Endocrinology Flashcards

Question

What is the phenotype of Child Growth Hormone Deficiency?

Answer 1

Ateliosis – proportional short stature but normal features/intelligence (achondroplasia – non-proportional) Mismatch between chronological age and skeletal (bone) age. Reduced lean body mass Delayed onset of puberty – augmentation with hCG/testosterone

Answer 2

Insulin tolerance test (ITT) tests hypothalamic:pituitary:adrenal axis Bolus of IV insulin Hypoglyceamia Physiological stress GH and cortisol released to buffer this GH measured every 15-30 mins for 2 hrs GH levels < 5ng/ml GHD OR < 3ng/ml severe GHD

Answer 3

Must be done BEFORE epiphyseal plates close Aim for “acceptable” final adult height Recombinant growth hormone used – Somatropin Daily injections of Somatropin More consistent plasma level using Sub-cutaneous rather than intra-muscular

Answer 4

Symptoms: Decreased energy level, Social isolation, Lack of positive well-being, Depressed mood, Increased anxiety. Signs: Increased body fat, LDL cholesterol, plasma fibrinogen Decreased insulin sensitivity, muscle mass, bone density, HDL cholesterol, extra-cellular fluid.

Answer 5

Incorporate iodine Thyroxine (T4): 93% metabolically active hormone Triiodothyronine (T3): 7% metabolically active hormone T3 has greater potency and shorter half life Calcitonin involved in plasma Ca regulation

Answer 6

Significantly increase metabolic rate Increase activity of mitochondria and Na/K ATPase Increase growth rate and brain growth in children Reduced sexual function and libido Cardiovascular increase Respiration increase Pscychoneurotic tendencies and muscle tremor Increase in gut motility Increase vitamin requirements Stimulation of carbohydrate and fat metabolism

Answer 7

TSH increases all the known secretory activities of the thyroid glandular cells. TSH causes… Increased proteolysis of stored thyroglobulin Increased activity of the iodide pump Increases “iodide trapping” rate Increased iodination of tyrosine Forms thyroid hormones. Increased size and secretory activity of thyroid cells Increased number of thyroid cells and infolding of follicle thyroid epithelium Releases thyroid hormones

Answer 8

Thyroid increase 2-3X normal size due to follicle hyperplasia. Symptoms include: High state of excitability, Heat intolerance, Increased sweating, Weight loss, Diarrhoea, Anxiety, Muscle weakness, Tremor of hands, Extreme fatigue, Inability to sleep, Exopthalmos.

Answer 9

Most common form of hyperthyroidism Autoimmune disease Antibodies raised against thyroid TSH receptor Thyroid-stimulating immunoglobulins (TSIs) bind TSH receptor and induce continual cell stimulation (~12 hours) Persistent high level of TSI-induced thyroid hormone secretion suppresses anterior pituitary TSH formation. TSH concentrations < normal (zero)

Answer 10

Not enough thyroid hormone Symptoms: Fatigue and extreme somnolence, Prolonged sleep periods (2 to 14 hrs/day), Extreme muscular sluggishness, Reduced heart rate, cardiac output, blood volume, Increased body weight, Constipation, Mental sluggishness, Failed growth functions- depressed hair growth of hair and scaliness of the skin, Myxoedema (oedematous body appearance).

Answer 11

Hashimoto’s disease: Autoimmune thyroiditis (inflammation), Gradual decline in thyroid hormone secretion, Gland destroyed. Myxoedema: Total lack of thyroid hormone, Non-pitting oedema Endemic Goitre: Enlarged thyroid gland, Insufficient dietary iodine Cretinism: Fetal extreme hypothyroidism, Poor growth, Impaired brain development

Answer 12

Excess PTH synthesis/secretion | Can be primary or secondary

Answer 13

Frequent cause of hypercalcaemia Third most common endocrine disorder Defect in parathyroid glands – benign tumour (rarely malignant) Increased PTH, calcitriol, Ca2+; decreased PO43- Normal calcitriol/phosphate changes signals seen which indicate normal kidney function but increased cell numbers mean PTH levels increased overall.

Answer 14

Arises through defective feedback control - compensation for hypocalcaemia. Usually associated with chronic kidney disease Concept of Renal Bone Disease: No renal response to PTH causing poor renal Ca2+ reabsorption, no vit. D activation, poor intestinal Ca2+ reabsorption (hypocalcaemia), High bone demineralisation as Ca2+ released - Renal osteodystrophy. Negative feedback mechanisms fail; PTH levels remain elevated.

Answer 15

Two major groups of adrenocortical hormones Mineralocorticoids Glucocorticoids Both have genomic effects, inducing changes in gene expression.

Answer 16

- Mineralocorticoids like Aldosterone: Zona glomerulosa ECF mineral balance (Na+, K+) - Glucocorticoids like Cortisol, Androgens, and some oestrogen: Zona fasciculata Increasing blood sugar - DHEA and Androstenedione: Zona Reticularis - Adrenaline and Noradrenaline: Adrenal medulla

Answer 17

Principal mineralocorticoid (90%) but Cortisol, (glucocorticoid) also gives some mineralocorticoid activity. Main actions: - Na+/water reabsorption - K+ homeostasis (generally secretion)

Answer 18

Primary aldosteronism, also known as primary hyperaldosteronism or Conn's syndrome, refers to the excess production of the hormone aldosterone from the adrenal glands, resulting in low renin levels. This abnormality is caused by hyperplasia or tumors. Many suffer from fatigue, potassium deficiency and high blood pressure which may cause poor vision, confusion or headaches. Symptoms may also include: muscular aches and weakness, muscle spasms, low back and flank pain from the kidneys, trembling, tingling sensations, numbness and excessive urination.

Answer 19

Severe renal NaCl wasting: Significant increased renal Na+Cl- loss, reduced [Na+]ECF, reduced plasma volume (Dehydration, Reduced blood pressure, Circulatory shock) Hyperkalaemia: Reduced renal K+ excretion, Increased [K+]ECF leading to Hyperkalaemia > 5 mmol/l and Cardiotoxicity. Mild acidosis becuase H+/K+ exchange less efficient Death within two weeks. Basis of Addison's disease.

Answer 20

Sweat glands - conservation of NaCl in hot environment Salivary glands - conservation of NaCl to prevent excessive loss in saliva Colon - Enhanced Na+ absorption, reduces faecal Na+ loss Without it: Poor absorption of Na+, Cl-, other anions, Poor water absorption gives Diarrhoea.

Answer 21

Principal glucocorticoid, accounts for ~95% activity. Corticosterone provides further activity. Follows a Circadian rhythm of secretion: - Highest early morning (~20mg/dl) - Low in evening/night (~5mg/dl) Involved in metabolic regulation, stress response (physical/mental) and defence against inflammation.

Answer 22

CARBOHYDRATE METABOLISM: Increased gluconeo- genesis: Hepatic gluconeogenic enzymes activated Amino acid mobilisation from extra-hepatic tissues Antagonism of insulin-induced hepatic gluconeo-genesis inhibition. FAT METABOLISM: Increased Fatty acid mobilisation, Oxidation of fatty acids, Metabolism favours fat burning not glucose. PROTEIN METABOLISM: Reduction in extra-hepatic cellular protein through decreased protein synthesis and amino acid transport, increased protein catabolism.

Answer 23

Trauma, infection, surgery, intense hot or cold, debilitating diseases, physical restraint, noradrenaline/sympathomimetic drugs, subcutaneous injection of necrotizing substances.

Answer 24

Stress on the body Hypothalamic release of CRH and hypophysial circulation in the pituitary In the anterior pituitary, corticotrophs release ACTH ACTH acts on zona fasciculata which causes the secretion of cortisol Cortisol has direct negative feedback on the anterior pituitary and the hypothalamus Cortisol acts to cause Gluconeogenesis, Protein Metabolism, Fat mobilisation and Lysosome stabilisation to relieve the stress.

Answer 25

Tissue damage causes release of pro-inflammatory mediators: Histamine, Bradykinin, Proteases, Prostaglandins, Leukotrienes which increase blood flow to area - Erythema. Increased capillary permeability causes exudation of virtually pure plasma and tissue fluid clots. Causes non-pitting oedema. Infiltration of leukocytes after several days or weeks leads to ingrowth of fibrous tissue facilitates healing.

Answer 26

- Stabilizes lysosomal membranes, reducing cell/ lysosome rupture - Decreases capillary permeability, preventing plasma exudation into tissues - Suppresses immune system, reducing Lymphocyte reproduction, T-lymphocyte numbers, Antibodies - Attenuates fever by reducing IL-1 release from white blood cells (key stimulus for hypothalamic temp control) - Decreases Extravasation of white blood cells into inflamed area and Phagocytosis of damaged cells - Inhibits synthesis of Prostaglandins and Leukotrienes

Answer 27

Primary Aldosteronism – Conn’s Syndrome Hypoadrenalism - Addison’s Disease Hyperadrenalism - Cushing’s syndrome

Answer 28

Hypoadrenalism Reduced adrenocortical hormone synthesis by adrenal cortices. Commonly caused by primary atrophy or injury of the adrenal cortices due to autoimmunity, TB or a tumour. Impaired pituitary function Reduced ACTH secretion means there is decreased cortisol and aldosterone production. Adrenal glands may atrophy because of a lack of ACTH stimulation. Glucocorticoid deficiency due to lack of cortisol production - failure to stimular gluconeogenesis, mobilise protein or fat. May lead to a Addisonian Crisis. Treatment: mineralocorticoids and/or glucocorticoids

Answer 29

Many abnormalities of Cushing’s syndrome ascribed to hyper-cortisolism. - Adrenal cortex adenomas - Abdominal carcinoma: “Ectopic” ACTH secretion” - Abnormal hypothalamic function: Increased CRH increased ACTH release - Anterior pituitary ACTH-secreting adenomas: Causes adrenal hyperplasia and excess cortisol secretion (Cushing's disease)

Answer 30

Cushing's disease: Excess anterior pituitary secretion of ACTH is primary problem (70%) Increased [ACTH]plasma and [cortisol]plasma Cushing's syndrome: Primary overproduction of cortisol by adrenal glands (~20-25%). Cortisol feedback inhibition reduces anterior pituitary ACTH secretion Fat mobilization to thoracic and upper abdominal regions. Excess steroids causes oedematous face. Androgenic potency may causes acne and hirsutism.

Answer 31

``` Exocrine function: Digestive enzymes through the pancreatic acini into Duodenum Endocrine function: Hormones into blood Insulin: b-cells Glucagon: a-cells Somatostatin: d-cells ```

Answer 32

INCREASED CARBOHYDRATE METABOLISM - increased hepatic glucose uptake, hepatic glycogen formation, decreases hepatic gluconeogenesis INCREASED FAT METABOLISM - increased fat storage, increased hepatic fatty acid synthesis, prevents fatty acid release in adipose tissue, promotes Glc uptake INCREASED PROTEIN METABOLISM - increased cellular amino acid uptake, increased transcription and translation, decreased protein catabolism, decreased gluconeogenesis

Answer 33

Decreased blood glucose reduces pancreatic insulin secretion. Decreased insulin secretion promotes hepatic Glycogen breakdown into glucose-6-phosphate (via glycogen phosphatase) and then into hepatic glucose (via glucose phosphatase).

Answer 34

Insulin and growth hormone act synergistically to each promote the uptake of different amino acids. No insulin OR growth hormone - minimal effect No insulin AND growth hormone - no growth

Answer 35

Hormone-sensitive lipases activity increases, causing triglycerides to be hydrolysed and an increased concentration of fatty acids in the plasma. Excess Acetyl-CoA formed so excess Acetoacetate synthesised, which is converted to ketone bodies causing Ketosis – metabolic acidosis. Protein catabolism increases, increased conc of protein in plasma (significant protein wasting).

Answer 36

Amino acids Arginine and Lysine If administered in absence of increased blood glucose, there are small increases in insulin secretion. If administered when blood glucose elevated, there is doubled glucose-induced insulin secretion. Amino acids potentiate glucose stimulus for insulin secretion. Links insulin to insulin-induced amino acid transport and protein synthesis

Answer 37

A number of hormones knowns as incretins: - Gastrin, Secretin, CCK - Glucagon-like peptide-1 (GLP-1) - Glucose-dependent insulinotropic peptide (GIP) Enhance insulin secretion when blood glucose elevated Inhibit a-cell glucagon secretion These GI hormones induce “anticipatory” increase in blood insulin. Significant augmentation of glucose-induced insulin secretion. Incretins used as drug targets (metformin, tolbutamide, gliclazide)

Answer 38

Fasting [Glucose]blood ~5mmol/l Sudden prolonged Glc increase (2-3X) initiates a biphasic insulin response. - Initial spike ~10x [insulin]plasma (secretion of preformed insulin, increase not maintained) - Slower increase ~20 mins later Higher [insulin]plasma reached

Answer 39

High insulin levels means that glucose utilised principally, fat utilisation depressed and excess blood glucose stored as liver glycogen, fat, and muscle glycogen. Low insulin levels means increased fat utilisation and nhibition of glucose use (except brain). Blood glucose levels determines the level of insulin (acts as a switch). Growth hormone, cortisol, adrenaline glucagon also involved.

Answer 40

Impaired carbohydrate, fat, and protein metabolism Type 1 diabetes (insulin-dependent) - lack of insulin secretion Type 2 diabetes (non-insulin-dependent) - decreased tissue sensitivity to insulin (resistance) Baseline [glucose]blood higher and peaks higher for longer. Normally returns to baseline within 2 hours. Signs: polyphagia, polydypsia, polyurea

Answer 41

Secreted by a-cells as response to decreased [glucose]blood. Functions diametrically opposed to insulin Principal effect to increase [glucose]blood Increased [glucose]blood –ve feedback on glucagon secretion

Answer 42

GLUCOSE METABOLISM: promotes Glycogenolysis and increases Gluconeogenesis, increasing blood glucose FAT METABOLISM: Activates adipose cell lipase and inhibits hepatic triglyceride storage, increasing availability of fatty acids Also acts to enhance heart strength, increases blood flow to kidneys, enhance bile secretion and inhibit gastric acid secretion.

Answer 43

Hypothalamus hormone Peptide structure Stimulates secretion of thyroid-stimulating hormone and prolactin by thyrotropes

Answer 44

Hypothalamus hormone Peptide structure Causes release of adrenocorticotropic hormone by corticotropes

Answer 45

Hypothalamus hormone Peptide structure Causes release of growth hormone by somatotropes

Answer 46

Hypothalamus hormone Peptide structure Inhibits release of growth hormone by somatotropes

Answer 47

Hypothalamus hormone | Causes release of luteinizing hormone and follicle-stimulating hormone by gonadotropes

Answer 48

Hypothalamus hormone Amine structure Inhibits release of prolactin by lactotropes

Answer 49

Anterior pituitary hormone Peptide structure Stimulates protein synthesis and overall growth of most cells and tissues

Answer 50

Anterior pituitary hormone Peptide structure Stimulates synthesis and secretion of thyroid hormones (thyroxine and triiodothyronine)

Answer 51

Anterior pituitary hormone Peptide structure Stimulates synthesis and secretion of adrenocortical hormones (cortisol, androgens, and aldosterone)

Answer 52

Anterior pituitary hormone Peptide structure Promotes development of the female breasts and secretion of milk

Answer 53

Anterior pituitary hormone Peptide structure Causes growth of follicles in the ovaries and sperm maturation in Sertoli cells of testes

Answer 54

Anterior pituitary hormone Peptide structure Stimulates testosterone synthesis in Leydig cells of testes; stimulates ovulation, formation of corpus luteum, and oestrogen and progesterone synthesis in ovaries

Answer 55

Posterior pituitary hormone Peptide structure Increases water reabsorption by the kidneys and causes vasoconstriction and increased blood pressure

Answer 56

Posterior pituitary hormone Peptide structure Stimulates milk ejection from breasts and uterine contractions

Answer 57

Thyroid hormones Amine structure Increases the rates of chemical reactions in most cells, thus increasing body metabolic rate

Answer 58

Thyroid hormones Peptide structure Promotes deposition of calcium in the bones and decreases extracellular fluid calcium ion concentration

Answer 59

Parathyroid hormone Peptide structure Controls serum calcium ion concentration by increasing calcium absorption by the gut and kidneys and releasing calcium from bones

Answer 60

Adrenal Cortex hormone Steroid structure Has multiple metabolic functions for controlling metabolism of proteins, carbohydrates, and fats; also has anti-inflammatory effects

Answer 61

Adrenal Cortex hormone Steroid structure Increases renal sodium reabsorption, potassium secretion, and hydrogen ion secretion

Answer 62

Adrenal medulla hormones Amine structure Same effects as sympathetic stimulation

Answer 63

Ovaries hormone Steroid structure Promotes growth and development of female reproductive system, female breasts, and female secondary sexual characteristics

Answer 64

Ovaries hormone Steroid structure Stimulates secretion of “uterine milk” by the uterine endometrial glands and promotes development of secretory apparatus of breasts

Answer 65

Placenta hormone Peptide structure Promotes growth of corpus luteum and secretion of oestrogens and progesterone by corpus luteum

Answer 66

Placenta hormone Peptide structure Probably helps promote development of some fetal tissues, as well as the mother’s breasts

Answer 67

Peptides: linear or ring structures, may bind to carbohydrates, stored in secretory granules, released in pulses or bursts, cleared by circulating enzymes Amines: use a-adrenoreceptors (PIP2 to IP3 which increases Ca and DAG which activates protein kinase C) OR b-adrenoreceptors (ATP to cAMP via adenylyl cyclase, activates cAMP-dependent protein kinase) Iodothyronines: 99% protein bound, incorportation of iodine on tyrosine molecules, conjugation to give T£ and T4. Cholesterol-derivates and steroids: VitD enters cells directly to nucleus, adrenocortical and gonal steroids enter cell and pass to nucleus to induce response, altered to active metabolite and bind to cytoplasmic receptor

Answer 68

- Thyroglobulin is synthesised and discharged into the follicle lumen - Iodide is actively transported into the cell from the blood - Iodide is oxidised to iodine - Iodine is attached to thyrosine in collois, forming DIT and MIT - Iodinated tyrosines are linked together to form T3 and T4 - Thyroglobulin colloid is endocytosed and combined by lysosome - Lysosomal enzymes cleave T3 and T4 from thytoglobulin

Answer 69

Steroid hormone diffuses through plasma membrane and binds to receptor Receptor-hormone complex enters nucleus and binds to GRE Binding initiates transcription of gene to mRNA mRNA directs protein synthesis

Answer 70

Basal secretion - continuously or pulsatile Superadded rhythms - day-night cycle Release inhibiting factors Releasing factors

Answer 71

Hormone metabolism - increased metabolism to reduce function Hormone receptor induction - induction of LH receptors by FSH in follicle Hormone receptor down regulation Synergism - combined effects of two hormones amplified Antagonism - one hormone opposes the other hormone

Answer 72

Hypothalamic neurons synthesise oxytoxin or ADH. Oxytoxin and ADH are transported down the axons of the hypothalamic-hypophyseal tract to the posterior pituitary. Oxytocin and ADH are stored in axon terminals in posterior pituitary. When hypothalamic neurons activated, hormones released.

Answer 73

Tumour mass effects Hormone excess Hormone deficiency Hormone tests are important for investigation. If hormone tests are abnormal, perform MRI pituitary.

Answer 74

GH binds to the liver and other tissues Produces insulin-like growth factor Skeletal - increased cartilage formation and skeletal growth Extraskeletal - increased protein synthesis, cell growth and proliferation Fat metabolism - increased fat breakdown and release Carbohydrate metabolism - increased blood glucose, anti-insulin effects

Answer 75

``` Accelerate food metabolism Increases protein synthesis Stimulation of carbohydrate metabolism Enhances fat metabolism Increase in ventilation rate Increase in CO and HR Brain development in foetal and postnatal life Growth rate accelerated ```

Answer 76

Appetite: the desire to eat Hunger: the need to eat Satiety: feeling of fullness (disappearance of appetite)

Answer 77

``` <18.5 Underweight 18.5-24.9 Normal 25.0-29.9 Overweight 30.0-39.9 Obese >40 Morbidly obese ```

Answer 78

``` Type 2 diabetes Hypertension Coronary heart disease Stroke Osteoarthritis Obstructive sleep apnea Carcinoma (breast, endometrium, prostate, colon) ```

Answer 79

Internal physiological drive to eat Feeling that prompts the thought of food and motivates food consumption External psychological drive to eat In the absence of hunger

Answer 80

Lateral hypothalamus (hunger centre) Ventromedial hypothalamic nucleus (satiety centre) NPY, MCH, AgRP, Orexin, Endocannabinoid increase desire to eat. a-MSH, CART, GLP-1, Serotonin decrease desire to eat. Peripheral factors like leptin (white fat) and insulin (pancreas) also have an impact. Gut peptides like Ghrelin, PYY, GLP1 and CKK. Central areas - NPY in arcuate nucleus Hypothalamus - POMC, MSH, Agouti-related peptide, MC3 and MC4 receptors

Answer 81

Increase in Leptin decreases appetite Expressed in white fat Binds to Leptin receptor (cytokine receptor family in hypothalamus), switches off appetite and is immunostimulatory. Blood levels increase after meal and decrease after fasting.

Answer 82

Structurally similar to NPY, binds NPY receptors. Secreted by neuroendocrine cells in ileum, pancreas and colon in response to food. Inhibits gastric motility and reduces appetite.

Answer 83

Receptors present in pyloric sphincter - delays gastric emptying, gall bladder contraction and insulin release.

Answer 84

Expressed in stomach. Action stimulates growth hormone release, stimulates appetite, Blood levels high when fasting, fall on re-feeding. Levels lower after gastric bypass surgery.

Answer 85

Proopiomelanocortin (POMC) is the pituitary precursor of circulating melanocyte stimulating hormone (α-MSH), adrenocorticotropin hormone (ACTH), and β-endorphin. If POMC is not present, ACTH deficiency.

Answer 86

Stretch receptors in stomach increase satiety Release of CCK, GLP, insulin, PYY increase sateity More long-term, leptin, nutrients and temp regulate satiety and hence energy balance

Answer 87

When serum Ca decreases, this is detected by the parathyroid and parathyroid hormone increases. This results in increased Ca reabsorption, increased bone modelling and increased Ca absorption. Small change in Ca, big change in PTH.

Answer 88

Appropriately - to maintain calcium balance | Inappropriately - to cause calcium imbalance

Answer 89

``` Parasthesia Muscle spasm: Hands and feet, Larynx, Premature labour Seizures Basal ganglia calcification Cataracts ECG abnormalities - long QT interval – Long QT interval ```

Answer 90

Low serum albumin means there is a low total serum calcium but not a low ionised calcium corrected calcium = total serum calcium + 0.02 * (40 – serum albumin)

Answer 91

Undermineralised bone - pseudofractures Vitamin D deficiency - lack of sunshine, dietary input Cannot absorb calcium (or phosphate)

Answer 92

Chvostek's sign: tap over facial nerve, look for spasm of facial muscles Trousseau's sign: inflate blood pressure cuff to 20mmHg above systolic for 5 mins - pointed hand

Answer 93

``` Thymic aplasia Immunodeficiency Cardiac defects Cleft palate Abnormal facies ```

Answer 94

Can be caused by surgical damage (removing the thyroid or neck cancer surgery) Radiation treatment Autoimmune effect - isolated or polyglandular type 1 Infiltration - haemochromatosis and wilson's disease

Answer 95

Low Calcium Low PTH High Phosphate Inappropriate response

Answer 96

Rare resistance to parathyroid hormone Sometimes seen in genetic disorders - Mutation with deficient Ga subunit. Signs: short stature, obesity, round facies, mild learning difficulties, subcutaneous ossification, short fourth metacarpals and other hormone resistance. Low Ca, High PTH, High Phosphate Appropriate behaviour

Answer 97

Pseudo phenotype Ca metabolism is normal PTH, Ca, Phosphate is normal

Answer 98

``` Thirst Polyuria Nausea Constipation Confusion - coma Renal stones ECG abnormalities - Short QT ```

Answer 99

Malignancy – bone mets, myeloma, PTHrP, lymphoma (80% due to a single benign adenoma on parathyroid) Primary hyperparathyroidism Thiazides Thyrotoxocosis Sarcoidosis Familial hypocalciuric / benign hypercalcaemia Immobilisation Milk-alkali Adrenal insufficiency Phaeochromocytoma

Answer 100

``` Renal failure (can't activate vitamin D) Can't absorb calcium from gut or kidnet Can borrow Ca from bone but only for a bit Increased Ca, PTH, PO4 Inappropriate response ```

Answer 101

All glucose comes from liver (and a bit from kidney) Breakdown of glycogen and gluconeogenesis Glucose is delivered to insulin independent tissues, brain and red blood cells Insulin levels are low Muscle uses FFA for fuel Some processes are very sensitive to insulin, even low insulin levels prevent unrestrained breakdown of fat

Answer 102

After feeding (post prandial) - physiological need to dispose of a nutrient load Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon 40% of ingested glucose goes to liver and 60% to periphery, mostly muscle Ingested glucose helps to replenish glycogen stores both in liver and muscle High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall

Answer 103

Islets of Langerhans in the endocrine pancreas a cells - secrete glucagon B cells - secrete insulin Paracrine 'crosstalk' between a and B cells is physiological

Answer 104

Glucose enters B cell by GLUT2 glucose transporter with help from glucokinase. Glucose undergoes metabolism. K channel closes and depolarises cell membrane Ca channel opens, Ca enters cell Insulin secretory granules secrete insulin

Answer 105

Insuliin binds to insulin receptor causing an intracellular signalling cascade. Intracellular GLUT4 vesicles mobilized to plasma membrane, glucose entry into the cell via GLUT4.

Answer 106

Supresses hepatic glucose output  Glycogenolysis  Gluconeogenesis Increases glucose uptake into insulin sensitive tissues (muscle, fat) Suppresses Lipolysis and Breakdown of muscle

Answer 107

``` Increases hepatic glucose output  Glycogenolysis  Gluconeogenesis Reduce peripheral glucose uptake Stimulate peripheral release of gluconeogenic precursors (glycerol, AAs) through lipolysis and muscle glycogenolysis and breakdown ```

Answer 108

Acute hyperglycaemia which if untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperosmolar Hyperglycaemic State ) Chronic hyperglycaemia leading to tissue complications (macrovascular and microvascular) Side effects of treatment- hypoglycaemia

Answer 109

``` Diabetic retinopathy Diabetic nephropathy Stroke Cardiovascular disease Diabetic neuropathy ```

Answer 110

Type 1 Type 2 Includes gestational and medication induced diabetes Maturity onset diabetes of youth (MODY), also called monozygotic diabetes Pancreatic diabetes “Endocrine Diabetes” (acromegaly/Cushings) Malnutrition related diabetes

Answer 111

Symptoms and random plasma glucose > 11 mmol/l Fasting plasma glucose > 7 mmol/l No symptoms - GTT (75g glucose) fasting > 7 or 2h value > 11 mmol/l (repeated on 2 occasions) HbA1c of 48mmol/mol (6.5%)

Answer 112

An insulin deficiency disease characterised by loss of beta cells due to autoimmune destruction Beta cells express antigens of HLA histocompatability system perhaps in response to an environmental event(?virus) Activates a chronic cell mediated immune process leading to chronic ‘insulitis’

Answer 113

Failure of insulin secretion leads to continued breakdown of liver glycogen and u nrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors and inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake Rising glucose concentration results in increased urinary glucose losses as renal threshold (10mM) is exceeded Failure to treat with insulin leads to increase in circulating glucagon (loss of local increases in insulin within the islets leads to removal of inhibition of glucagon release), further increasing glucose. Perceived ‘stress’ leads to increased cortisol and adrenaline. Progressive catabolic state and increasing levels of ketones.

Answer 114

A consequence of insulin resistance and progressive failure of insulin secretion (but insulin levels are always detectable) Impaired insulin action leads to - Reduced muscle and fat uptake after eating - Failure to suppress lipolysis and high circulating FFAs - Abnormally high glucose output after a meal - Even low levels of insulin prevent muscle catabolism and ketogenesis so profound muscle breakdown and gluconeogenesis are restrained and ketone production is rarely excessive

Answer 115

Type 1 diabetes Severe insulin deficiency due to autoimmune destruction of the B cell (initiated by genetic susceptibility and environmental triggers) Type 2 diabetes Insulin resistance and impaired insulin secretion due to a combination of genetic predisposition and environmental factors (obesity and lack of physical activity)

Answer 116

Control of symptoms Prevention of acute emergencies, ketoacidosis, hyperglycaemic hyperosmolar states Identification and prevention of long-term microvascular complications Limited evidence yet that glucose control per se reduces cardiovascular events (confirmed by recent clinical trials, ACCORD, ADVANCE) in the short-term But long-term follow-up indicates a modest reduction in IHD from tight glucose control if started at diagnosis HbA1c 50mmol/mol (6.5%) (as low as possible in those not on insulin or sulphonylureas)

Answer 117

Basal insulin: long-acting | Prandial/meal-time insulin: fast-acting (imitating normal insulin release after meals

Answer 118

Separation of basal from bolus insulin to mimic physiology Pre-meal rapid acting boluses adjusted according to pre-meal glucose and carbohydrate content of food to cover meals Basal insulin should control blood glucose in between meals and particularly during the night Basal insulin is adjusted to maintain fasting blood glucose between 5–7 mmol/L

Answer 119

T1: Autoimmune condition (β-cell damage) with genetic component Profound insulin deficiency T2: Insulin resistance Impaired insulin secretion and progressive β-cell damage but initially continued insulin secretion Excessive hepatic glucose output Increased counter-regulatory hormones including glucagon

Answer 120

Many people with T2DM require insulin – particularly later in the disease course or in individuals with poor glycaemic control on other medications In general, basal insulin is initiated followed by addition of a prandial insulin where necessary Long-acting basal insulin analogues are associated with lower risk of symptomatic, overall and nocturnal hypoglycaemia1 Prandial insulins mimic meal-time insulin secretion2 and their faster action allows for greater flexibility at mealtimes3 Premix insulins are also available

Answer 121

Human basal insulin: intermediate-acting, 90mins onset, peak action 2-4 hrs, duration 24 hrs e.g. NPH Basal analogues: steady state after 1-2 days, duration 24hrs, e.g. Detemir, Glargine U100 Rapid-onset analogues: 10-20mins onset, peak action 30-90mins, duration 2-5hrs e.g. insulin aspart, insulin lispo, insulin glulisine Human premixed 70/30: 30mins onset, peak action 2-8 hrs, duration 24hrs e.g. Mixtarol, Humulin M3

Answer 122

Advantages: Simple for the patient, adjusts insulin themselves, based on fasting glucose measurements Carries on with oral therapy Less risk of hypoglycaemia at night Disadvantages: Doesn’t cover meals Best used with long-acting insulin analogues which are considered expensive.

Answer 123

Advantages: Both basal and prandial components in a single insulin preparation Can cover insulin requirements through most of the day Disadvantages: Not physiological, Requires consistent meal and exercise pattern, Cannot separately titrate individual insulin compononents, increased risk for nocturnal hypoglycaemia and fasting hyperglycaemia if basal component does not last long enough Often requires accepting higher HbA1c goal of <7.5% or ≤8% (<58 or ≤64 mmol/mol)

Answer 124

Low plasma glucose causing impaired brain function neuroglycopenia 3mmol/l Clinical definition of hypoglycaemia: Mild: self-treated (but many episodes are asymptomatic) Severe: requiring help for recovery (Except in children) 3.9 mmol/L used clinically

Answer 125

``` Level 1 (Alert value): Plasma glucose <3.9 mmol/l (70 mg/dl) and no symptoms Level 2 (Serious biochemical): Plasma glucose <3.0 mmol/l (55 mg/dl) Non-severe: Patient has symptoms but can self-treat and cognitive function is mildly impaired Severe: Patient has impaired cognitive function sufficient to require external help to recover (Level 3) ```

Answer 126

Autonomic: trembling, palpitations, sweating, anxiety, hunger Neuroglycepenic: difficulty concentrating and speaking, confusion, weakness, drowsiness, dizziness, visual impairment Non-specific: nausea, headache

Answer 127

``` History of severe episodes HbA1c <6.5% (48 mmol/mol) Long duration of diabetes Renal impairment Impaired awareness of hypoglycaemia Extremes of age ```

Answer 128

``` Advancing age Cognitive impairment Depression Aggressive treatment of glycaemia Impaired awareness of hypoglycaemia Duration of MDI insulin therapy Renal impairment and other comorbidities ```

Answer 129

Reduced quality of life in both T1DM and T2DM May cause fear of hypoglycaemia May cause psychological morbidity

Answer 130

Seizures, comas, cognitive dysfunction, accidents, fear, poor quality of life, CVD risk

Answer 131

``` Low HbA1c; high pre-treatment HbA1c in T2DM Long duration of diabetes A history of previous hypoglycaemia Impaired awareness of hypoglycaemia (IAH)* Recent episodes of severe hypoglycaemia Daily insulin dosage >0.85 U/kg/day Physically active (e.g. athlete) Impaired renal function ```

Answer 132

Aim for lowest HbA1c not associated with frequent hypoglycaemia It may sometimes be appropriate to relax targets in patients with advanced disease, complications or limited life expectancy In such patients, aim for glucose levels low enough to minimize symptoms of hyperglycaemia

Answer 133

Aim for lowest HbA1c not associated with frequent hypoglycaemia HbA1c <7.0% (53 mmol/mol) is usually appropriate for recent-onset disease It may sometimes be appropriate to relax targets (e.g. severe complications, advanced co-morbidities, cognitive impairment, limited life expectancy, unacceptable hypoglycaemia from stringent control)

Answer 134

Discuss hypoglycaemia risk factors and treatment with patients on insulin or sulphonylureas Educate patients and caregivers on how to recognize and treat hypoglycaemia Instruct patients to report hypoepisodes to their doctor/educator Consider enrolling patients with frequent hypoglycaemiain a blood glucose awareness training programme

Answer 135

If on an SU (for T2DM), revise dose or consider changing to another drug class If on basal-bolus insulin, check BG before each meal every day Ensure medication is dosed correctly Consider insulin adjustments: Regular/soluble insulin → rapid-acting insulin NPH/isophane → insulin analogues Adjusting insulin in relation to exercise

Answer 136

Recognise the symptoms so that they can be treated Confirm the need for treatment Treat with 15g of fast-acting carbohydrate Retest in 15mins to ensure blood glucose is greater tjam 4.0mmol/l Eat a long-acting carbohydrate to prevent recurrence of symptoms

Answer 137

``` Increased erythropoetin, cortisol, noradrenaline High cardiac output Plasma volume expansion High cholesterol and triglycerides Pro thrombotic and inflammatory state Insulin resistance ```

Answer 138

``` Pre-Eclampsia Gestational Diabetes Obstetric cholestasis Gestational Thyrotoxicosis Transient Diabetes Insipidus Lipid disorders Postnatal depression Postpartum thyroiditis Postnatal autoimmune disease Paternal Disease ```

Answer 139

Fetal thyroid follicles and thyroxine synthesis occurs at 10 weeks Axis matures at 15-20 weeks Maternal T4 0-12 weeks regulates neurogenesis, migration and differentiation then fetal T4

Answer 140

2-3 % Prevalence - Overt hypothyroidism 0.3-0.5 % - Subclinical hypothyroidism 2-3 % Signs and symptoms usually predate the pregnancy: Weight gain, cold intolerance, poor concentration, poor sleep pattern, dry skin, constipation, tiredness,

Answer 141

``` 1st trimester 0.1-2.5 mIU/L 2nd trimester 0.2-3.0 mIU/L 3rd trimester 0.3-3.0 mIU/L 4 weekly for 20 weeks gestation Again 26-32 weeks ```

Answer 142

Autoimmune: Hashimotos, Atrophic thyroiditis Drugs: Lithium, Amiodarone, Iodine Deficiency Congenital Toxic nodule Post partum thyroiditis Subacute thyroiditis Hypopituitarism

Answer 143

Inadequate treatment: Gestational hypertension, Placental abruption, Post partum haemorrhage If untreated: Low birth weight, Preterm delivery, Neonatal goitre, Neonatal respiratory distress

Answer 144

``` Age >30 BMI >40 Miscarriage preterm labour Personal or family history Goitre Anti TPO Type 1 DM Head and neck irradiation Amiodarone, Lithium or contrast use ```

Answer 145

Symptomatic treatment- beta blockers are safe Anti-thyroid medication PTU Carbimazole (prevent thyroid peroxidase enzyme coupling and iodinating tyrosine residues on thyroglobulin reduce T3 and T4) RAI is contraindicated during pregnancy Surgical interventions- if intolerant, optimal timing 2nd trimester

Answer 146

TSH-R antibodies (TRAB/TBII) measured at 22-26 weeks If raised 2-3 fold or present fetal/neonatal thyrotoxicosis risk increased and surveillance needed Good to test current Graves, past Graves, previous neonate with Graves, etc

Answer 147

Transplacental cross over of TSH-R antibodies Occurs in 0.01 % of cases Management options anti-thyroid medication Associated with: IUGR, Fetal goitre, Fetal Tachycardia, Fetal hydrops, Preterm delivery, Fetal demise

Answer 148

``` Limited to the first half of the pregnancy Raised T4, Low/suppressed TSH Absence of thyroid autoimmunity Associated with hyperemesis gravidarum 5-10 cases/1000 pregnancies Multiple gestation Hydatidaform mole Hyperplacentosis Choriocarcinoma ```

Answer 149

A drug that modifies the action of thyroid hormone Potent anti-arrhythmic 37 % iodine by weight Lipid soluble Long elimination half life 14-18 % get abnormalities, Amiodarone Induced Hypothyroidism or Amiodarone Induced Thyrotoxicosis

Answer 150

Type 1 diabetics Graves disease in remission Chronic viral hepatitis Prevalence 7% Measure TSH 3 months post partum

Answer 151

Ipilimumab recently recommended by NICE for advanced melanoma Mode of action: monoclonal antibody, activates immune system by inhibiting CTLA-4 which normally downregulates immune system Can cause: Hypophysitis Hypothyroidism (thyroiditis related) Hyperthyroidism (thyroiditis related) Primary Adrenal Insufficiency

Answer 152

1 cm diameter Difficult to access Andenohypophysis - anterior part Neurohypophysis - posterior part (neural tissue, bright on MRI) Optic chiasm is above (enlargement affects visual ability)

Answer 153

Lies outside the blood-brain barrier The anterior pituitary has no arterial blood supply but receives blood through a portal venous circulation from the hypothalamus, bringing with it 'releasing factors', causing release of hormones.

Answer 154

Conductor of the orchestra (direct association with the hypothalamus) Regulates many things including growth, thyroid (under/overactivitiy), puberty and steroids.

Answer 155

Thyrotrophin releasing hormone is produced in the hypothalamus and passes down the venous plexus to the anterior pituitary. Here it binds to the TRH receptor causing cells to release TSH. TSH acts to produce T3 and T4. Secreted in a ratio of T4:T3 14/15:1 T4 is largely inactive so needs to be converted to T3 by deiodinases. T3 binds to the thyroid hormone receptor, translocated to the nucleus and has effects on gene transcription.

Answer 156

Gonadotrophin releasing hormone released by hypothalamus, acts on gonadotrophic cells in the pituitary to produce LH and FSH. LH required for the formation of testosterone FHS required for the formation of sperm If pituitary isn't working - infertility, reduced sex drive, erectile dysfunction.

Answer 157

Cortisol is required for life in the face of infection and trauma to the body. CRH acts on the pituitary which causes it to release ACTH which acts on the adrenal glands to release cortisol. Neg feedback, in the presence of cortisol, reduced CRH, reduced ACTH, reduced cortisol.

Answer 158

High GHRH and low SMS from hypothalamus signals the release of growth hormone in the pituitary. Circulation in the blood stream, GH binds to receptors in the liver to cause IGF-1 production (acts to provide neg feedback).

Answer 159

Dopamine is released from the lactotroph cells in the anterior pituitary to provide tonic inhibition of prolactin, preventing too much being produced in the pituitary gland. If there is a mass in the pituitary gland that stops dopamine release, there will be an increased level of prolactin.

Answer 160

Benign pituitary adenoma (in anterior pituitary) Craniopharygioma Trauma - compression/damage Apoplexy/Sheehans - bleeding into the pituitary Sarcoid/TB

Answer 161

Pressure on the local structures e.g. optic nerves - bitemporal hemianopia Pressure on normal pituitary - hypopituitarism Functioning tumour - prolactinoma, acromegaly, cushing's disease

Answer 162

Impact on superior nasal fibres - tunnel vision Impact on inferior nasal fibres - peripheral vision impaired Can map visual fields with a red pin If it impacts laterally - interfere with oculomotor nerve Can cause CSF leak if impacting sigmoid sinus Can impact brain stem (very rare)

Answer 163

``` Cause hypopituitarism Pale - low testerone, anaemic No body hair - low testerone Central obesity - low testerone, low growth hormone In women - menstrual dysfunction ```

Answer 164

Chronic, excessive and inappropriate elevated levels of circulating plasma glucocorticoids (cortisol) Red face, excess fat (no growth), truncal obesity, muscle wasting, bruising, thin skin, recurrent non-healing ulcers Increased and redistributed fat Protein catabolism causes muscle wasting, thin skin bruising Androgenic effects: hirsutism, acne

Answer 165

Tumour in pituitary Tumour elsewhere e.g. lung Both cause increase in ACTH Adrenal tumour (ACTH-independent) - tumour makes pituitary resistant to neg feedback

Answer 166

Carbohydrate metabolism - impaired glucose tolerance, diabetes Electrolyte disturbance - sodium retention, hypertension, hypokalaemia Immune suppression - susceptibility to infection Central effects - malaise, depression, psychosis

Answer 167

Urinary free cortisol Low dose dezamethasone suppression tests Late night/midnight serum or salivary cortisol

Answer 168

Reduced steroid dose Surgery to remove the tumour Radiotherapy to destroy the tumour Drugs to reduce the effect of cortisol on the body

Answer 169

``` Growth-hormone secreting tumour Increased IGF-1 Large hands, sweat a lot, very tall (if you get acromegaly before fusion of epiphyseal plates), thickened jaw, enlargement of soft tissue Mean age of diagnosis is 44 years olf Mean duration of symptoms is 8 years ```

Answer 170

``` Hypertension and heart disease Sleep apnea Insulin-resistant diabetes Arthritic Cerebrovascular events and headaches With co-morbidities, life expectancy decreased by 10 years ```

Answer 171

``` Acral enlargement Arthralgies Maxillofacial changes Excessive sweating Headache Hypogonadal symptoms ```

Answer 172

Ongoing and excess levels of GH in contract to normal spiking at set times. Normally after being given 75gm oral glucose GH decreases over 0-60mins. Acrogmegaly excluded if random GH <0.4 ng/ml and normal. If either abnormal proceed to 75gm glucose tolerance test Acromegaly excluded if IGF-1 normal and GTT nadir GH <1ng/ml

Answer 173

Restoration of basal GH and IGF-1 to normal levels Relief of symptoms Reversal of visual and soft tissue changes Prevention of further skeletal deformity Normalization of pituitary function

Answer 174

Pituitary surgery Medical therapy Radiotherapy

Answer 175

Prospect of cure and cost effective Will cause a rapid fall in GH Success is based on: Size of tumour: microadenoma 90% cure rate, macroadenoma <50% cure rate

Answer 176

``` Anasthetic complications Carotid artery injury CNS injury Haemorrhage Loss of vision Ophthalmoplegia Meningitis Nasal septum perforation Epistaxis and sinusitis Hypopituitarism Diabetes Insipidus ```

Answer 177

Damaging DNA, killing cells - Conventional - mult-fractional every day - Stereotactic - single fraction, less radiation to surrounding tissues - Gamma knife - very focused dose and planning Takes time Side-effects Expensive

Answer 178

``` Determinants of efficacy: GH level and size of tumour Can cause: Delayed response Hypopituitarism Rare secondary tumour Rare visual defects ```

Answer 179

Dopamine anatogonists - cabergoline Somatostatin analogues Growth hormone receptor anatogonists

Answer 180

Used to treat acromegaly Aims: control GH, IGF-1, improve well-being Carbergoline is more potent, with less side-effects than Bromocriptine Advantages: no hypopituitarism, oral administration, rapid onset Disadvantages: relatively ineffective, side effects

Answer 181

Used to treat acromegaly Can't use human somatostatin because of its short-half life and ability to bind all 5 receptor subtypes Octreotide - more specific, longer half life Lanreotide Injection once a month Aims: control GH, control IGF-1, clinical improvement Determinant of success: GH level, tumour size, SMS receptor expression Disadvantages: side effects, injection

Answer 182

``` Used to treat acromegaly A GH analogue, competitive anatagonist for GH receptor, inhibiting cross-dimerisation Half-life >70 hours Subcutaneous injection Very effective ```

Answer 183

Lactotroph cell tumour of the pituitary More common in women More common than acromegaly and cushing's

Answer 184

Local effect of tumour: headache, visual field defect (bilateral hemianopia), CSF leak Effect of prolactin: menstural irregularity, infertility, galactorrhoea, low libido, low testosterone in men

Answer 185

Macroprolactinoma Microprolactinoma Non-functioning pituitary tumour - compression of pituitary stalk Antidopaminergic drugs

Answer 186

Medical rather than surgery Dopamine agonists - cabergoline, bromocriptine, quinagolide Remarkable shrinkage usual with macroadenoma Microadenoma - small doses of cabergoline once a week

Answer 187

Cortisol is secreted in a very regulated way 10-1am low levels of cortisol Build up and up until peak at 7/8am Decrease and decrease over the day Many metabolic problems can disrupt this rhythm Glucocorticoids are second messengers from central (suprachiasmatic nucleus) to peripheral regions, using hormonal and neural signals to keep time across the whole body.

Answer 188

Primary - Addison's disease: most commonly autoimmune adrenalitis, caused by TB infection. Loss of production of glucocorticoid, mineralocorticoid and androgens. Secondary - Hypopituitarism: caused by pituitary macroadenoma, apoplexyl hypophyitis, metastasis, infiltration, infection, radiotherapy, congenital Tertiary - Suppression of HRA - steroids, oral, inhaler, creams

Answer 189

Symptoms: fatigue, weight loss, poor recovery from illness, adrenal crisis, headache Past history: TB, post-partum bleed, cancer Family history: autoimmunity, congenital disease Treatment: any steroids, Etomidate, Ketoconazole Signs: pigmentation Biochemistry: low Na, high K, eosinophilia, elevated TSH

Answer 190

Measured at 9am >500 nmol/l (unlikely), <100 nmol/l (likely) ACTH >22 ng/l (primary) <5 ng/l (secondary) Synacthen test >450 nmol/l (unlikely)

Answer 191

Primary: adrenal antibodies, very long chain fatty acids, 17-Hydroxyprogesterone, imaging, genetic Secondary: any steroids?, imaging, genetic

Answer 192

Goal: mirror the normal physiological state Hydrocortisone (pharmaceutical name for cortisol) twice or three times a day (15-25mg) In primary, also replace aldosterone with fludrocortisone

Answer 193

``` Hypotension and cardiovascular collapse Fatigue Fever Hypoglycaemia Hyponatraemia and hyperkalaemia ```

Answer 194

Take bloods (if poss) for cortisol and ACTH Immediate hydrocortisone 100mg IV, IM Fluid resusciatation Hydrocortisone 50-100mg IV/IM 6 hourly Primary: fludrocortisone 100-200ug When stable, wean patient to normal replacement over 24/72 hrs

Answer 195

Carry 10 10mg hydrocortisone tablets If unwell (fever/flu) take double dose of steroids If in doubt take double dose If vomiting or unwell take emergency injection of hydrocortisone If unable to have injection take 20mg hydrocortisone Ambulance

Answer 196

``` Poorly mimicking physiological pattern Increased morbidity and mortality Impaired quality of life Increased cardiovascular risk Osteoporosis ```

Answer 197

Investigational product Gradually released and absorbed over night (dealyed release due to PH coating) Taken twice daily Patients feeling better

Answer 198

Hyperthyroidism (2.5%) Hypothyroidism (5%) Goitre (5-15%)

Answer 199

Thyroglobulin and thyroid perioxidase (TPO) antibodies found in almost all patients with autoimmune hypothyroidism. Thyroid cell destruction is mediated by cytotoxic T cells and thyroglobulin and thyroid perioxidase may cause secondary damage. Uncommonly, antibodies against the TSH-receptors may block the effects of TSH.

Answer 200

``` Most common type of hyperthyroidism Swollen, red and protruding eyes - periorbital oedema Can lead to blindness Inappropriate attack of thyroid Cause: TSH-R antibodies Stimulate the receptor - hyperthyroidism Block the receptor - hypothyroidism ```

Answer 201

Baby receives antibodies via the placenta Neonatal hyperthyroidism has a poor prognosis - tachycardia and a failure to thrive Maternal TSAb levels will predict fetal outcome

Answer 202

Genetic and environmental factors Being female HLA-DR3 and other immunoregulatory genes contribute Environmental: stress, high iodine intake, smoking

Answer 203

During pregnancy, often autoimmune diseases get better - downregulation to protect the foetus. Graves disease and autoimmune thyroiditis often have a reduced impact during pregnancy but then overshoot postpartum.

Answer 204

Present in most Grave's disease patients Swelling in extraocular muscles Most likely due to autoantigen in the extraocular muscle that cross reacts with or is identical to a thyroid autoantigen. Fibroblasts produce glycosaminoglycans which cause water trapping (oedema and muscle swelling), interferes with architecture and can cause vision loss due to compression on the optic nerve.

Answer 205

Palpable and visible thyroid enlargement Variety of causes Most commonly sporadic non-toxic (euthyroid, diffuse, multinodular, solitary nodule, dominant nodule, benign/malignant) but can be autoimmune.

Answer 206

Overproduction of the thyroid hormone Leakage of preformed hormone from thyroid Ingestion of excess thyroid hormone

Answer 207

Grave's disease Toxic multinodular goitre Toxic adenoma

Answer 208

Iodine - substrate for making thyroid hormone Amiodarone Lithium Radioconstrast agents

Answer 209

Weight loss, tachycardia, hyperphagia, anxiety, tremor, heat tolerance, sweating, diarrhoea, lid lag and stare, menstrual disturbance.

Answer 210

Graves' specific: diffuse goitre, thyroid eye disease, pretibial myxoedema, acropachy MNG specific: multinodular goitre Adenoma specific: solitary nodule

Answer 211

Thyroid function to confirm biochemical hyperthyroidism Diagnosis of underlying cause Clinical history, physical signs are usually sufficient Supporting investigations

Answer 212

Thyroid function tests Primary: increased T4, T3, suppressed TSH Secondary: increased T4, T3, inappropriately elevated high TSH Supporting investigations - thyroid antibodies (TPO, Tg, TRAb) and isotope uptake scan

Answer 213

Antithyroid drugs (course or long-term) Radioactive I Surgery (partial, subtotal thyroidectomy)

Answer 214

Reduce the activity of the thyroid Thioramide - carbimazole (first-line), propylthioural (PTU), methimazole Decrease synthesis of new thyroid hormone PTU also inhibits conversion T4 to T3 Do not treat underlying cause but immune modifying effects are seen - decrease IL6 and reduction in antibofy titres

Answer 215

Titration regime (12-18 months) Block and replace regime with T4 (6-12 months) OR Short course to render euthyroid before I or surgery OR Long term treatment in patients unwilling to have I or surgery

Answer 216

Remission rates 30-50% No definite way to predict remission/relapse for an individual patient Poor prognosis factors: severe biochemical hyperthyroidism, large goitre, TRAb positive after course, male, young age of disease onset

Answer 217

Generally well tolerated Rash is most common Less common: arthralgia, hepatitis, neuritis, thrombocytopenia, vasculitis Usually occur within the first few months Resolve after stopping drug

Answer 218

Iodine is essential for thyroid hormone production I is actively transported by the Na/I symporter into thyroid follicular cells. Radioactive I taken up in the same way. Emits large B particles of moderate energy within a 1-2mm zone to ionize follicular cells and cause direact damage to DNA and enzymes, indirect damage via free radicals. Some gamma ray emission. Half life 8.1 days

Answer 219

Early effects: nercrosis of follicular cells and vascular occlusion Long term effects: shorter cell survival, impaired replication cells, atropy and fibrosis, chronic inflammation, late hypothyroidism

Answer 220

Near total thyroidectomy for Graves' disease and MNG | Near total thyroidectomy/lobectomy for toxic adenoma

Answer 221

Thyroid hormone levels are abnormally low Primary: absence/dysfunction of thyroid gland, most cases due to Hashimoto's thyroiditis Secondary/tertiary: pituitary/hypothalmic dysfunction

Answer 222

Primary: Hashimoto's thyroiditis, I therapy, thyroidectomy, postpartum thyroiditis, drugs, iodine deficiencym thyroid hormone resistance Secondary/tertiary: pituitary disease, hypthalamic disease

Answer 223

Thyroid agenesis, thyroid ectopia, thyroid dyshormonogenesis Resistance to thyroid hormones Isolated TSH deficiency

Answer 224

Iodine (inorganic/organic), iodide, iodinated contrast agents, amiodarone Lithium Thionamides Interferon-a

Answer 225

Fatigue, weight gain, cold intolerance, constipation, menstural disturbance, muscle cramps, slow cerebration, dry, rough skin, periorbital oedema, delayed muscle reflexes, carotenaemia, oedema

Answer 226

Primary: increased TSH, usually decreased T4 and T3 (may be low normal), positive titre of TPO antibodies in Hashimoto's Secondary/tertiary: TSH inappropriately low for reduced T4/T3

Answer 227

Of choice: synthetic L-thyroxine (T4) Older treatments: dessicated thyroid Requirements vary according to cause Caution in patients with IHD

Answer 228

Primary: dose titrated until TSH normalises, T4 half-life, check levels 6-8 weeks after dose adjustment Secondary/tertiary: TSH will always be low. T4 is monitored.

Answer 229

``` Macro: - Stroke - MI - Cardiovascular disease - Peripheral vascular disease - increases risk of amputations Micro - Diabetic retinopathy - leading cause of blindness - Diabetic nephropathy - Diabetic neuropathy ```

Answer 230

Affects 30-50% patients with diabetes evere pain in lower limbs - burning, praesthesia, hyperaesthesia, allodynia, worse at night (noctural exacerbation). Autonomic problems - orthostatic hypotension, gastroparesis, diarrhoea, constipation, incontinence, erectile dysfunction Insensitivity - foot ulceration, infection, amputation, falls, Charcot foot All lead to reduced quality of life. Cannot reverse neuropathy pathogenically, but can treat the symptoms.

Answer 231

Typical ‘glove and stocking’ sensory loss Significant motor deficit is not common Painful symptoms in 30%

Answer 232

Hypertension Poor diabetes control Lipidemia Microvascular complications are preventable through rigorous hyperglycaemic control

Answer 233

Good glycaemic control Tricyclic antidepressants / SSRIs Anticonvulsants (carbamazepine, Gabapentin) Opiods (Tramadol, oxycodone) IV lignocaine Capsaicin Transcutaneous nerve stimulation / acupuncture / spinal cord stimulators Psychological interventions / hypnosis - aware that chronic pain can easily lead to depression The best we can achieve is 50% pain relief in ⅓ of patients. Many patients still suffer considerably.

Answer 234

Common cause for hospital bed occupancy - expensive 15% of diabetics Increased risk of lower limb amputations and mortality Loss of sensitivity - patient cannot feel the trauma Most sensory neuron based, but can also affect motor nerve damage which causes high-arches and prominent heads of toes. Clawed appearance. Foot is deformed which means shoes don’t fit as well, increasing the risk of trauma. Can cause calluses with bleeding underneath. Sweating moisturises the skin keeping it supple, autonomic damage means that sweating is reduced leading to very dry feet. One of the biggest causes of ulceration is inappropriate footwear.

Answer 235

Test sensation – 10 gm monofilament – neurotips Vibration perception – Tuning fork – biothesiometer Ankle reflexes

Answer 236

Complication of diabetes Decreased perfusion due to macrovascular disease Sites: more distal 15-40 times more likely to have lower limb amputation Symptoms: Intermittent claudication - walk for a certain distance before needing to stop due to cramping Rest pain - waking up with intense pain in their feet, relieved by standing up and walking around

Answer 237

Diminished or absent pedal pulses Coolness of the feet and toes Poor skin and nails Absence of hair on feet and legs

Answer 238

Methods – Doppler pressure studies (ABI) – duplex arterial imaging/MRA Rationale – identify and confirm disease – predict healing or determine need for surgical intervention Doppler ultrasound – pressure at brachial, pedal and toe arteries Ankle Brachial Index (ABI) <0.9 abnormal 0.9 to 1.0 normal >1.3 non-compressible

Answer 239

Quit smoking Walk through pain - increase circulation to build up an ability to walk further before pain kicks in Surgical intervention

Answer 240

Screening to identify risk Education and providing orthotic shoes MDT foot clinic Pressure relieving footwear, podiatry, revascularisation, antibiotics

Answer 241

``` Diabetics WITH: Long duration diabetes Poor glycaemic control Hypertensive On insulin treatment Pregnancy ```

Answer 242

Effective way of detecting early DR DoH set up the National Screening Programme Eligibility: >11 yrs old Once registered patients receive an invitation letter 2 field retinal photography Screeners grade photographs and reports sent to GP

Answer 243

Pathogenesis – Micro-aneursyms Pericyte loss and smooth muscle cell loss Micro-aneurysms MA’s adjacent to or upstream of capillary gives non-perfusion ``` Pathogenesis - Leakage Basement membrane thickening Pericyte loss Reduces junctional contact with endothelial cells LEAKAGE ``` Pathogenesis - Ischaemia Pericyte loss, endothelial cells respond by increasing turnover > thickening > ISCHAEMIA Glial cells grow down capillaries > OCCLUSION Ischaemia/Occlusion > Proliferation

Answer 244

``` Laser Therapy Only proven treatment for DR The benefits outweigh the risks Aim is to stabilise changes Treatment does not improve sight OP treatment over one or more visits ``` Can be performed just at the periphery or scattered.

Answer 245

If treatment is given at the correct stage it is very effective Over 90% of severe sight loss prevented by laser for early proliferative retinopathy Laser of macular changes prevents 60% But many people report difficulty with night vision, tunnel vision, peripheral vision, drop in visual acuity, vitreous haemorrhage.

Answer 246

Hallmark is development of proteinuria - using a urine dipstick Followed by progressive decline in renal function Major risk factor for CVD Risk factors are poor BP and BG control Changes to glomerulus - thickening of the basal membrane, leakage of the matrix, destroying the architecture, clogs up the glomerulus and stops the filtration of the kidneys. Loss of integrity of the basal membrane means that there is an increased filtration of proteins which shouldn’t normally be there.

Answer 247

Many reasons for false positives - Exercise, infection, fever, congestive heart failure, marked hyperglycemia, marked hypertension, pregnancy, urinary tract infection, haematuria and menstruation So the measurements are confirmed with at least two specimens (preferably first morning midstream void), collected within a 3–6 month.

Answer 248

Microalbuminuria develops 5-10 yrs of diagnosis in T1 whereas Microalbuminuria can be present at time of diagnosis in T2. Data from the last 10 years show a decline in T1DM DN

Answer 249

``` Blood pressure control Glycemic control ARB / ACEi Proteinuria control - referred to dieticians Cholesterol control - with statins ```

Answer 250

Early treatment and prevention key to reducing T2DM burden Intensive diet and exercise programmes can delay onset or prevent T2DM Including use of metformin and thiazolidinediones

Answer 251

Sulphonylurea Incretin based agents SGLT-2 inhibitors Insulin

Answer 252

Poor glycaemic control increases metabolic rate and consequently, improving glycaemic control decreases metabolism. If calorie intake is not modified accordingly, then weight will increase. Improving metabolic control reduces glucosuria (excretion of glucose through the urine), thus fewer calories are lost in this manner. Normally, insulin suppresses food intake through its effect on CNS appetite control pathways. It has been suggested that this effect of insulin is lost in diabetes patients. Fear of hypoglycaemia may lead to increased snacking between meals, thus increasing calorie intake.

Answer 253

Incretins are hormones secreted by intestinal endocrine cells in response to nutrient intake Incretins influence glucose homeostasis via multiple actions including glucose-dependent insulin secretion, postprandial glucagon suppression, and slowing of gastric emptying.

Answer 254

Dipeptidyl-peptidase 4 (DPP-4) is an enzyme present in vascular endothelial lining which inactivates the incretin hormones GIP and GLP-1 DPP-4 Inhibitors are competitive antagonists of the DPP-4 enzyme - enhancing the effects of both GIP and GLP-1 Glucose dependent reduction in fasting and postprandial glucose levels in addition to decreasing glucagon secretion. Orally available Little effect on gastric emptying Do not cause nausea/ vomiting Low risk hypoglycaemia. Body weight unchanged

Answer 255

``` Injectable only Large increase in GLP-1 level Induces delay in gastric emptying Likely to induce nausea/ vomiting Induces weight loss = 3/4 kg Effects are mediated by GLP-1 Receptor ```

Answer 256

Thiazolidinediones Both effective glucose lowering agents Positive effects on the metabolic syndrome Contraindicated in CCF, high risk of fractures, macula oedema – it can make these conditions worse Becoming less popular

Answer 257

Empaglifozin, Dapaglifozin, Canaglifozin Current treatments are act as insulin secretagogues or sensitisers Work on the kidneys by reducing the reabsorption of glucose in the proximal convoluted tubule Don't cause weight gain Increased risk of genito-urinary infections SGLT-2i efficacy declines with increasing renal impairment May cause hypotension

Answer 258

BMI 35 with diabetes are eligible to be referred for bariatric surgery. Two procedures Roux-en-Y bypass: creating a small pouch from the stomach and connecting the newly created pouch directly to the small intestine Sleeve : a surgeon reduces the stomach to a sleeve-like shape by removing much of it. The surgery is irreversible and can help people lose a large proportion of their body weight

Answer 259

In the fasting state, All glucose comes from liver - Breakdown of glycogen - Gluconeogenesis (utilises 3 carbon precursors to synthesise glucose including lactate, alanine and glycerol) Glucose is delivered to insulin independent tissues, brain and red blood cells Insulin levels are low Muscle uses FFA for fuel

Answer 260

After feeding Physiological need to dispose of a nutrient load Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon 40% of ingested glucose goes to liver and 60% to periphery, mostly muscle Ingested glucose helps to replenish glycogen stores both in liver and muscle High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall

Answer 261

A number of circulating hormones, cytokines, and metabolic fuels, such as non-esterified (free) fatty acids (NEFA) originate in the adipocyte and modulate insulin action. An increased mass of stored triglyceride, especially in visceral or deep subcutaneous adipose depots, leads to large adipocytes that are themselves resistant to the ability of insulin to suppress lipolysis. This results in increased release and circulating levels of NEFA and glycerol, both of which aggravate insulin resistance in skeletal muscle and liver.

Answer 262

Vasopression and oxytocin are made in the paraventricular and supraoptic nuclei and transported to the posterior pituitary gland to be released into the bloodstream. PVN and SON receive afferent fibres from the osmoreceptors which determine whether signals are fired to cause secretion.

Answer 263

V1a -vasculature V2 - principal cells in the renal collecting tubules (reabsorption of water) V1b - pituitary

Answer 264

Osmoreceptors in hypothalamus (day to day) | Baroreceptors in brainstem and greater vessels (emergency)

Answer 265

In plasma osmolality is very similar to osmolarity but the concentration is slightly different as approx 6% of volume is made up of lipids and proteins.

Answer 266

282-295 mOsmol/kg

Answer 267

As you increased osmolality, there is an increase in vasopression release.

Answer 268

Lack of vasopression - cranial diabetes insipidus (uncommon but life-threatening) Resistance to the action of vasopressin - nephrogenic diabetes insipidus (uncommon but life-threatening) Too much vasopression - syndrome of ADH secretion (common and life-threatening)

Answer 269

Polyuria Polydypsia No glycosuria

Answer 270

Inappropriately dilate urine for plasma osmolality Serum osmo >300 and urine somo <200 Normonatraemia or hypernatraemia

Answer 271

Idiopathic Tumours - craniopharyngioma, germinoma, metastases Trauma Infections - TB, encephalitis, meningitis Vascular - aneurysm, infarction, Sherrlan's, sickle cell Inflammatory - neurosarcoidosis, Langerhan's histiocytosis, Guillain Barre, Granuloma

Answer 272

DIMOAD (Wolfram syndrome) Autosomal dominant Rarelt autosomal recessive

Answer 273

Cranial - absence of osmolality-related release of vasopression Nephrogenic - familial X-linked - V2 receptor defect Autosomal - aquaporin Z defect

Answer 274

AVP's instability makes it difficult to measure Water deprivation test Hypertonic saline infusion and measure AVP Copeptin measurement - there are equimolar amounts of AVP and Copeptin (cut off from same peptide), can be quickly and easily measured

Answer 275

``` Water deprivation test No access to water Then given 2ug of desmopression CDI will return to normal values in the plasma and urine osmolality NDI no effec ```

Answer 276

Treat any underlying condition Desmopressin - high activity at the V2 receptor Tablets, nasal spray or injection

Answer 277

Try to avoid precipitating drugs | High dose of desmopressin in congenital DI

Answer 278

Serum sodium <135mmol/l Biochemical severe <125mmol/l Normal serum sodium 135-144 mmol/l Usually caused by excess water rather than salt loss

Answer 279

Moderate Headache, irritability, nausea/vomiting, mental slowing, unstable gait, confusion/delirium, disorientation Severe Stupor/coma, convulsions, respiratory arrest

Answer 280

Immediate effect: water gain Rapid adaption: loss of sodium, potassium, chloride Slow adaption: loss of organic osmolytes

Answer 281

``` Plasma and urine osmolality Urinary Na, Glucose TFTs Assessment of cortisol Assessment of underlying causes ```

Answer 282

Fluid overload due to liver cirrohosis/liver, CHF - fluid restrict Normovolaemic in SIADH - fluid restrict Dehydrated in diarrhoea, burns, pancreatitis, diuretic - saline replacement

Answer 283

``` Syndrome of inappropriate antidiuretic hormone secretion Common cause of hyponatraemia Too much ADH Plasma Na is low Urine is inappropriately concentrated Increased GFR ```

Answer 284

Diagnose and treat underlying condition Fluid restriction <1 L/24 hours Sometimes demeclocycline/vaptan

Answer 285

White areas in the middle of the pons Massive demyelination of descending axons May take up to 2 weeks to manifest

Answer 286

``` Serum Na <105mmol/L Hypokalaemia Chronic excess alcohol Malnutrition Advanced liver disease ```

Answer 287

``` Tolvaptan - selective V2 receptor oral antagonist Competitive antagonist to AVP Causes profound 'aquaresis' Expensive Also licensed for SIADH ```

Answer 288

Anterior lobe - glandular tissue, accounts for 75% of total weight Posterior lobe - nerve tissue and contains axons that originate in the hypothalamus

Answer 289

``` Non-functioning pituitary adenomas Malignant pituitary tumours Metastases in the pituitary (breast, lung, stomach, kidney) Pituitary cysts Developmental abnormalities Primary tumours of the CNS Vascular tumours Malignant systemic diseases Granulomatous diseases Vascular aneurysms ```

Answer 290

Develops from the roof of the mouth, forms Rathke's pouch Stalk of Rathke's pouch degenerates, forming anterior pituitary fland Hypothalamus produces neural lobe, joined by infundibulum Intermediate lobe between the two

Answer 291

Arises from squamous epithelial remnants of Rathke's pouch Benign tumours although infiltrates surrounding structures Adamantinous - cyst formation and calcification Squamous papillary - well circumscribed Peak ages 5-14 years old, 50-74 years old

Answer 292

``` Solid, cystic, mixed tumour that extends into supra sellar region Raised ICP Visual disturbances Growth failure Pituitary hormone deficiency Weight increase ```

Answer 293

Derived from the remnants of Rathke's pouch Single layer of epithelial cells with mucoid, cellular, or serous components in cyst fluid Mostly intrasellar components, may extend into the parasellar area Mostly asymptomatic and small Present with headache, amenorrhoea, hypopituitarism, hydrocephalus.

Answer 294

Commonest tumour of the region after a pituitary adenoma Complication of radiotherapy Associated with visual disturbance and endocrine dysfunction Usually present with loss of visual acuity, endocrine dysfunction and visual field defects

Answer 295

Inflammation of the pituitary gland due to an autoimmune reaction More common in women Pregnancy or post-partum

Answer 296

Diagnosed between 20 and 60 years of age Most express gonadotropins or subunits Signs of aggressiveness: large size, cavernous sinus invasion, lovulated suprasellar margins

Answer 297

Complex because there are many hormones involved (GH, LH/FSH, ACTH, TSH and ADH) - may have deficiency in one or all. Circadian rhythms and pursatile so different concentrations at different times. Guiding principle - if the peripheral organ is working the pituitary is working

Answer 298

Primary hypothyroid - high TSH, low FT4 Hypopituitary - normal or low TSH, low FT4 Graves' disease - low TSH, high FT4 TSHoma - normal or high TSH, high FT4 Hormone resistance - normal or high TSH, high FT4

Answer 299

Primary hypogonadism - low T, high FSH/LH Hypopituitary - low T, normal or low FSH/LH Anabolic use - low T, suppressed LH

Answer 300

Before puberty - oestradiol is very low, low FSH/LH Puberty - pulsatile LH and oestradiol increases Post menarche - monthly menstural cycle with LH/FSH, mid cycle surge in LH and FSH and levels of oestradiol increasing throughout cycle Menopause/primary ovarian failure - high LH and FSH, low oestradiol

Answer 301

Oligo or amenhorrhoea with low oestradiol | Normal or low LH and FSH

Answer 302

Low cortisol (measured at 0900h) Low or normal ACTH Poor response to synacthen (to stimulate ACTH)

Answer 303

GH is secreted in pulses with greatest pulse at night Low or undetectable levels between pulses GH levels fall with age and are low in obesity

Answer 304

Measure prolactin or cannulated prolactin (3 samples over an hour to exclude effects of stress of venepuncture)

Answer 305

Stress Drugs - antipsychotics Stalk pressure Prolactinoma

Answer 306

Dynamic stimulation/suppression testing may be useful in select cases to further evaluate pituitary reserve and/or pituitary function

Answer 307

Preferred imaging study Better visualisation of soft tissues and vascular structures No exposure to ionizing radiation

Answer 308

Better at visualising bony structures and calcifications within soft tissues Better at determining diagnosis of tumours with calcifications such as germinomas, craniopharyngiomas, meningiomas May be useful when MRI is contraindicated such as in patients with pacemakers or metallic implants in brain/eyes

Answer 309

Less optimal soft tissue imaging compared to MRI Use of intravenous contrast media Exposure to radiation

Answer 310

GH - short stature, abnormal body composition, reduced muscle mass, poor quality of life LH/FSH - hypogonadism, reduced sperm count, infertility, mensturation problems TSH - hypothyroidism ACTH - adrenal failure, decreased pigment ASH - DI

Answer 311

Levothyroxine Aim to achieve levels to mid to upper half of reference tange Check level before dose Higher doses needed in pregnancy or patients on oestrogens

Answer 312

``` <60 years 0.2-0.4mg a day >60 years 0.1-0.2mg a day Aiming for mid range IGF-1 levels Measure IGF1 6 weeks after dose starts Should improve lipid profile, body composition and bone mineral density ```

Answer 313

Different types of formulations - gels, injections, oral Follow testosterone levels, FBC and PSA Should improve bone mineral density, libido, function, energy levels, sense of wellbeing, muscle mass and reduce fat.

Answer 314

Oral oestrogen or combined oestrogen/progesterone forumulations Can be transdermal, topical gel, intravaginal cream Reduced risk of CVD, osteoporosis and mortality

Answer 315

Different formulations - subcutaneously, orally, intra-nasally, sublingually Adjust according to symptoms Monitor sodium levels

Answer 316

Symptoms with... Random plasma glucose > 11mmol/L Fasting plasma glucose > 7mmol/L No symptoms with Fasting plasma glucose > mmol/L HbA1c 48 mmol/mol

Answer 317

Thirst - osmotic activation of hypothalamus Polyuria - osmotic diuresis Weight loss - lipid and muscle loss due to unrestained gluconeogenesis Hunger - lack of useable energy source Pruritis vulvae and balanitis Blurred vision - altered acuity due to uptake of glucose/water into lens

Answer 318

Onset is usually in childhood/adolescence (5-15 years) Can occur at any age and the spectrum of presentation depends on the rate of B cell destruction By the time someone is diagnosed, they have about 10% of functioning B cells left. Decreasing over lifetime

Answer 319

Usually presents in over 30s Onset is gradual Family history is usually positive

Answer 320

Can be difficult Type 2 is also diagnosed in younger patients, including childhood Type 1 patients can also be obese!

Answer 321

Associated with antibodies Anti-GAD, pancreatic islet cell antibody, islet antigen-2 antibody, ZnT8 Associated with other autoimmune diseases like Hypothyroidism, Addisons, Coeliac disease

Answer 322

Fat metabolism - reduced insulin leads to fat breakdown and formation of glycerol and free fatty acids Ketone bodies - free fatty acids impair glucose uptake, and are transported to the liver providing energy for gluconeogenesis, oxidised to form ketone bodies

Answer 323

Absence of insulin and rising counteregulatory hormones leads to hyperglycaemia and increased ketones. Glucose and ketones escape in the urine and lead to an osmotic diuresis and falling circulatory blood volume. Ketones (weak organic acids) cause anorexia and vomiting. Viscous cycle of increasing dehydration, hyperglycaemia and increasing acidosis eventually leading to circulatory collapse and death.

Answer 324

Hyperglycaemia (plasma glucose is usually <50mmol/l) Raised plasma ketones (urine ketones >2) Metabolic acidosis - plasma bicarbonate (<15 mmol/l)

Answer 325

Unknown (40-50%) Interccurrent illness - infection, MI Treatment errors Previously undiagnosed diabetes

Answer 326

Symptoms develop over days Polyuria, polydipsia, nausea, vomiting, weight loss, weakness, abdominal pain, drowsiness/confusion Signs: hyperventilation (kussmal breathing), dehydration, hypotension, tachycardia, coma

Answer 327

``` Hyperglycaemia (<50 mmol/l) High K on presentation despite total body K deficit (due to acute shift of K out cell with acidosis) HCO3 <15 mmol/l Raised urea and creatinine Urine ketone >2+ Blood ketone 3 ```

Answer 328

``` Rehydration (3L first 3 hours) Insulin (inhibits lipolysis, ketogenesis, acidosis, reduced hepatic glucose production, increase tissue glucose uptake) Replacement of electrolytes Treat underlying cause Treatment must be started without delay ```

Answer 329

``` Cerebral oedema Adult respiratory distress syndrome Thromboembolism Aspiration pneumonia Death ```

Answer 330

Relieve symptoms and prevent ketoacidosis | Prevent microvascular and macrovascular complications

Answer 331

30% Diabetic nephropathy | Also tend to develop proliferative retinopathy and severe neuropathy with major effect on quality of life.

Answer 332

Insulin treatment - twice daily mixture of short/medium acting insulin (with or without pre meal quick acting insulin) Balancing carbohydrate intake and exercise

Answer 333

Insulin goes through the subcutaneous route rather than straight into the bloodstream, so it will be different to normal release.

Answer 334

Shaking, fast heartbeat, sweating, dizziness, anxious, hunger, impaired vision

Answer 335

4.6 mM Inhibition of insulin secretion 3.8 mM Counter-regulatory hormone release (glucagon and adrenaline) 3.8-2.8 mM Autonomic symptoms: sweating, tremor, palpitations <2.8 mM Neuroglycopenic symptoms: confusion, drowsiness, altered behaviour, speech difficulty, incoordination <1.5 mM Severe neuroglycopenic: convulsions, coma, focal neurological deficit

Answer 336

Insulin pumps are small, computerized devices that mimic the way the human pancreas works by delivering small doses of short acting insulin continuously (basal rate). The device also is used to deliver variable amounts of insulin when a meal is eaten (bolus).

Answer 337

DAFNE is a method of managing type 1 diabetes for adults. DAFNE stands for Dose Adjustment for Normal Eating. The primary goal of DAFNE is to help diabetics live the most normal life possible, whilst keeping blood glucose levels stable and lowering the risk of diabetes complications.

Answer 338

Setting higher glucose targets will reduce the risk of hypoglycaemia but increase the risk of diabetic complications Setting lower glucose will reduce risk of compliciation but increase the risk of hypoglycaemia

Answer 339

``` Risk of hypoglycaemia Too arduous a treatment Risk of weight gain Interference with lifestyle Lack of sufficient training ```

Answer 340

2/3 of all patients can expect a good life expectancy with minor complications Tight glucose control will increase this proportion but sometimes at the expensive of hypoglycaemia and weight gain

Answer 341

``` Maturity-onset diabetes of the young Commonest type of mongenic diabetes Diagnosed <25 years Autosomal dominant - single gene defect altering beta cell function Tend to be non-obese ```

Answer 342

Transcription factor MODY Hepatic nuclear factor mutations alter insulin secretion, reduce beta cell proliferation ``` HNF1A mutation (MODY3) Very sensitive to suphonylurea treatment so often don't need insulin ``` HNF4A mutation (MODY1) Family history, young age-of-onset, non-obese Macrosomia, neonatal hypoglycaemia Glucokinase gene mutation (MODY2) GCK is the glucose-sensor of the beta cells and controls the release of insulin Mild diabetes, no treatment required

Answer 343

Parent affected with diabetes Absence of islet autoantibodies Evidence of non-insulin dependence - good control on low dose insulin, no ketosis, measurable C-peptide Sensitive to sulphonylurea

Answer 344

In type 1 diabetes C-peptide is negative within 5 years due to complete autoimmune beta cell destruction Type 2 and MODY C-peptide persists

Answer 345

First appears within the first 6 months of life and persists throughout the lifespan. Signs: small babies, epilepsy, muscle weakness

Answer 346

Mutations in Kir6.2 and SUR1 subunits of the beta cell ATP sensitive K channel Rising ATP closes the channel as a result of hyperglycaemia, depolarising the membrane and insulin is secreted. Mutations prevent the closure of the channel and thus beta cells are unable to secrete insulin. Sulphonylureas close the K ATP channels.

Answer 347

Maturally inherited diabetes and deafness Mutation in mitocondrial DNA Similar presentation to Type 2 Wide phenotype

Answer 348

Selective loss of adipose tissue | Associated with insulin resistance, dyslipidaemia, hepatatic steatosis, hyperandrogenism, PCOS

Answer 349

Inflammatory Acute - usually transient hyperglycaemia due to increased glycagon secretion Chronic pancreatitis - Alcohol - Alters secretions, formation of proteinaeceous plugs that block ducts and act as foci for calculi Stop alcohol and treat with insulin

Answer 350

Autosomal recessive Triad of cirrhosis, diabetes and bronzed hyperpigmentation Excess iron deposited in liver, pancreas, pituitary, heart, parathyroids Most need insulin

Answer 351

Common cause of cancer death Symptoms of pancreatic cancer include pain in the back or stomach, unintended weight loss and yellowing of the skin and eyes. Require subcutaneous insulin Prone to hypoglycaemia due to loss of glycagon function Frequent small meals, enzyme replacements, insulin pumps

Answer 352

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation Regulates chloride secretion Viscous secretions lead to duct obstruction and fibrosis Insulin treatment required to improve body weight, reduces infections, lung function, Improves quality of life and survival.

Answer 353

Acromegaly - excessive secretion of growth hormone, similar to type 2, insulin resistance rises Cushing's syndrome - increased insulin resistance, reduced glucose uptake into peripheral tissue Pheochromocytoma - catecholamine, usually adrenaline excess, increase gluconeogenesis, decreased glucose uptake

Answer 354

Glucocorticoids increase insulin resistance | Thiazides.protease inhibitors/antipsychotic can cause diabetes although the mechanisms are not clearly understood

Answer 355

1) Prepubertal: No pubic hair 2) Sparse growth of slightly curly pubic hair, mainly base of penis Testes > 3 mL (>2.5 cm in longest diameter) Scrotum thinning and reddening 3) Thicker, curlier hair spread to mons pubis Growth of penis in width and length; further growth of testes 4) Adult-type hair, not yet spread to medial surface of thighs. Penis further enlarged; testes larger, darker scrotal skin colour 5) Adult-type hair spread to medial surface of thighs Genitalia adult size and shape

Answer 356

1) Prepubertal: No pubic hair Elevation of papilla only 2) Sparse growth of long, straight or slightly curly, minimally pigmented hair, mainly on labia Breast bud noted/ palpable; enlargement of areola 3) Darker, coarser hair spreading over mons pubis Further enlargement of breast and areola, with no separation of contours 4) Thick adult-type hair, not yet spread to medial surface of thighs Projection of areola and papilla to form secondary mound above level of breast 5) Hair adult-type and distributed in classic inverse triangle Adult contour breast with projection of papilla only

Answer 357

Orchidometer measures testicular volume in mL

Answer 358

``` First visible change of puberty Induced by oestrogen Completed in about 3 years Effects of oestrogen on the breast - Ductal proliferation - Site specific adipose deposition - Enlargement of the areola & nipple May be unilateral for several months Other hormones involved in breast development: prolactin, glucocorticoids, insulin ```

Answer 359

``` Uterus Corpus : cervix ratio 1:2 Tubular shape Length 2-3 cm Volume 0.4-1.6 ml Endometrium single layer of cuboidal cells ``` Ovaries Volume 0.2-1.6 ml Non functional

Answer 360

``` Uterus Corpus : cervix ratio 2:1 Pear shape Length 5-8 cm Volume 3-15 ml Endometrium increased thickness ``` Ovaries Volume 2.8-15 ml Multicystic

Answer 361

Reddish in colour Thin atrophic columnar epithelium pH neutral Length 2.5-3.5 cm

Answer 362

Dulling of the reddish colour Thickening of the epithelium Cornification of the superficial layer (stratified squamous epithelium) pH acidic 3.8-4.2 Secretion of clear whitish discharge in the months before menarche Length 5-8 (-12)cm

Answer 363

Labia majora & minora increase in size & thickness Rugation & change in colour of the labia majora Hymen thickens Clitoris enlarges Vestibular glands begin secretion

Answer 364

Growth of pubic & axillary hair

Answer 365

Developmentally programmed peri-pubertal activation of adrenal androgen production Mild advanced bone age, axillary hair, oily skin, mild acne, body odour Developmental process where a specialized subset of cells arises forming the androgen-producing zona reticularis (ZR)

Answer 366

Puberty happens too soon It may be caused by tumors or growths on the ovaries, adrenal glands, pituitary gland, or brain. Other causes may include central nervous system problems, family history of the disease, or certain rare genetic syndromes. In many cases, no cause can be found for the disorder. 90% of patients female Treatment with GnRH super-agonist to suppress pulsatility of GnRH secretion

Answer 367

Precocious pseudopuberty is partial pubertal development that results from autonomous (gonadotropin-independent) production of testosterone in a prepubertal boy. Affected boys have premature virilization and rapid growth, but they do not produce sperm. Caused by increased androgen secretion, gonadotropin secreting tumours, ovarian cyst, oestrogen-secreting neoplasm, hypothyroidism, iatrogenic or exogenous sex hormones.

Answer 368

Idiopathic (constitutional) delay in growth and puberty due to delayed activation of the hypothalamic pulse generator. Occurs in about 3% of children In boys, delayed puberty often constitutional and functional (63%) In girls, delayed puberty less common and often organic Delay in puberty leads to delay in acquisition of secondary sex characteristics, psychological problems, defects in reproduction and reduced peak bone mass.

Answer 369

Lack of breast development by 13 yrs More than five years between breas development and menarche Lack of pubic hair by age 14 yrs Absent menarche by age 15-16 yrs

Answer 370

Lack of testicular enlargement by age 14 yrs Lack of pubic hair by age 15 yrs More than 5 years to complete genital enlargement

Answer 371

Constitutional delay of growth and puberty Single most common cause in both sexes More common in boys Extreme of the normal physiologic variation Diagnosis of exclusion More likely to be short for age with history of normal growth rate Delay in bone maturation, delay in adrenarche Frequently family history of late menarche in mother or sister or delayed growth spurt in father Onset of puberty corresponds better with bone age than chronological age

Answer 372

``` Complete red blood count U&E, renal, LFT, coeliac ab LH, FSH Testosterone/ Oestradiol Thyroid function, Prolactin DHEA-S, ACTH, Cortisol ```

Answer 373

Bone age Delayed bone age in GH deficiency Advanced bone age in precocious puberty

Answer 374

Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. The causes of primary hypogonadism include: autoimmune disorders, such as Addison's disease and hypoparathyroidism. genetic disorders, such as Turner syndrome and Klinefelter syndrome. severe infections, especially mumps involving your testicles.

Answer 375

Hypergonadotropic hypogonadism, also known as primary or peripheral/gonadal hypogonadism, is a condition which is characterized by hypogonadism due to an impaired response of the gonads to the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and in turn a lack of sex steroid hormones.

Answer 376

Hypogonadotropic Hypogonadism, is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis (HPG axis). Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary.

Answer 377

Hypogonadotrophic hypogonadism Failure of migration of GNRH neurons Multiple generic causes X-linked, autosomal recessive or autosomal dominant Mutations in Kal-1, FGF-receptor 1, prokineticin GnRH-receptor, GPR54 (normoosmic)

Answer 378

At birth oedema of dorsa of hands, feet and loose skinfolds at the nape of the neck Webbing of neck, low posterior hairline, small mandible, prominent ears, epicanthal folds high ached palate, broad cheast, cubitus valgus, hyperconvex fingernails Hypergonadotrophic hypogonadism, streak gonads Cardiovascular malformations Renal malformations (horseshoe kidney) Recurrent otitis media Short stature

Answer 379

Klinefelter syndrome (KS), also known as 47, XXY is the set of symptoms that result from two or more X chromosomes in males. The primary features are infertility and small poorly functioning testicles. Often, symptoms may be subtle and many people do not realize they are affected.

Answer 380

``` Primary hypogonadism Azoospermia, Gynaecomastia Reduced secondary sexual hair Osteoporosis Tall stature Reduced IQ in 40% 20-fold increased risk of breast cancer ```

Answer 381

Ethinyloestradiol (tablet) orOestrogen (tablets, transdermal) Start with low, gradual increasing doses to provide time for pubertal growth and gradual breast development Several incremental steps over 2 years until full adult replacement dose achieved Once full replacement dose achieved, progesterone should be added

Answer 382

Testosterone enanthate, IM injection most common method of pubertal induction and maintenance Increasing use of transdermal testosterone Several incremental steps of 2(-4) years until full adult replacement dose achieved

Answer 383

Patients with hypogonadotrophic hypogonadism potentially fertile Typical approach to fertility induction is pump administered GnRH-TX (requires intact pituitary) Or parenteral combination of gonadotrophin TX (LH/hCG and FSH)