General Pathology PDF

GENERAL PATHOLOGY Grace, Yna, Ja | FINALS NUTRITIONAL DEFICIENCIES stress and it can go into MALNUTRITION lysis. So you can have...

GENERAL PATHOLOGY Grace, Yna, Ja | FINALS NUTRITIONAL DEFICIENCIES stress and it can go into MALNUTRITION lysis. So you can have anemia because of the Malnutrition is a consequence of inadequate lack of carbohydrates in intake of proteins and calories or deficiencies in the body the digestion or absorption of proteins resulting in - When you lack carbohydrates in the body, the loss of fat and muscle mass, weight loss, and the next thing your body will burn is fats, generalized weakness (body malaise). that's why you have what you call a ★ Center of nutritional deficiencies ketogenic diet. ★ Not only lacking of nutrition, it can be because - The digestion of fats ends with the of too much nutrition beta-oxidation of fatty acids. Fats are Lower income countries - malnourishment, composed of fatty acids, and the process of starvation breaking them down is through ★ Healthy body is also a healthy mind beta-oxidation. The end products of Higher income countries - obesity beta-oxidation of fatty acids are keto acids: - acetone, - alpha-ketobutyric acid DIETARY INSUFFICIENCY - Ketone. - These 3 are ketogenic and can cause acidosis in the AN APPROPRIATE DIET SHOULD PROVIDE: body when they accumulate. This condition 1. Sufficient energy, in the form of is known as ketosis, which carbohydrates, fats, and proteins. can actually be observed." - On macromolecules, it composed of your - In diabetic patients, especially those with carbohydrates, proteins, lipids and nucleic type 1 diabetes, who cannot utilize sugar, the acids body starts using fats instead. When fat is - Nucleic doesn't count in diet broken down, ketones increase in the body, because its a genetic materials which are acidic. The body should not - Majority of foods should come from become too acidic; it needs to stay in a carbohydrates. Carbohydrates neutral state. comprise a big chunk of your - The end product of carbohydrate metabolism calories is combustion. When we say 'combustion,' - The division of food intake: it's the reaction with oxygen. So, - 60% should be carbohydrates react with oxygen to form coming from carbon dioxide, water, energy, and heat. The carbohydrates, combustion of carbohydrates only produces - 25% should come carbon dioxide and water—it doesn’t from fats/lipid, produce keto acids, which could make the and body acidic. That’s why it’s more favorable - 15% from the for the body to utilize carbohydrates rather proteins than fats. - Carbohydrates is the main source - Although fats provide more ATP, or energy, of energy in your body than carbohydrates, the degradation of fats - You cannot remove carbohydrate produces keto acids. because there are parts of our body 2. Amino acids and fatty acids to be used as that rely on glucose (which is only building blocks for synthesis of proteins and supplied by your carbohydrates), lipids. - like your brain comes from - Protein is important for growth, which is why sugars red blood cell does it's part of the 'go, grow, glow' foods. not contain mitochondria - 'Grow' foods are called that and nucleus, It just because they are mainly composed depends on anaerobic of protein-rich foods. respiration or the - 'Go' foods are energy-giving, mostly fermentation of your carbohydrates, sugars to produce two - 'glow' foods are fruits and molecules of ATP and vegetables, which provide a natural lactic acid, so without the glow because they contain energy coming from the collagen. ATP, your red blood cell - It’s better to eat fruits and vegetables rather can go into oxidative GENERAL PATHOLOGY Grace, Yna, Ja | FINALS than relying on collagen supplements. cells. 3. Vitamins and minerals, which functions as A deficiency of Vitamin B12 can lead to coenzymes or hormones in vital metabolic a type of anemia called megaloblastic pathways anemia. - Coenzymes are like helpers in certain reactions. For example, clotting factors need SEVERE ACUTE MALNUTRITION coenzymes, like Vitamin K, through a carboxylation reaction. Another important vitamin involved is biotin, which is Vitamin B7 WHO defined severe acute malnutrition (SAM) as (not B5). Biotin is essential for the maturation a state characterized by a weight for height ratio of clotting factors. Any reaction involving that is 3 standard deviations below the normal carboxylation requires biotin. range. PRIMARY MALNUTRITION - one or all of the ★ Standard deviation is a measure of how above components are missing normal or typical a value is within a SECONDARY MALNUTRITION - malabsorption, population. In a normal curve, the mean is at impaired utilization or storage, excess loss, or the center, and the standard deviations are at increased need for nutrients. the extremes, to the left and right. When we ★ impaired utilization, impaired absorption of the talk about standard deviation, we refer to how vitamins and minerals far a value is from the normal. For example, if someone is three standard deviations below Causes of insufficiency: the normal range, it means their height or weight is significantly lower than expected for POVERTY - poor individuals suffer from their age, which often indicates malnutrition. malnutrition and nutrient deficiency due to lack of Worldwide, about 50M children are affected by resources. SAM. ★ the poverty that creates disparity between the It is common in low income countries. classes 25% of children may be affected and where it is a ACUTE AND CHRONIC ILLNESS - the basal major contributor to the high death rates among metabolic rate rises in many illnesses, resulting in the very young increased daily requirements for all nutrients. SAM is previously called protein energy ★ So when you are sick, you need food. malnutrition (PEM) - spectrum of clinical CHRONIC ALCOHOLISM - alcoholic person may syndromes, all resulting from a dietary intake of suffer from malnutrition but more frequently on protein and calories that is inadequate to meet the vitamin deficiencies- thiamine, pyridoxine, folate, body's need. vitamin A, as a result of poor diet, defective ★ "When the dietary intake of protein is less gastrointestinal absorption, abnormal nutrient than the body's needs utilization and storage, increased metabolic needs. MARASMUS and KWASHIORKOR ★ two clinical presentations of severe acute ★ Vitamin B1, or thiamine is used in the liver to malnutrition." help detoxify. TWO PROTEIN COMPARTMENTS IN THE BODY: IGNORANCE AND FAILURE OF DIET ★ SOMATIC - stored in the skeletal muscles SUPPLEMENTATION - Ignorance is a bliss but "Your muscles are composed of not in nutrition. proteins, and particularly in your ★ Ex. Iron deficiency in infants fed exclusively organs, especially the liver. As we artificial milk diets (breast milk is the best discussed last time regarding edema, milk for babies up to 6 months). the main form of protein in the blood is SELF-IMPOSED DIETARY RESTRICTION - albumin, which is produced by the liver. anorexia nervosa, bulimia, and less overt eating In severe malnutrition, disorders affect individuals who are concerned ★ VISCERAL - stored in internal organs, about body image. primarily liver OTHER CAUSES - GI diseases, malabsorption The somatic compartment is affected more syndromes, genetic diseases, drug therapies, severely in marasmus, and the visceral surgeries (resection of intestines) compartment is depleted severely in kwashiorkor ★ In your intestine, there is a specific portion in the jejunum where Vitamin B12, or cobalamin, is absorbed. If this process is disrupted, you can develop a Vitamin B12 deficiency. Cobalamin is very important in the development and maturation of red blood GENERAL PATHOLOGY Grace, Yna, Ja | FINALS MARASMUS happens because the body has used up its protein stores due to protein deprivation in the Marasmus develops when the diet is severely diet. As a result, the liver becomes exhausted lacking in calories. from trying to produce protein. When there is ★ It is a deficiency, not primarily related to a decrease in protein in the liver, protein. hypoalbuminemia occurs, leading to a A child is considered to have marasmus when decrease in plasma oncotic pressure, which weight falls to 60% of normal for sex, height, and causes edema. sex. Children with kwashiorkor have characteristic skin A marasmic child suffers growth retardation and lesions with alternating zones of loss of muscle mass as a result of catabolism and hyperpigmentation, desquamation, and depletion of somatic protein. hypopigmentation, giving a "flaky paint" ★ When you're lacking carbohydrates, the body appearance. will start to break down fat for energy. Once ★ "Hyperpigmentation refers to darkly stained or the fat stores are depleted, the next source of darkly colored skin, energy is protein. So, when there’s a lack of ★ Desquamation refers to the shedding or carbohydrates, the body will deplete somatic peeling of skin. protein. This is why children with marasmus ★ Hypopigmentation, on the other hand, is the become very thin. However, the depletion of presence of lighter or white areas on the visceral protein occurs only marginally. skin." The visceral protein however is depleted only ★ There are also changes in the hair, such as marginally, so serum albumin levels are either loss of color, alternating bands of pale and normal or only slightly reduced EDEMA darker color, straightening, fine texture, and Due to loss of muscle and subcutaneous fat, the loss of firm attachment to the scalp. As a extremities are emaciated, by comparison, the result, hair may become brittle and lead to head appears too large for the body. hair loss. Anemia and manifestations of multivitamin ★ "Other features that distinguish Kwashiorkor deficiencies are present and there is evidence of from Marasmus include an enlarged fatty liver, immune deficiency, particularly of T cell- mediated which results from the reduced synthesis of immunity. carrier proteins that are part of lipoproteins. Without these carrier proteins, fats and KWASHIORKOR cholesterol cannot be properly transported out of the liver, leading to the accumulation of fat Kwashiorkor occurs when protein deprivation is within the liver, producing a fatty liver." relatively greater than the reduction in total ★ like marasmus vitamin deficiencies are likely calories. to be present as are defects in immunity and ★ Here, there are still calories, but the emphasis secondary infections which produce is on the reduction in protein—protein inflammation and a catabolic state that deprivation. aggravates malnutrition This is the most common form of SAM seen in African children, who have been weaned too early and subsequently fed, almost exclusively, a carbohydrate diet. ★ Early weaning means stopping breastfeeding too soon, and when you stop breastfeeding early and replace it with a carbohydrate-rich diet, like porridge, fruits, or rice, you neglect the protein requirements. Protein is crucial for growing children and babies because it is used as a building block for muscles. In kwashiorkor, unlike marasmus, a marked protein deprivation is associated with severe loss - "The total calorie intake of individuals with of visceral protein compartment, and the resultant Marasmus is significantly lower than the hypoalbuminemia gives rise to generalized or required daily caloric intake, but their visceral dependent edema. protein stores are not as severely depleted. ★ The visceral protein compartment is the one This is why they do not have edema, unlike that gets depleted. those with Kwashiorkor. In Kwashiorkor, ★ Marasmus does not have edema, whereas there is a severe deficiency in protein, which Kwashiorkor does, because there is a marked decrease in protein synthesis in the liver. This leads to the depletion of protein stores in the GENERAL PATHOLOGY Grace, Yna, Ja | FINALS liver. This causes generalized edema, or thyroid hormone release include cold intolerance, swelling, due to the decrease in plasma bradycardia, constipation, and changes in the skin oncotic pressure." and hair. ★ People with anorexia may also develop ANOREXIA NERVOSA AND BULIMIA thyroid problems, leading to symptoms such as cold intolerance, similar to hypothyroidism, Anorexia nervosa is self-induced starvation, constipation, and changes in skin and hair, resulting in marked weight loss; bulimia is a which may indicate either hypo- or condition in which the patient binges on food and hyperthyroidism." then induces vomiting. In addition, dehydration and electrolyte ★ They Are pushing their uvula to vomit abnormalities are frequently present. The skin These eating disorders occur primarily in the becomes dry and scaly previously healthy young women who have ★ they do not They only eat a little they also developed obsession with body image and only drink a little thinness. Increased fat in the marrow associated with a ★ "They have body dysmorphia, which is part of peculiar deposition of mucinous matrix material the obsessive-compulsive disorder (OCD) that is referred to as gelatinous transformation spectrum. It is a spectrum, with components is pathognomonic of anorexia. of both obsession and compulsion. In this ★ Increased fat in the marrow, or gelatinous condition, there is an obsession, which is a transformation, is pathognomonic, meaning it recurring thought in the mind that cannot be is diagnostic of a certain disease. When this removed unless something is done about it. occurs, it almost always points to anorexia. The compulsion part involves actions taken to The increase in fat is due to the lack of proper relieve or address the obsession. nutrition. ★ "What would be the compulsion? It could A major complication of anorexia nervosa (and involve purging the food you've eaten, hurting bulimia) is an increased susceptibility to cardiac yourself, or starving yourself to become arrythmia and sudden death, resulting from thinner." hypokalemia. The neurobiologic underpinnings of these ★ `"Due to electrolyte deficiencies and diseases are unknown, but it has been suggested dehydration, they can experience cardiac that altered serotonin metabolism may be an arrest, cardiac arrhythmia, or death, important component. particularly as a result of hypokalemia, or low ★ serotonin is the happy hormone potassium levels." ★ Give them antidepressants, which can help in In bulimia, binge eating is the norm. the recycling of serotonin. We have an Large amounts of food, principally carbohydrates, antidepressant called selective serotonin are ingested, followed by induced vomiting reuptake inhibitors, which can fix serotonin ★ "What they do is eat and eat because they problems. Psychological disorders are of want to enjoy food, but they don't want to gain neurobiological origin, not just because weight, so they induce vomiting. someone is being dramatic. There is Although menstrual irregularities are common, something happening in the brain, and it can amenorrhea occurs less than 50% of bulimic be treated with pharmacologic therapies and patients because weight and gonadotropin levels psychotherapy. remain near normal. The clinical findings in anorexia nervosa are ★ This is because they are still able to eat, but generally similar in SAM. since they induce vomiting, they are not Amenorrhea, resulting from decreased secretion absorbing all the nutrients. These are the of GRH and LH and FSH, is common and is major medical complications: electrolyte considered a diagnostic feature. imbalance, such as hypokalemia, which is ★ "Because of the lack of nutrients, your body also common in anorexia nervosa, and it can no longer function properly. Without predisposes the patient to cardiac arrhythmias nutrition, the brain struggles to produce and pulmonary aspiration." hormones. Specifically, the MAJOR MEDICAL COMPLICATIONS: gonadotropin-releasing hormone, which 1. Electrolyte imbalances (hypoK), which stimulates the glands to produce luteinizing predispose the patient to cardiac hormone (LH) and follicle-stimulating arrhythmias; hormone (FSH). This is why individuals with - They develop hypokalemia, similar to nutrient deficiencies may experience anorexia nervosa, which predisposes the amenorrhea or irregular menstruation, as LH patient to cardiac arrhythmias and and FSH are crucial in the menstrual cycle. pulmonary aspiration of gastric contents. Other common findings related to decreased Remember, when vomiting is induced, GENERAL PATHOLOGY Grace, Yna, Ja | FINALS gastric contents may be aspirated into the lungs, which can lead to aspiration pneumonia. Additionally, there is a risk of esophageal and gastric rupture due to the acidic contents from the stomach. 2. Pulmonary aspiration of gastric contents; and 3. Esophageal and gastric rupture - "They have this problem, and sometimes bulimic patients experience hoarseness because their larynx is affected by the repeated reflux of gastric contents into the esophagus and oral cavity. The treatment for bulimia involves psychotherapy." - "You can observe that in the center, the majority of the bone marrow is replaced by a mucinous matrix, which appears gelatinous. The red islands, which represent the normal marrow, are seen, but they are smaller because they have been replaced by this matrix material. As a result, there is little production of blood components, leading to anemia, which is very evident." GENERAL PATHOLOGY Grace, Yna, Ja | FINALS and differentiation, and regulation of lipid metabolism Vit A include retinol, retinal, retinoic acid, VITAMIN DEFICIENCIES which have similar biologic activities. Thirteen vitamins are necessary for health; Animal-derived foods such as liver, fish, vitamins A, D, E, K are fat-soluble, and all eggs, milk, and butter are important dietary others are water-soluble. sources of preformed Vit A. ○ If a substance is fat-soluble, it has Yellow, and leafy green vegetables such as the ability to be stored in the body carrots, squash, and spinach supply large because it can pass through the amounts of carotenoids, provitamins which lipid layer. This is because, as we can be metabolized to Vit A. know, like dissolves like. Fat can The most important carotenoid is B-carotene dissolve in a fat solution, and fats which is efficiently converted to Vit A. can pass through the lipid bilayer. Vit A is a fat-soluble vitamin, and its Since fats are not charged, they absorption requires bile, pancreatic cannot interact directly with the lipid enzymes, and some level of antioxidant layer. This means they do not get activity in the food. stuck in the middle but pass ○ Bile emulsifies the food through smoothly. Emulsification - it makes Fat-soluble vitamins are more readily stored the fat molecules able to in the body, but they may be poorly absorbed be dissolve in aqueous in fat malabsorption disorders. solution ○ Fat-soluble vitamins have the ability Retinol and B-carotene are absorbed in the to be stored in the body, and intestine, where B- carotene is also because of this, they are more likely converted to retinol. to cause toxicity. In contrast, Retinol is then transported in chylomicrons water-soluble vitamins are excreted going to the liver for storage - they are stored through urine, which is why they in the perisinusoidal cells of ITO. need to be taken regularly, typically ○ ITO cells in liver - storage of vitamin on a daily basis. Fat-soluble A vitamins, however, should be taken ○ Chylomicrons are lipoprotein that in smaller amounts and less carry fatty acids frequently. ○ Vit A can be stored ○ A vitamin deficiency can be primary, In healthy persons who consume an originating from a lack of dietary adequate diet, these reserves are enough to intake, or secondary, resulting from last for 6 months. issues with intestinal absorption or Once taken up to the peripheral tissues, transport in the blood, such as in retinol is oxidized to retinoic acid which is cases of malnutrition. A primary important in epithelial differentiation and deficiency occurs when there is growth. insufficient intake of the vitamin, while a secondary deficiency happens due to problems with absorption. ○ A deficiency of vitamins may be primary (dietary in origin) or secondary to disturbances in intestinal absorption, transport in the blood, tissue storage, or metabolic conversion. VITAMIN A The major functions of Vit A are maintenance of normal vision, regulation of cell growth GENERAL PATHOLOGY Grace, Yna, Ja | FINALS transmit visual stimulus going to the brain The change in opsin triggers a downstream changes which generates nerve impulses via neurons from the retina to the brain. 2. Cell growth and differentiation Activation of retinoic acid receptors (RARS) by their ligands causes the release of corepressors and the obligatory formation of heterodimers with another retinoid receptor, RXR. ○ Rar will bind to retinoid receptor The RAR/RXR heterodimers bind to retinoic acid response elements located in the regulatory regions of genes that encode receptors for growth factors, tumor suppressor gene, and secreted proteins. ○ - What you eat can be absorbed to intestines Through these effects, retinoids regulate cell via chylomicrons growth and differentiation, cell cycle control, - In intestines we have transport and other biological responses. molecules, which is lipoprotein ○ So they have a vital function in the - Then it will go to your lactyle differentiation and the proliferation - Lactyle- specialized of epithelial tissues transport system in Retinoids are used clinically for the treatment intestines where fats are of skin disorders such as severe acne and transported and circulated certain forms of psoriasis, as well as in the to the liver then convert treatment of acute promyelocytic leukemia. retinol to retinoic acid A different isomer, 13-cis-retinoic acid, has - Retinol is just a been used with some success in the transportation treatment of childhood neuroblastoma. form of vit a ○ Neuroblastoma most common - retinoic acid- malignancy in the eye active form of vit Vit A is very teratogenic, it can cause a congenital malformation VITAMIN A: FUNCTIONS VITAMIN A: DEFICIENCIES 1. Maintenance of normal vision Vit A deficiency occurs as a result of primary Cones and Rods are important in the visual malnutrition or secondary to conditions that pathway; Cones - sensitive to color, Rods - cause malabsorption of fats. important in reduced light. In children, stores of Vit A are depleted by The synthesis of rhodopsin from retinol infections, and the absorption of the vitamin involves: is poor in newborn infants. ○ (1) Oxidation to all-trans-retinal, Adult patients with malabsorption syndromes ○ (2) Isomerization to 11-cis-retinal, such as celiac disease, Crohn's disease and ○ (3) Covalent association with the colitis may develop Vit A deficiency in 7-transmembrane rod protein opsin conjunction with depletion of other to form rhodopsin. fat-soluble vitamins. A photon light causes the isomerization of ○ Crohn's disease and colitis are 11-cis-retinal to all-trans retinal, which inflammatory bowel diseases, its a dissociates from rhodopsin. Mal absorption of gird ○ The changes in rhodopsin is important because those changes GENERAL PATHOLOGY Grace, Yna, Ja | FINALS ○ You will have fat soluble vitamin light in the range of 290-315 nm (UVB deficiency when you have a radiation). problem in absorption ○ 7am to 9am - recommended time to go out for vitamin D The earliest manifestation of Vit A deficiency. This reaction results in the synthesis of is impaired vision, particularly in reduced cholecalciferol (1,25 light - NYCTALOPIA (night blindness) dihydroxycholecalciferol), known as vitamin ○ Low production of rod D3 - active form of Vit D. Persistent deficiency may lead to epithelial Under usual conditions of sun exposure, metaplasia and keratinization. about 90% of the required Vit D is Xerophthalmia (dry eyes) - first, there is synthesized by the skin. The remainder is supplied in the diet - deep sea fish, plants, dryness of the conjunctiva as the normal grains. lacrimal and mucus-secreting epithelium is In plants, Vit D exist as its precursor form replaced by keratinized epithelium. (ergosterol), which is converted to Vit D in - This is followed by a build-up of keratin the body. debris in small opaque plaques (Bitot spots) 1. Photochemical synthesis of Vit D from that progresses to erosion of the roughened 7-dehydrocholesterol in the skin and absorption of vitamín D from foods and corneal surface, softening and destruction of supplements in the gut. the cornea (Keratomalacia), and blindness, 2. Binding of Vit D from both the sources to Immunodeficiency plasma a1- globulin (D-binding protein Acute Vit A toxicity has been described in the [DBP]) and transport into the liver. consumptions in large amount the livers of 3. Conversion of Vit D into polar bears, whales, sharks, and even tuna. 25-hydroxycholecalciferol in the liver through Symptoms include headache, dizziness, the action of 25-hydroxylase enzyme. 4. Conversion of 25-hydroxycholecalciferol into vomiting, stupor, blurred vision, symptoms 1,25 dihydroxycholecalciferol - the most that may be confused with those of a brain active form of Vit D by the enzyme tumor (pseudotumor cerebri). 1a-hydroxylase in the kidneys. Use of retinoids in pregnancy should be The production of 1,25hydroxycholecalciferol avoided because of the well-established in the kidney is regulated by three main teratogenic effect. mechanisms: - Hypocalcemia stimulates PTH VITAMIN D - Hypophosphatemia upregulates The major function of Vit D is the ia-hydroxylase expression maintenance of adequate plasma levels of - Through negative feedback mechanism calcium and phosphorus to support VITAMIN D: FUNCTION metabolic functions, bone mineralization, Like retinoids and steroid hormones, and neuromuscular transmission. 1,25dihydroxycholecalciferol acts by binding ○ Correlated with calcium to a high affinity nuclear receptor which associates with RXR. It is a fat-soluble vitamin required in the In the small intestines, bones, and kidneys, prevention of bone diseases known as signals transduced via these receptors ○ RICKETS in children and regulate plasma levels of calcium and ○ OSTEOMALACIA in adults. phosphorus. Vit D can be acquired through exposure to Vit D has also immunomodulatory and sunlight. Supplementation should only be antiproliferative effects. considered to those who have altered VITAMIN D: CALCIUM AND PHOSPHORUS HOMEOSTASIS physiologic state or those who are Stimulation of intestinal calcium absorption - bed-bound and can't go outside. Vit D receptor and RXR causes the ○ The vitamin D that you get from the activation of TRPV6 which encodes a critical sunlight is the highest form of calcium transport channel. vitamin D Stimulation of calcium reabsorption in the VITAMIN D: METABOLISM kidneys - D3 increases calcium influx in the The major source of Vit D for humans is its distal tubules of the kidney by increased endogenous synthesis from a precursor, expression of TRPV5. 7-dehydrocholesterol, in a photochemical Interaction with PTH in the regulation of reaction that requires solar or artificial UV blood calcium - PTH regulates blood calcium GENERAL PATHOLOGY Grace, Yna, Ja | FINALS by increasing the resorption of calcium from the bones. - Both PTH and D3 enhance the expression of RANKL (receptor activator of NF-kB ligand) - RANKL binds to its receptor RANK located in preosteoclasts, thereby inducing the differentiation of mature osteoclasts. Increased osteoclastic activity = bone resorption Mineralization of bones - Vit D contributes to the mineralization of osteoid matrix and epiphyseal cartilage in both flat and long bones - It stimulates osteoblasts to synthesize the calcium-binding protein osteocalcin, which is involved in the deposition of calcium during bone development. VITAMIN D: DEFICIENCY AND TOXICITY Vit D deficiency leads to poor bone development or weak bone mineralization. - Rickets: deficiency of Vit D in children resulting in poor bone formation - Osteomalacia in adults Those that live in temperate countries may have Vit D deficiency states due to poor sunlight hence the supplementation of Vit D is required Prolonged sun exposure on the other hand does not produce Vit D toxicity but megadoses of oral supplementation. - In children, hypervitaminosis D can lead metastatic calcifications of soft tissues such as the kidney - In adults, it causes bone pain and hypercalcemia GENERAL PATHOLOGY Grace, Yna, Ja | FINALS OBESITY Ghrelin from the stomach, peptide YY It is defined as an accumulation of adipose (PYY) and glucagon-like peptide 1 tissue that is sufficient enough to impair (GLP1) from the ileum and colon, insulin health. from pancreas. Body Mass Index (BMI) - one of the most CENTRAL PROCESSING SYSTEM (Arcuate practical ways on how to measure fat nucleus of the hypothalamus) accumulation. The proportion of weight to ★ Comprising first and second order height (kg/m2). neurons that communicate with each Normal: 18.5-25 kg/m2 other. Overweight: 25-30 kg/m2 In the hypothalamus, the center for Obese: >30 kg/m2 neurohormonal control of energy intake However, obesity is described as both the and expenditure processes information true obese and overweight individuals. from the afferent system. Obesity is associated with T2DM, EFFERENT SYSTEM – consist of signals Dyslipidemia, CVD, hypertension, Cancer. generated by second order neurons and is The distribution of fats is associated with the organized along two pathways, catabolic and severity of the association of diseases - anabolic that control food intake and energy central or peripheral obesity. expenditure. Obesity is a major public health problem in higher income countries and an emerging health problem in lower income nations OBESITY AFFERENT SYSTEM ★ According to WHO, >1.9 B adults were LEPTIN- secreted by fat cells, and its output estimated to be overweight or obese is regulated by the adequacy of fat stores. globally in 2015. ★ BMI and body fat stores are directly ★ Women > Men related to leptin secretion. ★ With abundant adipose tissue, leptin No clear explanation to where obesity might secretion is stimulated and it crosses stem from - multifactorial. the blood-brain barrier and travels to the ★ Obesity is a disorder of energy hypothalamus, where it reduces food homeostasis intake by stimulating the first order ★ The two sides of the energy equation, neurons and second order neurons. intake and expenditure, are finely ★ When there are inadequate stores, regulated by neural and hormonal leptin secretion is diminished, food mechanisms so that body weight is intake is increased. maintained within a narrow range for Leptin does not only regulate food intake but years. energy expenditure. ★ Controlled and sensed by "lipostat" in ★ Abundance in leptin stimulates physical the body, it senses the quantity of activity, heat production, and energy energy stored and regulates food intake expenditure. as well as food ADIPONECTIN - "fat-burning molecule" - it stimulates fatty acid oxidation in skeletal ★ Inadequate = triggers anabolic circuits muscle, thereby reducing fatty acid levels. ★ Adequate = triggers catabolic circuits ★ Fatty acids can enter the blood-brain No clear explanation to where obesity might barrier and enter the hypothalamus. stem from - multifactorial. ★ They can be sensed by microglial cells; they will release inflammatory factors that appear to act on hypothalamic OBESITY: NEUROHORMONAL MECHANISM neurons to cause leptin resistance. ★ They promote beta oxidation of fatty acids. PERIPHERAL OR AFFERENT SYSTEM - collects and provides signals for the central GHRELIN - produced in the stomach and is processing system in the brain. the only known gut hormone that increases ★ Includes Leptin from the fat cells, food intake (orexigenic)- promotes food GENERAL PATHOLOGY Grace, Yna, Ja | FINALS intake (hunger) ★ Normally rises before meals and fall 1-2 OBESITY AND CANCER hours afterward There is an increased incidence of certain ★ This drop is attenuated in obese cancers in overweight people, including individuals compared with normal- cancers of the esophagus, thyroid, colon, and weight individuals. kidney in men and cancers of the esophagus, PYY and GLP-1 are secreted from endocrine endometrium, gallbladder, and kidney in cells in the ileum and colon (anorexigenic) women. ★ Plasma levels of PYY and GLP-1 are Elevated insulin levels low during fasting and increase shortly Peripheral conversion of fats – estrogen after food intake. via aromatase enzyme increases risk of ★ Both act centrally through the second ovarian, breast, cervical cancer, and cancers order neurons in the hypothalamus, that are responsive to estrogen. causing food intake. Adiponectin is reduced in obese individuals- ★ GLP-1 agonist - treatment for obesity adiponectin suppresses cell proliferation and and T2DM (Ozempic) promotes apoptosis. The proinflammatory state that is associated OBESITY: CLINICAL CONSEQUENCES with obesity may itself be carcinogenic. Central obesity is associated with an increase in all-cause mortality and is a known risk factor for a number of conditions including type 2 diabetes, cardiovascular disease and cancer. ★ Metabolic Syndrome - characterized by abnormalities of glucose and lipid metabolism coupled with hypertension and systemic proinflammatory state. ★ Caused by activation of the inflammasome by free fatty acids and excess levels of lipids in cells and tissue - stimulates secretion of IL-1 which induces systemic inflammation. Obesity is associated with insulin resistance and hyperinsulinemia - features of T2DM. Obese persons generally have hypertriglyceridemia and low HDL cholesterol levels, factors that increase the risk of coronary artery disease. Nonalcoholic fatty liver disease - can progress to fibrosis and cirrhosis. Cholelithiasis (gallstone) elevated cholesterol turnover leads to increased biliary excretion of cholester Obstructive Sleep Apnea (OSA) – structural deformities due to obesity. Marked adiposity is a predisposing factor for the development of degenerative joint disease (osteoarthritis) - due to wear and tear. Markers of inflammation, such as CRP and proinflammatory cytokines like TNF, are often elevated in obese persons, in particular people with central obesity.ol in bile - hypersaturation of bile = stone.