Gastrointestinal Flashcards
What is the effect of increased parasympathetic tone on gastrointestinal contractions?
May cause segmental contractions which inhibit progressive motility.
Increase exocrine gland secretion.
How do you distinguish the small colon on palpation?
Presence of faecal balls and an antimesenteric band that is palpable along the length of this segment if it is impacted.
Which electrolytes are lost in large volumes of gastric reflux or diarrhoea?
Na, K, Ca, Mg and HCO3
What are the potential mechanisms for increased lactate concentration in cases of colic?
- Large colon ischaemia
- Reduced perfusion to peripheral tissue due to hypotensive shock
- Generalised intestinal ischaemia may result in absorption of lactate from the lumen
- Increased blood viscosity reduces perfusion of capillary beds, exacerbating ischaemia and tissue hypoxia.
If oesophageal rupture is suspected or aspiration is a possibility which contrast material should be used for a contrast oesophogram?
Iodinated organic compounds in an aqueous solution should be used instead of barium.
What are the sites for the FLASH U/S examination of the abdomen?
Ventral abdomen, gastric window, spleno-renal window, left middle third of the abdomen, duodenal window, right middle third of the abdomen and thoracic window.
For an oral glucose absorption test, how much glucose is given, at what time point and what level should the peak be in blood glucose be, and what are the different levels of malabsorption cut offs?
1g/kg of d-glucose as a 20% solution in water via NGT
Peak at >85% above baseline glucose between 90-120min
Complete malabsorption is a peak <15% above resting,
Partial malabsorption is between 15-85% above resting.
What are the benefits of a xylose absorption test over a glucose absorption test and how is the protocol different?
d-Xylose absorption is not confounded by hormonal effects of mucosal metabolism of glucose as the glucose absorption test is.
Protocol is: 0.5g/kg d-xylose as a 10% solution; peak is between 60-90min but is a concentration between 20-25mg/dl.
What effects do the normal diet have on results of an oral glucose absorption test or an oral xylose absorption test?
OGAT: higher peaks in horses eating grass/hay compared with concentrates and from those at pasture compared with stabled.
OXAT: higher peaks in horses fed low-energy diet such as alfalfa chaff than those fed high-energy diets such as oat chaff, oats and corn.
List tests for assessing gastric emptying
- Contrast radiography in foals
- Nuclear scintigraphy for liquid or solid phase emptying
- Acetaminophen absorption and measurement in serum
- 13C-octane acid breath test using a labelled test meal and detection of the novel isotope in breath.
List the intestinal barriers against pathological invasion at the varying cellular levels.
Epithelium: tight junctions and mucous layer
Macrophages: resident macrophages in the lamina propria, submucosa and intestinal lymphoid organs are among the first to respond to infection.
Describe the events that lead to intestinal inflammation with epithelial breach.
Breach of the mucosal barrier initiates an inflammatory response through synthesis of pro-inflammatory chemokines (IL8) and cytokine (TNFα, arachidonic acid metabolites) by epithelial cells which then trigger influx of neutrophils and other leucocytes into the tissue.
Mast cells are sentinel cells that sense microbial invasion and release TNFα.
Macrophages within the lamina propria, submucosa and intestinal lymphoid tissue activate CD14 TLR4 complex which initiates transcription of TNFα and IL1β which synergise with LPS to amplify the macrophage response.
Once initiated, TNFα, IL1β and other proinflammatory products of neutrophils, monocytes, mast cells and eithelial cells amplify the inflammatory response, in part through release of nitric oxide and other nitrogen radicals which are microbicidal but also vasoactive.
List the four important changes that occur in the intestinal vasculature in response to inflammation.
- Alteration of blood flow (initially increased, then decreased due to increased viscosity with fluid loss and oedema, increased leucocyte margination, platelet adhesion etc)
- Increased vascular permeability (due to histamine, leucotrienes, prostaglandins and other inflammatory mediators cause endothelial cell contraction, creating leaky gaps)
- Increased adhesiveness of endothelial cells, leucocytes and platelets (cytokines stimulate endothelial cells to express adhesion molecules that support adhesion of leucocytes and platelets.
- Exposure of the basement membrane and activation of the complement, contact and coagulation cascades. (adhesion to the exposed basement membrane enables exposure of neutrophils and platelets to mediators of inflammation which activates the cells to release oxidants and proteases that injure the endothelium and can cause irreparable harm to the microvasculature). Marginated neutrophils begin to transmigrate between endothelial cells and this, if not closely regulated can worsen vascular leakage.
Why is neutrophil depletion considered protective in some models of GIT inflammation?
During the acute response neutrophils are activated to release products that are not only lethal to pathogens and proinflammatory but are also damaging to host cells and tissues.
What are the most potent stimuli for neutrophil activation at the site of inflammation?
Complement (specially C5a), cytokines (TNFa and IL1B), platelet activating factor (PAF), immune complexes and bacterial products
What are the main regulators/stimulators of mast cells?
Complement fragments (C3a, C5a and C4a) Neural pathways which respond to enteric pathogen invasion
What are some important roles of mast cells during intestinal inflammation?
- First line defense at epithelial barriers
- When activated the release histamine, proteases, heparin and cytokines, as well as inflammatory mediators including prostaglandins, PAF and leucotrienes.
- On the vasculature they increase endothelial permeability and cause vasodilation
- Mast cell derived mediated enhance epithelial secretion, including the mast cell protease tryptase which regulates GIT physiologic responses during inflammation, including intercellular junction integrity, motility and pain responses.
- Mast cell products alter intestinal motility, generally increasing it to enable expulsion of intestinal contents.
- Mast cell derived leucotrienes and TNFa have a crucial role in host defence against bacterial pathogens, including neutrophil recruitment, regulating dendritic cells and adaptive immune responses.
- Mast cells are phagocytic and can act as antigen presenting cells.
What is the function of complement fragments?
During activation of the complement cascade, soluble fragments of C3, C5 and C4 (C3a, C5a and C4a) are liberated. These anaphylatoxins are chemotactic for neutrophils, and activate neutrophils and mase cell degranulation as well as stimulating ROS.
What is the basic mechanism behind ischaemia-reperfusion injury?
Reperfusion of ischaemic tissue is associated with platelet and neutrophil clumping in the small vessels of the mucosa which can impede blood flow. Platelets are activated and adhere to exposed basement membrane and activated endothelial cells and provide a surface for leucocyte adhesion. The accumulation of platelets and leucocytes reduces vessel diameter and blood flow while potentiating local coagulation and thrombus formation. Various factors (histamine, leucotrienes, prostaglandins, thromboxane etc) from the activated leucocytes have a role in regulating local perfusion during inflammation. In addition, nitric oxide is a potent regulator of blood flow. However, many of the mediators affecting perfusion also affect endothelial permeability, altering osmotic and hydrostatic balance and tissue oedema, so in extreme cases local and systemic coagulopathies initiated by the vascular injury and absorption of microbial products and inflammatory mediats induce a hypercoaguable state and exacerbate thrombus formation and tissue injury/infarction
How does neutrophil migration damage endothelial and epithelial barriers?
To facilitate neutrophil migration to the site of inflammation they release serine proteases and metalloproteinases to liquefy tissue matrix proteins that make up intercellular junctions. These degradative enzymes are particularly damaging to basement membranes and the cellular barriers of the endothelium. However a similar effect occurs with the epithelium - TNFa and IFNy from activated neutrophils increases the permeability of tight junctions of enterocytes. Subepithelial accumulation of neutrophils can lead to deadhesion of the epithelial cells from the basement membrane and mild to severe ulceration. The end result is PLE and absorption of bacterial cell wall constituents.
What factors are thought to affect motility during diarrhoea?
- Invasive bacteria cause rapid bursts of motor activity in the colon that appear to decrease transit time through the large intestine.
- Absorption of endotoxin and release of inflammatory mediators such as prostaglandins disrupts the motility patterns of the large intestine, resulting in less coordinated contractions.
What are phagocyte derived reactive oxygen metabolites and what effects do they have on tissue?
Phagocytes produces superoxide radicals as a host defense mechanism to kill invading microorganisms. During inappropriate stimulation, as can occur with inflammation, trauma or ischaemia-reperfusion, increased levels of toxic oxygen species are produced causing marked tissue damage. Activated phagocytes secrete peroxidase enzymes into the extracellular space, which catalyse oxidation of Cl to yield HOCl which is 100-1000 times more toxic than O2- and is a non-specific oxidising and chlorinating agent that reacts with amines to form N-chloramines. The end result is marked tissue damage and altered permeability.
In what conditions is the GIT permeability to endotoxin/bacteria increased?
- Strangulating obstruction and bowel infarction
- Inflammation eg enteritis or colitis
- Bacterial overgrowth
- Intraluminal acidosis (eg grain poisoning/overload)
Which cytokines are of interest in the pathogenesis of endotoxaemia?
TNFa, the interleukins, chemokinse and growth factors such as granulocyte-monocyte colony stimulating factor.
What are the three conditions that occur when the pro- and anti-inflammatory responses are not balanced/controlled adequately?
- Predominance of proinflammatory response = SIRS
- Predominance of antiinflammatory response = CARS (compensatory antiinflammatory response syndrome)
- Combination = mixed antagonist response syndrome.
Which leucocyte is primarily responsible for endothelial cell damage?
Neutrophils - the damage is caused by oxygen-derived free radicals which are produced within endothelial cells through reactions involving neutrophil derived elastase and hydrogen peroxide molecules.
What is the primary cause of neutropenia in cases of endotoxaemia?
Neutrophil margination in the vasculature, especially of the lungs. This is facilitated by adhesion molecules on endothelial cells and leucocytes that interact and allow sticking of leucocytes to the endothelial lining of blood vessels.
What are the two manifestations of DIC?
A thrombotic syndrome leading to ischaemic organ failure or a fibrinolytic syndrome with uncontrolled haemorrhage; or a combination of the two.
Endotoxaemia activates which pathways of the coagulation cascade?
Intrinsic (via Factor XII); and
Extrinsic (via LPS-induced tissue factor expression and vascular injury).
What type of shock is associated with endotoxaemia?
Distributive shock (largely associated with vascular dysfunction in the periphery).
What is the pathogenesis of shock and organ failure with endotoxaemia?
Early in endotoxaemia there is widespread vasodilation leading to vascular pooling, decentralisation of flow, decreased pre-load and decreased effective circulating volume. The compensatory response is hyperdynamic with an initial phase of tachycardia, increased cardiac output and CVP, pulmmonary hypertension, peripheral vasoconstriction and increased peripheral vascular resistance. The decompensated stage involves progressive systemic hypotension, confounded by direct myocardial suppression via nitric oxide, increased vascular permeability, intravascular microthrombi and impaired tissue oxygen extraction leading to progressive metabolic acidosis and inhibition of normal cellular metabolism.
What are the external signs of hypodynamic shock?
Peripheral perfusion is compromised so MM become brick red or purple with a dark toxic line, capillary refill is prolonged, the extremities and skin become cold to the touch, the arterial pulse weakens and venous fill is decreased. With vascular endothelial damage and increased capillary permeability you get a muddy MM appearance and diffuse scleral redenning. Haemostatic abnormalities such as petechial haemorrhage may be seen.
What is the pathophysiology of renal failure secondary to endotoxaemia?
Ischaemic cortical necrosis and acute tubular necrosis occurs secondary to coagulopathy induced afferent arteriolar obstruction.
In addition to hypovolaemia, what is a common contributing factor to haemoconcentration and elevated total protein in cases of endotoxaemia?
Splenic contraction due to increased sympathetic stimulation, as well as influences from production of acute phase proteins and protein losses.
Alterations in which coagulation parameters might be seen with DIC?
- Prolonged prothrombin time (Factor VII consumption)
- Prolonged activated partial thromboplastin time (Factor VIII and IX consumption)
- Prolonged thrombin time
- Decreased antithrombin III activity
- Thrombocytopenia
- Decreased protein C and plasminogen activities.
In addition to anti-LPS antibodies in specifically formulated hyperimmune plasma, what other benefits does plasma have for horses with endotoxaemia and how much is required?
Manufacturers recommend a minimum dose of 1-2L for endotoxaemia, but a dose rate of 2-10mL/kg.
Additional active constituents that may be of benefit in patients with endotoxaemia induced coagulopathy include complement components, fibronectin, clotting factors, ATIII
What clinical/patient considerations should be made when administering polymixin B to ameliorate signs of endotoxaemia?
- Beneficial effects may be limited to the first 24-48hr after onset of endotoxaemia due to development of endotoxin tolerance
- Hypovolaemia and dehydration may exaccerbate toxic effects of polymixin B - attempts should be made to rehydrate or at a minimum improve peripheral tissue perfusion prior to administration
- If co-administration with other toxic products such as aminoglycosides rehydration is even more important, and close monitoring for side effects is important.
Why are NSAIDs effective in ameliorating the effects of endotoxin? And what dose is recommended?
Inhibition of COX inhibits prostanoid production; prostanoids have been identified as important mediators in inflammatory response.
Due to the findings that flunixin impairs recovery of intestinal barrier function and may increase mucosal permeability to LPS a reduced dose of 0.25mg/kg q6-8h has been recommended - at this dose flunixin inibits eicosanoid synthesis efficiently in a model of endotoxaemia.
co-administration of lidocaine (CRI) enhance recovery and decrease recovery time
What benefit may lidocaine be in cases of endotoxaemia?
In experimental models in rabbits lidocaine inhibited haemodynamic and cytokine responses to endotoxin if given immediately after LPS infusion. It also ameliorated the inhibitory effects of flunixin on recovery of mucosal barrier function following ischaemic injury in equine small intestine, hence it may have merit in endotoxaemic patients.
Because ATIII levels are frequently decreased in patients with coagulopathy (as can occur with endotoxaemia), addition of heparin to fresh frozen plasma can be effective, however has been associated with erythrocyte agglutination which can increase risk of microthrombosis. What is an alternate means of reducing the risk of coagulopathy?
Administration of low-molecular weight heparin at 50IU/kg SC q24h
Aspirin 10-20mg/kg q48h - irreversibly inhibits platelet COX activity to inhibit platelet aggregation and microthrombosis.
What are the gross findings with proximal enteritis?
Serosal surface may have varying degrees and distribution of bright red-dark red petechial and ecchymotic haemorrhages and yellow-white streaks.
The lumen is filled with malodorous red to brown-red fluid.
The mucosa surface is hyperaemic with varying degrees of petechiation and ulceration
Serosal fibrinopurulent exudate is a common finding in severe cases.
At a microscopic level, what are the findings with proximal enteritis?
Varying degrees of mucosal and submucosal hyperaemia and oedema, villous degeneration with necrosis and more severely, sloughing of villous epithelium. The lamina propria, mucosa and submucosa have varying degrees of granulocyte infiltration (mainly neutrophils) and the muscular layers and serosa may contain small haemorrhages.
Most severe lesions in the duodenum and proximal jejunum but may extend proximally to the gastric mucosa and aborally to the large colon.
What is the proposed eitiology of hepatic disease with proximal enteritis?
Ascending infection via the common bile duct, local absorption of endotoxin via the portal circulation, systemic consequences of endotoxin absorption, metabolic imbalances and hypoperfusion or hypovolaemia .
What are the two intracellular processes that control intestinal secretion and how do they do this?
Cyclic nucleotide (cAMP and cGMP) and calcium systems. cAMP can be induced by inflammatory mediators such as VIP and PGE2 and cGMP can be induced by bacterial enterotoxins. Increased intracellular Ca may be secondary to cyclic nucleotide-dependent release of stored Ca within the cell or from increased Ca entry across the cell membrane. The net effect is increased movement of Na and Cl into the mucosal cell from the interstitium, with secretion of Na and Cl into the intestinal lumen. Water follows the directional flux of Na and Cl.
In terms of acute abdominal discomfort, how can small intestinal obstruction be differentiated from proximal enteritis?
With small intestinal obstruction the signs of discomfort are typically consistent until correction. With proximal enteritis discomfort typically subsides after gastric decompression and volume replacement.
Why might metronidazole be indicated in cases of proximal enteritis?
Clostridium species have been suspected as a causative agent for proximal enteritis, hence metronidazole treatment may be appropriate. Penicillin has also been advocated although effects on dysbiosis may be more profound with penicillin.
Histologically what is the lesion seen with equine coronavirus?
Necrotising enteritis particularly of the jejunum and ileum with haemorrhage in the ventral colon in some cases.
What are the common clinicopathologic and diagnostic findings of alimentary lymphoma?
Anaemia, thrombocytopenia, neutrophilia or neutropenia, hypoalbuminaemia and hyperglobulinaemia.
Lymphocytosis is rare.
Enlarged mesenteric lymph nodes may be palpable.
Carbohydrate absorption tests usually reveal partial to total malabsorption indicative of a severely reduced surface area resulting from significant villous atrophy and extensive mucosal or transmural infiltration.
A biopsy is necessary for diagnosis.
What is the typical signalment for granulomatous enteritis and which breed seems predisposed?
Standardbreds are over represented.
Most horses are 2-3 yrs old and its possible there’s a genetic predisposition
The cause of granulomatous enteritis is unknown however a bacteria and a toxic agent have been implicated - what are they?
Mycobacterium avium and aluminium although the reliability of that case report is questioned.
What are the treatment options for granulomatous enteritis?
Long-term corticosteroids (often unrewarding)
Surgical resection of localised disease may be successful in some cases.
What are the clinical disorders associated with multisystemic eosinophilic epitheliotropic disease (MEED)?
Predominant eosinophilic infiltrate in the GIT, associated lymph nodes, liver, pancreas, skin and other structures accompanied by some degree of malabsorption and enteric protein loss.
What is the typical signalment of MEED affected horses and which breeds are over-represented?
Typically young horses aged 2-4yrs with SB and TB predominating.
What are the typical skin lesions with MEED?
Exudative dermatitis and ulcerative coronitis
Is systemic eosinophilia a common finding in MEED?
No, systemic eosinophilia is a rare finding despite extensive tissue eosinophilia.
What are the common haematological/clinical chemical abnormalities in cases of MEED?
Hypoalbuminaemia, elevations in GGT and ALP.
Which characteristics of the disease are typically associated with diarrhoea with MEED?
Segmental or multifocal granulomatous lesions with mucosal and transmural thickening and extensive ulceration
Is fibrosis a feature of affected tissue with MEED?
Yes
Where is Lawsonia intracellularis typically localised to in cases of proliferative enteropathy?
The cytoplasm of proliferative crypt epithelial cells of the jejunum and ileum. Preferentially infects proliferating cells, hence tropism for the crypt epithelium, and infection induces more rapid proliferation.
What is the incubation period for Lawsonia/proliferative enteropathy?
2-3 weeks.
What are the proposed risk factors for development of Lawsonia/proliferative enteropathy?
Weaning, transport, comingling/overcrowding, feed changes, antibiotics.
Which stain is required to detect Lawsonia intracellularis intracellularly?
Silver stain. Curved or comma shaped rods found clustered in the apical cytoplasm of hyperplastic crypt epithelium.
What biosecurity precautions should be taken in cases of Lawsonia intracellularis?
Affected animals should be isolated from unaffected animals for at least 1 week after institution of antimicrobial therapy to avoid shedding of organisms into the environment.
What are the general feeding recommendations for horses with chronic wasting disease and evidence of malabsorption?
Interval feeding small frequent meals of easily digestible food
Feeds with high fibre but low bulk
May tolerate increased dietary fat
Supplemental protein
Which is the most pathogenic serovar of Salmonella in horses?
Typhimurium
List risk factors for development of Salmonella
- High ambient temperatures (summer and fall)
- Transportation
- Antibiotic Tx
- Hospitalisation/prolonged hospital stay
- Dietary changes
- Immunosuppression
- Gastrointestinal disease (colic, diarrhoea etc)
- GIT or abdominal surgery
- General anaesthesia
- Leucopenia or laminitis during hospitalisation
Which factors of the host immune system are most effective at preventing infection with Salmonella?
- Mucosal antibody secretion and enterocyte-derived cationic peptides prevent colonisation of the mucosa
- Opsonising antibodies and activation of the complement cascade are important for fighting systemic invasion by S. enterica by increasing efficacy of phagocytosis and by direct bactericidal activity.
- Humoral immunity is often ineffective in preventing disease and dissemination once invasion occurs intracellularly.
- S. enterica is capable of surviving and multiplying within macrophages, rendering the humoral immune system ineffective.
How does Salmonella invade intestinal cells?
Invasion occurs through specialised enterocytes called M cells through self-induced uptake (type III secretory system) via the apical membrane of the M cell, often killing the cell in the process.
It then invades neighboring cells via the basolateral membrane eventually spreading the destruction of the epithelium beyond the principle area of attack
What is the effect of S. enterica enterotoxin on the development of inflammation and diarrhoea?
The enterotoxin induces secretion of Cl and water by colonic mucosal cells, triggers an inflammatory reaction in intestinal tissues including stimulation of chemokine and cytokine production resulting in recruitment of leucocytes and activation of resident mast cells and macrophages. In addition the enteric nervous system inhibits sodium and water absorption, causes motility disturbances and potentiates tissue injury. All of these contribute to enhanced pathogenicity and dissemination of S. enterica and pathogenesis of diarrhoea.
