Endocrine Flashcards

Question

Describe the causes of hypocalcaemia

Answer 1

* PTH deficiency Hypoparathyroidism: surgery, autoimmune, Mg deficiency * PTH excess Vitamin D deficiency: malabsorption, lack of sunlight, genetic syndromes, cirrhosis (defective 25-hydroxylation) Chronic renal failure: defective 1-alpha-hydroxylation Loss of calcium * Drugs: PPIs * Hypomagnesaemia (PTH resistance)

Answer 2

- Tetany Increased neuromuscular excitability Peri-oral numbness Muscle cramps, tingling of hands & feet Severe: carpopedal spasm, laryngospasm, seizures * Cardiac complications Dysrhythmia Hypotension ECG changes: prolonged QTc interval - Chronic features Basal ganglia calcification Cataracts Poor dentition Parkinsonism and dementia Skin changes

Answer 3

* IV calcium replacement if tetany/cardiac manifestations * May need magnesium infusion * Chronic management: vitamin D + oral calcium salts * Treat underlying cause

Answer 4

* PTH high Primary hyperparathyroidism: Adenoma of parathyroid gland Increased bone resorption and GI absorption Familial hypocalciuric hypercalcaemia (FHH) Tertiary hyperparathyroidism (renal failure) * PTH normal/low PTHrP: malignancy Vitamin D excess: overuse of supplements, sarcoidosis, lymphoma, TB Thiazide diuretics

Answer 5

Moans (neurological) * Depression, lethargy, fatigue, psychosis * Memory loss Bones (musculoskeletal) * Bone pain * Osteoporosis * Muscle weakness Stones (kidneys) * Polyuria, polydipsia * Nephrocalcinosis * Nephrogenic diabetes insipidus * Nephrolithiasis * Distal renal tubular acidosis * Chronic and acute renal insufficiency Groans (GI) * Nausea, vomiting, anorexia * Bowel hypomotility and constipation * Peptic ulcer disease, pancreatitis

Answer 6

Depends on severity; address underlying cause * Rehydration - isotonic 0.9% NaCl, patients often hypovolaemic * Bisphosphonates - zolendronic acid; inhibits osteoclasts & bone resorption * Calcimimetics - cinacalcet; activate parathyroid calcium receptor to produce less PTH * Calcitonin: increases renal calcium excretion & reduces bone resorption * Glucocorticoids: inhibit vitamin D production * Parathyroidectomy: if resistant to treatment

Answer 7

* PTH Released by chief cells in response to low ionised calcium levels Activates vitamin D in the kidney Increases bone resorption to release calcium into the bloodstream Increases renal reabsorption of calcium Controlled by a negative feedback loop (PTH suppressed when ionised calcium levels rise) * Active vitamin D (1,25-dihydroxycholecalciferol) Increases GI absorption of calcium Increases bone resorption

Answer 8

Osmoreceptors in macula densa detect low sodium levels > PGE2 > juxtaglomerular cells produce renin which converts angiotensinogen to angiotensin I, the converted to angiotensin II via ACE Stimulates synthesis and secretion of aldosterone in glomerulosa cells of adrenal cortex Angiotensin II - stimulates Na+/H+ exchange, increasing Na reabsorption Aldosterone - Na reabsorption in principal cells of distal tubule, collecting duct ADH - stimulated by low blood volume, increased serum osmolality and angiotensin II ADH increases water reabsorption by insertion of aquaporins into cortical collecting duct, decreases serum osmolality

Answer 9

* Hypovolaemia (Na and water deficit) Renal losses: diuretic excess, mineralocorticoid deficiency, salt-losing nephritis Extrarenal losses: burns, vomiting, diarrhoea * Euvolaemia (Na normal and excess water) SIADH, drugs, pain, psychiatric disorders, hypothyroidism, glucocorticoid deficiency * Hypervolaemia (Na and water excess) Nephrotic syndrome, cardiac failure, cirrhosis, acute & chronic renal failure

Answer 10

Excessive ADH secretion Low plasma osmolality, normal total body sodium, excess water Kidney inappropriately retains water so urine osmolality is high Clinical features (mild to severe) * often asymptomatic * mild confusion * gait instability * marked confusion, drowsiness * seizures Causes - Infective: esp respiratory tract infection, pneumonia * Primary brain injury: meningitis, brain surgery * Drugs: amitriptyline, SSRIs, carbamazepine, morphine, PPIs * Malignancy: small cell lung cancer

Answer 11

Diagnosis * Hyponatraemia with inappropriately low plasma osmolality * Urine osmolality > plasma osmolality * Absence of adrenal, thyroid, pituitary or renal insufficiency * No recent diuretic use Management - Severe and acute (unconscious or seizures) Infusion of hypertonic 3% saline: can increase serum sodium quickly * Less severe or chronic Treat underlying cause Fluid restriction, increase slowly Consider AVPR2 antagonists (controversial)

Answer 12

* Acute (sudden drop) Cerebral oedema Increased intracranial pressure Interstitial sodium and water forced out into CSF * Chronic (48h) Astrocytes lose intracellular solutes e.g. protein, phosphates Achieve same osmolality as plasma and decrease brain swelling Readaption during treatment: sudden rise in Na can cause osmotic demyelination syndrome

Answer 13

Causes: Unreplaced water loss: Diabetes insipidus Very high blood glucose (HHS - osmotic diuresis) GI and insensible losses Other: seizures/exercise, excess sodium ingestion (rare, usually in hospitals due to aggressive fluid resuscitation) Management: * Treat underlying cause & estimate total body water deficit * Avoid overly rapid correction (concern of cerebral oedema) * Use combination of saline and 5% dextrose

Answer 14

Mnemonic: FRIED SALT Fever (low) Restless (irritable) Increased fluid retention, increased blood pressure Edema Decreased urinary output, dry mouth Skin flushed Agitated Lethargy Thirst

Answer 15

Outer to inner - Zona glomerulosa: small cells in rounded clusters Production of mineralocorticoids: aldosterone, deoxycorticosterone * Zona fasciculata: large cells in parallel cords Production of glucocorticoids e.g. cortisol, corticosterone * Zona reticulata: closely packed cells in haphazard arrangement Production of androgenic steroids e.g. DHEA, DHEA sulphate, androstenedione Produce a small amount of glucocorticoids

Answer 16

Terminal stages are catalysed by 11-beta hydroxylase Effects: * Stimulates gluconeogenesis in the liver * Stimulates lipolysis in adipose tissue * Insulin antagonist * Increases breakdown of skeletal muscle protein * Memory, learning, mood * Immune suppression

Answer 17

* Catalysed by aldosterone synthase * Effects: Acts on principal cells in distal tubule and collecting duct Upregulates ENaC increasing apical membrane permeability for Na Stimulates K secretion into lumen Stimulates H+ secretion via H+ ATPase in intercalated cells in collecting duct Stimulates water and sodium reabsorption from gut, sweat, saliva in exchange for potassium

Answer 18

* Addison’s disease * Congenital adrenal hyperplasia * Adrenal TB

Answer 19

Autoimmune destruction of the adrenal cortex Associated with other autoimmune diseases like type I diabetes Clinical features: Anorexia, weight loss Hypotension, dizziness Abdominal pain, vomiting, diarrhoea Skin pigmentation Addisonian crisis - acute adrenal insufficiency Fatigue, weakness Abdominal pain, nausea, vomiting Hypotension, syncope Metabolic encephalopathy, shock

Answer 20

* 21-hydroxylase deficiency * Autosomal recessive * Lacking enzyme for steroid hormone synthesis * Accumulation of androgens but lack of cortisol & aldosterone

Answer 21

* Short synacthen test: measure plasma cortisol before & 30 mins after ACTH injection * Low sodium, increased potassium with increased renin * Adrenal autoantibodies * Hypoglycaemia * ACTH levels Should be increased Causes skin pigmentation as it is derived from pro-opiomelanocortin (POMC), which also produces melanocyte-stimulating hormone

Answer 22

* Do not delay treatment to confirm the diagnosis * Replace cortisol with hydrocortisone 15-30mg tablets daily Try to mimic circadian rhythm (higher dose in the morning) * Replace aldosterone with fludrocortisone * Patient education Sick day rules (double dose) Steroid warning card

Answer 23

Hypothalamic/pituitary problem: lack of CRH/ACTH * Iatrogenic Exogenous steroid use e.g. high dose prednisolone, dexamethasone, inhaled corticosteroid Anterior pituitary switches off ACTH production & cortisol is not produced Clinical features: same as primary adrenal insufficiency but no skin pigmentation (no increase in ACTH) and aldosterone production is intact (regulated by RAAS) Manage with hydrocortisone replacement * Tumours * Surgery/radiotherapy * Abscess

Answer 24

* Excess cortisol secretion Characterised by * Central obesity with proximal myopathy * Hypertension * Hyperglycaemia/diabetes * Depression/euphoria * Deep red striae * Buffalo hump * Easy bruising * Facial plethora

Answer 25

ACTH-dependent * Pituitary adenoma (Cushing’s disease) * Ectopic ACTH (carcinoid, carcinoma) * Ectopic CRH ACTH-independent * Adrenal carcinoma/adenoma * Nodular hyperplasia Iatrogenic * Due to prolonged high dose steroid therapy * Chronic suppression of ACTH and adrenal atrophy, low plasma cortisol level

Answer 26

* Establish cortisol excess: dexamethasone suppression testing, failure to suppress cortisol also 24h urinary free cortisol, late night salivary cortisol - both elevated * Establish source of cortisol excess Measure ACTH - Normal/high ACTH CRH stimulation test * No increase in ACTH: ectopic source of ACTH * Exaggerated increase in ACTH: pituitary adenoma (Cushing’s disease) * Undetectable ACTH: adrenal tumour

Answer 27

* Surgical Transsphenoidal pituitary surgery Laparoscopic adrenalectomy Removal of ACTH source * Medical Metyrapone/ketoconazole: inhibit cortisol production in the short-term

Answer 28

Autonomous production of aldosterone independent of its regulators (angiotensin II/potassium) Due to either single adrenal adenoma or bilateral adrenal nodules Commonest cause of secondary hypertension Clinical features * Significant hypertension * Alkalosis * Hypokalaemia

Answer 29

Catecholamine-secreting tumour of the adrenal medulla Hypertension and episodes of headaches, pallor, sweating and palpitations Diagnosis * Adrenal CT * Measure urinary catecholamines and metabolites Management - Adrenalectomy (pre-op prep with alpha 1 and beta 1 antagonists to block effects of catecholamine surge)

Answer 30

Made up of chromaffin cells * Pale stain, granular cytoplasm (secretory vesicles) * Cells are polyhedral and arranged in clumps, surrounded by rich vasculature * Secrete catecholamine hormones: adrenaline and noradrenaline Central adrenomedullary vein found here

Answer 31

* Autoimmune destruction of beta cells of the pancreas; insulin deficient * Usually early onset w/ severe presentation - Autoantibodies include IA2: insulinoma-associated antigen-2 GAD65: glutamic acid decarboxylase 65 ZnT8: zinc transporter IAA: insulin auto-antibody ICA: islet cell antibody

Answer 32

* Later onset, characterised by insulin resistance, associated with obesity and adipokines * Genetic predisposition combined with weight gain predisposes to dyslipidaemia * Insulin resistance causes beta cells to increase production of insulin > hyperinsulinemia (pre-diabetes & early diabetes) * This can result in hypertension, impaired glucose tolerance & fasting glucose * Eventually hyperglycaemia arises due to beta cell exhaustion and decreased insulin production (early and then late diabetes) Associated with advanced age & microvascular complications

Answer 33

Adiponectin: protective, reduces levels of free fatty acids Leptin: informs hypothalamus about amount of fat TNF-alpha: insulin receptor signalling interference IL-6: insulin receptor signalling interference

Answer 34

* Autosomal dominant * HNF-1-alpha: reduction in insulin production * Glucokinase: higher levels of glucose * HNF-4-alpha: reduction in insulin production * HNF-1-beta: reduction in insulin production * Neonatal: mutation affecting potassium channel

Answer 35

* Pancreatitis * Haemochromatosis * Cystic fibrosis * Steroid-induced * Acromegaly

Answer 36

Symptoms * Polydipsia, polyuria, nocturia * Weight loss * Fatigue * Loss of muscle bulk Family history - Suscepibility genes e.g. HLA DR3/4-DR2/8 Precipitating events - Bacteria, viruses (esp Coxsackie), cow’s milk, wheat proteins, vitamin D deficiency… Associated with other autoimmune conditions e.g. thyroid, coeliac

Answer 37

* Fasting blood glucose Normal: <=6mmol/L Impaired: 6.1-6.9mmol/L Diabetes: >=7mmol/L * Oral glucose tolerance test Normal:<=7.7mmol/L Impaired:7.8-11mmol/L Diabetes:>=11.1mmol/L * Glycosylated haemoglobin (HbA1c): average blood glucose over previous 2-3 months Pre-diabetes: 42-47mmol/mol Diabetes:>=48mmol/mol

Answer 38

* Inhibition of hepatic gluconeogenesis via inhibition of hepatic mitochondrial function * Side-effects Anorexia, nausea Diarrhoea Lactic acidosis

Answer 39

E.g. glibenclamide, gliclazide, glimepiride… Inhibit the ATP-sensitive potassium channel to increase insulin secretion Side-effects Weight gain Hypoglycaemia

Answer 40

E.g. pioglitazone Ligand for PPAR-gamma (peroxisome proliferator activated receptor gamma) PPAR-gamma is a transcription factor for triglyceride storage Thiazolidinediones stop inappropriate deposition of lipids in non-adipose tissues (which leads to insulin resistance) Side-effects Weight gain Anaemia Osteoporosis

Answer 41

E.g. acarbose Prevents hyperglycaemic peaks following a meal Prevents the cleavage of alpha glycosidic bonds in starch, slowing digestion Side-effects Flatulence Abdominal distension Diarrhoea

Answer 42

Incretins are gastrointestinal hormones that potentiate insulin secretion * Glucagon-like peptide 1 (GLP-1) Brain - promote satiety and reduces appetite Beta cells - enhances glucose-dependent insulin secretion in the pancreas Alpha cells - suppresses post-prandial glucagon secretion Liver - reduces hepatic glucose output Stomach - slows rate of gastric emptying * Gastric inhibitory peptide Rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4)

Answer 43

E.g. exenatide, liraglutide Mimic incretins but are not cleaved by DPP-4 Improve insulin secretion

Answer 44

E.g. sidagliptin, vildagliptin Inhibit DPP-endogenous incretin-mediated increase in insulin Side-effects: nausea and increased risk of heart failure

Answer 45

E.g. canagliflozin, empagliflozin, dapagliflozin Inhibit SGLT2 in PCT, increasing excretion of glucose in the urine (glycosuria), reducing hyperglycaemia Also reduces BP; cardioprotective Side-effects Genital candidiasis Dehydration DKA

Answer 46

* Flash glucose measuring (FGM)-FreeStyle Libre device Measures interstitial glucose every minute Doesn’t interrupt insulin flow Best for trends; high and low blood glucose alarms * Continuous glucose monitoring (CGM) Measures interstitial glucose every 5 minutes & communicates w/ insulin pump to adjust dose

Answer 47

* Conventional regime Injection 2x day No flexibility - same type of food at same time + no exercise mixed insulin (1/3 fast-acting, 2/3 long-acting) * Basal-bolus regime Intensive regime injections 4x day Long-acting insulin at night & fast-acting bolus with each meal Resembles physiological insulin release

Answer 48

* Insulin pump aka CSII (continuous subcutaneous insulin infusion) Only rapid-acting insulin (Novorapid) Delivers multiple basal rates, microboluses + correction doses Disadvantages: commitment, regular testing, CHO counting skills * Sensor augmented pump Sensor on the abdomen sends information to pump so it can adjust settings Predicted low glucose suspend - if the algorithm detects that the person will become hypoglycaemic, it suspends insulin

Answer 49

* Insulin deficiency blocks glucose uptake in peripheral tissues Proteolysis provides amino acids for gluconeogenesis Lipolysis leads to an increase in fatty acids delivered to hepatocytes; converted to acetyl CoA > acetoacetate > ketone bodies (ketosis) * Results in metabolic acidosis (pH < 7.3) as acidic ketone bodies reduce plasma pH * Increased renal excretion of H+ initially, then loss of bicarbonate ions (<15mmol/L) * Increased respiratory rate + later Kussmaul breathing (low pCO2 due to respiratory compensation) * Impaired renal compensation with worsening acidosis & renal hypoperfusion * Hyperglycaemia, osmotic diuresis and counterregulatory hormones

Answer 50

* Glucose and ketones freely filtered at the glomerulus * Maximum reabsorption threshold for glucose is exceeded * Increased solute concentration in tubular lumen causes osmotic gradient * Increased water loss in urine - profound dehydration (vomiting contributes to this) * Hyperaldosteronism arises as a result: increased potassium loss due to lack of GI and renal absorption * Serum potassium may be normal or high despite the depletion (lack of insulin prevents potassium from moving into cells)

Answer 51

Adrenaline * Glycogenolysis * Gluconeogenesis * Lipolysis Cortisol and growth hormone * Gluconeogenesis * Lipolysis * Inhibition of peripheral glucose uptake

Answer 52

* Hypovolaemia: IV fluids * Hyperglycaemia: IV insulin (after fluids), add 10% dextrose Start when plasma glucose is stable as fluids can make glucose fall * Potassium depletion: IV potassium chloride * Supportive NG tube Antiemetics Treat underlying cause

Answer 53

* Insulin deficiency, but sufficient to suppress lipolysis * Blockage of glucose uptake in peripheral tissues leads to hyperglycaemia * This drives osmotic diuresis & dehydration * Chronic renal impairment is common * Longer onset so more profound hypovolemia * Impaired thirst mechanism leads to lack of water replacement * Risk of central pontine myelinolysis and cerebral oedema due to large fluid shifts

Answer 54

DKA * Short history * Patient < 65 y/o, usually type I DM * No residual insulin * Hyperglycaemia & dehydration * Acidosis * Patient usually alert HHS * Insidious history * Patient > 65 y/o, usually type II DM * Residual insulin * Profound hyperglycaemia, dehydration and hypernatraemia * No acidosis * Patient often drowsy

Answer 55

* Causes Diabetes & drug-induced (diabetes medication) Insulinoma Excessive alcohol consumption Severe liver disorders e.g. cirrhosis, hepatitis Hormone deficiencies (adrenal and pituitary tumours) * Symptoms Initial - autonomic Tremor and sweating (mediated by adrenaline) Hunger (mediated by ACh and noradrenaline) Palpitations and anxiety Late - neuroglycopaenic Confusion and impaired consciousness level

Answer 56

* Mild (BM < 4mmol) 15-20g of fast-acting carbohydrate - Severe 15-20g of fast-acting carbohydrate If reduced consciousness level: IM glucagon (associated w/ nausea, vomiting) IV dextrose

Answer 57

Associated with frequent episodes of hypoglycaemia Unclear mechanism Autonomic dysfunction: no longer present with autonomic hypoglycaemic symptoms Complications: Nocturnal hypoglycaemia Driving restrictions

Answer 58

* Capillary damage Hyperglycaemia leads to structurally and functionally abnormal vessels > Increased capillary pressure > Thickened and damaged vessels > Endothelial damage w/ leakage of albumin & other proteins * Metabolic damage Most tissues need insulin to take up glucose but kidneys, retina and nerves don’t Glucose is absorbed and metabolised to sorbitol by aldose reductase Excessive glucose enters polyol pathway Sorbitol accumulates > less NADPH for cell metabolism > buildup of ROS and oxidative stress > cell damage

Answer 59

* Early (non-proliferative) Hyperglycaemia causes damage to small vessel wall & microaneurysms When vessel wall is breached, dot haemorrhages appear Protein and fluid left behind lead to hard exudates Micro-infarcts result in cotton wool spots * Later Damage to veins leads to venous budding and blockage of blood supply Proliferative retinopathy: ischaemia stimulates the production of VEGF > Neovascularisation and vitreous haemorrhage Fluid not cleared from macula results in macular oedema

Answer 60

* Prevention Stop smoking Good blood pressure control, good glycaemic control - Treatment Address risk factors Ophthalmic review > Laser > VEGF inhibitors (bevacizumab) > Vitrectomy

Answer 61

* Peripheral (sensory) neuropathy: most common Capillary damage including occlusion in the vasa nervorum Reduced blood supply to neural tissue leads to impairment in nerve signalling Affects sensory & motor function * Autonomic neuropathy > Cardiovascular: postural hypotension > Genitourinary: erectile dysfunction > Gastrointestinal: gastroparesis, gustatory sweating * Mononeuritis multiplex Painful, asymmetrical, asynchronous sensory & motor peripheral neuropathy Isolated damage to at least 2 separate nerve areas * Diabetic amyotrophy Pain & muscle wasting in thighs, hips, buttocks & legs

Answer 62

* Signs Diminished vibratory perception Decreased knee & ankle reflexes Reduced protective sensation e.g. heat, pain, pressure Diminished ability to sense position of toes and feet - Symptoms Numbness Prickling/tingling Aching/burning/lancinating pain Allodynia (unusual sensitivity to non-painful stimuli) esp in feet

Answer 63

* Renal hypertrophy and increased GFR Afferent arteriole vasodilates > increased glomerular pressure & thickening of basement membrane > capillary damage, shear stress on endothelial cells * Microalbuminuria Leakage of protein into urine (tiny traces of albumin) Calculate ACR (albumin:creatinine ratio) If present, treat with ACE inhibitor or ARB (angiotensin receptor blocker) to prevent progression to macroalbuminuria * Macroalbuminuria * End-stage renal failure

Answer 64

* Combination of neuropathy and peripheral vascular disease > Ulcers > Infection > Ischaemia Treatment * Debride (chiropodist) * Pressure relief (orthotist) * Treat infection * Circulation

Answer 65

* Numb foot Repetitive microtrauma Stress fractures * Dysregulated blood flow Increased bone turnover; fragile bone Treatment - Immediate immobilisation in plaster cast

Answer 66

* Coronary heart disease * Ischaemic heart disease * Congestive heart failure * Peripheral arterial disease

Answer 67

* Infections: fungal infection, influenza, pneumonia * Degenerative diseases * Depression * Cognitive disorders * Cirrhosis * Colon cancer

Answer 68

* Down a concentration gradient via facilitated diffusion using transporters (GLUT1-4) * Against a concentration gradient using energy provided by co-transport with sodium (SGLT1 & 2) > Absorbs glucose from gut lumen & reabsorbs glucose in kidney > Requires ATP for Na/K-ATPase to maintain electrochemical gradient

Answer 69

GLUT1: ubiquitous Molecules: glucose & galactose GLUT2: liver, pancreatic beta cell, kidney, small intestine Molecules: glucose, galactose, fructose GLUT3: brain, placenta, testes Molecules: glucose and galactose GLUT4: skeletal and cardiac muscle; adipocytes Molecules: insulin-responsive; high affinity for glucose GLUT5: in small intestine & sperm Molecules: fructose

Answer 70

Synthesis of * Fatty acids: generation of NADPH for reductive biosynthesis * Nucleotides (RNA, DNA): formation of ribose-5-phosphate Dehydrogenation of glucose-6-phosphate is the committed step

Answer 71

* Glucose converted to G6P via glucokinase * G6P converted to G1P via phosphoglucomutase * G1P converted to UDP-glucose using glucose-1-phosphate uridiyltransferase * UDP-glucose converted to glycogen using glycogen synthase (highly regulated)

Answer 72

* Glycogen converted to G1P using glycogen phosphorylase (highly regulated) * G1P converted to G6P via phosphoglucomutase

Answer 73

* Noradrenaline: liver and muscle Inhibits glycogen synthase and stimulates glycogen phosphorylase * Insulin: liver and muscle Secreted in response to high glucose Increase glucokinase, PFK, glycogen synthase Decrease G6Pase, F1,6bPase, PEPCK, glycogen synthase * Glucagon: liver Secreted in response to low glucose Decrease glucokinase, PFK, pyruvate kinase & glycogen synthase Increase G6Pase, PEPCK, F1,6bPase & glycogen phosphorylase

Answer 74

Synthesis of glucose from a non-carbohydrate source, occurs in the liver * Lactate: converted to pyruvate first * Pyruvate * Glycerol: converted to DHAP, intermediate in glycolysis * Certain amino acids: converted into pyruvate or various TCA cycle intermediates

Answer 75

Pyruvate converted to oxaloacetate using pyruvate carboxylase (PCOX) Oxaloacetate converted to phosphoenolpyruvate using phosphoenolpyruvate carboxykinase (PEPCK) Phosphoenolpyruvate converted to Fructose-1 6-bisphosphate using Fructose-1 6-bisphosphatase (F1, 6bPase) Fructose-1 6-bisphosphatase converted to fructose-6-phosphate Fructose-6-phosphate converted to glucose-6-phosphate Glucose-6-phosphate converted to glucose using glucose-6-phosphatase (G6Pase)

Answer 76

* First synthesised as a long polypeptide (preproinsulin) * Signal sequence is lost, forming proinsulin * Covalent links are formed between sulphydryl groups on cysteine residues * C-peptide chain is cleaved to form mature insulin > 2 polypeptide chains linked by sulphur bridges

Answer 77

Long precursor - proglucagon Alpha cell cleaves proglucagon into glucagon and other products Intestinal L cells and some neurons will cleave it differentially leading to the production of GLP-1 and GLP-2

Answer 78

Insulin binds to the insulin receptor (tyrosine kinase) found primarily in liver, striated muscle & adipocytes; receptor dimer autophosphorylates Phosphorylated tyrosine residues on the insulin receptor act as binding sites for other proteins (insulin receptor substrates) IRSs become phosphorylated by the insulin receptor, starting the signal transduction cascade Phosphatidylinositol-3’-kinase (PI3K) is activated Activates protein kinase B (Akt/PKB) Results in GLUT4 translocation to the cell membrane & transport of glucose into the cell

Answer 79

Glucagon binds to a G-protein coupled receptor (GPCR) found in hepatocytes Activates adenylyl cyclase Increases cyclic AMP cAMP stimulates cAMP-dependent protein kinase A (PKA)

Answer 80

Insulin stimulates fatty acid and triglyceride synthesis * Increases expression of fatty acid synthase, acetyl CoA carboxylase * Increases activity of lipoprotein lipase in adipocytes Also stimulates breakdown of cAMP: noradrenaline no longer able to stimulate lipolysis

Answer 81

* Glucose (6C) is broken down into glucose-6-phosphate via glucokinase * Glucose-6-phosphate is converted to fructose-6-phosphate using phosphoglucose isomerase * Fructose-6-phosphate is metabolised to fructose-1 6-bisphosphate via phosphofructokinase-1 (commitment step)

Answer 82

Fructose-1 6-bisphosphate is metabolised by aldolase into 2x 3C sugars: * Dihydroxyacetone phosphate: metabolised to glyceraldehyde-3-phosphate by triose phosphate isomerase * Glyceraldehyde-3-phosphate Glyceraldehyde-3-phosphate converted to 1,3-bisphosphoglycerate by glyceraldehyde-3-phosphate dehydrogenase 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate using phosphoglycerate kinase > converted to 2-phosphoglycerate (phosphoglyceromutase) converted to phosphoenolpyruvate (enolase) converted to pyruvate (pyruvate kinase)

Answer 83

Not present: anaerobic glycolysis - Pyruvate converted to lactate using lactate dehydrogenase Regenerates NAD+ to keep glycolysis going 2x ATP generated Present: aerobic glycolysis * Pyruvate transported into mitochondrion * Pyruvate + coenzyme A make acetyl coenzyme A via decarboxylation using pyruvate dehydrogenase * Produces 1x CO2 and 1x NADH + H+ * Requires vitamins as co-factors (thiamine) * Acetyl CoA then enters TCA cycle

Answer 84

* Esterification of 3 fatty acids + glycerol * Lipoprotein lipase hydrolyses triglycerides in chylomicrons/LDL on cell surface to provide fatty acids * Diacylglycerol acyl transferase (DGAT) re-esterifies fatty acids to triglycerides in cell to add to a lipid droplet * Glycerol derived from DHAP (glycolysis)

Answer 85

* Breakdown of triglyceride into glycerol + 3 fatty acids * Performed by hormone sensitive lipase (HSL) in adipose tissue * HSL is activated by cAMP-dependent phosphorylation (PKA) in response to noradrenaline in the fasted state * Inhibited by insulin

Answer 86

* Fatty acids are built 2 carbons at a time (limit is 16C) * Key regulatory enzymes > Acetyl CoA Carboxylase Fixes bicarbonate onto acetyl coA (uses ATP & biotin/vitamin B7) Forms malonyl CoA (Inhibits fatty acid oxidation via carnitine palmitoyl transferase) > Fatty Acid Synthase (FAS) 7 successive steps by multifunctional FAS Active in cytoplasm of lipogenic tissues Requires NADPH

Answer 87

To be transported into mitochondria, CoA is added to free fatty acids by acyl CoA synthetase > fatty acyl CoA To cross the inner mitochondrial membrane, fatty acids are shuttled across using the carnitine shuttle (carnitine palmitoyl transferase) CoA is replaced with carnitine using CPT I > fatty acyl carnitine Enters mitochondrial matrix and carnitine is replaced with CoA using CPT II > fatty acyl CoA In beta oxidation, carbon backbone is cleaved between alpha and beta carbons producing acetyl CoA for TCA cycle & 1x NADH, 1x FADH2

Answer 88

When fat is oxidised due to glucose unavailability, ketones are formed Examples: acetoacetate, beta-hydroxybutyrate, acetone Used by other tissues as a source of acetyl CoA (therefore ATP) Acetyl CoA + acetyl CoA = acetoacetyl CoA Acetoacetyl CoA - CoA = acetoacetate (can be converted to acetone & beta-hydroxybutyrate)

Answer 89

* Chylomicrons (synthesised in gut after a meal) Carry triglycerides from intestines to liver, muscle & adipose tissue * VLDL (very low density lipoprotein - synthesised in liver) Carry endogenously-synthesised triglycerides from liver to adipose tissue * IDL (intermediate density lipoprotein) * LDL (low density lipoprotein - synthesised in circulation from VLDL) Major cholesterol reservoir; taken up via LDL receptors on cells * HDL (high density lipoprotein - synthesised in liver) Absorb cholesterol released by dying cells “Reverse transport” to return cholesterol to liver; reduces circulating cholesterol

Answer 90

* Intestine Chylomicrons transport large lipids out of intestine via lacteals & drain into thoracic duct - Circulation Lipoprotein lipase (LPL) in capillary endothelium removed 3 fatty acids (stored in adipose tissue), leaving a chylomicron remnant (expresses ApoE protein) * Liver ApoE interacts with counterreceptor on liver & enters Chylomicron remnant is broken down & stored as free fatty acids and cholesterol

Answer 91

* Liver If lipids are required, cholesterol and free fatty acids can be made into a VLDL particle * Circulation VLDL can be acted on by LPL (removes 3 fatty acids for storage in adipose tissue) making IDL * Liver IDL acted on by hepatic lipase to form LDL * Peripheral tissue Tissues requiring LDL cholesterol express LDL receptors on their surface

Answer 92

* Same as triglyceride synthesis until diacyl glycerol (DAG) is made * Then combined with an alcohol Examples: * Phosphatidylinositol * Phosphatidylcholine * Phosphatidylserine

Answer 93

Essential fatty acids cannot be synthesised; obtained from diet e.g. polyunsaturated omega-3, omega-6 Functions: * Cell membrane formation * Proper growth & development * Brain & nerve function * Precursor for eicosanoids - prostanoids & leukotrines - needed in the inflammatory response

Answer 94

* Derived from endoderm; develops from 2 buds which emerge from the foregut * Ventral pancreatic bud: forms neck, body and tail of pancreas * Dorsal pancreatic bud: forms head & uncinate process of pancreas * Point of fusion between 2 buds creates pancreatic duct * During development, cells of the embryonic pancreas migrate from duct system and aggregate around capillaries > Create clusters nestled amongst the glandular tissue - islets of Langerhans

Answer 95

* Alpha cells: produce glucagon * Beta cells: produce insulin and amylin (slows gastric emptying, preventing hyperglycaemic peaks) * Delta cells: produce somatostatin * Epsilon cells: produce ghrelin, which stimulates hunger * Gamma cells: produce pancreatic polypeptide, which regulates exocrine & endocrine pancreatic secretion * VIP (vasoactive intestinal polypeptide) cells

Answer 96

* Head * Uncinate process: posterior to superior mesenteric artery + vein * Neck: sits on superior mesenteric artery + vein; behind neck, superior mesenteric vein + splenic vein join to form the hepatic portal vein * Body: * Tail: makes contact with the spleen & lies in splenorenal ligament

Answer 97

* Splenic artery: travels behind loops at superior border; branches include the arteria pancreatica magna * Superior and inferior pancreaticoduodenal arteries: supply head & uncinate process

Answer 98

* 2 highly vascular lobes on either side of trachea connected by isthmus + pyramidal lobe * Surrounded by thin fibrocollagenous capsule: septa extend inwards separating the gland into lobes * Contains follicles made up of a single layer of cells surrounding a lumen which contains colloid (largely thyroglobulin)

Answer 99

* When stimulated, follicular cells become columnar and lumen is depleted of colloid via endocytosis * Colloid cleaved by proteases within follicular cells, releasing thyroglobulin from T3 & T4 * T3 & T4 enter circulation, thyroglobulin recycled back to lumen * When suppressed, follicular cells become squamous and colloid accumulates in the lumen

Answer 100

Main storage mechanism for thyroid hormones Synthesised in rER of thyroid epithelial cells and secreted into lumen of follicle (colloid) Polypeptide backbone for synthesis and storage of thyroid hormones Iodine attachment to tyrosine residues on thyroglobulin is the preliminary step in thyroid hormone formation

Answer 101

* Iodide actively transported into follicular cells by sodium iodide transporter on basolateral membrane > diffuses to apex of cell & transported by prendrin into vesicles > fusion with apical cell membrane * Iodide oxidised to iodine > attaches to tyrosine residues on thyroglobulin * Process of organification happens, catalysed by thyroid peroxidase, in the presence of hydrogen peroxide in apical colloid facing cells * Forms monoiodotyrosine & diiodotyrosine (MIT/DIT) > 2x DIT form T4, 1x MIT + 1x DIT form T3 * Endocytosis of thyroglobulin, release of T3 & T4 after droplets fuse with lysosome and thyroglobulin is hydrolysed

Answer 102

Triiodothyronine (T3) acts at the cellular level (active hormone) L-thyroxine (T4) is a pro-hormone (released in greatest quantity) > deiodinated to T3 by deiodinase in the periphery (5’ deiodination, outer ring) Reverse T3 is produced by 5’ deiodination of the inner ring Different deiodinases found in different organs, allowing local control

Answer 103

* Free (0.5%) * Bound (99.5%) Bound to thyroglobulin, transthyretin and albumin

Answer 104

Cytosolic T3 is transported to the nucleus and binds to thyroid hormone nuclear receptor (TR) which influences gene expression Nuclear receptor binds T3 more avidly than T4 Alpha and beta T3 receptors vary between tissues > beta T3 found in brain, heart, liver, kidneys, pituitary Influence almost every system * Determinants of brain and somatic development * Skeletal: bone turnover * Cardiovascular: heart rate * Metabolic: lipids & glucose

Answer 105

* Calcitonin is produced by parafollicular cells (aka C cells or clear cells) * Peptide hormone which regulates calcium levels: > inhibits osteoclast activity > physiological antagonist to PTH > Inhibits renal calcium reabsorption

Answer 106

* Excess thyroid hormone production Causes: > Autoimmune - Graves' disease > Thyroiditis > Toxic adenoma > Multinodular goitre > Excess administration of thyroxine

Answer 107

* Low TSH high T4, primary cause is Graves’ disease * Weight loss * Tremor, sweating * Heat intolerance * Diarrhoea * Tachycardia, atrial fibrillation, warm peripheries * Hypertension * Palpitations

Answer 108

- Graves' ophthalmopathy Lid retraction and periorbital oedema Proptosis (exophthalmos) Diplopia Nerve compression (rare) * Pretibial myxoedema * Thyroid acropachy

Answer 109

* Anti-thyroid drugs > Thionamides: carbimazole, propylthiouracil * Surgery > Thyroidectomy * Radioactive iodine: destroys thyroid tissue in beta emission * Beta-blockers: sympathetic nervous system symptoms * Steroids: if thyroiditis or thyroid storm * Iodine: blocks hormone release (short-term)

Answer 110

* Inhibit iodide oxidation * Inhibition of thyroid peroxidase > Inhibit iodination of tyrosine > Inhibit coupling of iodotyrosines Carbimazole: Metabolised to methimazole via first-pass metabolism Side-effect: aplasia cutis, avoid during pregnancy Propylthiouracil: Side-effects: possible hepatotoxicity Side-effects for both: agranulocytosis (rare) & rash

Answer 111

* Autoimmune: Hashimoto’s thyroiditis * Thyroidectomy * Thyroiditis (viral) * Follow radio-iodine therapy * Drug-induced e.g. amiodarone, lithium, sunitinib * Secondary hypothyroidism (pituitary disease) * Severe iodine deficiency

Answer 112

* Hypotension & bradycardia * Cold intolerance * Depression, lethargy, poor concentration * Weight gain * Constipation * Hoarseness * Menorrhagia * Goitre * Dry skin and coarse thin hair * Anaemia * Slow relaxing reflexes

Answer 113

* Levothyroxine, metabolised to T3 Goals: euthyroid - resolve symptoms & normalised TSH Full suppression of TSH associated with atrial fibrillation and osteoporosis

Answer 114

Pituitary enlargement can result in compression of: * Optic canal (anterior) * Foramen spinosum - middle meningeal artery * Carotid canal - internal carotid (posterolateral) * Foramen ovale: mandibular branch of trigeminal nerve

Answer 115

Usually 4 endocrine glands on the posterior surface of the thyroid gland (range 2-6) Embedded in a fibrous capsule (their own or the thyroid’s); separated into nodules by thin fibrous septa Blood supply: inferior thyroid arteries Venous drainage: parathyroid veins

Answer 116

* Chief cells (aka principal cells) Detect ionised calcium levels and produce parathyroid hormone * Water clear cells Resting clear chief cells; contain pools of glycogen * Oxyphil cells: unknown function

Answer 117

Diffuse, irregular enlargement of the thyroid gland; moves when swallowing Characterised by hypertrophy & colloid cyst formation Can be caused by low iodine levels but patient can present with normal thyroxine

Answer 118

* Diabetic retinopathy Every year since age 12, if sight is threatened refer to ophthalmology * Diabetic nephropathy Every year since diagnosis, test for microalbuminuria > If present give ACE inhibitor or ARB * Diabetic neuropathy Check vibration sense, reflexes & pain every year > Review schedule is determined by risk Low: normal sensation and pulses, annual review Medium-moderate: absent pulses or neuropathy, every 3-6 months High: deformities or ulceration, every 1-3 months

Answer 119

DCCT: patients with type 1DM, conventional v intensive (basal bolus) UKPDS: patients with type 2DM, conventional v intensive Both trials show that intensive glycaemic control lowers HbA1c and reduces risk of microvascular complications (short-term) and cardiovascular disease (long-term)

Answer 120

* Maintenace therapy Oral - low bioavailability Sublingual Intranasal * Acute therapy Subcutaneous Intramuscular Intravenous (variceal bleeding/shock)

Answer 121

* Short-acting: usually for meal times to cover quick-acting carbohydrates Human e.g. Humulin S Animal e.g. Hypurin bovine neutral Analogues e.g. Novorapid * Intermediate/long-acting * Pre-mixed (short + long-acting insulin), given 2x/day

Answer 122

* Subcutaneous injection (common with pre-filled pens/cartridges) * Continuous subcutaneous insulin infusion (CSII) * Intravenous (acute illness) * Intramuscular

Answer 123

Hydrocortisone * Closest to physiological cortisol * Equal glucocorticoid & mineralocorticoid action Prednisolone - 4x glucocorticoid effect Dexamethasone & betamethasone - 30x potency of hydrocortisone, no mineralocorticoid effect Routes of administration - Topical, nasal, inhaled, oral, subcutaneous, intramuscular, intravenous

Answer 124

* Derived from enzymatic modification of cholesterol > Cholesterol is taken up from circulation or synthesised de novo from acetyl CoA > Rate-limiting step in cholesterol synthesis is HMG CoA reductase > Cholesterol is also taken up by cell as LDL, later broken down into esterified cholesterol and free cholesterol * Synthesis occurs mainly in mitochondria and smooth ER * Not stored prior to secretion as steroid hormones are lipid soluble * Immediately released upon synthesis & circulate in blood

Answer 125

Circulating oestrogens are a mixture of oestradiol and oestrone * Oestrone is secreted directly from ovary or converted from androstenedione * Oestradiol produced by the ovary is derived by direct synthesis in developing follicles or conversion of oestrone via aromatase

Answer 126

E.g. testosterone, dihydrotestosterone, androstenedione, dehydroepinandrosterone (DHEA) Synthesised from cholesterol in the testes, ovaries and adrenal gland

Answer 127

Synthesised from cholesterol & produced primarily in corpus luteum, placenta and adrenal glands

Answer 128

* Steroid hormone enters target cells and binds to a steroid hormone receptor (nuclear receptor superfamily) * Hormone-receptor complex enters the nucleus & acts as a transcription factor * Binds to a glucocorticoid response element (DNA sequence) in the 5’ flanking region of target genes * Binding initiates gene transcription to produce mRNA, which travels to cytoplasm and is translated into proteins > cell response

Answer 129

A/B: N-terminal domain C: DNA binding domain; contains 2 zinc fingers to bind DNA sequences D: Hinge region; controls movement of receptor to nucleus E: Ligand-binding domain; binds steroid F: C-terminal domain

Answer 130

Cortisol can bind to the mineralocorticoid receptor and its concentration is much higher than that of aldosterone Mechanism is needed to protect the mineralocorticoid receptor from illicit occupation by glucocorticoids 11 beta hydroxysteroid dehydrogenase (11-beta HSDII) catalyses the conversion of cortisol to cortisone (inactive) in selective tissues e.g. kidney > Allows aldosterone to function normally (enzyme inhibited by liquorice)