducting arms whilst extending the legs

Answer 62

* a complex interplay between external forces and host factors that counteract healing * injury mechanism eg friction, pressure, shearing, moisture * pressure exceeds arteriolar pressure of 30mmHg - prevents delivery of oxygen and nutrients to tissues * leads to hypoxia, metabolic waste accumulation and radical oxygen species release * host responses make patients more susceptible * lack of subcutaneous fat * malnutrition * sensory loss, immobility * complications eg infection, sinus tracts to underlying viscera, heterotopic calcification, development in longer term of chronic wounds and development of SCC due to chronic infection

Answer 63

* an inflammatory condition of the apocrine sweat glands * apocrine sweat glands drain into the hair follicle and inflammation of these glands and keratinocyte proliferation leads to plugging of hair follicle * this leads to follicle rupture and associated inflammatory response * secondary bacterial infection and perifolliculitis can then be established * leads to chronic foreign-body type granulomatous reaction * leading to inflammation, abscess, and presence of formed epithelial tract

Answer 64

* an increase in the hydrostatic pressure within a closed osteofascial space, causing decreased perfusion of muscles and nerves within a compartment * initially local trauma --\> bleeding and oedema * increased interstitial pressure due to bleeding and oedema * increased pressure overcomes intramuscular arteriolar pressure, so blood can't enter capillaries * vascular occlusion * myoneural ischaemia develops

Answer 65

* 3 or more contiguous ribs broken in two places * creates a segment of chest wall which moves independently * this segment of chest wall has paradoxical movement compared to the rest of the chest wall with breathing; when you breath in, usually chest wall will expand, but this segment will get sucked in due to the negative pressure, and instead cause damage to underlying lung parenchyma, causing pulmonary contusions and worsening the chest injury

Answer 66

* vessels of neck damaged due to stretching or impingement of the vessel wall as the head and neck are forcefully moved in flexion/extension or rotation * leads to an intimal tear with exposure of the subintimal layers to blood flow * consequent thrombosis formation, wall haematoma and occlusion * can also lead to pseudoaneurysm

Answer 67

* a blast wave is an over-pressure shock wave created by high-order explosives * primary blast injury * barotrauma itself - direct effect of the blast wave, usually causes damage at the interface between gas and fluid-containing organs e.g. tympanic membrane, lung, bowel related to over-pressure * secondary blast injury * occur due to patients being struck by projectiles - blunt and penetrating * tertiary blast injury * injuries produced by patients being thrown by the high winds produced by the blast - displacement-type injury * or by other structures falling on/hitting patient - usually blunt trauma * quaternary blast injury * all other injuries caused by the explosive e.g. burns, asphyxia, toxic inhalation injuries * quinary blast injuries * hyperinflammatory state that happens due to exposure to unconventional materials in the manufacture of the explosives * some say could also be due to things like radiation exposure if used in bomb

Answer 68

* causes coagulative necrosis of epidermis and a variable depth of the dermis; depends on temp, type of heat and duration of exposure * there are a number of systemic effects espec from severe burns * hypovolaemia from fluid losses * hypermetabolic state - muscle breakdown * impaired glucose tolerance * become immunosuppressed and are prone to infections * can develop renal failure due to fluid losses * ARDS * at risk of bacterial translocation and ileus

Answer 69

* when body is exposed to intense cold, it vasoconstricts to deliver heat to core tissues * so frostbite usually affects distal extremities e.g. fingers and toes, nose and ears * vasoconstriction leads to ice crystal formation within the extremities, causing cell membrane injury and endothelial cell damage * development of microvascular occlusion due to hyperviscous intravascular flow, and the slow flow due to the vasoconstriction which causes microthrombi * these two mechanisms lead to tissue ischaemia * first degree = hyperaemia and oedema w/o skin necrosis * second degree = large clear vesicle formation with hyperaemia and oedema * third degree = full-thickness subcutaneous tissue necrosis with haemorrhagic vesicle formation * fourth degree = full-thickness skin necrosis including underlying muscle, bone or other

Answer 70

* dynamic, four stage process that involves * initiation and formation of a platelet plug * propagation of clotting through the coagulation cascade * termination of clotting through anti-thrombotic control mechanisms * removal of the clot by fibrinolysis * coagulation cascade is the sequential activation of a series of proenzymes to active enzymes, leading to amplification of the response, and eventual haemostasis * haemostasis requires initially vasoconstriction and contraction, platelet activation and adhesion, activation of the clotting cascade (via intrinsic or extrinsic pathway); common pathway leads to factor 10 to 10a activation which activates prothrombin into thrombin and fibrinogen to fibrin (a clot) * then antithrombin-3 degrades the activated factors and fibrinolysis occurs due to plasminogen being changed to plasmin which degrades fibrin

Answer 71

* can be local thrombus, embolus or traumatic division; either way there is complete occlusion of a proximal vessel, usually in the absence of preformed collateral vessels; leads to severe ischaemia of limb * insufficient substrate (glucose) delivery and insufficient oxygen delivery * local anaerobic metabolism --\> lactic acidosis * failure of ATP pumps: cellular damage with K+ release, cytokine release and oedema from increased membrane permeability * oedema further impairs oxygen delivery and bacterial infections may be superimposed, espec in context of pre-existing disease * compartment syndrome = caused when local compartment pressure becomes greater than perfusion pressure * restoration of blood flow to ischaemic area results in: * generation of reactive oxygen species; attach to FAs in the phospholipid membrane and cause mechanical and functional derangements * also inflammatory infiltrate, leading to endothelial damage and cytokine production * post revascularisation, sudden return of venous blood to the systemic circulation which is high in the products of anaerobic metabolism - low in pH and high in potassium and lactate * leads to systemic inflammatory response; may lead to multiple organ dysfunction & failure, hypotension and arrhythmias * renal function may be further impaired by myoglobinurai * revascularisation of ischaemic muscle can lead to considerable swelling within fascial compartments of legs --\> increased compartment pressures causing venous compression, worsening oedema and if not treated promptly, permanent neuromuscular insult * pts at highest risk of this = prolonged ischaemia or ischaemia from embolic source

Answer 72

* a progressive and destructive neuroarthropathy which consists of subluxation, pathological fractures and permanent distraction of the foot * lack of sensation and repetitive microtrauma contribute to this, as well as the poor blood supply and the autonomic dysfunction * the nerve dysfunction also leads to poor proprioception and subluxation of joints * there's also increased blood flow to bones due to the autonomic activity - leads to increased osteoclastic activity to remodel the bone, and eventual development of a characteristic deformed Charcot foot

Answer 73

* aneurysms form when the structure or function of connective tissues to a vessel is compromised; characterised histologically by * destruction of elastin & collagen in tunica media and tunica adventitia * smooth muscle cell apoptosis w thinning of medial wall * infiltration of lymphocytes & macrophages * neovascularisation * 4 pathological mechanisms play central role * proteolysis of connective tissue - by MMPs & other proteases from macrophages & SM cells found in atherosclerotic plauqes * inflammation - inflammatory cytokine cascade released by lymphocytes & macrophages in aortic wall thought to stimulate protease activation * biomechanical stress * genetic influences - possibly relating to structure of elastin & collagen or a mutation affecting protease and protease-inhibitor activity * some external injuries can contribute such as trauma, vasculitis, infection (mycotic aneurysms)

Answer 74

* cross-reactivity of TSH receptor antibodies with tissues of retro orbital space - TSHR expressed primarily in thyroid but also in adipocytes, fibroblasts and other sites and appears to be closely aligned w the IGF-1 receptor * TSHR antibodies and activated T cells activate retroocular fibroblast and adipocyte TSHR and IGF-1 receptors and initiate a retro-orbital inflammatory environment * volume of both the extraocular muscle and retroocular connective tissue is increased, due to fibroblast proliferation, inflammation and the accumulation of hydrophilic glycosaminoglycans * accumulation of hydrophilic GAG --\> fluid accumulation, muscle swelling and increase in orbital pressure * these changes + retroocular adipogenesis, displace eyeball forward, leading to extraocular muscle dysfunction and impaired venous drainage * causes proptosis aka exophthalmos * Lid lag and stare believed to be caused by excess thyroid hormone and not necessarily from proptosis - lid lag and stare subside when hyperthyroidism treated * Lid lag = static condition in which the upper eyelid is higher than normal while the eye is in downgaze - due to increased contraction of levator palpebrae muscles of the eyelids * lid lag is different to von Graefe's sign, which is dynamic rather than static; is observed when the eye actively moves inferiorly form primary gaze and upper eyelid follows at a slower-than-normal rate; superior part of the iris (superior limbus) is often exposed during this slowed movement * once the downgaze is fixed, and if eyelid remains elevated, it may then be called lid lag * Stare = term used to describe appearance of excessive eyelid retraction; caused by increased tightness of levator palpebrae, different from proptosis (bulging of eye out of socket) as 2 distinct conditios and one can occur w/o the other * Lagophthalmos = inability to complete close eyelids; excessive upper lid retraction in thyroid eye disease can result in lagophthalmos and corneal exposure even while pt attempts to close their eyes

Answer 75

* chronic lymphocytic inflammatory condition * anti-thyroid antibodies * anti-thyroid peroxidase (anti-TPO) antibodies * anti thyroglobulin antibodies * infiltration of CD4 helper T cells * initial hyperthyroid state then hypothyroidism due to thyroid tissue destruction

Answer 76

* circulating Ca level, vit D level and phosphate level * sensed by the parathyroid gland, and increase PTH if * calcium low * vit D low * phosphate high * PTH works on * Kidney: * vit D activation (1 to 1,25 hydroxylation) * Ca reabsorption * PO4 excretion * Gut: calcium absorption (vit D activity) * Bone: osteoclast activation * increase Ca and PO4 levels

Answer 77

* AD inherited inactivating mutation of the gene that codes calcium sensing receptor * CaSR is expressed on surface of chief cells in PT glands and kidneys where it plays a key role in regulation of calcium balance through intracellular signalling * loss of function of Ca sensing receptor in PT gland leads to decreased sensitivity to calcium therefore higher concs of Ca are required to suppress PTH release - in effect 'resetting' serum calcium conc to a higher than normal level

Answer 78

* Autoimmune disorder with anti-TSH receptor antibodies. * Binds to TSH receptor on thyroid, leading to increased thyroid hormone production and thus hyperthyroidism * Goitre due to epithelial proliferation, stromal vascularity, lymphocytic infiltration * Ophthalmopathy due to * stimulation of oveer-expressed TSH-R in retro-orbital tissues of pts w Graves * volume of retro-orbital connective tissue & muscle is increased due to accumulation of extracellular matrix components, incl proteoglycans & hyaluronic acid * in most severe form, spasm of upper eyelid --\> retraction and visualisation of a larger amount of sclera than normal; can lead to lid lag & exacerbation of the already swollen conjunctiva * increased pressure --\> decreased oculomuscular movements, ophthalmoplegia, diplopia * +/- optic nerve damaage & blindness long-term if not corrected

Answer 79

* Aldosterone works on * Na/K ATPase in the principal cells (distal tuble) * Na absorption and H2O = hypertension * K release = hypokalaemia * also works on H ATPase in the intercalated cells (collecting tubles)

Answer 80

* hypokalaemic, hypochloraemic metabolic alkalosis with paradoxical aciduria * vomiting --\> loss of gastric hydrochloric acid (chloride and hydrogen ions) * leads to volume loss and a metabolic alkalosis * with progressive volume loss, kidneys preferentially keep sodium over potassium --\> hypokalaemia * as this becomes worse, kidneys switch and keep sodium and get rid of acid Bryan has * volume loss --\> renin-angiotensin-aldosterone pathway * angiotension II works on proximal tubule * Na-H-ATPase --\> loss of H + volume repletion * aldosterone: * NA-K-ATPase --\> volume repletion + hypokalaemia * H ATPase

Answer 81

Acute anuglation of SMA causing compression of D3, due to rapid weight loss and loss of fat pad around SMA

Answer 82

* atherosclerosis of coeliac, SMA, IMA * gradual decrease in blood flow to intestine * postprandial symptoms * may develop collateral pathways, therefore may not be evidence til late stage

Answer 83

* can be non-occlusive or occlusive * non-occlusive due to hypotension/shock * occlusive due to * thrombus * embolic event * venous thrombous * causes mucosal ischaemia first (why you get pain without peritonism) * disruption of microvascular integrity - capillaries damaged, increased mucosal permeability, blood may extravasate causing haemorrhagic foci & bowel wall thickening * progressive mucosal injury, leakage of protein, fluid and electorolytes - gas-producing organisms, pneumatosis, portal venous gas and peritonitis * can suffer from reperfusion injury with * oxygen free radicals * neutrophil inflammation * anaerobic metabolism leading to lactic acidosis * systemic response

Answer 84

* acquired false diverticulum due to increased mucosal pressure * mesenteric border * due to motor dysfunction of the myenteric plexus, disordered contractions, intraluminal pressure and herniation of mucosa

Answer 85

* Usual mechanisms to limit bacterial populations include: * Continued flow of luminal contents from peristalsis & myoelectric complex * Gastric acidity (acidity of gastric contents entering the small bowel) * Local effects of immunoglobulins * Prevention of reflux of colonic contents by ileocaecal valve * If any of these mechanisms are overcome, can get overgrowth of bacteria in SB * Under normal conditions, upper GI tract contains _\<10⁵bacteria/mL_, mostly gram-positive aerobes & facultative anaerobes * But w stasis, no of bacteria s, w excessive proliferation of aerobic & anaerobic bacteria: bacteroides, anaerobic lactobacilli, coliforms & enterococci likely to be present in varying numbers * Effects of bacterial overgrowth * Bile salt deconjugation & dihydroxylation in prox SB * Deconjugated bile salts are reabsorbed in jejunum; inadequate micelle formation to solubilize fat so fat and fat-soluble vitamins not absorbed well, also steatorrhoea * Unabsorbed fatty acids enter colon  lead to diarrhoea from increased net secretion of water and electrolytes from osmosis * Hypocalcaemia bc Ca gets bound to these free unabsorbed FAs and excreted * and because calcium is being bound to these fatty acids, it can’t bind to oxalate and help w excretion of oxalate from the body as usual – so oxalate gets absorbed and secreted by kidneys, leading to oxalate renal stones * Anaerobic bacteria compete for & bind B₁₂  malabsorption of B₁₂  macrocytic anaemia results * Bacteria can also catabolise CHO & protein – contribute to malabsorption and weight loss; and bacterial fermentation of unabsorbed carbs  hydrogen and methane gas

Answer 86

* alkaline * liquefactive necrosis - ?deeper penetration but less systemic effect * short term associated w vascular thrombosis and mucosal inflammation * results in sloughing and ulceration * 2 weeks: progressive thinning of wall & development of granulation * 1-3mo: fibrosis and re-epithelialisatoin * acid injury * painful on contact therefore ?less injury than alkaline * coagulation necrosis: thrombosis of underlying blood vessels --\> forms eschar

Answer 87

* Porto-systemic shunt between the azygos system and left gastric vein due to portal hypertension * submucosal engorgements: dilatation and bleeding risk with arteriolar vasodilatation * friable wall

Answer 88

* Paget's disease of the breast is an eczematous inflammatory condition, particularly involving nipple & areola, that's typically the epidermal manifestation of an underlying cancer (\>95% have underlying malignancy) * neoplastic cells of glandular differentiation (Pagetoid cells - large cells w pale cytoplasm & prominent nucleoli) interspersed between keratinocytes of nipple epidermis - don't invade dermal BM (ie CA in situ) * 2 competing theories re pathogenesis * Epidermotrophic disease (preferred) * Paget cells arise from underlying mammary adenoca & migrate along ductal system to enter epidermis and dermis of nipple-areola complex * supported by fact that 95% have an underlying intraductal or invasive malignancy & observation that Pagetoid cells and underlying carcinomas demonstrate similar IHC staining patterns * Transformation theory (out of favour) * Pagetoid cells = nipple keratinocytes that have undergone malignant transformation (Toker cells) * according to this theory, PD = in situ carcinoma of skin that's independent of any underlying ductal carcinoma * this theory = supported by observation that, often, overlying skin changes & underlying malignancy are discontinuous & sometimes genetically different

Answer 89

* a clinicopathological entity characterised by diffuse oedema & erythema involving majority of breast skin w or w/o an associated discrete underlying mass * diagnostic criteria (need all) * rapid onset of breast erythema, oedema and/or peau d'orange, and'or warm breast, w or wo an underlying palpable mass * duration of hx of ≤6mo * erythema occupying ≥1/3 of breast * pathological confirmation of invasive carcinoma (eg on core biopsy) * diagnosis mainly clinical; dermal invasion by cancer w/o the assoc typical clinical signs isn't IBC * underlying pathogenesis of changes = obstruction of dermal lymphatics by tumour emboli * histological hallmark = tumour emboli in dermal lymphatics but absence doesn't exclude diagnosis

Answer 90

* strong assoc w smoking (90% of pts); postulated that smoking is assoc w damage of the subareolar ducts, w tissue necrosis and subsequent infection; toxic substances in cigarette smoke may damage the ducts directly or there may be a localised hypoxic effect * periductal mastitis is also assoc w squamous metaplasia, which is likely a consequence of ongoing inflammation; has been suggested that squamous metaplasia may lead to partial duct obstruction due to build up of keratin and duct obstruction, w subsequent dilation and inflammation --\> secondary bacterial infection, duct damage and rupture wtih abscess formation * drains into periareolar region with fistulation and chronic inflammation * fibrosis and scarring may lead to nipple retraction/inversion * palpable masses & mamm changes may result from infection & scarring; these can make surveillance for breast ca more challenging NB not the same as duct ectasia, which usually affects older women & is characterised by distension of subareolar ducts w fibrosis, and is assoc w creamy or cheesy nipple discharge and inversion; dilated subareolar ducts may be apparent clincially and visible on imaging. Originally duct ectasia & periductal mastitis considered part of same clinical syndrome and 2 terms were used interchangeably; however, duct ectasia = age-related phenomenon and not assic w signif periolar inflammation or infection (and few women w duct ectasia have hx of prior periductal mastitis)

Answer 91

* disturbance of gut flora, usu from overgrowth of E coli and others * cirrhosis itself can lead to bacterial overgrowth due to * latered SB motility * hypochlorhydria due to PPI use * increased intestinal permeability * leads to bacterial translocation and not being able to clear this causes infection * via ascites * or mesenteric lymph nodes * lymphatic HTN leads to lymphatic rupture * first line defenses can't eradicate the bacteria --\> SIRS

Answer 92

* stagnation of salivary flow and supersaturation of compounds (Ca, Mg, ?PO4 or K) * inflammation, infection and local injury * more common in submandibular gland * long duct, draining against gravity * more mucinous (nidus for stone development) * higher calcium content

Answer 93

* causes: autoimmune, viral and bacteria * salivary stasis, permits retrograde seeding of salivary duct w oral flora * predisposed by stone, dehydration and anticholinergic drug

Answer 94

* HPV colonises oropharynx * 10% doesn't get cleared, causes chronic inflammation * HPV are incorporated into host genome, and produces E6 and E7 protein, that degrades p53 and inactivates retinoblastoma genes * leads to unregulated cell cycle, can't activate apoptosis * accumulation of further mutations, and cancer formation

Answer 95

* exact pathogenesis not clear but thought to be secondary to inflammation, acid and ischaemia leading to microciruclatory dysfunction +/- tension on the gastrojejnunal anastomosis * risk factors include smoking, H pylori, large gastric remnant, gastro-gastric fistula, tension, foreign body, NSAIDs

Answer 96

* predominantly secreted from the stomach and stimulates appetite and growth hormone release * most abundant in gastric fundus where it is produced in oxyntic glands by distinctive endocrine cells known as P/D1 cells * exercises a wide range of functions, including regulation of food intake and energy metabolism, modulation of cardiovascular function, stimulation of osteoblast proliferation and bone formation and stimulation of neurogenesis and myogenesis * in GI system, ghrelin affects multiple functions, including secretion of gastric acid, gastric motility and pancreatic protein output

Answer 97

* secreted mainly by white adipose tissue * immediate effect is to act on brain to regulate appetite

Answer 98

wall tension is greatest in the area with the largest diameter and thinnest wall

Answer 99

* parietal cells release acid from stomach (these cells also produce intrinsic factor) * most potent stimulator of acid secretion is through gastrin release * gastrin is released from G cells of pyloric glands * this travels in bloodstream to oxyntic glands in fundus and body of stomach where it acts on enterochromaffin-like cells - encourages secretion of histamine * histamine acts on the parietal cells and HCl is released via the H/K antiporter * alternatively, gastrin can stimulate parietal cells directly * acetylcholine released from vagus nerve can stimulate parietal cell directly

Answer 100

Duodenum. Vitamin C and low pH increases iron absorption

Answer 101

* occurs due to thiamine deficiency * get ataxia, nystagmus and memory disturbance; hallucinations, confusion and may become combative

Answer 102

* e.g. cyclosporin and tacrolimus * bind intra-cellularly and prevents the production of IL-2 which is a potent T cell activator, therefore prevents the release of cytokines from T helper CD4 cells

Answer 103

prevents purine synthesis which prevents cell division and therefore proliferation

Answer 104

* hyperacute - within minutes * immediate graft destruction due to ABO of HLA incompatibility - intravasuclar thrombosis or interstitial haemorrhage * due to host pre-formed Ab against the donor's HLA - arise from pregnancy, blood transfusion or previous rejection * when inflow is re-established, the antibodies bind to the HLA Ag and cause complement activation resulting in thrombosis and haemorrhage * kidney is most susceptible; liver appears to be resistant * acute - up to 6 months * usu T cell mediated or by Ab - common, in up to 20-30% of grafts - normally reversible by alterations in immunosuppression * delayed - months to years * most common cause of graft failure - eventual fibrosis from myointimal inflammation * pathophysiology not well understood

Answer 105

* infection * most common is in immediate post-op period espec 6-12wks; early recognition and aggressive treatment essential * donor-derived infections rare - CMV, HIV, Hep B and C, TB, trypanosoma cruzii * recipient-derived infecitons much more common - reactivation of latent CMV, EBV, HSV, VZV, PCP, HIV, parasites and fungi * bacteria * most common in peri-op period and prophylaxis shoudl be given * if latent TB or pts from Indian subcontinent - treatment for 6-12mo given * viral - CMV is biggest problem * malignancy * at particular risk of viral related cancers * EBV (transplant-related lymphoproliferative disease, non-hodgkin lymphoma) * HPV 16 and 18 (anal and cervical) * HSV8 (Kaposi sarcoma) * Hep B and C (liver) * increased risk of cutaneous malignancy, both non-melanoma skin cancers, SCC, BCC, Merkel cell carcinoma and malignant melanoma * melanoma (2-3x) appears to have same prognosis while SCC and BCC more aggressive * also at increased riskk for solid organ maliganncy - RCC (x15), testicular (x3), CRC (x2), liver

Answer 106

Transjugular intrahepatic porto-systemic shunt * Absolute contraindications: * severely elevated right heart pressure * severe pulmonary hypertension * severe CHF * severe encephalopathy * uncorrectable bleeding diathesis * active systemic or hepatic bacterial infection * unrelieved biliary obstruction * Relative contraindications: * complete hepatic vein obstruction * complete portal vein thrombosis * hepatocellular carcinoma * severe coagulopathy (INR \>5) * severe thrombocytpenia (plt \<20) * advanced liver dysfunction (bili \>5mg/dL or MELD \>17) * moderate pulmonary hypertension

Answer 107

* primary alterations within the gland = most common * Graves disease / diffuse toxic goitre - most common * Toxic multinodular goitre * Toxic thyroid adenoma * Thyroiditis (early stage) - Hasimoto's, De Quervain, post-partum thyroiditis * Thyroid malignancy w overproduction of thyroid hormone (v rare) * CNS disorders & icnreased TSH-produced stimulation of thyroid * TSH-secreting tumour of pituitary (rare) * O&G causes * Molar pregnancy w increased release of hCG (rare) - choriocarcinoma * Struma ovari (ovarian goitre) = ovarian teratoma containing mainly thyroid tissue * drugs/poisons etc * overdose of thyroid hormone (iatrogenic) * amiodarone toxicity * iodine-induced ('Jod-Basedow effect') * hyperthyroidism following admin of either iodine/iodide dietary supplement or contrast medium * typically presents in a pt w pre-existing nodular goitre or someone w endemic goitre who then relocates to an iodine-abundant geographic area

Answer 108

* thionamide class includes PTU, methimazole, carbimazole * block synthesis of thyroid hormone & inhibit iodination/organification of tyrosine and coupling of iodotyrosine molecules to form T3 and T4 * PTU also blocks peripheral conversoin of T4 to T3, making it useful for treatment of thyroid storm * less placental & breast milk transfer cf carbimazole so used in pregnancy/breastfeeding through increased risk of hepatotoxicity & some recommend changing back to carbimazole in third trimester * side effects of thionamides include: agranulocytosis (warn to stop if developing sore throat or fever & check neutrophil count before restarting), rash, arthralgia, neuritis * carbimazole - usu responds within 2wks - check TFTs in 4 wks * methimazole - metabolite of carbimazole * in thyroid storm use * rapid fluid replacement * high dose PTU (200-250 qid * beta blockers (2mg IV prolpanolol * propanolol * cholestyramine (binds T4, T3) * corticosteroids * iodine (prevents release of pre-formed thyroid hormone and facilitates surgery by reducing thyroid vascularity * cardiac monitoring * in life-threateninf circumstances, plasmaphoresis or plasma exchange may be effective in reducing T4 and T3 levels

Answer 109

* autoimmune-mediated destruction of thyrocytes * circulating autoantibodies to thyroid antigens (TgAb & TPOAb) --\> chronic autoimmune destructive process involving formation of immune complexes & complement in basement membrane of follicular cells --\> leads to infiltration of lymphocytes into thyroid follicles & eventually fibrosis, which decreases effective number of follicles needed to produce thyroid hormone * may have short thyrotoxic state prior to hypothyroidism * strong hereditary component & associated w other autoimmune disease * TgAb elevated in 60%, TPOAb in 95%

Answer 110

* synthesises catecholamines dopamine, NA and adrenaline from tyrosine by a series of steps via DOPA: tyrosine -- L-dopa -- dopamine -- norad -- adrenaline * the enzyme tyrosine hydroxylase, which controls the rate-limiting step, is largely confined to central & sympathetic nervous systems, and adrenal medulla * final step in converting norad to adrenaline is catalysed by PNMT which is induced by cortisol (present in adrenal medulla but not present in extra-adrenal sites) * after sympathetic stimulation of adrenal medulla --\> catecholamine release occurs by calcium-dependent process in which secretory granules fuse w cell membrane (exocytosis) * catecholamines * potent short-acting compounds w plasma half life 1min * their presence in synapses & circulation is negatively regulated by both reuptake & degradation - majority of released catecholamines are taken back up into presynaptic terminals of chromaffin cells & deaminated * remaining catecholamines enter systemic circulation --\> diverse effects * adrenaline & noradrenaline = metabolised by one or both of enzymes MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT) * initial methylation by COMT --\> metanephrine & normetanephrine (can be detected in plasma and urine) * final product after action of MAO & COMT produced in liver after deamination & methylation of catecholamines = VMA (vanillylmandelic acid) - is secreted along with metanephrines in urine * physiological effects of catecholamines * basal levels of secretion low; large increases in response to major physiologic or psychological stressors * exert their effects by binding to cell-membrane-bound a- and b-adrenoreceptors present in most tissues & organs * net effect of adrenal catecholamine release = to augment blood flow & O2 delivery to brain, heart & skeletal muscle, which are essential to fight or flight response, at expense of other organ systems * increase in HR, BP & CO, excitation of CNS, increased blood flow to muscles & decreased splanchnic perfusion * metabolic effects such as lipolysis, gluconeogenesis & glycogenolysis - to proide substrates for this action to occur * a-receptors have greater affinity for NA while b-receptors have greater affinity for adrenaline * stimulation of * b1 receptors in myocardium --\> inotropic & chronotropic (increased HR & contractility) * b2 receptors --\> smooth muscle relaxation in tissues such as uterus, bronchi & skeletal muscle arterioles (decreased TPR) * a1 receptors --\> vasoconstriction in tissues such as skin & GI tract (& reflex bradycardia and decreased CO) * a2 receptors --\> exist in presynaptic locations in CNS, where they mediate attenuation of sympathetic outflow * physiologic function of dopamine in circulation unknown - in pharmacologic dose stimulates b1 receptors & causes renal vasodilatation via a dopamine receptor --\> increased SBP +/- ?with preservation of renal blood flow

Answer 111

* rare disorder characterised by a number of signs & sx due to long-term effects of inappropriately elevated glucocorticoids * aetiology * exogenous steroid admin = most common cause * endogenous Cushing's syndrome * ACTH-dependent (85%) from either pituitary (75%) or ectopic (10%) origin * ectopic from: * carcinoid tumours (espec bronchial) * medullary thyroid cancer * small-cell lung cancer * neuroendocrine tumours * phaeochromocytoma * ACTH-independent or adrenal Cushing's (15%) * adrenal adenoma (90%) * adrenal carcinoma (10%) * rarely due to * ACTH-independent macronodular adrenal hyperplasia (AIMAH) - \<1% - characterised by bilateral nodular adrenal hyperplasia that's usu apparent on cross-sectional imaging * primary pigmented nodular adrenocortical disease (PPNAD) * may be assoc w other sx of Carney's complex e.g. myxomas, blue naevi & pigmented lentigines * pathophysiology * physiologic effects of glucocorticoids: * increased protein catabolism, increased hepatic glycogenesis & gluconeogenesis * permissive action --\> calorigenic, lipolytic, pressor effects * increased neutrophils, platelets, RBCs * decreased lymphocytes * decreased eosinophils (by increasing sequestration in spleen & lungs) * inhibition of phospholipase A2 and decreased cytokine secretion * large amounts may exert a mineralocorticoid action --\> salt & water retention * carcinomas - larger & more likely to concomitantly hypersecrete androgens * clinical * classic features: centripetal obesity, buffalo hump, moon facies, facial plethora, red-purple striae, hirsutism, loss of libido, menstrual irregularity, depression or psychosis, prox myopathy & easy bruising * also DM/IGT, HTN, osteopenia, poor growth in children * 5x excess mortality, primarily bc of cardiovasc complications

Answer 112

* Pathogenesis of DCIS remains poorly understood * thought that the developmental pathways for low- and int-grade DCIS = distinct from development of high-grade DCIS - can be explained partly in reference to biological markers * in sequence of progression from normal breast to DCIS, there is variable loss of chromosomal heterozygosity dependent on nuclear grade * low- and int-grade tumours show 16q loss, whereas there is 17q gain in high-grade lesions * likely that low-grade lesions arise from ER-positive ADH or LIN, and progress to low-grade ER-positive DCIS * high-grade lesions have no obvious precursor, unless they arise from usual ductal hyperplasia or ADH that expresses 17q gain * progression of well-differentiated/low grade DCIS to poorly differentiated/high grade DCIS or high-grade invasive cancer is uncommon * DCIS is defined as an abnormal proliferaiton of ductal epithelial cells with morphologic features of malignancy but no BM or stromal invasion; 2 or more ducts involved * composed of discrete spaces filled with malignant cells, usu w a recognisable basal cell layer composed of presumably normal myoepithelial cells * arises from TDLU of breast, and arborises usu within one duct system w/o forming a discrete mass * as cells inside ductal membrane grow, have a tendency to undergo central necrosis * necrotic debris in centre of duct undergoes coagulation --\> calcifies --\> leads to tiny, pleomorphic and frequently linear forms of microcalcs that can be seen on mamms * depending on growth pattern & presence or absence of comedo-type necrosis, may be identified as fine pleomorphic/granular, fine linear or fine linear branching on mammography * microcalcs, linear calcs: comedo * pleomorphic/granular calcs: non-comedo * 2 major subtypes: comedo and non-comedo * 4 major morphologic types (architectural growth patterns) - but usu mixed * comedo, solid, papillary/micropapillary, cribriform * low vs intermediate vs high grade according to nuclear size and pleomorphism

Answer 113

* papillary lesions = breaset lesions with a papillary growth pattern; include * intraductal papillomas (solitary or multiple) * benign intraductal papillomas * papillomas w a foci of atypia or carcinoma in situ * DCIS with a papillary growth pattern (incl intracystic papillary CA) * invasive papillary ca * papilloma = proliferation of epithelial & myoepithelial cells around a fibrovascular stalk * solitary/central type and peripheral/multiple type * diffuse papillomatosis (multiple papillomas) = defined as minimum of 5 separate papillomas within a localised segment of breast tissue * papillomas located away from the NAC = at higher risk of malignancy (20%) * difficult to reliably distinguish benign/atypical/malignant papillary lesions on core; when core shows papilloma w atypical cells, upgraded 67% of the time; when core shows no atypia, 5-20% upgraded to atypia or malignancy * atypical hyperplasia within a papilloma is assoc w a 7x increased risk for subsequent CA (usu in ipsilateral breast - this is in contrast to ADH/ALH)

Answer 114

* Oestrogen & progesterone receptors = nuclear hormone receptors located in cytosol of target cells; act as transcription factors in nuclei of luminal breast cells * Oestrogen receptor = ligand-dependent transcription factor composed of 2 receptors; ER-alpha and ER-beta * Aberrant expression of ER results in autonomous growth & proliferation, facilitating tumourigenesis * 70-80% invasive ca = ER +ve * PR expressed in response to ER activation (ER drives PR expression, thus PR serves as a marker of ER functionality) * 55% of tumours = both ER & PR +ve, and of these ~70% will have good response to endocrine therapy * If ER +ve/PR -ve, worse prognosis (quite rare) * 50% of ER -ve tumours will express PR receptors & some of these will respond to endocrine treatment * ER-alpha status is performed routinely w IHC; can be reliably assessed on core * Allred score = system that assesses frequency & intensity of reactivity of the tumour nuclei in ER and PR immunostaining * Tumour scores 0-5 in relation to % of ER +ve cells and 0-3 with regards to average intensity of staining (none, weak, moderate, strong) * Allred = sum of these, ranges from 0-8 * Allred score of 0-2 = ER neg, though robust data re what cut-off for defining ER positivity should be is lacking – so most recent recommendations state that reactivity in 1% or more of tumour cells should define a lesion as ER-positive * At molecular level, ER-positive tumours include the luminal A and luminal B subtypes= * Has been suggested these can be separated by level of proliferation present within tumour; controversial but can be quantified immunohistochemically by assessment of proliferation marker, Ki67; cut-off of 14% separates luminal A tumours from luminal B lesions and w prognostic value * Difficult to reproduce results between institutions using Ki67 and difficult to distinguish luminal A from luminal B

Answer 115

* HER-2 = human epidermal growth factor 2 * Product of erb-B2 gene, a proto-oncogene located on long arm of chromosome 17 * Proto-oncogenes = genes that regulate cell proliferation; damage done to the DNA that encodes a gene that’s critical to the cell cycle regulation changes a proto-oncogene into an oncogene, and only one mutation needed bc these genes work in a dominant manner * HER2 = part of epidermal growth factor receptor family * Tyrosine kinase receptor that sits on the surface of cells and an intracellular tyrosine kinase enzyme links the receptor to the internal machinery of the cell; when signalled/activated, it upregulates cell growth; amplification  protein over-expression (increased signals to breast cancer cells to divide and grow) * As a monomer is inactive, tyrosine kinase of HER2 is activated when the HER2 receptor heterodimerizes w other members of the family that have been bound by growth factors or when the HER2 receptor homodimerizes; no known ligand that binds to HER2 receptor * Amplified in 14-20% of breast cancers * Amplification independently predicts OS & DFS in node-positive pts * HER-2 protein overexpression measured by IHC & scored on a scale from 0-3+ based on amount of protein/receptor on cell surface * 0/1+ = negative (66.7% cases), 2+ (21.7%) equivocal/borderline, 3+ (11.6%) positive * If equivocal, send for FISH * FISH (fluorescence in situ hybridization) directly detects numbers of copies of HER2 gene on chr 17 in that cell; \>2 copies counted as positive * Trastuzumab & pertuzumab = antibodies directed against the extracellular domain of the HER-2 surface receptor & are effective treatment for HER-2-positive breast cancer

Answer 116

A common benign condition characterised by hyperplastic changes of unknown aetiology involving the GB wall and causing overgrowth of the mucosa, thickening of the muscular wall and formation of intramural diverticula/sinus tracts termed Rokitansky-Aschoff sinuses. Forms a tumour- like lesion of the gallbladder with no malignant potential and may involve the GB in a focal, segmental or diffuse form. Results in a slight intraluminal convexity, often marked by central umbilication. Usu found in fundus but may occur elsewhere.

Answer 117

* the result of the accumulation of triglycerides and cholesterol esters in lamina propria of GB wall * lipid deposits are grossly visible - lend GB wall a strawberry-like appearance - 'strawberry gallbladder' * vary in side and can be as large as 11cm

Answer 118

* caused by reduced defensive factors, increased aggressive factors or both * protective/defensive factors include: mucosal bicarb secretion, mucus production, adequate blood flow, growth factors, cell renewal, endogenous prostaglandins * damaging/aggressive factors include: excess HCl acid secretion, pepsins, ethanol ingestion, smoking, duo reflux of bile, ischaemia, NSAIDs, hypoxia, H pylori * although now clear most ulcers are caused by H pylori or NSAIDs, still important to understand all of other protective & causative factors to optimise treatment and ulcer healing and prevent disease recurrence

Answer 119

* NSAIDs are absorbed through stomach and SB and function as systemic inhibitors of the cyclooxygenase enzymes * these enzymes for the rate-limiting step of prostaglandin synthesis in GI tract * prostaglandins promote gastric & duo mucosal protection via numerous mechanisms, incl increasing mucin and bicarb secretion and increasing blood flow to mucosal endothelium * presence of NSAIDs disrupts these naturally protective mechanisms, increasing the risk of peptic ulcer formation in stomach and duo

Answer 120

* atherosclerotic peripheral arterial disease (most common) * persistent sciatic artery * get aneurysmal degeneration as it emerges from sciatic foramen; thrombosis and ischaemia * av age 59 * cystic adventitial disease * cyst formation in adventitia of artery due to implantation of mucin-secreting mesenchymal cells on adventitial wall during development * mainly men in mid 30s, most commonly popliteal * popliteal artery entrapment * particularly young athletes; compression of popliteal artery due to anatomical variation in relationship between popliteal artery and medial head of gastroc * fibromuscular dysplasia * non-atherosclerotic and non-inflammatory arterial disease which usu affects renal & carotid arteries; can also affect iliac, fem or pop * intra-arterial fibrotic webs that give rise to stenoses & post-stenotic dilatations giving a beaded appearance * can cause IC or microembolism; rarely CLI from arterial dissection * endofibrosis of iliac artery * competitive cyclists - IC w max exertion * Buerger's disease (thromboangiitis obliterans) * systemic vasculopathy assoc w tobacco use that affects medium-sized arteries and veins in limbs * vasospastic symptoms and superficial thrombophlebitis and may rapidly progress to CLI * ddx for chronic limb ischaemia: lumbar spine disease/spinal stenosis, neuropathy, degenerative joint disease, myopathy * reset pain ddx: diabetic neuropathy, night cramps, degenerative joint disease, gout

Answer 121

* classic presentation = 6 Ps * calf pain & tenderness w tense muscle compartment indicates severe muscle ischaemia or necrosis and often irreversible ischaemia * sensorimotor deficit indicative of muscle & nerve ischaemia - potential for salvage if treated promptly * initially leg is white w empty veins; after 6-12hrs, vasodilation occurs secondary to hypoxia of SM --\> caps then fill w stagnant deoxygenated blood --\> mottled appearance that blanches on pressure; partly reversible * if flow not restored rapidly, arteries distal to occlusion fill w propagated thrombus & caps rupture --\> fixed blue staining of skin that is a sign of irreversible ischaemia (mottled areas coalesce, no longer blanching)

Answer 122

* an idiopathic and relapsing inflammatory bowel disease which can also be associated with extra-intestinal manifestations * involves a transmural inflammatory process that can affect the GIT anywhere from mouth to anus with skip lesions * involves an interplay between environmental & genetic factors; probably results from a genetic predisposition to an abnormal interaction between the immune system and environmental factors * specific cause of exaggerated inflam response at mucosal level unclear * number of potential causes proposed - most likely being infectious, immunologic & genetic; other possibilities include environmental & dietary factors, smoking, psychological factors * strongest risk factor for development of disease is a first degre relative w Crohns and clinical pattern of disease (type, extent, extraintesitnal manifestations) often concordant amongst relatives * \>70 genes assoc w Crohn's identified; one of those most strongly & frequently replicated = NOD2 (assoc w ileal disease, younger age at onset and ileocaecal resection) * pathogenesis incompletely understood but * gut normally exists in state of tolerance to stream of microbial, dietary and other antigens in contact w mucosa but this tolerance & ability to suppress an immune-mediated inflam response = lost in IBD * in Crohn's there are defects in immunoregulation and increased mucosal permeability secondary to leaky paracellular pathways * defects in immunoregulation may includ: * disturbed innate immune mechanisms at epithelial barrier * problems w antigen recognition and processing by dendritic cells * effects of psychosocial stress via neuroimmunological interaction * cell-mediated repsonse in Crohn's is predominant * efector T cells (Th1) are activated and release proinflammatory cytokines which stimulate macrophages to release TNF alpha, IL1 adn IL6, and abnormal dendritic cell function may further drive inflammatory process * leukocytes enter from local circulation releasing further chemokines, amplifying inflammatory response * local & systemic response includes fever, acute phase response, hypoalbuminaemia, weight loss, increased mucosal epithelial barrier permeability, endothelial damage, increased collagen synthesis * due to immune dysregulation, inflammatory repsonse in intestinal mucosa proceeds unchecked --\> chronic inflammatory state * Macro: because Crohn's is transmural, may cause stricturing or fistulating disease, and because it is non-contiguluous, causes 'skip lesions' and 'cobble-stoning' * stiff, thick-walled bowel with fat wrapping +/- upstream dilatation * can have fibrinous exudate & adhesions on serosal surface * aphthous ulcers (on surface of submucosal lymphoid nodules) = earliest macroscopic lesions * serpiginous linear ulcers along mesenteric aspect +/- lead to fissuring and fistulae * Micro: * transmural inflammation, lymphocytic infiltration, non-caseating granulomata (appear late, only in 60-70%, diagnostic unless adjacent to ruptured crypts) * skip lesions, focal crypt abscesses, mucosal lymphoid aggregates w overlying ulceration, preservation of goblet cell mucin * (whereas UC - diffuse inflam w/o skip lesions, mucosa and LP, goblet cell depletion, crypt distortion and abscesses * in longstanding Crohns, increased risk of ca in SB & colon * in addition to GI symptoms, get systemic sx eg weight loss, anorexia, malaise and if extensive SB disease, decreased fat soluble vitamins; deficiencies of Mg, Zn, Vit C, Vit B; anaemia (usu iron def, less commonly B12/folate; if lose 50cm TI, vit B12 absorption abnormal; if 100cm, malabsorption of bile salts & fats * extraintestinal manifestations incl prothrombotic state * related to disease activity: acute arthropathy, aphthous ulceration, amyloidosis, eye complications, erythema nodosum, pyoderma gangrenosum * unrelated to disease activity: sacroiliitis, ank spond, chronic active hepatitis, cirrhosis, gallstones, renal calculi

Answer 123

* an idiopathic relapsing inflammatory bowel disease which can be associated with extra-intstinal manifestations * involves the lamina propria of the rectum and variable extent of the proximal colon; inflammation spares the anus and is continuous to its proximal extent * carries 8x higher risk of colorectal ca cf general population, with higher risk with more extensive, severe, long-standing disease, presence of PSC, FHx of CRC, presence of dysplasia * is an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host; multiple factors are potentially causative/protective * increased risk w alcohol * smoking: ex smokers 70% more likely to develop than never smokers but in those that have it, smoking is protective against disease severity & in those who quit, more likely to relapse * hygiene hypothesis - more common in urban pops, indoor living, smaller familis and middle upper SES * antibiotic use in first year of life increases risk * genetic risk - 30% of those w 1st degree rel get it and 10-20% of those w UC have a 1st degree rel w it * pathophysiology incompleteely understood; most widely accepted hypothesis is that it's an immune-mediated condition in a genetically susceptible individual, where disease onset is triggered by environmental factors that perturb the mucosal barrier, alter the healthy balance of the gut microbiota and abnormally stimulate gut immune responses * MICRO: diffuse inflammation w no skip lesions, involves only mucosa and lamina propria, goblet cell depletion, crypt distortion and abscesses * no deep fissuring ulcers * MACRO: * contiguous inflammation from rectum, confined to rectum & colon * mild inflammation - oedema, erythema, abnormal mucosal vascular pattern/loss of vascular pattern (submucosal vessels seen through transparent mucosa) = as a result of mucosa oedema (makes it appear opaque) * mod inflammation - superficial erosions, ulcerations & contact bleeding from scope trauma * inflamed & regenerated mucosa surrounded by ulcerations --\> development of pseudopolyps * longstanding chronic inflam changes - featureless microcolon - mucosal atrophy, muscular hypertrophy, decreased luminal diameter, loss of haustral folds * extra-colonic manifestations (20%, slightly lower than Crohns) * those that respond to colectomy: peripheral arthropathy, erythema nodosum, episcleritis * sometimes: pyoderma gangrenosum * don't respond: axial arthropathy, PSC, uveitis, scleritis

Answer 124

* several factors contribute to normal anal continence * contraction of puborectalis & ext sphincter * maintenance of angle between rectum & anal canal w abdominal pressure flattening the lower anterior rectal wall over the upper end of the canal * presence of mucosal cushions in the canal * internal sphincter, though assisting closure, can only maintain continence if no distension (which causes relaxation of the sphincter) * rectum can accommodate itself to receive a certain amount of colonic content w/o any significant increase in pressure * when increasing rectal pressure causes faeces to enter upper anal canal, the ext sphincter contracts & causes the contents to return back into the rectum * feeling of distension is conveyed within spnial cord by gracile tracts * defaecation is allowed to occur by release of cortical inhibition that developed during childhood training * pathways in spinal cord prob run with the lateral corticospinal fibres (like those for the control of micturition) * abdominal pressure is increased, puborectalis relaxes and the anorectal angle straightens with the relaxation of the ext sphincter and contraction of lower colon and rectum (via its parasympathetic supply) * incontinence will occur * following damage to ext sphincter eg in obstetrics & perineal operations * some cases may be due to pudendal nerve entrapment * in cerebral or spinal cord lesions, may be loss of cortical control

Answer 125

JC 3 phases - initiation, amplification, propagation Initiation: - Exposed collagen binds PLT and vWF - Exposed TF binds FVII - which activates FIX and FX - End result = Va, VIIa, IXa, Xa Amplification - Prothrombinase (Va/Xa) and Tenase (VIIIa/IXa) formed - Tenase activates Xa - Prothrombinase catalyses Thrombin (II) formation Propagation - Thrombin burst leads to fibrin production - Also generates more Va and VIIIa (for prothrombinase and tenase) - And XIIIa, which crosslinks fibrin