Pathophysiology of Endocrinopathies - Lab 1 PDF

Pathophysiology of endocrinopathies - Lab 1 Pathophysiology of adrenal disorders Adrenal anatomy - adrenal cortex - Zona glomerulosa / fasciculata /reticularis - Adrenal medulla - Secretion of epinephrine, norepinephrine - Hormones secreted - Aldosterone, cortisol, DHEA (influence reproductive tract...

Pathophysiology of endocrinopathies - Lab 1 Pathophysiology of adrenal disorders Adrenal anatomy - adrenal cortex - Zona glomerulosa / fasciculata /reticularis - Adrenal medulla - Secretion of epinephrine, norepinephrine - Hormones secreted - Aldosterone, cortisol, DHEA (influence reproductive tracts) Hypothalamic-pituitary-adrenal axis VIDEO Hyperadrenocorticism - Cushing syndrome - DOGS - Spontaneous disease - always chronic, the symptoms appear and worsens in the second half of life - Primary: adrenal-dependent hyperadrenocorticism. - ADH - adrenal-dependent Cushing syndrome. - 15-20% tumor - Secondary - pituitary-dependent hyperadrneocorticotism - PDH - Cushing disease - 80-85% tumours - Iatrogenic - caused by the doctors or owners actions Pituitary-dependent hyperadrenocorticism - Most common - Increased secretion (uncontrolled) of ACTH by pit. Gland —> bilateral hyperplasia of the adrenal gland —> increased synthesis of glucocorticoids (mostly cortisol) - Causes: pituitary adenoma or pituitary adenocarcinoma secreting ACTH - 80-90% cases of Cushing syndrome in dogs - Develop slowly, older animals > 6y, diagnosis is usually made at the age of 10. - Predispositions: schnauzer, boxers, poodle, dachshunds, beagle, German shepherd, small terriers. - 2 enlarged glands Adrenal dependent hyperadrenocorticism - ACTH independents, increase corticol secretion in one of the adrenal gland. - Cause: functional adrenal tumor, bending adenoma or malignant adenocarcinoma (possible of metastatic lesion in other regions) - Unilaterally enlarged adrenal gland - high cortisol concentration in blood - decreased secretion of corticotrophin-releasing hormone (CRH) and ACTH —> atrophy of contralateral gland and atrophy of non-tumor cells of the enlarged gland. - 10-15% cases of the cushnings syndrome in dogs - Diagnosis is usually made at the age of 11 - Predispositions: poodle, German shepherd, dash under, Labrador. - 1 small and 1 large gland Iatrogenic Cushing syndrome - Long-term glucocorticoid treatment (immune mediated diseases, mostly in small dogs, ex, IMHA - immune mediated haemolytic anemia) - Incidence in any age - Decrease secretion of CRH from hypothalamus and ACTH from pit.gland —> bilateral atrophy of adrenal cortex - Restoring the proper function of the adrenal gland may take several weeks - Clinical signs can appear in glucocorticoid overdose (ex, treatment of hypoadrenocorticism) VIDEO Symptoms of Cushing syndrome - Clinical signs are a result of long-term influence of excessive glucocortiocoid levels on almost all tissues of the body: - - - - - - - - Increased glucose o genesis in the liver, decreased glucose utilisation, in the muscle and adipose tissue (insulin resistance) - reduced cell sensitivity to insulin, diabetogenic action) Increased protein catabolism and reduced synthesis of proteins Increased lipolysis - release of FAs from adipose tissue and change in fat distribution Anti-inflammatory and immunosuppressive action Excess urinating (polyuria) - Cortisol increases renal perfusion and glomerular filtration rate - Impairment in renal responsiveness to anti diuretic hormone (vasopressin) Excess drinking (polydipsia) - As a consequence of the loss of water through urination - hypovolemia stimulated thirst center in the hypothalamus Excess appetite (polyphagia) - Cortisol has anti-insulin action, excess cortisol leads to decrease sensitive of insulin receptors also in the hunger center in hypothalamus Pendulous abdomen (abdominal distension) - Muscle atrophy and weakness of abdominal muscles (cortisol exerts proteolysis action) - Hepatomegaly - Increased glycogensis - glycogen accumulation - Fatty liver (liver Steatosis - FAs are released from the adipose tissue —> esterificatoin of FAs in the liver —> accumulation of TAGs in hepatocytes - Increased abdominal fat deposition - Permanently full bladder Exercise intolerance (muscle weakness) Panting (increased abnormal pressure on the diaphragm) Symeptrical alopecia - Variable intensity, hair loss around trunk and body except head and limbs. Cortisol increase proteolysis —> loss of hair follicles. Dull dry hair coat, w/o gloss, doesn’t not grow back after trimming. Hyperpigmentation Skin atrophy - Parchment skin, skin thinning, translucent skin, clearly vissable BVs on the abdomen. - Elastin and collagen deficiency in the dermis and subcutaneous tissue (cortisol increases proteolysis —> inhibition of cell division -> skin atrophy) Secondary cutaneous lesions can develop co,domes (bleakhead) (keratin and modified sebum that have accumulated in the sebaceous glands duct) Calcinosis cutis (cutenous calcifications - In advanced disease dystrophic calcification in the skin may develop - Ca deposition in the groin region and the back - Erythema and granulomatous inflammation develops around Ca crystals - - Pyodermatias, often accompanied by pruritus. - Skin becomes susceptible to trauma, secondary bacterial and fungal infections (potentiated by immunosuppressive action of glucocorticoids). Demodecosis can develop (5%) - Recurrent urinary tract infection (20%) as a result of immunosuppression. Feminisation of males, virilization of females Neurological symptoms of Cushing syndrome - cerebral neurons signs - Facial paralysis - Sudden blindness - Exophthalmos Symptoms of Cushing syndrome - panting - Coughing - Cyanosis - Mineralised airways bronchitis - Pulmonary thromboembolism is a common feature of the syndrome - Collapsing tranchea is a common concurrent disease (Yorkshire) - Radiological examination: - Foci or dystrophich calcification - trachea dn bronchi, adrenal tumours, sometimes in the abdominal vessels - Liver no agreement - Distended bladder - Vertebral osteoporosis in advanced disease. High cortisol concentration: - Inhibit bone matrix synthesis by decreasing osteoblast activity and increase osteoblast apotosis - Cause calcitriol deficiency —> decrease Absoption of Ca in GIT and increased excretion in kidneys —> hypocalcemia —> increased parathyroid hormone secretion —> osteoclast activation —> increased osteoporosis - Abdominal ultrasound - Large, hyperechoic liver (relative to fat) - 2 plump adrenals indicates PDH - ADH - one large and one small adrenal - Laboratory tests - CBC - Stress leukogram: neutrophil is, eosinophilia, lymph open is - Hyperglycemia (40-60%) - Hyperlidiemia - Increased hepatic enzyme activity (ALP) - Urine analysis: - Isosthenuria (urine of the dame total solute concentration as unaltered glomerular filtrate) but urine-concentrating ability is maintained - Often signs or urinary tract infection (immunosuppression) Complications of Cushing disease - Hypothyroidism - Hypertension - Thromboembolic pulmonary disease - Diabetes mellitus Hyperadrenocorticism (Cushing syndrome) - CATS Cushing syndrome in cats - feline cells express 2 times less cortisol receptors then canine cells (cat require 2 times higher glucocorticoid doses than dogs) - It’s rare in cats - Strictly associated with refractory diabetes mellitus - PDH - 75% - ADH - 25% Clinical signs: - polyuria, polydipsia, polyophaga are due to concurrent diabetes mellitus - Dermatological change - fragile skin syndrome - Alopecia - Hepatomegaly +/- pendulous abdomen - Muscle atrophy - Weight loss - Poor grooming Hypoadrenocorticism - Addisons disease, adrenal insufficiency) Addisons disease - occurs in 0.5 dogs per thousand - Solo practice vet should diagnose one new case every other year - If untreated, Addison can be fatal - If treated, prognosis is excellent - Median survival 7 years with treatment - Rare in cats - Deficiency of adrenal cortical hormones; chronic disease or a life-threatening acute condition - Clinical signs appear when 90% of adrenal gland stops functioning - Genetic predisposition in poodle Forms - primary - auto aggressive, infectious or neoplastic process that destroys adrenal cortex —> glucocorticoid (cortisol) and mineralocorticoid (aldosterone) deficiency. The most common - Secondary - neoplasia, inflammation or trauma of the hypothalamus -> lack of ACTH stimulation of the adrenal gland —> only glucocorticoid deficiency (cortisol) - Iatrogenic - incorrect treatment - After long-term glucocorticoid therapy when the drug is withdrawn abruptly —> only glucocorticoid deficiency - - Consequence of inadequate pharmacological management of Cushing syndrome —> depending on the drug used primary or secondary —> depending on the drug used primary or secondary. - Addisons disease is present After bilateral removal of the functional adrenal tumor (rarely) -> glucocorticoid and mineralocorticoid deficiency Primary Addisons disease - glucocorticoid (cortisol) and mineralocorticoid (aldosterone) deficiency - Action of aldosterone - Secretion regulated by renin-angiotensin system - - - - - In healthy patients: increased reabsorption of NA and Cl in kidneys and increased excretion of K = decreased urine V Aldosterone deficiency; - Excretion of huge amounts of Na and Cl —> hyponatremia and hypochloremia - K retention —> Hyperkalemia Consequences of hyponatremia: - Increase excretion of Na and Cl w urine -> polyuria increases loss of Na and Cl from the renal medulla -> decreased reabsorption of water in collecting tubule -> isosthenuria -> dehydration -> haemoconcentration -> decrease BP -> increased resistance in the circulation -> decrease renal perfusion and tissue perfusion —> prerenal azomtemia -> vomiting Consequence of Hyperkalemia: - Influence on cardiac rhythm -> decrease myocardial excitability, prolonged cardiac repolarization -> BRADYCARDIA -> ejection fraction -> enhanced cardiovascular disorders and increased prerenal azotemia - K -> influx of K into cells, outflow of H -> metabolic acidosis Effects of Glucocorticosteroid deficiency: - - - Impaired glycogenesis - Increased cells sensitivity to insulin -> increased tissue glucose utilization - Decrease glycogen synthesis in the liver - Impaired lipid synthesis - —> hypoglycaemia The symtoms of glucocorticosteroid deficiency worsens in stressful situation - lack of adaptive mechanisms Clinical signs: - Non-specific symptoms, present in many diseases, that is why Addisons disease is a diagnostic challenge - In chronic form: the symptoms appears and resolve: - Apathy, weakness and anorexia - Weight loss - Polyuri, polydipsi - Emesis(vomiting), sometimes diarrhea. - The symptoms usually resolve after rehydration or glucocorticoid admin. - In acute from predominant manifestation is hypovolemia shock - adrenal crisis (Addison crisis) - Significant dehydration - Pale mucous membranes - Slow capillary refill time - Bradycardia and weak pulse - Severe exercise intolerance - Diarrhea (other w blood), abdominal pain - In extreme cases shock and hypoglycaemic seizures Laboratory tests - CBC: lack of stress leukogram despite obvious symtoms of disease (sometimes eosinophilia and lymphocytosis), mild non regenerative anemia - Urine analysis: isosthenuria - Biochemical blood analysis: hypoglycaemia, additionally in primary Addisons disease - Hyperkalemia - Hyponatremia - Hypochloremia - Prerenal azotemia - Metabolic acidosis Addison = the great pretender - looks like many other diseases - Very young to older dogs - Chronic low grade signs - Electrolyte disturbance - Other biochemical changes - Azotaemia, anaemia, low albumin - Low glucose, high Ca, no stress leukogram (eosinophilia) Pathophysiology of diabetes mellitus Pancreas - anatomy - exocrine-secreting acinar cells - Islets of Langerhans - A cells - secrete glucagon - B cells - secrete insulin - Delta cells - secrete somatostatin - F cells - secrete pancreatic polypeptide Insulin - The most important anabolic hormone The primary target issues - liver, muscle, fat Glucagon is the main antagonist of insulin Diabetes mellitus - a group of metabolic diseases characterized by Hyperglycemia resulting from defects in insulin secretion, insulin actions or both. Types of diabetes mellitus - Type 1 (insulin-dependent) - absolute deficiency of insulin secretion due to autoimmune destruction of the b cells (DOGS) - Irreversible - Type 2 - 2 defects; insulin resistance, secondary b-cell dysfunction (CATS) - Reversible - Other specific types - secondary to disorders of the exocrine pancreas (pancreatitis, neoplasia), endocrinopathies, insulin antagonists (ex, glucocorticoids, progestins) - Type 4 - gestational diabetes - VIDEO on type 1 / 2 diabetes Diabetes mellitus - DOGS: Moslty type 1 diabetes - Permanent hypoinsulinemia, Irreversible disease - CATS: mostly type 2 diabetes, possible disease remission, stress Hyperglycemia - High risk breeds: Australian terrier - Low risk breeds: boxer Ethology - dogs - type 1-like diabetic mellitus - Autoimmune mechanisms, presence of autoAbs - Genetic factors and congenital disorder - Environmental factors, diseases and drugs, obesity, pancreatitis. Ethology - cats - type 2-like diabetes mellitus (insulin resistance) - Insulin resistance - environmental (age, male neutered cats) - Healthy b cells adapt to obesity and insulin resistance by increasing insulin secretion to maintain normal glucose tolerance - Secondary b-cell failure - Obesity -> aberration in glucose transport, lower expression of insulin signaling genes, decreased secretion of adiponectin -> insulin resistance Carbohydrate metabolism - Insulin deficiency/insulin resistance -> reduced glucose entry into the cell —> Hyperglycemia -> renal capacity for glucose reabsorption is exceeded - glucose is lost in the urine -> glucosuria -> osmotic Diuresis, polyuria (risk dehydration) -> polydipsia Eating behaviour - insulin deficiency/insulin resistance -> glucose does not enter satiety center cells so it is not inhibited -> stimulation of hunger center -> polyphagia (excessive hunger) + increase catabolic activity (weight loss) Lipid metabolism - lipolysis - hydrolysis of TAGs into nonesterified FAs and glycerol -> hypertriglyceridemia - Increased levels of NEFA are transported to the liver and undergo b-oxidation -> excess acetyl CoA -> ketone body production -> ketoacidosis - Increased levels of NEFA are transported to the liver -> increased hepatic synthesis of TAGs -> hepatic steatosis (fatty liver), Hepatomegaly, hyperlipidemia Ketoacidosis symptoms: - Lethargy, anorexia, reduced water intake, vomiting, dehydration, death The major complications excess glucose in organs would cause BV damage Chronic complicaitions - diabetic neprhopaty - Cataract and uveitis - dogs - Diabetic neuropathy - cats - Water-electrolyte imbalance - Increases susceptibility to infections Cataract and uveitis - DOGS - Caretact (lens opacities): - Absoption of glucose by the lenses, influx of water into the lens, altered osmotic relationships in the lens, swelling and tupture of the lens fibers, cataracts (blindness, irreversible process) - Lens-induced uveitis /anterior uveitis - Consequence of exposure of cataract lens protein to local ocular immune system (immune tolerance to the crystalline proteins does not develop) Diabetic neuropathy - cats - Demyelination and remyelination as well atonal degeneration and regeneration -> myelinated fiber loss -> diabetic neuropathy (hindlimb weakness, decreased ability to jump, plantigrade posture) Insulin regulation - don’t be in a hurry - It can take a few months (2-3m) prepare the owner - Control symptoms of hypoglycaemia to avoid it (lethaggry, weakness, head tilting, ataxia, seizures, and coma) - Severe hypoglycaemia is immediately life threatening Severe Hyperglycemia a problem only when prolonged Not quite enough insulin is better than a little too much Weight loss and exercise - weight loss can contribute to achieving diabetic remission in the cat - Weight loss can improve diabetic control and reduce insulin requirements in dogs - Obese dogs and cats are at greater risk for pancreatitis, which can be a life threatening complication of diabetes mellitus - Moderate excerise can increase mobilization of insulin - Strenuous exercise should be preceded by a reduction in insulin - Consistent exercise programs are the best Nutrition for diabetic dogs - high complex carbs (>50% dry matter) - Low glycemic index - High fiber (>10% dry matter) - Increased soluble fibers slow GI transits and potentiates insulin in tissues. - Increased insoluble fibers slow GI transit time, starch hydrolysis and glucose Absoption - Reduce fats to prevent pancreatitis Nutrition for diabetic cats - ideal diet for diabetic cats - >40% protein and <10% carbs as % of calories - Be careful with dry food - high in carbohydrates, very calorie dense - Stay Awar from food with gravy - high in carbs - High protein/lower fat is also the goal. Phagocytosis and intracellular killing - Lab 2 Phagocytosis and phagocytes - phagocytosis - Specific form of endocytosis where cells ingest (phagocytes) microbial pathogens and other solid matter including metal fillings, pigments or black C particles - Professional phagocytes of the immune system: - Macrophages - Neutrophils - Monocytes, immature dendritic cells, eosinophils, basophils - In these cells phagocytosis is a mechanism by which microorganisms can be contained, Killed and processed for Ag presentation - It represents a vital facet of the innate immune response to pathogens - It plays an essential role in initiating the adaptive immune response. Acute inflammation and initiation of phagocytosis - Acute inflammation begins with in seconds to minutes following the injury of tissues. - Events in acute inflammation 1. Increased BF, due to dilation of BVs (arteriolar) supplying the region. - vascular events 2. Increased permeability of the capillaries, allowing fluid and blood proteins to move into the interstitial spaces - vascular events 3. Migration of neutrophils, out of the capillaries and venues and into interstitial spaces - cellular events Acute inflammation - The inflammatory response is a body’s second line of defends gains invasion by pathogens. Why is it important that CF from the circulatory system have access to injured area 1. Damaged tissues release histamines increasing BF to the area 2. Histamines cause capillaries to leak, releasing phagocytes and CF into the wound. 3. Phagocytes engulf bacteria, dead cells and cellular debris 4. PLTs move out of the capillary to seal the wounded area Vascular events - the vascular events of the acute inflammatory response involve following processes: 1. Changes in vessel caliber and consequently, flow - vasodilation & increased BF (micro circulation; capillaries, arteriolar) 2. Increased vascular permeability - due to endothelial contraction or/and damage - Plasma escapes into the tissues - Blood cells are retained in the vessels 3. Formation of the fluid exudate - after a few minutes the BF decreases due to exudate adn, increased blood density and viscosity. - exudate - fluid rich in protein (and cellular elements) which leaks out of BV into nearby tissues in case of inflammation. - 3 possible patterns of increased leakage of fluid from vessels, which occur at different times following injury: - Response mediated by HISTAMINE = transient immediate respone that last for 30-60 min - Mediate vascular leakage - Response mediated by factor synthesised by local cells, ex. Prostaglandins, PLT activating factor, or plasma proteins, bradykinin, complements = delayed response that starts 2-3h after injury and last up to 8h. - Mediated vascular leakage - Response that is seen, burn or by a chemical toxin = a prolonged immediate response that occurs over 24h. - Non-mediated vascular leakage Cellular events A. margination - allows initiation of cellular events B. Rolling C. Adhesion D. Transmigration (diapedesis) E. Chemotaxis A: Margination - as BF begins to slow, blood cells begin to flow nearer to the vessel wall, rather than the axial stream - They allow leukocyte rolling. B: Rolling - bacterial products alarming from damaged tissues: THOMBIN, HISTAMINE ->. The expression of glycoprotein “p-selectine” on endothelial cells (normally stored in granules) Selectins expressed on endothelial cells tether neutrophils and stimulate them to roll - This binding is transient and neutrophils are took away from the surface by flowing blood - Neutrophils rolling along the surface of the endothelium in the BV - They gradually slows down and as they lose speed they finally line-up along the vascular endothelium and stop C: Adhesion - neutrophils express a protein - CD11a/CD18 that is an integrin <—> strong binding <—> glycoprotein expressed on the endothelial cells - ICAM-1 - Adhesion - neutrophils are attached firmly to the vessel wall despite the sheathing force of the BF BLAD and CLAD - these are genetic disorders - leukocyte adhesion deficiencies (LAD) in canine or bovine. - Both caused by defects in the integrin CD18 molecule - Defect prevents formation of functional CD11/CD18 complexes - No adherence, no migration, no aggregation of leukocytes - Increases susceptibility to infections. D: transmigration (diapedesis) - Diapedesis: neutrophils squeeze between the endothelial cells and the basement membrane - Neutrophil recognise the connection between endothelial cells by PECAM-rec. - to cross the basement membrane they release collagenase E: chemotaxis - neutrophils develop the ability to move actively, in a directional fashion, from vessels toward the area of tissue damage - How do neutrophils move to the area of tissue damage? - Amobeoid motion - How do they know where to go? - Chemotaxis Chemotaxis - chemotaxis of leukocytes - the movement of leukocytes from the vessel lumen into a damaged area that is mediated by substance known as chemotactic factors, that diffuse from the area of tissue damage - All granulocytes and monocytes respond to chemotactic factors and move along a concentration gradient - Chemoattractant can be endo or exogenous - Exogenous - Bacterial component, ex phorbol esters - Endogenous - C5a, C3a, fibrin, fibrinopeptides, LTB4, IL-8 - Chemotactic factors bind to receptor on the surface of leukocyte and activate secondary messenger systems - Stimulating increased intracytoplasmic Ca - The Ca then interacts with the cytoskeleton resultin in active movement of the cells Microbial activity of leukocytes - phagocytosis 1. Recognition and attachment 2. Engulfment 3. Killing and degradation 1: recognition and attachment - the process of phagocytosis begins with the beginning of: - Opposing and/or specific molecules on the pathogen surface - To cells surface receptors on the phagocyte that causes receptor clustering and trigger phagocytosis - Opsonisation - When pathogens are marked for ingestion and destruction by a phagocyte - They are oposinized either by immunoglobulins or by complement component or both. Opsonisation - Ig’s bind to micro-organism by their fab components - The Fc component stayed exposed - Neutrophils and macrophages have surface rec. (FcR - CD32) for the Fc fragment of immunoglobulin, and consequently bind to the micro-organisms prior to ingestion - CD32 (CR-1) is a surface rec. for C3b complement protein. Binding specific molecules on pathogen surface - Macrophages / neutrophils 1. Engulf pathogens 2. Initiate / sustain inflammatory response - they express rec. for many bacterial components - Bacterial carbohydrates, lipids, other pathogen - derived component An effect: - Phagocytosis stimulation, and secretion of “pro-inflammatory cytokines” 2: engulfment 1. Surrounding bound pathogen by the phagocyte membrane 2. Pathogen internalisation in a membrane enclosed vesicle - phagosome (endocytic vacuole) 3. Phagosome acidication - allows to kill most pathogens 4. Fusing phagosome to one or more lysosomes = a phagolysosom generates - lysosome - membrane enclosed granules that contain enzymes, proteins, peptides adn are microbicidal 5. Releasing lysosomal contents and destroy the pathogen - intracellular killing - Release of lysosomal products from the cell damaged local tissue due to proteolysis by enzymes such as elastase and collagenase 3: Killing and degradation - 2 possibilities: - A. The respiratory bust - oxidative killing - B. Lysosomal antimicrobial molecules activity - non oxidative killing A. The respiratory burst - oxidative killing - assembly of multi component enzyme NADPH oxidase (NOX) in the membrane of the phagosome - NOX catalysed the generation of beacterial products: - Hydrogen peroxide H2O2 - Hypochloride ions (OCl-) - Myeloperoxidase catalyses the reaction between H2O2 and intracellular halide ions (Cl, Br, I, SCN) to produce hypohalides (hypochlorous acid) B. Lysosomal antimicrobial molecules activity - non-oxidative killing - - Fever, thermoregulation - lab 3 - - a complex, orderly set of physiological reaction manifested by an increase in body temp Is a nonspecific adaptive response of the physiologically efficient thermoregulatory center and peripheral mechanism Purpose = restore intrinsic balance disturbed by the action of a pathogenic factor an component of body homeostasis in mammals and birds The resultant between heat generated by the body and heat dissipated to the environment. Thermogenesis - Shivering - produce metabolic heat through muscle contraction - Nonshivering - through metabolism in brown fat in young animals. (Highly specialised tissue), also due to heat producing Hormones (catecholamines, thyroid hormones, glucagon) Radiation - heat transfer from a warmer to a cooler object Conviction - heat transfer to movement of air (cool air) Evaporation Conduction - transfer of heat between 2 objects by direct contact Countercurrent heat exchanges 1. Warm blood from the body’s core travels down the leg in an artery 2. Arterial blood passes heat to cold blood coming back from the foot 3. Arterial blood is now cooler and will lose less heat to the environment as it travels through the foot 4. Cold venous blood from the foot is warmed before it returns to the body’s core Thermoregulator center - it works by comparing signals from thermometer with a temp reference system encoded in the centers neutrons - the biological standard for body temperature = a set point - Fever = a condition in which there has been a shot in the hypothalamic set point - Thermoregulatory center - Fever = a condition in which there has been a shift in the hypothalmic set point and body tempo is regulated at a higher level - Unlike overheating, thermoregulation in fever works just as efficiently as in healthy animals! Fever vs hyperthermia - Fever - Change in hypothalamic set point. The key does not defend itself against an increase in body temp - Subjected sensation of cold - Reduced heat release to the environment and increase heat production - Internal temperature lower than lethal by about 2 degrees - Administration of antipyretics lowers internal temp - Hyperthermia - Hypothalamic set point is constant. The body defended itself against an increase in body temp - Subjective sensation to heat - The increase in heat transfer to the environment is not enough to lower the body’s internal temperature Internal temp can reach a lethal temp Administration of antipyretics does not lose the internal temp. Causes of fever - injuries, burns/frostbites, Tumors - Exogenous pyrogens - Infectious and invasive agents - Bacteria/bacterial toxins - Viruses - Fungi - Parasites - Factors from disintegrated cells (necrosis) - Reactive oxygen species - Metabolites of arachidonic acid - Acute immune reactions - Acute immune hemolytic anemia - Post-vaccination reactions - Hypersensitivity reactions - All these —> macrophages/ monocytes/ dendritic cells/ lymphocytes —> IL-6/1 TNF-alpha (endogenous pyrogens) - Exogenous pyrogens stimulate endogenous pyrogens Exogenous pyrogens - Hemozoin = disposal product from digestion of blood from blood parasites - Exogenous pyrogens can’t cross BBB, but stimulate production of endogenous pyrogens which can croSs BBB, but non in a direct way. That is done by prostaglandins and corticoliberin. Endogenous pyrogens - they shift the set point in the thermoregulatory. Enter simultaneously view 2 pathways - Activation of the arachnoid acid cascade in the cell membranes of neutrons, two prostaglandins PGE2, and PGF2a, are formed from the released acid by cyclooxygenation - Stimulation of CrH (corticoliberin) secretion From hypothalamus - PGE2 and 2a, and corticoliberin directly shift the set point in the thermoregulatory center. - - Fever: neruohormonal, immunological and behavioural changes They act on: - Brain (hypothalamus) - inhibit appetite and increase the release of factors that cause drowsiness - Muscles - release of ama —> muscle weakness and muscle and joint pain, increase sensitivity to pain (PGE2) - Bone marrow - neutrophil mobilization - Immune system - stimulate T lymphocyte to produce cytokines and B lymphocytes to produce Abs, stimulate neutrophil activity - Metabolism - significant acceleration of catabolism, especially triglyceride mobilization and increased lipoprotein lipase activity, weight loss, cachexia - Hepatocytes- increase production of positive Acute phase reaction proteins and decrease synthesis of negative acute phase proteins. - spruces of endogenous pyrogens for the thermoregulation center - Vagus nerve stimulation, neurogenic fever - Inflammatory cells stimulate inflammation Stages of fever - increment stage - Increase body temp - Symptoms: - Subjective feeling of coldness - Muscle tension or chills - Muscle and joint pain, reluctualse to move, irritability - Pallor of the skin and mucous membranes, piloerection - Loss of appetite, drowsiness and increased thirst. - Fastigium stage, peak of fever - More fluctuations of body temp than during normal temp, never constant. - Symptoms from increment and decrement stage. - Decrement stage - Symptoms - Subjective sensation of heat - Increased cutaneous blood flow, hyperaemia of mucous membranes - Panting in dogs, cats, sheeps - Sweating in horses Course of fever Metabolism of fever - the increase in body temp in fever is achieved by parallel: - Reduction of heat release - Stimulation of heat generation - The intensity in metabolism is particularly high during the increment stage of fever - it increases 3-4 fold - During the peak fever - metabolism is about 15% more intense than in physiological state. Symptoms that accompany fever - acceleration of HR - beacaused increased catabolism threatens the development of metabolic acidosis - Increased reposration rate - restorioj of acid-base balance by increased removal of CO2 - Increased erythrocyte - Changes in blood - neutrophil —> leukocytosis, lymphopenia and eosinopenia - Decreased production of digestive juices — decreased in appetite - Oliguria—> proteinuria - the body accumulated water during increment stage and peak of the fever - Behavioural changes - PGE2, decrease pain tolerance Fever - mechanism of non-specific immunity - higher temp inhibits microbial proliferation - Higher temp inhibits siderophores synthesis in pathogenic bacteria - High temp decreases Fe availability to bacteria - High temp sis increased the activity of phagocytic cells - Synthesis if interferons and IL2 increase at higher time on - Induction of heat shock proteins synthesis in cells (HSP) Types of fever - Based on duration of fever - Acute fever - Less than 7 days - Subacute fevers - No more than 2 weeks - Chronic fever - More than 2 weeks. - Based on patterns of fever - Continuous / sustained - Remittent - Hectic / septic - Recurrent - Atypical / irregular - Intermittent - Undulant - periodic fever - One day fever - LEARN DIFFERENCES BETWEEN THEM Acute phase reaction Acute phase proteins -APPs - a group of species-specific plasma proteins whose concentration changed by min, 25% in the course of acute phase reaction 1. - - Positive acute phase proteins know what they do Production in inflammation increase Major - C-reactive protein, serum amyloid P/A Complement proteins - C1 inhibitor, C2/3/5, complement factor B Coagulation factors - Fibrinogen - Von willebrand factor Protease inhibitors - Alpha1-antitrypsin, a1-antichymotrypsin, a2-antiplasmin Metal-binding proteins - Ceruloplasmin, hepatoglobin, hemopexin Other proteins - Hepcidin, LPS-binding protein 2. Negative acute phase proteins - Know what they do - Production in inflammation decreases - Albumin and prealbumin - Transferrin ‹ Local circulatory disorders - Lab 4 Hyperaemia, ischemia, thrombus, embolism, infract Hyperaemia - increased and excessive amount of blood in BVs - Active hyperaemia - Due to increase flow of arterial blood in dialated capillaries - Congestion (passive hyperaemia) - Hyperemia resulting from an obstruction in the flow of blood from a body part - Also Called venous hyperemia Active hyperaemia - caused by increased flow of blood to an area by active dilation of both the arteriolar and capillaries. - It is associated with neurogenic, hormonal, and metabolic function. - Physiological - In working muscles - Following exertion (skin) - In digestive tract (after feeding) - Pathological - Early phase of inflammation - Decrease of fever - Epilepsy - Manifestation - Redness, increase temp, enlarged organ - Consequences - None, Hypertrophy Passive hyperemia - always pathological!! - Caused by a decreased outflow of blood from an area - Localized - Caused by pressure from mechanical or physical obstruction - Manifestation - Cyanosis, deceased temp, enlarged organ - Generalized - Resulting from cardiac or pulmonary disorders Malperfusion (ischemia) - insufficient supply of blood to an organ, inadequate to meet the metabolic demands to the tissue - Causes - Blocked or constricted artery - Cold, chemical stimulation, torsion, thrombosis, embolism - Hypotensjon - Shock (hemodynamic phase) - Adaptation - Vasodilation - adenosine (derived from ATP) induced - Opening of collateral circulation - Consequences: - Hypoxia, cell damage and deaths (necrosis or apoptosis) - Depend on: - The degree of arterial obstruction, functional conditions of the circulation, metabolic activity of the tissue, resistance to ischemia, magnitude and length of decreased BF - Ischemic infarct / necrosis - Atrophy - Ischemia-reperfusion injury - Ischemia-reperfusion injury: - Occurs after restitution of BF - Results from: generation of reactive O species, dysfunction of mitochondria, injury of endothelium, or neutrophil influx and activation. - Generation of ROS - Superoxide anion - is generated after the onset of reperfusion when xanthine oxidase combines w O and hypoxanthine - Then it’s converted into other radicals including the most potent hydroxyl radical - Mitochondrial dysfunction - Changes in membrane permeability, inactivated of respiratory chain, increased production of ROS. - Endothelial injury - XO-mediated damage by ROS (10-30s after the onset of reperfusion) - Impaired endothelial functions - Unregulated transcription of endothelium - Decrease NO release - No-reflow phenomenon - - Vasoconstriction is promoted also by PAH and TxA2 - Important cause of transplantation failure Inflammatory-like response: - Neutrophil infiltration and activation, tissue injury resulting from oxidants generation and these release of proteolytic enzymes - Eicosanoids generation - Increased No and peroxynitrite production Thrombus and blood clot - thrombus - intravascular clot - Coagulation - fibrin clot Thrombus - formed in Vigo clotted mass of blood (aggregate of PLTs, fibrin and CF w entrapment of cellular elements of the blood), attachment to the interior wall of a vein or artery sometimes occluding the lumen of the vessel Thrombosis - an abnormal vascular condition in which a thrombi (blood clots) develops in a BV and remain in place. Clots either block, or partially block a BV, that may lead to infraction, or death of tissue, due to a blocked blood supply. Thrombus vs blood clot - thrombus - intravascular clot - Result from impaired blood coagulation - Formed in Vivo, insideBV or the heart - Composed prim of PLTs and fibrin, w entrapment of only a few blood cells - Structure, solid mass, friable and firm. - Attached to the interior wall of a vein or artery - Coagulum - fibrin clot - Result from coagulation cascade - Formed in vivo outside BVs to prevent blood loss or in the heart or in a large BV after death - Composed of fibrin and blood cells - Rubbery, gelatinous - Lies loosely in the lumen of the blood vessels Thrombi formation - causes of thrombi fromation and thrombosis: - Changes in BF, BV wall, changes in the blood - Endothelial injury is critical for thrombi formation - Trauma, infectious agents, immune complexes, parasites, toxic - Abnormal BF - Slow down the blood flow, local turbulence - Changes in blood composition - Activation of CF, inherited and acquired deficiency of clotting inhibitors - Thrombophilia, dehydration, acidosis, polycythemia. Fate of thrombi - progression (enlargement of elongation) / propagation - Shrinkage Dissolution or emollition Organisation Replacement by CT Recanalization Calcification Consequence of thrombosis - depend on: - Type of BV - Dysfunction of BF - Collateral circulation - Ischemia, congestion, thromboembolism Embolism - obstruction in BV due to a blood clot or other foreign matter that gets stuck while travelling through the bloodstream Embolus - detracted thrombi, - Bacteria - abscesses are formed - Tumor tissue and normal tissue - Parasites, amniotic fluid, air bubbles Clinical importance - horses - thromboembolic Collic associated with s.vulgaris infection - Dogs, cats, horses - fibrocartilaginous embolism - Dogs, cats - in thyroid disorders - After surgery Infraction - local area of necrosis caused by occlusion of arterial supply or venous drainage - Classification - Ischemic infract - white, pale, anemic infract - Coagulative necrosis - Arterial insufficiency in organs with end arteries = single blood supply, kidney, heart - Hemorrhagic infract - red infract - Hemorrhagic necrosis - Venous insufficiency - Dual blood supply - Usually in the tissues that have a loose consistency (lungs) Fate of infarct - organisation - scar - Sequestration - sequestrum - Emollition - Calcification - Regeneration Clinical importance - hemorrhagic infract - - Lungs: - Calf - associated with bronchopneumonia - Dogs - associated with dirofilaria immitis infections and endocrine disorders - Intestines - Following volvulus, torsion, incarceration Ischemic infract - Kidney - Horses - associated s. Vulgaris infection - Cattle - associated with nephritis - Pigs - associated with endocarditis and erysipelas - Dogs - unknown ethology - Heart - Pigs - Dogs - associated w hypothyroidism - Salivary glands - Dogs and cats Cerebral stroke - a cerebrovascular, life-threatening event in which part of the brain is deprived of adequate O. - Ischemic strokes - Occur when the blood supply to the brain is interrupted, usually by a blood clot originating from the carotid arteries - Hemorrhagic strokes - Occur when there is bleeding into or around the brain - Rare in domestic animals: - In human: stroke is defined when clinical signs of cerebral damage persist for more than 24h - In human: usually a consequence of atherosclerosis. - CAT - In cats ischemic store is common (80%) ISCHEMIC - Hemorrhagic stroke usually results form inrtracranial or subarachnoid hemorrhage (head trauma) - Peracute onset of signs, some progression of signs could be expected form increased intracranial pressure. - DOG - Cerebral vascular accidents (CVA) - Can occure due to thrombosis or embolism in hypothyroidism and idiopathic hyperlipidemia - Hemorrhagic stroke usually result from intracerebral or subarachnoid hemorrhages (head trauma) - Intraparenchymal hemorrhage can occur w hypertension, secondary to hyperthyroidism, renal disease or hyperadrenocorticism. Cardiac rhythm disorders - electrocardiogram - Lab 5 - - phase 0 - rapid depolarization - Quick inside Na+ influx Phase 1 - early repolarization - Cl ions are transported into the cells, K ions to the extracellular space Phase 2 - plateau - Centripetal Ca-Na current and centrifugal K currents are equal Phase 3 - late repolarization - Centrifugal K current redominant Ca-Na current. Ions pumps begin their action Phase 4 - rest potential - Polarization state is maintained by Na-K pump Stimulation Passes through the heart Electrocardiogram is registered ECG recording - Electrocardiogram - the registration of electric activity of the heart based on the potentials registered on the skin. Electrodes - Red - R forelimb’ - Yellow - L forelimb Leads - - Green - L hindlimb Black electrode - R hindlimb registration of the potentials (mV) between electrodes 3 leads - Einthoven triangle - I - potential between R and L forelimb - II - potentials between R forelimb and L hindlimb - III - potentials between L forelimb and L hindlimb 6 horse, 12 leads only in humans Deflection and amplitude of the waves reflect the direction of stimulation in the heart Analysis of electrocardiogram isoelectric line - the basis - Waves: time, deflection, amplitude, morphology - Segments: time - Intervals - Evaluation of: the cardiac rhythm (organ, regularity, frequency) and the type of disorders (rate, origin) ECG interpretation - ask 5 questions; 1. What is the HR 2. 3. 4. 5. - a. Calculate HR Is the R-R or P-P interval regular? a. Also check intervals with in the complexes i. Ex, P-R Is there a P wave for every QRS-T? Is there a QRS for every P? Is there variation in the configuration of any of the complexes? Measure the amplitue and duration of waves Recognising abnormalities - artefacts - Movement of the patient, poor electrical contact - Physiology or pathology? - Respiratory irregularly - - - HR varies w respiratory rate, impulses originate in SA node - Irregular P-P internal - Physiological arrhythmias in horses Clinical significance: if affects CO’s? Disorders in the cardiac rhythm - tachycardia - fast rhythm - Bradycardia - slow rhythm - Arrythmia - irregular rhythm - Persistent - Paroxysmal - Disorders in the stimulation - Nomotopic - occuring at at normal place - SA node - Heterotropic/ectopic - arising from an abnormal site - Beats originating at some point other than the sinus node - Disorders in the flow of impulses - Heart blocks Disorder in rate and origin - nomotopic disorders - Sinus tachycardia/bradycardia/arrythmia/arrest, wandering arterial pacemaker - Heterotopic disorders - Premature supraventricular beats, ventricular premature contraction, Interpolated beats, supraventricular tachycardia, ventricular tachycardia, atrial flutter and fibrillation, ventricular flutter and fibrillation. - Heart blocks - SA block - Atrioventricular blocks - First degree, second degree mobitz type 1 (wenckebach type), second degree mobitz type 2, third degree Nomotopic disorders - sinus tachycardia - Sustained tachycardia that cannot be explained by pain or excitement - Increasing rate of impulses originating from tha SA node - Rapid HR, normal, waves - Sinus bradycardia - Decrease rate of impulses originating room the SA node - Slow sinus rhythm, normal waves - In horses may be physiological, related to the high vagal tone at rest - Physiological - when can be abolished by exercise or vagolytic/sympathimimetics drugs - Pathological when cannot be abolished by sympathethic stimulation - - Sinus arrythmia - Decreased electric activity (generation of hte impulses) of SA node and/or SA disorder in the flow of electric impulses - Sinus rate varies w/o any other abnormalities - Irregular P-P intervals - In horses may be physiological w high vagal tone at rest Sinus arrest - Periodical lack of impulses originating from SA node, no ectopic impulses - A pause in the normal cardiac rhythm, lastin for an interval that is not an exact multiple of the normal cardiac cycle - Periods with no cycles (PQRST) at all, delay may be grater than twice that of normal P-P interval - Wandering atrial pacemaker - The site of origin of the impulses controlling the HR shifts form one point to another in the atria, almos w every beat. - Abnormal P waves and P-Q intervals - Heterotopic disorders - supraventricular premature beats - Supraventricular premature depolarisations (SVPD) - Originate from ectopic focus in the atria of the AV node (called junctional premature beats) prior to impulsation from SA node - Heart cycles appear earlier than normal sinus cycles - Abnormal P wave and sometimes P-Q interval - - - - Interpolated beat - Special form of premature beat that does not interrupt the underlying sinus rhythm - Bigeminy (coupled rhythm) - normal heart beats w regulat ectopic ventricular or atrial beats - Normal heart beats is followed by a premature beats, so that the heart beat occur in pairs, sinus rhythm is not interrupted Ventricular premature beats - Ventricular premature depolarization (VPD) - Contraction due to an ectopic focus in the ventricular myocardium - No P wave, wide abnormal QRS - Frequent VPDs suggest myocardial hypoperfusion Supraventricular tachycardia - - Ectopic (no sinus) rhythm - a heart rhythm instead by a focus outside the SA node, where the impulses are generated more frequently Defined when more than 4 SVPDs occur in succession Abnormal P, P-Q,P wave after QRS Ventricular tachycardia - Abnormally rapid ventricular rhythm w aberrant ventricular excitation, generated in the ventricle - Defined if more than 4 VPDs occur in succession - Wide QRS - P waves unrelated to abnormal QRS or invisible, abnormal T waves - - Atrial flutter - Activation (usually ectopic) leads to 250-350 contractions/min - Changes morphology of P waves, no isoelectric line - Usually regular ventricular cycles - - Atrial fibrillation - Atrial arrhythmia marked by rapid randomized contractions of small areas of the atrial myocardium - The contractions have no hemodynamic effect - Ventricular rate - irregular, often rapid - Frequency of contractions reaches 360-600/min - No visible P waves, Atrial activity is represented by sawtooth-like deflections (F wave) not separated by isoelectric segments - Common pathological arrhythmia in horses - - - Ventricular flutter - Ectopic activation originates out of atrional region - Uncoordinated contraction of the cardiac muscle of the ventricles, making them quiver rather than contact properly - More than 250 ventricular contraction/min - Marked changes in QRS morphology - - Ventricular fibrillation Heart blocks - SA (sinus) block - Impairment of conduction from SA node to eh atria - Whole heart beat is dropped and characterized by the absence of a PQRST complex - P-P interval are an exact multiple of the sinus cycle - In horses physiological due to variation in parasympathetic tone, goes away w excitement or exercise - - First degree atrioventricular block - No clinical consequences, manifested only in ECG - Usually in AV node - P-Q prolongation - Normal PQRST morphology Mobitz 1 (wenckebach) second degree AV block - Not every impulse reaches destination - Characterized by a progressive prolongation of the P-Q interval w each P wave to the point when the P wave is no longer conducted (followed by QRS complexes) - Most common physiological arrhythmia in horses, goes away w exercise. - - Mobitz II second degree AV block - Some impulses do not reach their destination - Characterized by periodically occurring (constant pattern) nonconducted atrial impulse - lack of QRS and T after P wave. Protective in atrial fibrillation - - Third degree AV block - Complete heart block - Atrial contraction - due to impulses from SA node, ventricles timulated by pacemaker in AV junction - More P waves than the QRS complexes exist and no relationship exists between them (no conduction) Pathophysiology of neoplasia - lab 6 Definitions - neoplasm - Abnormal, uncontrolled, unstoppable autonomous tissue growth (cell proliferation), that arise from healthy tissue; clonal disease - Malignant - carcinoma, sarcoma, lymphoma