Ajman University Pathology Lecture Notes PDF

11/10/23 Good morning, medical students. Welcome to week 2 of the pathology course (POD 232) at Ajman University College of Medicine. Cell injury and cell adaptation Dr S. Steele Associate Professor of Pathology 11/10...

11/10/23 Good morning, medical students. Welcome to week 2 of the pathology course (POD 232) at Ajman University College of Medicine. Cell injury and cell adaptation Dr S. Steele Associate Professor of Pathology 11/10/23 Pathology Module Learning Goals: At the end of the lecture learners will know the general causes of cell injury and understand the major mechanisms/pathogenesis. Students will be introduced to the principles of reversible cell damage, irreversible cell damage and cellular adaptations. Learners will know the definitions of necrosis and apoptosis.  The causes of cell injury you should remember. Cell Injury The classic causes of cell injury include: Hypoxia – decreased oxygen Toxins - poisons Chemicals – salt, acid, base etc. Heat – increased temperature Cold – decreased temperature Trauma – acute physical damage Radiation – ultraviolet light, radioactivity Micro-organisms – bacteria, viruses Immune mechanisms – inflammatory damage Nutritional imbalance – fat, glucose Genetic abnormality/damage - mutation Examples of important causes of cell injury 3 will be discussed in the following slides.  The causes of cell injury you should remember. Cell Injury The classic causes of cell injury include: Chemistry Hypoxia – decreased oxygen Chemistry Toxins - poisons Chemistry Chemicals – salt, acid, base, free radicals etc. Physics Heat – increased temperature Learning lists is part of the Physics Cold – decreased temperature art of being a doctor. Here Physics Trauma – acute physical damage the list can be broken down Physics Radiation – ultraviolet light, radioactivity into the subjects of physics, chemistry and biology. Biology Micro-organisms – bacteria, viruses Biology Immune mechanisms – inflammatory damage Biology Nutritional imbalance – fat, glucose Biology Genetic abnormality/damage - mutation Examples of important causes of cell injury will be discussed in the following slides. Important4slide  Key Terminology Causes of cell injury – Hypoxia Ischaemia (reduced blood flow) Local e.g. thromboembolus Systemic e.g. cardiac failure or generalized atherosclerosis. Hypoxaemia (abnormally low concentration of oxygen in the blood) Low environmental oxygen e.g. high altitude Low haemoglobin concentration e.g. anaemia 27/01/2012 5  How do arsenic and cyanide damage cells? Causes of Cell Injury - Chemical Poisons (e.g. arsenic, cyanide) interfere with cellular metabolism. If ATP levels drop below critical levels, normal metabolism cannot be maintained and affected cells will die. So, now if you are asked a question like “What is the pathogenesis of cyanide toxicity?” you can answer that cyanide “inhibits cellular metabolism.” 6  How do arsenic and cyanide damage cells? Causes of Cell Injury - Chemical Poisons (e.g. arsenic, cyanide) interfere with cellular metabolism. If ATP levels drop below critical levels, normal metabolism cannot be maintained and affected cells will die. So, now if you are asked a question like “What is the pathogenesis of cyanide toxicity?” you can answer that cyanide “inhibits cellular metabolism.” Arsenic is converted into arsenate, a phosphate analogue that inhibits phosphate dependent reactions. Cyanide inhibits the electron transport chain in the mitochondrial inner membrane (Complex IV, cytochrome C oxidase). 7 Chemical cell injury – free radicals Free radicals are atoms or molecules containing an unpaired electron: O. Cl. CH. CBr. 3 3 These chemical species are very unstable and will react with any atom or molecule nearby in order to gain another electron to make up the pair. However in doing so they may create a chain reaction of free radical formation leading to widespread chemical damage. Causes of free radical formation include: Toxins e.g. CCl4, Carbon tetrachloride => DRY CLEANING The free radicals produced by CCl4 Irradiation can cause liver By-product of metabolism damage and fatty NO, nitric oxide change. Transition metals and redox reactions 8  Free radicals damage everything! Free radicals cause cellular damage by: Membrane lipid reactions Autocatalytic chain reaction. Interaction with proteins Protein fragmentation and protein-protein cross-linkage. DNA damage Single strand breaks (genomic and mitochondrial). So, free radicals damage lipid, protein and DNA – all the major components of a living cell!  So, the human body protects us from free radical damage in many ways. Free radicals – the defence Free radicals are removed in biological systems by…. Anti-oxidants For example, vitamin E, vitamin A, vitamin C (ascorbic acid) Storage proteins For example, transferrin, ferritin, ceruloplasmin Enzymes Catalase, superoxide dismutase, glutathione peroxidase 10 Causes of Cell Injury – Nutrition Excessive calorie intake or fat intake itself causes cellular and tissue alterations that are damaging; fat deposition is a significant problem. Fat accumulation in liver is called steatosis. Obesity can cause this. Fat cell Liver tissue Alcohol can cause this. Fatty liver of pregnancy can kill. 11  A small amount of injury can lead to adaptation of the cell, instead of death. Excessive cell injury can overcome the cell’s ability to adapt. Reversible Mild injury Normal cell Adaptation Ex inj cess ur y ive Injurious agent Irreversible Irreversible injury: Cell injury A) Severe cell membrane damage. B) Severe nuclear damage. Can lead to cell death - Necrosis = Death of groups of “necrosis.” connected cells in a tissue or organ. Important12slide Pathogenesis of cell injury Irreversible biochemical changes Irreversible Massive (why?) intracellular calcium accumulation. Multifarious enzyme activation. Severe damage to the cell membrane allows calcium ions to move down their concentration gradient into the cell and activate nucleases that severely damage and destroy DNA. 13  Whatever the type of injury, common cellular and biochemical events occur in the cell…... General Pathogenesis of Cell Death Pathological stimuli/injury Intracellular biochemical changes REVERSIBLE Structural changes (Especially to the plasma membrane) IRREVERSIBLE Cell death There comes a point at which cell death and hence tissue death is inevitable.  How does heat or cold cause cellular damage? Back to other causes of cell injury: Causes of Cell Injury – Physical Direct Physical Effects Exposure of tissue to extreme heat or cold results in direct injury that is often irreversible, resulting in a pattern of coagulative necrosis. What do you think that coagulative necrosis means? 15  How does heat or cold cause cellular damage? Causes of Cell Injury – Physical Direct Physical Effects Exposure of tissue to extreme heat or cold results in direct injury that is often irreversible, resulting in a pattern of coagulative necrosis. What do you think that coagulative necrosis means? Cold Hot 16 Undenatured protein Denatured protein  Pathological subtypes of necrosis Different tissues die in different ways. Types of necrosis: Liquefactive Necrosis - brain Coagulative Necrosis - heart Coagulative necrosis Liquefactive necrosis Fat necrosis Fat Necrosis - Caseous necrosis Caseous Necrosis - lung pancreas Learn this Important slide  Solid change occurring in solid tissues! Coagulative necrosis tends to occur in solid tissues. Cells have died but the basic shape and architecture of the tissue remains. Classic sites of coagulative necrosis are the heart and the kidneys. The affected tissue maintains its solid consistency. Coagulative necrosis often occurs as a result of ischaemia (like a blood clot stopping blood flow). The dead cells may be replaced by regenerative cells (as occurs in the liver) or, more usually, by scar tissue (fibrosis). Important18slide  A clinical example of coagulative necrosis A very recent heart attack! Wavy fiber change “wavy eosinophilia” Abnormal tissue Elongation and narrowing of Normal myofibrils. tissue Heart muscle cells are very sensitive to adequate perfusion – complete blood flow blockage leads to irreversible damage in approximately 60-90 minutes.  Liquid change occurring in softer tissues! Liquefactive necrosis usually occurs in soft tissues The dead tissue is virtually completely dissolved. This is believed to occur through proteases released by neutrophils. A classic site of liquefactive necrosis is the brain. What is a protease and what 20 does it do?  Fat necrosis occurs in fatty tissues! Fat necrosis Results from the action of lipases released into adipose tissue. Traditional examples are pancreatitis and trauma to the breast. Free fatty acids accumulate, bind Ca2+ and precipitate as calcium salts. These precipitates are grossly visible as pale yellow/white nodules (= firm lumps). These nodules are visible on mammograms and can lead to false positive tests for cancer. Important slide  Tissue death in tuberculosis - TB Caseous necrosis. “Caseous” = “cheesy” => TB Accumulation of mixed and dead cellular debris situated in the centre of a granuloma. It is white/creamy in colour. The necrosis is the result of longstanding chronic inflammation as the body has failed to clear the TB mycobacteria at that site. Hence the caseous necrosis will include dead lung cells, dead neutrophils, dead macrophages and dead mycobacteria. Central necrosis is called caseous necrosis. Important22slide  Planned cell death not injury related cell death. Apoptosis = “Programmed cell death” Is a distinct reaction pattern which represents programmed self- destruct (or suicide). Cells actually expend energy in order to die. Apoptosis is “a physiological way for a cell to die”, seen in a variety of normal situations. Examples include embryological development and tissue atrophy. 23  HOW CELLS ADAPT Adaptations are reversible changes in the size, number, phenotype, metabolic activity, or cell functions. Adaptations occur in response to changes in their environment – stimuli or injuries. There are several types of adaptation: -plasia means cell Hyper- means multiplication! greater! -trophy means cell Hypo- means size change! less! A- means no or not! Important slide  Definition Definition of hypertrophy: “An increase in cell size due to an increase in cell substance.” It is not just due to size alone because an osmotic increase in cell size is not considered a form of hypertrophy. Hypertrophy may be pathological or physiological. Physiological Hypertrophy Can be due to increased functional demand. Can be due to hormonal stimuli. Physiological hypertrophy Pathological hypertrophy Important slide In your pairs please What is happening here and what is its significance? What is happening here and what is its significance? Left ventricular hypertrophy. This commonly occurs as part of heart failure - often on a background of hypertension. Pathological hypertrophy  The definition of hyperplasia. Hyperplasia Increase in the number of cells within an organ or tissue, usually resulting in an increased mass of the organ or tissue. The hyperplasia may be pathological or physiological. Important slide  Atrophy = Not growth ATROPHY Reduction in the size of an organ or tissue as a result of a decrease in cell size and/or number plus diminished function. Can you list four classical causes of atrophy? Major Categories/Causes of Atrophy “Use it or lose it!” Decreased function (“Disuse Atrophy”) For example: Limb immobilisation (fracture) Consider what happens to Muscle fibre atrophy (disuse) the size of a broken leg after being in a cast. Bone atrophy (includes osteoporosis et al.) Loss of innervation (“Denervation Atrophy”) For example: Muscle atrophy in nerve transection Muscle metabolism and function relies on nerve supply. Diminished blood supply Aging brains become For example – ischaemic brain atrophy shrunken and atrophic. Slow development of atherosclerotic disease Causes progressive atrophy due to ischaemia. Inadequate nutrition For example protein calorie malnutrition – use of skeletal muscle as energy source – starvation. Loss of endocrine stimulation For example menopausal breast, vagina and endometrium. Pressure atrophy For example staying seated for long periods! ?? Local effect on blood supply. Important slide  Almost the last slide! Hypoplasia Failure (decrease) in the development of an organ resulting in the failure to attain the normal size and shape of the affected organ. For example, congenital hypoplastic kidney and thyroid hypoplasia. This is a developmental issue rather than just a cell injury or cell adaptation process.  Occurs as a result of an injurious stimulus. Important slide METAPLASIA Metaplasia is defined as the reversible change from one differentiated cell type (epithelial or mesenchymal) into another differentiated cell type: Squamous metaplasia caused by schistosomiasis in the bladder. Squamous metaplasia in the lungs caused by smoking. Glandular metaplasia in Barrett’s oesophagus – caused by reflux oesophagitis. Learn these examples  These books are optional additional resources, for greater understanding of the topics. References - Books Advanced: 1) Robbins and Cotran Pathologic Basis of Disease 10th edition by Vinay Kumar, Abul K. Abbas, Jon C. Aster - 2020 Less advanced: 2) Oxford Handbook of Clinical Pathology (Oxford Medical Handbooks) by James Carton - 2017 Clinical aspects: 3) Oxford Handbook of Clinical Medicine by Ian B Wilkinson et al., - 2017