Pathology PDF

Pathology Causes of disease What is Pathology? The study of disease and disease processes by scientific methods It is an abnormal variation in the structure/function of any body part. What is disease? Abnormality of structure or function due to 1. Primary genetic defects in the structural f...

Pathology Causes of disease What is Pathology? The study of disease and disease processes by scientific methods It is an abnormal variation in the structure/function of any body part. What is disease? Abnormality of structure or function due to 1. Primary genetic defects in the structural framework of the organism and/or its function - Chromosome abnormalities (Down’s) - Gene defects (haemophilia, cystic fibrosis) Example: Bifid Uterus, Haemophilia (lack of clotting factors), Huntington’s disease (abnormal protein is toxic nerve cells in basal ganglia 2. Acquired defects due to external (environmental) causes but affected by genetic factors, may be abnormal structure or function Example: Malignant melanoma in sun exposed skin, compound fracture and iodine deficiency The disease process Four aspects of the disease process form the core of pathology Aetiology - cause of origin Pathogenesis - how the disease develops Changes in Morphology Clinical Significance Aetiology Genetic - Chromosomal abnormalities, inherited single gene defects Acquired - infections, nutrition, chemical, hypoxia, physical due to environmental factors but influenced by genetic factors - multifactorial (polygenic) Pathogenesis Mechanism of how disease develops The response of the cells or tissue to the cause Changes in Morphology Structural alterations - first indication of disease in DNA, organs and cells Clinical Significance Functional consequences of the changes in morphology: 1. The clinical Features: symptoms and signs 2. The course: acute, chronic and relapse 3. The prognosis: recovery/survival, mortality, morbidity Hypoxia Hypoxia is the decrease in oxygen in tissues, loss of blood supply, loss of oxygen capacity in blood (anaemia) Psychogenic An acquired mental disease from drugs, alcohol, tobacco …  The Respiratory System Respiratory Infections Frequent Most common - Upper Respiratory Tract by viruses Upper tract - nose, larynx, trachea, main bronchi Lower tract - bronchi, lungs, terminal bronchi Pulmonary Sepsis in the Upper and lower respiratory tract Upper: Nose, larynx, sinuses and trachea and is very common, mild, transient and viral Lower: Bronchi, Terminal Bronchi and lung parenchyma and is serious, mortality, caused by bacteria, viruses and fungi and secondary to irritants Defences of Respiratory Tract Pneumonia occurs when the defence mechanisms are impaired: Cough reflex due to coma, drugs Nasal hairs, turbinates Ciliary apparatus due to smoke Secretion of IgA antibodies Phagocytic activity by alveolar macrophages due to alcohol, tobacco Accumulation of secretions due to cystic fibrosis or bronchial obstructions Alveolar fluid Cell mediated immunity Patients with chronic disease, cancer patients (chemo), HIV Infections Infections may be: Primary - viral, bacterial, fungal, mycroplasmic Secondary bacterial - after a viral infection Secondary to irritants Upper Respiratory Tract Sepsis Viral Common cold - caused by rhinovirus Acute inflammation of eyes and throat with congestion and watery exudate Secondary bacterial infection - green discharge Viral sore throat - adenovirus Pharyngitis, conjunctivitis - congestion and watery exudate secondary infection - purulent Influenza - influenza virus Accompanied by fever, lassitude and depression May progress to pneumonia Bacterial Uncommon in developed countries, secondary to conditions which depress resistance (viral infections/bronchitis) Colonises noes and throat Acute laryngitis / epiglottitis Swelling and inability to breath Irritation by pollutants like smoke  Lower Respiratory Tract Sepsis Pneumonia - an infection of alveolar spaces, alveolar exudates polymorphs, fibrin, oedema fluid resulting in consolidation Classification: Morphology Bronchopneumonia, lobar pneumonia Aetiology Clinical setting Bronchopneumonia 1. Inflammation starts in bronchi 2. Immune system - polymorphs and fibrin 3. Spreads to adjacent alveoli 4. Patchy foci coalesce - small patches of inflammation (foci) merge together 5. Consolidation - the solidification of lung tissue 6. Widespread and bilateral 7. Rarely heals with fibrosis (unlike other types of pneumonia) Lobar Pneumonia - Due to a virulent organism Majority are caused by Streptococcus pneumonia 1. Starts in alveoli 2. Exudate flows to bronchioles and alveoli - spreads luminally 3. Immune system - polymorphs, fibrin, oedema fluid in alveoli 4. Involves all lobe of the lung 5. Consolidation - the solidification of lung tissue 6. Treated in majority of cases Aetiology Bacterial Fungal Viral Aspiration Radiation Allergic mechanism Pneumonia: Clinical Setting Community Acquired Acute Pneumonia Common and follows a viral infection Clinical Presentation - Onset abrupt - high fever, chills, chest pain, cough Risk - Occurs more often in chronic disease - heart failure, COPD, diabetes and immunodeficiency syndromes Types: Lobar or bronchopneumonia Diagnosis - sputum examination shows gram-positive diplococci, blood cultures positive Treatment - Responds to Penicillin Complications: pleural adhesions, lung abscess, septicaemia, death Commoner complications with lobar but complete resolution is common Nosocomial Pneumonia - Pneumonia acquired in hospital Gram negative rods Invasive procedures increase risk of infection Pneumonia in Immunocompromised host  Viral Pneumonia Interstitial Pneumonia Infiltration by histiocytes and lymphocytes No alveolar exudate Initially atypical pneumonia and generally mild Severe if debility, alcoholism, immunocompromised Low mortality unless epidemic or secondary bacterial infection Causes: Influenza Virus type A/B, RSV, Adenovirus, Rhinoviruses, SARS Pulmonary Tubercolosis Mycobacterium tuberculosis - droplet infection from an individual with active TB Primary Tuberculosis Primary lesion is a ghon focus (small area of inflammation) below the pleura in mid lung Tubercles composing of epithelial granulomas with caseation Bacteria spreads to hilarious lymph nodes Ghon focus and nodes heal with fibrosis/calcification TB survives in foci and becomes source of later infection Patient develops cell mediated immunity to antigens of the tubercle bacillus - positive tuberculin skin test Increase resistance to subsequent infection Secondary Tuberculosis People previously sensitised by a primary lesion A new infection or by reactivation of microbe - in chronic disease, steroid therapy and HIV Apex of the upper and lower lobes Foci heal with fibrosis and calcification Haemoptysis with erosion of a vessel in lung coughing up of caseous material (lung cavities) provides a source of infection to other lung Spread via lymph and blood spreads tuberculosis throughout the body Chronic Obstructive Pulmonary Disease (COPD) Refers to emphysema and chronic bronchitis, which are accompanied by chronic or recurrent obstruction to air flow within the lung The increase in smoking and environmental pollution has lead to increase in COPD Chronic Bronchitis Persistent cough with sputum production for at least three months in at least 2 years middle aged men especially smokers smoke predisposes to infection by interfering with ciliary action and causing direct damage to epithelium Emphysema condition of the lung characterised by abnormal permanent enlargement of the air spaces distal to the terminal bronchiole, with destruction of their alveolar walls related to smoking pathogenesis Proteases (elastase) Antiproteases (antielastase) Elastin destruction in alveolar walls Development of emphysema In smokers there is lung infection with increase neutrophilic and macrophages, which produce elastase resulting into lung damage Prognosis With severe emphysema, cor pulmonale (heart disease secondary to lung disease) and congestive heart failure develops Death due to heart and respiratory failure Asthma Increased responsiveness of bronchial tree to various stimuli, resulting in paroxysmal construction of the bronchial airways triggered by exposure to an allergen Bronchospasm triggers severe dyspnoea and wheezing Between attacks asymptomatics An unremitting attack, status asthmatics may prove fatal Lungs are over distended Bronchi are occluded by thick mucus plugs eosinophilia and oedema in bronchial walls hypertrophy pf bronchial smooth muscle Types of Asthma allergic (atopic) - specific allergens commonest, triggered by dust, food, pollens, family history, classic type 1 (IGE Hypersensitive reaction) occupational asthma after repeated exposure, fumes/gases, chemicals nonatopic - respiratory tract, hyper infection, reactive airways hyper reactive airways which respond to non-specific irritants - cold, exercise and stress asthma is associated with obesity and more common in boys Type 1: anaphylactic hypersensitive hay fever, asthma exposure to allergens high IGE produced activates mast cells and basophilic to release granules mainly histamine constricts smooth muscle, vasodilation and increased vascular permeability Primary malignant lung tumors Epithelial Tumors: These make up 90-95% of primary lung cancers. non small cell carcinoma 70-80% squamous cell 25-40% Adenocarcinoma: 25-40% Large Cell: 10-15% Small Cell Carcinoma (SCLC): Accounts for 20-25% oftumorselial lung cancers. Oat Cell Carcinoid (Low Grade): 1-5% Lymphoma: This is another type of primary lung malignancy but less common in comparison to epithelial tumors. Bronchial carcinoma Incidence: male to female 2:1, peak 50s to 60s Fatality: commonest fatal in men, in women second to breast/colon associated with smoking but risk diminishes on stopping smoking spread and metastasis local: lung, hilarious tissue, blood vessels, pericardium, pleura, oesophagus lymphatics: hilarious first, para tracheal, cervical blood: liver, adrenal glands, brain, bone non metastatic systemic effects finger clubbing, cachexia, neurological syndromes paraneoplastic syndromes hormone production: ACTH/ADH/PTH small cell or squamous cell prognosis is generally poor surgical resection when practical (20-30% of patients with 30-40% of 5 years survival) Squamous carcinoma arises in a main bronchus from squamous bronchial epithelium, metaplastic from respiratory epithelium a large friable man, which may ulcerate, projecting into lumen with stenosis of the bronchus extends into surrounding lung may erode into adjacent blood vessels may arise from a peripheral brnochus Adenocarcinoma peripheral tumours originate from glandular epithelium Neuroendocrine carcinoma Arises in a main bronchus and originates from endocrine cells in epithelium Produce hormones: ACTH (adenocorticotrophic hormone) ADH (antidiuretic hormone) PTH (parathyroid hormone) secondary tumours multiple nodules breast, kidney and testicular tumours are common  Endocrine Most endocrine glands are controlled by hormones produced in the anterior pituitary, under control of substances produced in the hypothalamus (hypothalamic-pituitary axis) Hormone excess - Primary overproduction by gland - Secondary to excessive tropic hormones Hormone deficiency - Primary underproduction by gland - Secondary to insufficient tropic hormones Hormone resistance - Target organ resistance - Failure to activate hormone Effects of non-functioning tumours - Local pressure and invasion - Metastatic disease Pituitary hyperfunction Main causes: pituitary adenoma Classification by their activity - Functioning (they secrete hormones) - Non-functioning Classification by their size - Microadenomas (< 10 mm) o symptoms due to excess hormones - Macroadenomas (> 10 mm) o pressure effects (e.g. on optic chiasma: diplopia, bitemporal hemianopsia) o destruction of normal pituitary gland (hypopituitarism) o infarct/haemorrhage of the pituitary gland (pituitary apoplexy) GH-Secreting adenoma - Gigantism(childhood) or acromegaly(adults) - Gigantism occurs before fusion of the epiphyses → bone growth (in length) - Acromegaly: enlargement hands and feet → bone growth (in thickness) Acromegaly - Enlarged hands and feet - Enlarged nose, mandibular prognathism, enlarged tongue - Irregular bone formation → limited joint mobility, nerve compression, pain - Deepened, husky voice - Reduced glucose tolerance - Hypertension - Cardiovascular complications Prolactinomas - Most common type of hyperfunctioning adenoma - Prolactin-secreting adenoma - Usually asymptomatic in men and older women - In younger women: galactorrhoea, amenorrhoea, infertility Cushing syndrome - ACTH-secreting adenoma → Cushing disease Hypopituitarism Failure of pituitary secretion which may affect one or several hormones - Causes: o Pituitary tumour/surgery/irradiation o Hypothalamic dysfunction/tumours o Head injury o Sheehan syndrome (post-partum hypopituitarism, ischaemic necrosis of the Lack of GH - Childhood → pituitary dwarfism, retarded sexual development - Adults → lethargy, diminished muscle mass, obesity Hypothyroidism Insufficient production of thyroid hormones (T3 and T4), resulting in myxoedema in adults and cretinism in children - Causes: o Auto-immune thyroiditis (e.g. Hashimoto thyroiditis) o Excessive surgical resection of thyroid gland o Severe iodine deficiency o Treatment with radioiodine o Anti-thyroid drugs (e.g. lithium, amiodarone) o Hypopituitarism (reduced TSH) Adult → Mixoedema - Weight gain (↓ basal metabolic rate - BMR) - Body temperature falls, cold intolerance - Lethargy and apathy - Constipation - ↓ respiratory and heart rates - Skin thickened, non-pitting oedema due to increase in mucopolysaccharide ground substance - Lack of ovulation, diminished libido Newborn → Cretinism - Impaired physical growth and mental development - Irreversible, unless treatment is given early - Deaf mutism - Endemic cretinism o Areas of iodine deficiency o Reduced incidence due to iodine addition to salt - Sporadic cretinism o Congenital hypoplasia or absence of the thyroid Hyperthyroidism Thyrotoxicosis = excessive quantities of circulating thyroid hormones (T3 and T4) - Causes: o Graves’ thyroiditis (exophthalmic goitre) (>80%) o Hyperfunctioning (“toxic”) multinodular goitre (10%) o Hyperfunctioning (“toxic”) adenoma ( 80%) o Parathyroid hyperplasia (~ 15%) o Parathyroid carcinoma (~ 2%) - Effects: o ↑ Ca++ o Formation of renal calculi (sometimes leading to renal failure) o General muscle weakness o Metastatic calcification Secondary hyperparathyroidism Parathyroid hyperplasia as response to hypocalcaemia Tertiary hyperparathyroidism After a long period of secondary hyperparathyroidism Development of an autonomous nodule in the hyperplastic parathyroid Results in hypercalcaemia Hypoparathyroidism - Causes: o Surgical removal of parathyroid (e.g. accidentally during thyroidectomy) o Auto-immune disease (rare) o Congenital deficiency (e.g. DiGeorge syndrome)  FLUID AND ELECTROLYTE DISORDERS Water homeostasis and disorders Water is the major component of the human body: - 50% (females) or 60% (males) of body weight - 75% of infants - 2/3 intracellular fluid (ICF) - 1/3 extracellular fluid (ECF) o 25% intravascular o 75% interstitial space (third space) Mechanisms of water loss: - Lungs (breathing) - Skin (sweating) - Gastrointestinal (urine, stool) Regulation of water intake: - Thirst triggered by receptors in the hypothalamus (in response to ↑ plasma osmolality or ↓ blood volume) Regulation of water excretion: - Vasopressin (ADH) released by the posterior pituitary o increases kidney reabsorption of H2O - Aldosterone released by the adrenal gland cortex o increases kidney reabsorption of Na+ and secretion of K+ Dehydration Dehydration = deficiency in total body water (TBW) Hypovolemia = decrease in the volume of circulating blood in the body Can result from: - Inadequate fluid intake - excessive fluid loss - combination of both - third-space fluid shift Causes of inadequate fluid intake: - Reduced thirst perception (e.g. elderly) - Impaired ability to drink (e.g. dysphagia) - Inability to seek appropriate water and food (e.g. infant, disabled person, coma) - Environmental drought or no access to safe drinking water - Poor fluid management (e.g. hospital inpatients) Causes of excessive fluid loss: - Excessive sweating (fever, exercise, hot climate) - Excessive GI loss (e.g. vomiting, nasogastric drainage, diarrhoea) - Excessive diuresis (e.g. osmotic loss accompanying the glycosuria of diabetes mellitus - polyuria, aggressive diuretic therapy) - Extensive burns - Severe bleeding - Diabetes insipidus (failure of the posterior pituitary to produce ADH or kidney insensitivity to ADH) Third-space fluid shift - Third-spacing = excessive movement of fluid into the interstitial space o Pleural effusion o Ascites o Burn o Pancreatitis o Acute intestinal obstruction o Hypovolemia Dehydration: pathophysiology - Loss of body fluids → increase in Na and other blood solutes’ concentration (↑ osmolality) - Normal compensation mechanisms to restore fluid balance: o Shift of water molecules from the cells into the blood o Increased water intake (thirst) o Increased water retention in kidneys (concentrated urine) Symptoms: - Dry skin - Dry mouth lips tongue - Constipation - Dark (concentrated) urine - Headache - Weakness, dizziness - Irritability, confusion - Tachycardia Complications: - Decreased cardiac output ‚hypotension ‚ hypovolemic shock - Decreased perfusion to tissues and organs ‚renal failure, multiple organ dysfunction syndrome - Death Treatment: - Replace lost fluids and electrolytes - Oral fluids (mainly water) - Oral rehydration solutions (especially for infants) - Intravenous fluids (for severe dehydration) Water overload and oedema - Causes of excessive total body water (TBW):Inappropriate production of ADH (e.g. small-cell lung carcinoma) - Increased Na+ concentration (e.g. excessive tubular reabsorption, such as in aldosterone-secreting tumour of the adrenal cortex) - Excessive parenteral infusion of fluids (e.g. in patients with impaired renal function) - Oedema = excess of fluid (mainly water) in the interstitial space of a tissue - Serous effusion = excess of fluid (mainly water) in a serous cavity o Transudate = due to high pressure, low protein content o Exudate = due to inflammation/tumor, high protein content - Share common pathogenetic mechanisms Pathogenic mechanisms Classification of oedema into 4 pathogenetic categories: - Inflammatory (due to increased vascular permeability) - Venous (due to increased intravenous pressure) - Lymphatic (due to obstruction of lymphatic drainage) - Hypoalbuminaemic (due to reduced plasma oncotic pressure) Electrolyte homeostasis and disorders Na+k+ - Sodium and potassium are among the most abundant electrolytes in plasma - Sodium is primarily an extracellular ion - Normal sodium plasma levels: 135-145 mmol/L o ↑ Na+ = Hypernatraemia o ↓ Na+ = Hyponatraemia - Potassium is primarily an intracellular ion - 98% in the intracellular compartment (muscle, skin, subcutaneous tissue, RBC) and 2% in the extracellular compartment (blood) - Small changes in plasma concentration can underestimate possible larger changes in intracellular concentrations - Normal plasma potassium levels: 3.5-5 mmol/L o ↑ K+ = Hyperkalaemia o ↓ K+ = Hypokalaemia Hypernatraemia - Hypernatraemia = high sodium levels - Excessive Na+ intake - Decreased Na+ excretion (Na+ retention) o (e.g. Conn’s syndrome: hyperaldosteronism) - Reduced free water (dehydration) o (e.g. fever, diabetes insipidus) Pathophysiology - Blood is hypertonic compared to ICF → water moves from ICF to ECF → cellular shrinkage Signs & symptoms - Symptoms usually when Na+ >155 mmol/L - Mainly neurologic symptoms (due to brain shrinkage) - Altered mental status (mild confusion, lethargy, coma) - Seizures - Parenchymal/subarachnoid haemorrhage, subdural haematoma - Rhabdomyolysis (due to osmotic damage to muscle membranes) - Important slow correction (rapid correction of hypernatraemia can cause cerebral oedema/seizures) Hyponatraemia - Hyponatraemia = low sodium levels - Excess free water (water retention) (e.g. kidney failure, heart failure, hepatic cirrhosis) - Decreased Na+ intake - Excessive Na+ loss o (e.g. vomiting, diarrhoea, osmotic diuresis, diuretics, severe sweating, Addison’s disease: chronic adrenal insufficiency) Pathophysiology - Blood is hypotonic compared to ICF → _water moves from ECF to ICF → _cellular swelling Signs & symptoms - Symptoms usually when Na+ < 125 mmol/L - Mainly neurologic symptoms (due to cerebral oedema within the rigid skull → increased intracranial pressure) o Nausea, vomiting, headache, confusion o Seizures, coma, death - Acute symptomatic hyponatremia is a medical emergency - Important slow correction (rapid correction can cause central pontine myelinolysis, osmotic demyelination syndrome) Hyperkalaemia - Hyperkalaemia = high potassium levels - Excessive K+ intake - Reduced K+ excretion o (e.g. renal failure) - Increased K+ exit from cells into the ECF o (e.g. extensive tissue necrosis: chemotherapy, extensive burns, haemolysis, rhabdomyolysis) Signs & symptoms - Cardiac muscle: o ECG changes (peaked T waves) o Cardiac arrhythmias (up to ventricular fibrillation, and asystole) - Skeletal muscle: o weakness, fatigue, paralysis - Intestinal smooth muscle: o stimulates intestinal motility with diarrhoea - Severe hyperkalaemia (> 7 mmol/L) is a medical emergency - risk of cardiac arrest & respiratory paralysis Hypokalaemia - low potassium levels - Decreased K+ intake - Excessive K+ loss o (e.g. vomiting, diarrhoea, diuretic therapy) - Increased K+ entry from ECF into cells o (e.g. alkalosis, insulin use) Signs & symptoms - Cardiac muscle: o ECG changes (flat T waves) o Cardiac arrythmias - Skeletal muscle: o weakness, paralysis, myopathy - Intestinal smooth muscle: o reduced motility with paralytic ileus Electrolyte homeostasis Ca++ - Normal plasma calcium levels: 2.2-2.5 mmol/L o ↑ Ca++= Hypercalcaemia o ↓ Ca++= Hypocalcaemia - Regulated by: vitamin D metabolite [ 1,25(OH)2D ] o parathyroid hormone [PTH] o and their effects on: § intestinal absorption § renal tubular reabsorption § osteoclastic activity Hypercalcaemia - high calcium levels - Excessive Ca++ intake (e.g. parenteral nutrition) - Increase in bone resorption (e.g. extensive skeletal metastases) - Excessive vit D production (e.g. vit D intoxication) - Excessive PTH production (e.g. primary hyperparathyroidism) - Hypercalcemia of malignancy (e.g. many solid tumors produce PTH-related peptide or PTHrP)  Signs and symptoms Hypocalcaemia - Low calcium levels - Intestinal malabsorption of Ca++ - Vit D nutritional deficiency - Reduced vit D production (e.g. renal insufficiency) - Inhibition of bone resorption (e.g. biphosphonates) - ↓ Ca++ stimulates release of PTH (secondary hyperparathyroidism) → ↑PTH Levels - Hypoparathyroidism → ↓PTH levels Signs and symptoms - Present for moderate-severe hypocalcaemia - Paraesthesia of fingers, toes, facial muscles (due to increased neuromuscular irritability) - Seizures - Tetany = involuntary muscular contractions → laryngospasm, bronchospasm (latent tetany can be elicited after stimulation) - Chvostek’s sign = twitching of circumoral muscles in response to tapping facial nerve anterior to ear - Trousseau’s sign = carpal spasm induced by inflation of BP cuff Acid-base homeostasis and disorders Acidosis and alkalosis - Deviations of the pH outside the normal range: o Acidosis = pH < 7.35 o Alkalosis = pH > 7.45 - Further classified as: o Respiratory (insufficient/excessive CO2 elimination from the lungs) o Metabolic (non-respiratory mechanisms) - There are 4 possible combinations (acute/chronic): o Respiratory acidosis o Metabolic acidosis o Respiratory alkalosis o Metabolic alkalosis - The body attempts to restore the pH by varying the rate of respiration (CO2 elimination due to hyper- or hypo-ventilation) or by adjusting renal tubular function (H+ excretion, HCO3- reabsorption) → compensation Acidosis - Respiratory acidosis (low pH, high pCO2) - Due to alveolar hypoventilation or inadequate gas exchange in the lungs (CO2 retention) Examples: COPD, pneumonia, respiratory depression (drugs, CNS trauma) - Metabolic acidosis (low pH, low HCO3-) - Due to excessive production of acids or inadequate excretion of acids (H+ retention) Examples: diabetic ketoacidosis, diarrhoea, renal failure Alkalosis - Respiratory alkalosis (high pH, low pCO2) - Due to alveolar hyperventilation (excessive elimination of CO2) Examples: anxiety-hyperventilation syndrome, pain, fever - Metabolic alkalosis (high pH, high HCO3-) - Due to excessive loss of acids or excessive production of HCO3- Examples: prolonged vomiting, nasogastric drainage, excessive bicarbonate administration  Cardiovascular System Ischaemic Heart Disease (IHD), also known as Coronary Heart Disease (CHD) or Coronary Artery Disease (CAD), occurs when there is an insufficient blood supply to meet the heart's metabolic needs. This shortage of blood flow is typically caused by atheroma—a buildup of fatty deposits (plaque) in the walls of the coronary arteries that supply the heart muscle (myocardium) with oxygen-rich blood. Reduced blood flow: The restricted blood supply leads to inadequate oxygenation of the heart muscle, particularly during times of increased demand (e.g., exercise or stress). Myocardial scarring: In cases of prolonged ischemia, damage occurs to the heart muscle (myocardium), leaving scar tissue, which may lead to reduced heart function. The key factors that influence this are: I. Blood Supply Issues 1. Coronary Artery Atheroma: o The most common cause of IHD is the development of atheroma (plaque) in the coronary arteries. This can partially or fully block blood flow. o Atheroma can also lead to thrombosis (clot formation), which can acutely block a coronary artery. 2. Other Causes of Reduced Blood Flow: o Coronary Artery Spasm: Temporary constriction of a coronary artery, which reduces blood flow. o Emboli: Rarely, a clot or material can travel from another part of the body and block a coronary artery. o Vasculitis: Inflammation of the blood vessels, which can reduce blood flow, though this is rare. 3. Systemic Causes (Less Common): o Reduced Cardiac Output: A general reduction in the heart’s ability to pump blood (e.g., in heart failure). o Hypotension: Low blood pressure reduces the force pushing blood through the coronary arteries, and this is more likely in patients already suffering from coronary artery disease. II. Increased Demand on the Heart 1. High Cardiac Output States: o Conditions such as thyrotoxicosis, exercise, or stress raise the body's overall demand for oxygen, including the heart. 2. Anaemia: o Low red blood cell count reduces the oxygen-carrying capacity of the blood, meaning the heart must work harder to supply tissues with oxygen. 3. Hypertension: o High blood pressure increases the workload on the heart, as it has to pump against higher resistance. Acute Coronary Syndrome (ACS) refers to a spectrum of conditions associated with sudden, reduced blood flow to the heart, and it is commonly caused by complications of atheroma (plaque) in the coronary arteries. ACS can occur in both individuals with known atherosclerosis or in previously asymptomatic patients. Key mechanisms leading to ACS include: 1. Rupture of Plaque (about 25% of cases): o This triggers superimposed thrombosis (clot formation) at the site of the rupture, leading to blockage of the coronary artery and potentially causing a heart attack. 2. Fissuring of Plaque and Intraplaque Haemorrhage (about 75% of cases): o This allows haemorrhage (bleeding) within the plaque, causing it to expand. o The enlarged plaque may further obstruct the coronary artery, and superimposed thrombosis can worsen the blockage. 3. Other Possible Mechanisms: o Coronary Artery Spasm: Transient constriction of the coronary artery can reduce blood flow, sometimes triggered by drugs (e.g., cocaine), stress, or cold exposure. The consequences of Acute Coronary Syndrome (ACS) vary depending on the severity of the coronary artery blockage, the extent of myocardial (heart muscle) damage, and the body's compensatory mechanisms. 1. No Change Size of Vessel is large, Collateral vessels (alternate routes), Tissue Damage (reversible): In some cases, ACS may not lead to significant permanent damage due to: 2. Functional Disturbances on Exercise Stable Angina: o Chest pain/discomfort that occurs predictably with exertion and resolves with rest. It indicates a partial blockage but not an acute event. Unstable Angina: o Chest pain occurs even at rest or with minimal exertion. This represents a more severe restriction of blood flow and is a warning sign of an impending myocardial infarction (heart attack). 3. Myocardial Infarction (Heart Attack) A heart attack results in more severe consequences: Loss of Cells (Myocardial Necrosis): o Prolonged ischemia leads to the death of heart muscle cells, which do not regenerate. This causes permanent damage to the heart. Abnormal Function of Survivors: o The surviving heart muscle cells may function abnormally due to injury or remodeling of the heart. This can result in reduced heart function and heart failure. 4. Sudden Death Due to fatal arrhythmias (irregular heartbeats) frequently associated with: Severe Coronary Atherosclerosis:  o Sudden death is often linked to severe atherosclerosis, where 80-90% of cases have >75% narrowing of one or more coronary arteries. Previous History of Heart Disease: o Individuals who have experienced prior angina, myocardial infarction, chronic heart failure, or even those without prior warning signs, are at increased risk of sudden death. Myocardial Infarction (Heart Attack) occurs when part of the heart muscle (myocardium) dies because it doesn't get enough oxygen-rich blood. This happens due to a blockage in one of the coronary arteries that supply the heart. Necrosis means that heart cells in the affected area die because of ischemia (lack of oxygen). The site of the heart attack depends on which coronary artery is blocked and where that blockage occurs. Different arteries supply different parts of the heart. The size of the heart attack depends on: o How much of the artery is blocked and for how long. o Whether there are collateral vessels (alternative blood vessels) that can supply blood to the affected area, reducing damage. The risk factors for myocardial infarction (MI) are the same as those for atheroma (plaque buildup). Multiple risk factors have a synergistic effect, meaning they multiply the overall risk: 1 factor: Doubles the risk (×2). 2 factors: Quadruples the risk (×4). 3 factors: Increases the risk sevenfold (×7), especially when factors like smoking, high cholesterol (hyperlipidaemia), and high blood pressure (hypertension) are combined. Causes of Myocardial Infarction (MI): 90% of cases are due to a blockage (occlusion) in a coronary artery. o 25%: Plaque rupture or ulceration damages the artery lining, leading to thrombosis (clot formation). o 75%: Plaque fissures with bleeding into the plaque and/or formation of a thrombus. 10% of cases result from a drop in blood pressure, reducing blood flow to the heart. Myocardial Infarction (MI) occurs when a plaque in a coronary artery is damaged by: Ulceration or rupture, which triggers the formation of a thrombus (clot) over the plaque. Fissures in the plaque cause bleeding into the plaque, further blocking the artery. This makes angina become unstable and more severe, often leading to a heart attack. When the artery is finally blocked: This can lead to a transmural infarction, where the entire thickness of the heart muscle is affected. The resulting damage can cause electrical disturbances in the heart, leading to arrhythmias. These arrhythmias can be fatal, potentially causing sudden cardiac arrest. If a person survives a myocardial infarction: The dead heart tissue is replaced by fibrosis, which is the formation of scar tissue. Coronary Arteries and Their Normal Supply 1. Left Anterior Descending (LAD) Coronary Artery:  o Supplies the anterior wall of the left ventricle (LV). o Also supplies the anterior septum (the wall between the left and right ventricles). 2. Right Coronary Artery (RCA): o Supplies the posterior wall of the left ventricle. o Also supplies the posterior septum. 3. Circumflex Coronary Artery: o Supplies the lateral wall of the left ventricle. Myocardial Infarction (MI) can occur due to a 10% incidence of a fall in blood pressure, particularly in individuals who already have severe coronary artery atheroma (plaque buildup). This condition leads to: Subendocardial Infarction: This type of infarction affects the inner 1/3 to 1/2 of the heart muscle wall. In these cases, there is typically no thrombus (clot) formation involved, as the decreased blood pressure alone leads to inadequate blood flow and oxygen supply to the heart muscle, particularly in areas supplied by the affected coronary arteries. Complications of Myocardial Infarction (MI): Muscle Damage: Death of heart muscle cells due to lack of oxygen. Disorderly Contraction: The damaged heart muscle may not contract properly, leading to irregular heart rhythms (arrhythmias). Ineffective Pumping Action: The overall heart function declines, resulting in reduced blood flow to the body, which can lead to symptoms like fatigue, shortness of breath, and heart failure. Early Complications of Myocardial Infarction (MI): 1. Sudden Death: often due to arrhythmias (irregular heartbeats). 2. Arrhythmia: o Fast Pulse: Conditions like ventricular tachycardia (rapid heartbeat) or ventricular fibrillation (chaotic heart rhythm) can lead to sudden cardiac arrest. o Slow Pulse: Heart block (impaired electrical conduction) may cause bradycardia (slow heart rate), potentially leading to serious complications. 3. Acute Heart Failure: o The heart may struggle to pump effectively due to extensive muscle damage, leading to symptoms like shortness of breath and fatigue. 4. Cardiogenic Shock: o A severe condition where the heart cannot pump enough blood to meet the body’s needs, resulting in 70% mortality if not promptly treated. 5. Mural Thrombus: o A blood clot that can form on the heart's wall post-MI, which can lead to emboli (clots traveling to other parts of the body), potentially causing further complications like stroke or organ damage. Complications of Myocardial Infarction: Rupture of the Left Ventricle (LV) 1. Timing: o Rupture of the left ventricle typically occurs 3 to 7 days after a myocardial infarction due to the weakening of the heart muscle. 2. Cardiac Tamponade: o A life-threatening condition where blood accumulates in the pericardial sac surrounding the heart, preventing it from filling and pumping effectively. 3. Rupture of Septum or Papillary Muscle: 4. Pericarditis: o Inflammation of the pericardium Late Complications of Myocardial Infarction (MI): 1. Deep Vein Thrombosis (DVT): o Occurs in about 30% of patients after MI, primarily due to reduced mobility and venous stasis. However, fatal pulmonary embolism is rare. 2. Chronic Heart Failure: 3. Dressler’s Syndrome: o An autoimmune reaction occurring weeks to months after MI, characterized by pericarditis (inflammation of the pericardium). It involves the production of antimyocardial antibodies, leading to chest pain and other symptoms. 4. Ventricular Aneurysm: o A bulging of the heart wall may develop at the site of the infarction, potentially leading to complications like heart failure or arrhythmias. 5. Re-infarction: o Patients who have had an MI are at increased risk of having another heart attack (re-infarction) due to ongoing coronary artery disease and risk factors. Heart Failure occurs when the heart cannot pump enough blood to meet the body's needs. It can be acute or chronic. Acute Heart Failure: This type arises suddenly and can be caused by: Coronary artery occlusion: A blood clot blocks blood flow to the heart. Arrhythmias: Irregular heartbeats disrupt normal pumping. Heart rupture: A tear in the heart muscle can severely impair function. Pulmonary emboli: A blood clot in the lungs reduces oxygen supply. In acute heart failure, a patient may either die, recover, or develop chronic heart failure depending on the underlying cause and treatment received. Chronic Cardiac Failure develops gradually when the heart cannot meet the increased demands for blood circulation. The heart muscle initially hypertrophies (grows in bulk) in response to increased workload. Over time, this adaptation fails, leading to dilation of the heart and a decline in contractility (the heart's ability to pump effectively). Causes of Chronic Cardiac Failure: 1. Hypertension: Increased blood pressure forces the heart to work harder, leading to hypertrophy and eventually failure. 2. Ischaemic Heart Disease: Reduced blood flow to the heart muscle causes damage and weakening over time. 3. Valvular Heart Disease: Dysfunction of heart valves can disrupt blood flow and strain the heart. 4. Lung Disease: Conditions like chronic obstructive pulmonary disease (COPD) can lead to heart strain and failure. 5. Anaemia: A lack of red blood cells reduces oxygen delivery to tissues, forcing the heart to work harder to meet the body's needs. Varicose Veins are dilated veins that become so enlarged that their valves can no longer close properly, allowing blood to flow backward (reflux) instead of returning to the heart. Prevalence: Varicose veins are more common in females than males. Risk Factors: 1. Obesity: Excess weight increases pressure on the leg veins. 2. Pregnancy: Hormonal changes and increased blood volume during pregnancy can lead to vein dilation. 3. Prolonged Standing: Spending long periods in a standing position can elevate pressure in the leg veins, contributing to their enlargement and stretching of the vein walls. Hypertension: Global Impact: Causes around 7.1 million deaths per year. Prevalence: Affects 15-20% of the population in developed countries. Mortality Rates: Men have 1.5 to 2 times higher mortality rates than women. Racial Disparities: More common in Black Americans than in White Americans, potentially due to genetic factors. Hypertension: Definition: Hypertension is defined as having a sustained blood pressure higher than normal levels, specifically: o Systolic: Above 120 mmHg o Diastolic: Sustained at levels higher than 90 mmHg Characteristics: o Increased cardiac output is often observed in individuals with hypertension. Types of Hypertension: 1. Primary (Essential or Idiopathic): o Accounts for about 95% of cases. o The exact cause is unknown. 2. Secondary: o Accounts for about 5% of cases. o Caused by underlying diseases or conditions that affect blood pressure, such as kidney disease, hormonal disorders, or certain medications. o Arterial Blood Pressure = Cardiac output x Peripheral resistance Pathogenesis of Primary Hypertension The exact cause of primary hypertension is unknown in 85-90% of cases, but several factors are believed to contribute: 1. Genetics: o Polygenic inheritance suggests multiple genes are involved. o Some genetic factors relate to how the body handles sodium. 2. Hormonal Factors: o Involvement of the renin-angiotensin-aldosterone system (RAAS): § Angiotensinogen and angiotensin II receptors play roles in blood pressure regulation. § Increased levels of renin can also contribute to hypertension. 3. Sodium and Potassium Transport: o Abnormal transport mechanisms of sodium and potassium across cell membranes may disrupt normal blood pressure regulation. 4. Salt Intake: o The role of salt in hypertension remains controversial: § While prevalence correlates with sodium intake, there is significant familial and individual variationin susceptibility to salt. § Increased sodium levels in arterial wall cells may lead to an increase in cell calcium, further affecting vascular tone and blood pressure. 1. Cardiac Output: o Influenced by water and electrolyte balance, particularly sodium and potassium levels, which are regulated by the kidneys and adrenal glands. o Also affected by catecholamines (such as adrenaline and noradrenaline) produced by the adrenal glands, which increase heart rate and contractility. 2. Peripheral Resistance: o Controlled by the muscle tone in arterioles. o Regulated by: § Autonomic Nerves: Catecholamines released from the adrenal glands can affect vascular tone. § Renin-Angiotensin System: § Activation of this system leads to increased arteriolar tone, resulting in increased peripheral resistance. § Higher peripheral resistance contributes to increased diastolic pressure. 1. Sympathetic Nervous System Overactivity: o Increased activity of the sympathetic (autonomic) nervous system raises vascular tone in response to: § Cold exposure § Stress and emotional states § Postural changes (e.g., standing up quickly) o This overactivity can lead to sustained vasoconstriction and increased blood pressure. 2. Renin-Angiotensin System (RAS):  o The RAS plays a crucial role in blood pressure regulation: § Plasma renin levels are normal in about 60% of individuals with hypertension. § Angiotensin II is a potent vasoconstrictor that stimulates the sympathetic nervous system, further elevating blood pressure. § Angiotensin II is produced from angiotensin I by the action of angiotensin-converting enzyme (ACE). o ACE Inhibitors: Medications that block this enzyme reduce the formation of angiotensin II, leading to vasodilation and lower blood pressure. 3. Genetic Factors: o Mutations in genes related to angiotensin II receptors and angiotensinogen can contribute to the pathogenesis of primary hypertension by altering the normal regulatory mechanisms of blood pressure. Secondary Hypertension: Causes 1. Renal Causes (Majority): Renovascular Hypertension: o Renal artery stenosis: Narrowing of the renal artery, leading to reduced blood flow to the kidneys and activation of the renin-angiotensin system. Renal Parenchymal Disease: o Chronic Glomerulonephritis (GN): Inflammation of the kidney’s filtering units. o Chronic Renal Failure (CRF): Progressive loss of kidney function. o Polycystic Kidney Disease: Genetic disorder causing cyst formation in kidneys. o Chronic Pyelonephritis: Recurrent kidney infections leading to scarring. o Diabetic Nephropathy: Kidney damage due to diabetes. o Renin-secreting tumors: Tumors that produce excess renin, increasing blood pressure. 2. Miscellaneous Causes: Coarctation of the Aorta: Narrowing of the aorta that can raise blood pressure in the upper body. Pre-eclampsia: A pregnancy complication characterized by high blood pressure. Alcohol Abuse: Chronic alcohol consumption can elevate blood pressure. Steroids / Estrogens: Hormonal treatments can cause fluid retention and increased blood pressure. 3. Adrenal Causes: Cushing's Syndrome: Excess cortisol production leading to hypertension. Conn's Syndrome: Primary hyperaldosteronism with excess aldosterone secretion. Phaeochromocytoma: Tumor of the adrenal gland producing catecholamines that raise blood pressure. Congenital Adrenal Hyperplasia: Genetic disorders affecting adrenal hormone production. 4. Other Endocrine Diseases: Acromegaly: Excess growth hormone leading to increased blood pressure.  Hyperthyroidism: Increased thyroid hormone levels can elevate heart rate and blood pressure. Hypothyroidism: May cause increased peripheral resistance and elevated blood pressure. Hyperparathyroidism: High levels of parathyroid hormone can affect calcium metabolism and blood pressure. Consequences of Hypertension 1. Increased Cardiac Output: o The heart must work harder to maintain higher arterial pressure, leading to an increase in cardiac output. 2. Left Ventricular Hypertrophy (LVH): o As a response to the increased workload, the left ventricle hypertrophies (thickens). While this adaptation helps initially, it can eventually lead to problems. 3. Heart Failure: o When the compensatory mechanisms of the heart reach their limits, the heart becomes less efficient and can enter heart failure, where it cannot pump blood effectively to meet the body's needs. 4. Increased Risk of Atheroma: o Chronic hypertension accelerates the development of atheroma (plaque buildup) in the arteries, leading to a higher risk of cardiovascular events. 5. Myocardial Infarction: o The risk of myocardial infarction (heart attack) is elevated due to both the increased strain on the heart and the potential for plaque rupture or blockage in coronary arteries. Consequences of Hypertension on the Kidneys 1. Kidney Damage: o Hypertension can lead to damage in the kidneys due to its effects on the small blood vessels (arterioles) that supply the renal tissue. 2. Vascular Changes: o Chronic high blood pressure causes thickening of the vessel walls (hypertrophy) and leads to plasma insudation (leakage of plasma components into the vessel walls). This thickening narrows the lumen of the small vessels, reducing blood flow to the kidney tissues. Consequences of Hypertension on the Brain 1. Stroke: o Chronic hypertension significantly increases the risk of stroke, particularly hemorrhagic stroke, which occurs when a blood vessel in the brain ruptures. 2. Hemorrhage: o The constant high pressure exerted on the walls of small blood vessels in the brain can cause them to weaken and eventually rupture. This leads to bleeding within the brain (intracerebral hemorrhage) or the surrounding spaces (subarachnoid hemorrhage). Consequences of Hypertension on the Eyes 1. Retinal Exudates: o Chronic hypertension can lead to changes in the retinal blood vessels, resulting in retinal exudates. These are deposits of lipids or proteins that leak into the retinal tissue due to damage to the blood vessels. Hypotension 1. Definition: o Hypotension is when blood pressure is abnormally low. 2. Causes: o Severe Hemorrhage: Significant blood loss can lead to a drop in blood pressure. o Shock: A critical condition where the body doesn't get enough blood flow. o Myocardial Infarction: A heart attack can impair the heart’s ability to pump effectively, leading to low blood pressure. 3. Consequences: o Inadequate blood supply to the brain can result in unconsciousness. If left uncorrected, it can lead to death. 4. Postural Hypotension: o This occurs when blood pressure suddenly drops upon standing up quickly, particularly in the elderly. o It is caused by a delayed response from pressure receptors in the neck (around the carotids), leading to dizziness or lightheadedness. DISORDERS OF GROWTH AND DIFFERENTIATION Growth – increase in size and mass. Synthesis of materials. Differentiation - cell acquires specialist features Morphogenesis – usually referred to embryonal development; process of organ formation Cell turnover – balance between growth and apoptosis Apoptosis – programmed cell death; facilitated by endogenous endonucleases – Autodigestion Regenerative abilities of cells Labile cells: o Constantly dividing with a high turnover rate. o Excellent regenerative ability. o Examples: Skin, gastrointestinal lining, bone marrow. Stable cells: o Low turnover rate but can regenerate if needed. o Examples: Liver, kidney, and pancreas. Permanent cells: o Do not regenerate. o Once damaged, they are replaced by scar tissue. o Examples: Neurons (brain), cardiac muscle cells (heart). Organs exposed to environmental factors tend to have better regenerative abilities due to the need for constant repair. Cell Cycle 1. Interphase: The phase when the cell is not dividing, divided into: o G1 Phase: Cell growth and preparation for DNA synthesis; crucial for regeneration capacity. o S Phase: DNA replication occurs, producing identical sister chromatids. o G2 Phase: Further growth and preparation for cell division, synthesizing necessary proteins. 2. M Phase (Mitotic Phase): The division phase where the cell undergoes: o Mitosis: Division into two identical daughter cells. o Meiosis: Division that produces gametes with half the chromosome number. Key Points: Interphase is focused on growth and DNA replication. M Phase is where actual cell division occurs. Cell Death Apoptosis, or programmed cell death, is a vital process for maintaining homeostasis by eliminating damaged or unnecessary cells. Key Features: Histological Characteristics: o Fragmented Membrane-Bound Bodies: Cells undergo changes including: § Cell Shrinkage: Cytoplasm condenses; the cell shrinks. § Chromatin Condensation: Chromatin in the nucleus condenses and fragments. § Formation of Apoptotic Bodies: The cell breaks into small vesicles that can be engulfed by neighboring cells or immune cells, minimizing inflammation. Significance in Malignant Tumors: o Rapid Turnover: In tumors, high cell turnover can lead to increased apoptosis, indicating treatment effectiveness or tumor aggressiveness. o Diagnostic Feature: Histological analysis of tumor samples can reveal apoptotic bodies, aiding in assessing tumor behavior and response to therapies. Determinants of Growth 1. Fetal Growth: o Intricate Internal System: Fetal growth relies on a complex interplay of factors. o Hormonal Influence: Few hormones cross the placenta, primarily sex steroids, which are often inactivated. 2. Endocrine System: o Growth-Mediating Hormones: Key hormones that promote growth include: § IGF-1 and IGF-2 (Insulin-like Growth Factors) § Insulin § Sex Hormones (estrogen and testosterone) § Growth Hormone (GH) § Thyroid Hormones o Disorders of these hormones can lead to growth problems in individuals. 3. Physiological Growth Spurts: o Sex Differences: Girls typically experience growth spurts earlier than boys, leading to initial differences in height, although boys eventually catch up and surpass girls during puberty. 4. Steroids: o Types of Steroids: § Sex Steroids: Promote growth. § Mineralocorticoids: Primarily involved in regulating electrolyte and fluid balance.  § Corticosteroids: Can inhibit growth, particularly when present in excess. Role of Insulin in Growth 1. Importance in Fetal Growth: o Insulin is a crucial hormone for growth, especially during fetal development. It promotes cellular growth and metabolism. 2. Diabetic Mothers and Large Birth Weight: o Reason for Increased Birth Weight: Babies born to diabetic mothers often have larger birth weights (macrosomia) due to elevated maternal blood sugar levels. o Mechanism: High sugar levels in the mother can cross the placenta, leading to increased glucose availability in the fetal circulation. o Fetal Response: In response to the excess glucose, the fetus produces more insulin, which promotes growth and fat deposition, resulting in larger body size at birth. 3. Not an Increase in Stature: o While insulin contributes to increased birth weight, it does not necessarily lead to an increase in stature (height) in the long term. This is primarily due to the influence of other growth factors and hormonal interactions postnatally. Factors Affecting Stature 1. Sex: o Males > Females: Males generally tend to be taller than females, largely due to the influence of sex hormones like testosterone, which promotes greater growth during puberty. 2. Genetics: o Inherited Traits: Tall parents are more likely to have tall children, as genetics play a significant role in determining stature. o Chromosomal Abnormalities: Genetic disorders or chromosomal abnormalities can lead to growth disorders, affecting normal development. 3. Nutrition: o Maternal Nutrition: While the fetus can adapt to poor maternal nutrition during pregnancy, postnatal nutrition becomes more important for growth. o Environmental Factors: Factors such as smoking, alcohol, and drug use can negatively impact fetal growth and development, leading to growth restrictions. Hypertrophy An increase in the size of cells without cell division (no mitosis). Types: o Physiological Hypertrophy: § Examples: Post-pubertal breast enlargement, muscle growth in response to exercise. o Pathological Hypertrophy: § Examples: Left ventricular hypertrophy due to high blood pressure or heart disease. Hyperplasia Definition: An increase in the number of cells, which requires mitosis (cell division). Types: o Physiological Hyperplasia: § Examples: Growth of the uterus during pregnancy, breast tissue enlargement. o Pathological Hyperplasia: § Example: Benign prostatic hyperplasia (BPH), where there's an abnormal increase in prostate cell number. Atrophy A decrease in the size of a tissue or organ due to a reduction in the size or number of cells. It can be either physiological (normal) or pathological (disease-related). Pathological Atrophy: Decreased Function (Disuse): Occurs when a body part is not used, such as muscle wasting after prolonged immobilization. Loss of Innervation: When nerves supplying a muscle are damaged, leading to muscle shrinkage. Loss of Blood Supply: Reduced blood flow (ischemia) causes tissues to shrink due to lack of nutrients and oxygen. Pressure Atrophy: Prolonged pressure on an organ or tissue leads to atrophy. Lack of Nutrition: Insufficient nutrients cause tissues to waste away. Loss of Endocrine Stimulation: Hormonal deficiency, such as decreased estrogen after menopause, can lead to atrophy of hormone-dependent tissues (e.g., uterine atrophy). Hypoplasia A developmental failure leading to reduced growth of an organ or tissue, usually due to defective morphogenesis (formation). Differentiation Differentiation is the process by which cells become specialized to perform specific functions. This is crucial in development, allowing various cell types to form tissues and organs. Key Processes in Differentiation: 1. Genetic Factors: o Differentiation is tightly regulated by genetic instructions, which guide cells on what functions to adopt. 2. Transcriptional Control: o The decision-making process in differentiation primarily happens at the transcriptional level. Specific transcription factors bind to DNA, controlling which genes are transcribed into mRNA. 3. Key Stages: o Transcription: This stage involves the formation of mRNA from a DNA template in the nucleus, driven by transcription factors. o Transport: The newly formed mRNA is transported from the nucleus to the ribosomes in the cytoplasm. o Translation: Ribosomes translate the mRNA into proteins (gene products), which carry out cell-specific functions. Agenesis – failure of organ development Atresia – failure of development of a lumen in a tubular structure; example oesophagus Hypoplasia – failure of an organ to attain its normal size Dysgenesis – persistence of embryonic structures – ie mature tissue does not form Ectopia – presence of mature tissue in an abnormal site NUTRITIONAL AND ENVIRONMENTAL DISORDERS Nutritional disorders Metabolic disorders Disorders of carbohydrate metabolism - Biochemical processes involved in the formation, breakdown, and interconversion of carbohydrates. - Glycogen storage diseases o Caused by enzyme deficiencies affecting glycogen synthesis, breakdown, or glycolysis. o Primarily affect muscle and/or liver cells. o Genetic or acquired (inborn errors of metabolism due to defective enzymes). o Multiple types exist, each corresponding to a specific deficient enzyme caused by a defective gene. Diabetes Mellitus - Common Endocrine Disorder o A group of metabolic disorders with sustained high blood sugar levels. - Causes: o Insulin deficiency: Pancreas not producing enough insulin. o Insulin resistance: Body cells unresponsive to insulin's effects. - Symptoms: o Polyuria (frequent urination) o Polydipsia (excessive thirst) o Weight loss o Blurred vision o Fatigue o Genital itchiness (often due to C. albicans infection) - Complications (if untreated): o Cardiovascular problems o Eye damage o Nerve damage o Kidney damage o Diabetic ketoacidosis (DKA), hypoglycemia - Types of Diabetes: o Type 1: Autoimmune, insulin deficiency. o Type 2: Insulin resistance, commonly linked to lifestyle factors. o Gestational diabetes: Develops during pregnancy. o Other types: § MODY (Maturity Onset Diabetes of the Young)  § Exocrine pancreatic defects (e.g., pancreatitis, pancreatectomy, cystic fibrosis) § Endocrinopathies (e.g., Cushing’s syndrome, hyperthyroidism, hypothyroidism) § Infections § Drugs (e.g., glucocorticoids) - Risk Factors: o Type 1: Genetics, environmental factors. o Type 2: Obesity, sedentary lifestyle, genetics. - Diagnosis Methods: o Fasting blood glucose (FBG) o Oral glucose tolerance test (OGTT) o HbA1c (glycated hemoglobin) - Treatment: o Type 1: Insulin replacement therapy. o Type 2: Anti-hyperglycemic medications (e.g., metformin) and lifestyle changes (diet, exercise). Disorders of lysosomal storage o Rare inherited metabolic disorders caused by defects in lysosomal function. o Results from a deficiency in a single enzyme required for metabolizing lipids, glycoproteins, or mucopolysaccharides. o Inherited primarily in an autosomal recessive (AR) manner; a few are X- linked recessive. o All lysosomal storage disorders involve abnormal accumulation of substances inside the lysosome Disorders of lipoproteins ad lipid metabolism o Abnormalities of apoproteins § Eg. Altered ApcoC2 leading to increase in chylomicrons in the blood (familiar apoprotein C2 deficiency/Type Ib hyperlipoproteinemia) o Enzyme defects § E.g. decreased lipoprotein lipase leading to increase in chylomicrons in the blood (familial hyperlipoproteinemia) o LCD receptor defects § Type IIa hyperlipoproteinemia (Familial hypercholesterolemia) Deficiency of LDL receptors causing increased LDL levels § Type IIb Hyperlipoproteinemia (familial combined hyperlipidaemia) Decreased LDL receptors and increased ApoB levels leading to elevated LDL and VLDL levels. Disorders of amino acid metabolism - Albiism o Complete or partial absence of pigment in the skin, hair and eyes o Caused by defective tyrosine 3-monooxygenase (tyrosinase) enzyme. o Tyrosinase synthesize melanin from amino acid tyrosine Cystic Fibrosis - Genetic disorder (autosomal recessive). - Caused by a mutation in the gene for cystic fibrosis transmembrane conductance regulator (CFTR) protein. - CFTR regulates the production of sweat, digestive fluids, and mucus. - Non-functional CFTR leads to thick, sticky secretions instead of normal thin secretions. - Primarily affects the lungs, but also impacts the pancreas, liver, kidneys, and intestines. - Long-term issues include: o Breathing difficulties, coughing up mucus. o Frequent lung and sinus infections. o Poor growth, fatty stools, clubbing of fingers, and infertility in most men. - Diagnosed through a sweat test and genetic testing. Fat-Soluble Vitamins - Includes Vitamin A, D, E, and K. - Stored in the liver. - Can be toxic in excess. Water-Soluble Vitamins - Includes the Vitamin B group and Vitamin C. - Not stored extensively in the body, so regular intake is required. - Generally non-toxic in excess. Minerals - C, H, O, N are the main building blocks of life. - Ca, P, Mg are primarily found in bone. - Na, K, Cl are electrolytes present in plasma and cells. - S is found in amino acids like methionine. - Trace elements include Fe, Zn, Cu, Co, I, F, Cr, Mn, and others. Obesity - A worldwide problem resulting from an imbalance between energy intake (calories) and energy expenditure. - Body mass index = weight/height Obesity A worldwide problem Results from imbalance between input and storage and expenditure of energy Body mass index BMI (kg/m2) = weight / height2 Causes of Obesity - Excessive Calorie Intake: o Commonest cause. o Due to physiological factors, stress, and social reasons. o Leptin: Produced by fat cells, it inhibits food intake and increases energy expenditure. o Leptin receptors are located in the hypothalamus. o Exercise increases caloric use, and growing children require more calories. - Genetic Factors: o Differences in leptin levels may explain BMI variations. o A possible gene for obesity exists but interacts with environmental factors (e.g., diet, socio-economic status). § Identical twins don't always have the same weight; adopted children often resemble their adoptive family in weight. - Socio-Economic Factors: o Obesity is linked to low education, high alcohol intake, quitting smoking, and getting married. o Weight gain is common during adolescence, pregnancy, mid-life (especially in women), and after marriage (especially in men). - Endocrine Causes (uncommon): o Cushing's syndrome, hypothyroidism, Non-Insulin Dependent Diabetes Mellitus (NIDDM). - Energy Expenditure: o Metabolism slows in mid-30s, leading to weight gain. o Exercise increases energy expenditure, including activities like: o Walking, cycling, dancing, ice-skating, swimming, jogging. Clinical consequences of obesity - A central distribution of fat (more typical of men) carries a higher risk for morbidity than peripheral distribution (more typical of women) - Time of onset is also important: obesity in childhood increases risk for morbidity - Diseases: Coronary artery disease, Cerebrovascular disease (stroke), NIDDM with insulin resistance of tissues, Hypertension, Osteoarthritis and back pain, Gallstones, Obesity hypoventilation syndrome Principles of Treatment of Obesity - Appropriate Diet o Reduce energy intake through a balanced diet of proteins, carbohydrates, and fats. o Emphasis on a permanent change in eating habits. o 80-100% of people regain weight after dieting; thus, lower energy intake must be maintained after weight loss. - Increase Energy Expenditure o Exercise should be increased unless contraindicated (e.g., severe heart disease). - Drug Therapy o Diet pills are generally not recommended as weight is usually regained after stopping the medication. o Sympathomimetic amines (e.g., amphetamines) were used but discontinued due to risks of abuse and mortality. o Orlistat: Inhibits pancreatic and gastric lipase, reducing fat absorption when taken with meals. - Surgery o Considered when other methods have failed and BMI > 40. o Sleeve gastrectomy: Permanently reduces stomach size, causing early satiety with smaller food intake. Protein-energy malnutrition - Occurs when the body's need for protein and energy is not met by the diet. - Endemic in some parts of the world; affects infants/children in poor families and adults in cases of: o Inadequate food supply (e.g., starvation, alcoholism). o Malabsorption. o Increased requirements (e.g., infection, trauma). o Psychological conditions (e.g., anorexia nervosa). Physiological Effects: - Loss of adipose tissue and tissue protein. - Thin skin (loss of elasticity). - Anaemia (low haemoglobin), electrolyte losses, and low heart rate. - Low blood pressure (BP) and impaired gastrointestinal (GI) function (bacterial overgrowth, diarrhoea, malabsorption). - Endocrine dysfunction (amenorrhoea) and immune deficiency (prone to infections). Manifestation in Children - Marasmus: o Due to lack of both protein and energy. o Common in infancy. o Growth retardation and wasting (loss of fat and skeletal muscle mass). o Associated vitamin and trace element deficiencies. - Kwashiorkor: o Due to lack of protein but adequate energy intake. o Seen in older children. o Growth failure, loss of skeletal muscle mass, but subcutaneous fat is preserved. o Generalised or limb oedema. - Other symptoms: o Severe skin exfoliation. o Hair changes (straight, brittle, discoloured). o Hepatomegaly. o Impaired albumin and transferrin synthesis. o Anaemia and vitamin deficiencies, particularly Vitamin A. Environmental diseases Physical injury Mechanical Trauma Abrasion: o Superficial injury confined to the body surface. o Caused by scraping or detachment of the epidermis due to sliding contact. Bruises/Contusions: o Caused by blunt trauma that crushes blood vessels, allowing blood to escape into tissues. o Blood may spread through loose tissues and migrate under the influence of gravity. Lacerations: o Tearing wounds caused by blunt trauma. o Involve the full thickness of the skin and may involve subcutaneous tissues or internal organs. o Wound margins are irregular. Incised Wounds: o Caused by sharp objects with a clean cutting edge. o Wound margins are straight and not bruised. o Two types: § Cuts/Slashes: Length greater than depth. § Stab Wounds: Depth greater than length. Puncture Wounds: o Include stab wounds inflicted by a pointed instrument. o Small surface marking but with a penetrating track. Fractures: o Can be considered "lacerations of bones" caused by direct or indirect trauma. Radiation Types of Radiation - Electromagnetic Spectrum: o Ionizing Radiation: § Short wavelength, high frequency (e.g., X-rays, γ-rays). o Non-Ionizing Radiation: § Long wavelength, low frequency (e.g., ultrasound (US), radio waves, microwaves, infrared (IR), ultraviolet (UV)). Particles: - Cause ionization of target molecules. Sources of Radiation - Cosmic Rays: o From solar and galactic origins; contain UV radiation, increasing the risk of skin cancer and cataracts. Radioactive Elements: - Found in the earth (e.g., uranium, radon); pose danger to miners (linked to lung carcinoma). Human-Generated Sources: - Industrial processes - Nuclear weapons. - Medical procedures (diagnostic and therapeutic). - Consumer products (e.g., radio waves, microwaves). Tissue Damage - Depends on the biological effect of radiation, specifically how much energy is lost per unit of distance traveled before impact. - Exposure to electromagnetic fields is linked to increased cancer risk, particularly leukaemia. - Particles from radioactive decay are linked to lung carcinoma. Mechanism of Tissue Damage Ionization of Atoms: - Energy transfer occurs when radiation encounters cells, leading to ionization where electrons are separated from atomic nuclei (e.g., X-rays, gamma rays). Non-Ionizing Radiation: - Transfers less energy, causing excitations of electrons (e.g., UV radiation). Types of Damage - Direct Effect: o Damage to specific sites or molecules (direct theory). - Indirect Effect: o Ionization leads to radiolysis of water, generating free hydroxyl radicals ( OH) that damage cell membranes, nucleic acids, and enzymes (indirect theory). Damage by ionizing radiation: - Damage to DNA: o Can lead to: § Immediate cell death. § Cell death at next division. § Genome alterations: Making cells more susceptible to neoplasia (cancer). - Mild damage may be repaired by DNA repair mechanisms. - Irreparable damage can lead to mutations. Radiotherapy: - Exploits the fact that abnormal cells have less efficient DNA repair. - Therapeutic dose depends on the radiosensitivity of abnormal tissue and nearby normal tissues. - Cells with high turnover (e.g., blood, skin) are more radiosensitive. Effects on Tissues and Cells - Acute Effects: o Due to heavy dose exposure over a short period. o Depletes stem cells, reducing cell numbers below levels required for regeneration. § Early signs: Vomiting, hair loss, fatigue, slow wound healing. § Continued exposure: Diarrhoea, cytopaenias, skin changes, lymphoedema, fibrosis, lung damage. § Late effects: Endothelial damage and damage to lungs, CNS, bones, kidneys, liver. - Chronic Effects: o Due to low-level radiation over a long period. o Usually, there is time for repair, and there may be no observable effects. o Effects include: § Genetic: Offspring affected if sperm/egg is irradiated. § Somatic: Can be carcinogenic. § In Utero: Irradiation can affect the developing embryo/foetus, leading to: Intrauterine death. Growth retardation. Developmental abnormalities. Childhood cancers. Chemical and drug injury Therapeutic Agents - Examples: o Analgesics, Antihistamines, Anticonvulsants, Hypnotics, Tranquillizers, An xiolytics, Antidepressants. - Predictable Adverse Drug Reactions: o Same in all individuals. o Dose-related. o Recognized complications of specific drugs. - Immunological or Idiosyncratic Reactions: o No predictable reaction. o No relation to dose. o More likely or more severe on second exposure. Non-Therapeutic Agents - Household or Industrial Examples: o Corrosives, Acids, Kerosene, Fertilizers (e.g., organophosphates), Heavy metals (e.g., lead). o May be due to accident or suicide. - Diagnosis: o Requires high suspicion. o Laboratory samples: Blood, Urine, Bile, Gastric contents, Feces, Hair, Nails. Drugs of Addiction - Examples: o Depressants, Stimulants, Hallucinogens, Solvents. Dangers of Addiction - Physical dependence: Withdrawal symptoms. - Psychological dependence. - Tolerance: Need for higher doses. - Personality deterioration: Social/moral decline. - Physical deterioration. - Accidental death from overdose. - Accidents while under the influence. - Specific illnesses related to certain drugs. Intravenous Drug Use - Damage to peripheral veins: Thrombosis, phlebitis, ulcers. - Infections: Skin abscesses, bacterial infections, HIV, Hepatitis B and C. - Accidental artery injection: Leads to thrombosis and gangrene. - Embolism to lungs and liver from impurities. Environmental Exposure - Contaminants in the Environment - Lead, Pesticides, and Insecticides are implicated in various diseases. Occupational Exposure - Asbestos (dockyard workers): Can cause bronchial carcinoma and mesothelioma. - Beta-naphthylamine (rubber, cement, dye industries): Causes urinary bladder cancer. - Uranium (miners): Causes lung carcinoma. Air Pollution - Gases, fumes, volatile metals, and particles can be harmful to humans. - Examples of pollutants: o Ozone, Nitrogen dioxide, Sulphur dioxide, Carbon monoxide, Lead. o Pollution is typically worse in urban and industrial areas. Tobacco Smoking - Adverse Effects o Chronic bronchitis and emphysema. o Peptic ulcers. o Myocardial infarction. o Arteriosclerosis. o Increased risk of abortion, perinatal mortality, and reduced birth weight. o Cancers: § Mouth, oesophagus, larynx. § Lung. § Kidney and urinary bladder. § Pancreas. § Cervix. § Smoking also increases risk when combined with other carcinogens, e.g., asbestos. - Risk Factors o Risk is cumulative and related to amount smoked. o Other factors: § Depth of smoking. § Age of onset. § Occupational exposure. § Genetic factors. § Passive Smoking § Passive smoking is harmful and linked to similar health risks.  Haemopoeitic and lymphoid system Haemopoiesis Sites of haemopoiesis: Diagnostics involve bone marrow aspiration. Stem cells: Pluripotent and committed stem cells. Functions: o Red cells: Oxygen transport. o White cells: Immunity. o Platelets: Clotting. Reticuloendothelial system: Macrophage function. Erythropoiesis Key hormone: Erythropoietin. Requirements: Minerals, vitamins, amino acids, porphyrins. Red cell features: Membrane structure. Anaemia: o Clinical features. o Classification: Micro, macro, normocytic; based on size and etiology. Iron Deficiency Anaemia Causes: Inadequate intake, poor absorption, blood loss. Example: Coeliac disease (gluten allergy). Symptoms: Fatigue, brittle nails, pale skin, spoon-shaped nails (koilonychia). Diagnosis: Ferritin, serum iron, TIBC, marrow iron stores. Therapy: Iron supplements. Megaloblastic Anaemia Causes: Deficiency of Vitamin B12 or folate (intake, malabsorption, loss). Key conditions: Pernicious anaemia (antibodies to intrinsic factor). Diagnosis: B12 assays, Schilling’s test, folate levels. Therapy: Vitamin supplements. Aplastic Anaemia Definition: Pancytopenia due to bone marrow failure. Causes: Idiopathic, autoimmune, toxins (e.g., benzene), radiation, infections (e.g., hepatitis). Symptoms: Fatigue, infections, bleeding (due to reduced red cells, white cells, and platelets, respectively). Mechanism: Immune-mediated destruction of hematopoietic stem cells. Severity: Based on cell counts and bone marrow findings. Therapies: Immune suppression, bone marrow transplantation. Myelodysplastic Syndrome Definition: A group of disorders caused by defective blood cell production in the bone marrow. Mechanism: Clonal abnormalities in hematopoietic stem cells. Incidence: Common in older adults. Diagnosis: o Blood smear showing dysplastic cells. o Bone marrow biopsy. Classification: Based on genetic and morphological criteria (e.g., WHO classification). Outcome: Risk of progression to acute myeloid leukemia (AML). Management: Supportive care, including transfusions and growth factors. Marrow Infiltration Examples: o Fibrosis (myelofibrosis, extramedullary haemopoiesis). o Haemopoietic tumours: Leukemias, lymphomas, myeloma. o Non-haemopoietic tumours, storage diseases. Anaemia of Chronic Disease (ACD) and Acute Event-Related Anaemia (AERA) ACD: Associated with chronic conditions like infections, autoimmune diseases, or malignancies. o Mechanism: Iron sequestration, reduced erythropoiesis. AERA: Occurs after acute events like surgery or trauma. Diagnosis: ACD is distinguished from iron deficiency by normal/high ferritin and low TIBC. Outlook: Improves with treatment of the underlying condition. Haemolytic Anaemias Classification: o Intrinsic: Hereditary spherocytosis, G6PD deficiency, sickle cell anaemia. o Extrinsic: Autoimmune hemolysis, infections like malaria. Clinical features: Jaundice, splenomegaly, dark urine. Diagnosis: Blood smear, reticulocyte count, Coombs test (autoimmune). Examples: G6PD deficiency (triggered by drugs), thalassemia (genetic disorder of hemoglobin synthesis). Polycythaemia Definition: Increased red cell mass, sometimes due to reduced plasma volume. Types: o True: Myeloproliferative disorders like polycythaemia vera. o Pseudopolycythaemia: Due to dehydration. Symptoms: Headache, visual disturbances, risk of thrombosis. Management: Phlebotomy, cytoreductive therapy. Platelets Thrombocytopenia: Causes include bone marrow failure, increased destruction (e.g., ITP). Thrombocytosis: Reactive (e.g., inflammation) or primary (e.g., essential thrombocythemia). Complications: Risk of bleeding or thrombosis. Management: Depends on severity and cause. White Blood Cells (Immune System) Granulocytes: o Neutrophils: Phagocytosis, elevated in infections. o Monocytes: Precursor to macrophages. o Eosinophils: Allergic responses, parasitic infections. o Basophils: Histamine release. Leukaemia Pathogenesis: Clonal defect, stem cell mutation, starts in bone marrow. Types: o Acute vs chronic. o Myeloid vs lymphoid, bilineage. Lymphocytes B-lymphocytes: o 1/3 of circulating lymphocytes. o Function: Immunoglobulin production (humoral immunity). T-lymphocytes: o 2/3 of circulating lymphocytes. o Function: Cellular immunity (e.g., infected cell lysis, graft rejection). o CD4/CD8 ratio: 2:1. Diseases: o AIDS: HIV infects T-helper cells. o EBV: Infects B lymphocytes. Slide 15: Myeloma Characteristics: Plasma cell malignancy in marrow. Features: Pancytopenia, lytic lesions, fractures, hypercalcaemia, hypogammaglobulinaemia. Risks: Infections, renal impairment (monoclonal immunoglobulins). Slide 16: Lymphoma Malignant proliferation: B or T lymphocytes. Types: o Hodgkin’s vs non-Hodgkin’s. o Classification of non-Hodgkin’s: Low vs high grade, nodal vs extranodal. DISORDERS OF BONES AND JOINTS Disorders of the bones Anatomy of a long bone - Diaphysis - Epiphysis - Metaphysis - Compact bone - Spongy bone - Osteoblasts - Osteocytes - Osteoclasts - Bone remodelling (resorption + deposition) Fracture: A breach in the continuity of a bone Fracture causes: 1. Traumatic fractures o Involve normal bones o Substantial trauma ( eg. sudden fall) 2. Stress fractures o Involve healthy athletes o Repeated episodes of minor trauma (eg marching, sport training) 3. Pathological fractures o Involves bones weakened by diseases ( eg tumours) o Trivial injury (eg. Minor fall) or spontaneously Fractures Type 1: classification based on relationship with the environment - Open fracture: a fragment of bone breaks through the skin - open wound - Closed fracture: fracture is not exposed to the environment Type 2: classification based on displacement - Displaced fracture: the bone ends are no longer straight - Non-displaced fracture: normal alignment of bone segment Type 3: Classification based on fracture pattern - Linear fraction: Parallel to the long axis of the bone - Transverse fracture: Perpendicular to the long axis of the bone - Oblique fracture: Oblique angle with the long axis of the bone - Spiral fracture: The fracture plane rotates along the long axis of the bone  - Comminuted fracture: The bone is broken into multiple fragments - Avulsion fracture: A fragment of the bone is pulled away Types 4: - Complicated fractures: involving adjacent structures (e.g. blood vessels, nerves) - Greenstick fractures: incomplete break, bowing appearance, typically children Signs and symptoms - Pain and tenderness - Swelling (oedema) - Limitation to movement - Broken skin with protruding bone Complications - Damage vessels/nerves (bleeding numbness) - Infection - Fat embolism - Poor healing Treatment: bone immobilisation Fracture healing steps: 1. Hematoma formation 2. Fibrocartilaginous 3. Bone callus formation 4. Bone remodelling Healing requires immobilisation of the approximated bone ends May be impaired by: - Local factors (e.g. excessive movement, extensive bone necrosis, poor blood supply, severe soft tissue injury, infection, interposition of soft tissue in the fracture gap, wide separation of the fractur ends) - General factors (e.g. poor nutrition, steroid therapy, elderly) Osteoporosis Definition: - Low bone mineral density (BMD) - Due to altered bone microstructure(porous bone), but normal mineralisation(normal calcium content) - Resulting in increased fragility and susceptibility to fractures Epidemiology - Common in elderly, especially post-menopausal females Pathogenesis: loss of coupling in the bone remodelling process – loss of bone mass - Peak bone mass, depends on: genetic potential, adequate nutrition, physical activity - Age related bone loss (from 4th decade loss of 1% per year, after menopause in females 3-5% per year) - Additional bone loss from other causes Pathological findings: - Spongy bone o Fewer and thinner trabeculae o More affected (greater metabolic activity) - Compact bone o Enlargement of haversian canals o Thin cortex Classification a) Generalised o Primary § Postmenopausal – type 1 § Senile – type 2 § Excessive alcohol abnd smoking are also involved o Secondary § Eg. Steroid therapy, cushing’s syndrome… b) Localised o After immobilisation, e.g. limb fracture or joint diseases Diagnosis - Bone mineral density is usually measured by bone density scan at 3 sites: o Spine (vertebrae) o Hip (femur veck) o Wrist (radius) Clinical features: - Clinically silent until complications develop - Screening of individuals at risk Complications: 1. Pathological fractures o Femoral neck (hip) o Colles’ fracture of the distal radius (wrist) 2. Skeletal deformities, due to vertebral body collapse (wedge fracture) o Progressive loss of height o Kyphosis o Severe localised back pain Prevention and treatment - Regular exercise To maximize peak bone mass - Increased dietary intake of calcium and vitamin D and reduce rate of bone loss - Drugs (e.g. bisphosphonates inhibit bone resorption) Bone tumours Classifications - Primary – uncommon - Secondary (metastasis) Primary bone tumours are further subdivided o Benign o Malignant (locally aggressive, frequent metastases) Another classification based on the line of differentiation of the neoplastic cells o Bone-forming o Cartilage-forming Bone metastases Types: - Osteolytic: destruction of normal bone (most common) - Osteoblastic: deposition of new bone (e.g. prostate carcinoma) - Commonly from: breast, prostate, lung, kidney… - In breast and prostate carcinomas, bone metastases may present early in the course of the disease but still good prognosis - Complications of metastases: o Hypercalcaemia o Pathological fractures o Spinal cord compression (vertebral metastases) Rickets and osteomalacia Definition - Inadequate mineralisation of the bone matrix (low calcium and phosphate), due to vitamin D deficiency → reduced bone strength Rickets – children – bone deformities Osteomalacia -adults – susceptibility to fractures Aetiology Deficiency of active metabolites of Vitamin D Vitamin D (active metabolite) functions: 1. Stimulate intestinal absorption of calcium 2. Stimulate bone calcium metabolism Disorders of the joints Anatomy of a synovial joint - Synovial cavity - Synovial fluid - Synovial membrane - Articular cartilage o = hyaline cartilage covering the articulating bones - Articular capsule - Diarthroses Osteoarthrosis (OA) Definition - Degeneration of articular cartilage - Mainly large weight-bearing joints - Primarily a degenerative disease (minimal inflammation) → the term “osteoarthrosis” is more appropriate than “osteoarthritis” Epidemiology Most common joint disorder A major cause of morbidity in all societies 30-50% of adults > 65 years Classification Primary OA: no obvious predisposing cause Secondary OA: predisposing conditions - Abnormality of the articular surfaces (e.g. injury, fractures) - Abnormal stress on the joint (e.g. obesity, chronic overuse in particular occupations/sports) - Previous inflammation (e.g. rheumatoid arthritis, septic arthritis) Clinical features - Usually large weight-bearing joints (e.g. hip, knee) - Pain (exacerbated by movement, relieved by rest) - Stiffness during inactivity, limitations of movement - Audible or palpable crepitus (creaking joint during movement) - Bone spurs (osteophytes) – may cause deformities and limitations of movements Bone Spurs (Osteophytes) Definition: Outgrowth of cartilage at the edge of a bone that becomes ossified (turns into bone). Common Locations: o Distal Interphalangeal Joints: Heberden’s nodes (palpable osteophytes). o Proximal Interphalangeal Joints: Palpable osteophytes also found here. Spondylosis Definition: Degenerative changes in the spine characterized by osteophytic outgrowths. Effects: Narrowing of the spinal canal (spinal stenosis) → impinges on the spinal cord and nerve roots. Diagnosis - Clinical examination - Xray – loss of joint space and deformities of articular surface Treatment - Surgical replacement of the joint by a prosthesis Rheumatoid Arthritis (RA) Definition: A systemic inflammatory disorder, often involving joints, known as rheumatoid arthritis. It is an autoimmune disorder characterized by the presence of rheumatoid factor (autoantibody). Nature: Progressive and can become disabling over time. Epidemiology Typically affects individuals between 35-55 years, more common in females than males (3:1 ratio). Children: Can also affect children, known as juvenile rheumatoid arthritis (Still's disease) Rheumatoid Disease: Pathogenesis Exact Cause: Still unknown. Contributing Factors: o Genetic Predisposition: Involves specific genes such as HLA-DR4 and HLA-DRB1. o Rheumatoid Factor: § An autoantibody directed against native immunoglobulins. § Its role remains uncertain—could be a provoking factor or just a marker. § Found in approximately 75% of patients (seropositive). § Higher titres are associated with severe arthritis and multisystem involvement.  Major Changes: Primary: Chronic inflammatory synovitis. Secondary: Progressive erosion of articular cartilage → joint damage and deformities (ankylosis). Deformities Due To: Loss of articular cartilage. Damage to joint capsule and surrounding structures. Clinical Features Symptoms: o Joint pain, tenderness, warmth, and swelling. o Morning stiffness. o Symmetrical polyarthritis. Progression: o Early Stage: Small joints (hands, feet: MCF, MTF). o Late Stage: Larger joints (knees, ankles, hips, cervical spine, TMJ). o Adjacent Issues: Muscle wasting and osteoporosis. Course: Remissions and relapses. Typical deformities Boutonniere Deformity of the Thumb MCP Joint: Flexion. IP Joint: Hyperextension. Swan Neck Deformity PIP Joint: Hyperextension. DIP Joint: Flexion. Ulnar drift MCP joints: ulnar deviation Extra-Articular Manifestations of Rheumatoid Disease Heart: Pan-carditis (myocarditis, endocarditis, pericarditis). Lungs: Rheumatoid nodules, chronic interstitial fibrosis, pleuritis. Sjögren’s Syndrome: Dry eyes and mouth. Anaemia: Associated with chronic disease. Subcutaneous: Rheumatoid nodules. Vasculitis: Inflammation of blood vessels. Rheumatic Fever Cause: Disordered immune reaction to Group A Streptococcus infection (GAS/GABHS = Streptococcus pyogenes). Age Group: Common in children aged 5-15 years. Onset: Develops 1-5 weeks after streptococcal pharyngotonsillitis (strep throat) or scarlet fever. JONES criteria (major) Joints (polyarthritis) O pan-carditis Nodules Erythema marginatum Sydenham Chorea Gout Definition: Painful acute inflammatory response due to tissue deposition of urate crystals, leading to acute arthritis. Pathogenesis Cause: Formation of urate crystals from high levels of uric acid in the blood (hyperuricaemia > 0.5 mmol/L). Uric Acid: o Byproduct of purine breakdown, found naturally in the body and in foods (meat, seafood, beer). Triggers: Acute attacks can be precipitated by factors that alter uric acid levels (stress, fatty food, beer, wine, etc.). Acute Gout: Clinical Features Type: Acute inflammatory monoarthritis (90% of cases). Common Joint: Metatarsophalangeal joint of the first toe (~70%). Other Joints: Can also occur in the ankle. Symptoms: o Abrupt onset of acute attack. o Affected joint is warm, tender, and painful. o May be associated with fever. Gout: Chronic Complications Chronic Arthritis and Tophaceous Gout: o Tophi: Deposits of uric acid in joints or soft tissues. o Commonly found around the pinna of the ear. Renal Disease: o Uric Acid Kidney Stones. o Renal Failure.  GASTROINTESTINAL TRACT Squamous cell carcinoma of the esophagus: 1. Primarily affects elderly individuals, with a higher prevalence in males. 2. Associated with tobacco and alcohol use, as well as gastroesophageal reflux disease (GORD). 3. Often detected at a late stage, leading to a poor prognosis. 4. If identified early, the prognosis can be favorable. 5. Confirmed through biopsy. Adenocarcinoma of the esophagus: 1. Accounts for 50% of esophageal cancers. 2. Often arises from Barrett's esophagus, which is associated with gastroesophageal reflux disease (GORD) and a hiatus hernia. 3. Involves processes like inflammation, ulceration, metaplasia, and dysplasia, with a 5-10% risk of progression to cancer. Adenocarcinoma of the stomach: 1. Constitutes over 90% of stomach cancers, with about half of these cases occurring in the antrum. 2. Accounts for 3% of all cancer deaths. 3. Primarily affects the elderly, with a poor prognosis unless detected early. 4. Includes infection with Helicobacter pylori, autoimmune gastritis, and smoking. 5. Less than 1% of cases develop following a peptic ulcer. Acute gastritis: 1. Acute gastritis involves inflammation of the stomach lining, often with superficial ulceration. 2. Causes: o Medications: Commonly triggered by drugs such as NSAIDs and aspirin. o Lifestyle Factors: Alcohol and smoking can also contribute. o Other Causes: Chemotherapy, infections, and severe stress (e.g., from severe burns) are also associated with acute gastritis. o Chronic Helicobacter gastritis (most common): 1. Associations: o Linked to the development of peptic ulcers. o Intestinal Metaplasia and Dysplasia: Chronic inflammation can lead to cellular changes, increasing cancer risk. o Prolonged infection with Helicobacter pylori is associated with an elevated risk of gastric cancer. 2. Managed with antibiotic therapy to eradicate H. pylori infection. Autoimmune Gastritis 1. Often linked to pernicious anemia. 2. Involves autoantibodies against intrinsic factor (IF) and parietal cells, leading to vitamin B12 deficiency. 3. Primarily affects elderly individuals. Reactive/Chemical Gastritis 1. Causes: o Bile Reflux: Backflow of bile into the stomach can cause irritation. o Medications: NSAIDs and aspirin are common contributors. Peptic ulcer disease: 1. Results from an imbalance between the stomach’s defense mechanisms (e.g., mucus, bicarbonate) and aggressive factors (e.g., acid, pepsin). 2. Typically found in the antrum of the stomach and the duodenum. 3. Helicobacter pylori infection is a primary contributing factor. 4. Treatment: o Medications: Proton pump inhibitors (PPIs) and antacids are used to reduce acid and promote healing. o Surgery: Required for complications such as bleeding, perforation, or obstruction. Small intestine: 1. Adenocarcinoma (uncommon) 2. Other Tumors: o Carcinoid Tumors: Neuroendocrine tumors that can secrete hormones. o Gastrointestinal Stromal Tumors (GISTs): Arise from the interstitial cells of Cajal in the gut wall. o Lymphomas: Malignancies affecting lymphatic tissue within the intestine. 3. Malabsorption Syndromes: o Coeliac Disease: Affects approximately 1 in 100 individuals. § Pathophysiology: Known as gluten-sensitive enteropathy; triggered by gluten ingestion. § Diagnosis: Presence of antitransglutaminase antibodi