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Clinical Guide – Chapters 1-6Familial Hypercholesterolemia-An inherited genetic disorder that leads to an accumulation of cholesterol in the bloodstream. The problem lies in the defective cell-surface LDL (Low-density lipoprotein, which binds cholesterol in the blood for cellular uptake) receptors, which inhibits cholesterol from being able to leave the blood. Over time, this can lead to Atherosclerosis beneath the endothelial layer of the blood vessel walls which can create obstructions and/or closures of the affected blood vessel, resulting in decreased blood supply to the affected area. Some common conditions associated with Hypercholesterolemia are Ischemia, Stroke, Heart attack, and Heart Disease. For example, if the Coronary arteries, which carry oxygenated blood to the myocardium, have any obstruction or closure due to Atherosclerosis, it may lead to Myocardial Infarction and/or Cardiac Disease. Tay-Sachs Disease-A fatal autosomal recessive genetic disease characterized by disordered lipid storage, where harmful quantities of Ganglioside GM2, a fatty substance (a glycosphingolipid + sialic acid + sugar chains) that accumulates in nervous tissues and nerve cells of the brain and spinal cord (CNS). Infants lacking a specific Lysosomal enzyme (β-hexosaminidase A) cannot degrade Ganglioside GM2, so it accumulates in toxic amounts within neurons and causes damage, resulting in disordered mental development, blindness, hearing loss, and limb spasms. Death follows quickly, about 1.5 years after birth. Tay-Sachs usually starts to present when the affected infant loses the ability to turn over, sit or crawl at around 3-6 months of age. Gaucher’s Disease (Type 1, 2, &3)-A genetic disorder causing a lack of expression in a gene that codes for Glucocerebrosidase enzyme. A deficiency of this enzyme can result in the accumulation of harmful substances in the organs (including the Liver, Spleen, Bones (and marrow), Lungs, CNS)-The accumulation of these toxic substances causes damage and disordered function in tissues and organs. There are 3 subtypes: >Type 1: Most common but does NOT affect the Central Nervous System (CNS, includes brain and spinal cord). Symptoms and presentation vary among patients but can include bone disease and pain, anemia (low red blood cell count), an enlarged spleen and liver (Hepatosplenomegaly), and Thrombocytopenia (low blood platelet count) which can cause easy bruising. Type 1 affects both children and adults. >Type 2: Typically affects infants and involves severe degradation of the CNS. This form presents with most of the above listed symptoms, and in addition can include abnormal eye twitching, seizures and progressive brain damage that can lead to rapid, early death. >Type 3: Causes the same symptoms listed in Type 1 with some additional effects on the CNS. Patients may live into adulthood since the progression of brain and spinal cord damage occurs much more slowly than in Type 2.-Symptoms: Vary and depend on type, but include bone pain & fractures, enlarged spleen, enlarged liver, lung disease, seizuresAneuploidy-An abnormal number of chromosomes caused by abnormal disjunction in Meiosis II, resulting in genetic disorders.Down Syndrome (Trisomy 21)-Results from a Trisomy on chromosome 21 and can be related to the mother’s age at the time of conception. Bone development is affected, resulting in a shorter stature than average, and a smaller skull and eyes. The Central Nervous System (CNS) is also affected, resulting in disordered mental development, sensory issues, lower than average IQ (in some cases), disordered speech, large tongue, and difficulties with socializing. Individuals with Down Syndrome are not always infertile.Klinefelter Syndrome (Trisomy XXY)-A form of intersexuality where the individual has a sex chromosome XXY trisomy and male external genitalia, but may also have a uterus and fallopian tubes, smaller than average testicles, longer legs, breasts, wide rounded hips and narrow shoulders with little or no hair growth on the face and chest. Patient cannot reproduce normally. This can be caused by active increased female hormones like estrogen, which leads to the formation of female secondary sex characteristics or can be caused by a deficiency of Anti-Müllerian Hormone, which inhibits paramesonephric ducts from becoming the female reproductive organs. Deficiency of testosterone and an extra X chromosome causes feminization of the body, but external genitals are male.Turner Syndrome (Monosomy XO)-Intersexuality caused by Monosomy of the sex chromosomes, where only one X chromosome is expressed. The patient presents as female, but will not experience menstruation, and will achieve puberty later in life than average. This disorder is characterized by disordered mental development, short stature, weak jaw development, osteoporosis, scoliosis, cardiovascular disorder, and disorders of the sensory organs connected to the brain (ears, eyes) resulting in deafness and blindness.Marfan Syndrome-An autosomal dominant genetic defect of chromosome 15 that results in excessive synthesis of Fibrilin-1 protein, which is necessary for the production of the elastic fibers in connective tissue. The presentation of Marfan Syndrome may vary by patient and the specific tissues affected, but is typically characterized by abnormally long limbs compared to their torso, long thin fingers and toes, taller than average height, cardiovascular abnormalities including an enlarged heart (Cardiomegaly), enlarged aortic vessels (which makes them weaker and can be fatal), thicker Myocardial muscle (which can blood volume output), Lung weakness (vulnerable to collapse), and issues with vision (nearsightedness, glaucoma, early cataract formation). Ehlers-Danlos Syndrome-A condition resulting from a host of genetic connective tissue disorders, typically caused by the mutation of a gene involved in the synthesis of Collagen Type I & Type III. This mutation results in the excessive synthesis of Collagen I & III, causing extreme elasticity of the skin & joints. >Symptoms: fragile tissues, loose and unstable joints that may dislocate frequently, joint and musculo-skeletal pain, fragile skin that is vulnerable to severe bruising and tearing, slow would healing and excessive scar tissue formation, scoliosis and poor muscle tone. Can affect the heart and blood vessels. Symptoms and severity vary by patient.Hyperglycemia-Normal blood glucose is 70-110mg/dL, symptoms occur above 120 mg/dL, and irreversible damage occurs around 350 mg/dL. Hyperglycemia can increase Insulin production even though it can be caused by an Insulin deficiency/Insulin receptor damage. >Symptoms: -Vasculopathy: destruction of blood vessels which can lead to local bleeding, obstruction of blood vessels, hypertension, and obstructed circulation to organs and tissues. Atherosclerosis can occur, as well as heart disease, Renal failure, and decreased nutrient absorption in GI. -Neuropathy: can damage neuron cells when glucose can’t enter cells, damages the ANS, CNS, and PNS, optic nerves (blindness), Brachial plexus and Lumbosacral plexus damage (motor and sensory disorders in the upper & lower limbs, and difficulties with defecation & urination). -Glucosuria: destroys Nephrons because they can’t reabsorb the excess glucose, resulting in excess glucose in the urine, increased osmotic pressure in filtration tubes (because Nephrons are attempting to dilute the glucose in the urine). This can later result in Polyuria and Proteinuria. -Polyuria: Dehydrates the body in an attempt to dilute the urine, associated with frequent urination, Hypotension, decreased blood volume, decreased Renal filtration (leading to Hypertension), and Renal failure. -Proteinuria: tissue damage in Nephrons caused by glucose results in proteins filtering into the Nephrons and into the urine. -other symptoms: anxiety, nosebleeds, sleep disorders, dehydration, GI and respiratory issues.Hypoglycemia-blood glucose concentration below 50-60 mg/dL, can cause CNS coma, confusion, heart palpitations, tremors, anxiety, sweating, hunger, nausea, vomiting, blurred vision, headache, irritability, fatigue, dry mouth. >Treatment: Glucagon injection, increased sugar in the diet.Myasthenia Gravis-An auto-immune disease where antibodies can recognize and bind Acetylcholine receptors on the post-synaptic membrane of muscle cells. This blocks Acetylcholine from binding at its receptors and inhibits its signal from reaching the target muscle cell. Inhibition of Acetylcholine results in inhibited muscle contractions and muscle weakness. >Symptoms: any involved muscle will be fatigued and weak, resulting in drooping arms, weak legs, difficulties with speech, swallowing and fine motor control, shortness of breath and dizziness, drooping facial muscles >Treatment: Acetylcholinesterase (AchE) inhibitors, such as Neostigmine or Hemicholinium, block the degradation of Acetylcholine for reabsorption into the neuron so that it stays in the synaptic cleft for a longer period of time and allows the remaining unblocked receptors to bind enough Acetylcholine for a stronger muscle cell stimulus. Pheochromocytoma-A tumor of the Adrenal Medulla (part of the adrenal gland above the kidneys that secretes hormones) that secretes excessive amounts of Catecholamines (Nor/Epinephrine, Nor/Adrenaline, dopamine) and excess 3-methoxy-4-hydroxy-mandelic acid (VMA), which is used in Urinary metabolism of these Catecholamines. >Symptoms: Hypertension, High blood pressure, severe headaches, nausea, vomiting, sweating, rapid/increased heart rate, palpitations, tachycardia, nosebleeds, anxiety, dizziness, sleep disorders, shortness of breath, fatigue, weight loss, muscle spasms >Treatment: Adrenalectomy (surgical removal of adrenal gland), Atenolol or Propranolol (β1-blockers), Prazosin (α1-blocker), blood pressure medication and dietary changes, Hormone Replacement Therapy.Parkinson’s Disease-A dopamine deficiency due to the lack of secretion by the Substantia Negra (black substance) in the brainstem, which is involved in the control of movement. Nervous damage causes a drop in the synthesis of dopamine. Symptoms include tremors, stiffness, slow movement, motor issues, loss of balance, involuntary movement, muscle rigidity and contractions, disordered sleep, speech impairments, anxiety, and fatigue. Treatments include L-dopa, a precursor to dopamine which can cross the Blood Brain Barrier to help synthesize new dopamine (dopamine cannot cross the Blood Brain Barrier and must be synthesized within it, after L-dopa crosses over). Anesthetics block synaptic transmission and nerve conduction to alleviate some involuntary movements and wild neural firings.Schizophrenia-A condition caused by an excess of dopamine secreted by the Substantia Negra of the brain stem resulting in symptoms such as delusion, amnesia, confusion and disorientation, isolation, disorganization, mood swings, speech disorders (characterized with rapid frenzied speech), fatigue, and a lack of motor coordination. There is no cure, but symptoms can be managed with lifelong medication and therapy. Cystic Fibrosis-A genetic disease marked by a mutation of the gene that codes for CFTR (Cystic Fibrosis Transmembrane Regulator), a plasma membrane glycoprotein that acts as a Cl- ion channel embedded in the apical membrane (outward facing surface) of the epithelial cell layer of the affected organ’s lumen. The specific defect in the gene causes Cl- to be pumped out of the cell in large amounts with no way back into the cell, which causes an intracellular ion imbalance that results in compensatory excretion of Na+ ions out of the cell. This forms NaCl in the lumen, a Hyperosmotic environment that then pulls H2O from the cells to balance out the salt concentration. This attracts white blood cells to induce local inflammation. In the outer-membrane tissues of the sweat glands, lungs, pancreas, GI tract, spermatic chord, and ovaries where CFTR lines their lumen-facing surface, excessive amounts of thick mucous is produced in response to the swelling and inflammation, which can obstruct the lumen and cause disorders in the affected tissue/organ.-Symptoms: >Spermatic Cord or Ovaries: infertility; in females specifically this can result in irregular menstruation and ovulation. >Pancreatic lumen: pancreatitis, which can cause a deficiency of pancreatic endocrine products (Insulin and Glucagon), and deficiency of pancreatic exocrine products (digestive enzymes lipase, amylase, and protease), which results in maldigestion and malabsorption of nutrients, and a lack of glucose absorption by cells. >Respiratory System: obstruction and inflammation of bronchial airway, frequent respiratory infections, productive cough. If the inflammation and mucous production is severe enough in newborns it can be fatal. >GI Tract: inflammation in the lumen of the small or large intestine can cause abdominal pain, vomiting, nausea, maldigestion and malabsorption of nutrients, severe diarrhea which can lead to dehydration and electrolyte imbalance (Na+, Cl-, K+, Ca2+)-Treatment: the only option is to manage symptoms with synthetic steroid Cortisol to suppress inflammationEdema-A condition characterized by fluid retention (swelling) in tissue of a localized area. Fluid can build up inside the cells and interstitial space due to injury, inflammation, or infection. Edema can compress and destroy the cells causing tissue damage and disordered function of the tissue or organ affected.-Causes: >A reduction in the concentration of Albumin protein in the blood plasma (osmotic imbalance) >Localized destruction of capillaries as a result of trauma, congenital disorder, or genetic condition >Localized destruction of lymphatic vessels, which then leak lymph fluid into the interstitial spaceGalactosemia-An autosomal recessive genetic disorder characterized by a deficiency of the galactose-1-phosphate uridyltransferase enzyme, which is responsible for the degradation and absorption of galactose sugar from lactose. The lack of enzyme results in a toxic accumulation of galactose in the GI tract, which causes diarrhea, severe dehydration, malabsorption of Na+ and Ca2+ electrolytes (muscle weakness, fatigue), inflammation and damage in the Liver, Renal failure, infertility and ovarian failure, developmental disorders, and cataract formation in the eyes. Avoidance of dairy products (lactose) and sources of galactose is best for this patient.Marasmus-A condition of severe malnutrition caused by a lack of protein and low calories in the diet over a long period of time. Marasmus presents with a severely reduced body weight with loss of adipose tissue in locations where larger fat deposits typically are (hips and thighs), lack of energy, easily fatigued, loose folds of skin over the buttocks and underarms, weakened immune system, dry and/or peeling skin, irritable behavior, hair presenting with a “flag sign” (strips of hair lacking pigment), severe diarrhea, dehydration, stunted growth in children, and loss of muscle tone and mass. Cachexia (wasting syndrome) is typically associated with Marasmus, as it is associated with severe weight loss, muscle atrophy, loss of appetite and fatigue. >Treatment: we can attempt to balance the patient’s electrolytes to support cellular activity and recommend a specialized diet administered carefully over time to avoid Refeeding Syndrome (feeding too quickly can fatally overwhelm the body with metabolic activity).-Kwashiorkor: a separate condition that often presents in Marasmus, it more specifically relates to severe malnutrition due to a lack of protein in the diet while caloric intake is normal or near normal. >Symptoms: Edema (fluid retention) in the GI tract due to the osmotic imbalance caused by a lack of protein to digest, a fatty and enlarged Liver, which both contribute to a distended abdomen, or “pot-belly” appearance even though the patient’s limbs will be very thin. Swelling and localized edema in the feet and ankles, hair loss, skin dermatitis and loss of pigment, and loss of teeth are also common signs.Atherosclerosis -the accumulation of cholesterol/fat/lipids (with connective tissue composed of collagen and elastic fibers, smooth muscle cells, Calcium deposits, and some inflammatory cells like Macrophages and T-cells) as “intimal plaques” or “atheroma” under the endothelial layer of blood vessel walls of the medium and large arteries, which can attract and accumulate Ca2+, causing calcification (hardening) of the blood vessel walls. Calcification can weaken blood vessels, making them susceptible to rupture, resulting in localized internal bleeding. If it doesn’t rupture, it may obstruct the blood vessel over time. Hypercholesterolemia (lipid disorder), smoking, & drinking can increase the risk of developing Atherosclerosis, which increases the risk of Myocardial Infarction or stroke. Thyroid issues can also cause Atherosclerosis, as the Parathyroid can secrete Parathyroid Hormone (PTH) in excess, causing Hypercalcemia (which puts large amounts of Ca2+ in contact with any developing plaque formations). The accumulation of fatty plaque under the endothelial lay activates growth factors involved in cell proliferation & cell growth, attracts white blood cells (like Neutrophils) that cause local inflammation, and creates an accumulation site for Ca2+. Common arteries affected include the coronary arteries, carotid artery, cerebral arteries, the aorta and its branches, and the major arteries located in the limbs. If condition worsens it may result in Stroke, muscle damage, blood vessel damage, organ damage >Causes: Diabetes, chronic cigarette use, familial predisposition, Hypercholesterolemia or Hyperlipidemia (also known as Dyslipidemia), sedentary lifestyle, obesity, and hypertension. >Symptoms: “tight” feeling chest pains, and shortness of breath. The obstruction of arteries can cause Angina, a deficiency in blood flow and supply, which can also cause pain.Ketosis/Ketoacidosis-A condition that can occur as a result of Diabetes (Type I, typically) or a prolonged diet lacking in carbohydrates (includes glucose), where the body compensates for the lack of metabolic glucose by instead metabolizing fatty acids from fat and destroyed muscle cells for energy, a process called Ketogenesis that results in acidic by-products called ketone bodies (acetoacetate, acetone, and β-hydroxybutyrate [a carboxylic acid]). Ketosis occurs when large amounts of ketone bodies are produced in an attempt to fuel the body when it is lacking in glucose (or unable to utilize glucose), but excessive amount of ketone bodies can result in Ketoacidosis, a harmful condition where the pH of the blood drops as ketone bodies accumulate and acidify the body’s tissues. Normally ketone bodies can be filtered out through the Renal system to urine (Ketonuria), and acetone can be released through respiration (resulting in a fruity scent on the breath) but excessive amounts of ketone bodies and lack of treatment can’t efficiently filter ketone bodies out of the body in large enough amounts, and the accumulation begins to cause damage. >Symptoms: Frequent urination, increased feeling of thirst and dehydration, sweet fruity breath and heavy labored breathing, nausea and vomiting, dizziness and confusion as acidic ketone bodies build up in Central Nervous System (CNS) tissue which can ultimately lead to a CNS coma, and death >Treatment: If the cause of Ketosis is Diabetes Type I, then we can administer insulin to support intracellular uptake of glucose. We can also administer an IV drip of saline solution or, in more severe cases of Ketoacidosis, an IV drip of sodium bicarbonate solution to buffer the blood back to a more neutral pH.Diabetes Mellitus (includes all types of diabetes)-Type I Diabetes: An autoimmune disease where antibodies destroy Pancreatic β-cells (which produce insulin) which results in the insulin deficiency characteristic of Type I Diabetes. Since Insulin is important for intracellular uptake of glucose, the Insulin deficiency leads to Hyperglycemia (given there is no issue with glucose reabsorption from GI). Over time, Hyperglycemia destroys blood vessel walls (vasculopathy), resulting in tissue damage, Atherosclerosis, and local bleeding in any affected areas: >in Cardiac tissue it can cause Heart disease, which can lead to myocardial infarction >in Renal tissue it can lead to Nephropathy, hypertension, and Renal failure >in nervous tissue it can lead to Neuropathy/Polyneuropathy in the central (CNS), peripheral (PNS), and autonomic (ANS) nervous systems. Neurons starve because they can’t uptake/utilize glucose, which causes nervous tissue destruction. This can lead to Optic Nerve (CN II) damage which leaves the patient at risk for blindness, and peripheral nerve damage in the Lumbosacral Plexus or Brachial Plexus may lead to motor or sensory disorders. -If blood glucose levels rise above 300 mg/dl, patient can also develop Glucosuria (glucose in urine). Glucose in the urine increases osmotic pressure in nephron filtration tubes, causing the tubes to absorb more H2O, leading to Polyuria (frequent urination). Polyuria can decrease blood pressure and blood volume as it dehydrates the patient, causing extreme thirst (Polydipsia). Over time the glucose destroys tissue (Nephropathy) and leads to decreased Renal Filtration Rates, Hypertension, and Edema.-Ketoacidosis can also develop in patients as the body breaks down fatty acids into acidic ketone bodies as alternative fuel generation (in the absence of intracellular glucose), resulting in decreased pH in the blood (acidic blood). This can cause ketonuria (ketone bodies in the urine) and a CNS coma. >Treatment: periodic insulin injection (intravenous or subdermal), no oral insulin supplementation because insulin protein is degraded in the GI. Insulin introduced into the bloodstream allows cells to uptake glucose for consumption, and as a result blood pH should increase back to neutral pH (as the cells stop generating ketone bodies in favor of glucose). Weight loos and dietary changes are recommended to relieve symptoms.-Type II Diabetes: cause is genetic, a defect in the cell-surface Insulin receptor structure that makes it resistant to Insulin binding, meaning its ability to uptake glucose is compromised. Symptoms are similar, but the treatment is different. >Treatment: Exercise and dietary changes are recommended (avoidance of carbohydrates & sugars). Metformin medication decreases blood glucose levels by prolonging Insulin receptor’s exposure to Insulin hormone, which increases the chance Insulin with bind to any remaining functional receptors (facilitates cellular glucose absorption this way).-Steroid Diabetes: NOT caused by Insulin, but instead caused by excess Cortisol, which normally maintains and increases blood glucose levels, so an excessive amount causes Hyperglycemia. -Insipidus Diabetes (Type III): A deficiency in ADH causes disordered salt and water metabolism, resulting in Polyuria (frequent urination) and Polydipsia (extreme thirst) and dehydration, not associated with glucose.-Gestational Diabetes: Occurs as a result of Pregnancy and is normally temporary. This condition mimics Type II, where Insulin receptors become resistant to binding insulin, but it’s not as severe. Light exercise and dietary changes are recommended for the duration of the pregnancy. More frequent check-ups for both mother and fetus with a physician and temporary blood glucose monitor is also recommended.Ischemia-A condition characterized by tissue damage as a result of a lack of blood-flow, and therefore a lack of oxygen being delivered to the tissue for cellular aerobic respiration. A lack of blood-flow can be due to vasoconstriction, blood vessel obstruction (clot or atherosclerosis), or blood vessel damage. Ischemic tissues begin to compensate with anaerobic respiration, and the resulting lactic acid by-product causes a feeling of soreness and pain in the affected tissue. Ischemic tissue is also starved of nutrients usually delivered by the blood, and over time cells will accumulate metabolic waste due that would normally be filtered out to the blood, both of these factors also contribute to cell death and tissue damage. IF the restriction of blood flow is severe enough it can lead to localized paresthesia, paralysis and tissue necrosis in a short amount in time. In the heart, myocardial ischemia can lead to chest pains (angina pectoris), infarction, and long-term heart disease. ................
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