Module 6 Endocrine Flashcards

Question

Hormones and cells in glucose homeostasis

Answer 1

Alpha cells: Glucagon (glucose agonist): hyperglycaemic effect, stimulates glucose production from the liver (glycogenolysis and gluconeogenesis; other functions on energy homeostasis and appetite. Beta cells: Insulin released with high blood glucose, stimulates glycogen production via hypoglycaemia (increased glucose uptake); inhibits glucagon production. Delta cells: ~5% of the cells; secrete Somatostatin, a paracrine inhibitor of glucagon and insulin release. Somatostatin release also regulated by β-cells providing a feedback mechanism. PP cells: F-cells or pancreatic polypeptide (PP) cells, located in the periphery of islets, secrete PP – released post-prandially and has effects on metabolism, GI motility, and appetite.

Answer 2

Autoimmune disease in which pancreatic beta cells are destroyed and thus not enough insulin is produced Incidence ~ 3 in 1000 Often develops before age 15 and seldom after 40 May be triggered by viruses and/or toxins Tendency toward ketosis (developing keto-acidosis) – Why? Patient requires insulin supplement (exercise and diet are key)

Answer 3

Impaired b-cell function and/or resistance of tissues to Insulin ~ 3% of population (many undiagnosed), roughly 90% of cases Onset usually > 40 years Associated with lack of physical activity and/or obesity

Answer 4

kidney damage, defined by proteinuria (microalbuminuria) and reduced GFR. Peripheral nerve dysfunction, sensory, focal/multifocal, autonomic neuropathies. Macrovascular complications of diabetes microvascular complications; diabetic retinopathy

Answer 5

Damage to vessels and cells reflects the glucose concentration and duration of exposure. Glucose can be converted to sorbitol which is an osmotic stresser. Production of advanced glycation endproducts (AGEs). Glycation is a non-enzymatic adduction of targets by glucose. Not the same as glycosylation.

Answer 6

Thirst Polyuria/nocturia/ incontinence in the elderly Tiredness Blurred vision (lens changes shape and size) Recurrent thrush Recurrent infections Feeling of unwell/poor concentration Weight loss – yes in Type 1, not always Type 2 Mood changes Micro or macro-vascular problems

Answer 7

FPG  7 mmol No food or drink for at least 8 hours 2 hour glucose  11.1mmol during an glucose tolerance test A1C  48mmol/mol (6.5%) Using an accepted and standardized laboratory test If classic symptoms of high glucose = any glucose  11.1 mmol

Answer 8

More acute onset in Type 1 Type 2 progressive disease and symptoms more gradual Symptoms might be not realised and put down to other things Type 2 diabetes takes on average 10 years to present IF IN DOUBT – TREAT AS TYPE 1 !

Answer 9

Peptide hormones are translated on the RER as a pre-prohormone. This initial translational product is then cleaved to a prohormone which then undergoes further post-translational processing to produce the hormone which is then stored in secretory vesicles of the endocrine gland.

Answer 10

Hormone or neurotransmitter Preganglionic fibres stimulate a mixture of epinephrine and norepinephrine into bloodstream. (80% epinephrine and 20% norepinephrine).

Answer 11

Arachidonic acid derived hormones are involved in a number of processes involved in the regulation and control of inflammatory responses.

Answer 12

The precursor for all steroid hormones is CHOLESTEROL Cholesterol can be synthesised de novo but usually comes from diet (LDL) and is stored as cholesterol ester. There are 4 families of lipid soluble steroid hormones Corticoids Progestins Androgens Estrogens- Secreted by: Adrenal cortex- cortisol & aldosterone Ovaries- oestrogen & progesterone Testes- Testosterone

Answer 13

Unlike peptide hormones, most steroid secreting cells do not store hormone but synthesize them as required Slower time for steroid hormone to act

Answer 14

Water soluble hormones e.g. peptide hormones and those derived from phenylalanine and arachidonic acid Signal via cell membrane receptors and activation of enzymes and other molecules via G protein coupled receptors or Tyrosine kinase coupled receptors Lipid soluble hormones e.g. Steroid or thyroid hormones readily cross cell membranes Signal via intracellular cytoplasmic or nuclear receptors and modulation of gene expression

Answer 15

inhibition of hypothalamic tropic hormones by the anterior pituitary tropic hormone.

Answer 16

the hormone whose secretion is stimulated by the tropic hormone generally feeds back to the hypothalamus (and often the anterior pituitary as well) to inhibit secretion of the tropic hormone.

Answer 17

Initial fight or flight A slower resistance response Exhaustion

Answer 18

Increase in bone resorption and decreases collagen formation EPO is increased, which stimulated RBC, it decreases NO, and increases constriction, decreases permeability It also increases effectiveness of catecholamines and so increases BP Immunosuppressive and anti-inflammatory actions Decreases calcium absorption from kidney Cortisol stimulates the release of amino acids from muscle. Liver utilises these to make glucose. The increase in glucose stimulates insulin release. Cortisol inhibits the insulin-stimulated uptake of glucose in muscle via GLUT4 transporter. Many effects on fetus. Required for lung development at correct stage

Answer 19

Cushing’s Disease: Increased ACTH due to pituitary defect/pituitary tumour Cushing’s Syndrome: Increased glucocorticoid due to ectopic sources of ACTH (small cell lung cancer) or Adenoma of adrenal gland Ectopic ACTH syndrome Addison’s Disease (primary adrenal insufficiency): Adrenals cannot produce sufficient steroids - poor BP control ,Increased ACTH- hyper pigmentation, refer to actions of cortisol

Answer 20

Low Dose test (1mg) Injection (or take orally) low dose of Dexamethasone. The normal situation would result in suppression of cortisol levels In patient with excess production (e.g. Cushing’s disease) cortisol suppression is limited with this test If cortisol remains high after low-dose DEX test, is raised in the urine 24 hr test and shows loss of diurnal variation – Diagnose Cushing’s High dose test (2mg): 2mg Dex 6 hourly for 48 h; 0900h plasma cortisol measurements taken. In Cushing’s disease, the cortisol level will decrease to <50% of pre-test value (in CD, tumour doesn’t produce as much ACTH as ectopic ones and so some of the feedback is retained in response to this dose of dex) If suppression is less than 50% then ACTH source is outside of pituitary e.g. Adrenal tumour or ectopic ACTH secretion (as these tumours usually result in greater levels of ACTH than pit tumours)

Answer 21

Start with measurement of pituitary and target organ hormone in blood taken at 0900h. In HPA axis Normal plasma ACTH at 0900h is <50ng/L Normal cortisol at 0900h is 140-690 nmol/L If abnormal need to do dynamic testing using stimulation test ACTH Stimulation Test for Adrenal Insufficiency (synacthen test): The ACTH stimulation test is very specific for HPA axis. Blood cortisol and/or urine cortisol are measured before and after an injection with synthetic form of ACTH. After an injection of ACTH blood and urine cortisol levels rise. Patients with adrenal insufficiency respond poorly or not all.

Answer 22

To perform when the synacthen test is abnormal in order to establish possible cause of adrenal insufficiency (secondary/pituitary or tertiary/hypothalamic). Blood cortisol levels are measured before and after (30, 60, 90, and 120 minutes after) synthetic CRH injection (i.v.). Patients with Primary Adrenal insufficiency (Addison’s) : high ACTH, but not cortisol production. Patients with Secondary adrenal insufficiency deficient cortisol responses and absent or delayed ACTH responses- (Absent ACTH response points to the pituitary; a delayed ACTH response points to the hypothalamus)

Answer 23

The main function of the hypothalamus is to maintain homeostasis by: Autonomic Function Control Endocrine Function Control Motor Function Control Food and Water Intake Regulation Sleep-Wake Cycle Regulation Circadian rhythm Temperature regulation Emotional and behavioural responses Different hypothalamic regions or nuclei are involved

Answer 24

An extension of the hypothalamus, containing neural tissue consisting of the axon terminals of neurons originating in the hypothalamus which extend downwards as a large bundle behind the anterior pituitary. Composed of: The pars nervosa(neural lobe) Infundibular stalk Median eminence

Answer 25

The adenohypophysis can be subdivided into three distinct lobes: Pars distalis (anterior lobe) Pars intermedia (intermediate lobe) Pars tuberalis

Answer 26

Neurons with cell bodies in the supra and paraventricular nuclei of hypothalamus project into posterior pituitary Directly releasing hormones into venous drainage Neurons with cell bodies in medial hypothalamic nuclei projecting into median eminence releasing tropic hormones into pituitary portal veins Tropic hormones influence cells in anterior pituitary to produce hormones circulating in the body

Answer 27

Tropic hormones: regulate the secretion of other hormones into the anterior pituitary, travelling from the median eminence via a unique system of portal veins. Neurohormones: synthesised in specialised neurons in the supraoptic and paraventricular nuclei of the hypothalamus. They pass down the axons and are stored in the distended parts of the axons in the posterior pituitary.

Answer 28

Thyrotrophin-releasing hormone (TRH) Gonadotrophin-releasing hormone (GnRH) Corticotrophin-releasing hormone (CRH) Growth hormone-releasing hormone (GHRH) Somatostatin (GHIH) Prolactin-releasing hormone (PRH) Dopamine (also referred to as PIH)

Answer 29

Following synthesis, the peptides are packaged into secretory vesicles, which are transported to the axon terminals in the posterior pituitary. They are released by exocytosis upon a neuronal signal (neuroendocrine reflexes). Antidiuretic hormone (ADH; also called vasopressin) Kidneys are the target cells. Hormone released by increasing water reabsorption. Oxytocin Uterus and Breast are the target cells. Hormone released by pressure in the uterus of pregnant woman.

Answer 30

ADH acts to promote water conservation by the kidney by increasing the permeability of the distal tubular epithelium to water. The main stimulus for ADH release is increased osmotic pressure of water in the body, which is sensed by osmoreceptors in the hypothalamus. The other major stimulus is volume depletion, which is sensed by baroreceptors. Other stimulants for ADH release include pain, stress, emesis, hypoxia, exercise, hypoglycaemia, cholinergic agonists, β-blockers, angiotensin, and prostaglandins. Inhibitors of ADH release include alcohol, α-blockers, and glucocorticoids.

Answer 31

A lack of ADH produces central Diabetes Insipidus. An inability of the kidneys to respond normally to ADH causes nephrogenic Diabetes Insipidus. In the absence of ADH, urine output increases more than 10 fold. Removal of the pituitary gland usually does not result in permanent Diabetes Insipidus because some of the remaining hypothalamic neurons produce small amounts of ADH.

Answer 32

Two major targets: The myoepithelial cells of the breast The smooth muscle cells of the uterus Major functions: Milk ejection reflex Uterine smooth muscle contraction Both examples of positive feedback regulation

Answer 33

The release of oxytocin from the posterior pituitary is stimulated by tactile sensory inputs from the nipple The binding to oxytocin receptors on the myoepithelial cells, cause the myoepithelial cells to contract, and resulting in increased intra-lumenal (intramammary) pressure and ejection of milk from the alveolar lumen.

Answer 34

Failure to progress in labour and difficulty breast feeding

Answer 35

Primary disorders are extremely rare Often hypothalamic disorders mimic pituitary disorders Usually results in decreased secretion of hormones Exception being prolactin (as prolactin is under inhibitory control by the hypothalamus) Causes of Hypothalamic disorders Trauma/surgery Radiotherapy Hormone excess: (SIADH), disconnection hyperprolactinaemia Hormone deficiency: Cranial DI, congenital GnRH deficiency Primary glial tumours of the hypothalamus

Answer 36

Basophils: Corticotroph 15-20% Thyrotroph Gonadotroph Acidophils:Somatotroph 40-50% Lactotroph

Answer 37

ACTH is peptide synthesized as part of a larger prohormone, proopiomelanocortin (POMC) trough a translational processing mediated by different enzymes called prohormone convertases. MSH (melanocyte-stimulating hormones) exist in three forms:α, β, and γ and they are products primarily of the intermediate lobe of the pituitary gland. MSH is well known for its ability to stimulate melanogenesis and is involved in the energy balance.

Answer 38

POMC harbours the peptide sequence for ACTH, α- and β-MSH, endorphins (endogenous opioids), and enkephalins

Answer 39

Circulates as an unbound hormone with a short half-life up to 10 min ACTH secretion exhibits a diurnal variation pattern (highest in early morning) ACTH binds to the melanocortin-2 receptor (MC2R) on cells in the adrenal cortex and can also bind malanocortin-1 receptor (MC1R) on melanocytes Cleavage of POMC to generate ACTH is important in appetite pathways as failure is thought to cause monogenic obesity Binding to MC2Rs in the adrenal cortex: Stimulates hydrolysis of stored cholesterol ester to provide cholesterol for steroid synthesis. Increase the expression of enzyme Desmolase important for cholesterol conversion to pregnenolone Stimulates glucocorticoid (cortisol) release from the zona fasciculata of the adrenal cortex Promotes, in the long term, growth and survival of two zones of adrenal cortex.

Answer 40

ACTH secretion happen in a pulsatile manner and shows a pronounced diurnal pattern, with a peak in early morning and again in late afternoon During sleep steroid demand is low so levels of these are at their lowest. ACTH levels increase early before awakening, stimulating cortisol production –This is known as the cortisol awakening response (CAR).

Answer 41

MSH decreases appetite Increases skin pigmentation (MSH and beta lipotropin stimulate release of melanin by melanocytes). Responsible for tanning (UV activates p53 which switches on transcription of POMC gene) May be involved in sexual arousal CRH stimulates its release and dopamine inhibits its release MSH is increased in Cushing’s and Addison’s disease In Addison’s increased skin pigmentation is mostly due to excess ACTH (ACTH can bind to MSH receptors)

Answer 42

TSH is a pituitary glycoprotein hormone composed of an α-subunit, called the α-glycoprotein subunit (α-GSU), and a β-subunit (β-TSH). The half-life is around 60 min. Essential for normal growth and development, stimulates every aspect of thyroid function. Also strong tropic effect, stimulating hypertrophy, hyperplasia, and survival of thyroid epithelial cells. The production is stimulated by the thyrotropin-releasing hormone (TRH), which is released according to a diurnal rhythm (highest during overnight hours, lowest around dinnertime).

Answer 43

The gonadotroph is a dual hormone producer in that the same cell secretes FSH and LH (also called gonadotropins Gonadotropins are involved in the control of sexual differentiation, steroid hormone synthesis and gametogenesis In males, LH and FSH involved in spermatogenesis; LH stimulates the testosterone synthesis pathway; FSH stimulates the maturation of spermatozoa in the Sertoli cells. In females, LH and FSH stimulates estrogen biosynthesis and regulate hormones involved in the menstrual cycle; FSH stimulates follicle development

Answer 44

The lactotroph produces prolactin (PRL). The lactotrope differs from the other endocrine cell types of the adenohypophysis : The lactotrope is not part of an endocrine axis, therefore PRL acts directly on non-endocrine cells to induce physiologic changes. The production and secretion of PRL is predominantly under inhibitory control by the hypothalamus through the neurotransmitter, dopamine. The disruption of the pituitary stalk and the hypothalamo-hypophyseal portal vessels results in an increase in PRL levels, but a decrease in ACTH, TSH, FSH, LH, and GH.

Answer 45

Most abundant pituitary cell type - Produce Growth Hormone GH (also called Somatotropin). About 50% is bound to GH-binding protein (GHBP) which increases the half-life of GH (max 20 min) secretion is under dual control by the hypothalamus: Growth hormone releasing hormone (GHRH) from the arcuate nucleus of the hypothalamus stimulates synthesis and secretion of GH. GHRH is released in a pulsatile fashion and causes a similar pulsatile release of GH Somatostatin (GHIH) from the periventricular nucleus of the hypothalamus inhibits synthesis and secretion of GH. Somatostatin inhibits the effect of GHRH on the somatotrophs

Answer 46

Acts as a hormone & a trophic factor Promotes synthesis & secretion of insulin-like growth factors (IGFs and somatomedins) from the liver to promote mitosis & cellular differentiation for growth. Anabolic & growth effects Increases bone length & width prior to epiphyseal closure IGFs stimulate both bone & cartilage growth anti-insulin-like synergises with cortisol

Answer 47

GH is not the only hormone necessary for normal development: Thyroid hormone Growth severely stunted in hypothyroid children Hypersecretion does not cause excessive growth Insulin Deficiency often blokes growth Hyperinsulinism often stimulates excessive growth Androgens Play role in pubertal growth surge, stimulates protein synthesis in many organs Oestrogens Effect on growth prior to bone maturation are not well understood

Answer 48

Gigantism: Excessive GH production before Puberty. Pituitary dwarfism: insufficient of GH production. Laron Syndrome: Growth Hormone resistance due to a genetic defect in the expression of GH receptors.

Answer 49

Anatomical relations: Anterior = sphenoid sinus, tuberculum sellae Posterior = dorsum sellae, basilar artery, pons Superior = diaphragma sellae (dura mater), optic chiasm Inferior = sphenoid bone (hypophyseal fossa) Lateral = cavernous sinus (venous blood)

Answer 50

Anterior lobe of pituitary (adenohypophysis) Pars distalis makes up most of adenohypophysis - contains chromophil cells Acidophils and basophils containing various pituitary hormones in secretory granules (see other pituitary endocrine lectures) Pars tuberalis surrounds stalk Pars intermedia is region between two lobes

Answer 51

Posterior pituitary (neurohypophysis) Consists of pars nervosa and communicating pituitary stalk (infundibulum) Does not contain hormone-synthesising cells Instead contains long axons of secretory neurons from the hypothalamus. The cell bodies of these neurons are located in hypothalamic nuclei e.g. supraoptic nucleus These neurons secrete two hormones: Anti-diuretic hormone (ADH) AKA vasopressin Oxytocin

Answer 52

Superior hypophyseal artery (from internal carotid) helps to supply blood to hypothalamus and forms the primary capillary bed (plexus) Neuropeptides released from hypothalamus enter the primary capillary bed and then long hypophyseal portal veins that descend further into the anterior lobe of the pituitary Hypophyseal portal veins then form a secondary capillary bed (plexus) within anterior pituitary Anterior pituitary hormones are released into the secondary capillary bed before draining into hypophyseal veins and the cavernous sinuses

Answer 53

Paraventricular nucleus and supraoptic nucleus of hypothalamus These hypothalamic neurons have long unmyelinated axons which descend into the posterior lobe of the pituitary gland Hypothalamic nuclei are neurosecretory: hormones are synthesised inside the neurons and transported through their axons into the posterior lobe of the pituitary Herring bodies: dilated endings of neurons for temporary storage of hormones ADH and oxytocin released into capillary beds and drain into hypophyseal veins and the cavernous sinus

Answer 54

An intracranial dural venous sinus on either side of the pituitary gland, lateral to the sella turcica and the body of the sphenoid bone The cavernous sinus will receive venous blood from the Cerebral veins Ophthalmic veins Emissary veins via the pterygoid plexus Hypophyseal veins from the pituitary gland Venous anastomoses between the facial vein and the ophthalmic veins are a potential route whereby infection can spread from an extracranial site (the face) to the intracranial space around the brain Contents of each side of the cavernous sinus: Superior  inferior O culomotor nerve T rochlear nerve O phthalmic branch of trigeminal nerve M axillary branch of trigeminal nerve Medial to lateral C arotid artery (internal carotid) A bducens nerve T rochlear nerve

Answer 55

Danger triangle” of the face (nose, upper lip) where an infection can spread via venous anastomoses to the cavernous sinus

Answer 56

Endocrine disturbances – may lead to overproduction of anterior pituitary hormones e.g. growth hormone (gigantism or acromegaly) Optic chiasm compression (bitemporal hemianopia)

Answer 57

Anterior lobe (adenohypophysis) Derived from surface ectoderm from developing oral cavity (Rathke’s pouch) Starts growing from week 4 Loses connection to oral cavity by week 8 Posterior lobe (neurohypophysis) Derived from neuroectoderm (neural tube ectoderm) arising from the floor of the future diencephalon of the brain Still connected to hypothalamus via infundibulum

Answer 58

Pharyngeal hypophysis (aberrant hypophysis) Ectopic anterior pituitary tissue located in the roof of the nasopharynx Ectopic pituitary tissue can also be found within the sphenoid bone (intraosseous) or in the hypophyseal fossa inferior to the pituitary gland (suprasellar/intracranial) Craniopharyngioma Tumour of persistent embryonic tissue associated with Rathke’s pouch (surface ectoderm) May be non-functional (benign) or functional (secretory) Often associated with visual disturbances, headache and pituitary dysfunction

Answer 59

inherited defect in an enzyme involved in the production of cortisol and aldosterone Several possible types >90% of CAH due to deficiency of 21b-hydroxylase Decreased negative feedback inhibition result in excess ACTH release - prolonged ACTH hyperstimulation results in hyperplasia of the adrenals (hence, the name of the condition)

Answer 60

Secondary insufficiency: Lack of ACTH production tumour/damaged pituitary Adrenal suppression / atrophy long-term, high-dose glucocorticoid use

Answer 61

hyperaldosteronism Abnormally large amount of aldosterone produced common cause = tumour Results in the retention of Na+, and hence increased water retention, increased K+ elimination - polyuria, hypokalaemia, weakness The main clinical finding in Conn's is hypertension Treatment: Surgery, aldosterone receptor antagonist e.g. spironolactone

Answer 62

The right adrenal gland is triangular shaped The left adrenal gland is semilunar shaped

Answer 63

Different embryological origins: Cortex from mesoderm (epithelial tissue) Medulla from neural crest Cortex: 5th week proliferation of mesothelium cells, penetrate mesenchyme - second wave encloses cortex Medulla: neural crest cells form medially and are then enclosed

Answer 64

Closely packed clumps of secretory cells arranged in ovoid clusters near capillaries (chromaffin) that have a strongly basophilic cytoplasm. The cells have secretory granules which contain either epinephrine or norepinephrine. When fixed in potassium bichromate, the medullary cells become brown. Therefore, they are called chromaffin cells. The color is the result of a reaction between chromate and epinephrine or norepinephrine. With the typical H&E stain, the cells appear as somewhat stellate-shaped cells containing a rather prominent, round nucleus. A fine network of capillaries branch throughout the medulla and numerous larger venules draining blood from the sinusoids of the cortex into the central medullary vein.

Answer 65

Zona Glomerulosa ZG: cells arranged in clusters (glomeruli) Mineralocorticoids Zona Fasciculata ZF: rows of lipid-laden cells arranged radially in bundles of parallel cords (fasces) Glucocorticoids Zona Reticularis ZR: tangled network of cells androgens Medulla: chromaffin cells arranged in ovoid clusters near capillaries. cetecholamines

Answer 66

1) Activation of the renin-angiotensin system related to a decrease in Na+ and decrease in Blood Pressure. 2) Direct stimulation of the adrenal cortex by increase in blood K+ concentration Primary site of action is the distal tubules of the kidney nephron where it promotes Na+ retention into the blood and enhances K+ elimination into the urine filtrate

Answer 67

Increased: Appetite Blood pressure Insulin resistance Gluconeogenesis, lipolysis Decreased: Fibroblast activity (wound healing) Immune and inflammatory activity Bone formation

Answer 68

Tumour of Adrenal medulla that release excessive catecholamine form the chromaffin cells. The tumours can manifest with highly variable presentations From rare and progressive hyper-catecholaminergic episodes, through relatively sustained hypertension, to severe and clinically malignant disease, complicated by hypertensive crises, stroke, acute myocardial infarction and numerous other conditions. The "rule of tens" for pheochromocytomas: 10% are bilateral, 10% are extra-adrenal, 10% are malignant.

Answer 69

Episodic pounding headache Palpitations and Tachycardia Diaphoresis

Answer 70

Lipid metabolism: T3 stimulates fat mobilization, leading to increased concentrations of fatty acids in plasma. T3 also enhance oxidation of fatty acids. Carbohydrate metabolism: Thyroid hormones stimulate almost all aspects of carbohydrate metabolism, including enhancement of insulin-dependent entry of glucose into cells and increased gluconeogenesis and glycogenolysis to generate free glucose. Growth & Development: Thyroid hormones essential for normal growth in children. Normal levels of thyroid hormone are essential to the development of the foetal and neonatal brain. Cardiovascular system: Increases heart rate, cardiac contractility and cardiac output. Promote vasodilation, which leads to enhanced blood flow to many organs. Central nervous system: Both decreased and increased concentrations of thyroid hormones lead to alterations in mental state. Too little thyroid hormone, and the individual tends to feel mentally sluggish, while too much induces anxiety and nervousness. Reproductive system: Normal reproductive behaviour and physiology is dependent on having essentially normal levels of thyroid hormone. Hypothyroidism is associated with infertility

Answer 71

Cell membrane - Stimulates the Na+/K+ATPase pump - Increased demand for metabloites e.g. glucose Mitochondria - Stimulates growth, replication & activity; basal metabolic rate is raised. - Increased heat production, oxygen demand, HR and stroke volume Nucleus - Increases the expression of enzymes for energy production - Lipolysis, glycolysis & gluconeogenesis increased to raise blood metabolite levels and cellular metabolite levels Neonatal cells - Cell division & maturation - Essential for development of CNS & skeleton

Answer 72

Synthesis of TH requires: Tyrosine Iodine Thyroglobulin (Tgb) Body stores adequate tyrosine Iodine dietary intake necessary Inadequate intake  goitre Iodination of salt in UK and USA Rice iodine enrichment Normal intake 150 micrograms/day of which 125 micrograms taken up by the thyroid

Answer 73

1) Iodide (I-) trapping by follicular cells against electrochemical gradient (rate limiting step!) Na+/K+ATPase-dependent Na+/I- symporter-basal surface of follicular cell 2 & 3) A pendrin channel (specialized Cl-/I- cotransported) transports the I- at the apical membrane Synthesis of thyroglobulin in vesicles (TGB) & its release via exocytosis into colloid. The TGB vesicles express thyroid peroxidase (TPO) which is released upon fusion with the membrane and immediately results in Oxidation of two iodides (I-) to I2 by thyroperoxidase (TPO) 4) Iodination of tyrosine residues in TGB to T1 then T2 by TPO 5) Coupling/ conjugation of T1 & T2 to form T3 & T4 (ratio about 1:13) also by TPO 6) Uptake (pinocytosis) & lysosomal digestion of TGB to release thyroid hormones by follicle cells (stimulated by TSH and megalin receptors). Other degradation products are recycled by the pendrin transporter 7 & 8) Secretion of T3 & T4 into blood & transportation by primarily thyroxine-binding globulin (TBG)

Answer 74

T3 (biologically active) Formed from T4 by 5’-deiodination in thyroid (20%) and peripheral tissues. Deiodinases maintain cellular and serum concentrations of T3 and the expression of these enzymes changes according to thyroid hormone status. T3 binds to nuclear thyroid receptors that complex with retinoid X receptor (RXR) The receptor complex binds to the thyroid response elements for initiation of transcription T4 50X more in plasma that T3 80% is metabolised to T3 & rT3. 20% is conjugated and excreted. T4 is tightly bound to plasma proteins compared to T3

Answer 75

Inhibit TSH: Corticosteroids, Dopaminergic drugs Inhibits T3 +T4 production: Lithium, Carbimazole Inhibit TBG: Corticosteroids, Androgens Decrease conversion of T4 to T3: Beta blockers Increase TBG and TSH: Oestrogens

Answer 76

Those due to excess of hormones (hyperthyroidism or thyrotoxicosis) Tachycardia, heat intolerance warm moist skin, goitre increased appetite and weight loss, anxiety and tremor Those related to deficiency of hormones (hypothyroidism) Bradycardia, cold intolerance, dry thin hair and skin, goitre, fatigue and depression

Answer 77

Thyroid hormones - T3 and T4 Produced in thyroid glands under control by TSH TSH released by thyrotropic endocrine cells in anterior pituitary gland upon stimulation by TRH produced by hypothalamus T3 / T4 suppress TSH at pituitary level and TRH at hypothalamus level

Answer 78

Fasting leads to reduced leptin production Leptin control thyroid hormone synthesis at hypothalamus level PVN (direct) – reduced TRH release ARC (indirect) - reduced POMC. Increased AgRP / NPY. All suppress PVN TRH release Reduced TRH leads to reduction in TSH level – low T3 and T4

Answer 79

Transport: Binding to Thyroid binding globulin (70%), transthyretin (10%), 20% ablumin Tissue deiodinase Activity modulated by many factors: diet, disease, stress, drugs…..etc Presents an extra HPT axis level of control on thyroid hormone effects on body functions T3 internalised then translocates to nucleus, binds to Thyroid hormone receptor acting as transcription factor on Transcription Response Element (TRE), initiating metabolic gene transcription.

Answer 80

Protein, carbohydrate and lipid metabolism Stimulates protein and triglyceride synthesis Stimulated production of glucose Also stimulates catabolism of glucose, proteins, and triglycerides Calorigenic BMR  (heart, skeletal muscle, liver and kidneys most sensitive) O2 consumption  Sweating  Increased body temperature Growth and development Enhances GH secretion Production and effectiveness of IGF-I  Essential for CNS development (Synaptogenesis, axon proliferation) Essential for normal bone formation Essential for mammary gland development Need for normal menstrual cycle Cardiovascular/respiration Heart rate  Force of contraction  Indirect effects: Cardiac output , Peripheral resistance  , O2 delivery to tissues  β adrenergic receptors , Sensitivity to sympathetic stimulation 

Answer 81

Thyroid stimulating hormone (TSH) produced by the anterior pituitary binds to TSH receptor(TSHR)s expressed by thyroid follicular cells to stimulate TH production. Thyroid Stimulating Immunoglobulins (TSI) are autoantibodies against Thyroid Stimulating Hormone RECEPTOR (TSHR). When binding to TSHR, TSI crosslinks receptors and initiates intracellular signalling activating thyroid follicular cells, mimicking the stimulation by TSH to instruct the production and release of thyroid hormones. Hyperactive follicular cells extend into the colloid causing a ‘scalloping’ effect Extensive vacuoles indicate hyperactivity of thyroid hormones packaging and release

Answer 82

Abnormal levels of thyroid-stimulating immunoglobulins (Graves’ disease) Hyper-secreting thyroid tumour (Toxic multinodular goitre, toxic adenoma) Secondary to excess hypothalamic or ant. pituitary secretion Iatrogenic causes (e.g. amiodarone, lithium)- See Marshall’s for details

Answer 83

CD4 T helpers activate B cells into plasma cells producing autoantibodies High levels of autoantibodies: Anti-thyroid peroxidase Anti-thyroglobulin Cytotoxic T Lymphocyte (CTL)s also induce thyroid cell death An autoimmune thyroiditis, thyroid acini are progressively destroyed by immunological processes, and the gland becomes diffusely infiltrated by the lymphocytes. When thyroid cells are destroyed (apoptosis or necrosis), thyroid hormones released in circulation – initial increase in circulating T4 / T3 Followed by hypothyroidism due to decreased TH production by less thyroid cells

Answer 84

Goitrogens: agents (drugs and foods) that decrease production of TH by thyroid: Thionamides: (Inhibit TPO (thyroid peroxidase)) – What does TPO do? -methimazole (10x more potent) -propylthiouracil -carbimazole (formulary drug) Iodides Oldest remedy, now used in conjunction with thionamides Observe effects within 24 hours, Maximum effect: 10 –15 days Inhibit TH release (paradoxical action), inhibit organification of iodide Decreased size and vascularity of hyperplastic gland Radioactive Iodine (131I)

Answer 85

On each side of trachea is lobe of thyroid Weighs approx. 25g Highly vascularised (80-120ml blood/min) Contains LARGE store of thyroid hormones and iodine Thyroid gland can readily “trap”/sequester iodine from the blood Secretes two iodine rich bioactive hormones: Triiodothyronine (T3) and Thyroxine (T4)

Answer 86

Spheres of follicles composed of follicular cells and parafollicular cells Follicular cells produce thyroid hormone, stored in colloid lumen Parafollicular cells (C cells) make calcitonin

Answer 87

Absence or severe deficient thyroid gland Primary cause (approx. 75%) – Incomplete development of thyroid gland Others: Enzyme deficiency approx. 10% Hypothalamic – pituitary axis defects approx. 10%

Answer 88

2 pairs: upper and lower parathyroid glands Situated on the dorsal side of the right and left lobes of thyroid gland.

Answer 89

Principal (Chief) cells - Predominant and secrete PTH. Oxyphil cells - Eosinophilic cells with unidentified function, appearing with age.

Answer 90

Excessive production of PTH caused by a single adenoma confined to one of the glands.

Answer 91

Overproduction of PTH secondary to a chronic abnormal stimulus for its production - e.g. vit D insufficiency or hypocalcaemia

Answer 92

Transfer provides natural experimental evidence of the role of TSH autoantibodies.

Answer 93

Graves’ ophthalmopathy: observed in ~20% of patients. Condition affects connective tissue behind the eyes leading to swelling, redness, conjunctivitis, exophthalmos (often bilateral). Pre-tibial myxedema: ~5% of Graves’ disease patients, infiltrative dermopathy, arises from effects of inflammation on tissue glycosaminoglycans (GAGs) which drives edema.

Answer 94

Primary myxedema, dermal inflammation, absence of goitre, can involve TSHR blocking antibodies. Part of the spectrum of thyroid autoimmune diseases.

Answer 95

Intrinsic factor (IF) binds Vit B12 to facilitate its update. Blocking antibodies to IF or binding antibodies to the IF-B12 complex reduce/block Vit B12 updake, a cofactor required for nucleotide synthesis of rbcs, hence can cause pernicious anaemia.

Answer 96

Autoantibodies bind directly to glomerular basement membranes

Answer 97

autoantibodies to epidermal cadherin

Answer 98

Immune complexes of DNA/anti-DNA/nucleosomes in the blood. Skin involvement in SLE: ‘butterfly’ rash. Can be photosensitive Vasculitis in SLE.