Endocrine Pathophysiology PDF

Disorders of Endocrine Function Thyroid gland – Normal regulation – Hypothyroidism – Hyperthyroidism Adrenocortical Steroids – Normal regulation – Adrenal insufficiencies Endocrine Pancreas – Normal function – Diabetes Mellitus Type 1 Type 2 Addison’s Disease – Glucocorticoid excess Cushing’s syndro...

Disorders of Endocrine Function Thyroid gland – Normal regulation – Hypothyroidism – Hyperthyroidism Adrenocortical Steroids – Normal regulation – Adrenal insufficiencies Endocrine Pancreas – Normal function – Diabetes Mellitus Type 1 Type 2 Addison’s Disease – Glucocorticoid excess Cushing’s syndromes 1 Disorders of Endocrine Function Tertiary defect Hypofunction: – Gland dysfunction Genetic, aging Infection, inflammation Neoplasm – Receptor defects – Feedback defects Hyperfunction: – Excessive stimulation Hyperplasia Tumor secreting H’s – Receptor defects – Feedback defects + Secondary defect + Primary defect + 2 Thyroid Gland Tertiary defect (-) Normal regulation Secondary defect TRH = Thyrotropin releasing H TSH = Thyroid stimulating H T3 = Triiodothyronine (active)Primary defect T4 = Thyroxine (-) (+) (+) (many) 3 Hypothyroidism (Myxedema) (3 main types) 1. Primary hypothyroidism - thyroid gland failure – – Congenital - failure of gland to form Acquired: (Most common) Thyroidectomy (removal) Radiation therapy (destroy the gland) Hashimoto's Disease (Thyroiditis): – – – – Plasma levels of: TRH Increase TSH Increase T3/T4 Less Major cause of hypothyroidism in adults Autoimmune disease - antibodies destroy the thyroid gland 5 female : 1 male prevalence Presence of goiter; Yes (Increase in TSH leads to enlargement) 2. Secondary hypothyroidism - pituitary gland failure (no goiter) 3. Tertiary hypothyroidism - hypothalamic failure (No4 Tissue infarction/stroke, infection, radiation, etc. goiter) Goiter Goiter Hypothyroidism Signs/Symptoms: – Children: slowing of growth and development, mental development. Onset in infancy = cretinism Routine neonatal screening – Adult: general slowing of metabolic functions - Myxedema: see figure/table in BB – Hard, non-pitting edema; on face = “puffy face” Myxedematous coma: – Following chronic/uncontrolled hypothyroidism Can lead to : Severe hypothermia, hypoventilation, CV collapse, coma Treatment: – Levothyroxine (Synthroid®) - 100% synthetic T4 7 Pretibial myxedema Burning or prickling sensation; usually felt in the hands, arms, legs, or feet. 9 Hyperthyroidism (Thyrotoxicosis) (2 main types/etiologies) Etiology: 1. Graves Disease (60-90% of cases) Autoimmune disease – –affects women more than men (5-7:1) Onset “more common" between the ages of 20 and 50 Body produces a thyroid stimulating immunoglobulin – Etiology: IgG mimics TSH = ↑T3/T4 from thyroid 2. Adenoma of thyroid = benign growth, but ↑T3/T4 from thyroid 10 Hyperthyroidism (Thyrotoxicosis) Symptoms - see handout: – Thermogenesis (heat), tachycardia (increase), cardiac hypertrophy, weight loss, insomnia, difficulty in remaining still, anxiety, heat intolerance, exophthalmos (protruding eyes), etc. Would a goiter be present in Graves disease? Yes, the TSH-like IgG overstimulates the thyroid gland Treatment: – Drug therapy (e.g., propylthiouracil= inhibits t3/4 synthesis) – Radiation therapy 11 – Surgical removal (all or part) of thyroid gland 12 Fill in the table below: Increased, decreased, no significant change [Plasma] Primary Hypothyroidism Graves Disease Hashimoto’s Disease TRHsecreting tumor TSHsecreting tumor TRHSuppressing tumor TSHSuppressing tumor TRH Levels Inc Dec Inc Inc Dec Dec Inc TSH Levels Inc * Inc Inc Inc Dec Dec T3 & T4 Levels Dec Inc (via IgG) Dec Inc Inc Dec Dec Hyper- or hypothyroidism Hypo- Hyper- Hypo- Tertirary, Hyper Secondary, Hyper Hypo- Hypo- * Endogenous 13 Disorders of Endocrine Function Thyroid gland – Normal regulation – Hypothyroidism – Hyperthyroidism Adrenocortical Steroids – Normal regulation – Adrenal insufficiencies Endocrine Pancreas – Normal function – Diabetes Mellitus Type 1 Type 2 Addison’s Disease – Glucocorticoid excess Cushing’s syndromes 14 Adrenal Gland Regulation Increased cortisol: Flight or Fight response – Carbohydrate metabolism Dec peripheral glucose use – Inhibit glucose use by skeletal muscle, save it for heart and brain (conserves it for brain energy) Stimulate liver to Increase gluconeogenesis (increase glucose concentration) – Lipid metabolism: Inc lipolysis = inc FFA (free fatty acids, energy sources for muscles) – Protein metabolism: Inc aa = inc conversion to glucose in liver (break down skeletal muscle to free up aa, which is then going to be used to make glucose) – Anti-inflammatory and immunosuppression effects: get sick during stressful times, increase in cortisol and are not able to fight off things as well CRH = Corticotropin Releasing Hormone ACTH = Adrenocorticotropic Hormone + Mineralcorticoid (aldosterone) +Androgens Metabolic, anti-inflammatory, immunosuppressive effects 15 Blood Concentrations of Cortisol Vary Throughout the Day 6a 12p 6p Adrenal Insufficiencies 1. Primary: Autoimmune adrenalitis (80% of cases), TB, AIDS, Sepsis, etc. – Addison’s Disease - destruction of the adrenal cortex 2. Secondary: Dr. Thomas Addison - 1855 – Hypopituitarism, surgical AP gland removal 3. Tertiary: – Hypothalamic disorders Tissue infarction/stroke, infection, radiation, etc. 4. Iatrogenic: (decreased endogenous cortisol via negative feedback loop for long periods of time) – Rapid withdrawal of glucocorticoid therapy produces S/S (e.g., hydrocortisone, dexamethasone, etc) 17 Adrenal Insufficiencies Signs/symptoms: Decreased mineralocorticoid effects: Decreased aldosterone production – Hypernaturia and diuresis, hyperkalemia, dehydration, hypotension, decreased CO Decreased glucocorticoid effects: Decreased cortisol – Poor stress tolerance, hypoglycemia, lethargy, weakness, anorexia, weight loss Decreased androgens: – Males - little/no effects – Females - sparse axillary/pubic hair, decreased libido(?) 18 Excess Glucocorticoids Cushing Syndromes Four main forms/etiologies: 1. Pituitary form - Cushing’s disease/syndrome: – Excess pituitary ACTH, usually from a tumor 2. Adrenal form: > 60% of cases ~10-20% of cases – Majority = adrenal adenomas, rarely adrenal carcinoma 3. Ectopic (paraneoplastic) form: ~10-15% of cases – A non-pituitary, ACTH secreting tumor (e.g., SCLC) 4. Iatrogenic form: – Long-term glucocorticoid therapy for treatment of nonendocrine disorders (Hydrocortisone, dexamethasone, 19 etc.) Cushing disease (ectopic or paraneoplastic) (esp., SCLC) Drug-induced Cushing Syndromes (Excess cortisol) Signs/symptoms: 1. Peculiar fat deposits - ‘buffalo hump’, ‘moon face’, and increased abdominal deposition 2. Muscle wasting - thin extremities 3. Osteoporosis - back pain, rib fractures, etc. 4. Hyperglycemia 5. Na+ retention and HTN - mineralocorticoid effects 6. Immunosuppression = increased infections 7. Emotional instability 8. Hirsutism, menstrual irregularities in females 21 Cushing Syndrome Essentially similar S/S of excess cortisol regardless of cause (pituitary, adrenal, iatrogenic) 22 Cushing Syndromes Endogenous Cushing’s disease: ACTH Cortisol Increase Increase Decrease Increase Excess ACTH from pituitary Functional adrenal tumor: Excess ACTH from adrenal gland Iatrogenic: Decrease Long-term glucocorticoid therapy, excess “cortisol” from drug effects Decrease 23 Disorders of Endocrine Function Thyroid gland – Normal regulation – Hypothyroidism – Hyperthyroidism Adrenocortical Steroids – Normal regulation – Adrenal insufficiencies Endocrine Pancreas – Normal function – Diabetes Mellitus Type 1 Type 2 Addison’s Disease – Glucocorticoid excess Cushing’s syndromes 24 Diabetes Mellitus Greek: “going through” : Latin: “honey” or “sweet” ~ 23.6 million Americans have DM – only ~17.9 million have been diagnosed Economic burden of DM = ~$174 billion in 2007 Leading cause of blindness in adults ages 20 to 74 years Leading contributor to kidney failure Accounts for ~71,000 lower-limb amputations annually ~2/3 of deaths in DM patients are caused by a CV event 1922 – Banting (1/2 Nobel Prize, 1923) & Best discover insulin 1930s – Himsworth’s insulin sensitivity studies (UK) Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2007. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease 25 Control and Prevention, 2008. Disorders of the Endocrine Pancreas Diabetes Mellitus Pancreas - 2 cell/tissue types: Exocrine Endocrine A. Acini – digestive enzymes B. Islets of Langerhans: Alpha cells - secrete glucagon Beta cells - secrete insulin Effects of insulin 26 Diagnostic Criteria for Diabetes (1) A fasting plasma glucose (FPG) of ≥126 mg/dL, or (2) A 2-hour plasma glucose level ≥200 mg/dL following a standard 75 g oral glucose load (oral glucose tolerance test [OGTT]), or (3) A glycated hemoglobin (HbA1C) >6.5%, or (4) Classic symptoms of hyperglycemia plus a random plasma glucose of ≥200 mg/dL 27 https://www.diabetes.org/diabetes/a1c/diagnosis HemoglobinA1C Values reflect average blood glucose levels during the previous 2–3 months The predicted half-life of erythrocytes Evidence supports its correlation with diabetic complications Advantages of HbA1C : no need to fast, reflects [glucose]p over time Types of Diabetes Mellitus Type 1: destruction of Beta cells (5-10% of DM pts) A. Immune-mediated (95% of Type 1’s) Genetic predisposition ~30% concordance in identical twins Environmental trigger (e.g., infection)Molecular mimicry? E.g. one coxsackie virus infection has been associated with T1DM T-cell mediated hypersensitivity B. Idiopathic (unknown cause) (5% of Type 1’s) Strong genetic component, but unknown etiology 29 Stages in the development of type 1 diabetes mellitus ~60-70% decrease in B-cell mass Still undiagnosed Hyperglycemia We lose more beta cells, plasma glucose levels are normal but their response to an oral glucose tablet, so when we challenge them its going to stick around a lot longer. Natural History of Type 1 DM 31 Types of Diabetes Mellitus Type 2: Hyperglycemia with insulin – 90-95% of pts diagnosed with DM Resistance can occur 10-20yrs – Insulin resistance before hyperglycemia is evident – Associated with Metabolic Syndrome: Diagnosed if 3 or more of the following are present: – Fasting glucose: > 100mg/dL* – Abdominal obesity: Males > 40in; Females > 35in – HTN: BP > 130/85 mmHg* – Hyperlipidemia: TG (triglycerides) > 150mg/dL* – Low HDL (low good cholesterol): < 50mg/dL (females); 200mg/dL) Hyperglycemia (FPG >126mg/dL) Process = years to decades 34 Clinical Presentation of Diabetes Mellitus Prevalence (in USA) 0.3%, age 20 years 35 Acute Complications of Diabetes Hyperglycemia: – Glucosuria – when plasma glucose levels exceeds renal reabsorption (~200mg/dL) – Osmotic diuresis results in dehydration, producing: Three “polys” of diabetes—polyuria, polydipsia, and polyphagia Common symptoms in Type 1 and symptomatic Type 2 patients Weight loss (dehydration/loss of calories) can occur Diabetic ketoacidosis – Lack of insulin effects – stimulates lipolysis, forming FFA which are converted to ketones in liver – Polyuria, N/V, marked fatigue, metallic-fruity breath, etc. – Can progress to hyperglycemic hyperosmolar state: Severe cellular dehydration, N/V/gastric stasis, visual problems, acidosis, electrolyte imbalances, seizures, coma, etc. Treated with insulin and by replacing water and electrolytes (Na+/K+) 36 Type 1 – lack of insulin or Type 2 – lack of response to insulin Pathogenesis of diabetic ketoacidosis and hyperglycemic hyperosmolarity Normal insulin effects: Decreases gluconeogenesis Decreases lipolysis Increases SM glucose uptake and protein synthesis 37 Acute Complications of Diabetes Hypoglycemia – Excess insulin therapy or oral hypoglycemic drugs, fasting, increased exercise, medication changes, etc. – Blunted counter-regulatory mechanisms (glucagon, gluconeogenesis in liver, etc.) – Lack of glucose for CNS: ANS activation: tachycardia/palpitations, shaking, sweating, anxiety, hunger, etc. If progresses - headaches, vision problems (diplopia- double vision), altered behavior, confusion, seizures, coma – Treatment: Provide a source of CH2O, carbohydrate 38 2 Chronic complications of DM 1 Neuropathies: – Nerve ischemia, demyelination – Somatic & autonomic nerves 1 3 3 3 4 1 Retinopathies, cataracts, etc. 3 Macrovascular disease: 1 – CAD, stroke, PAD, HTN 3 2 Skin ulcers 4 – Neuropathy + vasculopathy 4 Nephropathy – Glomerulosclerosis, failure 5 Poor wound healing 1 5 3 5 Example Chronic Complications of Diabetes: Macrovascular Atherosclerotic macrovascular disease – – – – – In both, but especially Type 2 DM (~75% of deaths) Coronary artery disease (MI) Cerebral vascular disease (Stoke) Peripheral vascular disease (PAD) Erectile dysfunction in males (Atherosclerosis) Type 2 DM and Metabolic syndrome: Central obesity [waist ≥102 cm for males; ≥88 cm for females] Elevated fasting plasma glucose [≥100 mg/dL] Elevated blood pressure [≥130/≥85 mm Hg] Elevated triglycerides [≥150 mg/dL], low HDL-cholesterol [