Pathophysiology Exam 2024 PDF

Correction guideline Pathophysiology exam 2024 Exam guidelines: The exam assignment contains six main themes with sub-questions. In the assessment, the exam is evaluated in its entirety and the six themes are weighted equally. It is emphasized that the answers are clearly structured and phrased in English in a concise fashion in accordance with the pathophysiological terminology. Exam Terminology: State/Name Give the relevant points briefly – you don’t need to make a lengthy discussion. Describe Give details of processes, properties, events and so on. (This can be seen as the 'what is it?' command verb. For this you will need to provide a series of points, which usually need to be linked, that includes (all) the main features.) Explain Give detailed reasons for an idea, principle or result, situation, attitude and so on. (This is the 'how does something work/do?' command. For this you will need to provide an explanation with reasoning. You will need to use words such as 'because' or 'therefore' to help you to provide explanations.) % correct Grade 0-20 -3 21-50 0 51-58 2 59-66 4 67-78 7 79-84 10 85-100 12 1 Correction guideline 1. Pulmonary embolism a) Describe the definition and the main mechanism of pulmonary embolism? b) State the 3 main contributing factors in the formation of thrombosis in the venous system (also described in the Virchow's triad)? c) State at least 2 main risk factors for pulmonary embolism? d) Describe the hemodynamic (pressures in the heart, blood pressure, heart rate) and respiratory (pO2, pCO2, respiratory rate) consequences of an acute severe pulmonary embolism. e) Through which heart valves does a venous embolism travel before it causes a pulmonary embolism (state the respective heart valves in the correct order)? f) How do you think pulmonary embolism could be treated? Describe briefly. Answer: a) Pulmonary embolism is a blockage of an artery in the lungs by a blood clot (thrombus) that originates in the venous system and moves through the venous bloodstream (embolism). The origin of an embolism is often from a vein in the leg (deep vein thrombosis). b) The Virchow's triad explains the development of thrombosis - alterations in blood flow (venous stasis) - factors in the vessel wall (vascular injury) - factors affecting the properties of the blood (hypercoagulability) c) Main risk factors for pulmonary embolism - Immobility - Orthopedic surgery at or below the hip - Cancer (due to secretion of pro-coagulants) - Pregnancy - Obesity - Long-haul flight - Estrogen-containing medication (transgender hormone therapy, menopausal hormone therapy and hormonal contraceptives) - Genetic dispositions associated with hypercoagulability (factor V Leiden, prothrombin mutation G20210A, protein C deficiency, protein S deficiency, antithrombin deficiency, hyperhomocysteinemia and plasminogen/fibrinolysis disorders) - Acquired thrombophilia (antiphospholipid syndrome, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria) d) Hemodynamic and respiratory consequences: - Increase in the right ventricular pressure and drop in peripheral blood pressure (hypotension) and rise in heart rate (tachycardia) - Reduction in pO2 (hypoxemia), no change or increase in pCO2 (hypocapnia), increase in respiratory rate (tachypnea) e) Through which heart valves does a venous embolism travel before it causes a pulmonary embolism? - 1.) Tricuspid valve -> 2.) Pulmonary valve f) Treatment is mainly based on the dissolving /removal of the thrombus - Anticoagulation - Thrombolysis - Surgery 2 Correction guideline 2. Heart Failure with reduced ejection fraction a) Describe briefly “Heart Failure with reduced ejection fraction” (heart failure with reduced left ventricular pump function). b) Explain the pathophysiology of chronic (not acute) heart failure with reduced ejection fraction. c) State at least 2 common causes of heart failure with reduced ejection fraction. d) Explain in detail hemodynamics and the occurrence of “shortness of breath” in a patient with heart failure with reduced pump function of the left ventricle. e) State at least 1 typical signs of a patient with heart failure with backward failure of the right ventricle. Answer a) Description of heart failure with reduced ejection fraction Heart failure is not a disease but a syndrome – a combination of signs and symptoms – caused by the failure of the heart to pump blood to support the circulatory system at rest or during activity. (It may develop when the heart fails to properly fill with blood during diastole (filling failure), resulting in a decrease in intracardiac pressures or in ejection during systole, reducing cardiac output (pump failure) to the rest of the body.) b) Pathophysiology of heart failure with reduced ejection fraction Heart failure is caused by any condition that reduces the efficiency of the heart muscle, through damage or overloading. Over time, these increases in workload, which are mediated by long-term activation of neurohormonal systems such as the renin–angiotensin system and the sympathoadrenal system, lead to fibrosis, dilation, and structural changes in the heart. In a normal heart, increased filling of the ventricle results in increased contraction force by the Frank–Starling law of the heart, and thus a rise in cardiac output. In heart failure, this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. c) Common causes of heart failure with reduced ejection fraction - Coronary artery disease (including myocardial infarction/ heart attack) - Valvulary heart disease (Aortic valve stenosis, Mitral valve insufficiency) - Infection/ Myocarditis - Other cardiomyopathies/ dilated cardiomyopathy - High blood pressure/ hypertension - Arrhythmias (atrial fibrillation) - Alcohol/drugs d) Left-sided heart failure and shortness of breath The left side of the heart receives oxygen-rich blood from the lungs and pumps it to the rest of the circulatory system in the body (except for the pulmonary circulation). Failure of the left side of the heart causes blood to back up into the lungs (congestion). Shortness of breath: - Exertion-induced shortness-of-breath (when walking or active, as activity of large muscle groups require a larger cardiac output, which the failing heart cannot match). - Increased respiratory rate and labored breathing (nonspecific signs of shortness of breath) due to the development of pulmonary edema (fluid accumulation and congestion in the alveoli). - Cyanosis, indicates deficiency of oxygen in the blood, is a late sign of extremely severe pulmonary edema and insufficient supply of oxygenated blood. e) Signs of backward failure of the right ventricle - pitting peripheral edema or anasarca - ascites - liver enlargement - spleen enlargement - Elevated central venous pressure/ dilated jugular veins 3 Correction guideline 3. Gastritis and Peptic ulcer disease a) Define gastritis. b) State at least one type of chronic gastritis. c) State at least one possible complication associated with a chronic gastroduodenal infection. d) Damage to the gastroduodenal mucosa may result in the development of peptic ulcer disease. Define ulcer. e) Explain the pathophysiological factors leading to ulcer formation. f) State at least one complication of peptic ulcer disease. g) Describe the treatment goals for a patient with peptic ulcer disease. Answers a) Gastritis is a histological term used to describe inflammation of the gastric mucosa (the presence of white blood cells). It can be classified further based on the time course and type of inflammatory cells (acute vs chronic), etiology and anatomical localization. b) Helicobacter pylori gastritis, atrophic gastritis, chemical gastritis c) Gastric atrophy, (peptic ulcer disease), gastric adenocarcinoma, mucosa associated lymphoid tissue; mucosal barrier break d) An ulcer is a break or discontinuation in the inner lining of the stomach or duodenum that extends beyond the muscularis mucosa. e) The lining of the stomach is normally protected from the acidic luminal content and pepsin by a tight, epithelial membrane covered by a thick bicarbonate enriched mucus, epithelial renewal and a generous blood supply. The mucosal defense can however be overwhelmed when the stomach lining is also affected by infection with helicobacter pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), exposure to alcohol, bile or other chemicals. (HP infection results in mucosal inflammation due to damage elicited by the virulence factors of HP). (NSAIDs inhibits prostaglandin synthesis. Prostaglandins are important regulators of mucus secretion, blood flow, bicarbonate secretion, epithelial renewal). f) Hemorrhage, perforation/penetration, gastric outlet obstruction. g) Eradication of helicobacter pylori, cessation of NSAIDs use, in case of gastric ulcer biopsies to rule out malignancy, endoscopic follow up to ensure ulcer healing. 4. Multiple Sclerosis (MS) is the inflammation and destruction of myelin predominantly in the central nervous system a) Describe at least one potential risk factor associated with an increased likelihood of developing Multiple Sclerosis (MS). b) Explain the pathophysiology of Multiple Sclerosis, highlighting the stages of lesions involved in the disease. c) Describe at least two clinical manifestations associated with Multiple Sclerosis, considering its impact on neural conduction. d) Compare and contrast the underlying mechanisms involved in the inflammatory and neurodegenerative processes of Multiple Sclerosis, elucidating their respective impacts on disease progression. 4 Correction guideline e) Describe at least one courses of disease progression seen in Multiple Sclerosis, outlining the distinctive characteristics. Answer: a) MS is more prevalent among individuals of Northern European ancestry and less common in Asia, Africa, and northern South America. Family history of MS increases the risk; there's a 10% to 20% chance for a person with MS to have a family member with the condition. People carrying the human leukocyte antigen (HLA-DR2) haplotype are at a higher risk for MS. b) MS is presumed to be an immune-mediated disorder affecting genetically susceptible individuals. Lesions, termed plaques, evolve through two stages: Initial stage: Development of small inflammatory lesions. Subsequent stage: Lesion extension, consolidation, demyelination, and gliosis. The specific antigen triggering the immune response against CNS proteins remains unidentified. c) Clinical manifestations vary based on lesion location. Commonly affected areas include the optic nerve (visual fields), corticobulbar tracts (speech and swallowing), and corticospinal tracts (muscle strength). Symptoms range from paraesthesias (numbness, tingling) to abnormal gait, bladder dysfunction, vertigo, fatigue, and psychological manifestations (mood swings, depression, memory loss). d) Inflammatory processes in MS involve immune cells attacking myelin, leading to demyelination and lesion formation, primarily in the early stages of the disease. This inflammation contributes to acute relapses. Neurodegenerative processes, occurring progressively, involve axonal damage and loss, leading to permanent disability and chronic neurological decline. These processes, often seen in later stages, contribute to the progressive disability characteristic of MS. e) Relapsing-remitting MS: Episodes of acute worsening followed by recovery and stability between relapses. Secondary progressive disease: Gradual neurological deterioration, with or without acute relapses, in individuals with a prior relapsing-remitting course. Primary progressive disease: Continuous neurological decline from symptom onset. Progressive relapsing MS: Gradual neurological deterioration from symptom onset, accompanied by subsequent relapses. 5. Acromegaly refers to Growth Hormone (GH) excess occurring in adulthood or after the epiphyses of the long bones have fused a) State at least one primary cause (etiology) of acromegaly. 5 Correction guideline b) Describe the role of Insulin-like Growth Factor 1 (IGF-1) in the pathophysiology of acromegaly, emphasizing its relationship with Growth Hormone (GH) and its impact on tissue growth. c) Describe the potential complications associated with untreated or inadequately managed acromegaly, considering both physical manifestations and systemic health risks. d) Explain the clinical manifestations seen in acromegaly in relation to its pathophysiology, encompassing both growth-related changes and metabolic effects. e) Explain the association between Diabetes Mellitus (DM) and acromegaly, considering the underlying metabolic alterations caused by the condition. Answer: a) The most common cause of acromegaly is the presence of GH-secreting adenomas (somatotrope adenomas) in the pituitary gland. Other causes include hypothalamic tumors leading to excessive secretion of growth hormone-releasing hormone (GHRH) and ectopic secretion of GHRH by nonendocrine tumors or, rarely, GH secretion by nonendocrine tumors. b) IGF-1, produced in response to GH stimulation, mediates the growth-promoting effects of GH. In acromegaly, elevated GH levels lead to increased IGF-1 production, promoting tissue growth even after skeletal maturity. This excess IGF-1 contributes to the clinical manifestations observed in acromegaly, such as soft tissue enlargement and organ hypertrophy. c) Untreated acromegaly can lead to various complications, including cardiovascular issues like hypertension, cardiomyopathy, and increased risk of heart failure. Physical complications involve joint problems due to tissue overgrowth, sleep apnea, vision impairment due to optic nerve compression, and increased risk of certain cancers. Systemic health risks include metabolic abnormalities like diabetes mellitus, worsening insulin resistance, and increased susceptibility to infections. d)  Clinical manifestations arise from excess GH and IGF-1, stimulating tissue growth despite skeletal maturity.  Soft tissue enlargement includes hands, feet, facial bones, nose, jaw, forehead, dental problems, respiratory changes, joint pains, and organ enlargement.  Metabolic changes involve altered fat and carbohydrate metabolism, insulin resistance, glucose intolerance, increased insulin secretion, and potential diabetes mellitus development. e)  Excessive GH and IGF-1 levels cause disruptions in fat and carbohydrate metabolism, resulting in insulin resistance and glucose intolerance.  Chronic elevation of GH can overstimulate beta cells, potentially causing them to fail, leading to impaired glucose regulation and the development of DM.  (Reported DM prevalence in acromegaly ranges from 12% to 54%.) 6 Correction guideline 6. Hypertension is a sustained elevation of blood pressure. a) Explain the difference between primary (essential) hypertension and secondary hypertension, highlighting their distinct characteristics and implications for clinical management. b) State two non-modifiable risk factors for hypertension. c) State at least two modifiable risk factors contributing to hypertension and explain their influence on blood pressure regulation. d) Describe the physiological mechanisms through which increased salt intake contributes to hypertension, emphasizing the impact on kidney function and blood pressure regulation. e) Explain the clinical manifestations of hypertension and their association with target-organ damage. f) State at least one disease where hypertension is a leading cause and explain the relationship between hypertension and its impact on this disease. Answer: a) Primary hypertension refers to elevated blood pressure without a specific underlying cause, while secondary hypertension results from identifiable conditions like kidney disease or hormonal disorders. Primary hypertension comprises the majority of hypertension cases and requires lifestyle modifications and medication for management. Secondary hypertension necessitates treating the underlying condition causing high blood pressure. b) Age: Hypertension is more common in adults due to arterial stiffness and declining kidney function with age. Genetics and Family History: Individuals with a family history of high blood pressure have a higher likelihood of developing hypertension. c) Dietary Factors: High salt intake leads to salt sensitivity, affecting blood pressure regulation. Fat and cholesterol contribute to dyslipidemia, increasing arterial resistance. Tobacco and Alcohol: Smoking and excessive alcohol consumption elevate blood pressure, increasing the risk of hypertension. Obesity and Fitness: Excess weight and low fitness levels are linked to hypertension due to their impact on blood lipid levels and sympathetic nervous system activation. d) Elevated salt intake disturbs the balance of sodium and potassium in the body, affecting kidney function. This imbalance leads to water retention and increased blood volume, raising blood pressure. The kidneys, crucial in regulating blood pressure, respond to excess salt by altering the excretion of sodium, ultimately influencing blood pressure levels. e) Primary hypertension is often asymptomatic but can lead to long-term damage in organs like the kidneys, heart, eyes, and blood vessels. 7 Correction guideline Increased perfusion pressure can damage target organs, while raised intravascular pressure harms vascular endothelial cells, increasing the risk of atherosclerotic vascular disease and impaired organ function. f) Ischemic Heart and Brain Disease: Hypertension significantly contributes to the development of atherosclerosis, leading to reduced blood flow to the heart and brain, resulting in heart attacks and strokes. 8 Correction guideline Pathophysiology RE-exam 2024 Exam guidelines: The exam assignment contains six main themes with sub-questions. In the assessment, the exam is evaluated in its entirety and the six themes are weighted equally. It is emphasized that the answers are clearly structured and phrased in English in a concise fashion in accordance with the pathophysiological terminology. Exam Terminology: State/Name Give the relevant points briefly – you don’t need to make a lengthy discussion. Describe/Define Give details of processes, properties, events and so on. (This can be seen as the 'what is it?' command verb. For this you will need to provide a series of points, which usually need to be linked, that includes (all) the main features.) Explain/Discuss Give detailed reasons for an idea, principle or result, situation, attitude and so on. (This is the 'how does something work/do?' command. For this you will need to provide an explanation with reasoning. You will need to use words such as 'because' or 'therefore' to help you to provide explanations.) % correct Grade 0-20 -3 21-50 0 51-58 2 59-66 4 67-78 7 79-84 10 85-100 12 1 Correction guideline 1. Asthma a) Describe at least two risk factors associated with asthma development. Answer:  Genetic predisposition for the development of an immunoglobulin E (IgE)-mediated response to common allergens.  Family history of asthma, allergies, antenatal exposure to tobacco smoke and pollution, and multiple potentially overlapping genetic predispositions. b) Explain the pathophysiology of asthma. Answer: Asthma is characterized by airway obstruction, bronchial hyperresponsiveness, airway inflammation, and in some cases, airway remodeling. It involves an exaggerated hyperresponsiveness to various stimuli, with inflammatory cells such as eosinophils, lymphocytes, and mast cells contributing to inflammation and damage to the bronchial epithelium. T-helper (2) cells respond to allergens by stimulating B cells to produce IgE, leading to an allergic response and inflammation. c) Describe the role cytokines play in the pathogenesis of asthma. Answer: Cytokines, including tumor necrosis factor (TNF)-α and interleukin 4 (IL-4) and IL-5, contribute to the pathogenesis of bronchial asthma by affecting bronchial epithelial and smooth muscle cells. TNF-α, for instance, increases migration and activation of inflammatory cells and contributes to airway remodeling. IL-4 and IL-5 are involved in the proinflammatory response and allergic reactions in asthma. d) Explain the clinical manifestations during a prolonged asthma attack. Answer: In a prolonged asthma attack, air becomes trapped behind narrowed airways, leading to hyperinflation of the lungs. This results in increased residual volume (RV), decreased inspiratory reserve capacity, and forced vital capacity (FVC). Accessory muscles are required to maintain ventilation, causing dyspnea and fatigue. Alveolar ventilation effectiveness declines, causing hypoxemia and hypercapnia. Pulmonary vascular resistance may increase, leading to elevated pulmonary arterial pressure and increased work demands on the right heart. e) Describe how respiratory infections impact asthma. Answer: Frequent viral respiratory infections can exacerbate asthma or even lead to its development. These infections, especially when frequent at an early age, may exaggerate the T2H response, predisposing the airways to allergic responses and IgE production. Additionally, viral infections are known triggers for asthma exacerbations. f) Describe the differences in symptoms between a mild asthma attack and a severe one. Answer: In a mild asthma attack, symptoms may include chest tightness, slight increase in respiratory rate with prolonged expiration, and mild wheezing. A cough may accompany the wheezing. In contrast, severe attacks are characterized by the use of accessory muscles, distant breath sounds due to air trapping, loud wheezing, fatigue, moist skin, and significant shortness of breath to the point where the person can speak only one or two words before needing to breathe again. 2 Correction guideline 2. Obesity a) Define overweight and obesity, and explain how they are measured. Answer: Overweight and obesity are conditions characterized by an excess accumulation of body fat, leading to health complications. They are measured using the Body Mass Index (BMI), calculated by dividing an individual's weight by the square of their height. b) Describe the classification of obesity according to BMI and explain its significance in determining health risks. Answer: Overweight is defined as a BMI of 25 or greater, while obesity is defined as a BMI of 30 or greater. This classification is crucial as higher BMI levels correlate with increased health risks such as cardiovascular disease, diabetes, and certain cancers. c) Describe and discuss three factors contributing to the development of obesity, considering both genetic and environmental influences. Answer: Several factors contribute to the development of obesity, including genetics, environment, and behavior. Genetic predispositions influence how our bodies store and regulate fat, while environmental factors like food availability and sedentary lifestyles play significant roles. Behavioral factors such as eating habits and physical activity levels also contribute. Understanding these multifaceted influences is essential for effective obesity prevention and management. d) Describe and discuss two types of obesity based on fat distribution on the body and explain the differences in health risks associated with each type. Answer: Obesity can be classified into two types based on fat distribution: upper body (android) and lower body (gynoid). Upper body obesity, also known as central or abdominal obesity, is associated with a higher risk of cardiovascular disease and metabolic complications. Lower body obesity, often termed pear-shaped, carries a lower risk of such complications due to the distribution of fat primarily in the hips and thighs. e) Describe and explain the pathophysiological disturbances linked with obesity, including insulin resistance, dyslipidemia, inflammation, and sleep apnea. How do these disturbances contribute to the development of obesity-related complications? Answer: Obesity is linked to various pathophysiological disturbances, including insulin resistance, dyslipidemia, inflammation, and sleep apnea. Insulin resistance is a key feature, leading to impaired glucose regulation and an increased risk of type 2 diabetes. Dyslipidemia involves abnormal levels of lipids in the blood, contributing to cardiovascular disease risk. Chronic inflammation associated with obesity exacerbates these risks. Additionally, obesity increases the likelihood of developing sleep apnea, a condition characterized by interrupted breathing during sleep, further compromising overall health. 3 Correction guideline g) Explain the various strategies employed in the management and treatment of obesity. Compare and contrast lifestyle interventions, pharmacological approaches, and bariatric surgery in terms of efficacy and potential risks. Answer: Management of obesity involves a multifaceted approach, including lifestyle modifications, pharmacological interventions, and, in severe cases, bariatric surgery. Lifestyle modifications focus on dietary changes, increased physical activity, and behavior therapy to promote sustainable weight loss. Pharmacotherapy includes medications that regulate appetite and metabolism. Bariatric surgery is reserved for individuals with severe obesity and significant health risks. Each approach has its benefits and risks, and the choice depends on individual circumstances and medical advice. 3. Alzheimer Disease (AD) a) Describe two risk factors associated with Alzheimer Disease (AD), and how they contribute to its development? Answer: Age and genetic predisposition are two significant risk factors for Alzheimer Disease (AD). Advancing age increases the likelihood of developing AD, with individuals over 65 being at higher risk. Additionally, genetic factors, such as mutations in genes like amyloid precursor protein (APP) and Apolipoprotein E-e4, play a role in familial cases of AD, accelerating its onset and progression. b) Describe the major microscopic features of Alzheimer Disease (AD) and their contribution to neurodegeneration. Answer: Alzheimer Disease (AD) is characterized by neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles consist of hyperphosphorylated tau protein, while amyloid plaques are dense aggregates of amyloid beta (Aβ) peptides. These pathological features contribute to neuronal degeneration, synaptic loss, and cognitive decline in AD patients, ultimately leading to functional impairments. c) Describe three clinical manifestations commonly observed in individuals with Alzheimer Disease (AD). Answer: Common clinical manifestations of Alzheimer Disease (AD) include loss of short-term memory, difficulties with language (aphasia), and changes in behavior such as depression, agitation, and sleep disturbances. These symptoms progressively worsen as the disease advances, impacting daily functioning and quality of life. d) Describe the course and progression of Alzheimer Disease (AD) in affected individuals. Answer: Alzheimer Disease (AD) follows an insidious and progressive course, typically spanning 8 to 10 years from diagnosis to end-stage. Various stages of the disease have been identified, ranging from mild cognitive impairment to severe dementia. Symptoms worsen over time, affecting memory, cognition, and functional abilities, ultimately leading to profound disability and dependency on caregivers. e) Explain the role of neurotransmission disruption in the pathophysiology of Alzheimer Disease (AD). Answer: Disruption of neurotransmission, particularly involving neurotransmitters like acetylcholine (ACh), glutamate, and gamma-aminobutyric acid (GABA), contributes to cognitive impairments in Alzheimer Disease (AD). Alterations in cholinergic transmission and 4 Correction guideline glutamatergic signaling are associated with synaptic dysfunction and neuronal loss, leading to cognitive decline and behavioral symptoms observed in AD patients. 4. Thyrotoxicosis (hyperthyroidism) a) State at least two etiologies (causes) of Thyrotoxicosis. Answer: Thyrotoxicosis can result from various causes, including hyperactivity of the thyroid gland (hyperthyroidism), Graves disease, multinodular goiter, adenoma of the thyroid, thyroiditis, and iodine-containing agents that induce thyroid dysfunction. b) Explain the cause of Graves disease. Answer: Graves disease is an autoimmune disorder characterized by abnormal stimulation of the thyroid gland by thyroid-stimulating antibodies, specifically thyroid-stimulating hormone receptor antibodies (TSH-R antibodies). These antibodies mimic the action of TSH and bind to TSH receptors on thyroid follicular cells, leading to excessive production and secretion of thyroid hormones. c) Describe the clinical manifestations of Graves disease in relation to its pathophysiology, including effects on metabolism, nervous system, and eyes. Answer: Graves disease results in a hypermetabolic state due to increased oxygen consumption and utilization of metabolic fuels. This leads to symptoms such as nervousness, irritability, weight loss despite increased appetite, tachycardia, palpitations, excessive sweating, muscle cramps, and heat intolerance. The increased sympathetic nervous system activity contributes to manifestations resembling excessive sympathetic activity. Ophthalmopathy, affecting up to one-third of patients, results from accumulation of T lymphocytes sensitized to antigens along thyroid follicular cells and orbital fibroblasts, leading to symptoms such as exophthalmos, lid retraction, diplopia, visual loss, and corneal ulceration. d) Describe at least one method of treating Thyrotoxicosis. Answer: Thyrotoxicosis can be treated by reducing the level of thyroid hormone through various methods. One approach is the eradication of thyroid tissue using radioactive iodine therapy, which selectively destroys thyroid cells. Surgical removal of part or all of the thyroid gland is another option. Additionally, drugs known as antithyroid medications can be used to inhibit the production of thyroid hormone or block its action on peripheral tissues. e) How does Graves disease affect the eyes, and what are potential complications associated with this condition? Answer: Graves disease can cause ophthalmopathy, characterized by symptoms such as exophthalmos (bulging eyes), lid retraction, diplopia (double vision), visual loss, and corneal ulceration due to incomplete eyelid closure. Complications of ophthalmopathy may include tethering of extraocular muscles leading to diplopia, optic nerve involvement resulting in visual impairment, and corneal ulceration due to exposure keratitis. Ophthalmopathy symptoms may worsen after certain treatments like radioiodine therapy, and smoking can aggravate the condition. 5. Acute inflammation 5 Correction guideline a) Describe the primary aim of acute inflammation, and explain why it is crucial for tissue homeostasis? Answer: The primary aim of acute inflammation is to initiate a host protective response in local tissues and blood vessels following injury. It plays a critical role in restoring tissue homeostasis by removing injurious agents and limiting tissue damage, ultimately facilitating tissue repair and regeneration. b) Name at least two triggers that can initiate acute inflammation and explain how they provoke the inflammatory response. Answer: Acute inflammation can be triggered by various stimuli, including infections, immune reactions, trauma (blunt or penetrating), physical or chemical agents (e.g., burns, frostbite, irradiation), and tissue necrosis. These triggers induce inflammation by activating inflammatory mediators and signaling pathways, leading to changes in blood vessel permeability and recruitment of immune cells to the site of injury. c) Describe the two major phases of acute inflammation, and their primary components. Answer: The two major phases of acute inflammation are the vascular phase and the cellular phase. The vascular phase involves changes in blood vessels at the site of injury, leading to increased blood flow and vascular permeability. The cellular phase involves the recruitment and activation of leukocytes, mainly polymorphonuclear neutrophils (PMNs), to the site of injury for host defense. d) Explain the vascular phase of acute inflammation in detail, including the sequence of events and the cardinal signs of inflammation. Answer: The vascular phase begins with vasoconstriction followed by rapid vasodilation, mediated by lipid mediators and vasoactive products. This leads to increased blood flow, causing heat and redness (cardinal signs of inflammation). Vascular permeability increases, resulting in protein-rich fluid (exudate) leakage into tissue spaces, causing swelling, pain, and impaired function (other cardinal signs). Stagnation of blood flow and clotting help localize microorganisms. e) Explain the cellular phase of acute inflammation, focusing on the recruitment and activation of leukocytes at the site of injury. Answer: The cellular phase involves the delivery of leukocytes, mainly PMNs, to the site of injury. Steps include endothelial activation, adhesion and margination, transmigration, and chemotaxis. Leukocytes adhere to endothelial surfaces and migrate into tissues through complementary adhesion molecules. Chemotaxis guides leukocytes toward the injury site, where they perform phagocytosis and cell killing to remove pathogens and cellular debris. f) Explain how phagocytosis contribute to the cellular phase of acute inflammation, and what are their roles in host defense? Answer: Opsonization of microbes by complement factor C3b and antibodies facilitates recognition by neutrophil receptors, enhancing phagocytosis. Phagocytosis involves the engulfment of microbes by leukocytes, followed by degradation using lysosomal enzymes and oxygen radicals. These processes are crucial for host defense, enabling the clearance of pathogens and tissue debris, thereby promoting resolution of inflammation and tissue repair. 6. Cystic fibrosis (CF) a) Describe who is primarily affected by cystic fibrosis (CF) 6 Correction guideline Answer: CF primarily affects children and is the major cause of severe chronic respiratory disease in this age group. It is estimated that about 30,000 children and adults in the United States are affected by CF, with over 10 million individuals being asymptomatic carriers of the defective gene. b) Explain the causality, genetics, and cellular mechanisms underlying cystic fibrosis (CF), focusing on the role of the cystic fibrosis transmembrane regulator (CFTR) gene and its protein product. Answer: CF is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, located on chromosome 7. The CFTR protein functions as a chloride channel in epithelial cell membranes. Mutations in the CFTR gene lead to excessive thickening of mucus, particularly in the lungs and pancreas. The most common mutation, delta F508, results in a severe phenotype by impairing chloride channel function and causing misfolding of CFTR proteins. c) Describe two clinical manifestations of cystic fibrosis (CF), detailing their relationship to the pathophysiology of the condition. Answer: Respiratory manifestations of CF are characterized by the accumulation of thick mucus in the bronchi, impairing mucociliary clearance and leading to chronic lung infections. This can result in chronic bronchiolitis, bronchitis, and eventually bronchiectasis. Additionally, CF predisposes individuals to chronic infections, particularly with organisms like Pseudomonas aeruginosa, exacerbating pulmonary inflammation and respiratory decline. Pancreatic involvement in CF often leads to malabsorption, malnutrition, and symptoms such as abdominal discomfort, diarrhea, and steatorrhea due to impaired digestive enzyme secretion. d) Discuss the respiratory manifestations of cystic fibrosis (CF) in detail, including the structural changes in the airways and the role of chronic infections. Answer: CF respiratory manifestations involve the accumulation of thick mucus in the bronchi, impairing mucociliary clearance and leading to chronic lung infections. Initially, chronic bronchiolitis and bronchitis may develop, progressing to bronchiectasis over time due to structural changes in the bronchial wall. Chronic infections, especially with Pseudomonas aeruginosa, further exacerbate respiratory decline and inflammation, contributing to the progression of CF lung disease. e) Explain the variability in pancreatic involvement seen in individuals with cystic fibrosis (CF), and discuss common symptoms associated with pancreatic dysfunction. Answer: Pancreatic involvement in CF varies widely among individuals, ranging from mild impairment to severe deficiency. Symptoms of pancreatic dysfunction include malabsorption, malnutrition, abdominal discomfort, diarrhea, and steatorrhea. In newborns, meconium ileus can occur, causing intestinal obstruction. Additionally, CF individuals are at risk of developing diabetes mellitus, with approximately 30% of adults with CF developing this condition. f) Describe the challenges in treating cystic fibrosis (CF), particularly in correcting the underlying genetic defects, and discuss the need for alternative treatment approaches. Answer: Currently, there are no approved treatments for correcting the genetic defects in CF. Management primarily focuses on symptomatic relief, prevention of complications, and improving quality of life. Therapies include airway clearance techniques, antibiotic therapy for lung infections, pancreatic enzyme replacement, and nutritional support. Emerging therapies, such as CFTR modulators, aim to correct CFTR protein function and address the underlying cause of the disease, offering potential alternatives for CF treatment. 7 UNIVERSITY OF COPENHAGEN FACULTY OF HEALTH AND MEDICAL SCIENCES Exam in Pathophysiology SMTK12011E MSc Programme in Biomedical Engineering MSc Programme in Quantitative Biology and Disease Modelling 1. Semester March 1st, 2023 (4 hours) The exam assignment consists of two pages including the front page. Exam guidelines: The exam assignment contains six main themes with sub-questions. In the assessment, the exam is evaluated in its entirety and the six themes are weighted equally. It is emphasised that the answers are clearly structured and phrased in English in a concise fashion in accordance with the pathophysiological terminology. Exam Terminology: State Give the relevant points briefly – you don’t need to make a lengthy discussion. Describe Give details of processes, properties, events and so on. (This can be seen as the 'what is it?' command verb. For this you will need to provide a series of points, which usually need to be linked, that includes (all) the main features.) Explain Give detailed reasons for an idea, principle or result, situation, attitude and so on. (This is the 'how does something work/do?' command. For this you will need to provide an explanation with reasoning. You will need to use words such as 'because' or 'therefore' to help you to provide explanations.) Permitted aids: Without aids Practicalities You are not allowed to leave the examination room during the first 30 minutes and the last 30 minutes of the exam. Electricity (power, features) are not available. Mobile phones must be turned off and handed to the invigilator 1 1. Anemia is a disease involving red blood cells a) Describe definition of Anemia and the four primary causes of Anemia b) Explain at least one situation where anemia is a result of decreased production of red blood cells c) Explain etiology and pathogenesis of Iron Deficiency Anemia d) State where dietary iron mostly come from e) Explain why pregnant women require extra iron f) State at least two clinical manifestations of anemia g) State at least one common treatment of iron deficiency 2. Neoplasm involves tissue growth a) Describe definition of neoplasm b) Describe difference between benign and malignant neoplasms c) State at least two characteristics that distinguish benign and malignant neoplasms d) Describe what an adenoma is 3. Lung cancer a) State the major cause of lung cancer b) State another commonly recognized exposure associated with lung cancer c) Describe definition and characteristics of lung cancer d) Describe characteristics of Small Cell Lung Cancers 4. Heart Failure a) State which age group that is primarily affected by heart failure b) State at least two common causes of heart failure c) Describe the classification of heart failure that includes four stages d) Explain why people with heart failure can have shortness of breath during exercise 5. Chronic kidney disease a) Describe and define chronic kidney disease (CKD) and the progression of the disease into stages b) State at least one main cause of CKD c) Describe the best measure of overall function of the kidney and how is it estimated d) Explain how the clinical manifestations of CKD occur and when they become evident 6. Obesity a) Describe definition of overweight and obesity and how it is classified and calculated b) Explain at least three potential contributors to development of obesity c) State the two types of obesity based on distribution of fat d) Describe the health risks and pathophysiological disturbances associated with obesity e) Describe how obesity is managed/treated and the treatment goals? 2 UNIVERSITY OF COPENHAGEN FACULTY OF HEALTH AND MEDICAL SCIENCES Exam in Pathophysiology SMTK12011U MSc Programme in Biomedical Engineering MSc Programme in Quantitative Biology and Disease Modelling 1. Semester February 17th, 2021 (4 hours) The exam assignment consists of three pages inclusive the front page. Exam guidelines: The exam assignment contains six main themes with sub-questions. In the assessment, the exam is evaluated in its entirety and the six themes are weighted equally. It is emphasised that the answers are clearly structured and phrased in English in a concise fashion in accordance with the pathophysiological terminology. Exam Terminology: State Give the relevant points briefly – you don’t need to make a lengthy discussion. Describe Give details of processes, properties, events and so on. (This can be seen as the 'what is it?' command verb. For this you will need to provide a series of points, which usually need to be linked, that includes (all) the main features.) Explain Give detailed reasons for an idea, principle or result, situation, attitude and so on. (This is the 'how does something work/do?' command. For this you will need to provide an explanation with reasoning. You will need to use words such as 'because' or 'therefore' to help you to provide explanations.) Permitted aids: Without aids Practicalities You are not allowed to leave the examination room during the first 30 minutes and the last 30 minutes of the exam. Electricity (power, features) are not available. Mobile phones must be turned off and handed to the invigilator Exam guidelines: The exam assignment contains six main themes with sub-questions. In the assessment, the exam is evaluated in its entirety and the six themes are weighted equally. It is emphasised that the answers are clearly structured and phrased in English in a concise fashion in accordance with the pathophysiological terminology. 1 Correction guideline: NB! Everything in (parenthesis) and non-bold is extra and not necessary for full answer of the questions. Full answer is highlighted in bold and without (parenthesis). Answers are written in direct coherence with the text in Porth´s Essentials of Pathophysiology 5th edition, Tommie Norris 1. Asthma is a chronic disorder of the airways. a) Describe at least two risk factors for asthma b) Explain the pathophysiology of asthma c) Describe changes found in the small airways leading to airway obstruction during an acute asthma attack d) Explain clinical manifestations during a prolonged asthma attack a) (The strongest risk factor for developing asthma is a) genetic predisposition for the development of an immunoglobulin E (IgE)-mediated response to (common) allergens. (IgE is the antibody involved in causing allergic reactions and inflammation). Other risk factors for (childhood) asthma include family history of asthma, allergies, (antenatal) exposure to tobacco smoke and pollution, (and multiple potentially overlapping genetic predispositions. Asthma severity is impacted by several factors including genetics, age of onset, pollution exposure, atopy, degree of exposure to triggers, environmental triggers such as tobacco smoke and dust mites, and the presence of gastroesophageal reflux disease or respiratory infections) b) (Asthma is a chronic disorder of the airways that causes episodes of) airway obstruction, bronchial hyperresponsiveness, airway inflammation, (and, in some, airway remodeling). (The common denominator underlying asthma is) an exaggerated hyperresponsiveness to a variety of stimuli. Airway inflammation manifested by the presence of inflammatory cells (particularly eosinophils, lymphocytes, and mast cells) and by damage to the bronchial epithelium contributes to the pathogenesis of the disease. T-helper (2 (T2H)) cells respond to allergens (and helminths (intestinal parasites)) by stimulating B cells to differentiate into IgE-producing plasma cells, (produce growth factors for mast cells, and recruit and activate eosinophils. In people with allergic asthma, T-cell differentiation appears to be skewed toward a proinflammatory T2H response. Although the molecular basis for this preferential differentiation is unclear, it seems likely that both genetic and environmental factors play a role.) Cytokines also have an apparent role in the chronic inflammatory response and complications of asthma. Tumor necrosis factor (TNF)-α and interleukin 4 (IL-4) and IL-5 participate in the pathogenesis of bronchial asthma through their effects on the bronchial epithelial and smooth muscle cells. Studies suggest that TNF-α, an inflammatory cytokine that is stored and released from mast cells, plays a critical role in the initiation and amplification of airway inflammation in people with asthma. TNF-α is credited with increasing the migration and activation of inflammatory cells (i.e., eosinophils and neutrophils) and contributing to all aspects of airway remodeling, including proliferation and activation of fibroblasts, increased production of extracellular matrix glycoproteins, and mucous cell hyperplasia. It has been determined that frequent viral respiratory infections predispose people with asthma to experience an exacerbation of their disease. In fact, frequent viral respiratory infections may also cause the development of asthma in some people. When these respiratory infections are frequent at an early age, there is evidence that the T2H response is exaggerated. When the CD4 T2H cytokines IL-4, IL-5, and IL-13 are released, the airways are predisposed for an allergic response, which favors the production of IgE.) c) (Asthma attacks may occur spontaneously or in response to various triggers, respiratory infections, emotional stress, or weather changes. Asthma is often worse at night, referred to as nocturnal 2 asthma. Studies of nocturnal asthma suggest that there is a circadian and sleep-related variation in hormones and respiratory function. The greatest decrease in respiratory function occurs at about 4:00 AM, at which time cortisol levels are low, melatonin levels high, and eosinophil activity increased.) (People with asthma exhibit a wide range of signs and symptoms, from episodic wheezing and feelings of chest tightness to an acute, immobilizing attack. The attacks differ from person to person, and between attacks, many people are symptom free. A mild attack may produce a feeling of chest tightness, a slight increase in respiratory rate with prolonged expiration, and mild wheezing. A cough may accompany the wheezing. More severe attacks are accompanied by use of the accessory muscles, distant breath sounds due to air trapping, and loud wheezing. As the condition progresses, fatigue develops, the skin becomes moist, and anxiety and apprehension are obvious. Sensations of shortness of breath may be severe, and often, the person is able to speak only one or two words before taking a breath. At the point at which airflow is markedly decreased, breath sounds become inaudible with diminished wheezing, and the cough becomes ineffective despite being repetitive and hacking. This point often marks the onset of respiratory failure.) During an asthmatic attack, the airways narrow because of bronchospasm, edema of the bronchial mucosa, and mucus plugging. Expiration becomes prolonged because of progressive airway obstruction. (The amount of air that can be forcibly expired in 1 second (forced expiratory volume in 1 second [FEV1.0]) and the peak expiratory flow (PEF) rate, measured in liters per second, are decreased. A fall in the PEF to levels below 50% of the predicted value during an acute asthmatic attack indicates a severe exacerbation and the need for emergency department treatment). d) During a prolonged attack, air becomes trapped behind the occluded and narrowed airways, causing hyperinflation of the lungs. (This produces an increase in the residual volume (RV) along with a decrease in the inspiratory reserve capacity (tidal volume + inspiratory reserve volume) and forced vital capacity (FVC). As a result, more energy is needed to breath (to overcome the tension already present in the lungs,) and the (accessory) muscles (e.g., sternocleidomastoid muscles) are required to maintain ventilation and gas exchange. This increased WOB further increases oxygen demands and causes dyspnea and fatigue. (Because air is trapped in the alveoli and inspiration is occurring at higher residual lung volumes, the cough becomes less effective. As the condition progresses, the effectiveness of alveolar ventilation declines, and mismatching of ventilation and perfusion occurs, causing hypoxemia and hypercapnia. Pulmonary vascular resistance may increase as a result of the hypoxemia and hyperinflation, leading to a rise in pulmonary arterial pressure and increased work demands on the right heart.) 2. Atherosclerosis is the hardening of the arteries characterized by the formation of fibrofatty lesions in the intimal lining of large- and medium-sized arteries a) Describe five risk factors for development of atherosclerosis b) Explain the development of atherosclerotic lesions as a progressive process involving four steps. c) Explain how atherosclerotic plaques (lesions) produce their effects and why atherosclerosis may have clinical consequences. d) State when (time course) clinical manifestations typically occur for a patient a) (The major risk factor for atherosclerosis is) hypercholesterolemia and elevations in LDL cholesterol levels. (Hypercholesterolemia is one of several risk factors for atherosclerosis that can be modified by dietary and lifestyle changes and medications.) Additional risk factors include increasing age, family history of heart disease, and male sex. Genetically determined alterations in lipoprotein and cholesterol metabolism (have also been identified. Males are at higher risk for development of atherosclerotic coronary vascular disease than premenopausal females. After 3 menopause, the incidence of atherosclerosis-related diseases in women increases, and the frequency of myocardial infarction in men and women tends to equalize.) Cigarette smoking, obesity and visceral fat, hypertension, and diabetes mellitus are also risk factors for atherosclerosis. (Toxins that enter the bloodstream with cigarette smoking can damage endothelial tissue. Prolonged smoking of one pack or more per day doubles damage to the endothelium. Stopping smoking reduces risk of endothelial damage significantly. The presence of either hypertension or diabetes mellitus increases the risk for atherosclerosis by twofold. When hypertension and diabetes mellitus exist together, the risk increases eightfold. In the presence of hypertension, diabetes, and hyperlipidemia, the risk increases 20-fold. Other factors associated with an) increased risk for atherosclerosis include physical inactivity, (stressful life patterns,) increased blood levels of C-reactive protein (CRP), (and serum homocysteine levels. CRP is an acute-phase reactant protein of the inflammatory process and has been noted within some atherosclerotic plaques, further implicating inflammation in plaque formation. Blood levels of CRP serve as a clinical marker of risk for atherosclerotic vascular disease). b) The development of atherosclerotic lesions is a (progressive) process involving (a) endothelial cell injury, (b) migration of inflammatory cells, (c) (SMC proliferation and) lipid deposition, and (d) (gradual) development of the atheromatous plaque (with a lipid core). A) (The vascular endothelium consists of a single layer of cells with cell-to-cell attachments that protects subendothelial layers from interacting with blood components). (Smoking, elevated LDL levels, immune mechanisms, and mechanical stress associated with hypertension share the potential for causing) endothelial injury with adhesion of monocytes and platelets. B) Early in the development of atherosclerotic lesions, endothelial cells express selective adhesion molecules that bind monocytes and other inflammatory cells that initiate the atherosclerotic lesions. After monocytes adhere to the endothelium, they migrate between the endothelial cells to localize in the intima of the vascular wall. Monocytes then transform into macrophages, which engulf lipoproteins, particularly LDL. Activated macrophages become foam cells when they release toxic oxygen species that oxidize the engulfed LDL. C) (The recruitment of monocytes and their transformation into foam cells is protective because it removes excess lipids from circulation. However, accumulation of foam cells in the vessel wall eventually leads to lesion progression. Macrophages produce growth factors that contribute to migration and proliferation of SMCs and elaboration of extracellular matrix (ECM) in the vascular wall.) Ultimately, foam cell macrophages die, depositing necrotic cellular debris and lipids within the vascular wall. D) (Atherosclerotic plaques consist of SMCs, macrophages, and other leukocytes; ECM, including collagen and elastic fibers; and intracellular and extracellular lipids. Typically, the superficial fibrous cap is composed of SMCs and dense ECM. Beneath and to the side of the fibrous cap is the “shoulder” consisting of macrophages, SMCs, and lymphocytes. Below the cap is a central core of lipid-laden foam cells and fatty debris.) Rupture, (ulceration, or erosion of a vulnerable) fibrous cap may lead to hemorrhage into the plaque or thrombotic occlusion of the vessel (lumen). c) (Clinical manifestations of atherosclerosis typically do not become evident for 20 years or longer. Clinical manifestations depend on the vessels involved and the extent of vessel obstruction.) Atherosclerotic plaques (lesions) produce their effects through narrowing of the vessel and production of ischemia, (sudden) vessel obstruction because of plaque hemorrhage or rupture, thrombosis and formation of emboli resulting from damage to the vessel endothelium, or aneurysm formation because of weakening of the vessel wall. (In larger vessels, important complications are thrombus formation and weakening of the vessel wall. In medium-sized arteries, ischemia and infarction because of vessel occlusion are more common. Although atherosclerosis can affect any organ or tissue, the arteries supplying the heart, brain, kidneys, lower extremities, and small intestine are most frequently involved.) 4 d) Clinical manifestations of atherosclerosis typically do not become evident for (20) years (or longer). 3. Diabetes Mellitus refers to a group of common metabolic disorders characterized by hyperglycemia resulting from imbalances between insulin secretion and cellular responsiveness to insulin. Type 2 DM accounts for the majority of cases of diabetes. a) Describe at least two risk factors for type 2 diabetes b) Explain the three metabolic abnormalities associated with type 2 diabetes and how type 2 diabetes develops. c) Describe how weight loss would impact insulin resistance and blood glucose level in type 2 diabetes d) How/when would the presence of type 2 diabetes often be detected for the first time? e) Describe the difference between type 1 and type 2 diabetes with regards to insulin deficiency a) (Many people with type 2 diabetes are adults and) overweight; (however, recent trends indicate that type 2 diabetes has become a more common occurrence in adolescents and children with) obesity, (NB! in book: a condition termed MODY. not correct) (Although autoimmune destruction of the beta cells does not occur, people with type 2 diabetes eventually may require insulin. Therefore, the previous terms related to type 2 diabetes, such as adult-onset diabetes and non–insulin-dependent diabetes, can generate confusion and are thus obsolete.) Type 2 diabetes has a strong genetic component. (A number of genetic and acquired pathogenic factors have been implicated in the progressive impairment of beta-cell function in people with prediabetes and type 2 diabetes. (Although the insulin resistance seen in people with) type 2 diabetes (can be caused by a number of factors, it is) strongly associated with obesity and physical inactivity b) The metabolic abnormalities associated with type 2 diabetes are 1. Insulin resistance 2. Deranged secretion of insulin by the pancreatic beta cells 3. Increased glucose production by the liver In contrast to type 1 diabetes, where absolute insulin deficiency is present, people with type 2 diabetes can have high, normal, or low insulin levels. Type 2 diabetes (T2D) is a heterogeneous condition that describes the) presence of hyperglycemia in association with relative insulin deficiency. Insulin resistance is the decreased ability of insulin to act effectively on target tissues, especially muscle, liver, and fat. It is the predominate characteristic of type 2 diabetes and results from a combination of factors such as genetic susceptibility and obesity. Insulin resistance initially stimulates an increase in insulin secretion, often to a level of modest hyperinsulinemia, as the beta cells attempt to maintain a normal blood glucose level. In time, the increased demand for insulin secretion leads to beta-cell exhaustion (and failure). This results in elevated (postprandial) blood glucose levels and an eventual increase in glucose production by the liver. (Because people with type 2 DM do not have an absolute insulin deficiency, they are less prone to ketoacidosis compared to people with type 1 diabetes.) In type 2 DM, the basal hepatic insulin resistance is manifested by a hepatic overproduction of glucose despite (a fasting) hyperinsulinemia, (with the rate of glucose production being the primary determinant of the elevated FPG in people with type 2 diabetes. Although the insulin resistance seen in people with type 2 diabetes can be caused by a number of factors, it is strongly associated with obesity and physical inactivity. Specific causes of beta-cell dysfunction in type 2 DM are unclear; however, it appears that in both type 1 DM and type 2 DM, there may be an increased apoptosis of pancreatic beta cells in response to the stress of hyperglycemia. A major factor in people with metabolic syndrome that leads to type 2 diabetes is obesity. (People with obesity have) increased resistance to the action of insulin and impaired suppression of glucose production by the liver, resulting in both hyperglycemia and hyperinsulinemia. (The type of obesity is an important consideration in the development of type 2 5 diabetes. People with upper body (or central) obesity are at greater risk for developing type 2 diabetes and metabolic disturbances than people with lower body (or peripheral) obesity. Waist circumference and waist–hip ratio, which are both surrogate measures of central obesity, have been shown to correlate well with insulin resistance.) c) A loss of 5% to 10% of body weight has the potential to improve (ie. decrease) insulin resistance and lower blood glucose levels. (In type 2 DM, adipose tissues are among the tissues that demonstrate inadequate response to insulin, contributing to the pancreatic response of hyperinsulinemia to attempt to reduce the hyperglycemia. Overexpression of insulin receptors also may occur. Normally, cellular response to insulin binding stimulates two intracellular pathways—the phosphoinositide 3-kinase (P13K) pathway and the mitogen-activated protein (MAP) pathway. In type 2 DM, the P13K pathway does not maintain its function; this P13K functional decline contributes to decreased nitric oxide production from endothelial cells and to a decrease in the translocation of the GLUT-4 proteins that facilitate glucose entry into cells. Nitric oxide is a powerful endothelial- derived relaxing factor, which promotes vasodilation. Therefore, the decline in nitric oxide production contributes to vasoconstriction and increased vascular resistance. In type 2 DM, the MAP pathway that is also stimulated by the binding of insulin to cellular insulin receptors continues to function. The actions of stimulation of the MAP pathway include stimulation of the vasoconstriction molecule endothelin-1, along with increased expression of adhesion molecules and smooth muscle stimulation, all of which further contribute to the increased risk of development of atherosclerosis in type 2 DM.) Insulin also normally signals the inhibition of lipolysis; however, the insulin resistance in type 2 DM causes increased lipolysis with increased release of FFAs. The liver transforms these FFAs into triglycerides and very-low-density lipoproteins. The net results of the combined systemic inflammation, increased oxidative stress, endothelial dysfunction, and increased blood lipids all contribute to the constellation of metabolic alterations that are present in the metabolic syndrome— including dyslipidemia, hypertension, vascular pathology, and abnormal coagulation.) d) Type 2 DM usually develops more insidiously, often existing for years without detection until diagnosed during a (routine medical) examination (or care for other conditions). e) In contrast to type 1 diabetes, where absolute insulin deficiency is present, people with type 2 diabetes can have high, normal, or low insulin levels. Type 2 diabetes (T2D) is a heterogeneous condition that describes the presence of hyperglycemia in association with relative insulin deficiency. 4. Glomerulonephritis is an inflammatory process that involves glomerular structures in the kidney. a) Describe the triggering event or origin for most primary cases and many secondary cases of Glomerulonephritis b) Describe the two types of immune mechanisms that have been implicated in the development of glomerular disease c) Describe the cellular changes that occur with glomerular disease a) (It is the second leading cause of kidney failure worldwide and ranks third, after diabetes and hypertension, as a cause of chronic kidney disease in the United States. There are many causes of glomerular disease. The disease may occur as a primary condition in which the glomerular abnormality is the only disease present, or it may occur as a secondary condition in which the glomerular abnormality results from another disease, such as diabetes mellitus or SLE.) The causative agents or triggering events that produce glomerular injury include immunologic, nonimmunologic, and hereditary mechanisms. Most cases of primary and many cases of secondary glomerular disease probably have an immune origin. Although many glomerular 6 diseases are driven by immunologic events, (a variety of nonimmunologic metabolic (e.g., diabetes), hemodynamic (e.g., hypertension), and toxic (e.g., drugs, chemicals) stresses can induce glomerular injury, either alone or along with immunologic mechanisms. Hereditary glomerular diseases such as Alport syndrome, although relatively rare, are an important category of glomerular disease because of their association with progressive loss of renal function and transmission to future generations.) (Antigens responsible for development of the immune response may be of endogenous origin, such as autoantibodies to deoxyribonucleic acid in SLE, or they may be of exogenous origin, such as streptococcal membrane antigens in poststreptococcal glomerulonephritis. Frequently, the source of the antigen is unknown.) b) Two types of immune mechanisms have been implicated in the development of glomerular disease: a) Injury resulting from antibodies reacting with (fixed) glomerular antigens (or antigens planted within the glomerulus) b) Injury resulting from circulating antigen–antibody complexes that become trapped in the glomerular membrane c) The cellular changes that occur with glomerular disease include increases in glomerular or inflammatory cell number (proliferative or hypercellular), (basement) membrane thickening (membranous), and changes in noncellular glomerular components (sclerosis and fibrosis). (An increase in cell numbers is characterized by one or more of the following: proliferation of endothelial and mesangial cells, leukocyte infiltration (neutrophils, monocytes, and, in some cases, lymphocytes), and formation of crescents (half-moon–shaped collections of proliferating epithelial cells and infiltrating leukocytes) in the Bowman space. Basement membrane thickening involves deposition of dense, noncellular material on the endothelial and epithelial sides of the basement membrane or within the membrane itself. Sclerosis refers to an increased amount of extracellular material in the mesangial, subendothelial, or subepithelial tissue of the glomerulus. Fibrosis refers to the deposition of collagen fibers. Glomerular changes can be diffuse, involving all glomeruli and all parts of the glomeruli; focal, in which only some glomeruli are affected and others are essentially normal; segmental, involving only a certain segment of each glomerulus; or mesangial, affecting only mesangial cells.) 5. Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormone a) State at least two etiologies (causes) of Thyrotoxicosis b) Explain the cause of Graves disease c) Describe the clinical manifestations in relation to the pathophysiology of Graves disease, including effects on metabolism, nervous system and eyes d) Describe at least one method of how Thyrotoxicosis could be treated a) (In most instances,) thyrotoxicosis is due to hyperactivity of the thyroid gland, or hyperthyroidism. (The most common cause of) hyperthyroidism is Graves disease, (which is accompanied by ophthalmopathy, dermopathy, and diffuses goiter. Other causes of hyperthyroidism are multinodular) goiter, adenoma of the thyroid, and thyroiditis. Iodine-containing agents (can induce hyperthyroidism as well as hypothyroidism.) b) (Graves disease is a state of hyperthyroidism, goiter, and ophthalmopathy. It affects approximately 0.5% to 1% of the population under 40 years of age). Graves disease is an autoimmune disorder characterized by abnormal stimulation of the thyroid gland by thyroid-stimulating antibodies (TSH receptor antibodies) that act through (/activate) (the normal) TSH receptors. (It may be 7 associated with other autoimmune disorders such as myasthenia gravis. The disease is associated with a major histocompatibility complex class 1 chain–related gene A (MICA), with genotypes MICA A5 correlated with Graves disease and MICA A6/A9 being preventive for Graves disease.) c) (Many of the manifestations of hyperthyroidism are related to the) increase in oxygen consumption and use of metabolic fuels associated with the hypermetabolic state, as well as to the increase in sympathetic nervous system activity that occurs. Hyperthyroidism resembles those of excessive sympathetic nervous system activity, suggesting that thyroid hormone may heighten the sensitivity of the body to the catecholamines or that it may act as a pseudocatecholamine. With the hypermetabolic state, there are frequent complaints of nervousness, irritability, and fatigability Weight loss is common despite a large appetite. Other manifestations include tachycardia, palpitations, shortness of breath, excessive sweating, muscle cramps, and heat intolerance. The person appears restless and has a fine muscle tremor. (Even in people without exophthalmos, there is an abnormal retraction of the eyelids and infrequent blinking such that they appear to be staring. The hair and skin are usually thin and have a silky appearance. Atrial fibrillation occurs in 10% to 15% of adults with hyperthyroidism.) The ophthalmopathy, which occurs in up to one-third of people with Graves disease, is thought to result from accumulation of T lymphocytes sensitized to antigens along thyroid follicular cells and orbital fibroblasts that secrete cytokines. (The ophthalmopathy of Graves disease can cause severe eye problems, including tethering of the extraocular muscles resulting in diplopia; involvement of the optic nerve, with some visual loss; and corneal ulceration because the lids do not close over the protruding eyeball (because of the exophthalmos). (The ophthalmopathy usually tends to stabilize after treatment of the hyperthyroidism. However, ophthalmopathy can worsen acutely after radioiodine treatment. Some physicians prescribe glucocorticoids for several weeks surrounding the radioiodine treatment if the person had signs of ophthalmopathy. Ophthalmopathy can also be aggravated by smoking, which should be strongly discouraged.) d) The treatment of hyperthyroidism is directed toward reducing the level of thyroid hormone. This can be accomplished with eradication of the thyroid gland with radioactive iodine, through surgical removal of part or all of the gland, or the use of drugs that decrease thyroid function and thereby the effect of thyroid hormone on the peripheral tissues. Antithyroid drugs prevent the thyroid gland from converting iodine to its organic form or block the conversion of T4 to T3 in the tissues 6. Neurocognitive Disorders due to Alzheimer Disease (AD) account for 60% to 80% of all cases of Neurocognitive Disorders a) State two risk factors for Alzheimer Disease b) Explain the pathophysiology of Alzheimer Disease, including description of the major microscopic features of the disease c) State at least 3 clinical manifestations of the disease d) State the course/progression of the disease a) (Alzheimer disease (AD) occur in middle or late life. The disorder affects more than 5.2 million in the United States and may be the sixth leading cause of death in the United States.) The risk of development of AD increases with age. (It is estimated that almost 50% of people 85 years of age and older live with Neurocognitive Disorders (NCD) because of AD, with two thirds being women. Familial AD is caused by) mutations (in amyloid precursor protein (APP), presenilin 1 (PS -1), PS-2, and Apolipoprotein E-e4). Inherited early-onset AD symptoms appear before the age of 8 65 years and represent 1% to 2% of AD cases. Studies suggest) genetic factors (contributing to AD are like those in Down syndrome.) b) AD is characterized by cortical atrophy and loss of neurons, particularly in the parietal and temporal lobes. Pathogenic aspects of AD are not completely understood but are thought to be a combination of neurotransmission disruption, oxidative stress, neuroinflammation, (and other factors). (Neurotransmitters with a significant role in AD pathogenesis include ACh, GABA, NMDA, and L-arginine. Arginine metabolism is thought to be altered in the hippocampus. Other neurotransmitters may play a role in oxidative stress, which is known to be involved in AD. Studies suggest decreased cholinergic transmission in the brain is associated with cognitive impairments. Additional studies have shown interaction of amyloid beta (Aβ) with cholinergic receptors. Disrupted signaling in the cholinergic and glutamatergic systems at the cortex causes hippocampus, amygdala, frontal cortex, and parietal defects. The classic neuropathologic findings in AD are neurofibrillary tangles and amyloid (neuritic) plaques. The major microscopic features of AD are related to widespread cellular degeneration and diffuse synaptic and neuronal loss, and neurofibrillary tangles. The neuritic plaques are dense aggregates of Aβ. Current genetic, pathologic, and biochemical and cellular studies support an imbalance between the production and removal of Aβ, causing accumulation as a key factor in the pathogenesis of AD. (Familial AD is caused by mutations in amyloid precursor protein (APP), presenilin 1 (PS-1), PS-2, and Apolipoprotein E-e4). (These mutations lead to changes in Aβ. The dominant component of the amyloid core is Aβ, a peptide derived from the proteolysis of a larger membrane-spanning APP. There is increasing evidence that Aβ is the critical molecule in the pathogenesis of AD. The neurofibrillary tangles, found in the cytoplasm of abnormal neurons, consist of fibrous proteins wound around each other in a helical fashion. These tangles are resistant to chemical or enzymatic breakdown and persist in brain tissue long after the neuron in which they arose has died and disappeared. A major component of the paired helical filaments is an abnormally hyperphosphorylated form of the protein tau, an axonal microtubule-associated protein-enhancing microtubule assembly.) c) The hallmark symptoms are loss of short-term memory, difficulty with language, and changes in behavior. Depression, agitation, and sleep disorders are common in this disorder. d) AD follow an insidious and progressive course, with an average survival of 8 to 10 years after diagnosis. Various stages of the disease have been recognized, ranging from four to seven stages identified by the Alzheimer’s Association. All are characterized by progressive degenerative changes. 9 Correction guideline Pathophysiology exam 2022, January 7 NB! Everything in non-bold is extra and not necessary for full answer of the questions. Answers are written in direct coherence with the text in Porth´s Essentials of Pathophysiology 5th edition, Tommie Norris Exam guidelines: The exam assignment contains six main themes with sub-questions. In the assessment, the exam is evaluated in its entirety and the six themes are weighted equally. It is emphasised that the answers are clearly structured and phrased in English in a concise fashion in accordance with the pathophysiological terminology. Exam Terminology: Describe Give details of processes, properties, events and so on. (This can be seen as the 'what is it?' command verb. For this you will need to provide a series of points, which usually need to be linked, that includes (all) the main features.) Explain Give detailed reasons for an idea, principle or result, situation, attitude and so on. (This is the 'how does something work/do?' command. For this you will need to provide an explanation with reasoning. You will need to use words such as 'because' or 'therefore' to help you to provide explanations.) State Give the relevant points briefly – you don’t need to make a lengthy discussion. % correct Grade 0-20 -3 21-50 0 51-58 2 59-66 4 67-78 7 79-84 10 85-100 12 1 Correction guideline 1. Parkinson Disease (PD) is a disorder of basal ganglia function in the brain. a) Describe the primary brain abnormality in PD and the cellular characteristics. b) Describe the two factors that interact and which are believed to cause PD. c) Describe and potentially explain at least 2 clinical manifestations in relation to the pathophysiology of PD d) State whether PD can be cured Answer: a) The primary brain abnormality in PD is the degeneration of the pigmented nigrostriatal dopamine neurons. Some residual nerve cells are atrophic, and few contain Lewy bodies, which are spherical, eosinophilic cytoplasmic inclusions. Lewy bodies are produced inside degenerated neurons in many people with PD or parkinsonism. b) It is believed that PD is caused by an interaction of environmental and genetic factors. Several pathologic processes (e.g., oxidative stress and mitochondrial disorders) that might lead to degeneration have been identified. Some environmental factors have also been identified, including contact with specific agricultural pesticides and rural living with private wells, especially if the area has been sprayed with herbicides and pesticides. Smoking cigarettes and drinking coffee are linked to a lower risk of PD. Multiple genes illustrate there are different types of PD: the recessive form causes a milder set of symptoms compared to the dominant form, which resembles the more complex and severe form of PD with Lewy bodies. Alpha-synuclein is one of the major components of the Lewy bodies. Mutations in a gene coding the protein parkin is associated with an autosomal recessive, early-onset form of PD. The parkin protein acts as an enzyme in the ubiquitin-conjugating system that targets defective and abnormally folded proteins for destruction. Loss of normal parkin function is postulated to cause abnormal proteins to aggregate and cause neurodegenerative changes. Several new diagnostic tools are available regarding genomic, proteomic, transcriptomic, lipidomic, and metabolomic molecules and signaling pathways. There are also syndromes that can cause parkinsonism but not idiopathic PD such as 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine–induced parkinsonism, postinfectious parkinsonism, striatonigral degeneration, and progressive supranuclear palsy where the common finding is loss of pigmented dopaminergic neurons in the substantia nigra. c) Tremor is the most visible manifestation of the disorder and affects mainly the hands and feet; head, neck, face, lips, and tongue; or jaw. It is characterized by rhythmic, alternating flexion and contraction movements (4 to 6 beats/minute) that resemble rolling a pill between the thumb and forefinger. The tremor is initially unilateral, occurs when the limb is supported and at rest, and disappears with movement and sleep. The tremor eventually progresses bilaterally. Rigidity is the resistance to movement of flexors and extensors throughout the full range of motion. It is most evident during passive joint movement and involves jerky, ratchet-like movements that require considerable energy to perform. Flexion contractions may develop due to rigidity. As with tremor, rigidity usually begins unilaterally but progresses bilaterally. Bradykinesia is the slowness in initiating and performing movements and difficulty with sudden, unexpected stopping of voluntary movements. Unconscious associative movements occur in disconnected steps rather than in a smooth, coordinated manner. People with bradykinesia may freeze in place while walking and feel as if their feet are glued to the floor, especially when moving through a doorway or preparing to turn. When walking, they lean forward and take small, shuffling steps without swinging their arms, and have difficulty changing their stride. People with advanced-stage parkinsonism are at risk of falls, fluctuations in motor function, neuropsychiatric disorders, and sleep disorders. Loss of postural reflexes predisposes to falling, often backward. Emotional and voluntary facial movements become limited and slow with progression, and facial expression becomes stiff and masklike. There is loss of 2 Correction guideline the blinking reflex and a failure to express emotion. The tongue, palate, and throat muscles become rigid, and the person may drool because of difficulty in moving and swallowing saliva. Speech becomes slow and monotonous, without modulation, and poorly articulated. Because the basal ganglia also influence the autonomic nervous system, people with PD often have excessive and uncontrolled sweating, sebaceous gland secretion, and salivation. Autonomic symptoms, such as lacrimation, dysphagia, orthostatic hypotension, thermal regulation, constipation, impotence, and urinary incontinence, may be present, especially late in the disease. Cognitive dysfunction may also be an important feature in PD. Severe dementia is seen in about 20% of people with PD. Deficits in visuospatial discrimination, frontal lobe executive function, and memory retrieval are typical of the cognitive dysfunction seen in people with PD. Deficits in executive functioning may be among the earliest signs of cognitive decline, as evidenced by difficulty in planning, starting, and carrying out tasks. Dementia is usually a late manifestation of the disease, and the rate of decline is slow compared with Alzheimer disease. d) Treatment only manages the symptoms; there is no treatment that will fully prevent disease progression. 2. Cystic fibrosis (CF) is a chronic respiratory disease a) State the overall age group first affected by CF b) Explain the causality, genetics, cellular mechanisms and pathophysiology, including lungs and pancreas, of CF c) Describe at least 3 clinical manifestations in relation to the pathophysiology of CF d) State whether CF can be cured Answer: a) CF, which is the major cause of severe chronic respiratory disease in children, is an autosomal recessive disorder involving the exocrine glands in the epithelial lining of the respiratory, gastrointestinal, and reproductive tracts. CF affects about 30,000 children and adults in the United States, and more than 10 million persons are asymptomatic carriers of the defective gene. b) The defective gene, cystic fibrosis transmembrane regulator (CFTR), and its protein product cause excessive thick mucus that obstructs lungs and the pancreas. In addition to chronic respiratory disease, CF is manifested by pancreatic exocrine deficiency and elevation of sodium chloride in the sweat. Nasal polyps, sinus infections, pancreatitis, and cholelithiasis also are seen with CF. Most boys with CF have congenital bilateral absence of the vas deferens with azoospermia. CF is caused by mutations in a single gene on the long arm of chromosome 7 that encodes for the CFTR, which functions as a chloride (Cl−) channel in epithelial cell membranes. There are greater than 1000 possible CFTR changes that can occur. However, the most common CFTR gene mutation is called the delta F508, in which the deletion of the amino acid phenylalanine at the 508 position results in a severe phenotype. Due to the deletion of this amino acid, chloride channels are misfolded and are not inserted into the cell membrane. Others have a partial loss or mutation of the CFTR gene, so their phenotype is less severe and often goes unnoticed until they have an acute injury such as pneumonia and may need intubation and mechanical ventilation. The impact on impaired Cl− transport due to the CFTR gene mutation ultimately affects the reabsorption of NaCl, which results in high concentrations of NaCl in the sweat of people with CF. The impaired transport of Cl− ultimately leads to a series of secondary events, including increased absorption of Na+ and water from the airways into the blood. This lowers the water content of the mucociliary blanket coating the respiratory epithelium, causing it to become more viscid. The resulting dehydration of the mucous layer leads to defective mucociliary function and accumulation of viscid secretions that obstruct the airways and predispose to recurrent pulmonary infections. Similar transport abnormalities and pathophysiologic events take place in the pancreatic and biliary ducts and in the vas deferens in boys. 3 Correction guideline c) Respiratory manifestations of CF are caused by an accumulation of viscid mucus in the bronchi, impaired mucociliary clearance, and lung infections. Chronic bronchiolitis and bronchitis are the initial lung manifestations. However, after months and years, structural changes in the bronchial wall lead to bronchiectasis. In addition to airway obstruction, the basic genetic defect that occurs with CF predisposes to chronic infection with a surprisingly limited number of organisms, the most common being Pseudomonas aeruginosa. Pseudomonas aeruginosa, in particular, has a propensity to undergo pathogenesis. Early colonization can cause recurring pulmonary infections. Pulmonary inflammation is another cause of decline in respiratory function in people with CF and may precede the onset of chronic infection. Pancreatic function is often abnormal to some degree with people with CF. Malabsorption and malnutrition may often be present along with symptoms of abdominal discomfort and diarrhea. Steatorrhea, diarrhea, and abdominal pain and discomfort are common associated symptoms. In the newborn, meconium ileus may cause intestinal obstruction, a fatal condition if left untreated. The degree of pancreatic involvement is highly variable. In some children, the defect is relatively mild, and in others, the involvement is severe and impairs intestinal absorption. In addition, people with CF should be tested for diabetes mellitus because 30% of adults develop diabetes. d) No approved treatments for correcting the genetic defects in CF 3. Hypothyroidism can occur as a congenital or an acquired defect with low thyroid hormone levels a) Describe when in life (or how) the two types develop b) Describe the three causes/defects that can lead to congenital hypothyroidism development c) Explain the pathophysiology of congenital hypothyroidism and the two most common clinical manifestations d) Describe how congenital hypothyroidism can be treated and its effects on the most serious clinical manifestation. e) Describe at least two clinical manifestations of acquired hypothyroidism in relation to pathophysiology Answer: a. Congenital hypothyroidism develops prenatally and is present at birth. Acquired hypothyroidism develops because of primary disease of the thyroid gland or secondary to disorders of hypothalamic or pituitary origin. b. Congenital hypothyroidism is a common cause of preventable intellectual disability. Hypothyroidism in the infant may result from a congenital lack of the thyroid gland or from abnormal biosynthesis of thyroid hormone or deficient TSH (Thyroid stimulation hormone) secretion. With congenital lack of the thyroid gland, the infant usually appears normal and functions normally at birth because hormones have been supplied in utero by the mother. c. Thyroid hormone is essential for normal growth and brain development, almost half of which occurs during the first 6 months of life. If untreated, congenital hypothyroidism causes intellectual disability and impairs physical growth. The manifestations of untreated congenital hypothyroidism are referred to as cretinism. However, the term does not apply to the normally developing infant in whom replacement thyroid hormone therapy was instituted shortly after birth. Many countries throughout the world now routinely perform neonatal screening to detect congenital hypothyroidism during early infancy. Premature or sick newborn infants need to be screened with a comprehensive serum thyroid profile to prevent missing primary hypothyroidism in these infants. Transient congenital hypothyroidism (characterized by high TSH levels with low or normal thyroid hormone 4 Correction guideline levels) has been recognized more frequently since the introduction of neonatal screening. The fetal and infant thyroid gland is sensitive to iodine excess. Iodine can cross the placenta, be excreted in breast milk, and is also readily absorbed by infant skin. Transient hypothyroidism may be caused by maternal or infant exposure to substances such as povidone–iodine used as a disinfectant (i.e., vaginal douche or skin disinfectant). Antithyroid drugs such as propylthiouracil and methimazole can also cross the placenta and block fetal thyroid function. d. Congenital hypothyroidism is treated by thyroid hormone replacement. Evidence indicates that it is important to normalize T4 levels as rapidly as possible because a delay is accompanied by poorer psychomotor and mental development. When early and adequate thyroid hormone replacement treatment is implemented for congenital hypothyroidism, the risk of intellectual disability is very low. e. Hypothyroidism may affect almost all body functions. The manifestations of the disorder are related largely to two factors: the hypometabolic state resulting from thyroid hormone deficiency and myxedematous involvement of body tissues. The hypometabolic state associated with hypothyroidism is characterized by a gradual onset of weakness and fatigue, a tendency to gain weight despite a loss of appetite, and cold intolerance. As the condition progresses, the skin becomes dry and rough and the hair becomes coarse and brittle. The face becomes puffy with edematous eyelids, and there is thinning of the outer third of the eyebrows. Gastrointestinal motility is decreased, producing constipation, flatulence, and abdominal distention. Delayed relaxation of deep tendon reflexes and bradycardia are sometimes noted. CNS involvement is manifested in mental dullness, lethargy, and impaired memory. 4. The most severe clinical consequence of liver disease is liver failure. a. State two causes of liver failure b. Explain at least three clinical manifestations in relation to the pathophysiology of liver failure c. Describe treatment goal of alcoholic cirrhosis d. State the most (only) effective treatment in liver failure Answer: a) Liver failure may result from sudden and massive liver destruction, as in fulminant hepatitis, or be the result of progressive damage to the liver, as occurs in alcoholic cirrhosis. Whatever the cause, 80% to 90% of hepatic functional capacity must be lost before liver failure occurs. In many cases, the progressive decompensating effects of the disease are hastened by concurrent conditions such as gastrointestinal bleeding, systemic infection, electrolyte disturbances, or superimposed diseases such as heart failure. b) The manifestations of liver failure reflect the various synthesis, storage, metabolic, and elimination functions of the liver. Hematologic Disorders: Liver failure can cause anemia, thrombocytopenia, coagulation defects, and leukopenia. Anemia may be caused by blood loss, excessive red blood cell destruction, and impaired formation of red blood cells. A folic acid deficiency may lead to severe megaloblastic anemia. Changes in the lipid composition of the red blood cell membrane increase hemolysis. Because factors II, VII, IX, and X and proteins C and S are synthesized by the liver, their decline in liver disease contributes to bleeding disorders. Malabsorption of the fat-soluble vitamin K contributes further to the impaired synthesis of these

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