Metabolism PDF

Metabolism  1. Pathophysiology of regulation of food intake and body mass. Mental anorexia. Bulimia. Basal metabolic rate and factors influencing energy metabolism: RDI- reference daily intake- the amount of nutrient that sufficient for 97-98% of population in USA. Energy Metab...

Metabolism  1. Pathophysiology of regulation of food intake and body mass. Mental anorexia. Bulimia. Basal metabolic rate and factors influencing energy metabolism: RDI- reference daily intake- the amount of nutrient that sufficient for 97-98% of population in USA. Energy Metabolism: Energy is measured in heat units called calories- is the amount of heat/ energy required to raise the temperature of 1 g of water by 1 Celsius degree. Energy storage- Adipose Tissue: More than 90% of body energy is stored in the adipose tissues of the body. Energy Expenditure: The expenditure of body energy results from 5 mechanisms of heat production (thermogenesis): 1) Basal Metabolic Rate/ Resting Energy Equivalent. 2) Diet- induced thermogenesis- Describe the energy used by the body for digestion and absorption of food after ingestion (8% of total energy expended). 3) Exercise- induced thermogenesis- The type & length of the activity, and the person’s weight & physical fitness determine the amount of energy expended for physical activity. 4) Non exercise activity Thermogenesis (NEAT)- refers to the energy expended in maintaining posture and in activities such as fidgeting. (~7% of daily energy expenditure). 5) Thermogenesis in response to changes in environmental conditions- Shivering & Non shivering (caused by SY activation) thermogenesis in response to cold. The amount of energy used varies with age, body size, rate of growth, and state of health. Basal Metabolic Rate (BMR): BMR = amount of energy that the body expends when at rest in a naturally temperature environment (digestive system shouldn’t be working= 12 hours fast). This number tells how much energy you need to sustain your vital organs like your brain (19%), kidney, liver (consume 27%, highest), heart, lungs, skin, muscles, and your nervous system. The BMR constitutes 50%- 70% of body energy needs. 10% goes to food digestion and 20% to physical activity. BMR is measured using an instrument called- indirect calorimeter that measures a person’s rate of O2 use. O2 is measured under basal conditions: full night of sleep, after fasting of at least 12 hours, without pre-activity, in warm & comfortable room. Normal BMR values (average): a. Men: 2700-2900 kcal/day b. Women: 2000-2100 kcal/day Women have lower BMR because they have higher percentage of adipose tissues.  RMR (resting metabolic rate) = It is the whole-body metabolism during a time period in resting conditions (kcal/day), taking in account extra influencing factors („Real steady state“). 110%BMR = RMR Factors Influencing Energy Metabolism: 1. Body Size ▪ ↑Body Size (e.g. Height) → ↑BMR Increase BMR Decrease BMR 2. Body Fat ▪ ↑Body Fat (Obesity) → ↓BMR 3. Age ▪ Initial ↑Age (kid to teen) → ↑BMR ▪ Later ↑Age (teen to adult to elderly) → ↓BMR 4. Gender ▪ Males BMR > Female BMR (2700 > 2000) 5. Hormones ▪ Thyroid Hormones → ↑BMR ▪ Catecholamines → ↑BMR 6. Exercise ▪ ↑Physical Activity → ↑BMR 7. Nutrition ▪ Spicy Food (pepper/mustard) → ↑BMR ▪ Caffeine & Alcohol → ↑BMR (in attempt to restore homeostasis). 8. Fever ▪ Fever → ↑BMR (in attempt to restore homeostasis). Regulation of hunger and satiety: Neurohumoral regulation: ▪Central – hypothalamic centers ▪Peripheral – glycaemia, total fat mass ✓Short-term regulation: Glycaemia increase, insulin increase, stomach distension ✓Long-term regulation: Total fat mass → leptin → production directly comparable with body fat Hypothalamic Hunger & Satiety centers: The ARCUATE NUCLEUS controls both the Hunger & Satiety centers. This control is achieved by 2 types of neurons: 1. Orexigenic Neurons → Stimulate the HUNGER center. promote anabolism ↓ metabolism. 2. Anorexigenic Neurons → Stimulate the SATIETY center. Promote catabolism. ↑ metabolism. The control of food intake can be short- term (orexigenic- increase feeding & anorexigenic- decrease feeding), intermediate- and long- term regulation. The intermediate- and long- term regulation is determined by the amount of nutrients that are in the blood and in storage sites. decreased blood glucose → hunger. increase breakdown of lipids (eg: keto acids) → decrease in appetite. Orexins are also promote wakefulness: deficiency in orexin (hypocretion=Hcrtr2) will cause Narcolepsy- over sleepiness.  Orexigenic (ghrelin, PPAR, NPY) and anorexigenic (leptin, melanocortin, GLP) substances: Substance Type of Neurons it Secreted from Hypothalamic Receptor of Binding Stimulates Neuropeptide Y Orexigenic Hypothalamus Y-Receptors (Y1-Y5) (NPY), gouti related protein (AGRP) and hypocretin (Hcrtr) Ghrelin Orexigenic Stomach & Growth-Hormone Secretagogue Duodenum (Before Receptor (GHSR) meal). Growth hormone Orexigenic Pituitary gland Leptin (long term) Anorexigenic Adipocytes Leptin-Receptor (LEP-R) Peptide YY Anorexigenic Intestine (L-cells) Y-Receptors (Y1-Y5) slow gastric emptying and inhibit motility Insulin and amylin Anorexigenic β-cells of Pancreas Insulin Receptor (IR) GLP-1 (glucagon- Anorexigenic L-cells of the Glucagon-Like Peptide 1 Receptor like- peptide = intestine (GLP1R)- enhance insulin secretion incretin) α-MSH Anorexigenic Hypothalamus Melanocortin-1 Receptor (MC1R) Cholecystokinin Anorexigenic I cells in intestine Slow food emptying from stomach (CKK) Pancreatic peptide Anorexigenic Pancreas Adipocytes release leptin in proportion to the amount of fat stores. Stimulation of leptin receptors in the hypothalamus→ decrease appetite & food intake + increase metabolic rate and energy consumption + decrease insulin release from beta cells, which decreases energy storage in fat cells. CART= cocaine and amphetamine regulated transcription.  Regulating Factors of Hunger & Satiety: 1. GI hormones Before meal → Ghrelin (from the stomach) → ↑Hunger. During & after meal → GLP-1 (from the intestine) → ↓Hunger. 2. Adipose Tissue ↑Adipose tissue → ↑Leptin → ↓Hunger. 3. Temperature Cold → ↑Hunger → ↑food intake →↑Metabolic rate → ↑Heat formation. Higher food intake leads also to ↑fat formation → insulator. Vice versa with heat. This phenomenon is caused by interaction between the thermoregulation & food intake centers of the hypothalamus. 4. Insulin Insulin is secreted from the β-pancreatic cells in response to blood glucose, which is elevated during & after meal. Insulin → ↓Hunger. 5. Oral Receptors ↑Quantity of food has passed through the mouth → Receptors signal the hypothalamus → ↓Hunger. Malnutrition & Starvation: Malnutrition not eating enough food or not eating enough healthy food. Refers both to under nutrients or over nutrients. Refer to number of diseases each with specific cause related to one or more nutrients. Among the causes of malnutrition are: 1) ↓ intake of nutrients- social (poverty & ignorance), anorexia (mental, disease, drugs), pain, self- imposed dietary restriction. 2) ↓ assimilation- decreased digesting ability. 3) ↑ losses- diarrhea (intolerance, bulimia, infections, drugs), vomiting, chronic bleeding, nephrotic syndrome. 4) ↑ needs- physiological (pregnancy), pathological (cancer, sepsis, burns). Fasting: It is the abstinence (‫ )התנזרות‬from Some/All foods and/or drinks for a period of time. Starvation: It is a massive reduction of energy intake, which leads to weight loss. Primary and secondary concept Malnutrition: primary- occurs due to direct dietary factors and inadequate nutrient intake. It is primarily caused by a lack of access to or the consumption of an insufficient quantity or quality of food. Secondary- occurs when an individual's body cannot adequately absorb, utilize, or retain the nutrients from the food they consume, even if the diet is nutritionally adequate. This condition is often related to underlying health problems or physiological factors. Common causes of secondary malnutrition include gastrointestinal disorders (e.g., celiac disease, Crohn's disease, or chronic diarrhea) that impair nutrient absorption, metabolic disorders (e.g., diabetes or hyperthyroidism) that affect nutrient utilization, and chronic illnesses (e.g., cancer or HIV/AIDS) that increase nutrient requirements or lead to nutrient loss. Malabsorption: Primary- caused by a dysfunction or abnormality within the gastrointestinal system itself. This condition is typically intrinsic to the digestive system and often has a genetic or congenital component. Celiac disease is a common example of primary malabsorption. In celiac disease, the immune system reacts to gluten. Other examples of primary malabsorption include congenital sucrase-isomaltase deficiency (CSID), congenital lactase deficiency, and abetalipoproteinemia. Secondary- occurs because of an external factor or an underlying medical condition that affects the absorption of nutrients. Gastrointestinal diseases: Conditions such as Crohn's disease, ulcerative colitis, and chronic pancreatitis can disrupt the normal functioning of the digestive system and impair nutrient absorption. Surgery infections, Medications, Autoimmune disorders Characteristics: More often: diarrhea Least common: constipation  Simple and stress starvation. Changes in the organism during Fasting or Starvation: Sort-term starvation: (72 hours) With short periods of starvation, there is diminished insulin and increased glucagon and catecholamine secretion leading to glycogenolysis and lipolysis. Hydrolysis of triglycerides in adipose tissue releases fatty acids (FFAs) and glycerol into the circulation where they are transported (FFAs bound to protein) for fuel to organs such as skeletal and cardiac muscle, the kidney and the liver (source of ketones). The glucose needs of the brain and erythrocytes are met initially from glycogenolysis (24 h) but later from gluconeogenesis. Metabolic rate increases initially but begins to decrease after 2 days. Long-term starvation (more than 72 hours): gluconeogenesis is dependent on protein degradation and AA supply to liver. The body prevent total proteins depletion by decrease metabolism and fatty acids, that provide energy to cardiac and skeletal muscle cells and ketone bodies sustain brain tissue. Some glucose is still needed as fuel for brain tissue. Stress starvation This occurs when the individual is not only starved but subject to the metabolic response to trauma, sepsis, and critical illness. In this situation, the normal adaptive responses of simple starvation, which conserve body protein, are over-ridden by the neuroendocrine and cytokine effects of injury. Metabolic rate rises rather than falls, ketosis is minimal, protein catabolism accelerates to meet the demands for tissue repair and of gluconeogenesis and there is glucose intolerance. Salt and water retention is exacerbated and this may result in a kwashiorkor-like state with oedema and hypoalbuminaemia. The latter may also be exacerbated by protein deficiency. 1. Simple starvation: type 1- Poor nutritional supplementation (e.g. poverty): marasmus without hepatomegaly (e.g. anorexia nervosa) complete starvation. type 2- Malnutrition such as kwashiorkor with hepatomegaly- intake of sugar but not enough proteins. 2. non-simple starvation: 1. Kwashiorkor-like syndrome: stress (disease) 2. chronic diseases leading to malabsorption. 3. chronic diseases leading to cachexia (e.g. anorexia Il-1 beta) 4. aging or immobility leading to sarcopenia. Criterion Short-Term Starvation Long-Term Starvation or Long-Term Fasting Time Period of Intake Reduction Up to 72 hours More than 72 hours Biochemical Processes taking place Glycogenolysis Lipolysis o Starts 4-6 hours from last meal. o TAG → FFA → Ketones + ATP. o Takes place for 4-8 hours. o ↑↑Ketones → Ketoacidosis. o After it, Gluconeogenesis occurs. o After adipose sources deplete, proteolysis Gluconeogenesis begins. o Starts after Glycogenolysis ends. Proteolysis o Proteins & Fats → Glucose. o Proteins → Intermediates of Krebs Cycle. o Can take place for several days. o ↑↑Proteolysis → Tissue malfunctions. Final Result(s) Progression to Long-Term Marasmus/Kwashiorkor Starvation. Death simple starvation -Protein- Energy Malnutrition: body weight in most cases of protein- energy malnutrition. Protein- energy malnutrition in undeveloped population is commonly divided into: 1) Marasmus- protein & calorie deficiency. 2) Kwashiorkor- protein deficiency. Marasmus Kwashiorkor (most common is hospitals) Severe deficiency of all nutrients Definition Severe protein deficiency with high carbohydrate diet (protein, calorie) Insufficient food intake. Etiology Breast milk to solid food (usually lack protein) GIT disturbances & malabsorption. -Progressive loss of skeletal muscle - Severe protein deficiency → hypoalbuminemia (loss of and subcutaneous fat. visceral protein) → ↓ Oncotic pressure → ↑Transudation -Visceral protein not depleted, →Generalized Edema. Pathogenesis serum albumin normal or slightly - lack of immune mediators because of protein deficiency. decrease. -Immune function impaired → infection occur, additional stress. - Underweight (BMI < 18). - Ascites, cause very distended abdomen. - Large head when compared with - Physical and mental retardation. body. - Fatty liver because insufficient apolipoprotein to - Growth retardation/failure. transport fat. - Muscle wasting; dry & dull hair, - Discolored hair. wrinkled skin, diarrhea is common. - Desquamating skin (‫)קשקשים‬. Symptoms - Cachexia. - Anorexia. - Extreme apathy. - Skin lesion. - Hepatomegaly with fat infiltration. - Cold extremities. - ↓CO & Tachycardia. - Anemia. The pathologic changes for both types include humoral & cellular immunodeficiencies resulting from protein deficiencies and lack of immune mediators. There is impaired synthesis of pigments of hair & skin (hair color may change and the skin may become hyperpigmented) because of lack of substrate (tyrosine) & coenzyme. Stress starvation - Malnutrition in trauma & illness (secondary malnutrition) : In industrialized societies, protein- energy malnutrition most often occurs secondary to trauma or illness. Kwashiorkor- like protein malnutrition- occurs most commonly in association with hypermetabolic acute illnesses, such as trauma, burns, and sepsis. Marasmus- like secondary protein- energy malnutrition typically results from chronic illnesses such as COPD, congestive heart failure, cancer, and HIV infection. In people with severe injury/ illness, net protein breakdown is accelerated and protein rebuilding disrupted. protein deficiency effect on: A) Liver- ↓hepatic synthesis of serum proteins→ ↓levels of serum proteins→ ↓immune cells→ wound healing is poor & the body is unable to fight against infections. B) GIT- mucosal atrophy→ loss of villi in small intestine→ malabsorption. C) Heart- ↓myocardial contractility & CO. D) Respiration- muscles of breathing become weak→ respiratory function becomes compromised as muscle proteins are used as a fuel source. Malnutrition indicators  Main criteria and changes in anorexia nervosa, bulimia, binge eating orthorexia, cachexia: Main Risk factors (for all 3): Gender - Females > Males Traumatic Events - Sexual Assault, PTSD. Mental Disorders - Depression, Anxiety, Personality Disorders, early after puberty. BMI= BODY MASS INDEX Kg/m2 Classification referred to WHO Classification Traffic light color BMI in kg/m² Underweight Yellow up to 18,5 Normal weight Green from 18,5 to 25,0 Overweight Yellow from 25,0 to 30,0 Obese Red over 30,0 Glycemic index- value assigned to foods based on how quickly those foods cause increase in blood glucose level. High glycemic index = foods that release glucose fast. Measurement Body composition is often analyzed by Bioelectric Impedance Analysis (BIA). Low-level electrical signals safely pass through the foot (sometimes foot and hand) to electrodes/sensors on the platform. The signal passes easily with fluid in the muscles and other tissues but encounters resistance (impedance) when it passes through body fat that contains little liquids. The impedance values are then estimated and converted to body composition values on the base of previous comparison with scientific data. 1) Anorexia Nervosa: Eating disorder that usually begins in teenagers and is characterized by determined dieting, often accompanied by compulsive exercise/vomiting & other purging behavior, resulting in sustained low weight. The causes are multifactorial, include genetic influence, personality traits or perfectionism, anxiety disorders, family history of depression and obesity. 2 types: 1) restricting- eating small amount of food 2) binge/ purge- eating large amount and then puke. Difference with bulimia is that in anorexia the body weight is low while in Bulimia it can be normal. Diagnostic criteria for AN: body weight usually less than 85% from normal body weight. A) Refusal to maintain a minimal normal body weight for age & height. B) Intense fear of gaining weight or becoming fat. C) Disturbance in the way one’s body size, weight, or shape is perceived- loss of confidence. D) Amenorrhea (‫)היעדר וסת‬. The effects on systems: a) Most frequent complication is amenorrhea & loss of secondary sex characteristics with decreased levels of estrogen, which eventually can lead to osteoporosis. b) Bone loss. c) Constipation. d) Electrolytes abnormalities- ↓K, Mg+2, PO43- e) Cardiac muscle loss(→↓heart size) → bradycardia, orthostatic hypotension (+↓BP upon standing), CHF+ ↓protein → EDEMA. f) muscle loss→ low creatinine; fatigue, weak muscles→ Diaphragm- difficulties in breathing. h) Brain atrophy & encephalopathy → ataxia, confusion, and even death. i) Endocrine system disability: ✓Gonads function disturbance: amenorrhoea, infertility and libido depletion ✓Thyroid gland disturbance: mild hypotyroidism ✓Adrenal gland hormones – inconsequential ✓IGF-1 levels decrease - synthetized in liver, support anabolic effect of STH → fat tissues and muscles mass loss j)Anemia, leucopenia, thrombocytopenia, complement decrease k) GIT disturbances: ✓Stomach slow motility, jejunum dilatation, constipation 2) Bulimia Nervosa: Defined by the recurrent binge eating and activities such as vomiting, fasting, excessive exercise, and use of diuretics, laxatives to compensate for that behavior. Diagnostic criteria for BN: A) Recurrent binge eating- at least 2 times per week for 3 months. B) inappropriate compensatory behaviors such as self- induce vomiting, abuse of laxatives or diuretics, fasting, etc. C) Self- evaluation that is unduly influenced by body shape and weight. D) determination that the eating disorder does not occur exclusively during episodes of AN. E) Consequences of vomiting, diuretic and laxatives use: ▪Metabolic alkalosis with hypokalaemia, chloride and hydrogen ions loss ▪Arrhythmias ▪Kidney disorders (kaliopenic nephropathy) ▪Esophagus inflammation, caries (vomiting) ▪Myenteric plexus degeneration (laxatives) F) Frequent menstruation period disturbances Permanent amenorrhea is not present People with BN are with normal body weight. Diagnostic criteria for BN include subtypes which distinguish people who compensate by purging (vomiting or abuse of laxatives or diuretics) and those who use non purging behaviors (fasting or excessive exercise). BN may cause dental disorders (sensitive teeth, periodontal disease) and fluid & electrolytes disorders (metabolic acidosis & hypokalemia, chloride and hydrogen loss ). 3) Binge- Eating Disorder: Characterized by recurrent episodes of binge eating at least 2 days per week for 6 months and with at least 3 of the following: A) Eating rapidly. B) Eating until becoming uncomfortably full. C) Eating large amount when not hungry. D) Eating alone because of embarrassment. E) Disgust, depression, or guilt because of eating episodes. Orthorexia (Nervosa): Eating disorder characterized by excessive preoccupation (‫ )עיסוק‬with eating food believed to be healthy. Main Features of patients: Obsessive focus on meal choice & planning. Food is regarded as source of health, rather than as a pleasure. Distress or Disgust when in proximity to prohibited foods. Moral judgment of others based on dietary choices. Distorted body image. Cachexia: Cachexia definition: Cachexia has been defined as a loss of lean tissue mass, involving a weight loss greater than 5% of body weight in 12 months or less in the presence of chronic illness or as a body mass index (BMI) lower than 20 kg/m2. In addition, usually three of the following five criteria are required: 1) decreased muscle strength. 2)fatigue. 3)anorexia. 4)low fatfree mass index 5)an increase of inflammation markers such as C reactive protein or interleukin (IL)-6 as well as anemia or low serum albumin. Multifactorial pathophysiology: 1. The inflammation: TNF (which is also nicknamed 'cachexin' or 'cachectin') induces proteolysis and breakdown of myofibrillar proteins 2. Tumor-derived molecules (e.g. proteolysis-inducing factor) induce protein degradation 3. Alteration in feeding control loops in cachexia: high levels of leptin, a hormone secreted by adipocytes, block the release of neuropeptide Y leading to decreased appetite despite the high metabolic demand for nutrients. sarcopenia: Sarcopenia is a condition that focuses on muscle loss. Loss of muscle mass and function, especially muscle strength and gait speed, associated with aging occurs in sarcopenia. it causes because of degeneration of neuromuscular junction and high oxidative stress. the amount of creatinine in the blood will be low because creatinine produces in muscles and they are not function. Obesity Obesity is defined as having excess body fat accumulation with multiple organ-specific pathologic consequences. Overweight & Obesity result from an energy imbalance of eating too many calories and not getting enough physical activity. Factors contributing to the development of both include genetics, metabolism, behavior, environment, culture, socioeconomic status, and some medical conditions/ drugs such as thyroid disorder, Cushing syndrome, and polycystic ovarian syndrome. Diagnosis: 1)BMI exceed 30 kg/m2 2) waist circumference- most beneficial to determine cardiovascular risk. 3) ratio belt/hip Types of obesity: 1) Upper body obesity, also called central, abdominal, visceral, or male (android) obesity. Characterized by apple shape body, release of adipokines (TNF- alpha & adiponectin) and FAs directly to the liver before entering the systemic circulation, have greater impact on hepatic function. increased risk of cardiovascular diseases, type 2 diabetes, and metabolic syndrome. In men, Waist- Hip ratio > 1 is indication of this obesity. In women > 0.8. 2) Lower body obesity, also called peripheral, gluteal- femoral, or female (gynoid) obesity. Characterized by pear shape. Less harmful. Health risks associated with obesity: Obesity is the 2nd leading cause of preventable death in the US in adults under 70, and the 3rd leading cause in all ages. Obesity affects almost every system in the body; Increased Cardiac diseases, Hypertension. Increased Hypertriglyceridemia. Decreased HDL cholesterol. Reaven's syndrome- Increased risk for DM type 2. Causes fatty liver disease. Increased risk for obstructive sleep apnea, gastric reflux, and gall bladder disease. Limited mobility & increased joint disorders. decrease estrogen secretion- In women- contribute to infertility, higher risk pregnancy, maternal hypertension, and difficult in labor & delivery. In men- impotence. Increase the risk for certain cancers including endometrial, colon, gallbladder, prostate, kidney, and postmenopausal breast cancer. Prevention: Involve modification of lifestyle behaviors to promote healthy life and physical activity. Treatment: A) Dietary Therapy- caloric restriction & diet consumption. B) Physical Activity- also reduces CVD & diabetes risk. C) Behavior Therapy. D) Pharmacotherapy- The medications divided into:  1. Reduction of food intake via the CNS. 2. Action primarily outside the brain. E) Weight- Loss (Bariatric) surgery Refeeding Syndrome: Occurs in severely malnourished person when nutritional therapy starts. Pathogenesis: During starvation, mineral deficiencies causes PO4, Mg, Ca and K to move out the cell into plasma→ when refeeding starts, ↑ insulin→ ↑ mineral and ion uptake into cell→ plasma concentration of ions becomes dangerously low→ hypophosphatemia, hypomagnesemia, hypokalemia, hyponatremia, hypocalcemia→ congestive heart failure, cardiac dysrhythmias, muscle weakness, and death. Prevention: Slowly initiating refeeding, about 20 Kcal/Kg/ day for the 1st few days and closely monitors the plasma PO4, K, Mg and Ca level. Major principle of parenteral nutrition: enteral nutrition- nutrition administration via physiological pathway. Simple and cheap. Using tubes or stoma that direct food to different GIT parts. severe dysphagia (eg head injury, stroke, motor neurone disease) major, full-thickness burns postoperative period when oral intake is limited massive small bowel resection, in combination with parenteral nutrition low-output enterocutaneous fistulae Parenteral nutrition- supply in malnutrition. If enteral nutrition is not tolerated/efficient, or contraindicated ▪ Disadvantage – intestine atrophy with decrease in mucosal enzymes and following mucous barrier disturbance. determination of malnutrition: –body mass index (BMI) below 18.5 kg/m2 – unintentional weight loss greater than 10% within the last 3–6 months – BMI less than 20 kg/m2 and unintentional weight loss greater than 5% within the last 3–6 months Indications: Malnutrition  Digestive disturbances  Malabsorption  Mental anorexia  Organic anorexia  Intestine fistulas  GIT stenosis  Ileus  GIT operations  Ulcerous colitis  Multiple injuries  Head injuries  Fire injuries  Peritonitis  Sepsis  Renal failure  Liver failure  Pancreatitis  Crohn´s disease Administration: Peripheral veins- short-term or middle-term parenteral nutrition Central vein ▪ In long-lasting parenteral nutrition ▪ In intensive care – parenteral nutrition + quantity of electrolytic solutions ▪ In low capacity of peripheral veins ▪ If no guaranteed to keep functional cannula in the periphery.  2. Lipoprotein metabolism disorders - hyperlipoproteinemia, primary and secondary, hypolipoproteinemia, lipidosis. Proportion of proteins, cholesterol, triglycerides, and phospholipids in lipoproteins of different types. Class TAG Cholesterol PL’s Proteins Apolipoproteins Chylomicron 90% 5% 3% 2% B48, CII, E VLDL 60% 20% 15% 5% B100, CII, E LDL 8% 50% 22% 20% B100 HDL 5% 25% 30% 40% A1, A2, CII, E Types of lipoproteins: Class Synthesis Site Degradation Site Main Functions APO’s involved o CII – activates LPL Chylomicrons Enterocytes {as Liver o Transports dietary lipids from o E – Binds to liver for nascent} the intestines to other locations degradation. in the body (extrahepatic tissue o B48 & liver) o CII – activates LPL VLDL Liver Plasma- becomes o Transports endogenous (from o B100 IDL/LDL liver) TAG, to periphery- o E extrahepatic tissue {then becomes IDL}. o B100 – binds to liver for LDL Plasma- from 75% Liver o Transports C & CE to cells by degradation. IDL combining with LDL receptors. 25% periphery receptors recycle to cell surface. o A1 – Activates LCAT HDL Enterocytes & Liver o Reverse Cholesterol transport. o E – Binds to liver for Liver From the body to the liver. degradation. o Reservoir of apoproteins. o CII. o Antioxidant.  Role of different types of LP in development of different diseases: A) Chylomicrons: It is a physiological carrier for lipids. Its level does not indicate any disease. B) HDL: It is called good cholesterol because it ↓ serum cholesterol (reverse cholesterol transport). ↓ HDL level is a criterion of metabolic syndrome, which is a risk for coronary heart disease, non- alcoholic fatty liver disease, DM, and cancers. C) VLDL & Lipoprotein (a): ↑ level is correlate to ↑ CHD risk. LDL & VLDL are usually measured together for better assessment of CV risk. Lipoprotein (a) similar in structure to LDL, contribute to atherogenesis (process of atherosclerosis) and ↓ fibrinolysis because it is structurally like plasminogen. D) LDL: high serum LDL is a strong indicator for CHD because LDL is key in plaque formation in atherosclerosis. Pathogenesis of Atherosclerosis by LDL: 1. Tissue inflammation → monocytes migrate to endothelium → become macrophages. 2. Macrophages possess high levels of “Scavenger Receptors A” {SR-A}. 3. SR-As allow endocytosis of many ligands, such as oxidized LDL {oxLDL}. 4. SR-As are not inhibited by increased intracellular cholesterol!!! 5. Cholesterol accumulates in the macrophages → “Foam Cells” 6. Foam Cells accumulate → forming the atherosclerotic plaque. Note: LDL is oxidized to oxLDL {causes formation of foam cells} by presence of ROS & NO. This oxidation is inhibited by antioxidants such as Vitamins C, E & A. Types of Dyslipoproteinemia: Dyslipoproteinemia/ Dyslipidemia= Abnormal concentration of lipoprotein in blood. Xanthomas= Xanthomas are fatty deposits that build up under the skin. Abetalipoproteinemia- lack of apolipoprotein B. Etiopathogenesis: AR deficiency of ApoB48, ApoB100→ deficiency of chylomicron, VLDL, and LDL. Manifestation: Affect infants with severe fat malabsorption, steatorrhea (presence of excess fat in feces), failure to thrive- development (↓ fat soluble vitamins). Treatment: restriction of LCFA, large doses of oral vitamin E.  Hypoalphalipoproteinemia = AD mutations in genes encoding for HDL or APO A1. Pathogenesis: 1. Mutation → ↓HDL or ↓HDL uptake by the liver → ↑HDL degradation. 2. ↓Blood HDL → ↑risk of Atherosclerosis (less resistance to LDL). Classification of hyperlipidemias: Hyperlipidemia classification is based on the type of lipoprotein involved. Most cases of hyperlipidemia are probably multifactorial. Can be classified as primary/ secondary hypercholesterolemia. Primary- developed independent of other health problems or lifestyle behavior (genetic basis). Or dietary. Secondary- associated with other health problem & behaviors. DM, hypothyroidism, pancreatitis. There may be a defective synthesis of the apoproteins, lack of receptors, defective receptors, or defects in the metabolism of cholesterol in the cells that are genetically determined. Familial hypercholesterolemia (AD): absence/ decrease LDL receptors→ no LDL uptake. Hypercholesterolemia is further divided into 5 classes: a. Class 1- complete loss of receptor synthesis. Very rare. b. Class 2- transport of LDLR from ER to Golgi is impaired. Most common. c. Class 3- LDLR cannot bind to LDL normally. d. Class 4- LDLR cannot internalized after bind to LDL. e. Class 5- LDLR & LDL cannot dissociate inside the endosome and move back to the surface.  Signs & Symptoms in Homozygous FH: LDL cholesterol levels may rise to 1000 mg/ dL. (Normal~ excretion. ↑ protein pool→ ↑ growth, pregnancy, tissue repairs etc. c. Negative nitrogen balance: nitrogen excretion > intake→ burns, fever, hyperthyroidism, fasting, malnutrition. Detoxification of nitrogen: Metabolism of AA produce ammonia (NH3), which is toxic for the body (especially CNS). a. Peripheral tissue and brain: peripheral cells convert ammonia into→ nontoxic glutamine, using glutamine synthase, than glutamine is transported to the liver. b. Skeletal muscle: NH3 combined with alpha- KG→ glutamate→ pyruvate & alanine→ alanine is transported to the liver. (also produce glutamine) c. Liver: liver converts NH3 into urea through urea cycle→ urea is released into blood & filtered and excreted by the kidney. d.kidney: convert glutamine (by glutaminase) to glutamate (transport to brain) and NH+4 that can excrete by urine. Nitrogen excretion disorders: a. Hepatic Encephalopathy: Liver cirrhosis→ ↓ NH3 detoxification into urea→ hyperammonemia→ reaches the brain→ metabolized into glutamine by astrocyte→ cytotoxic edema (glutamine is osmotically active) and deplete glutamate (ammonia+ glutamate→ glutamine)→↑ ICP (intracranial pressure) & ↓ neurotransmitters (glutamate)→ brain dysfunction. Furthermore, cirrhosis→ portal hypertension→ portosystemic shunting→ NH3 from gut enters systemic circulation→ hyperammonemia. b. Azotemia: Renal failure→ ↓ urea excretion→ ↑ urea in blood (uremia)→ uremic encephalopathy (toxic effect on brain). c. GIT: Overgrowth of gut flora→ ↑ NH3→ if portal circulation is impaired→ NH3 enters systemic circulation→ CNS toxicity.  Changes of plasma protein levels in inflammation: General Function Increased Acute-Phase Proteins Decreased Acute-Phase Proteins Coagulation Factors Fibrinogen (factor I) / Prothrombin (factor II) Factor VIII Plasminogen Protease Inhibitors α1-Antitrypsin Inter-α-Antitrypsin α1-Antichymotrypsin Transport Proteins Haptoglobin- transport hemoglobin Transferrin Hemopexin- transport heme (↓Transferrin → ↓blood Fe → ↓utilization by Ceruloplasmin- transport Cu microbes) Ferritin (↓Fe availability to microbes) Complement System C1s, C2-C5, C9 Properdin = Factor P (Regulator of Complement) Others Serum-Amyloid A (SAA) - ↑Opsonization Albumin - degraded to yield AA for other necessary proteins. C-Reactive Protein (CRP) - ↑Opsonization Prealbumin - degraded to yield AA for other necessary proteins. α1 & β-Lipoproteins Blood protein deficiency disorders: Phenylketonuria (PKU): AR inborn disorder, which is characterized by mutations of Phenylalanine-Hydroxylase (PAH) gene. PKU is seen in children as soon as they start intake of food containing Phenylalanine. The neural damage of phenylalanine is IRREVERSIBLE! Pathogenesis: 1. Mutation of PAH gene → defected/deficient PAH → ↓Tyrosine synthesis from Phenylalanine. 2. Phenylalanine goes through an alternative metabolic pathway → ↑↑Phenylpyruvate.  3. Main consequences: Cause Consequence(s) ↓Tyrosine Synthesis 1. ↓Tyrosine → ↓Catecholamine Synthesis → Neural Defects (seizures, jerking movements, attention problems, intellectual disability). 2. ↓Tyrosine → ↓Tryptophan Synthesis → ↓Serotonin → mood & mental disorders. 3. ↓Tyrosine → ↓Melanin synthesis → Photosensitive Skin, Hypopigmentation (Blue-Eyes, Blond Hair). ↑↑Phenylpyruvate 1. ↑↑Phenylpyruvate → Accumulates in Neurons → Neurotoxicity → Mental Retardation. 2. Phenylpyruvate is also excreted in urine → Phenylketonuria. Treatment of PKU = Restrictive Diet (no phenylalanine or aspartame). high tyrosine diet. Albinism: AR inborn disorder, which is characterized by absence or defect of the enzyme Tyrosinase. ↓Tyrosinase Activity → ↓Melanin → Fair skin, Blue-Eyes, Blond Hair Albinism is seen from a very young age. Pathogenesis: 1. ↓Tyrosinase Activity → ↓synthesis of DOPA from tyrosine. 2. ↓DOPA → ↓Melanin Synthesis. Main consequences: a) ↓Melanin → Skin hypopigmentation → Skin photosensitivity → ↑risk of skin cancers. b) ↓Melanin → Iris hypopigmentation→ ↑eye photosensitivity → ↑risk of Blindness. Alkaptonuria: AR inborn disorder, which is characterized by absence or defect of the enzyme Homogentisate dioxigenase (HGD). HGD is involved in the breakdown pathway of Phenylalanine & Tyrosine. Pathogenesis: 1. ↓HGD → ↑↑Homogentisate (an intermediate of the breakdown). 2. ↑↑Homogentisate → Accumulates in tissues (black pigment) → damage to tissues. 3. Accumulations are visible as DARK-RED color in C.T =ochronosis (the color of Homogentisate).  Locations of accumulation: o Cartilage (= Ochronosis) o Heart Valves o Kidney → Stones o Some is excreted in urine (→ dark-red urine) Homocysteinuria: AR inborn disorder, which is characterized by deficiency of the enzyme cystathionine β synthase (CBS). Homocysteine is a metabolite of Methionine. CBS Activity: Serine + Homocysteine → Cystathionine + H2O. Pathogenesis: 1. ↓CBS → ↓Cystathionine synthesis → ↑↑Homocysteine. 2. ↑↑Homocysteine → Accumulates in tissues → damage. Locations of accumulation: o Musculoskeletal system → long limbs, irregular spine (both resemble Marfan syndrome). o CNS → mental disorders, seizures. o Eyes → Cataract, Glaucoma o Vessels → Atheroma, Atherosclerosis, Thrombosis. o Some is excreted in urine (→ Homocysteinuria). o Symptoms can appear also at B12, B6 and folate deficiency. (Acquired).  Urea-Cycle Disorders (& Ammonia Toxicity): Urea Cycle → Liver (mitochondria & cytoplasm). These disorders are characterized by AR deficiency of an enzyme(s) involved in urea cycle. Main aim of Urea Cycle = Detoxification of Ammonia! Pathogenesis: 1. Enzyme Deficiency → ↓Urea Cycle → ↑↑Ammonia. 2. ↑↑Ammonia → CNS toxicity → CNS defects. 3. Ammonia CNS Toxicity mechanisms: a) NH3 + Glutamate = Glutamine → ↓Glutamate neurotransmission of CNS + glutamine is highly osmotically active and when accumulate cause brain edema. b) NH3 + α-Ketoglutarate = Glutamate → ↓α-Ketoglutarate → ↓TCA cycle of neurons. 4. Disorders of the metabolism of purines, pyrimidines, and sugars - hyperuricemia and gout, glycogenosis, galactosemia - etiology, clinical stage, prevention, consequences. Role of external and internal factors in uric acid metabolism: Uric Acid metabolism: Uric acid is the end product of purine degradation. 2/3 of uric acid is generated endogenously by the body while 1/3 comes from dietary purines. In small amounts uric acid acts as anti- oxidant, but in higher levels it acts as pro- oxidant where it increases levels of free radicals→ causes other inflammatory changes. UA is a byproduct of protein metabolism that normally assist with removal of nitrogen waste from the body. Normally, purine is produced in the body through de novo pathway from precursors and salvage pathway from degraded purine base. in most mammals uric acid degrade to allantoin by Uricase that is more soluble and better excreted. 1) External Factors: a. Obesity o Obesity (↓renal clearance ↑uric acid production) → ↓Excretion of Urate → ↑Urate (the form of uric acid in the blood). b. Thiazides Diuretics o Thiazides (increase the excretion of sodium and water in the urine. When the kidneys excrete more sodium and water, they tend to reabsorb more uric acid) → ↓Uric Acid renal clearance → Hyperuricemia. c. Lead Poisoning o Lead → ↓Excretion of Urate → ↑Urate (“Saturnine Gout”). d. Excessive Alcohol Consumption o Alcohol drinks → may contain Lead → ↓Excretion of Urate → ↑Urate. e. High fructose corn syrup consumption High concentration of fructose causes rapid accumulation of AMP: Increases the body pool of purines Lactic acid is a by-product of fructose metabolism: Lactate decreases urate excretion 2) Internal Factors: a. Age o Gout is slowly developed, thus usually do not appear before the age of 30. b. Genetics o HGPRT (hypoxanthine- guanine phosphoribosyl transferase) Deficiency → ↑Xanthine → ↑Uric Acid. o ↑↑Purine Synthesis and/or Breakdown → ↑↑Uric Acid. c. Kidney Functions o ↓Renal Function → ↓Uric Acid excretion → Hyperuricemia. Hyperuricemia (HU): Elevated levels of uric acid in the blood (>6 mg/dL). Caused by ↓excretion or ↑production of uric acid. HU causes can be primary (↑ uric acid levels due to purine over production & kidney inability to excrete purine, excessive dietary purine intake) and secondary (due to another disease/ condition such as, cancer, chemotherapy, medication, ↑ATP degradation). a. ↓ excretion: caused by renal failure, generally rare & mostly idiopathic. b. ↑ production: 1. Lesch- Nyhan syndrome: deficiency of HGPRT→ no salvage pathway→ excess purine production. 2. Tumor lysis syndrome: release lots of DNA into blood that will be degraded into uric acid. 3. Myeloproliferative: neoplastic proliferation of specific cell line→ ↑ cell turnover→ ↑ purine degradation. Pathogenesis and principal clinical features of gout: inflammatory arthropathy characterized by painful and swollen joints caused by precipitation of uric acid crystals. Risk factors: male, hypertension, obesity, DM, dyslipidemia. Most people with hyperuricemia do not develop gout. Gout disorders include acute gouty arthritis with recurrent attacks of severe articular & periarticular inflammation. Primary gout - refers to when the cause of the hyperuricemia is unknown (idiopathic) or caused by an inborn error in metabolism which characterized primarily by hyperuricemia & gout. Secondary gout- is when the cause of hyperuricemia is known but the gout is not the main disorder. E.g excessive purine intake, increased purine nucleotide turnover, accelerate ATP degradation. pathogenesis: 1. Above factors → ↑Blood Uric Acid (Hyperuricemia). 2. ↑↑↑Blood Uric Acid → precipitation → Monosodium-Urate (MSU) crystals. 3. MSU crystals → deposited mainly in the Synovial Fluid of joints (but also in CT). 4. MSUs are phagocytized by tissue macrophages → Inflammasome → activates IL-1β & IL-8. 5. IL-1β & IL-8 → initiate Inflammation →↑Chemokines → ↑Chemotaxis of WBCs. 6. Neutrophils & Monocytes → Phagocytosis of MSUs. 7. Phagocytosis of MSUs → Release Lysosomal Enzymes → ↑Tissue Damage → gout. Tophi= nodular deposits of monosodium urate crystals that accumulate in and around joints and soft tissues in individuals with chronic gout These manifestations appear in 3 clinical stages of the disease: 1. 1st - Asymptomatic Hyperuricemia o ↑Blood Uric Acid. o Asymptomatic. o May persist throughout life. 2. 2nd - Acute Gouty Arthritis o Blood Uric Acid > 6.8 mg/dL → MSU crystals → attacks of arthritis. o These attacks are mono-articular (involve 1 joint). 3. 3rd - Tophaceous Gout (chronic) o Begins at least 3 years from the first gouty arthritis attack. o Urate levels are too high → ↓↓Excretion → formation of Tophi. o The high levels of MSU may cause Gouty Renal Stones → Renal Failure. Clinical Notes of Gout: Main location of Gouty Arthritic Attacks → metatarsal- phalangeal joint of the great toe (50%). Main locations of formation of Tophus → Helix of the Ear & Great toe. Each tophus consists of a deposit of urate crystals, surrounded by a granuloma.  Main Principles of Prevention & Treatment of Gout: 1) Treatment for the acute Gouty attacks: a. NSAIDS → treat the acute inflammatory attack of Gout. b. Intra- articular deposition of corticosteroids. c. Hydrocortisone → ↓Inflammation & Pain (via Lipocortin). d. Ice (methamphetamine) → may relieve the inflammatory response. 2) Long-Term Treatment: a. XO inhibitors (Allopurinol) → inhibit xanthine oxidase→ ↓Uric Acid synthesis. 3) Main Prevention: a. ↓Body weight b. Avoid Alcohol Intake c. ↑Intake of Low-fat milk products, Cherries & Soybeans → all assist in reducing the gouty episodes. Examples of glycogen storage diseases- Glycogenoses (von Gierke, Pompe diseases): Glycogen-Storage Diseases, GSDs= inherited (AR) deficiencies of enzymes involved in the metabolism of Glycogen. There are 7 GSD (GSD type I – type VII). Each GSD is characterized by accumulation of substrates of different reactions of glycogen metabolism. Usual places of glycogen deposition: Cytoplasm, Nucleus (e.g. von-Gierke). Unique place of glycogen deposition: Lysosomes (in Pompe Disease). Examples of GSDs: Type of GSD Deficient Enzyme Clinical Manifestations Type I = Von-Gierke Disease Glucose-6-Phosphatse a) ↑Glycogen Storage → Hepatomegaly (Enlargement of the (Hepatic) (Glycogenolysis) Liver). b) ↓Glycogenolysis → Hypoglycemia. c) Accumulate also in kidney Type II = Pompe Disease Lysosomal Glucosidase = Acid a) Glycogen storage in the heart → Cardiomegaly! → Cardio- (Miscellaneous) Maltase respiratory failure → Death. (Glycogenolysis) b) Glycogen Storage in the liver lysosomes → mild Hepatomegaly. c) Glycogen Storage in Skeletal muscles → Myopathy → muscle fatigue. Type V = McArdle Disease Glycogen Phosphorylase a) ↓Glycogenolysis → Muscle Fatigue (& post- exercise muscle (Myopathic) (Glycogenolysis) cramps). b) ↓Glycogenolysis → ↓Glycolysis → exercise intolerance with pain. c) ↓Glycogenolysis → ↓energy to mm. → muscle damage →Myoglobinuria.  Hepatomegaly Cardiomyopathy Pathophysiology of Galactosemia & Fructosemia (Seen in Children): Criterion Galactosemia Fructosemia Definition AR genetic deficiency of metabolic enzymes of AR genetic deficiency of metabolic enzymes of Galactose metabolism. Fructose metabolism. ** Can be also Galactokinase deficiency- ** Can be also Essential fructosuria- defective congenital deficiency of galactokinase→ fructokinase→ hexokinase converts fructose to alternative pathway- aldolase reductase convert fructose- 6p→ release into blood → fructosuria galactose to galactitol→ release into blood→ & fructosemia. galactosemia, galactosuria. Main Deficient Enzyme Galactose-1-P Uridyltransferase (GALT) Fructose-1-P Aldolase (Aldolase B) Trigger Infant begins feeding (lactose is present in breast Consumption of fructose containing food. milk and normal formula). Pathogenesis - Steps 1. ↓GALT → ↑↑Galactose-1-P. 1. Aldolase B → ↑↑Fructose -1-P. 2. Galactose-1-P accumulates in tissues. 2. Fructose -1-P accumulates in tissues→ ↓phosphate→ inhibit glycogenolysis &gluconeogenesis. Main Tissues of Accumulation Liver Liver Brain Muscles Eyes RBCs Clinical Manifestations Vomiting Vomiting Hypoglycemia →↓Glycolysis Hypoglycemia →↓Glycolysis Growth Failure Growth Failure Jaundice (Liver Failure) Jaundice (Liver Failure) Mental Retardation Hepatomegaly Cataract Seizures Treatment Galactose/Lactose-Free Diet Fructose/Sucrose/Honey-Free Diet Mnemonic- FAB GUT: Fructose is to Aldolase B as Galactose is to UrydilTransferase.  Pathophysiology of porphyria – etiology, types, main clinical features: Porphyria = Genetic deficiency of an enzyme involved in Heme Synthesis. Involved excretion of porphyrins in the urine. The urine is often described as red or port- wine color because porphyrins behave like pigments. General Pathogenesis: 1. Genetic deficiency of different enzymes → ↑Accumulation of Porphyrin Substrate + ↓Heme. 2. ↑Accumulation of Porphyrin Substrate in tissues → damage. Classifications of Porphyrias: According to damage 1. Acute Intermittent Porphyria = AD deficiency of porphobilinogen deaminase. Causes NS damage and might also cause skin damage. 2. Cutaneous (Cutanea Tarda) Porphyria = AD deficiency of uroporphyrinogen decarboxylase. Causes only skin damage. Caused mainly by liver diseases. According to location of enzyme deficiency 1. Hepatic (Liver) 2. Erythropoietic (Marrow) Subtype Deficient Enzyme Accumulation of substances Clinical Manifestations Acute Porphobilinogen Porphobilinogen & ALA Severe abdominal pain, Red/ Brown Intermittent Deaminase urine color, Neuropathy, Psychiatric Disorders. Compare with other porphyries doesn’t cause photosensitive reaction. Cutanea Tarda Uroporphyrinogen Uroporphyrin Severe Photosensitivity because (most common) Decarboxylase porphyrins create ROS when exposed to light→ ROS cause damage to epithelial cells→ blisters. Lead poisoning & Hb synthesis: Lead → Inhibition of ALA-Synthase → ↓ALA → ↓Hb → Microcytic anemia 5. Disturbances of vitamins metabolism – examples and consequences. Recommended Doses of Vitamins per Day: Vitamin Recommended Daily Dose Vitamin A 600 μg = 5000 IU Vitamin D 5 μg = 400 IU Vitamin E 10 mg = 15 IU Vitamin K 80 μg Vitamin B1 1.4 mg Vitamin B2 1.6 mg Vitamin B3 18 mg Vitamin B5 6 mg (Patothenate) Vitamin B6 2 mg Vitamin B7 (Biotin) 30 μg Vitamin B9 (Folic 400 μg Acid) Vitamin B12 6 μg Vitamin C 75 mg Role of vitamin A in epithelium differentiation and keratinization and consequences of its deficiency: Vitamin A refers to retinol, retinal, and retinoic acid (butter, milk, cheese, egg yolk). Carotenoids are provitamin (carrots, green vegetables, sweet potato, pumpkin) that can metabolized into vitamin A. ITO cells in the liver stores the majority of vit. A. Fat- soluble vitamin, required bile for absorption. Physiologic Function: 1. Normal vision- vit. A is metabolized into rhodopsin (light sensitive pigment) by oxidation of all- trans- retinal→ 11- cis- retinal→ attached to opsin→ rhodopsin (rods) iodopsin (cons) 2. Cell growth & differentiation- vit. A bind to retinoic acid receptor→ transcription of genes necessary for differentiation of mucus secreting ep, epithelization, capillary formation, and collagen synthesis. 3. Stimulate immunity- vit. A can ↑ immunity to infections. Consequences of vit. A deficiency: 1) Night Blindness a. Vitamin A (Retinal) → component of Rhodopsin. b. ↓Vitamin A → ↓Rhodopsin Production. c. ↓Rhodopsin formation → ↓Light absorbance by the rods. d. ↓Light absorbance (cannot adapt to darkness) → ↑Visual Threshold (i.e. more light is required to see) → night blindness. 2) Squamous Metaplasia: affects many organs. a. Eye: it causes xerophthalmia (dry eyes) and severe deficiency cause corneal keratomalacia (destruction of cornea). b. Lung: squamous metaplasia of upper respiratory tract→ ↓ mucus clearing ability→ respiratory infection. c. Kidney: desquamation of keratin debris in urinary tract→ ↑ risk of renal stones. d. Skin: hyperplasia & hyper keratinization of epidermis→ dermatitis due to plugging the ducts. follicular hyper keratinization- keratin accumulation around follicular cells. e. Urothelium 3) Increase susceptibility to infection: ↑ mortality & morbidity of common infections like measles, pneumonia, and diarrhea. Vitamin A Toxicity: Acute toxicity: clinical manifestations- headache, blurred vision, vomiting, death. Chronic toxicity: clinical manifestations- weight loss, vomiting, dryness of lips, bone & joint pain, hyperostosis, hepatomegaly with fibrosis, predisposition to bone fractures( due to stimulation of osteoclasts). Congenital malformation: clinical manifestations- synthetic retinoids for acne; not recommended during pregnancy, cause CNS, cardiac, and craniofacial defects. Carotinemia: Excess vitamin A precursors. Usually from eating too many carrots, or artificial “suntanning” pills. Clinical manifestations- Yellow- orange colored skin (mainly palms & soles), Sclera remain white.  Vitamin D Metabolic Pathways: Pathophysiology of vit.D (Calciferol) deficiency – osteomalacia, cardiovascular disorders, cancer, immune disorders, rickets: Sources: 1. Endogenous: skin produce 7- dehydrocholesterol→ UV waves in sunlight converts it→ cholecalciferol (vit. D3). 2. Exogenous: Ergosterol (vit. D2) in plants is a provitamin that can be converted to vit. D in the body. Regulation of conversion in the kidney: 1. Hypocalcemia→ stimulate PTH secretion→ ↑ α1- hydroxylase synthesis→ ↑ conversion to the active form of vit. D. 2. Hypophosphatemia→ ↑ α1- hydroxylase synthesis→ ↑ conversion. 3. Negative feedback→ ↑ 1,25- dihydroxy vit. D in blood→ inhibit enzyme→ ↓ conversion. Physiologic functions: Vit. D bind to nuclear receptor and induce transcription of target genes. 1. Increase intestinal Ca absorption- vit. D induce transcription of Ca transport channels in enterocytes in duodenum. Increase Calbindin production and Ca PO cotransport. 2. Increase renal Ca reabsorption- ↑ Ca reabsorption in the distal tubules by ↑ transcription of Ca transport channels as well. 3. Regulate blood calcium & phosphate- Normocalcemia- bone mineralization, Hypocalcemia- bone resorption. A. To ↑ Ca: both PTH & vit. D → bind to RANK on osteoblasts→ osteoblast produce RANKL cytokines → accumulate macrophage to create osteoclast →↑ bone resorption→ ↑Ca & PO4 in the blood. B. To ↓ Ca: vit. D stimulate osteoblasts to synthesize osteocalcin (Ca binding protein)→ promotes Ca deposition during development. Consequences of vit. D defficiency: 1) Osteomalacia & Rickets: Both are bone disorders due to decreased mineralization of osteoid→ soft bones. Etiology: Limited exposure to sunlight. Dietary deficiency of vit. D or Ca. Decreased vit. D absorption (pancreatic insufficiency, biliary tract obstruction, extensive small intestine disease). Impaired vit. D metabolism. Renal disorder. Pathogenesis: hypocalcemia→ ↑ PTH secretion→ ↑ plasma Ca & ↓ PO4→ mineralization needs both Ca & PO4, so mineralization cannot proceed (↓ mineralization of the bone). a. Vitamin D → ↑Ca GIT-absorption (forms Calbindin in the enterocytes) + ↑Ca deposition in bones (physiology). b. ↓Vitamin D → ↓Ca deposition into bones → ↓Mineralization of bones. Manifestation: In Adults → Osteomalacia (Decreased Bone Density) → ↑risk of osteoporosis. Cause bone pain, tenderness, pathological fracture, hyperparathyroidism. In Children → Rickets (Failure of Endochondral Ossification) & impaired growth. Overgrowth of growth plate → bone deformity (long bones), growth restriction due to pathological fractures. Growth retardation. Nowadays, Rickets are much less common due to early supplementation of Vit. D to babies. 2) Cardiovascular Disorders a. Vitamin D → acts intracellularly on DNA → CVD preventive effects: o ↓Renin Synthesis → ↓BP o ↑Insulin Sensitivity → ↓Blood Glucose → ↓DM. o ↑Synthesis of cardiac MMPs → ↑Cardiac tissue remodeling after injury. o ↑Vascular Compliance ↓↓↓ ↓Vitamin D → ↑Risk of CVDs! 3) Cancer b. Vitamin D → acts intracellularly on DNA → causes anti-cancerous effects: o Maintains cellular differentiation o ↓Cancer cell growth o Stimulates apoptosis (when needed) o ↓Tumor Angiogenesis ↓↓↓ ↓Vitamin D → ↑Risk of Cancer! 4) Immune Disorders a. Vitamin D → acts intracellularly on DNA of WBCs → Regulation of Immune Responses. b. ↓Vitamin D → ↓Regulation of Immunity → 2 consequences: ↑Autoimmunity ↑Susceptibility to Infections.  Vitamin E (Tocopherol) deficiency (rare) as the cause of oxidative stress: only a Tocopherol have influence on human. Sources: From vegetable oil, margarine, green & leafy vegetables, egg yolk, and butter. Oxidative Stress a. Vitamin E → Antioxidant → Protects from lipoperoxidation of membrane PUFAs, protect on vit. A & the oxidation of LDLs as well. b. ↓Vitamin E → ↑↑Lipoperoxidation of many cells → cell damage. c. Depending on affected cells, consequences are the following: Muscles → Myopathies. Neurons → Ataxia, Dysarthria (motor speech defect). RBCs → Anemia. erythrocytes hemolysis. Retina → Retinopathy. WBCs → Immune impairments. Vit. E toxicity: Rare & is the least toxic of the fat-soluble vitamins. May enhance the effects of anticlotting medication. Coagulation disorders related to vitamin K deficiency: Sources: Intestinal flora is the major source of vit K as it constantly synthesizes vit. K. Dietary source: green & leafy vegetables. Physiologic functions: Vit. K is essential for synthesis of clotting factors 2,7,9,10, prothrombin & proteins C & S (anticoagulant regulators proteins within the liver). Causes of deficiency: Vit. K deficiency is unlikely unless intestinal flora is disrupted. 1. Antibiotic therapy- can wipe out intestinal flora, causing ↓ synthesis of the vitamin. 2. Malabsorption- vit. K need bile acid for absorption. Gall bladder or liver disease can ↓ bile synthesis & secretion.  Vit. K deficiency: Coagulation Disorders- Coagulopathy: ↓ Vit. K → ↓ clotting factors → ↓ hemostasis ability→ spontaneous or prolonged bleeding→ petechiae- tiny, pinpoint-sized red or purple spots that appear on the skin or mucous membranes. purpura- larger purple or red patches on the skin that result from bleeding under the skin. ecchymosis- larger bruise. Wound healing- vit. K prevents excessive bleeding that can form hematoma and interrupt healing. Prothrombin time (PT) will increase during vit. K deficiency. But partial thromboplastin time (PTT) is normal Etiology, pathogenesis and main clinical manifestations of water-soluble vitamins (B1, B2, B6, B12, C, folic acid) metabolism disorders: Etiology: Dietary insufficiency, malabsorption, or ↑ demand, which is the main cause, because the water- soluble vitamins are not stored in the body. Vitamin C (Ascorbic acid): Sources: Broccoli, sweet & hot peppers, potato, spinach, strawberry. Physiologic functions: 1. Vit. C is essential co factor for hydroxylase that hydroxylate procollagen to form collagen. 2. Requires for enzymatic reactions in neurotransmitters synthesis (catecholamines). 3. Antioxidant. 4. Important for immune system functions. 5. facilitate iron absorption. 6. Carnitine transport FA into cells. Consequence of vit. C deficiency: Scurvy: a. Vitamin C → cofactor of Hydroxylases during Collagen Synthesis. b. ↓Vitamin C → Impaired collagen. c. Impaired Collagen causes: Fragile blood vessels → ↑bleedings. ↓formation of granulation tissue → Impaired Wound Healing. Impaired formation of bones & teeth (collagen is 95% of their matrix). ↓Carnitine synthesis (insert FA into cells) → muscle fatigue & pain. Vitamin B1 (Thiamine)→ ‫פרשת רמדיה‬ Sources: Dietary source- pork, liver, whole grain, and nuts. Physiologic functions: Works as thiamine pyrophosphate (TPP), which: 1) is an essential cofactor for glucose metabolism (pyruvate decarboxylase complex). 2) In the brain, TPP maintains normal AA neurotransmitter level. Etiology: High nutritional relay on white rice (no husk → no B1), e.g. far east. Diseases/operations of GIT → ↓B1 absorption. Alcoholism. Pathogenesis: deficiency→ ↓ glucose metabolism→ ↓ energy → brain is vulnerable to ↓ glucose metabolism. ↓Thiamine → ↓TPP synthesis → ↓Acetyl-coA synthesis→ ↓ATP synthesis→ Tissue Damage. Consequences: 1. Beriberi: ↓ATP in NS → Paralysis, Mental Defects. ↓ATP in CVS → Heart Failure, Weak vessel walls. ↓ATP in GI → Vomiting, Abdominal Pain. ↓ATP → ↑anaerobic glycolysis → Lactic Acidosis 2 types of Beriberi exist: 1) wet beriberi- affect cardiovascular system- systemic vasodilation that cause cardiomyopathy. 2) dry beriberi- affect nervous system by demyelination of peripheral nerves. 2. Wernicke–Korsakoff syndrome (WKS): ↓ATP in NS → Brain Atrophy Mainly seen in association to alcohol abuse: ↑Ethanol → ↓B1 storage in liver. Clinical manifestation: ophthalmoplegia, ataxia, confusion, balance & movement issues. Vitamin B2 (Riboflavin= FAD): Sources: Dietary sources- liver, meat, milk, and yogurt. Physiologic function: Required for cellular respiration. Requires in many redox reactions. Etiology: As it is found in wheat, B2 deficiency is relatively uncommon. Mainly due to insufficient intake. Predisposition- drinking excessive amounts of alcohol. Pathogenesis: ↓Riboflavin → ↓FAD & FMN. Consequences: Ariboflavinosis: Stomatitis- inflammation of the mouth mucosa. Growth impairment Migraines & Fatigue Red-Itchy eyes. Vitamin B3 (Niacin): Sources: Liver, meat, fish, peanuts Physiologic functions: Serves as a precursor for NAD & NADP which are important coenzymes in many redox reactions and in many metabolic pathways of lipid, carbohydrates, and proteins. Niacin also involved in DNA repair. Also important for cellular respiration → ETC. Etiology: High nutritional relay on corn (no B3), e.g. South America. Tryptophan deficiency (it is converted in the body into Niacin). Excess of Leucine → inhibits NAD synthesis. Malabsorption-associated diseases (e.g. crohn’s). Pathogenesis: ↓Niacin → ↓NAD formation. Consequences: Pellagra (3 “Ds”): Diarrhea Dermatitis Dementia Vitamin B6 (Pyridoxine): Sources: dietary sources- meat, fish, shellfish, green & leafy vegetables, whole grain products. Physiologic functions: PLP (pyridoxal 5-phosphate), the metabolic active form of vit. B6 involved in many metabolic pathway, neurotransmitters synthesis, histamine synthesis, Hb synthesis & function, and gene expression. PLP is a coenzyme for many reactions including decarboxylation and transamination. Etiology: Elderly Alcoholics Some medications (anticonceptions, anticonvulsants). Pathogenesis: ↓Pyridoxine → ↓Pyridoxal-5-P (PLP). Consequences: ↓Synthesis of GABA → Neuropathies → Seizures. ↓ALT & AST activities → ↓AA Gluconeogenesis → ↓Glucose Tolerance. Atrophic Glossitis- "smooth tongue" loss of tongue papillae. Cheilosis- inflammatory condition that causes cracking, crusting, and scaling of the corners of the mouth. Vitamin B9 (Folic Acid): Sources: Dietary sources- liver, green & leafy vegetables. Physiologic functions: After it is absorbed → converted into dihydrofolate → tetrahydrofolate → cofactor for DNA synthesis. Etiology: Insufficient Intake. Gender (Women tend for deficiency). Alcoholism. Prolonged UV light exposure (e.g. tanning beds). ↓Intestinal Absorption (e.g. during crohn’s, Coeliac). Pathogenesis: ↓Folate → ↓DNA synthesis → ↓Cell Proliferation. Consequences: 1. Megaloblastic Anemia (Folate-Associated Anemia): Impaired RBC hematopoiesis → Macrocytic Anemia (Big unstable RBCs). Macrocytic Anemia → weakness, fatigue, headaches. Influence also WBC creation- big and unfunctional WBC. Decrease platelets production. Megaloblastic Anemia → type of Macrocytic Anemia! 2. Fetal Growth Defects: Pregnant women with folate deficiency → ↓DNA synthesis of fetus DNA synthesis of fetus → ↓Growth + Neural tube defects. 3. Depression: Folate is required for the synthesis of Serotonin. ↓Folate → ↓Serotonin → Depression. 4. atherosclerosis and plaque formation: Participate in the conversion of Homocysteine to methionine. Homocysteine accumulation cause endothelial cells to secrete cytokines that cause inflammation that will lead to atherosclerosis. Vitamin B12 (Cobalamin): Sources: Dietary sources: meat, fish, shellfish, green & leafy vegetables. Physiologic functions: It is a cofactor in DNA synthesis, and in both AA & FA metabolism. It is particularly important in the normal functioning of the nervous system via the role in the synthesis of myelin. Also is important in the maturation of developing RBCs in the bone marrow. Etiology: Insufficient intake. Deficiency of Intrinsic Factor (IF) – required for the absorption. Anti-reflux drugs → ↓Gastric HCl → ↓activation of pepsin → ↓B12 release from foods → ↓absorption. Surgical removal of the intestines → ↓absorption. Untreated coeliac disease → GI mucosal damage → ↓B12 absorption. Malabsorption: ↓ Intrinsic factor (IF) (damage to parietal cells). Atrophic gastritis due to: Autoimmune atrophic gastritis: most common cause of vitamin B12 deficiency H. pylori infection Gastrectomy Reduced uptake of IF-vitamin B12 complex in terminal ileum due to: Alcohol use disorder, Crohn disease, celiac disease, Pancreatic insufficiency Surgical resection of the ileum Malnutrition- vegetarian diet, pregnancy  Consequences + all folic acid consequences: 1. pernicious Anemia (B12-Associated Anemia): A. B12 → Cofactor of DNA Synthesis. B. ↓B12 → ↓DNA synthesis → Impaired Hematopoiesis. C. Impaired Hematopoiesis → Pernicious Anemia = type of Macrocytic Anemia. 2. Neural Defects: o Demyelination of posterior and lateral column of the spinal cord o B12 → co-factor in 2 specific biochemical processes: a) Methylmalonic acid → Succinyl-coA: ↓B12 → ↓Succinyl-coA → ↓TCA cycle → ↓ATP synthesis → neural defects. b) Homocysteine → methionine (also B6 & B9 are cofactors) ↓B6/9/12 → ↓Methionine → ↓S-Adenosylmethionine (SAM) → 2 effects: o ↓Epinephrine Synthesis (Adrenal Gland). o ↓Inactivation of Catecholamines (SAM is required for COMT). cause ataxia of lower limbs, numbness and can propagate to full paraplegia  6. Disorders of micronutrients and trace elements metabolism - examples, consequences. Recommended Dose of Main Micronutrients & Trace Elements: Trace Element Recommended Main Function(s) Daily Dose Iron (Fe) 15 mg o Main component of Heme. o Main Proteins with Heme: Hb Catalase CYP-450 Iodine (I) 150 μg o Component of T3 & T4. Copper (Cu) 2 mg o Component of Cyt. C (ETC). o Component of SOD. Zinc (Zn) 15 mg o Component of many enzymes (100-300). o Stabilizes cell-membranes & DNA. o Testosterone production o Antioxidant Magnesium (Mg) 350 mg o Prosthetic group of many enzymes (> 300). o Inhibits Ca influx → ↓muscle contraction & neurotransmission. o Mediates immunity (WBCs Oxidative Burst). o Supports fibrinolysis. Fluorine (F) 3.5 mg o Component of teeth (Fluoroapatite). Selenium (Se) 35 μg o Component of many Enzymes (Selenoenzymes), which are Antioxidants. o Regulates the metabolism of carcinogens by CYP-450. Manganese (Mn) 5 mg o Essential for metabolism of the Antioxidant System (e.g. SOD). Normal pathway of Fe metabolism: The majority of Fe is bound to Hb in RBC and myoglobin in muscle. 30% is stored in macrophage and hepatocytes as ferritin or hemosiderin. Sources of iron- body absorbs about 1-2 mg of Fe every day to balance out the loss of Fe every day to maintain homeostasis. Protein in Fe metabolism- A) Ferritin: IC iron storage protein. Without Fe is called apoferritin. B) Transferrin: transport protein for iron in the blood. Without Fe is called apotransferrin. C) Hemosiderin is aggregates of ferritin, which is a pigment. 1. Digestion & Absorption of Fe from GIT: ▪ Fe is absorbed in all parts of the small intestine. ▪ Fe+2 makes up only a small fraction of the total Fe in the food. ▪ Fe can be absorbed only as Fe+2 (Not Fe+3!!): Fe+2 is the only form that crosses membranes. Fe+3 is the form of storage. ▪ Ferro-reductase: A membrane-bound enzyme of the enterocyte reduces Fe+3 → Fe+2. Requires Vitamin C as cofactor. ↑Fe+2 → ↑Fe absorption. ▪ Fe+2 absorption - Steps: a. Into the enterocyte: via Divalent-Metal Transporter 1 (DMT-1). b. Enterocyte to the blood: via Ferroportin (regulated by Hepcidin- produced by the liver & responsible for the regulation of iron metabolism). Hepcidin binds to ferroportin→ induce internalization→ less ferroportin on cell membrane. ↑ Hepcidin → ↓ Fe absorption and vice versa. 2. Fe transport in the blood & Storage: ▪ Fe transport in the circulation is via Transferrin (= Fe + Apotransferrin). ▪ Storage is mainly in Ferritin & Hemosiderin forms. ▪ Transferrin can give Fe to tissues for storage, but also: To the liver to form enzymes (Cytochromes). To the Bone Marrow to form Hb during erythropoiesis. 3. Hb Degradation & iron excretion: ▪ Hb → Biliverdin → Bilirubin (by macrophages = RES cells). ▪ Fe is released from Hb during this degradation and is stored back in the ferritin pool. ▪ Some Fe is still excreted: 0.6 mg/day male, 1.3 mg/day female. ▪ Bilirubin is conjugated in the liver, and then is excreted by the intestines (as Stercobilin) or by the kidneys (as Urobilin).  Functions of iron: 1) Carries O2 to the tissues from the lungs. 2) Transport electrons within cells. 3) Integral part of important enzyme reactions (cofactor for cytochrome P450). Etiology of Iron Deficiency & Iron overload: 1. Iron Overload: ▪ Hereditary Hemochromatosis (HH) (iron accumulation) → AR disorder. ▪ Severe Hemolysis. ▪ Multiple Blood Transfusions. ▪ Excessive Fe Supplementation. 2. Iron Deficiency: ▪ Anemia (Sideropenic). ▪ Excessive or Chronic Bleeding. ▪ Insufficient Intake. ▪ Malabsorption GI diseases. ▪ Hypovitaminosis C. ▪ Gender (Females → Menstruation → Blood Loss). ▪ ↑ Iron requirement (during growth & hematopoiesis). Pathogenesis & main clinical manifestations of Sideropenic (Iron- Deficiency) Anemia: Sideropenia = Iron deficiency in the plasma. Pathogenesis: a) ↓Fe → ↓Heme Synthesis → Anemia (Microcytic). Clinical Manifestations: Pallor (Pale color Skin due to ↓Fe) → Face, Conjunctive & Palms. Koilonychia (Concaving of the Nails). Cold intolerance. Reduced resistance to infections. Altered behavior. Glossitis Fatigue & Weakness → due to lower ATP synthesis. Dyspnea → compensatory mechanism. Hair Loss Fainting → due to higher tendency of the brain to feel deoxygenated. Normal Pallor Koilonychia  Iron deficiency consequences: 1) ↓ Work capacity & productivity. 2) Permanently impaired development. 3) ↑ Morbidity & Mortality from infections. 4) ↓ Growth. Pathogenesis & main clinical manifestations of Hemochromatosis: Hemochromatosis = Excessive accumulation of Hemosiderin in tissues. Pathogenesis: a) ↑↑Fe/↑Hemolysis → ↑Deposition of iron in tissues as Hemosiderin → Hemosiderosis. b) Excessive Hemosiderosis → Tissue Damage. Clinical Manifestations: Hepatic deposition → liver damage → Cirrhosis & ↑ risk of Hepatocellular carcinoma. Pancreatic deposition → islets damage → ↓Insulin → DM type I. Cardiac deposition → Cardiomyopathy→ Arrhythmia. Joint deposition → Arthritis (inflammation, pain, stiffness, and swelling in the joints). Skin deposition → “Bronzing” of the skin. Types of hemochromatosis: Primary hemochromatosis- Know as hereditary hemochromatosis (HH)- AR disease of HFE gene. mutation of HFE gene → ↓ Hepcidin level → ↑ intestinal absorption of iron→ net gain of 1 g/ year→ excess iron stored in cells as hemosiderin→ toxic to tissues because iron produce ROS through Fenton reaction→ oxidative stress. Secondary hemochromatosis- Due to acquired causes of iron overload, usually by frequent transfusion. Laboratory diagnostics of Fe content in the organism: S = Serum  Cu-dependent disorders of metabolism- Wilson’s disease: Cu is essential; for many metabolisms in the body. Therefore, Cu deficiency have profound impact on cellular metabolism. Wilson’s disease = AR mutation of ATP7B gene that encodes for Cu transporting ATPase → causes excessive Cu accumulation in the liver, brain & kidneys. Treatment → ↓Cu intake, ↑Cu excretion. Pathogenesis: 1. ATP7B gene mutation → ↓Cu ATPase pump → 2 results: a. ↓Cu transferring to the bile → ↓Excretion. b. ↓Cu insertion into Cerruplasmin (which is supposed to carry Cu in the blood). 2. The 2 results → ↑↑Cu deposition in the liver, brain & kidneys. 3. ↑↑Tissue Cu → ↑ROS formation → Tissue damage (DNA, enzymes etc.). Clinical Manifestations (begin as young as 4 Y): Brain Deposition → Classic Neuromuscular Triad: Intention Tremors (shaking) Dysarthria (indistinct speech) Dystonia (defected muscle tonicity) Cornea Deposition → Kayser-Fleischer Rings. Liver Deposition → Cirrhosis + ↑plasma Cu + ↓Cerruplasmin. Kidney→ Renal dysfunction. Role of iodine deficiency in pathology of thyroid gland: Iodine is a crucial component of T3 & T4. ↓Iodine → ↓Synthesis of Thyroid Hormones → Hypothyroidism. Etiology: Dietary insufficiencies. Clinical manifestation: 1) Goiter Formation: Most commonly recognized consequence- enlarged thyroid due to hyperplasia. ↓Iodine → ↓ T3 & T4 → Hypothyroidism→ ↑ TRH from pituitary→ ↑TSH → ↑Proliferation of Thyroid parenchyma (hyperplasia) → ↑size of thyroid (goiter). 2) Cretinism: Severely cease of physical & mental growth due to congenital T3, T4 deficiency. It is associated with maternal iodine deficiency.  Disorders of Zn, Mg, F, Se, Mn & Co metabolism: Trace Element Function Deficiency Overload Zinc Used as cofactor o Impaired Growth o ↓Cu & Fe absorption from GIT→ Cu for many enzymes (↓Testosterone) & Fe deficiency. o Hypogonadism Acrodermatitis enteropathica: o Loss of appetite o Hair Loss, Eczema o Memory loss o Lowered Smell & Taste o Diarrhea Magnesium Inhibits Ca o Hyperexcitability o ↓Peristalsis → Diarrheas channel in o Cramps o Muscle fatigue neuromuscular o Tetany o Paralysis junction, o Seizures preventing Ca o Arrhythmia influx. o PTH needs Mg→ Hypocalcemia. Fluoride Not essential o ↓Teeth Strength o ↓Neurodevelopment (Infants) mineral but it o Dental Caries o Skeletal Fluorosis → damage & pain binds to Ca & to bones. strengths the bone o Dental Fluorosis → hypo- and enamel→ mineralization of Enamel. prevents osteoporosis & dental caries. Selenium Essential for many o ↑Oxidative stress: o Selenosis: antioxidants and ↓ Cataracts Garlic Odor of Breath risk of prostatic Mental impairment GI disorders cancer by Cirrhosis Hair & Nails defects inhibiting cell Thyroid Cirrhosis cycle. malfunction Manganese o Joint Pain & Arthritis o Manganism = destruction of o Hearing Loss dopaminergic neurons. Resembles o Loss of Sex Drive Parkinson. o Infertility o Poor growth o Skeletal abnormalities Cobalt Part of the o ↓B12 → pernicious o Nausea & Vomiting cobalamine (vit. Anemia, ↓SAM o ↑RBC synthesis → ↑Blood Viscosity B12) o Cardiomyopathy o Thyroid Malfunction → Goiter