N715 Exam 3 Pt 4 PDF

Summary Hormonal regulation is responsible for many (if not most) of the processes which maintain physiological homeostasis.​ Endocrine processes occur through the release of substances into circulation (unlike autocrine and paracrine signals)​ Steroids (synthesized with cholesterol...

Summary Hormonal regulation is responsible for many (if not most) of the processes which maintain physiological homeostasis.​ Endocrine processes occur through the release of substances into circulation (unlike autocrine and paracrine signals)​ Steroids (synthesized with cholesterol) and thyroid hormone are lipophilic, and easily cross the cells membrane. They are smaller, and carried in circulation on a carrier/transport protein​ Water soluble hormones circulate freely, act fast, but cannot cross the plasma membranes​ Hormones can regulate cellular processes, change them, or change DNA coding DIABETES  Diabetes Mellitus is a group of diseases characterized by hyperglycemia and insulin dysfunction (resistance or deficiency).​ Type 1 DM, Type 2 DM, Gestational DM (GDM).​ Additionally, specific subtypes from other causes (e.g. neonatal diabetes, steroid-induced hyperglycemia, cystic fibrosis).​ Chronic disease with serious complications contributing to increased morbidity and mortality. Pancreas: Normal Physiology  BG is coregulated by pancreatic α and β cells through negative feedback.​ GLUCAGON​ ○ secreted by α cells in response to hypoglycemia and SNS activation.​ ○ Stimulates glycogenolysis in the liver and gluconeogenesis to raise BG.​ ○ Repressed by insulin secretion.​ INSULIN​ ○ Synthesized by β cells from proinsulin.​ C-peptide is cleaved by proteolytic enzymes into active form.​ ○ Secretion stimulated primarily by increased blood glucose levels.​ +GI hormones and PNS.​ ○ Reduced secretion with hypoglycemia, high insulin levels, and SNS stimulation. Insulin: Physiology In the body, insulin:​ ○ Promotes glucose uptake primarily in the liver, muscle, and adipose tissue.​ ○ Increases synthesis of proteins, carbohydrates, lipids, and nucleic acids.​ ○ Stimulate storage of glycogen in hepatocytes and skeletal muscle following a meal.​ ○ Stimulate hepatocytes to make and store triglycerides in adipose tissue.​ ​At the cellular level:​  ○ Glucose is the source of energy for cellular respiration, but needs to be let in.​ ○ Insulin binds to cell surface receptor tyrosine kinase which starts a cascade of events leading to the uptake of glucose by the cell through glucose transporters (GLUT4).​ ○ Also facilitates the intracellular transport of potassium, phosphate, and magnesium. Type 1 Diabetes Idiopathic type 1 DM:​ ○ Etiology unknown.​ ○ 10% of type 1 DM.​ ○ No evidence of β cell autoimmunity, with varying degrees of insulin deficiency.​ ○ Strong genetic component.​ Autoimmune type 1 DM:​ ○ Etiology genetic and environmental factors.​ ○ 90% of type 1 DM.​ ○ Slowly progressive autoimmune destruction of β cells of the pancreas.​ ○ Strong genetic associations with HLA class II allele abnormalities; HLA-DQ and HLA-DR.​ Polygenic, several genes associated with type 1 DM.​ PATHO OF T1DM  ○ Genetic abnormality in HLA-II alleles loss of self-tolerance.​ ○ Cellular and humoral immunity stimulation.​ ○ T-cytotoxic cells and macrophages.​ ○ Autoantibodies (mostly IgG) against islet cells​ ○ Often presence of other auto-antibodies glutamic acid decarboxylase (GAD), the protein tyrosine phosphatase IA-2, and/or zinc transporter 8.​ T-cell mediated.​ IL-1, IL-2, IL-6, TNF- α, IFN-γ.​ Th1 cytokines recruit and activate macrophages and T- cytotoxic cells.​ Autoimmune and inflammatory responses to β cells lead to loss of β cell mass and function and eventually β cell apoptosis and death.​ Onset of glucose intolerance and hyperglycemia.​ ○ NO INSULIN Destruction of β cells.​ Reduced peripheral tissue metabolism of glucose ​ Stimulates glucagon → additional glucose released results in hyperglycemia.​ ○ Glucose accumulates in the blood and appears in urine.​ An osmotic diuretic, leads to increased loss of water and electrolytes activation of thirst and clinical manifestation of polydipsia.​ ​Lack of insulin causes excessive metabolism of proteins and fats.​ Tissue catabolism → clinical manifestations of polyphagia and weight loss.​  Rapid mobilization of triglycerides leads to increased levels of plasma free fatty acids.​ ○ Fat metabolized into ketone bodies excess results in DKA. Type 2 Diabetes -- RESISTANCE Is known as non-insulin dependent DM.​ Characterized by insulin resistance and a progressive decrease of insulin secretion by β cells.​ Associated with genetic abnormalities and environmental influences.​ Polygenic genetic association.​ ○ Most mutations in non-coding sections​ ○ Genes that code for β cell mass, β cell function, proinsulin and insulin molecular structures, insulin receptors, hepatic synthesis of glucose, glucagon synthesis, and cellular responsiveness to insulin stimulation.​ PATHO OF T2DM -- INSULIN RESISTANCE + OBESITY ○ Insulin resistance is the suboptimal response to insulin at peripheral insulin-sensitive, target tissues​ especially the liver, muscle, and adipose tissue.​ ○ It is associated with increases in BMI and visceral fat in sensitive individuals.​ “fat threshold” when disease presents varying on the individual.​  ○ Adipokines-- proinflammatory cytokines contribute to systemic inflammation, insulin resistance and are associated with macrophages leading to destruction of β cells. This also contributes to vascular dysfunction.​ ○ mitochondrial dysfunction from decreased insulin-induced mitochondrial activity ○ Decreased insulin receptor density which directly correlates to insulin resistance in type 2 DM.​ ○ Other metabolic dysfunctions​ Along With insulin resistance, pancreatic alpha cells are less responsive to glucose inhibition which leads to abnormally high glucagon secretion and subsequent hyperglycemia.​ PATHO OF T2DM -- DEFECTIVE INSULIN SECRETION ○ Defective insulin secretion in the pathophysiology of type 2 DM.​ ○ Defects in pancreatic insulin secretion → increased glucose production in the liver → hyperglycemia → defects in insulin effect on target tissues due to insulin receptor defects → insulin resistance → persistent state of hyperglycemia → type 2 DM: metabolic alteration, inflammation, and cell death.​ ○ The β cells eventually cannot adequately increase insulin secretion to overcome insulin resistance.​ Fat can also accumulate in the pancreas and contribute to β cell dysfunction.​ Hyperglycemia causes stress response → islet inflammation and β cell apoptosis. Clinical Manifestations of Diabetes Complications of Diabetes T2DM can have DKA though usually associated w/ T1DM ​ NONKETOTIC HYPERGLYCEMIC STATE – HYPEROSMOLAR (HHS) -- dehydrated from osmotic shifts, altered mental state HYPO/HYPERTHYROIDISM The thyroid gland is essential for regulating metabolism and influencing many bodily functions through hormone production.​ Hypothyroidism​ Underactive thyroid​ Reduced hormone production​ Hyperthyroidism​ Overactive thyroid​ Excess hormone release​  Graves’ Disease​ Most common cause of hyperthyroidism​ Autoimmune process Thyroid Structure:​ Butterfly-shaped endocrine gland that produces two hormones:​ Thyroxine (T4)- Inactive form​-- largely converted to T3 Triiodothyronine (T3)- Active form​-- regulate metabolism The thyroid gland consists of spherical structures called thyroid follicles. Each follicle is made up of thyroid epithelial cells (also called thyrocytes) that surround a central lumen filled with a protein-rich substance called colloid.​ Colloid contains thyroglobulin (Tg) -- protein for thyroid protein synthesis Importance of Iodine Uptake & Transfer ○ Essential for thyroid hormone production​ ○ Thyrocytes concentrate iodine from the bloodstream via sodium-iodine symporter (NIS)​ ○ Iodine is then transported to the follicular lumen by pendrin transporter Hypothalamic-Pituitary-Thyroid (HPT) Axis  ○ Secretion of thyroid hormones is regulated by (HPT)-axis​ Hypothalamus releases thyrotropin-releasing hormone (TRH)​ TRH stimulates pituitary gland to secrete TSH​ TSH signals thyroid to produce and release T3 and T4​ T3 and T4 levels in blood are sufficient, the provide negative feedback to hypothalamus and pituitary to reduce TRH and TSH release​ Thyroid Hormone Receptor Activation​ ○ T3 binds to thyroid hormone receptors (TRs) converting receptor into an activator of transcription Thyroid Hormone Effects ○ The binding of thyroid hormones to their nuclear receptors activates or represses target gene transcription, which in turn influences:​ Energy production and metabolism​ Energy inc metabolism of carbs, fats, proteins Heat generation​ Thermogenesis via coupling proteins in brown fat adipose tissue​ Development and differentiation​ CNS, bones, muscles  Cardiovascular system Inc HR, cardiac contractility, & cardiac output ○ HYPOTHYROIDISM Primary Hypothyroidism: Dec T3, T4, inc. TSH; autoimmune thyroiditis, surgery, radiation for hypothyroidism and cancer tmnt, & iodine ​ Secondary Hypothyroidism: dec. TSH dt pituitary disorder that cause dec T3 & T4; pituitary gland tumors or tmnt of the tumors, e.g. TBI or subarachnoid hemorrhagic, metabolic disorders/syndrome (insulin resistance, hyperglycemia, obesity, endothelial dysfxn)​ Tertiary Hypothyroidism: dec. TRH dt hypothalmic dysfxn and dec. TSH, T3, & T4 Myxedema Coma​ Medical emergency​ Decreased LOC​ Hypothermia without shivering​ Hypoventilation​ Hypoglycemia​ Lactic acidosis Graves’ Disease: Type II Hypersensitivity Reaction Type II Hypersensitivity Reaction Recap​ Antibody-mediated hypersensitivity reactions​ Tissue specific​ B cells become self reactive and form antigen-antibody complexes leading to attack of self antigens Thyroid stimulating antibodies/immunoglobulins (TSIs) – bind to TSH receptors (mimic TSH) overstimulate receptors lead to hyperplasia of thyroid gland and hyperthyroidism​ Excess secretion of TH (T3, T4) hormones cause clinical manifestations of hyperthyroidism​ Adaptive Immunity -- Closer Look at B-cells & T-cells Autoreactive T cells and B cells become TSHR-sensitized.​  Sensitized B cells secrete TSHR autoantibodies​ T-cells → initiate the autoimmune response​ Foreign thyroid antigens → B-cells produce TSIs → inflammation and tissue damage​ Proinflammatory cytokines (IL-2, IL-7) release → activate TSHR-reactive immune cells​ B-cells produce large amounts of TSIs and form memory cells​ Thyroid Follicular Cells & Antigen Presentation Human Leukocyte Antigen (HLA) class I antigens​ HLA class II: typically expressed by antigen-presenting cells​ Interferons (INF-gamma)​ Play a role in antigen-specific T cell proliferation HYPERTHYROIDISM ← from AHA  A -- Goiter and neck fullness​ B -- Graves ophthalmopathy – protruding eyes​ C – pretibial myxedema​ D – myxedema of hands causing clubbing appearance​ If untreated can cause thyroid storm – life threatening Graves’ Ophthalmopathy​ Dermopathy (pretibial myxedema) Thyrotoxic Crisis (thyroid storm)​ A thyroid storm is a rare but potentially fatal complication in those with undiagnosed or under treated Graves’ disease.​ Triggers are often physiologic stress like infection, pulmonary or CV disorders, trauma, seizures, surgery, obstetric complications, or dialysis.​ HYPERADRENALISM V HYPOADRENALISM Hyperadrenalism occurs when the adrenal glands are "overactive" and produce excess​ hormones. Symptoms and management depends on which hormone is being​ overproduced​ ○ Cushing's syn rome- overproduction of cortisol​ Hypoadrenalism results from the adrenal cortex's inability to produce sufficient adrenocortical hormones. Categorized as either primary, secondary, or tertiary adrenal insufficiency. Addison's disease is a chronic condition that occurs when the adrenal glands cannot produce enough hormones, primarily cortisol and/or aldosterone.​ ○ Rare condition​ Prevalence of 3 5-1 40 cases per million people​ Incidence of 4 million people per year​ ○ Risk factors​ Autoimmune diseases​  Infections​ Genetics​ Medications​ Females​ 30-50 yrs old Adrenal Gland - Normal Physiology ○ Adrenal Gland:​ ○ Outer Cortex​ Zona Glomerulosa – the outer layer of the cortex that primarily produces the mineral corticosteroid steroid aldosterone​ Zone Fasciculata – the middle layer of the cortex that secretes glucocorticoid cortisol, cortisone and corticosterone​ Zona Reticularis- the inner layer of the cortex that secretes mineral corticosteroids (aldosterone), adrenal androgens & estrogens,and glucocorticoids​ ○ Inner medulla​ Chromaffin Cells store and secrete catecholamines like epinephrine and norepinephrine directly into the bloodstream​ Phy si ological stresstriggersexo cytosis ofthegranu lesfro mthe chromaffin​cells leading to release of catecholamines into bloodstream​ Secretion of adrenal catechol Glucocorticoids  ○ Increase the blood glucose concentration: o promoting gluconeogenesis in the liver o decreasing uptake of glucose into muscle cells, adipose cells, lymphatic cells suppressing insulin secretion ○ Released under stress conditions ○ Suppress immune system and inflammatory responses o Adaptive immunity glucocorticoid mediated inhibitory effect on the proliferation of T lymphocytes o Innate immunity- inhibition of antigen presentation of dendritic cells and decreased activity of PRR on surface macrophages PRR – pathogen recognition receptors o Suppress synthesis, secretion and actions of chemical mediators involved in inflammatory & immune responses ○ Potentiate effects of catecholamines ○ Inhibition of bone formation & ADH Cortisol  ○ Type of glucocorticoid that is the main secretory product of the adrenal cortex. Circulates the body primarily bound to plasma protein trancortin but also attaches to albumin and can even be circulating in free form to diffuse into cells Regulated primarily by the hypothalamus and the anterior pituitary gland ACTH stimulates cells of the adrenal cortex to immediately synthesize and secrete cortisol Feedback Mechanism ○ Three functions in regulating the secretion of ACTH: ○ 1) Negative feedback effects of high circulating levels of cortisol ○ 2) diurnal rhythms with peak levels during sleep ○ 3) Psychological and physiological stress increases ACTH secretion Hormones of Adrenal Gland ○ Mineralocorticoids: Aldosterone Conserves sodium by increasing activity of the sodium pump of epithelial cells in the nephron Secretion is primarily regulated by the renin angiotensin system (RAAS) Angiotensin II is the primary stimulate of aldosterone synthesis and secretion Sodium & potassium levels may directly affect aldosterone secretion ACTH acutely stimulates aldosterone secretion ○ Adrenal estrogen & Androgens Healthy adrenal glands secrete minimal amounts of estrogen and androgens ACTH appears to be the main regulator  Androgenic substances secreted by the cortex are converted by peripheral tissues to stronger androgens HYPOADRENALISM Types of Hypoadrenalism ○ * Primary Hypoadrenalism (Addison's Disease) Directly damaged adrenal glands from autoimmune attack * Results in low production of cortisol and sometimes aldosterone Increased ACTH levels due to loss of negative feedback ○ * Secondary Hypoadrenalism * The pituitary gland fails to produce enough ACTH and therefore does not receive stimulation to produce cortisol (lack cortisol) ○ * Tertiary Hypoadrenalism * Caused by inadequate release of corticotropin-releasing hormone (CRH) from the hypothalamus * This results in reduced levels of ACTH and cortisol production Result of prolonged use of corticosteroids PATHO of Addison’s Disease ○ Addison disease results from low corticosteroid and mineralocorticoid levels, with elevated ACTH due to disrupted feedback. ○ - The autoimmune form (idiopathic) causes adrenal atrophy via autoantibodies and T cells attacking the adrenal glands. o Autoimmune adrenalitis leads to a loss of mineralocorticoid, glucocorticoid, and adrenal androgen hormones. o It can occur alone as Addison's disease or as part of autoimmune polyglandular syndromes (Michels, A., & Michels, N. (2014). ○ It often appears with other autoimmune disorders like Hashimoto thyroiditis and can be inherited as an autosomal recessive trait, with small, misshapen adrenal glands.  Clinical Manifestations ○ Symptoms begin with weakness and easy fatigability ○ * Hyperpigmentation of the sin ○ * Weight loss and decreased appetite ○ * Depression, mental imbalance, behavioral changes ○ * Hypoglycemia ○ * Hypotension ○ * Body hair loss or sexual dysfunction in women ○ * Anorexia, nausea, vomiting, diarrhea ○ * Adrenal crisis: fatigue, vascular collapse due to hypotension, renal shut down, hyponatremia, hyperkalemia HYPERADRENALISM PATHO of Cushing’s Disease ○ Excess of endogenous secretion of ACTH ○ 1) ACTH-Dependent Hypercortisolism: excess ACTH stimulates excess production of cortisol and there is loss of feedback control of ACTH secretion (80% of cases) Secretion of both cortisol and adrenal androgen is increased, and cortisol releasing hormone (CRH) is inhibited ○ 2) ACTH-Independent Hypercortisolism: cortisol secretion from a rare benign or malignant tumor of one or both adrenal glands Secreting tumors of the adrenal cortex secrete only cortisol which leads to the hypercortisolism Clinical Manifestations ○ Weight gain Especially in abdomen, face, and neck → characteristic MOON FACE & BUFFALO HUMP ○ Hypertension (HTN) Dt water and sodium retention ○ Hypokalemia Dt water and sodium retention ○ Sodium & water retention ○ Immune suppression! → more prone to infections ○ Hyperglycemia dt cortisol’s effect on blood sugar → inc risk diabetes Endocrine Quiz Responses Water soluble hormones act upon cellular processes by activation of second messengers Oxytocin production and release is further stimulated by inc contractions of the uterus during labor = positive feedback loop A patient comes to his NP for follow up after hospitalization for uncontrolled atrial fibrillation. During his admission, his TSH was checked and found to be normal. One week later, he is exhibiting signs of thyrotoxicosis. What question should the NP immediately ask this patient? ○ “Were you started on a drug to control the abnormal rhythm?” Autoimmune cells which cause excessive production and release of T3 & T4 are thyroid-stimulating immunoglobulins (TSIs) The NP sees a patient with COPD who takes 10 mg Prednisone daily and likely has developed pneumonia. The patient is tachycardic, hypotensive, and dizzy. The NP recognizes that stress dose steroids are needed because: ○ This pt is on chronic steroids and may develop adrenal crisis when under stress  Key pathological process in T1DM is pancreatic beta cell destruction Excessive release of cortisol from adrenal glands in Cushing syndrome results in altered mental status (AMS) and cognition Epinephrine is produced in the adrenal medulla and is considered a hormone & neurotransmitter because it’s released into the bloodstream for delivery to target cells T2DM is associated w/ insulin resistance, meaning that the body is producing the hormone but it’s not being utilized by the cells. This represents the phenomenon of downregulation of available receptor sites Hormones which are lipophilic and largely composed of cholesterol are steroids Application Hour Notes Negative feedback loops ○ HPT axis ○ Calcium Parathyroid gland -> parathyroid hormone (PTH) -> calcium retrieves from bone Positive feedback loops ○ Oxytocin (Pitocin in synthetic form) - contractions Primary endocrine disorder -- the organ is the target of the disorder (e.g. Graves disease w/ thyroid) Secondary endocrine disorder -- the pituitary is not releasing the trophic hormone properly First messenger - lipid can go straight through Second messenger - e.g. cAMP; would be a pepsinogen; require a reaction and can be case for larger fats that cannot get through like corticosteroids ○ E.g. TSH primary pathway - bind to thyroid - trigger G-coupling cascade DIABETES ○ “Key” = the insulin (coins not the right currency) ○ T2DM - insulin in the cell but no key to utilize the insulin on the glucose contained the machine ○ 10-15 grams of glucose when pt hypoglycemic ○ Where patho meets pharm: Why don’t SGLT2 inhibitors or GLP1 receptor agonists help in T1DM? Beta cell destruction - don’t have any way to make insulin to get the glucose into the cells for use GLPs would help insulin to get into the cell - but pt lacks the insulin to get into the cells SGLT - driving sugar out before it drives the blood glucose up Patient w/ a high A1C would benefit from GLP1 & SGLT2 and if have high BMI, it can help to remove the glucose; even if these meds are more for T2DM SGLT2 and GLP1 HAS to be added with giving insulin ○ Individuals in HHS may have blood glucose >1000 yet they are not ketotic. What type of metabolic acidosis is occurring? What’s the difference?  HHS still have some carbs, have more lactic acid from carbohydrate breakdown and they have anion gap, so the acidosis is more mild (pH ~7.3), and they still have some insulin; have classic 3P’s, lethargy, & AMS/altered LOC, visual disturbances, delirium and coma More so triggered by dehydration and infection; top priority airway management and rapid IV vol replacement to stabilize Metabolic result of dec insulin effect and inc glucagon -> lactic acid Can be associated w/ MI, stroke, PNA DKA has lower pH compared to HHS, ketones and acid from fat breakdown Thyroid Disease ○ Symptoms of thyroid disease are numerous and varied? Hypothyroidism  Hyperthyroidism ○ Where is the problem occurring w/ Graves’ disease? Secondary hypothyroidism, affecting the pituitary ○ How do you correlate thyroid testing w/ patho? T3, T4, TSH, symptoms, scanning Primary v secondary v tertiary hypothyroidism Adrenal Function: Addison’s Disease ○ What are clinical findings for pts experiencing Addison’s? ○ Why is it that they will not respond to fluid resuscitation? ○ What will “fix” the immediate problem? Pts will need stress dose / corticosteroids → Pt going into surgery, infection, emotional stress (significant life changes, occupation, etc.) ○ Why does this correct the problem (temporarily) at the cellular level? Adrenal Function: Cushing’s ○ Hypotension, RAAS unable to activate with hypoadrenalism; aldosterone - sodium & water retention Week 13: Cancer 1. Describe the basic processes resulting in malignant transformation and tumor progression 2. Describe the characteristics of cancerous cells and tissues 3. Apply the biology of cancer to specific forms of malignancy 4. Examine risk factors for various forms of cancer and the role of epigenetics, or the influence of environment on cellular replication Cancer Biology Cancer is a heterogeneous complex of individual diseases, not a single disease At the cellular and molecular level, more like a few diseases caused by genetic alterations and defective cell function that are “similar” Each individual cancer cell possesses different biological characteristics, even cancers of the same type. The differences can be great or very subtle due to the many distinct populations of cancer cells that can reside within a single tumor. Genetic alterations can results from nature or nurture Normal cells: mitosis ○ Cell cycle, cell divides to make two identical “daughter” cells ○ - Ordered set of events, highly regulated ○ - 4 basic steps: Chromosomal duplication Chromosomal segregation Nuclear division Cytoplasmic division  ○ - Complicated process, further subdivided into 5 phases: ○ - Monitored on multiple levels by checkpoints ○ - When a checkpoint is triggered – cellular division stops ○ Cell division is a tightly regulated event. ○ Involves intricate pathways of signaling and checkpoints that prevent the dividing of cells containing damaged DNA. ○ - A cell in the cell cycle has 3 options: continue to grow by dividing and remaining in the cell cycle, take a temporary break to rest by re-entering G0, exit the cell cycle permanently to the post-mitotic state. Cancers result from either mutations or polymorphisms, distinction is the frequency in which they occur ○ 1) Polymorphisms - occur in at least 1% or pop [or more] ○ 2) Mutations -> occur in