pathology

• Diabetes mellitus


  Elevated blood glucose levels= hyperglycaemia
• Genetic predisposition to type 1 diabetes

  • Abnormal expression of HLA/MHC cell surface antigens can lead to destruction of that cell
• Type 2 diabetes


  • Insulin resistance is due to an impaired insulin receptor activity which leads to little or no GLUT4 translocation
  • Insufficient uptake of glucose into peripheral cells
  • Results in hyperglycaemia despite adequate production of insulin
  • Genetic defects in the downstream signalling pathways of the insulin receptor
• Lipotoxicity


  Increased triglyceride accumulation(steatosis) in the skeletal muscles and in the liver combined with increased inflammation in these tissues
• Glycation


  • Glucose binds to an amino acid on a protein
  • Eventually forms stable advanced glycosylation end products
• Glycation causes modification of protein structure


  • Glycation impairs function of the proteins
  • Damage to the blood vessels and nerves and structural changes in connective tissue
• Macro-angiopathy(large vessels)


  • Cardiovascular atherosclerosis
  • Increased risk of myocardial infarction and ischemic stroke
  • Diabetics also have elevated levels of plasminogen activator inhibitor-1(PAI-1)- inhibits fibrinolysis and therefore acts as a pro-coagulant in the formulation of plaques
• Micro-angiopathy


  • Damage to small blood vessels
  • Result in kidney failure and blindness
• Nephropathy


  • Risk factors include poor diabetic control and duration of diabetes
• Retinopathy


  • Diabetic retinopathy is a major cause of irreversible blindness
  • Damage to small blood vessels results in- ischemia, neovascularization
• Peripheral neuropathy


  • Affects aldose reductase enzyme in schwann cells
  • Lead to glycation damage to myelin
  • Degeneration of axons and nerve demyelination
  • Numbness, loss of fine touch
• Diabetic foot


  • Peripheral vascular disease + diabetic neuropathy leads to increased propensity for injury and combined with increased susceptibility to infection -> gangrene
  • Disease affecting the innermost layer of large and medium sized arteries
  • Appears as focal thickenings called plaques which are deposits of fibrous tissues and lipids
• Tunica Intima


  Endothelial cells separated by tight junctions, scattered myointimal cells
• Tunica Media


  Smooth muscle cell layers(regulate flow by contraction, stabilise EC by secreting ECM)
• Tunica Externa


  Connective tissue, contains fibroblasts, leucocytes, nerves, lymphatics, blood vesels
• Positive risk factors


  • Hyperlipidaemia
  • Cigarette smoking
  • Hypertension
  • Diabetes mellitus
• Negative risk factors(protect)


  • High levels of circulating high density lipoproteins
  • Physiological response of a blood vessel to injury
  • Prevent blood loss by "pluggin leaks" in injured vessels
• Endothelial cells inhibit haemostasis by


  • Producing enzymatic and chemical inhibitors of platelet activation: Nitric Oxide
  • Producing antithrombins on their surface
• Haemostasis is accomplished during injury by cooperation between

  1. Endothelial cells-produce endothelin which causes vasoconstriction and von Willebrand factor which promotes platelet adhesion, produce tissue factor=thromboplastin which activates coagulation cascade

  2. Platelets-Become activated by collagens, secrete Thromoxane A2, vasoactive amines and ADP, these signals promote a combination of vasoconstriction and platelet aggregation

  3. The Clotting cascade=coagulation cascade
• Coagulation cascade


  1. Inert circulating zymogens are sequentially activated

  2. Initiated by tissue factor

  3. Second to last step is activation off thrombin-catalyses fibrinogen to fibrin monomers

  4. Fibrin monomers then polymerise into fibrin strands and form a meshwork with fused platelets to form a stable plug
• Thrombosis


  • Occurs when physiological mechanisms of haemostasis are activated inappropriately
  • Thrombi is composed of: fibrin and platelets and entrapped red and white blood cells
• Causes of changed blood flow


  • Arteries or cardiac chambers: turbulence- narrowing
  • Veins: stasis- compressed veins, blood viscosity
• Emboli


  An embolus is an intravascular mass carried by blood flow from its point of origin to a distant site
• Possible causes of ischaemia


  • Spams of vessel
  • Capillary blockage
  • Shock
  • External and internal occlusion
• Susceptibility of cell types to ischaemia

  • Neutrophils least sensitive
• Effects of ischaemia


  • Most damage: Infarction=necrosis of most/all cells
  • Apoptosis
  • Reduced ATP availability important
  • Activation of signalling cascades
• High-grade tumors


  Poorly differentiated and more aggressive than low-grade tumors
• Staging: TNM classification


  • T= tumor size and local invasion T-= carcinoma in situ(no local invasion)
  • N=regional lymph node involvement, N0= no nodes
  • M= distant metastases; M0= no metastasis, followed by M1 for metastasis
• Environmental factors


  • Infectious agents
  • Diet and obesity
  • Exposure to environmental carcinogens
  • Reproductive history
  • Smoking and alcohol
• Chronic inflammation or tissue injury

  • Proliferating cells most at risk of developing the genetic lesions that lead to carcinogenesis
• Certain forms of hyperplasia


  Barrett esophagus
• Neoplasia


  A type of new tissue growth that continues despite the absence of stimulus
• Tumour


  Refers to any tissue mass, solid or liquid filled benign or malignant
• Cancer


  Refers to malignant tumour or neoplasms which have potential to spread
• Differentiation


  • Refers to the appearance/morphology of cells compared to normal cells of the same tissue
  • Well differentiated tumour cells look and function like normal cells of the tissue
• Tissues and organs


  • Sense infection and tissue injury/damage
  • Most of immune cells resides in intestine and gut
• Hyperchromatic


  • Large, variably shaped nuclei
• Metaplasia


  Replacement of one type of cell with another type;reversible
• Metaplasia


  • Oesophagus=squamous reflux
  • Stomach=glandular epithelium
• Dysplasia


  Disordered growth