CELL Pathology - Notes from Year 1 PDF

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CELL PATHOLOGY      

List the causes of cell injury List the mechanisms of cell injury Define (and give examples of) hyperplasia, hypertrophy, atrophy, metaplasia and dysplasia Describe the morphological changes associated with reversible and irreversible injury Describe the differences between apoptosis and necrosis Define the terms necrosis, ulcer, degenerative, sublethal injury

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Causes of cell injury: not isolated and usually occur together Oxygen deprivation – ischaemia, severe respiratory problems, loss of oxygen carrying capacity of blood Chemical agents – nicotine, poisons, drugs, alcohol, environmental pollutants Infectious agents – protozoa, bacteria, viruses Immunological reactions – hypersensitivity by the immune system Genetic defects – inborn errors of metabolism Nutritional imbalances – deficiencies, excesses and lack of appropriate tissue Physical agents – X-rays, trauma, thermal injury, electric shocks Aging Cellular response to injury: type of injury, duration and severity Consequences of an injurious stimuli: type of cell, status (stage of proliferation), adaptability and genetic makeup Vulnerable intracellular systems Cell membrane integrity ATP generation Protein synthesis Genetic apparatus integrity Mechanisms of cell injury Multiple secondary effects occur rapidly as the structural and biochemical components of a cell are integrally related Cellular function is lost before death and before morphological changes are seen. Cellular adaption to injury ATROPHY: shrinkage in cell size (or organ) by the loss of cell substance Can be pathological (disuse) or physiological (uterus decreases in size after parturition) Examples: 1.Pernicious Anaemia: associated with gastric atrophy  loss of gastric parietal cells  lack of intrinsic factor  impaired absorption of vitamin B-12 2.Dementia: cerebral atrophy  loss of neurons and connections between them  progressive impairment of memory and intellectual function HYPERTROPHY: increase in cell size leading to an increase in organ size Can be pathological (cardiac hypertrophy in response to stress, hypertension, MI or neurohormones) or physiological (cardiac hypertrophy in response to exercise or pregnancy) Examples: 1.Enlargement of uterus cells during pregnancy

1. 2. 3. 4. 5. 6. 7. 8.    1. 2. 3. 4.   -

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2.Muscle hypertrophy: strength training  increased sarcoplasmic volume or increased contractile proteins  adapted myocyte HYPERPLASIA: increase in the number of cells in an organ Can be physiological (hormonal which increases functional capacity of tissue when needed and compensatory which increases tissue mass after damage) or pathological (excessive hormonal stimulation or growth factors) EXAMPLES: 1.Proliferative endometrium: induced by oestrogen 2.Carcinoma: excessive growth factors stimulate hyperplasia  lots of mitosis (pathological hormonal hyperplasia)

3.Wound healing: response of connective tissue cells in wound healing  proliferating fibroblasts aid in repair 4.Female puberty: proliferation of the glandular epithelium of the female breast (hormonal hyperplasia) 5.After hepatectomy: proliferation of residual liver cells  regeneration of liver (compensatory hyperplasia) METAPLASIA: reversible change in which one adult differentiated cell type is replaced by another differentiated cell type. Causes precursor cells to change their cell fate but does not change existing differentiated cells. Represents an adaptive substitution of cells that are sensitive to stress by cell types that are better able to withstand the adverse environment. Can be pathological (chronic irritation, disruption of DNA methylation patterns, vitamin A deficiency) or physiological EXAMPLES: 1.Cervix: during puberty and first pregnancy, cervix increases in volume  endocervical epithelium everts onto the ectocervix  exposed to the acid pH of the vagina which is the stimulus for the metaplastic change  initially at crypts to tips of the endocervical villae which fuse eventually  columnar epithelium is replaced by squamous epithelium 2.Barrett’s Oesopaghus: refluxed gastric acid  base of oesophagus undergoes columnar metaplasia  squamous epithelium is replaced by intestinal-like columnar cells DYSPLASIA: precancerous cells which show the genetic and cytological features of malignancy but do not invade the underlying tissue Irreversible (unlike metaplasia), pathological EXAMPLES: 1.Cervical cancer screening: high-grade cervical dysplasia can lead to cervical cancer  early detection can make it easier to treat 2.Barrett’s oesophagus: changed cells have a higher chance of developing dysplasia  low-grade dysplasia in Barrett’s.

 Morphological changes associated with REVERSIBLE INJURY - Light Microscopic Changes 1.Fatty Change: caused by alcohol  abnormal accumulation of fatty acids in liver cells (parenchymal cells)

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2.Cellular Swelling: cells balloon and degenerate  increased intracellular accumulation of water Morphological changes associated with IRREVERSIBLE INJURY Nuclear Changes 1.Karyolysis: progressive dissolution of the chromatin and eventual disappearance of the nucleus 2.Pyknosis: nucleus becomes smaller, DNA condenses, tightly packed chromatin 3.Karyorrhexis: pyknotic nucleus undergoes fragmentation into many clumps or pieces Light Microscopic Changes 1.Coagulative necrosis: area of necrosis in which the gross and microscopic architecture of the tissue and some of the cells are preserved. Dead cells appear in a ‘state of coagulation’ (cooked appearance) for a few days) and eventually liquefy. Nuclei are pyknotic or absent. Examples: myocardial infarction, certain acute acting toxins (mercury chloride), toxin produced by certain bacteria (Fusiformis necrophorus) and mild burns. 2.Liquefactive necrosis: area of necrosis that disintegrates very rapidly into a liquid mass resulting in a loss of cellular and architectural outlines. Examples: old cerebral infarct 3.Caseous necrosis: combination of coagulative and liquefactive necrosis where the gross and microscopic architecture of the tissue is lost but the necrotic tissue is not completely liquefied. Associated with diseases where granulomatous lesions occur. Usually remains in place for a long time – does not liquefy or disappear. Appears ‘white and cheesy’. Examples: pulmonary TB 4. Fat necrosis: involves adipose tissue - activated lipases split the triglyceride esters of adipose tissue into fatty acids and glycerin  fatty acids combine with metallic ions (calcium) to form a soap  fat within adipose tissue cells is replaced by soap. Occurs in body cavities like the abdomen and beneath skin. Examples: acute pancreatitis Apoptosis: programmed cell death. Active energy-dependent process (sufficient ATP required for cells to fragment their DNA in an ordinary, structured way) Pathway (P53 = key enzyme which triggers the pathway) 1.Injured cell shrinks in size as nucleus (pyknotic) and cytoplasm shrinks 2.Apoptotic bodies, formed by fragments of cytoplasm containing fragments of nucleus, bud off from the cell 3.Apoptotic bodies are phagocytosed by macrophages in tissues Causes 1.Embryogenesis 2.Deletion of auto-reactive T cells in thymus 3.Hormone-dependent physiological involution (when hormones are withdrawn) 4.Cell deletion in proliferating populations 5.Variety of mild injurious stimuli that cause irreparable DNA damage  triggers cell suicide pathways (more toxic stimuli last for a longer duration = necrosis, milder stimuli = apoptosis) Necrosis: premature death of cells in living tissues caused by disease, physical, chemical injury or interference with blood supply Pathway 1.Injured cell swells 2.Cell is broken down by enzymatic digestion 3.Cell membrane integrity is lost 4.Cellular contents leak into surrounding tissue (enzymes + organelles) 5.Stimulates inflammatory response by neutrophil accumulation Differences between necrosis and apoptosis

Necrosis (energy-independent)

Apoptosis (energy-dependent)

Death of sheets of cells

Death of single cells; surrounding cells are normal

Always associated with inflammation

Not usually associated with inflammation

Always pathological

May be either physiological or pathological

Ulcer: break in the skin extending to all its layers or break in the mucous membrane lining the alimentary canal that fails to heal. It is often accompanied by inflammation.  Degenerative: deterioration and loss of specialized function of the cells of a tissue or organ. Changes can be caused by a defective blood supply or by disease. Degeneration may involve deposition of calcium salts, fat or fibrous tissue in the affected organ/tissue. Sublethal injury: damage to cell is minimal  damage is seen as swelling of membrane bound organelles   cell can survive and injury is not lethal

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HAEMODYNAMIC DISORDERS • • • • • •

Describe the causes and consequences of oedema at different sites. Define thrombosis & give causes and potential consequences of such an event. Define embolism & know the importance of pulmonary embolism in clinical practice. Describe possible causes of haemorrhage and potential outcomes. Define shock and identify the possible causes and mechanisms. Define infarction and describe possible causes, including atherosclerosis.

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OEDEMA: abnormal increase in interstitial fluid Causes: 1.Raised hydrostatic pressure 2.Reduced osmotic pressure 3.Disruption to the capillary bed: increase in vessel wall permeability 4.Lymphatic obstruction: impairs interstitial fluid clearance

5.Sodium retention in the interstitial space 6.Inflammation/injury: may occur due to allergic reactions when mast cells release histamine into tissue Can be localized (pulmonary, cerebral) or generalized (subcutaneous tissues, serous cavities) Pulmonary oedema: caused by raised pulmonary capillary hydrostatic pressure due to pulmonary venous congestion.  Fluid accumulation in the air spaces and parenchyma of lungs  Impaired gas exchange and respiratory failure  Most common cause is left ventricular failure: diseased or overwork left ventricle cannot pump out blood received from the lungs  pressure increases inside the left atrium  pressure increases in the veins and capillaries of the lung  fluid is pushed through the capillary walls into the interstitial space then into the alveolar spaces.  Non-cardiac causes: lung infections (oedema in swollen areas only), exposure to certain toxins, kidney disease (excess fluid build up when they cannot remove waste properly), adverse drug reactions (heroin, cocaine, aspirin, chemotherapy), acute respiratory distress syndrome (lungs suddenly fill with fluid and inflammatory WBC) and high altitudes.  Symptoms: breathlessness (dyspnoea), orthopnoea (breathlessness is worse), pneumonia (fluid in alveolar spaces predisposes to bacterial infections, enlarged heart. Cerebral oedema: disruption to the cerebral capillaries  Breakdown of the normal capillary barrier  Can occur due to head trauma  Usually occurs in brain tissue around intracranial lesions like cerebral contusions, haemorrhages, infarcts and tumours  Rise in intercranial pressure  brain herniation + death  high ICP can be reduced by inducing dehydration  raising the head, infusing isotonic fluids, steroids and osmotic diuretics (mannitol) Generalised oedema: widespread accumulation of fluid in subcutaneous tissues and serous cavities (cavity lined with a serous membrane)  Complex and multifactorial pathophysiology  Key factor: activation of renin-angiotensin-aldosterone system  stimulates renal sodium retention  sodium is retained in IF  build up of fluid  Common causes: left ventricular failure (rise in hydrostatic pressure), hepatic failure and nephrotic syndrome (fall in osmotic pressure + increase in wall permeability due to changes in the BM of kidney glomerulae capillaries)  Symptoms: pitting peripheral oedema (swelling of tissues due to fluid accumulation – usually lower limbs), pleural effusions (fluid accumulates in the pleural cavity), ascites (fluid accumulates in peritoneal cavity)  THROMBOSIS: pathological clot formation in blood vessels (circulatory system) Abnormal activation of the haemostatic system (vessel repair mechanisms to prevent excessive bleeding) which leads to blood clot formation in uninjured vessels

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Can occur in arteries, veins and the heart Virchow’s triad: 3 factors that predispose to thrombosis 1.Vessel wall: endothelial injury  shear stress, hypertension, cigarette smoke. 2.Blood flow: interrupted blood flow due to turbulence (many platelets and mediators come into contact with vessels), stasis (normal flow stops), mitral stenosis (narrowing of the mitral valve) and varicose veins (enlarged veins) 3.Blood coagulability: alterations in blood constituents  determined by levels of factors that participate in the coagulation cascade. Primary = genetic. Secondary = acquired through oral contraceptive pills, malignancy, smoking and pregnancy. Venous thrombosis: blood clot that forms within a vein (rich in fibrin and red blood cells – ‘red clots’)  Stasis of blood + increased blood coagulability  Mostly form in deep leg veins (deep vein thrombosis)  Potential complication: pulmonary embolism Arterial thrombosis: blood clot that forms within an artery (rich in platelets, fewer RBC than venous thrombi – ‘white clots’)  Changes in vessel wall due to atherosclerotic plaques  Stenosis: artery narrows  ischaemia of the tissue supplied by the artery  Occlusion: complete blockage of the artery  infarction of the tissue supplied by the artery Cardiac thrombosis: thrombosis affecting the coronary circulation  Stasis of blood in a cardiac chamber  Left atrial thrombosis  atrial fibrillation  Left ventricular thrombosis  myocardial infarction  Consequences: 1. Most thrombi are completely resolved: undergo organization into fibrous tissue and recanalisation (restoration of the blood vessel lumen following thrombotic occlusion by restoration of the channel or formation of new channels) = clinically silent 2. Systemic embolisation: thrombus detaches and enters circulation  can lead to occlusion  lack of oxygen to the tissues  EMBOLISM: detached mass within the circulatory system that is carried in the blood to a site distant from its point of origin Can lodge in small vessels  blockage Thromboemboli: most are fragments of dislodged thrombus Venous thromboemboli: blood clot forms in the veins  breaks free  travels to the heart  embolus travels through the heart  blocks a blood vessel in the lung  Major pulmonary artery: emboli lodging causes instantaneous death as blood cannot travel from the lungs to the left side of the heart.  Medium sized artery: emboli lodging causes breathlessness  Small arteries: emboli lodging causes subtle symptoms of breathlessness, chest pain, dizziness (hardest to diagnose)  About 30% of patients with pulmonary embolism die  risk of death increases with diagnosis time. Arterial thromboemboli: sudden interruption of blood flow to an organ/body part due to an embolus adhering to an artery wall.  Cerebral arteries  stroke  Mesenteric arteries  small bowel infarction

 Lower limbs  acute lower limb ischaemia Other rare types of emboli:  Fat emboli: embolism of bone fracture or fat droplets  caused by physical trauma  Septic emboli: embolism of pus-containing bacteria  Amniotic fluid emboli: amniotic fluid, fetal cells, hair or other debris enters the mother’s blood stream via the placenta into uterine veins  triggers an allergic reaction HAEMORRHAGE: extravasation (leakage of fluid out of its container) of blood due to vessel rupture  Due to traumatic rupture OR intrinsic disease of the vessel (atherosclerosis etc.) Major vessel rupture  Acute haemorrhage  Hypovolaemia: decreased blood volume which leads to hypotension  Shock  Death  Examples: ruptured abdominal aortic aneurysm, ruptured thoracic aortic dissection Small vessel rupture  Can be fatal at a vital site  example: brainstem haemorrhage (complication of hypertension) Formation of solid haematoma: can be fatal in an enclosed cranial cavity  causes high ICP + tonsillar herniation Chronic low grade haemorrhage  Iron deficiency anaemia  Example: bleeding from colonic carcinoma SHOCK: generalized failure of tissue perfusion (nutritive delivery of arterial blood to a capillary bed in the  biological tissue)  inadequate substrate for aerobic cellular respiration Causes 1.Pump failure: acute myocardial infarction 2.Peripheral circulation failure: hypovolaemia (loss of blood or blood plasma), sepsis (systemic microbial infection), anaphylaxis (hypersensitivity)  circulatory collapse 3.Massive trauma 4.Burns 5.Hypokalaemia: low blood potassium Circulatory collapse  ischaemia of multiple organs (heart, lungs, gut, kidneys and brain – most metabolically active organs are most vulnerable) Symptoms: patient looks grey, feels clammy, tachycardia, hypotension, acidosis (build up of acidic waste products), low urine output, drowsiness, cerebral disturbance, death. Treatment: rapid treatment required to prevent multiple organ failure and death + restore circulatory status  INFARCTION: tissue necrosis due to ischaemia (caused by decreased blood supply) Most are due to artery obstruction: thrombosis overlying a complicated atherosclerotic plaque, thromboembolus. This causes myocardial infactions, cerebral infarctions (wedge shaped area of decreased density in right MCA territory shown in CT scan), small bowel infarctions. Can also occur due to venous obstruction: tissue becomes massively suffused with blood  appears dark purple or black. This causes testicular torsion (spermatic cord to a testicle twists and cuts of blood supply), sigmoid volvulus (bowel obstruction with a loop of bowel whose nose has abnormally twisted on itself) Development of infarct depends on: 1.Nature of vascular supply: venous, arterial

2.Rate of development of occlusion 3.Vulnerability of tissue to hypoxia 4.Blood oxygen content Infarcts heal by repair: granulation tissue is laid down  replaced by a fibrous scar  structural integrity is maintains but permanent loss of functional tissue ATHEROSCLEROSIS: inflammatory disease of large and medium sized systemic arteries characterized by  formation of lipid-rich plaques in the vessel wall Very common – especially in developed countries Risk factors  Age: increasing risk with older age  Gender: higher risk for males  Obesity  Diabetes mellitus  Hypertension  Smoking  Hyperlipidemia Key initiator: endothelial injury  ‘response to injury’ hypothesis  inflammatory + fibroproliferative response  atherosclerosis Oxidised LDL is a potentially potent driver of atherogenesis Early atheroma: 1.60% develop into quiescent plaques with limited inflammation = asymptomatic 2.20% develop into stable plaques with limited inflammation = symptoms of inducible, reversible ischaemia in the supplied organ (exercise leads to angina pectoris, chronic lower limb ischaemia) 3.20% develop into vulnerable plaques with intense inflammation = prone to rupture, thrombosis overlies them which leads to acute ischaemic events (acute coronary symptoms, unstable angina, cerebral infarction, acute lower limb ischaemia, myocardial infarction)

INFLAMMATION   

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Understand basic pathology of acute, chronic and granulomatous inflammation Recognise the histological features of these Understand the long term sequelae of inflammation, including wound healing

Inflammation: reaction of living vascularised tissue to sub-lethal cellular injury Evolutionary development to protect against infection and trauma Function: a protective response which removes the cause of injury and initiates repair of injured tissue May be acute (hours/days), subacute, chronic (weeks/months) Many different cell types/soluble mediators Local or systemic Non-specific (but mediators are also important in ...