Module 7: Endocrine and Metabolic Disorders PDF

Module 7: ENDOCRINE AND METABOLIC DISORDERS Outline Background Disorders of the Pituitary Gland Disorders of the Thyroid Gland Disorders of the Adrenal Cortex Type 1 and Type 2 Diabetes Mellitus The Endocrine System The endocrine system collectively monit...

Module 7: ENDOCRINE AND METABOLIC DISORDERS Outline Background Disorders of the Pituitary Gland Disorders of the Thyroid Gland Disorders of the Adrenal Cortex Type 1 and Type 2 Diabetes Mellitus The Endocrine System The endocrine system collectively monitors and respond to changes homeostasis Endocrine tissues synthesize and release hormones which are transported in blood and bind to receptors on distant cells. Lecture Video: Hormones Respond to changes in the cellular environment. These changes can be from a chemical Factor such as blood glucose or calcium levels, another endocrine Factor such as a hormone from one endocrine gland controlling another endocrine gland or neural stimulus. This is achieved by positive or negative feedback systems ○ Positive is when a neural chemical or endocrine response increases the synthesis and secretion of a hormone.  ○ Negative feedback which is the most common occurs when changing chemical, neural, or endocrine response to a stimulus Decreases the synthesis or secretion of a hormone in the endocrine system. ○ The lack of positive or negative feedback often results in pathological changes in hormone production In general endocrine disorders can be broadly based on their effect on the endocrine organ, the direction of change meaning whether you have a hyper or hypofunction resulting in more or less of a specific hormone and the underlying mechanism leading to disorder. A primary disorder would result from a dysfunction of the endocrine gland leading to the inability to produce adequate amounts of biological free or active hormone. ○ The secondary disorder is the release of signaling molecules that regulate the hormones secretion is impaired. Endocrine Disorders Broadly categorized based on the endocrine organ affected, the direction of change, and the underlying mechanism Direction of change ○ Hyperfunction ○ Hypofunction Mechanism of Change ○ Primary Disorder Directly affects the endocrine organ ○ Secondary Disorder Affects the release of signaling molecules that regulate hormone secretion by the endocrine organ Disorders of the Pituitary Gland Hypothalamic-Pituitary Connection The hypothalamus senses changes in the cellular environment In response, the hypothalamus secretes ‘releasing’ or ‘inhibiting’ hormones through neuronal connections directly to the pituitary gland, triggering the release of hormones into the blood. Posterior Pituitary (Post SI DM) Hyperfunction Syndrome of Inappropriate Antidiuretic Hormone Secretion Hypofunction Diabetes Insipidus Anterior Pituitary (Anti Ad Damage) Hyperfunction Hyperpituitarism ○ Pituitary Adenoma Hypofunction Hypopituitarism ○ Often due to damage or the presence of a tumor Syndrome of Inappropirate ADH Secretion SIADH is an endocrine disorder characterized by excessive antidiuretic hormone (ADH) secretion Often caused by ADH secreting tumors ADH stimulates water reabsorption in the collecting ducts and distal tubules of the kidney Increased ADH production results in water retention and a decrease in the osmolarity of the extracellular fluid ○ Sodium is the most concentrated electrolyte in extracellular fluid ○ Excessive ADH secretion therefore causes hyponatremia Lecture Video: ADH regulates Water balance in the vasculature Osmo receptors in the hypothalamus monitor blood for solute concentrations if there is any increase in solute concentration. The hypothalamus signals for the pituitary to release antidiuretic hormone. Antidiuretic hormone then travels in the blood to the kidneys binding to The receptors on the cells and the collecting ducts. This triggers the movement of aquaporins to the luminal membrane allowing water to reabsorb as water flows back into the blood the cell concentration has decreased. With excess antidiuretic hormone production water reabsorption increases in osmolarity as the extracellular fluid decreases Critically this results in hyponatremia Clinical Manifestations Thirst  Decreased appetite Fatigue Impaired senses Can eventually lead to confusion, lethargy and convulsions These Clinical manifestations are directly related to the hyponatremia caused by the excess water retention Diabetes Insipidus (3P’s Polyuria, Polydipsia, Low Production Characterized by low ADH production with low levels of ADH. Less water is reabsorbed in the kidneys resulting in a greater volume of water making it into the bladder resulting in the three P’s. Endocrine disorder characterized by impaired ADH production ○ Results in polyuria (frequent urination), polydipsia (frequent drinking) and hypotonic urine production (from all excess water in the urine) ○ Hyperosmolar extracellular fluid from the lack of water and body fluids. ○ Can be also caused by impaired renal responses to secreted ADH Neurogenic form has many causes ○ Is an endocrine disorder where lesions of the hypothalamus or pituitary gland interfere with the antidiuretic hormone synthesis transporter release. This is contrary to the nephrogenic form which is due to an inadequate response to antidiuretic hormone in the kidney. ○ Pituitary lesions from surgery or traumatic brain injury, congenital malformations, genetic disorders, autoimmune reactions, infections, medications, pregnancy Renal water excretion is enhanced, leading to hyperosmotic extracellular fluid ○ Hypernatremia can become medical emergency Lecture Video HYPERPITUITARISM : Pituitary Adenoma Benign, slow-growing tumors that arise from endocrine cells of the anterior pituitary Tumor cells secrete the hormone of the cell type that they originated from, resulting in excessive and unregulated hormone production ○ Often growth hormone and prolactin Larger tumors can place pressure on surrounding portions of the anterior pituitary, which can lead to hormone hyposecretion ○ Often luteinizing hormone and follicle stimulating hormone Thyroid Gland Disorders The thyroid gland is composed of two lobes which lie on either side of the trachea located in the neck. The thyroid gland produces thyroid hormone which controls the rate of metabolic processes throughout the body the thyroid gland is composed of follicular cells and para follicular cells or C cells. Follicular cells secrete the iodine containing thyroid hormones the follicles are composed of follicular cells that surround a viscous glycoprotein called a colloid ○ These contain the hormone precursors needed for synthesis ○ the C cells secrete calcitonin a hormone involved in calcium homeostasis that works opposite parathyroid hormone ○ the thyroid gland produces two types of thyroid hormones T4 and T3 these hormones that derive from them amino acid after addition of three or four iodide atoms respectively These hormone circulated in the blood bound to plasma proteins moving to target cells where they alter the expression of genes related to metabolism These hormones can affect growth maturation of tissue cell metabolism heat production and oxygen consumption The third hormones are regulated through a negative feedback loop involving the hypothalamus, the anterior pituitary and the thyroid gland.  Thyroid gland produces thyroxine (T4) and triiodothyronine (T3) through the addition of iodine to the amino acid tyrosine ○ 90% T4 and 10% T3 Once secreted, these hormones circulate in the blood bound to plasma proteins ○ They enter target cells and alter gene expression ○ Affect growth and maturation of tissues, cell metabolism, heat production and oxygen consumption T4 and T3 production is stimulated by thyroid stimulating hormone (TSH) released by the anterior pituitary TSH secretion is promoted by thyrotropin-releasing hormone (TRH) produced by the hypothalamus Alterations of Thyroid Function Hypofunction Hyperfunction Primary Disease of thyroid gland Directly affects thyroid hormone production Secondary Alteration of hypothalamic production TRH and/or Anterior pituitary producing TSH Primary Hypothyroidism Characterized by low T3 and T4 levels and high TSH levels Chronic lymphocytic thyroiditis AKA Hashimoto’s disease Autoimmune destruction of thyroid gland ○ Due to Infiltration of autoreactive B and T cells ○ Presence of thyroid autoreactive antibodies in circulation ○ Leads Follicular damage which makes the thyroid hormone, causing the Ant Pit to release TSH because of the low levels Most common cause of hypothyroidism in developed countries Female:Male ratios as high as 7:1 Iodine Deficiency (most common) Most common cause of primary hypothyroidism worldwide Which results in defective hormone synthesis Congenital hypothyroidism (rare) Occurs in infants Due to absence of thyroid tissue or hereditary defects in T3/T4 synthesis Clinical Manifestations Decreased metabolism and heat production ○ Decrease metabolism causing Weight gain ○ Cold intolerance Lethargy Goiter ○ This results from decrease circulating thyroid hormone ○ Leads to increase TSH production from Ant. Pit. ○ TSH then stimulates thyroid tissue to grow (proliferate) in an attempt to increase the production of thyroid hormone. This causes the Goiter to develop Myxedema ○ This is an alteration in the composition of the dermis ○ In the dermis connect to fibers are separated by increased amounts of proteins mucopolysaccharides which form complexes that draw water into the tissue resulting in edema around the eyes and in feet as well as thickening of the tongue which can result in slurred speech  ○ Cutaneous edema caused by deposition of connective tissue Periorbital edema, pretibial edema, puffy face with dry skin Myxedema Coma ○ This is a state of decompensated hypothyroidism. stressful events such as an infection myocardial infarction or stroke can precipitate this myxedema coma. ○ This occurs more often in the elderly. ○ Medical emergency characterized by diminished consciousness, hypothermia, hypoventilation, hypotension, hypoglycemia and lactic acidosis Primary Hyperthyroidism Too much thyroid hormone is a cause of primary hyperthyroidism or thyroid toxicosis. Characterized by high T3 and T4 levels secreted by the thyroid gland and low TSH levels Graves disease is the most common cause of hyperthyroidism and is an autoimmune disease that results in the stimulation of the thyroid gland. Graves' disease Autoimmune disorder characterized More common in females than males (approximately 5:1) Most common form of hyperthyroidism in many developed countries Thyroid follicular cells present TSH receptor to immune cells via MHC II B cells become activated and differentiate into plasma cells (IgG) Plasma cells secrete antibodies against TSH receptor ○ Known as thyroid stimulating immunoglobulin (TSI) ○ Activates TSH receptor Increased T3 and T4 production Follicular cell hypertrophy Follicular cell hyperplasia Elevated T3/T4 levels inhibit TSH production Lecture: T cells become sensitized to thyroid antigens and stimulate B cells to produce IgG antibodies that bind to TSH receptors. These antibodies are called thyroid stimulating immunoglobulins. Binding of these auto antibodies simulate follicular cells causing the synthesis and secretion of thyroid hormone independent of TSH.  Now in this case the negative feedback regulation of hormone production is intact but it's overrated by the immunological stimulation. Similar to hypothyroidism goiters can also form Due to the immunological stimulation of the thyroid, thyroid hormone secretion or the hyperproliferation of follicular tissues. When there is more follicular tissue more thyroid hormone can be produced in response to a stimulating signal from either TSH or an autoantibody. These growth of molecular tissues can result in a single or multiple nodules. when nodules are present this condition is considered toxic multinodular goiter.. Toxic Multinodular Goiter Enlargement of thyroid gland ○ Nodules begin to form Increased T3/T4 production More common in elderly and often takes years to develop TSH no longer required for growth of thyroid and T3/T4 secretion Clinical Manifestations Increased metabolic rate and heat production Weight loss Heat intolerance Goiter (like in Grave’s disease) Pretibial myxedema Exophthalmos ○ Bulging of eyes Thyrotoxic Crisis ○ Acute and severe exacerbation ○ Can be lethal if left untreated ○ Characterized by High fever, fast and irregular heartbeat, vomiting, diarrhea, and agitation.  Disorders of the Adrenal Cortex Adrenal Gland Located on top of the kidney Consists of the inner adrenal medulla and the outer adrenal cortex Contain 2 Separate Portions Medulla and Cortex Adrenal medulla ○ Component of the sympathetic nervous system ○ Cells of the Medulla are called Chromaffin cells The Secretes norepinephrine and epinephrine into the systemic circulation. Adrenal cortex ○ Further divided into zona glomerulosa, zona fasciculata and zona reticularis Zona Glomerulosa: Produces mineralocorticoids including aldosterone Zona Fascia: Makes cortisol, cortisone, and corticosterone. Zona Reticularis: Secretes sex hormones like androgens, and estrogens and a small amount of glucocorticoids. Cortisol Secretion (Stress Hormone) Cortisol is a stress hormone and production secretions are initiated by the Hypothalamus. It is bound to the plasma protein transcortin. Hypothalamus releases corticotropin releasing hormone (CRH) in response to a stressor. Then anterior pituitary makes ACTH promoted by corticotropin-releasing hormone (CRH), Cortisol secretion is stimulated by adrenocorticotropic hormone (ACTH) Cortisol and ACTH provide negative feedback regulation of the cortisol secretory pathway Cortisol (Glucocorticoid) Immunosuppressant Promotes protein catabolism in skeletal muscle cells Elevates circulating glucose levels ○ Promotes gluconeogenesis and inhibits insulin receptor signalling ○ Conversely, it promotes glycogen synthesis in liver Increases bone resorption and decreases bone formation by getting calcium into the blood for muscle contraction. By doing this it provides the muscles the needed resources to respond to an immediate threat Focus on Cortisol Secretion: (Cortisol is Adding Cush) Hyperfunction :Cushing's Syndrome Hypofunction: Addison's Disease Hyperfunction Cushing Syndrome Endocrine disorder characterized by elevated circulating cortisol levels (hypercortisolism) Cushing Syndrome are tumors within the adrenal cortex that produce excessive amounts of Cortisol. Primary The negative feedback loop is still intact (Hyp. to AntPit to Adrenal) Tumors of the adrenal cortex produce excessive levels of cortisol ○ Cells do not require ACTH to stimulate cortisol release ○ Patients exhibit Low ACTH levels due to negative feedback inhibition by cortisol Endocrine disorder characterized by elevated circulating cortisol levels (hypercortisolism) Secondary Can be due to ectopic production of ACTH or CRH by certain types of tumors, e.g. small cell carcinoma of the lung and anterior pituitary tumors Cushing disease ○ Anterior pituitary tumor secretes high levels of ACTH, which stimulates cortisol synthesis and secretion Most common cause of endogenous Cushing Syndrome ○ Patients exhibit elevated ACTH levels and ACTH secretion is not under negative feedback regulation  Can also be caused by exogenous corticosteroids used to treat various conditions as well. Clinical Manifestations Weight gain, especially in the face, trunk and upper back ○ Central obesity, moon face, buffalo hump Glucose intolerance ○ Do to the cortisol induced insulin resistance. ○ amino acids are used for fuel instead of Protein synthesis. Muscle wasting and thinning of limbs ○ Protein catabolism ○ Enhanced cortisol production also results in protein wasting which results in thinning of the limbs. Osteoporosis: bone resorption outpaces bone formation. Purple striae and bruising ○ Loss of collagen results in a weakened integumentary system. ○ This also weakens the structural support around the small vessels making blood vessels more susceptible to rupture and therefore more easily bruised. Hypertension ○ Cortisol increases sensitivity to catecholamines leading to vasoconstriction. Suppression of immune system Hypofunction Addison’s Disease Chronic endocrine disorder characterized by destruction of the adrenal cortex and impaired adrenal cortical hormone secretion Form of Primary Hypocortisolism ○ ACTH levels are high and cortisol levels are low ○ Aldosterone and androgen production may also be reduced Typically caused by autoimmune destruction of adrenal cortex ○ Autoantibodies targeting adrenal cortical cells or enzymes involved in cortisol synthesis are present in 70% of patients Can also be caused by infections, medications and traumas Incidence of approximately 0.62 per 100,000 Onset typically between 30-60 years of age More common in females than males Clinical Manifestations Muscle weakness Fatigue ○ Due to hypoglycemia Weight loss Hypotension Women may lose some secondary characteristics. Diabetes Mellitus The Pancreas Accessory gastrointestinal organ located behind stomach between spleen and small intestine Exocrine Gland ○ Produces digestive enzymes and bicarbonate Endocrine Gland ○ Produces hormones that enter the circulation ○ Houses the islets of Langerhans Alpha Cells – secrete glucagon Beta Cells – secrete insulin Delta Cells – secrete somatostatin and gastrin Insulin Produced by pancreatic Beta cells Secreted in response to elevated levels of blood glucose Triggers glucose uptake into muscle and adipose tissues cells through the movement of glucose transporters (GLUT4) to the cell membrane Glucose can be immediately used as an energy source or stored as glycogen or fat for later Target cells include skeletal muscle, cardiac muscle, liver, and adipose tissue. Insulin binds to the tyrosine receptor on the surface of the plasma membrane leading to Auto Force phosphorylation of the insulin receptor substrate 1, or IRS1. This initiates a signaling Cascade by phosphorylating other cellular proteins. A key effect of insulin and adipose tissue and muscle tissue is a movement of glucose transporter four (GLUT4) to the plasma membrane. This allows glucose enter the cells and to get used, this removes it from the blood and decreasing blood glucose As blood glucose Falls there is less glucose entering the pancreas. this decreases the synthesis of insulin and allows the alpha cells to begin releasing glucagon.  Group of clinically heterogeneous disorders characterized by chronic hyperglycemia and glucose intolerance ○ This results in disturbed carbohydrate fat and protein metabolism Most common endocrine disorder ○ 3 million Canadians are currently living with diabetes mellitus (Canadian Diabetes Association) Most common forms: Type 1 Diabetes Primary β cell defect/failure Type 2 Diabetes Insulin resistance with inadequate insulin secretion Gestational Diabetes Glucose intolerance diagnosed during pregnancy Diagnosis of Diabetes FPG ≥7.0 mmol/L ○ Fasting = no caloric intake for at least 8 hours or A1C ≥6.5% (in adults) ○ Using a standardized, validated assay in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes or 2hPG in a 75 g OGTT ≥11.1 mmol/L or Random PG ≥11.1 mmol/L ○ Random = any time of the day, without regard to the interval since the last meal Type 1 Diabetes Mellitus Endocrine disorder characterized by atrophy of the pancreas and destruction of pancreatic beta cells Results in impaired insulin production – Hyperglycemia is not evident until 80-90% of beta cell function is lost Usually diagnosed