Pathophysiology Flashcards
Sepsis
Life-threatening organ dysfuction caused by a dysregulated host response to infection.
- Defined by the Sepsis 3 criteria: Confirmed or suspected infection + 2 positive qSOFA factors:
- Hypotension < 100 systolic
- Altered GCS <15
- Tachypnoea RR>22
- Infection causes activation of innate immune system through recognition of PAMPS (pathogen associated molecular patterns)
- Release of cytokines (TNFa, IFg, IL 2,6,8) from macrophages, neutrophils, mast cells
- Systemic effects
- Vasodilatation of vessels and increased permeability
- Recruitment of further inflammatory cells to the area
- Activation of complement, leukotriene and prostaglandin pathways
- Activation of coagulation cascade causing microthrombi and DIC
- Increased oxygen demand decreased ATP of cells
- Anaerobic metab and Lactate acidosis
- Failure to maintain osmotic, ionic and pH homeostasis
SIRS
Dysregulated host repsone to inflammation or infection. Requires
HR >90
WBC 4<>12
RR> 20
Temp <36>38
- Imbalance of proinflammatory and anti-inflammatory processes
1. Tissue damage leads to cytokine production (TNF, IFG, IL 2,6,8 by macrophages, neutorphils and Mast cells
2. Systemic effects of cytokines
- recruit inflamamtory cells
- Vasodilataion
- Release of stess hormones NAd, vasopressin
- Activation of renin:Ang system
- Activation of complement and coagulation pathways
- Increased permeability of tissues and endothelium
3. Compensatory anti-inflammatory response.
- Mediated by IL4,10 which inhibit further cytokine production
Septic shock
Presence of sepsis and decreased end organ perfusion, despite adequate fluid resuscitation.
- Requires vasopressors to maintain BP > MAP of 65, and end organ hypoperfusion demonstrated by lactate > 2.0
HAemorrhoids
Pathologically dilated arteriovenous cushions of the anal canal.
- Congestion of the anal cushions due to decreased venous return oft he middle and superior rectal veins caused by strainging, obesity, pregnancy and the erect position
- Relaxation and disruption of the longitudinal conjoint coat and Treitz’s muscle fibres and Parks ligaments allow the cushion to slide on the internal sphincte
- Repeated sliding causes mucosal congestion, prolapse and further damage which perpetuates the cycle.
Mesenteric ischaemia
Acute life-threatening condition caused by interruption of blood supply to the gut, caused by thrombosis, embolus or low-flow states
- Impaired delivery of oxygen and nutrients leads to anaerobic metabolism, with lactic acid production
- Initial mucosal ischaemia leads to pain out of proportion
- Disruption of microvascular integrity with haemorrhages and thickening of small bowel
- Gradual progression of ischaemia to transmural necrosis, with translocation of bacteria, pneumotosis, peritonitis and portal venous gas
- Reflex vasodilatation of collateral vessels leads to reperfusion injury (free radicals, toxic by-products of tissue injury)
- Results in both local and systemic injury
Chronic pancreatitis
Inciting event occurs due to direct acinar damage or obstruction of pancreatic drainage
Repeated attacks lead to:
- Production of profibrogenic cytokines
- Proliferation of myofibroblasts
- Secretion of collagen and remodelling of ECM leading to fibrosis
- Acinar atrophy, dilatation of pancreatic duct and wasting of the gland with calcifications
- Exocrine and endocrine insufficiency
Additional abnormal neural pain pathways occur leading to abberant CNS perception of pain
Acute pancreatitis
Acute inflammatory condition of the pancreas, characterised by 2 pathological phases
1. Acute inflammation
- Inciting event combined with ductal obstruction or reflux damages acinar cells
- Local inflammation causes innate immune cells to release cytokines and pro-inflammatory mediators
- Proinflammaotry response outbalances anti-inflam response leading to SIRS and MODS
- Autodigestion
- Abnormal activation of proteolytic enzymes
- Trypsin release facilitates zymogenic cascade, which overwhelms trypsin inhibitor.
- Hypoperfusion and erosion into vessels leads to necrosis
Diverticulitis
Multi-factorial disease contributed to by genetics, lifestyle and medications
- Genetic alteration in neuromusculature in the vessel wall, leading to impaired colon wall integrity
- Elevated colonic pressure
- Altered microbiome due to bacterial stasis and fecoliths cause altered microbial metabolism
- Impaired mucosal barrier function
- Defective immune regulation and host response, leading to pro-inflammatory cytokines, adherent bacteria and bacterial translocation
Shock
Acute circulatory failure causing inadequate tissue perfusion and oxygen delivery to meet cellular metabolic needs, leading to cellular hypoxia, cellular death and organ dysfunction
- Impaired perfusion causes hypoxia and anaerobic metabolism leading to buildup of lactate and decreased ATP stores
- Dysfunciton of cell membrane ion pumps, causing intracellular oedema, 3rd space leakage and altered intracellular pH and function
- Systmemic acidosis leads to endothelial dysfunction and activation of inflammatory cascades
- Further reduction in non-essential central tissue perfusion by humeral and microcirculatory feedbakck mechanisms to restore central circulating volume
- Compensatory mechanisms such as increased cardiac output and peripheral vasoconstriction initially provide a reversible situation
- Progression of shock leads to overwhelmed compensatory mechanisms and symtpoms of organ dysfunction occur, eventually irreversible end - organ damage
Graves disease
Autoimmune condition of hte thyroid whereby autoantibodies to the TSH receptors lead to increased stimulation of the receptors and activation of thyroid cellular function and hormone production, leading to thyrotoxicosis.
- Cross reactivity to receptors in the retro-orbital space cause proptosis, hypertrophic eye muscles leading to decreased eye movements and periorbital oedema
Cross reactivity to receptors in the dermal fibroblasts of the lower limb cause pretibial myxoedema and increased formation of connective tissue in the legs
Multinodular goitre
Diffuse follicular hyperplasia due to stimulation of the gland by TSH in the presence of stimulating factors (Goitregen - brassicas, drugs, iodine deficiency)
- Nodular proliferation due to haemorrhage, and resulting scarring and involution of the gland
- Eventual acquisition of functional autonomy leads to toxic multinodular goitre
Obesity
Excess body weight which occurs due to a complex series of signals and responses via the gut-brain-endocrine axis, which leads to an imbalance of energy intake vs energy expenditure. Factors contributing include:
- Genetics
- Environmental
- Sociocultural factors
- Inflammation: Adipose tissue produces leptin in proportion to fat mass, and also adipocytokines which causes low grade inflammation
- Metabolic: impairment in insulin signalling secondary to inflammatory state causes metabolic sequalae
- Impaired endothelial dysfunction
- Alteration in Gut hormones such as ghrelin, NPY cause increased hunger and food uptalke, whilst GLP1 and CCK decrease food intake and slow gastric emptying
DCIS
DCIS is an insitu disease defined by the dysplasia of ductal cells within the confines of the basement membrane.
- Increasing dysplasia of ductal cells in terms of nuclear polymorphism, increased mitoses, prominent nucleoli, large nuclei and necrotic material in high grade DCIS forming calcifications
- DCIS is a precursor to invasive cancer with approximatley 30% progressing to from low grade to high grade DCIS or IDC over 30 years
Pagets disease of nipple
Insitu malignancy of the skin of the nipple and areolar complex. 2 broad theories of pathophysiology
- Epidermitrophic theory: Malignant cells develop in the breast and migrate out via the ducts onto the nipple and areolar
- Transformation theory: Skin cells undergo malignant transformation, independent of ductal cells
Pseudomembranous colitis
Acute infective colitis, caused by infection with clostridium difficile infection
- Anaerobic gram positive, spore forming, toxin producing bacillus
- Acute overgrowth commonly caused by the use of antibitoics and in those with impaired immune systems or impaired physiology
- Release of Toxin A and Toxin B leads to impaired signal transduction and cytoskeleton structure, which causes disruption of tight junctions, ulceration, loss of intestinal barrier function and neurophilic colitis
- Inflammation causes intestinal fluid secretion, mucosal injury and activation of neutrophils which localise in pseudomembranes
- Pseudomembranes form from ulceration, release of serum proteins, fibrin, mucous and inflammatory cells
Appendicitis
Inflammatory process of hollow viscera caused by initial inflammation of the wall (obstruction often involved but not essential)
- Bacterial overgrowth within the appendix spreads into the wall causing neutrophilic exudate and fibropurulent serosal reaction
- Locaslised ischaemia due to increased pressure in the lumen and wall of the appendix
- Perforation occurs in up to 40% of cases, leading to abscess and peritonitis
colorectal cancer pathways
Adenoma to carcinoma sequence
- 75% of cancers
- Progression from adenoma to caricnoma due to stepwise mutations causing increased dysplasia.
APC, KRAS/BRAF, SMAD4, p53
- Mostly L sided cancers
Sessile pathway
- Mutation of Kras or BRAF mutations leading to sessile lesions
- Can have hypermethylation of MLH1 causing microsatellite instability
- Mostly right sided
Microsatellite pathway
- up to 5% of CRC
- AD mutations of MMR genes.
- Causes microsatellite instability
- Formation of proximal tumours
Crohns disease
Chronic inflammatory condition characterised by transmural inflammation
- Decreased immunoregulation
- Increase mucosal permeability and mucosal damage causes a local and systemic response
- Excessive T helper call activation, leading to macrohage release of TNFa, IL1,IL6
- Abnormal dendritic cell function
- Leucocyte recruitment and release of cytokines
Ulcerative colitis
Chronic inflammatory condition affecting the mucosa and submucosa of the colon and rectum
- goblet cell depletion and crypt abscesses leading to mucosal ulceration, destruction and atrophy
perianal abscess and fistula in ano
Cryptoglandular theory
- Blockage of the crypts leads to mucous buildup within the gland which then gets infected
- Rupture of the abscess through the muscle and skin leads to chronic and recurrent inflammation
Anal fissure
Longitudinal tear of the mucosa of the anal canal, commonly occuring at 12 and 6 o clock.
- Increased internal sphincter tone
- Constipation and firm stools leads to increased shearing force of mucosa overlying the anococcygeal body.
- Relative ischaemia of 6 and 12 o clock positions due to muscle supply from laterally and hypertonic sphincter
- Repeated cycles of non-healing due to sphincter hypertonia, repeated trauma and relative tissue ischaemia
ARDS
Acute lung injury caused by an inciting event such as injury or infection.
- Damage to the endothelium and epithelial cells of the alveoli
- Leakage of protein-rich fluid into the alveoli
- Impairment of gas exchange and lung mechanics, can be worsened by ventilator injury
- Impairment of reabosrption of fluid and surfactant production due to damaged epithelium
acute renal failure
Acute injury or dysfunction of the kidney, leading to inability to adequately control electrolyte, fluid and metabolic functions.
Pre-renal causes
- Hypovolaemia
- Cardiac failure
- Renal artery obstruction
- Sepsis
- Abdominal compartment syndrome
Intra-renal
- ATN
- Nephrotoxins (contrast, NSAIDS, gentm vanc, NSAIDS, ACEi, diuretics, immunosuppressants)
- Rhabdo (myoglobin)
- Haemolysis (Hb)
Post-renal
- Outlet obstruction (BPH, stones, tumour, diverticulitis)
tetanus
Nervous system disorder caused by infection with clostridium tetani
- Obligate anaerobe that lives in the soil and gut of animals in spore form.
- Produces tetanus toxin, which is a metalloprotease
- The bacterium travels via retrograde axonal transport, and cleaves neurotransmission products to alter neuronal signalling
- Net effect is dis-inhibition of anterior horn cells, leading to muscle spasm and autonomic instability
Hyperparathyroidism
Increased parathyroid levels caused by primary secondary or tertiary causes
Primary: high TPH in the setting of high calcium
- Adenoma
- Parathyroid hyperplasia
- Parathyroid caricnoma
- familial syndromes
Secondary: High PTH in the setting of low PTH
- Impaired kidney function impaired production of calcitriol
- Inadequate calcium intake or absorption
- Vit D deficiency
Diabetes mellitis
Disorders of abnormal carbohydrate metabolism characterised by hyperglycaemia
- Type 1: Autoimmune destruction of the B cells leading to insulin deficiency
- Type 2: Increased insulin resistance at tissues leads to progressive loss of insulin secretion
Hyperglycaemia leads to:
Microvascular disease
- Nephropathy
- Neuropathy
- Retinopathy
Macrovascular disease
- PVD
- Cardiovascular disease
Salivary gland stones
Stagnation of salivary flow occurs due to dehydration, medications or stricture
- Inflammation of the gland or duct, localised injury and bacteria can serve as a nidus for stone formation
- Submandibular duct more prone to stones due to long duct running against gravity and with alkaline properties, high mucin and calcium content
branchial cleft cysts
Swellings in the neck, due to embryological failure of the branchial clefts to involute during foetal development.
- Normally the 2nd arch grows over the 2nd cleft, and the trapped ectoderm dissapears.
- 2nd clefts can remain as cyst and is a swelling at the anterior border of SCM, connected via a track to near the palatne tonsil, passing between the internal and external carotid arteries
Thyroglossal duct cyst
Remnant cyst of the neck, resulting from the incomplete involution of the thyroglossal tract responsible for the embryological development of the thryoid
- Normally, the thyroid develops from the 2nd branchial pouch in week 4 from a diverticulum at the foramen cecum and descends down in the neck, anterior to hyoid bone to its place in the inferior neck.
It separates into 2 lobes linked by an isthmus
The residual tract dissapears by week 10, with the most distal part of this remaining as the pyramidal lobe
- Failure to involute results in either a cyst, tract or sinus, which can result in a midline cyst, swellling or sinus that is prone to infection and has a malignant potential.
Zenkers diverticulum
False pulsion diverticulum of mucosa and submucosa through Killians triangle, which is a muscle weakness of the posterior wall of the pharyngo-oesophageal junction, where the transverse fibres of cricopharyngeus and oblique fibres of inferior constrictor muscles meet.
- Diverticulum develops due to altered upper oesophageal sphincter function, abnormal oesophageal motility or oesophgeal shortening
Gallstones
Gallstones are made up of cholesterol, bilirubin, bile salts, fatty acids and various minerals. Formation of gallstones occurs when there is 3 components
- Supersaturation of one of the elements of the above, leading to precipitation of that element into crystal form
- Hypokinesis of the gallbladder allowing precipitation of the components
- Nucleation of the crystals to form stones, often with mucin serving as a nidus for stone growth
ITP
Autoimmune disorder of unknown cause, where auto antibodies are produced against platelet membrane proteins GPIIb/IIIa
- Production of antibodies by T helper cells leads to cell-mediated destruction of the cells in the spleen by macrophages, as well as in some other tissues in the body (liver, bone marrow, splenunculi, lymph nodes).
- Results in increased clearance of platelets as well as reduced production, leading to clotting impairment
Cirrhosis
Chronic parenchymal liver injury secondary to diffuse fibrosis and nodular remodeling, which leads to disturbance of liver microcirculation and perfusion
- Hepatocellular injury and necrosis
- collagen deposition and fibroblast activity
- Loss of fenestrations in sinusoidal epithelial cells
- Repeated cycle of necrosis, fibrosis and regeneration
Portal hypertension
Increased pressure within the portal system leading to formation of collateral and port-systemic anastamotic shunting
- Initial increase in pressure in portal circulation, most commonly due to cirrhosis (scarring, fibrosis, and increased resistance within liver vessels)
- Compensatory dilatation of the splachnic vessels leads to development of collaterals and shunting of up to 90% of flow through portosystemic connections
- Gastro-oesophageal
- Falciform ligament
- Anal canal
- Retroperitoneum
- Stomal or parastomal
