Non-Communicable Diseases: Atherosclerosis PDF

2 PARTS: ORAL EXAM ON 7 JANUARY (RUSCICA) AND ANOTHER ON 27, IT CAN REPEAT. 2-3 QUESTIONS Communicable diseases are illnesses that are caused by infectious agents (like bacteria, viruses, fungi, or parasites) and can be transmitted from one person, animal, or environment to another. These diseases...

2 PARTS: ORAL EXAM ON 7 JANUARY (RUSCICA) AND ANOTHER ON 27, IT CAN REPEAT. 2-3 QUESTIONS Communicable diseases are illnesses that are caused by infectious agents (like bacteria, viruses, fungi, or parasites) and can be transmitted from one person, animal, or environment to another. These diseases spread through direct contact, contaminated surfaces, bodily fluids, or even air. Examples include: ✓ Influenza (flu) ✓ Tuberculosis ✓ HIV/AIDS ✓ malaria ✓ COVID-19 Non-communicable diseases (NCDs), on the other hand, are not caused by infectious agents and cannot be transmitted from person to person. These diseases often result from genetic, lifestyle, or environmental factors and tend to develop over time. Common examples include (the 4 main type): Heart disease, Heart and blood vessel disease (also called heart disease) includes numerous problems, many of which are related to a process called atherosclerosis Cancer Diabetes Chronic respiratory diseases (like asthma) ATHEROSCLEROSIS Atherosclerosis is a chronic vascular disease that affects the blood vessels. It starts in the inner layer of larger arteries and is caused by the build-up of fatty deposits, called plaques. These fibroinflammatory lipid plaques (atheromas), grow in size to protrude into the vascular lumen making the arteries narrower. This buildup narrows the arteries, making it harder for blood to flow through. If a blood clot forms on the plaque, it can completely block the blood flow, which can lead to a heart attack or stroke. Normally, blood vessels carry oxygen-rich blood to the heart muscles, allowing them to work properly. But in atherosclerosis, when plaques form in the coronary arteries, blood flow to the heart is reduced. As a result, the heart muscle doesn't get enough oxygen. If the blockage is severe, the heart muscle cells die, causing a heart attack, also known as myocardial infarction. 1. Plaque formation: Fatty deposits, called plaque, begin to form on the walls of the arteries. This process is often triggered by factors like high cholesterol, high blood pressure, smoking, or an unhealthy diet. 2. Narrowing of arteries: As plaque accumulates, the arteries narrow, reducing the flow of oxygen-rich blood to organs and tissues. 3. Hardening of arteries: Atherosclerosis causes the arteries to become stiff and less flexible. This makes it harder for the arteries to expand and contract properly, which affects the flow of blood. An electrocardiogram (ECG or EKG) is a test that measures the electrical activity of the heart and is often used in stroke and heart disease evaluations. An ECG can detect changes in the heart's electrical activity, indicating that parts of the heart are not receiving enough oxygen. it helps identify heart problems that could be caused by or related to plaque buildup in the arteries. If an artery is completely blocked by plaque, the ECG may show significantly reduced or absent blood flow to the affected area of the heart. This can confirm the presence of ischemia (lack of oxygen) or heart muscle damage. Removing or treating a blockage in the arteries, typically caused by atherosclerosis (plaque buildup), is crucial to restore normal blood flow and prevent complications such as heart attack or stroke. The treatment options fall into two main categories: lifestyle changes and medications or medical procedures like angioplasty or surgery. →While the blockage can be removed or treated, the fatty deposits (plaque) that caused the buildup may remain in the arteries, and continuous monitoring and lifestyle changes are important to prevent further complications like heart attacks or strokes. Medical Procedures and Surgeries to treat conditions such as coronary artery disease, where plaque buildup restricts blood flow to the heart: Angioplasty: A minimally invasive procedure in where a catheter with a balloon at its tip is inserted into the blocked artery. The balloon is inflated (gonfiato) at the blockage site to widen the artery, pushing the plaque against the artery walls and widening the artery to restore blood flow. Stenting: Often performed along with angioplasty, a small stent is placed in the artery to keep it open. The stent remains in the artery permanently to prevent future blockages. Coronary Artery Bypass Graft (CABG): is used for more severe blockages, especially when multiple arteries are blocked. A surgeon takes a healthy blood vessel from another part of the body, such as the leg, and grafts (innesta) it around the blocked artery to create a new path for blood to flow to the heart. This bypass restores proper circulation to the heart muscle. What is cholesterol? Cholesterol is a type of fat (lipid), it was Discovered in 1815 by Michel Eugène Chevreul who named the substance “cholesterin”. In the Early 1900s: Scientists began connecting cholesterol to cardiovascular diseases. One of the most important experiments was performed in 1913 by Russian pathologist Nikolai Anichkov: he fed rabbits a high-cholesterol diet. The rabbits developed fatty deposits in their arteries, resembling atherosclerosis, showing the relationship between cholesterol and arterial disease. → To confirm the presence of cholesterol, Anichkov used a method called Sudan staining: Sudan is lipophilic dye, therefore is insoluble in water but dissolves in fat, that color fats and oils red, making it easier to detect fat in tissue samples. In Anichkov’s experiment, he applied the Sudan stain to sections of the rabbit's arteries, and under a microscope, the lipid deposits in the artery walls turned red. This confirmed that cholesterol and fats were building up in the arteries, which could lead to conditions like atherosclerosis. The Sudan staining technique is used to identify lipids (fats) in tissue sections, making it a crucial tool for visualizing cholesterol deposits in arteries. STEP OF DAMAGE: 1. Endothelial dysfunction/damage,  Atherosclerosis begins with endothelial dysfunction. In healthy state, the Endothelial cells that line the inner surface of blood vessels are tightly joined together. This helps maintain a selective barrier that regulates the movement of substances (like nutrients and waste) between the blood and surrounding tissues, while also helping to control blood flow. However, when the endothelium is exposed to risk factors like high cholesterol, high blood pressure (hypertension), smoking, and high blood sugar (hyperglycemia), it can become dysfunctional. These factors damage the endothelial cells, causing them to lose their normal barrier function. As a result, the permeability of the arterial wall increases, allowing harmful substances, such as low-density lipoproteins (LDL)—often referred to as "bad cholesterol"— to penetrate into the inner layer of the artery, called the tunica intima. 2. LDL Cholesterol Infiltration and Oxidation: Inside the artery wall, LDL becomes oxidized (oxLDL), a process that triggers a strong inflammatory response, The oxidized LDL accumulated activates endothelial cells causing the endothelial cells to express adhesion molecules *= VCAM-1 – ICAM1= which attract white blood cells - monocytes (type of leukocyte) to the site of injury. → Normally monocyte move freely through the blood vessels and don’t attach to endothelial cells but when endothelial cells are exposed to damage (like that caused by oxidized LDL), they will express adhesion molecules that can capture nearby white blood cells, Once attached, Guided by chemical signals called chemokines, monocytes migrate through the damaged endothelial and enter into the subendothelial space.= monocyte migration is a key step in the development of atherosclerosis. 3. Inflammatory Response: adhesion of monocytes and its transimigration is allowed by chemokines and chemoattractant proteins which guide the monocytes toward the site of infiammation. The body perceives the oxidized LDL as harmful, leading to an immune response. 4. Leukocyte differentiation: monocytes in the tunica intima differentiate into macrophages a type of immune cell specialized in engulfing and digesting cellular debris, pathogens, and lipids. They produce reactive oxygen species (ROS) which oxidize LDL particles, converting them into oxidized LDL (oxLDL), a highly inflammatory form of LDL. OxLDL plays a central role in promoting atherosclerotic plaque formation.These macrophages try to engulf the oxidized LDL particles but become overloaded, turning into foam cells (fat-laden cells that form part of the plaque). The foam cells secrete inflammatory cytokines, to attract more macrophages and other immune cells to the site, amplifying the inflammatory response. Foam cells ultimately die releasing its lipid content- including cholesterol - which contributes to the formation of a “necrotic” core within the plaque. It is quickly engulfed by other macrophages. The saturated environment facilitates the transition of cholesterol from a soluble form to a solid crystalline form = cholesterol crystals. These crystals and the accumulation of lipid and the fragments of dead cells, also accumulation of calcium, further amplify the local inflammation. Foam cells release inflammatory cytokines and growth factors like IGF1 which stimulate the proliferation and the migration of SMCs. This perpetuates the local inflammatory response and attract more immune cells, such as T-cells and additional monocytes, to the site. 5. Migration of smooth muscle cells and fibrous cap Formation: This chronic inflammation stimulates the migration and proliferation of smooth muscle cells SMC from the middle layer (media) to the inner layer (intima). When endothelial cells are damaged, they also release signals, including inflammatory cytokines and growth factors, that promote SMC to the site of injury or inflammation. In response to the inflammatory and growth signals, SMCs undergo a phenotypic change, became like macrophages: shifting from a contractile phenotype to a synthetic phenotype. This change allows them to secrete inflammatory cytokines into the intima and extracellular matrix (ECM) proteins like collagen, elastin, and proteoglycans. These proteins form a fibrous cap over the developing atherosclerotic plaque, which helps  initially stabilize the lesion. Excessive migration and proliferation of SMCs can narrow the artery lumen, reducing blood flow. When the narrowing exceeds 50%, blood flow may become insufficient, especially during increased demand, such as during physical exertion or stress. This reduction in blood flow can lead to ischemia (insufficient blood supply), which can impair tissue function and increase the risk of complications, including damage to the heart's left ventricle. 6. MMPs degrade the fibrous cap by breaking down collagen and other matrix components, leading to plaque destabilization: In response to inflammation, macrophages and smooth muscle cells (SMCs) produce MMPs. Inflammatory cytokines like IL-1 and TNF-α stimulate the production of MMPs -matrix metalloproteinases. MMPs are enzymes that play a key role in the progression of atherosclerosis. These enzymes help break down the extracellular matrix (ECM) proteins, like collagen, elastin, and proteoglycans, which are found in the fibrous cap covering the developing atherosclerotic plaque. As a result, the fibrous cap becomes too thin and unstable and the plaque becomes more prone to rupture. MMPs also influence the proliferation and migration of vascular smooth muscle cells (VSMCs) within the plaque. In atherosclerosis, When MMP activity increases, it can lead to abnormal growth of VSMCs, contributing to the thickening of the arterial wall and plaque formation. a. →MMPs, matrix metalloproteinases are critical in remodeling the ECM, causing inflammation, and promoting plaque instability. They help break down the fibrous cap, making the plaque more likely to rupture, which can lead to dangerous events like heart attacks or strokes 7. Plaque rupture: Excessive MMP activity can break down the fibrous cap that stabilizes plaques, leading to plaque rupture. When the fibrous cap ruptures, the underlying lipid core (rich in cholesterol, oxLDL, and dead cells) is exposed to the bloodstream. This exposure triggers the formation of a blood clot (thrombus), which can partially or completely block the artery, leading to events like a heart attack or stroke. Plaque Formation → begins with the accumulation of foam cells, these foam cells form a fatty streak in the artery wall. Over time, as more LDL particles, foam cells, and other immune cells accumulate in the artery wall, the fatty streak grows and transforms into a more advanced plaque. This process leads to the narrowing of the arteries and can result in reduced blood flow. *Molecules Overexpressed in Endothelial Cells → Oxidized LDL and risk factors activate endothelial cells. Once endothelial cells are activated, they overexpress - produce too much of - specific molecules that promote inflammation and contribute to the development ofatherosclerosis. These molecules include: VCAM1 (Vascular Cell Adhesion Molecule-1) and ICAM-1 (Intercellular Adhesion Molecule-1) = help immune cells (such as monocytes) to adhere to the endothelium and move into the artery wall, contributing to inflammation and plaque formation. LDL Receptors = Endothelial cells start to produce more LDL receptors. These receptors allow more LDL cholesterol (the "bad cholesterol") to enter the artery walls. o The Relationship Between LDL Receptors and Stroke Risk LDL Receptors (LDLRs) are cell-surface proteins found primarily in the liver and other tissues. Their main role is to bind LDL (low-density lipoprotein) often called "bad cholesterol," in the bloodstream and internalize them, helping to remove LDL from circulation. This process helps regulate cholesterol levels and prevents the buildup of cholesterol in the arteries, which is crucial for maintaining cardiovascular health. However, certain genetic factors like Familial Hypercholesterolemia and physiological factors (age and gender) can impair the function of LDL receptors, leading to increased levels of LDL cholesterol in the bloodstream and a higher risk of stroke: - FH = is a genetic disorder characterized by a deficiency of LDL receptors, leading to very high LDL cholesterol levels and a significantly increased risk of stroke. When the function or number of LDL receptors is impaired, LDL particles are not efficiently cleared from the bloodstream, leading to high levels of circulating LDL. Individuals with this condition have a significantly increased risk of premature cardiovascular diseases, including strokes. - Stroke incidence increases with age, particularly for individuals over 65 years old, as the body experiences natural changes in vascular health. Aging leads to arterial stiffening and impaired blood flow, which contribute to a higher likelihood of stroke. - Men tend to experience strokes at younger ages, while the risk for women increases significantly after menopause. Estrogen has a protective effect on blood vessels, and its reduction after menopause can increase stroke risk. Additionally, testosterone levels typically decline with age, low testerone levels have been associated to changes in body composition, increased fat mass, decreased muscle mass, and potential cardiovascular risks. Studies have shown that men with testosterone levels within the optimal range tend to have lower cardiovascular disease rates compared to those with low or high levels. VEGF (Vascular Endothelial Growth Factor) = endothelial cells also release VEGF which stimulates the growth of new blood vessels (angiogenesis) in the plaque, making it more unstable. TNF-α (Tumor Necrosis Factor-alpha) and IL-1β (Interleukin-1 beta) = activated endothelial cells release these pro-inflammatory cytokines, which promote more inflammation and cause more immune cells to move into the artery wall. They also cause the overexpression of adhesion molecules and LDL receptors, creating a vicious cycle of inflammation that worsens the plaque buildup. Consequences of Endothelial Molecule Overexpression →Promotion of Inflammation: Overexpression of adhesion molecules and inflammatory cytokines enhances the adhesion and infiltration of immune cells and increase the immune response, causing more inflammation. The inflammation promotes the progression of atherosclerosis. →Altered Endothelial Function: Overactivated endothelial cells lose their ability to regulate vascular tone and coagulation, leading unwanted blood clotting, which can increase the risk of a heart attack or stroke. →Increased Vascular Permeability: The overexpression of adhesion molecules can increase the permeability of the endothelial barrier, facilitating the entry of lipids and inflammatory cells into the arterial wall. As these substances accumulate, they contribute to the formation of plaques. Trends in Cardiovascular Disease (CVD): Since about 2010, there has been a decrease in cardiovascular disease (CVD) cases in many parts of the world, thanks to better medical treatments, public health campaigns, and greater awareness of prevention. BUT now there is a plateau situation probably due to lifestyle habits (high rates of obesity, unhealthy diets, and lack of exercise) which have not improved enough to further reduce CVD cases. These lifestyle habits continue to put many people at risk for heart disease and stroke. To overcome this plateaux situation, it is important to focus on prevention. This means encouraging people to make healthier choices, such as eating balanced meals, exercising regularly, avoiding smoking, and managing stress. DEVELOPMENT OF INITIMAL LESIONS AND PRODISPOSITION TO ATHEROSCLEROSIS Intimal lesions tend to form in vascular regions predisposed to plaque development, such as arterial branch points and curves. These regions are more prone to endothelial dysfunction due to irregular blood flow patterns. Endothelial injury is a early step in plaque formation and it can be triggered by: - Microorganisms, hyperlipidemia, hypertension, and immune responses. - Hemodynamic shear stress, this mechanical force, at branch points, makes the endothelium more susceptible to damage. How Blood Flow Affects the Endothelium: Laminar vs. Turbulent Blood Flow Blood flow exerts a mechanical force, called hemodynamic shear stress, on the endothelial cells that line blood vessels. This force plays a critical role in vascular health, influencing how endothelial cells function and respond to inflammation. Blood flow in straight parts of arteries is usually smooth and unidirectional, known as laminar flow. This type of flow is healthy for the endothelium because it stimulates the production of nitric oxide (NO), a substance which: Relaxes blood vessels - Prevents platelet aggregation ans clot formation – reduces inflammation in blood vessels. Therefore laminar flow triggers "protective transcription factor" in the endothelium to keep it healthy and increases levels of antioxidants, like superoxide dismutase (SOD), which protect cells from damage by harmful molecules called reactive oxygen species (ROS). → ex. Internal mammary arteries = these arteries with fewer branches are generally less prone to plaque formation due to more consistent laminar blood flow. In contrast, in areas like branch points, curves and bifurcations, blood flow becomes turbulent. This irregular, multidirectional flow creates regions of low and oscillatory shear stress, predisposing them to damage and dysfunction. In addition, the turbulent flow disrupts the production of NO and the other protective mechanisms. Without these defenses, the endothelium becomes weaker and more vulnerable to damage and inflammation, leading to the buildup of atherosclerotic plaques. → Arteries with more branches or bifurcations such as the bifurcated carotid artery and the coronary arteries are more prone to plaque formation.  At branch points, endothelial cells exposed to disturbed flow exhibit dysfunction. This dysfunction leads to the increased expression of adhesion molecules: ICAM-1 which facilitates the adhesion and transmigration of circulating monocytes into the subendothelial space. Once inside, monocytes differentiate into macrophages and contribute to plaque formation by engulfing lipids and transforming into foam cells. Studies show higher ICAM-1 expression in areas like the carotid bifurcation or coronary artery bifurcations, where plaques are most common. Reducing ICAM-1 expression may help prevent or slow plaque formation, particularly in these high-risk areas. Lifestyle Modifications for Cardiovascular Health: Adopting a heart-healthy lifestyle can help maintain healthy shear stress patterns and reduce atherosclerosis risk. Regular physical activity, a balanced diet low in saturated fats, and smoking cessation can prevents excessive mechanical stress on the endothelium, reducing the likelihood of endothelial dysfunction and plaque formation. Aging significantly impacts cardiovascular health and the process of atherosclerosis: with age, there is an increase in oxidative stress due to an imbalance between ROS production and antioxidant defenses. Oxidative stress can damage endothelial cells and promote the oxidation of LDL cholesterol, which accelerates plaque development. Aging leads to arterial stiffness, which alters hemodynamics - Regions of disturbed flow become more pronounced, predisposing these areas to atherosclerosis. Moreover, Over time, the endothelium's capacity to repair itself diminishes, increasing its vulnerability to injury. ATHEROSCLEROSIS PLACQUE GROWTH AND COMPLICATIONS Over time, plaques can grow and cause complications: Hemorrhage into Plaque: Fragile blood vessels formed by neovascularization within plaques may leak, leading to internal hemorrhage. This does not always rupture the plaque but increases its size, worsening the degree of arterial narrowing (stenosis). Structural Changes: Advanced plaques can undergo: - Surface erosion or ulceration: Exposes the plaque’s contents to blood. - Fissure formation - Calcification: Hardening of the plaque. - Aneurysm formation: Weakening of the arterial wall Severe Stenosis or Occlusion: Progressive plaque growth can severely narrow or block the arterial lumen, restricting blood flow to tissues. Plaque Rupture: Rupture of the plaque’s fibrous cap exposes its inner contents, triggering thrombosis (clot formation) that can block the artery, leading to acute events like: heart attack, stroke, pulmonary embolism. HEMOSTASIS => is a tightly regulated physiological process that prevents excessive bleeding following blood vessel damage. It involves a complex interplay between the vessel wall, platelets, and coagulation factors to ensure blood clot formation at the site of injury. Inadequate hemostasis may result in hemorrhage. HEMORRHAGE => excessive bleeding that occurs if any component of hemostasis is impaired. it can lead to severe complications, including hypotension, shock, and death.  THROMBOEMBOLISM => arises from inappropriate blood clot (thrombi) formation or migration of clots. This condition is a significant cause of morbidity (disease or illness) and mortality, driving conditions like: Myocardial infarction (MI) – stroke – pulmonary embolism INFLAMMATION => is the body’s protective response to infection, injury, or cellular damage. It aims to: 1. Eliminate harmful agents 2. Repair tissue after injury. Key step of inflammation are: (PAG 38) 1- Recognition: Sentinel cells (macrophages, dendritic cells) detect harmful agents using specialized receptors. 2- Recruitment: Leukocytes and plasma proteins are delivered to the injury site through blood flow. 3- Removal: Phagocytes engulf and destroy harmful substances and debris. 4- Regulation: The response is terminated once the threat is eliminated to prevent excessive damage. 5- Repair: Damaged tissue is replaced via cell regeneration and connective tissue deposition. Healthy Arteries: Contain resident macrophages in the adventitia, primarily derived from monocytes after birth. These macrophages are involved in immune surveillance and repair. Studies in mice indicate that Dendritic cells and neutrophils are also present in the arterial wall, contributing to vascular homeostasis. Atherosclerotic Lesions: Neutrophils are recruited to plaques via chemokines like CCL5, Once activated, they release proteases = Degrade extracellular matrix, destabilizing plaques and Reactive oxygen species (ROS) = Promote low-density lipoprotein (LDL) oxidation, which accelerates leukocyte recruitment and foam cell formation. DIABETES MELLITUS It is a group of metabolic disorders characterized by a common phenotype: the hyperglycemia (high blood sugar levels). The main types of diabetes include: 1. type 1 = An autoimmune condition where the body's immune system attacks the insulin- producing beta cells in the pancreas. This leads to little or no insulin production. Typically develops in childhood or adolescence but can occur at any age. 2. type 2 = is Characterized by insulin resistance, where the body’s cells do not respond properly to insulin. There is a gradual decline in insuline production over time. it’s strongly associated with obesity, physical inactivity, and genetic predisposition. More common in adults but increasingly seen in younger populations due to rising obesity rates. 3. gestational diabetes mellitus (GDM) = Develops during pregnancy due to hormonal changes that cause insulin resistance. Typically resolves after delivery, but women with GDM have a higher risk of developing T2DM later in life. COMMON DIAGNOSTIC METHODS FOR DIABETES To diagnose diabetes, healthcare professional use a combination of diagnostic tools and laboratory tests to measure blood glucose levels and evaluate long-term glucose control. These methods include: 1. A1C TEST (GLYCATED HEMOGLOBIN TEST): It measures average blood sugar levels over the past 2–3 months by analyzing the percentage of glycated hemoglobin in red blood cells. The A1C test is based on a natural spontaneous non-enzymatic reaction in which glucose binds to hemoglobin in red blood cells. When glucose enters the bloodstream, the aldehyde group of the glucose molecule binds covalently to the amino terminus of the beta-globin chain of hemoglobin, forming what is known as glycated hemoglobin (HbA1c). The reaction leads to the formation of a Schiff base (an imine), which undergoes a rearrangement (Amadori rearrangement) to form a stable ketoamine. Once glucose is attached to hemoglobin, it stays there for the lifespan of the red blood cell (approximately 90-120 days). So the amount of glycated hemoglobin (HbA1c) is directly proportional to the average level of glucose in the blood over the past 2-3 months. The higher the blood sugar levels, the greater the percentage of HbA1c, meaning a higher A1C value. The A1C result is expressed as a percentage (%), which corresponds to the amount of glycated hemoglobin in the blood. A1C levels below 5.7% are considered normal, but levels of 6.5% or higher confirm diabetes. The instrument used to measure A1C levels is commonly known as an A1C analyzer or hemoglobin A1C testing device. A1C testing can be done using laboratory equipment or at- home kits, which provide results in minutes from a small blood sample. 2. FPG (fasting plasma glucose): measures blood glucose after at least 8 hours of fasting. 3. OGTT (Oral Glucose Tolerance Test): assesses how the body processes sugar. a. Fasting: After fasting (no food or drinks except water) a blood sample is taken to measure baseline glucose also called fasting blood glucose. b. Drinking the Glucose Solution: Then, the patient will be asked to drink a glucose solution containing 75 grams of sugar dissolved in water (the solution is saturated with glucose). After drinking the glucose solution, blood samples will be taken at specific intervals (30 minutes, 1 hour, and 2 hours) to measure blood glucose levels over time and to monitor how your body processes the sugar. c. The results of these glucose measurements can be plotted on a graph to create a OGTT glucose tolerance curve that provides a visual interpretation of how your body handles sugar over time: in a Normal Response: fasting Blood glucose is below 100 mg/dL. And 1 hour after the intake Blood glucose levels peaks below 140 mg/dL, returning to normal within 2 hours: Insulin works effectively. In Prediabetes: glucose level spikes higher than in a normal response and stays elevated for longer, exceed 140 mg/dL, The curve doesn’t drop back to normal after 2 hours, forming a flatter peak.  In Diabetes: fasting blood glucose is elevated, often above 126 mg/dL, after 1 hour Blood glucose levels exceed > 200 mg/dL and glucose remains above 200 mg/dL after 2 hours, indicating that the body is not efficiently using insulin to lower blood sugar. Glucose is the primary energy source for cells, especially for neurons. Cells metabolize glucose through key biochemical pathways, including glycolysis, Krebs cycle and oxidative phosphorylation to produce energy in the form of ATP. Blood glucose levels - glycemia must remain stable. Regulation: Under physiological conditions, glycemia is maintained constant through a balance between storage and release processes: 1. In the postprandial phase (after eating) → glucose storage. glucose can be stored as glycogen in the liver and muscles (glycogenosynthesis) or can be converted into triglycerides and stored in adipose tissue (lipogenesis). 2. In the fasting phase (low glucose levels)→ glucose release Glycogen in the liver and muscles can be broken down into glucose and released in bloodstream (glycogenolysis) or Stored triglycerides in adipose tissue undergo breakdown (lipolysis) and β-oxidation of fatty acids provides energy. Also, glucose can be synthesized de novo (gluconeogenesis) using amino acids, glycerol or ketone bodies. The tissues involved in glucose storage are: muscles (essentially as glycogen), adipose tissue (essentially as triglycerides or long-term energy reserves) and liver (stores as both glycogen and triglycerides). THE LIVER AND PANCREAS play critical roles in regulating blood glucose levels, ensuring a balance between glucose production, storage, and utilization. The liver is central to maintaining blood glucose homeostasis by regulating glycogenolysis (during fasting) and gluconeogenesis (during prolonged fasting). It acts as a glucose reservoir, releasing or storing glucose as needed to maintain stable blood glucose levels. The pancreas regulates glucose metabolism through its endocrine function, specifically through the islets of Langerhans. This endocrine portion of the pancreas consists of clusters of specialized cells that release hormones directly into the bloodstream: α cells → produce glucagon (protein hormone with hyperglycemic action) increases blood glucose levels by stimulating glycogenolysis and gluconeogenesis in the liver. β cells → produce insulin (a protein hormone, composed of two chains connected by disulfide bonds, with a hypoglycemic action) allows to reduce blood glucose levels, the glycimia, by stimulating glucose uptake into muscles and adipose tisse. δ cells → produce somatostatin (polypeptide hormone responsible for the intrapancreatic regulation of glucagon and insulin secretion) The process by which glucose stimulates insulin secretion from beta (β) cells in the pancreas: In pancreatic β cells, glucose enters these cells through a special transporter called GLUT2. This transporter has a high capacity for glucose and balances blood and intracellular glucose levels. Once inside the β cell, glucose undergoes glycolysis and the citric acid cycle to produce ATP (adenosine triphosphate). → The increased ATP (associated to increased glucose metabolism), closes potassium (K⁺) channels in the cell membrane, trapping potassium ions and causing the cell membrane depolarization to become positively charged. This depolarization opens calcium (Ca²⁺) channels, allowing calcium to flow into the cell. The influx of calcium triggers the release of insulin from storage granules into the bloodstream through a process called exocytosis. Continuous glucose stimulation also promotes the production of new insulin in β cells. INSULIN SYNTHESIS =It is synthetised as proinsulin (prohormon containing A and B chains linked by the connecting C peptide) and is packed in secretory vescicles where specific enzymes convert proinsulin into mature insulin by excising C-peptide. Thus, when mature granules are secreted into the circulation by exocytosis, insulin and an equimolar ratio of C-peptide are released (1:1 ratio). → C-peptide can be used as a marker of endogenous insulin secretion. - C-PEPTIDE TEST C-peptide has a longer half-life in circulation compared to insulin, which makes it a stable Indicator of Insulin Production. C-peptide levels reflect the amount of insulin being produced by the pancreas. Higher levels indicate more insulin production, while lower levels suggest reduced or absent insulin production. C-peptide testing can aid in the differentiation between Type 1 and Type 2 diabetes, especially when clinical presentation is ambiguous. - Normal C-Peptide Levels: Indicate that the pancreas is producing a sufficient amount of insulin. In this case, if hyperglycemia (high blood sugar) is present, it suggests insulin resistance rather than a lack of insulin → type 2 - Low C-Peptide Levels: Suggest that the pancreas is not producing enough insulin, which is typical in T1DM. Here, there is a loss of beta-cell function leading to insufficient insulin secretion→ type 1 INSULINE FUNCTION: Insulin is the main regulator of the blood glucose levels. It is released in the blood stream by β cells when blood sugar levels rise. Once released, insulin travels to insulin-responsive tissues such as muscle cells and adipose (fat) tissue. When insulin binds to its receptors on these cells, it triggers the movement of vesicles containing GLUT4 to the cell membrane. The GLUT4 transporter then allows glucose to enter the cells. in this way, it promotes the uptake of glucose into cells, helping lower blood glucose levels (hypoglycemic effect). However, if insulin is secreted but does not function properly (such as in insulin resistance), glucose is unable to enter the cells effectively, and it remains in the bloodstream, leading to hyperglycemia. (In contrast, Glucagon works oppositely to insulin by increasing blood glucose levels when needed.) Consequences of Hyperglycemia, often seen in conditions like diabetes mellitus. Glycosuria: (glucose in urine) When blood glucose levels are too high, the kidneys can no longer reabsorb all the glucose. As a result, glucose spills over into the urine. Polyuria: (a lot urine) Since glucose is osmotically active, water tends to follow it resulting in an increase in urination. Polydipsia: (excessive thirst) the increased urine output leads to dehydration To counter (contrastare) this fluid loss, the body triggers excessive thirst. Polyphagia: (excessive hunger) Even though there is a lot of glucose in the bloodstream, insulin resistance or deficiency prevents glucose from entering the cells. In response adipose tissue starts breaking down fat, lipolysis and muscle proteins for energy. lipolysis process produces ketone bodies in the liver (fat broken down in free fatty acids> the liver turns the fatty into ketone bodies = acetoacetic acid and beta-hydroxybutyric acid). As the body is in a catabolic state, this results in weight loss, but the lack of energy makes the person feel extremely hungry. Diabetes Described in 1500 BC: diabetes was first described like a mysterious disease that caused intense thirst, excessive urination, and weight loss. In 250 BC, the name "diabetes" was introduced, meaning "to go through", emphasizing the excessive fluid loss associated with the condition, while "mellitus" was later added to indicate the sweet nature of the urine due to elevated glucose levels. TODAY: DM is classified based on the pathogenic process that leads to hyperglycemia (etiologic classification). There are two main type of DM: T1DM -T2DM, both of which are preceded by a stage of abnormal glucose homeostasis known as pre-diabetes. The most common type is T2DM, which accounts for around 90% of all diabetes cases. 1. Type 1 DM: is usually diagnosed early at 10-14 years.It represents about 10% of all diabetes cases worldwide and is incurable and cannot be prevented. T1DM is a chronic autoimmune condition characterized by the absolute deficiency of insulin which occurs due to the destruction of insulin-producing beta cells in the pancreas. In type 1 diabetes the body's immune system mistakenly attacks its own cells, specially a type 4 hypersensitivity cell-mediated immune response occurs. The body’s T cells attack and destroy the beta cells in the pancreas. The distruction is linked to a genetic abnormality in the HLA system, which impairs the immune system’s ability to differentiate between self and non- self. The loss of self-tolerance in T cells allows them to recruit other immune cells to target and destroy beta cells. This autoimmune process occurs in genetically predisposed individuals and may be triggered by environmental factors such as: viral infections – exposure to certain chemical compounds - early contact with cow's milk proteins. Losing beta cells means less insulin is produced, causing glucose to accumulate in the blood. Without insulin, glucose cannot enter the cells, leading to hyperglycemia, which leads to 4 main clinical symtoms: polyphagia-glycosuria - plyuria and polydipsia. TREATMENT → Although people with T1DM cannot produce insulin, their bodies still respond to external insulin. Therefore, it can be managed effectively with insulin therapy which helps transport glucose into cells and lowers blood sugar levels. A severe COMPLICATION of T1DM → is diabetic ketoacidosis DKA: occurs when the body, unable to use glucose for energy, breaks down fat instead, producing ketone bodies (acetoacetate and beta-hydroxybutyrate) as an alternative energy source. The ketones accumulation makes the blood acidic, leading to ketoacidosis. ->The acidic blood can disrupt multiple organ systems + Patiens may develop Kussmaul respiration + a shift in potassium levels causes hyperkalemia. DKA can occur even in individuals undergoing insulin therapy. 2. TYPE 2 DM: is the most common form of diabetes, accounting for 90% of cases. it can be prevented through lifestyle changes. T2DM is a progressive disease, is characterized by a gradual progression of metabolic changes, particularly involving insulin secretion and insulin sensitivity. It is caused by a combination of genetic predisposition factors + environmental factors (poor diet, lack of exercise, and obesity. The progression of T2DM involves three interconnected defects: 1- Insuline resistance = b-cells produce insulin but cells don’t respond effectively. As a result GLUT4 doesn’t traslocate on the cell-surface, preventing glucose from entering cells. The exact reason why cells don’t respond isn’t fully understood but some risk factors include obesity – lack of exercise- hypertension. For exaple, an excess of adipose tissue releases inflammatory substances such as adipokines that contribute to insulin resistance.  2- Increased insulin secretion and Beta-Cell Dysfunction = Over time, the pancreas tries to compensate for insulin resistance by producing more insulin (hyperinsulinemia) this leads to beta cell hypertrophy and hyperplasia, an increase in number and size of beta cells. B cells also secrete a protein called amylin which can builds up and form toxic aggregates in the pancreas. Eventually, beta cells become exhausted and dysfunctional, undergo hypotrophy and die off reducing insulin production further. As beta cells decline, the remaining functional cells must work harder to meet the body’s insulin demands, leading to further strain and deterioration. 3- Increased hepatic glucose production = The liver produces excessive glucose, even when blood glucose levels are already elevated, exacerbating hyperglycemia. It leads to the common 4 sympoms. A severe COMPLICATION of T2DM → (DKA doesn’t usually develop) is Hyperosmolar hyperglycemic state HHS where high blood glucose causes dehydration. Glucose is osmotically active and pulls water out of cells, leaving them dehydrated. TREATMENTS: - METFORMIN is primarily prescribed for T2DM to help manage insulin resistance by improving the body’s response to insulin and decreasing glucose production in the liver. BUT weight loss-exercise-healthy diet and antidiabetic meds can be enough to reverse some of insulin resistance and keep blood sugur level in check. - SGLT2 INHIBITORS Help lower blood glucose by blocking SGLT2 transporter and preventing the reabsorption of glucose in the kidneys, leading to its excretion in urine. → Two sodium-glucose transporters (SGLTs) are responsible for glucose reabsorption in the body: SGLT-1 (gut and kidney) and SGLT-2 (Accounts for 90% of glucose reabsorption in the kidneys), both play a critical role in preventing glucose loss in urine by reabsorbing glucose filtered through the glomeruli. COMPLICATION OF DIABETES Acute Complications: requiring immediate attention and correction of blood glucose and electrolyte balance. if I can’t use glucose, have to switch to another form of energy: fat and proteins. fat →Diabetic Ketoacidosis (DKA): More common in Type 1; due to severe insulin deficiency leading to fat breakdown and ketone production > treatment: fluids for dehydration, insulin to lower blood glucose, elettrolytes like potassium help to revers acidosis. Hyperglycemic Hyperosmolar State (HHS): More common in Type 2; characterized by extreme hyperglycemia and dehydration. Chronic Complications: are long-term complication, develop over years of uncontrolled blood sugar levels and can be categorized into: VASCULAR DAMAGE: Microvascular Complications: primarily affect small blood vessels and include: o Diabetic Retinopathy = is a progressive eye disease caused by damage to retinal blood vessels from high blood sugar levels. Leading to vision loss and blindness. o Diabetic nephropathy = is kidney damage due to hyperglycemia, causing chronic kidney disease (CKD) or end-stage renal disease (ESRD). The progression of diabetic nephropathy typically involves several stages, which can span 10 to 15 years or more, often including a prolonged silent period. After the silent period, chronic hyperglycemia  causes structural changes in the kidney's glomeruli, compromising their filtration ability. This results in a gradual decline in the glomerular filtration rate (GFR). Elevated glucose levels lead to protein glycation, which damages the glomerular filtration barrier and increases its permeability. This damage allows proteins, especially albumin, to leak into the urine, a condition known as proteinuria. Proteinuria indicates compromised kidney function and reflects the progressive decline in the integrity of the filtration barrier caused by prolonged exposure to high blood sugar levels. o Diabetic Neuropathy = is nerve damage caused by prolonged hyperglycemia, leading to a decrease in sensation in the toes and fingers. It typically affects: ▪ Peripheral neuropathy: Affects the extremities (hands and feet) and can lead to tingling, pain, and loss of sensation, to increase the risk of injuries and infections, especially in the feet. ▪ Autonomic neuropathy: Affects the autonomic nervous system which controls involuntary functions like heart rate, it can cause issues with heart rate, blood pressure regulation, digestion, and bladder control. Macrovascular Complications: These affect larger blood vessels and increase the risk of cardiovascular disease: o Coronary artery disease: Increased risk of heart attacks and heart failure. In large vessels there is an accelerated process of atherosclerosis and a greater predisposition to platelet aggregation. o Cerebrovascular Disease: Higher risk of strokes and transient ischemic attacks. Hypertension: High blood pressure is common in diabetes and contributes to cardiovascular risks. o Peripheral artery disease Reduced blood flow to the limbs, leading to pain, ulcers, or even amputation → Diabetic Foot, often ulcers can get severe and need to be amputated. NON VASCULAR COMPLICATIONS: Involve neuropathy, gastrointestinal tract, genitourinary system, skin issues -Dry skin GESTIONAL DIABETES: GDM a subtype of diabetes While GDM shares some similarities with Type 2 Diabetes, particularly insulin resistance, it is unique in that it occurs specifically during pregnancy, typically in the third trimester, due to hormonal changes. During pregnancy, the body naturally undergoes physiological insulin resistance. This means that the body’s ability to use insulin becomes less efficient, which ensures that enough glucose is available for the developing fetus. In this state, the mother’s body shifts its energy metabolism from carbohydrates to lipids (fatty acids), allowing glucose to be directed across the placenta to nourish the fetus. This is a normal, physiological process designed to support fetal growth and development. During pregnancy, the placenta produces a hormone 191 aa protein called Human Placental Lactogen (hPL), which contribute to increase insulin resistance in the mother and decreased glucose reabsorbtion. ✓ Hpl plays several important roles that are crucial for both maternal and fetal health. It is essential in preparing the mother's body for lactation by promoting the development of mammary glands and enhancing milk production. It increases in proportion to the weight of  the placenta and represents an indicator of good placental function. The secretion of hPL is inversely related to human chorionic gonadotropin (hCG). This is crucial for maintaining pregnancy and supporting fetal growth as the placenta matures. ✓ One of hPL’s primary functions is to promote insulin resistance in the mother, ensuring that more glucose is available to the fetus. This shift prioritizes fetal growth over maternal energy needs. Additionally, hPL facilitates diffusion of glucose through the placental membrane and penetration into the fetal circulation To compensate for this insulin resistance, caused by hPL, the pancreas’s mother undergoes physiological β-cell hyperplasia, which is an increase in the number of insulin-producing β-cells in the pancreas. This adaptation helps the body maintain normal blood glucose levels by increasing insulin production to overcome the insulin resistance. However, if the insulin resistance becomes too severe and the pancreas cannot produce enough insulin to compensate, the woman may develop gestational diabetes. This results in elevated blood glucose levels, which can pose risks to both the mother and the fetus. GDM is usually diagnosed between 24 and 28 weeks of pregnancy.--> GDM requires careful management to prevent complications for both the mother and the baby, such as having a larger baby (macrosomia), premature birth, or an increased risk of developing type 2 diabetes in the future for both the mother and child. → Infants born to mothers with gestational diabetes are at a higher risk of being larger than average (macrosomia) due to excess glucose crossing the placenta, leading to excessive fetal growth. The increased size of the baby, especially in the shoulders, can lead to complications during delivery, such as shoulder dystocia = is a specific type of delivery complication where the baby's shoulders are too broad ( ampie) to pass through the birth canal after the head has emerged. → Pre-term birth: Babies born prematurely are at high risk of breathing problems because the lungs are one of the last organs to fully develop →Post-birth complications in newborns: Respiratory Distress Syndrome (RDS) Hypoglycemia (Low Blood Sugar) due to excess insulin produced in response to high maternal blood sugar levels during pregnancy, and after birth, the baby’s insulin production may remain high Elevated bilirubin levels in the blood, leading to yellowing of the skin and eyes. Spontaneous Regression = GDM often resolves spontaneously after delivery, However, 2/3 of women with gestational diabetes are likely to develop it again in future pregnancies. Additionally, gestational diabetes is a marker for an increased long-term risk of cardiovascular diseases, such as heart attacks. Even if blood sugar levels return to normal after childbirth, women with a history of gestational diabetes should focus on a healthy lifestyle. Glycemic Index (GI) is a numerical scale that ranks (classifica) carbohydrates in food based on their impact on blood glucose levels. It measures how quickly a particular food raises blood sugar levels after consumption compared to pure glucose. The glycemic index assigns a value to foods, with glucose itself having a GI of 100. Foods with a lower GI (less than 55) are absorbed more slowly and result in a more gradual increase in blood glucose levels, which is beneficial for blood sugar control. Conversely, High GI (70 and above): Foods that cause a rapid increase in blood sugar (white bread, sugary drinks, and processed snacks). → Understanding the GI of foods is important for managing diabetes, as it helps guide dietary choices to maintain stable blood glucose levels.  For managing Type 2 Diabetes and GDM, lifestyle changes are essential: Choosing a low-GI foods in diet can help maintain stable blood glucose levels and Regular physical activity improves insulin sensitivity and helps manage weight. Diabetes insipidus (DI) is a condition characterized by excessive urination (polyuria) and extreme thirst (polydipsia) due to an inability to concentrate urine. Unlike diabetes mellitus, DI results from a dysfunction in water balance, not glucose metabolism. The condition arises when the body's mechanism for regulating water reabsorption in the kidneys is impaired, leading to the production of large amounts of dilute urine. Physiologycal mechanism to maintain water balance: Hypothalamus => The primary hormone involved in water balance is Antidiuretic Hormone (ADH): → also known as vasopressin, is a hormone produced in the hypothalamus and released from the posterior pituitary gland in response to increased blood osmolarity. Osmoreceptors in the hypothalamus detect changes in blood osmolarity and when osmolarity increases, due to dehydration, ADH is released into the bloodstream, signaling the kidneys to reabsorb more water, reducing urine output. Kidney Response => ADH acts on V2 receptors in the renal tubules, triggering a cascade that causes translocation of aquaporin-2 (AQP2) water channels to the membrane of the renal tubules. This process increases the permeability of the renal tubules, allowing water to be reabsorbed into the bloodstream and reducing urine output. In DI this mechanism fails due to two primary causes. There are 2 main types of diabetes insipidus, which impact the ADH mechanism differently: 1- Central Diabetes Insipidus: occurs when the hypothalamus or pituitary gland fails to produce or release adequate ADH, often as a result of trauma, surgery, tumors, or infections. 2- Nephrogenic Diabetes Insipidus: arises when the kidneys do not respond properly to ADH. This insensitivity can result from genetic defects, medications such as lithium, or kidney disorders. Consequences of Impaired ADH Function: When ADH levels are insufficient or when the kidneys do not respond to it appropriately, excessive water loss in urine occur. - Increased Urine Output: The kidneys fail to reabsorb sufficient water, resulting in excessive urination (polyuria). The urine produced is dilute and can lead to dehydration. - Increased Thirst: The loss of large volumes of water leads to dehydration, triggering extreme thirst (polydipsia) as the body attempts to compensate for the water loss. A common symptom is nocturia, where individuals frequently wake at night to urinate, significantly impacting their quality of life.  NAFLD Non-alcholic Fatty Liver Disease is a progressive spectrum of liver conditions, from fat accumulation to chronic liver damage, caused by the accumulation of fat in hepatocytes, unrelated to alcohol consumption. It begins with Steatosis (fatty liver) where fat accumulates in liver cells and appears as clear or white vacuoles on histology. Steatosis is typically asymptomatic and is reversible with lifestyle changes, but becomes abnormal when fat content exceeds 5% of hepatocytes, potentially leading to liver dysfunction. If left untreated, steatosis can progress to → Non-Alcoholic Steatohepatitis (NASH) a more advanced stage characterized by inflammation, hepatocyte injury (ballooning degeneration), and early fibrosis. NASH can further progress to→ Cirrhosis the final stage of NAFLD, involving extensive fibrosis, irreversible liver scarring, and structural damage. It significantly increases the risk of liver failure and hepatocellular carcinoma. 1. STEATOSIS, or fatty liver, is the earliest stage of NAFLD, characterized by the accumulation of fat (primarily triglycerides) in more than 5% of hepatocytes in the absence of significant alcohol intake 100 mg/dl) which is a precursor to the development of type 2 diabetes. Insulin resistance is strongly correlated with the accumulation of triglycerides in the liver and as insulin resistance worsens, fat accumulation in the liver increases. When insulin resistance occurs, the liver becomes less responsive to insulin, leading to higher blood glucose levels. This excess of glucose and free fatty acids (FFAs) are delivered to the liver, where they promote de novo lipogenesis—the synthesis of fat. This process leads to an increase in fat accumulation within hepatocytes, which is the hallmark of steatosis. As steatosis progresses, the liver’s ability to respond to insulin further declines, creating a vicious cycle: fat accumulation in the liver exacerbates insulin resistance, and insulin resistance leads to more fat being stored in the liver. This means that as fat accumulates in the liver, the liver becomes even less responsive to insulin, and the body’s overall ability to process glucose is impaired. Over time, the accumulation of fat in liver cells causes inflammation and further liver damage, contributing to the progression of Non- Alcoholic Fatty Liver Disease (NAFLD). → thus, hepatic steatosis is inversely correlated with systemic insulin sensivity  Tissue-Specific Mechanisms under INSULINE RESITANCE: ADIPOSE TISSUE -> In insulin resistance, adipose tissue becomes less responsive to insulin. This impairs the normal process of fat storage and leads to increased lipolysis (FAT breakdown, in Adipose Tissue). As a result, more free fatty acids (FFAs) are released into the bloodstream. These FFAs are transported to the liver, where they are stored as triglycerides, contributing to fat accumulation in liver cells (hepatocytes). Additionally, insulin resistance causes inflammation in adipose tissue, as the excess fat storage stresses the fat cells. This inflammation attracts pro-inflammatory macrophages to the tissue, which release cytokines such as TNF-α and IL-6, promoting systemic inflammation and worsening insulin resistance. LIVER -> In the liver, insulin resistance leads to High Lipogenesis (Fat Synthesis). Under normal conditions, insulin inhibits lipogenesis in the liver but when insulin resistance occurs, the liver becomes more active in producing fat from excess glucose and fatty acids. This fat is stored as triglycerides, contributing to the development of fatty liver disease (steatosis). In conditions like obesity, insulin resistance, and high-carbohydrate diets → especially those rich in fructose, the liver’s process of DNL DE NOVO LIPOGENESIS becomes overactive, contributing to hepatic steatosis. While some fatty acids undergo β-oxidation to produce energy, the liver receives more FFAs than it can oxidize, leading to an imbalance where more fatty acids are being synthesized (lipogenesis) than oxidized. This imbalance contributes to fat accumulation (steatosis). Furthermore, β-oxidation generates reactive oxygen species (ROS), which cause oxidative stress in the liver. This oxidative stress promotes inflammation, and further liver damage. As fat accumulates in the liver, this can trigger inflammation →, The accumulation of fat in the liver also activates Kupffer cells (liver macrophages), which release inflammatory cytokines. These cytokines promote fibrosis (scarring) and worsen liver damage. Pro-inflammatory cytokines worsen insulin resistance, creating a vicious cycle where inflammation drives more insulin resistance, steatosis, and liver damage. In addition, insulin resistance in the liver causes an increase in gluconeogenesis (glucose production), called as High hepatic blood sugar (HBS despite the presence of high blood sugar. This contributes to hyperglycemia (elevated blood glucose levels), which increases metabolic stress and further promotes lipogenesis, creating a vicious cycle of insulin resistance, fat accumulation, inflammation, and liver damage. De Novo Lipogenesis => is the process by which the liver converts excess glucose/fructose into fat. This process is particularly active in insulin resistance and when there is an overload of carbohydrates. Glucose → DNL begins when glucose enters hepatocytes (which are insulin-independent) through GLUT2 transporters, Inside the cells, glucose is phosphorylated by glucokinase to form glucose-6-phosphate (G6P) and it is metabolized through glycolysis to produce pyruvate which enters the mitochondria. Inside the mitochondria, piruvate is converted into acetyl-CoA by the pyruvate dehydrogenase complex. Acetyl-CoA is crucial for energy production through the citric acid cycle, but when there is an excess of glucose (insulin resistance), the citric acid cycle becomes overwhelmed with energy. Therefore, the excess acetyl-Coa is converted into citrate, which come back into acetyl-CoA into the cytoplasm. → is the precursor for fatty acid synthesis: Acetyl-CoA is then converted into malonyl-CoA by the enzyme acetyl-CoA carboxylase (ACC). Next, fatty acid synthase (FAS) uses malonyl-CoA  and acetyl-CoA to produce long-chain fatty acids, which are converted into triglycerides (TGs). The liver stores some of these triglycerides, contributing to steatosis (fatty liver), and the rest are packaged into very low-density lipoproteins (VLDL) and released into the bloodstream = leads to Dyslipidemia (abnormal lipid levels in the blood). Fructose→ When fructose is consumed in excess, from sugary drinks, fructose bypasses normal metabolic regulation, leading to rapid fat production in the liver. Fructose enters hepatocytes via GLUT5 transporters, is rapidly phosphorylated by fructokinase to fructose-1- phosphate F1P is rapidly split into glyceraldehyde and dihydroxyacetone phosphate (DHAP) intermediates => are quickly converted into glycerol-3-phosphate after in pyruvate, which follows a similar path to glucose, leading to acetyl-CoA production in the mitochondria. Since fructose metabolism is rapid and unregulated, large amounts of acetyl-CoA accumulate, driving fatty acid synthesis through DNL. The combination of insulin resistance and fructose consumption activates SREBP-1c Sterol Regulatory Element-Binding Protein 1c, promoting the transcription of genes involved in lipogenesis, further driving fat production. - GUT MICROBIOME IN FRUCTOSE METABOLISM: fructose metabolism in the liver can be affected by the microbiome. Excess fructose that reaches the colon is fermented by gut bacteria into short-chain fatty acids (SCFAs) primarily Acetate which travels from the gut to the liver via the portal vein. Once in the liver, acetate enhances de novo lipogenesis (DNL) pathway to generate fatty acids and triglycerides, further contributing to hepatic fat accumulation, thereby contributing to the development of hepatic steatosis (fatty liver). Some bacteria also convert fructose into alcohol (ethanol), This occurs more frequently in individuals with an altered gut microbiome. Ethanol is toxic to liver cells, causes oxidative stress, inflammation, and liver damage, worsening conditions like Non-Alcoholic Steatohepatitis (NASH). This interaction between fructose metabolism and the gut microbiome amplifies liver fat deposition and injury. This is similar to the damage caused by alcohol consumption, despite the fact that the ethanol originates from gut bacteria rather than external sources. MUSCLE-> in insulin resistance (IR), muscle cells become less responsive to insulin, GLUT4 translocation doesn’t occur and conseguently glucose is not absoorbed from the bloodstream and is not used for eenrgy or stored as glycogee. Reducing glucose uptake occur and plasma glucose levels remain elevated. The liver compensates by converting this excess glucose into fatty acids via lipogenesis, worsening hepatic fat accumulation anc contributes to steatosis. Insulin resistance (IR) is considered the central driver factor that links various metabolic abnormalities, which collectively contribute to the progression of steatosis and metabolic syndrome. These abnormalities include: - dyslipidemia = refers to abnormal lpids levels in the blood characterized by triglyceride levels exceeding 125 mg/dL. It increases FFAs to the liver, promoting fat accumulation in hepatocydes and worsening steatosis - hypertension = High blood pressure, particularly when systolic levels reach 160 mmHg or higher, can impair insulin's ability to regulate glucose metabolism. leading to higher levels of circulating glucose and FFAs, both of which contribute to fat deposition in the liver.  - Abdominal obesity = measured by waist circumference (Men: Waist circumference > 102 cm - Women: Waist circumference > 88 cm) reflects harmful visceral fat stores, which is closely linked to insulin resistance and other metabolic risk factors. Visceral fat located around internal organs, releases FFAs and pro-inflammatory adipokines, exacerbating insulin resistance and increasing the risk of fatty liver. - Type 2 diabetes= Insulin resistance and obesity, which drive type 2 diabetes, are responsible for over 85% of steatosis cases. The combination of hyperglycemia and increased FFA flux to the liver accelerates fat accumulation and can lead to the progression of NALD. THE PATHOGENESIS OF STEATOSIS is a complex, multi-step process involving disruptions in lipid metabolism, insulin signaling, inflammation, and oxidative stress. The accumulation of fat in liver cells occurs when there is an imbalance between lipid uptake, lipid synthesis, and lipid export in liver cells. Lifestyle factors play a significant role in the development and progression of steatosis. in many cases, both steatosis and NASH can be reversed or improved significantly through lifestyle changes. Key Factors in the Development of Steatosis: Diets rich in calories = Diets rich in saturated fats and refined carbohydrates are primary drivers of liver fat accumulation. Sugary beverages and fast food are particularly harmful. High fructose uptake=, increases liver fat accumulation by promoting de novo lipogenesis (fat synthesis) and reducing fat export from the liver. Physical inactivity = is a major risk factor for the development of NAFLD. Lack of exercise contributes to obesity, insulin resistance, and impaired lipid metabolism. Regular physical activity helps reduce visceral fat, improves insulin sensitivity, and enhances fat oxidation, reducing the likelihood of fat accumulation in the liver. EVOLUTION AND COMPLICATIONS OF STEATOSIS Steatosis is a systemic disorder: The impact of steatosis extends beyond the liver, affecting multiple systems due to interconnected metabolic and inflammatory disruptions. While fat accumulation primarily occurs in the liver, the underlying metabolic and inflammatory disturbances influence the functioning of other body systems. → The fatty liver promotes a metabolic dysfunction/ promotes systemic inflammation / leads to higher cardiovascular risk / is linked with type 2 diabetes-metabolic syndrome-obesity. In the early stages of NAFLD: Steatosis and Early NASH are highly dynamic conditions where fat accumulation and liver inflammation are often reversible through: ✓ lifestyle changes such as improved diet, weight loss, and regular physical activity ✓ Modulation of lymphocyte populations and modulation of macrophage activity: can help reduce inflammation and improve liver function over time.→ In the early stages of NASH, The immune response, including intrahepatic lymphocyte populations (CD8+ T cells and natural killer T cells) and macrophage infiltration, plays a central role in the progression of  liver damage in NASH. These immune cells, while initially intended to protect the liver, can promote inflammation and contribute to liver damage if they become dysregulated. While, advanced stages of NAFLD, (Severe Fibrosis or Cirrhosis), are less reversible but damage progression can still be slowed with lifestyle changes, medications, and managing underlying conditions like diabetes or hypertension. DIAGNOSIS STEATOSIS IS A SILENT DISEASE , also called "asymptomatic" fatty liver, is typically diagnosed incidentally during routine medical exams (IR) but the patient doesn't experience symptoms. GOLD STANDARD-LIVER BIOPSY: Liver biopsy is considered the gold standard for diagnosing and assessing the severity of liver diseases, particularly MAFLD/NAFLD, which includes a spectrum of liver conditions from simple steatosis (fatty liver) to more severe stages like NASH, fibrosis, and cirrhosis. It remains the most definitive method for evaluating liver histology, including the degree of fat accumulation, the presence of inflammation, and the extent of fibrosis (scarring). Liver biopsy involves taking a small tissue sample from the liver for histological examination under a microscope. This procedure allows for: 1- Quantifying Fat Accumulation (degree of steatosis) 2- Identifying Inflammation (degree of inflammation) 3- Assessing Fibrosis. (degree of fibrosis) Liver biopsy has several limitations: Liver biopsy is invasive procedure that carries risks, such as bleeding, pain, and infection. Sampling Error: The liver is a large organ, and a biopsy sample may not fully represent the entire liver. It is more expensive than non-invasive methods (Fibroscan – serum biomarkers) Normal Histology of the Liver: a normal liver has a smooth and organized appearance with clear hepatocytes and a balanced architecture. Histological Features of STEATOSIS: hepatocytes contain large lipid droplets, but the liver's lobular architecture remains intact. This stage is often reversible and represents the accumulation of fat without significant liver damage. NASH Histological Features: In NASH, hepatocytes swell and appear blue due to vacuolization and cytoplasmic swelling "blue spot". Where ballooning degeneration of hepatocytes occurs due to oxidative stress and fatty acid accumulation. It marks a more severe stage of fatty liver disease with inflammation and early fibrosis. Ballooning is challenging to detect: Liver biopsies are typically small, and the sampling may not represent the entire liver adequately. This can lead to underestimating or overestimating the presence of ballooned hepatocytes and other histological features. But Artificial Intelligence can significantly improve diagnosis by reducing variability in assessment. Cirrhsis Histological Features: Loss of normal architecture, nodular appearance and widespread fibrosis, It represents an advanced, irreversible stage of liver damage. HCC Histological Features: shows a disorganized architecture with with tumor nodules and vascular invasion, indicating liver cancer. NAFLD Activity Score (NAS), is a widely used scoring system to assess the severity of NAFLD and its progression. It evaluates three key histological features: 1. Steatosis: The extent of fat accumulation in liver cells. It is scored on a scale from 0 to 3 based on the percentage of hepatocytes affected: Grade 0: 66% of hepatocytes affected) 2. Ballooning: The degree of hepatocyte (liver cell) injury or swelling, which indicates cell damage often due to oxidative stress. Ballooning degeneration is a hallmark of NASH. Grade 0: No ballooning Grade 1: Mild ballooning Grade 2: Severe ballooning 3. Lobular Inflammation: The presence of inflammatory cells (mainly neutrophils) in the liver lobule. Grade 0: No inflammation Grade 1: Mild lobular inflammation (few inflammatory cells) Grade 2: Moderate lobular inflammation Grade 3: Severe lobular inflammation The NAS is calculated by adding the individual scores of steatosis, ballooning, and lobular inflammation → the total NAS score ranges from 0 to 8, but a score ≥ 5 suggests the presence of NASH. NAS reflects liver inflammation and injury but does not assess fibrosis, which is more indicative of chronic and long-term liver damage. Fibrosis is not included in the score beacuse it’s less reverisble. It is typically assessed separately from NAS. Fibrosis assessment is crucial for understanding the extent of permanent damage caused by conditions like NAFLD and NASH. NON-INVASIVE METHODS TO ASSESS STEATOSIS SEVERITY, which can help diagnose fatty liver and monitor its progression without the need for liver biopsy: Imaging Techniques like FibroScan (Elastography): This test measures liver stiffness, which helps assess fibrosis (scarring). Serum Biomarkers and Scores: liver enzymes like → Alanine Aminotransferase (ALT) = Elevated ALT levels are often associated with liver fat accumulation and damage, It is commonly used as an indicator of liver injury →.Aspartate Aminotransferase (AST): Elevated AST levels can also suggest liver damage, GENETIC VARIANTS OF STEATOSIS Steatosis, or fatty liver, is influenced by both lifestyle and genetic factors. Several genes have been identified that contribute to the risk and progression of non-alcoholic fatty liver disease (NAFLD). It's estimated that genetic factors contribute to approximately 50% of the risk in developing steatosis. This has been supported by various studies including:  ✓ twin studies, which show that monozygotic (identical) twins share more similar liver fat levels compared to dizygotic (fraternal) twins, highlighting the significant role of genetics in NAFLD development. These studies suggest that liver fat content is highly heritable, with an estimated heritability of over 50%. ✓ Further evidence comes from family studies. A large-scale study in Hispanic families, a group with a high prevalence of NAFLD, found that liver fat content was highly correlated among family members, even after accounting for other metabolic factors like obesity and insulin resistance. First-degree relatives (such as parents, siblings, or children) of people with NAFLD are at a higher risk of developing fatty liver disease, reinforcing the genetic influence. Several genetic variants have been strongly associated with increased liver fat accumulation and the development of NAFLD.These genetic factors contribute to the familial clustering of NAFLD, as certain mutations are more common in specific populations and tend to run in families. Key Genetic Variants: The PNPLA3 gene variant is the most well-studied genetic risk factor for NAFLD. It has been shown to run in families and is strongly associated with increased liver fat, inflammation, and fibrosis. 2008: A study of Mexican-American families found that liver fat content was highly heritable and the PNPLA3 variant has been strongly associated with an increased risk of non-alcoholic fatty liver disease (NAFLD) and its more severe forms. This mutation causes a substitution of isoleucine (I) to methionine (M) at the position 148 of the protein. This change impairs hydrolyzing activity -> less hydrolysis of triglycerides which start to be accumulated in the liver. The I148M variant is particularly common in certain populations, such as Hispanic/Latino populations, who have a higher prevalence of NAFLD. Individuals with the I148M mutation should pay close attention: Diet and Nutrition, Avoid sugary beverages, processed foods, and refined carbohydrates. TM6SF2 variant mutation involves a substitution of glutamic acid (E) to lysine (K) at position 167 of the protein which is involved in lipid processing and export. It is predominantly expressed in the liver and small intestine. The TM6SF2 protein is localized in the endoplasmic reticulum (ER) and membranes of liver cells (hepatocytes), where it helps in the secretion of very-low-density lipoprotein (VLDL), which transports triglycerides in the bloodstream. This mutation impairs VLDL secretion, leading to triglyceride buildup in liver cells. Individuals with this variant often show elevated levels of alanine aminotransferase (ALT), a marker for liver injury, suggesting liver dysfunction. MBOAT7 gene variant: encodes a membrane-bound enzyme, which is localized to the endoplasmic reticulum (ER) and the plasma membrane of cells, where it facilitates the acylation of phospholipids. The MBOAT7 protein transfers fatty acids (acyl groups) to phospholipids, a process essential for lipid metabolism, membrane structure, and cell signaling. In the liver, this process is critical for the synthesis of phospholipids, which in turn plays a role in lipid storage, lipid signaling, and cell membrane functions. Mutations in this gene, such as rs641738 C>T, impair the enzyme’s ability to properly modify phospholipids. The MBOAT7 mutation has been associated with an increased risk of progression from simple fatty liver (steatosis) to more severe forms of liver disease, The genetic screening should be done at least in obese subjects. It is important to understand if the individuals are carriers  HYPERTENSION CARDIAC CYCLE -> The cardiac cycle is the sequence of events in one complete heartbeat, involving the contraction (systole) and relaxation (diastole) of the heart chambers to pump blood effectively. A complete cycle lasts about 800 milliseconds (ms) at rest, with diastole taking approximately 500 ms and systole about 300 ms. During exercise, when the heart rate increases, the diastolic phase shortens significantly. These stages of contraction and relaxation occur in a highly coordinated sequence, ensuring that blood is continuously and efficiently circulated to supply oxygen and nutrients to the body while removing waste products. The heart has four chambers: two atria (upper chambers) that collect blood and two ventricles (lower chambers) that pump blood out. The heart also has valves between these chambers ensure one-way blood flow and prevent backflow. The cardiac cycle is divided into three main stages: 1. Diastole (Isovolumic Relaxation, diatolic Filling): Both the atria and ventricles are relaxed. Blood flows into the atria, The pressure in the atria keeps the atrioventricular (A-V) valves open, allowing blood to flow passively into the ventricles. This passive filling accounts for 70–80% of the ventricular volume, the ventricles relax without changing their volume as all valves are closed. Diastole is the longest phase and allows the heart to fill with blood. 2. Atrial Systole (Atrial Contraction, Extra Filling): The atria contract to push the remaining 20–30% of blood into the ventricles. This ensures the ventricles are fully filled with blood, preparing them for the next phase of powerful contraction. 3.Ventricular Systole (Ventricular Isovolumic Contraction, Pumping): The ventricles contract, with no change in volume, closing the atrioventricular (AV) valves (to prevent backflow into the atria) and the pressure in the ventricles exceeds that in the arteries (pulmonary and aorta), forcing the semilunar valves open and ejecting blood into the circulation. o The right ventricle pumps deoxygenated blood to the lungs through the pulmonary artery. o the left ventricle pumps oxygenated blood to the rest of the body through the aorta. Therefore each side of the heart has distinct roles: The right side sends blood to the lungs for oxygenation, while the left side pumps oxygenated blood to the body. ELECTRICAL CONDUCTION SYSTEM→ The cardiac cycle is initiated and coordinated by the heart's intrinsic electrical conduction system: This process begins with the SINOATRIAL SA NODE, located in the right atrium, which acts as the primary pacemaker of the heart. The SA node generates electrical impulses at a rate of 60- 100 beats per minute (bpm) due to its spontaneous automaticity. These impulses spread through the right and left atria, causing atrial depolarization and triggering atrial contraction. The electrical impulse then travels to the ATRIOVENTRICOLAR AV NODE, which serves as a secondary pacemaker with an intrinsic rate of 40-60 bpm if the SA node fails. The AV node slows down the electrical signal slightly to allow the ventricles time to fill with blood from the atria. After this brief delay, the impulse moves into the BUNDLE OF HIS. Which splits into two branches: the right bundle and the left bundle. These branches rapidly conduct the electrical signal to the Purkinje fibers. The Purkinje fibers transmit depolarization to the right and left ventricular myocardium which triggers the ventricles to contract. This coordinated contraction of the ventricles pumps blood  to the lungs and the rest of the body. the ventricular cells act as a backup pacemaker with an intrinsic rate of 20-45 bpm. The heart's electrical activity can be observed on an electrocardiogram (ECG), which records the electrical impulses as they move through the heart. The major features of an ECG include: P wave: Represents atrial depolarization (SA), triggers atrial contraction. PR interval = is the time period from the initiation of the P wave to the beginning of the QRS complex, It indicates the time it takes for the electrical signal to travel through the atria and the atrioventricular (AV) node, allowing the atria to contract before the ventricles. QRS complex: Represents ventricular depolarization, triggering ventricular contraction. Where R wave represents the depolarization of the large ventricular muscle cells, creating a strong electrical signal. T wave: Represents ventricular repolarization, which signals ventricular relaxation. ECGs are recorded on special paper divided into gridlike boxes →there are small booxes (1 mm²) that are grouped into larger boxes. The horizontal axis represent time (seconds) while vetically shows the amplitude of the electical signal. This grid helps measure the timing and strength of the heart's electrical activity during each heartbeat. HEART RATE HR = is the number of times the heart beats in one minute (measured in beats per minute bpm). A faster heart rate increases the volume of blood pumped over a particular period of time STROKE VOLUME SV = is the volume of blood ejected during ventricular contraction (systole). It is calculated as the difference between the volume of blood in the ventricles at the end of diastole (end- diastolic volume, EDV) and the volume remaining at the end of systole (end-systolic volume, ESV). Thus,stroke volume SV =EDV- ESV, because Not all the blood in the heart is pumped out during contraction; some remains as ESV. CARDIAC OUTPUT CO= is the total amount of blood pumped by the heart in one minute (expressed in liter/min). It reflects the heart's efficiency as a pump and depends on factors like HR, SV, contractility, preload, and afterload. It is measured by multiplying the heart rate (HR) by the stroke volume (SV): CO = SV *HR PRELOAD = It determines the degree of myocardial distension, refers to the amount of stretch of the heart’s ventricular walls before they contract. An intrinsic property of myocardial cells is that the force of their contraction depends on the length to which they are stretched: the greater the stretch (within certain limits), the greater the force of contraction. An increase in the distension of the ventricle will therefore result in an increase in the contraction force, which will increase cardiac output. AFTERLOAD = It’s the force/ the resistance that the ventricles need to overcome to eject blood, especially the left ventricle when pumping blood into the aorta. it is largely dependent on the arterial blood pressure and vascular tone If the blood vessels are narrow (due to constriction), the resistance increases, raising afterload. ARTERIAL PRESSURE (also called blood pressure BP) is the force exerted by blood against the walls of arteries, It is mainly influenced by two key factors: Cardiac output (CO) -> The amount of blood the heart pumps per minute. It depends on: o Stroke volume (SV): The volume of blood ejected from the heart with each beat, influenced by how strongly the heart contracts (preload-myocardial contractility). o Heart rate (HR): The number of times the heart beats per minute.  Peripheral resistance (PR) -> The resistance that blood encounters as it flows through the smaller blood vessels (arterioles and small arteries). It is determined by functional and anatomic changes in the small arteries and arterioles. o Vascular structure -> Conditions like atherosclerosis (stiffening or thickening of arteries) increase resistance by making vessels less flexible. o Vascular function -> changes in blood vessel diameter, often due to: ➔ vasoconstriction (narrowing of blood vessels increases resistance) ➔ vasodilation (widening decreases resistance). ➔ These changes are influenced by hormones, such as catecholamines which include epinephrine (adrenaline) and norepinephrine (noradrenaline), which regulate vessel tone and overall cardiovascular function. SODIUM/SALT CAN INFLUENCE BLOOD PRESSURE: Sodium (Na⁺) is the most abundant extracellular ion and plays a crucial role in regulating the extracellular fluid volume (ECF). How Sodium Affects extracellular Fluid Volume? Sodium affects water balance in the body because water tends to follow sodium. This is because water moves by osmosis, flowing to areas where there is a higher sodium concentration. As sodium levels rise, the body retains more water, leading to an increase in blood volume. This, in turn, raises the amount of blood pumped by the heart (cardiac output) and consequently, blood pressure. More sodium = more water retention = larger blood volume. The kidneys are primarily responsible for regulating sodium levels in the body, by removing excess sodium through urine, maintaining balance. If sodium intake is too high (like from too much salt in the diet) than what the kidneys can excrete, sodium begins to accumulate in the body. As a result, more water is also retained to balance the sodium, and this raises blood volume, cardiac output which can elevate blood pressure. Excess sodium can overstimulate the cardiovascular system, causing Na-Cl dependent hypertension (high blood pressure): Sodium affects blood pressure in three main ways: 1. Neural processes (Adrenergic Reflexes) => The nervous system controls short-term blood pressure regulation through the release of neurotransmitters: o Norepinephrine: Increases heart rate and narrows blood vessels, raising blood pressure. o Epinephrine (Adrenaline): Similar to norepinephrine, but with a broader effects, increasing heart rate, narrowing blood vessels, and boosting metabolism, which raises blood pressure, especially during stress or exercise. o Dopamine: Helps regulate blood vessel tone and kidney function, causing blood vessels in the kidneys to widen (vasodilation), which can help lower blood pressure. These neurotransmitters work together with the renin-angiotensin-aldosterone system (RAAS) to maintain blood pressure balance. 2. hormonal (endocrine and paracrine) => homones like mineralocorticoids (e.g., aldosterone) can increase sodium reabsorption of sodium by the kidneys. If too much aldosterone is produced, more sodium is retained, which cause blood vessels to narrow (vasoconstriction) increases blood volume and raises blood pressure. 3. vascular processes=> Sodium can cause blood vessels to constrict (narrow), increasing vascular resistance and raising blood pressure. Autoregulation of Blood Flow = Many vascular beds (groups of blood vessels that supply specific organs or tissues) can adjust their own blood vessel diameter to control blood flow, ensuring it stays relatively constant, even when factors like blood pressure change. When arterial pressure increases due to sodium-induced volume expansion, these vascular beds must increase resistance to maintain a steady blood flow to the organs. Relationship Between Blood Pressure and Resistance: Blood flow is determined by the pressure through the vessels (P) and the vascular resistance (R) the blood encounters. When arterial pressure (P) increases, the body compensates by increasing vascular resistance (R) to maintain constant blood flow (Q) to organs like the brain, heart, and kidneys. if sodium intake increases, it raises blood pressure → To maintain steady blood flow, the body increases resistance in blood vessels through vasoconstriction, which narrows the vessels. RAAS The Renin-Angiotensin-Aldosterone System (RAAS) is a key system in regulating blood pressure and fluid balance in the body. How it works: 1. TRIGGERING OF RAAS Norepinephrine and epinephrine are released primarily by the sympathetic nervous system during stress, low blood pressure, or physical activity. These two chemicals bind to β1-adrenergic receptors on juxtaglomerular cells (specialized cells in the kidney) which release renin, an enzyme). 2. RENIN ACTIVATION Renin cleaves a protein called angiotensinogen (produced by the liver) into angiotensin I, which is an inactive precursor, decapeptide (10 aa) 3. CONVERSION TO ANGIOTENSIN II Angiotensin I is converted into the active octapeptide angiotensin II by an enzyme called angiotensin-converting enzyme (ACE), mainly in the lungs. Angiotensin II is a potent vasoconstrictor, meaning it narrows blood vessels, which increases vascular resistance and raises blood pressure. 4. EFFECTS OF ANGIOTENSIN II Angiotensin II binds to AT1 receptors on cells in blood vessels and other organs, leading to: Vasoconstriction (narrowing of blood vessels), which directly raises blood pressure enhances sympathetic nervous system activity, causing more norepinephrine release. This creates a positive feedback loop, amplifying the effects of RAAS and increasing blood pressure even further. Aldosterone secretion from the adrenal zona glomerulosa 5. ALDOSTERONE ROLE Aldosterone is a potent mineralocorticoidthat helps regulate sodium and water balance in the body, by increasing sodium reabsorption. It acts on the kidneys, specifically on principal cells in the distal convoluted tubules and collecting ducts. Aldosterone binds to a receptor called the mineralocorticoid receptor (MR), a nuclear hormone receptor, that provides the activation of specific genes triggering a cascade of events that increases the number and activity of epithelial sodium channels ENaC. These channels allow sodium ions (Na⁺) to be reabsorbed from the urine back into the bloodstream while potassium (K⁺) is excreted. As sodium is retained, water follows by osmosis, leading to increased blood volume, increasing the total volume of blood in the circulatory system which further raises blood pressure. 6. CORTISOL ROLE  The body also has a hormone called cortisol, which is similar to aldosterone and can bind to the mineralocorticoid receptor (MR). This is due to the MR has structural similarities to the glucocorticoid receptor (GR), which is cortisol normal receptor. In the bloodstream, cortisol levels are much higher than aldosterone levels. However, the body has a mechanism to prevent cortisol compete with aldosterone for the MR and cause inappropriate effects, such as uncontrolled sodium retention. Recap The renin-angiotensin-aldosterone system (RAAS) regulates arterial pressure through two main actions: THE VASOCONSTRICTOR PROPERTIES OF ANGIOTENSIN II - THE SODIUM RETAINING PROPERTIES OF ALDOSTERONE. There are three primary factors that trigger the release of renin, an enzyme that starts the RAAS cascade: 1) Decreased NaCl (Sodium Chloride) Transport in the distal portion of the Thick Ascending Limb of the Loop of Henle. When the sodium chloride (NaCl) concentration is lower in the distal part of the thick ascending limb of the loop of Henle, this decrease is detected by the macula densa cells of the juxtaglomerular apparatus (structure in the kidneys that regulates renal function) which signal the juxtaglomerular cells to secrete renin to increase sodium and fluid retention, which will raise blood pressure. 2) Decreased Pressure or Stretch Within the Renal Afferent Arteriole (Baroreceptor Mechanism). If there is a drop in blood pressure or blood flow to the kidneys, baroreceptors in the renal afferent arteriole sense this change and stimulate renin release to help raise blood pressure. 3) Sympathetic Nervous System Stimulation of Renin-Secreting Cells via β1-Adrenergic Receptors Norepinephrine, released by sympathetic nerve terminals, stimulates β1- adrenergic receptors located on the juxtaglomerular cells of the kidney. Activation of these β1 receptors directly promotes the secretion of renin. PRIMARY HYPERTENSION Primary hypertension accounts for about 80–95% of high blood pressure cases. It has no single identifiable cause. Instead, it arises from a combination of environmental factors and genetic influences. → Environmental factors include: dietary salt intake, stress, obesity, lack of exercise, alcohol consumption, and smoking. Genetic factors suggesting that certain genetic variants influence the regulation of blood pressure. SECONDARY HYPERTENSION The remaining 5–20% of hypertensive cases fall under the category of secondary hypertension, where a specific underlying cause can be identified. RENOVASCULAR HYPERTENSION is a form of secondary hypertension caused by problems with the renal arteries that supply blood to the kidneys. It is a potentially curable form of hypertension that results from an occlusive lesion (a blockage or narrowing) in one or both of the renal arteries. This leads to a reduction in blood flow to the kidneys, which triggers the renin-  angiotensin-aldosterone system (RAAS), raising blood pressure as a compensatory mechanism. There are two main groups of patients at risk for this condition: o Older patients with atherosclerosis = Often involves plaque formation at the origin of the renal artery. This can obstruct blood flow in the renal arteries. More common. o Patients with fibromuscular dysplasia (FMD) = especially affects younger white women. It is characterized by abnormal cellular growth in the walls of medium and large arteries, including the renal arteries. The lesions are often bilateral and tend to occur in the distal