Endocrinology Flashcards
In a pituitary adenoma, which is the first hormone to fall?
Gonadotrophins (sex hormones), then GH and ACTH. ACTH rarely falls due to an anterior pituitary adenoma.
Prolactin increases!
What is the Mx for a pt with metastatic insulinoma (inoperable) having hypos?
Somatostatin
What is the most common cause of a hot nodule (one are lighting up on technetium thyroid scan?
Activating somatic mutations of the TSH receptor
What is the most common cause of hyperosmolar hypnoatraemia?
Hyperglycaemia
Is the urine dilute or concentrated in DI?
Dilute
Cannot concentrate urine in DI
Urine osmo > 600
Urine osmo
T/F. Hyponatraemia is associated with OP.
True
Vasopressin is an effective Tx for hyponatraemia? T/F
True
Hyponatraemia with urine Cosmo
Primary polydipsia
Low solute intake
Beer protomania
Hyponatraemia with urine osmo >=100. Urine Na
Means low effective arterial blood volume If ECF expanded consider - HF - LF - nephrotic sundrome
If ECF reduced, consider
- Diarrhoea, vomiting
- Third spacing
- remote diuretics
Hyponatraemia with urine osmo >= 100, Urine Na >30 mol/L. DDx?
Diuretics or kidney disease. If no, then consider: If ECF reduced consider: - Vomitng - primary adrenal insufficiency - renal salt wasting - cerebral salt wasting -occult diuretics
If ECF normal, consider
- SIADH (euovolaemic hypotonic hyponatraemia with inappropriately dilute urine and normal renal Na handling)
- secondary adrenal insufficiency
- occult diurectis
What changes do you get with anorexia nervosa in regards to: LH, FSH, oestrodial and testerone GH Cortisol TSH, T3, T4, rT3
Low LH, FSH oestrodial and tester one
High GH, low OGF-1
High cortisol due to hypothalamic-pituitary renal axis activation
Low/normal TSH, low T3, rT3 is high
Paragnagliomas. DDx for sympathetic PGL and parasympathetic ganglioma?
Sympathetic PGL - adrenal: phaeo 70% - Extraadrenal 10% Parasympathetic - Head and Neck PGL. Carotid tumours
What is the management of a pituitary adenoma on MRI?
Basic WU - PRL, IGF-1
Macro, >1 cm 0.2%. Clinical evaluation for hypopit/hypersecretion, mass effect.
Growth over time occurs in 10%
Why is PTU preferred in the 1st trimester of pregnancy?
Carbimazole embryopathy
Why is thionamide (carbimazole) preferred in 2nd trimester?
Hepatic toxicity of carbimazole
How much should you increase thyroxine in pregnancy?
Increase by 30%.
What are the changes in TSH, TBG in pregnancy?
TSH decreased in 1st TM
Oestrogen increase TBG
MOA of Na-glucose cotransporter 2 (SGLT2) inhibition?
Action on promximal tubule. Inhibits glucose absortpion -> glycosuria
Dabagliflozin/canagliflozin
Inhbits HbA1c lowering by 0.5-1.0%
No hypoglycaemia
200-600 ml extra fluid loss so caution with loop diuretic
Risk of genito-urinary infection esp women 8% vs 1%
What are the adverse effects of testosterone replacement?
Erthrocytosis/elevated haematocrit is a CI. Common AE.
Increased CV events in TT
Worsens untreated cases if OSA
Somatostatin analogues. MOA of Somatostatin, Pasireotide, Octreotide/Lantrotide?
Somatostatin act primarily through 1,2,3,4,5 receptor somatostatin subtypes
Pasireotide act primarily through 1,2,3 and 5 receptor somatostatin subtypes
Lantreotide/Octreotide act primarily through 2 SS receptor type
What somatostatin expression is excreted by a GH screwing, cortisol secreting, promactinoma and carcinoid tumour?
carcinoid SST2
GH-secreting - SST2 and SST5
Cortisol secreting SST5
Prolactinoma SST5
What are the risk associated with oestrogen replacement therapy in post menopausal women?
Stroke, VTE
Fracture risk decreased
What are the risk associated with oestrogen replacement therapy in post menopausal women?
CAD Stroke VTE Breast cancer Fracture risk and colorectal cancer risk decreased
Is transdermal or oral route preferred in post menopausal HT?
Transdermal as less AE
What tests are performed for Pheo? which medications interfere with the test?
24 hr fractionated catecholamines/metanephrines (sen and spec)
Plasma fract metanephrines (sen but not specific)
Interference - nicotine, paracetamol, sotalol, methyldopa, TCAs
Chromogranin A is secreted by pheo and elevated in 80% of cases
What are the Ddx in Hypophosphataemia in 24 hour urine low PO4 and high PO4?
Low urine = appropriate = intestinal (decreased intake, EtOH, Vit D def, PO4 binders) or cellular shift (referring syndrome, glucose infusion, salicylate poison, hyperventillation, catecholamines, resp alkalosis)
High urine = inappropriate = renal wasting -> HPTH or tubular defect e.g. FGF23 medicated Tumour induced osteomalacia if 1,25D low
What are the most specific signs of Cushing’s syndrome?
Skin atrophy
Striae
Easy brusing
Proximal myopathy
What are the expected levels (high/low) for the following disease for ACTH, Cortisol, High dose DST, MRI?
Cushing’s disease Ectopic ACTH Adrenal adenoma Adrenal carcinoma Iatrogenic glucocorticoids Primary adrenal insufficiency Secondary adrenal insufficiency
Cushing’s disease - ACTH normal/high, Cortisol high, DST suppressible, MRI adenoma
Ectopic ACTH - ACTH high, cortisol high, DST not suppressible, MRI NAD
Adrenal adenoma - ACTH low, cortisol high, DST N/A, Adenoma
Adrenal carcinoma- ACTH low, cortisol high, DST N/A, carcinoma
Iatrogenic glucocorticoids - Low/undetectable ACTH, cortisol low/undetectable, urine cortisol high
Primary adrenal insufficiency - ACTH high, cortisol low
Secondary adrenal insufficiency - ACTH low/Normal, cortisol low
Which drug can induce Cushing’s syndrome?
ARVT in HIV
What changes do you expect with Renin and Aldosterone in:
- primary hyperaldosteronism e.g. bilateral adrenal hyperplasia 60%, Conn’s 35%, familial hyper, pure aldos producing adenoma
- secondary hyperaldosteronism e.g. renal artery stenosis, diurectis
- apparent mineralocorticoid excess?e.g. exogenous mineralo, cushing’s sydnrome, Licorice, Liddle (activating mutation of collecting tubule sodium channel
1 = renin low, aldosterone high
- Renin high, aldosterone high
- renin low, aldosterone low
Pt has been on zoledronic acid for 3 years or 5 years of alendronate/risedronate. Nest step?
If DEXA -2.5, can cease Tx and DEXA in 2 years
When should you start bisphosphonate on a pt on steroid therapy?
If > 3months duration and > 7.5 mg/d with T score
MOA PTU?
blocks conversion of thyroxine to triiodothyronine in peripheral tissue
does not inactivate existing thyroxine and triiodothyronine stores in circulating blood)
MOA Carbimazole?
a prodrug after absorption and is converted to the active form methimazole. Prevents thyroid peroxide enzyme by couling and iodinating tyrosine residues on thyroglobulin hence reducing the production of T3 and T4 (thyroxine)
Tx of thyroid storm (Thyrotoxicosis crisis)?
Most important management is large amounts of glucocorticoids
IV propanolol to interrupt the physiologic response to excess thyroid hormone
High dose thionamide (PTU or carbimazole) to block new hormone synthesis
Iodide - blocks release of preformed hormones
Iodinated contrast agent, propanolol and corticosteroids to block peripheral conversion of T4-T3
PTU blocks conversion but not carbimazole.
Klinefelters. Genetic mutation, Clinical presentation?
The most common congenital abnormality causing primary hypogonadism.
Most common genotype is 47, XXy, extra X chromosome.
Clinical:
Gynaecomastia
Small firm testes
Behavioural and learning abnormalities
Shy, tall, awkward
Fragile X. Mutation? Clinical presentation?
X-linked disorder.
Most fequent form of inherited intellectual disability.
Caused by decreased or absent levels of fragile X mental retardation protein (FMRP) due to loss of function mutation in the fragile X mental retardation 1 (FMR1) gene located at Xq27.3.
Loss of function caused by unstable expansion of CGG repeat at 5’untranlated region.
Clinical: Long and narrow face Prominent forehead and chin (prognathism) large ears testicular enlargement (vol > 25 ml) Developmental delay Delayed language development ADHD, anxiety and ASD
Benefits of metformin?
Glycaemic efficacy No weight gain No hypos General tolerability Favourable cost
T1DM having elective procedure. Mx of long acting basal insulin the night before?
Halve the dose
MOA of insulin?
Insulin binds to heterotetrameric receptor on the cell membrane of target cells.
Binding results in conformational change of the alpha-subunits that enables ATP binding to the beta subunits intracellular domain.
ATP binding leads to activation of a tyrosine kinase in the beta subunit that autophosphorylates the receptor.
The phosphorylated receptor in turn phosphorylates other protein substrates beginning with insulin receptor substrate 1 and 2.
What is pseudohypoparathyroidism?
A condition associated primarily with resistance to the parathyroid hormone.
Pts have low calcium and high phosphate
PTH is appropriately high due to hypoclacaemia
MOA of Biguanides, sulfonylureas, Thiazoledinediones, DPP-4 inhibitors, GLP-1 analogs
Biguanides
- increase insulin sensitivity, reduces hepatic gluconeogenesis, increases peripheral glucose uptake
Sulfonylureas
- stimulate insulin release from pancreatic B cells
Thiazoledinediones
- bind and activate PPAR-y receptors which contributes to decreasing hepatic gluconeogenesis and increasing peripheral insulin sensitivity
DPP-4 inhibitors e.g. sitagliptin
Inhibit dipeptidyl peptidase‑4 (DPP‑4) thereby increasing the concentration of the incretin hormones glucagon-like peptide‑1 and glucose-dependent insulinotropic polypeptide; glucose-dependent insulin secretion is increased and glucagon production reduced.
GLP-1 analogs - act like human GLP-1, increases insulin and inhibits glucagon
What is the most specific test for the Dx of GH deficiency?
IGF-1 measured in an insulin tolerance test
What is the earliest sign of renal disease n T1DM?
microalbuminaemia
Which hormone is first affected in pituitary apoplexy?
ACTH -> lack of cortisol and features of addisonoian crisis i.e. hypotension, hyponatraemia, hypoglycaemia and hyperkalaemia
Then TSH and LH, FSH
What is the first hormone affected in anterior pituitary adenoma?
Gonadatrophin (LHand FSH) first to fall then
GH then ACTH.
ACTH rarely falls due to an anterior pit adenoma.
If you disconnect the pit from the hypothal (Sx or injury) all releasing anterior hormones are cut off therefore levels will fall.
Prolactin will increase as dopamine inhibition is lost.
How does the hypothalamus control the ant and post pituitary?
Anterior pit by means of hormones
Post pit by direct nerve stimulation (neurohypophysis)
What is Sheehan’s syndrome?
A post partum infarct of the pituitary that results in anterior hypopit and sometime affects the post put causing Central DI.
Suspect in postpartum pt with electrolyte disturbance and low TSH.
Pt with Grave’s disease. FNAC of nodule reveals atypic of undetermined significance (Bethesda category 3). Nodule shows benign sonographic characteristics. Mx?
Total thyroidectomy.
High risk of malignancy.
Thyroid nodule shows atypical cells of undetermined significance (ACUS) or Follicular lesions of undetermined significance (FLUS). Mx?
Repeat FNA in 2-3 months.
If ACUS/FLUS, Sx based on clinical grounds (size, growth, pattern) or molecular testing.
What is the role of the following in Glucose control. Glucagon GH Cortisol Adrenaline GLP-1
Glucagon - promotes gluconeogenesis and glycogenolysis (break down glycogen to glucose)
GH - promotes gluconeogenesis and glycogenolysis (break down glycogen to glucose)
Cortisol - Promotes gluconeogenesis and increases insulin resistance by decreasing translocation of GLUT4 receptors. However it also increases glycogen synthesis (as does insulin)
Adrenaline - reduces awareness to hypoglycaemia and can be explained by decreased sensitivity of B-adrenergic receptors in long standing DM
GLP-1 - incretin, not a hormone e.g. exanatide and liraglutide.
Increases insulin secretion from the pancreas in a glucose dependent manner.
Decreases glucagon secretion from the pancreas by engagement of a specific G-protein coupled receptor.
What is the most common hormone secreted by pituitary adenoma? Followed by..
Prolactin (lactotroph adenomas), 44% Results in hypogonadism in male and females Non- functioning adenomas, 22% Somatotroph (GH) adenomas, 8.6 Corticotroph (ACTH), 1.2
What best explains the MOA of PTH in increasing the serum calcium concentration?
Stimulates the synthesis of 1-alpha hydroxylase in the proximal tubules and thus the conversion of calcidiol to calcitriol (1,25 DH).
Increasing the reabsorption of calcium from the renal tubules leading to increased intestinal absorption, increased bone resorption and decreased renal calcium excretion and increased phosphate excretion.
Hormone profile of premature ovarian failure?
high FSH and low oetrodial
normal LH and 17-OH progesterone
Hormone profile of menopause?
High FSH
Low oestrodial due to negative feedback,
Role of FSH?
Females- responsible for the early growth of follicles (follicle stimulating hormone). Produced by granulosa cells if the ovaries by aromatisation.
Males - maintains the spermatogenic epithelium by stimulating Sertoli cells
Role of LH?
Females - responsible for the final maturation of the ovarian follicles and subsequent oestrogen secretion from them
Males - trophic to the Leydig cells which secrete testosterone into the bloodstream
How do prolactinomas cause ammenorrhea?
Inhibit FSH and LH vis inhibition of GnRH so these hormones are usually low to normal rather than elevated
Congenital adrenal hyperplasia. Defect? Presentation? Dx?
Recessive condition. Defective conversion of 17 alpha hydroxyprogesterone to 11-deoxycortisol ->decrease cortisol -> increase ACTH -> normal cortisol but increase androgens.
Presentation: Females present as: Ambiguous genitalia clitoral enlargement common urethral vaginal orifice Males present as: salt losing adrenal crisis (hypoNa, HyperK andFTT)
Dx: measure 17-hydroxyprogesterone (precursor in the pathway), a substrate for 21 hydroxylase. very high levels is diagnostic.
Then ACTH stimulation test is the GOLD standard -> increased 17-hydroxyprogesterone
Primary hyperparathyroidism, Aetiology? Ix findings?
Parathyroid adenomas or hyperplasia Ix: Elevated PTH Raised plasma and urinary Ca ALP elevated Phosphate reduced
Secondary hyperparathyroidism. Aetiology? Ix findings?
Compensatory hypertrophy of all four glands due to hypocalcaemia (due to CKD or malabsorption)
Ix:
PTH elevated
Ca low or normal
What secretes PTH-related protein? Ix findings?
Secreted by squamous cell tumours, breast and renal tumours
Responsible for 80% of hypercalcaemia in malignancy and acts on same receptors as PTH
Serum Ca raised and PTH low
Steps in thyroid hormone synthesis.
- Iodide trapping by the thyroid follicular cells
- Diffusion of iodide to the apex of cells
- Transport of iodide into the colloid
- Oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues within thyroglobulin molecules in the colloid
- combination of 2 diiodothyrosine (DIT) molecules to form a tetraiodothyronine (thyroxine, T4) or MIT with DIT to for a triiodothyronine (T3)
- Uptake of thyroglobulin from colloid not follicular cell by endocytosis, fusion of thyroglobulin with a lysosome and photolysis and release of T4, T3, DIT and MIT
- release of T4 and T3 into the circulation
- Deiodination of DIT and MIT to yield tyrosine
T3 is formed from monodeiodination of T4 in the thyroid and in peripheral tissues
Steps in Vitamin D synthesis.
Vitamin D3 absorbed from skin, D2 from dietary intake
Converted in liver to Calcidiol, 25- hydroxyvitamin D
Converted in kidney to Calcitriol, 1, 25-dihydroxyvitamin D
Calcitriol causes increased intestinal absorption of Ca, increase bone resorption and decreased renal calcium and phosphate excretion.
Calcitriol mediates its biopic effects by binding to Vitamin D receptor.
Vitamin D binds to RANK on osteoclast inducing bone resorption.
What is the Mx of gestational diabetes?
Insulin for Type 1 and 2 DM.
Metformin - crosses placenta. No evidence it is harmful but not recommended.
Gliblecanide - limited passage to placenta but can cause neonatal hypoglycaemia and therefore not recommended
Antihypertensive recommended in pregnancy?
Methyldopa
ACEI teratogenic
Post pregnancy hyperglycaemia in pt with T1DM. Cause?
Insulin resistance common feature of late pregnancy and is a necessary adaptation to allow provision of maternal nutrients to the growing effects.
What is insulin site lipoatrophy?
Complication associated with all types of insulin and estimated prevalence of 3.6%.
Could lead to erratic insulin absorption
What is the role of adiponectin?
an anti-inflammatory cytokine produced by adipocytes
Enhances insulin sensitivity
In liver, inhibits gluconeogenic enzymes
In muscle, increases glucose tranport and enhances fatty acid oxidation
reduced in metabolic syndrome
Role of Grehlin?
Stimulates recreation of GH, increases food intake and produces weight gain
Most abundant in the gastric funds and levels decrease after eating
Role of Glucagon like peptide 1? AE?
stimulating glucose dependent insulin release from the pancreatic islets
Restores 1st and second phase insulin response to glucose
Slows gastric emptying, inhibit inappropriate post meal glucagon release and reduce food intake
N/V and weight loss
MOA of Leptin?
Decreases content of neuropeptide Y (potent stimulator of food intake) and increases the content of alpha melanocyte stimulating hormone (in hypothalamus) to inhibit food intake
Role of Peptide YY?
Produced in ileum, stimulated by incomplete digested nutrients.
Inhibits vaguely stimulated gastric acid secretion.
Inhibits gastric emptying and intestinal motility ti delay delivery of additional food to the intestine.
Do Not Confuse with Neuropeptide Y, a potent stimulator of food intake!
What are the LH and FSH concentrations in primary vs. secondary hypogonadism?
Primary (testes):
FSH and LH increased to try and increase hormones
Secondary (pituitary ir hypothalamus):
FSH and LH normal to low
Clinical features of hypogadasim?
Decreased testicular size, normal vol is 20-25 ml
Infertility
What is the common cause for abnormality in binding of testosterone to sex hormone binding globulin?
Obesity
What do you measure if you suspect hypogonadism?
Total serum testosterone:
testosterone reaches max at 8am and min at 8pm
Sperm analysis:
Normal is > 15 million sperm/ml
Normal more than 40% motile
LH
FSH
Tx for hyogonadism? CI to therapy?
Methyltestosterone - metabolised slowly by liver
Long acting testosterone IM q10-14 weeks
CI: Prostate or breast cancer LUTs HCT > 50 Uncontrolled HF
Mx of Gestational DM. Monitoring, BSL targets, Tx?
Measure post prandial BSL QID
Targets are:
Fasting 5.3 or less
1 hr post prandial - 7.8 or less
2 hr post prandial 6.7 or less
Tx:
Diet and exercise.
Basal bolus
Mixed insulin regime BD
Glibenclamide and met form increasingly used.
Gliblenclamide causes neontal hypos
Metformin crosses placenta, no long term AE known
How is growth hormone secreted?
Pulsatile
Peak hormone activity occurs one hr after sleep
Exercise, trauma, sepsis and low BSL stimulate secretion
How is insulin secreted?
Basal (unstimulated) insulin is pulsatile with a periodicity if 9-14 minutes
Loss of pulsatile secretion is one the earliest signs of beta cell dysfunction is patients destined to have T1DM
How is adrenaline secreted?
Resting concentrations are normally
How is testosterone secreted?
In young adult men testosterone levels begin to rise on falling asleep and peak at about the 1st time of REM and remain at the same levels until awakening
HypoNa: Electrolyte profile for Primary polydipsia?
Urine Na
HypoNa: Electrolyte profile for SIADH?
Serum osmo > 100 but less than 275 Urine osmo > 100 Euvolaemic Urine Na > 40 Normal thyroid and adrenal function (exclude hypothyroidism and mineralocorticoid deficiency) No recent use of diuretics
HypoNa: Electrolyte profile for CHF, cirrhosis and nephrosis?
Urine osmo > 100
Urine Na
HypoNa: Electrolyte profile for vomiting, diarrhoea and burns?
Urine osmo > 100
Urine Na
What is the most common AE of 8 mm prolactinoma?
Tx?
Amenorrhea.
Hyperprolactinaemia causes hypogonadism -> infertility, oligomenorrhea and less often galactorrhea, hirsutism.
Galactorrhea unusual to occur e.g. even in post menopausal women who are hypo-oestrogenic, galactorrhea is rare.
Tx:
Dopamine agonist e.g. bromocriptine
Sx if compression
What is the most common cause of morning hyperglycaemia?
Nocturnal GH secretion and hypo-insulinaemia
Most severe episodes of hypoglycaemia occur at night
Pregnancy and Grave’s. When should Thyroid Abs be checked and why?
3rd trimester. High risk of neonatal thyrotoxicosis is 5 x ULN
measure T4 and TSH soon after birth
Tx with propranolol/atenolol and methimazole
Note- TSh receptor crosses BBB and 1.5% of neonates will have hyperthyroidism.
What are the genetic mutations in B cell function causing DM. Types, onset, Tx?
- HNF-4a (5%)
- Teens to 30s
- progressive hyperglycaemia
- frequent microvascular complications - Glucokinase (15%)
- presents from birth with reduced birth weight
- little deterioration with age
- minimal risk of diabetes complications - HNF1 - alpha (70%)
- teens to 20s
- progressive hyperglycaemia
- normal risk of DM complications
- sensitive to sulphonylureas - IPF -1 (MODY)
What is the most common genetic B cell defect?
HNF1 - alpha (70%)
- chromosome 12
- teens to 20s
- progressive hyperglycaemia
- normal risk of DM complications
- sensitive to sulphonylureas
Why does acute pituitary apoplexy cause a flase negative short synacthen test?
APA causes acute hypoadrenalism
Normal synacthen test as adrenal glands are still functioning normally and will respond to ACTH delivered.
MOA of neuropeptide Y
Energy conserving neuropeptide
Increases food intake and storage of energy as fat
MOA of agouti-related protein (AgRP)?
Promote feeding, weight gain, reduces energy expenditure and increases fat stores
MOA Carbimazole
Inhibiting TPO activity thereby preventing the synthesis of new thyroid hormone
MOA PTU
Prevents synthesis of new thyroid hormone and inhibits conversion of T4 to T3
MOA prednisone in hyperthryoidism
Decreases T4 to T3 conversion
MOA of Iodine
Blocks release of T4
Dereases thyroidal iodide uptake and decreases iodide oxidation and organification
Blocks release of thyroid hormones (Wolff-Chaikoff effect)
MOA of propranolol in thyroid disease
Reduces sympathetic hyperactivity
Decrease peripheral conversion of T4-T3
What is a potent stimulus of GH deficiency?
Insulin induced hypoglycaemia
Which occurs first in the development of renal disease?
Glomerular hyperfiltration and hyperperfusion occurs first in the development of renal disease before the onset of any measurable clinical changes.
Microalbuminuria has a variable course.
It’s progression to macroalbuminuria (>3 g/d) is unpredicatable and does not always lead to development of nephropathy.
Which diabetic agent is most likely to induce fasting hypoglycaemia?
Sulphonylureas e.g glicazide
Binds to sulphonylurea receptors on the surface of pancreatic beta cells -> insulin release
What is the Bethesda category for thyroid nodule cytopathalogy and corresponding Mx recommendations? 6 categories
Non-diagnostic or unsatisfactory
- repeat FNA with US guidance
Benign
- Clincial FU
Atypia of undetermined significance
- repeat FNA
Follicular neoplasm or suspicious for a follicular neoplasm
- Surgical lobectomy
Suspicious for malignancy
- Near total thyroidectomy or surgical lobectomy
Malignant
- Near total thyroidectomy
In a pt with T1DM, which counter regulatory hormone is likely to be reduced?
Glucagon
In pts with T1DM for > 5 years, adrenaline is the main defense against hypoglycaemia because the pancreatic alpha cell glucagon secretory response to hypoglycemia is irreversibly lost
Glucose counter regulatory hormones. Which are rapid acting and which are slow acting in hypoglycaemic event?
Rapid acting
- glucagon
adrenaline
Slow acting
- GH
- cortisol
3-4 hrs in chronic hypoglycaemia
What is the MOA of corticosteroid induced OP fractures?
Corticosteroids reduce bone formation and viability of osteoblast and osteocytes.
Bone loss usually occurs at sites rich in trabecular bone esp vertebral bodies, ribs, distal radius and can alos occur in cortical bones in the upper femur.
What is the most common tumour producing ADH?
SMALL cell lung cancer others: Head and neck cnacer Olfactory neuroblastoma extra-pulmonary small cell carcinomas
What features are most specific for Cushing’s syndrome?
Abnormal fat distribution - supraclavicular and temporal fossae Proximal muscle weakness Wide purple striae Decreased linear growth Continued weight gain as a child
Pt post thyroidectomy followed by radioactive iodine remnant ablation. What is the most useful marker for determining relapse?
Thyroglobulin
Anti-GAD levels predict the likelihood of T1DM in a patient with poorly controlled diabetes. T/F
True
In a pt with long term T2DM who is compliant to diet and medication, what is the main cause for worsening glycaemic control?
Decreased insulin secretion
How do you test for diabetic gastroparesis?
Gastric emptying study
How does obesity affect testosterone concentrations?
Suppresses sex hormone binding globulin and results in decreased total testosterone concentrations
Which medication is safe in patients with ESRF and cannot tolerate oral bisphosphonate. Tx?
Denosumab
RANK ligand monoclonal Ab
No dose adjustment required in renal failure’
What is the MOA of Teriparatide?
Active form of human PTH, increases osteoblast action ->increase BMD
Indication:
Postmenopausal osteoporosis when there is a high risk of fractures and other agents are unsuitable
Primary osteoporosis in men when there is a high risk of fractures and other agents are unsuitable
Corticosteroid-induced osteoporosis in patients at high risk of fractures
What is the pathophys of PCOS?
Hyperinsulinaemia
What is the main mechanism of HypoNA in DKA?
Extracellular shift of H2O due to hyperosmolarity
Signs and symptoms of Pseudo-Cushing’s disease?
Alcohol consumption - high GGT
Cortisol and ACTH elevated
24 hr urinary cortisol elevated
Hyponatraemia. Serum osmo
Low effective arterial blood volume. Causes:
Diarhhoea
Vomiting
Third spacing - burns, pancreatitis, trauma
dehydration
remote diuretics
Hyponatraemia. Serum osmo
Low effective arterial blood volume. DDx:
HF
Liver cirrhosis
Nephrotic syndrome
Causes of SIADH?
Malignancy Pul infections CNS infections Drugs Basically everything!
Mx of SIADH?
A syndrome of too much water!
Fluid restriction
Give extra solute so the kidney can happily make concentrated urine while getting rid of water e.g. eggs salt, protein, urea
Consider vasopressin 2 receptor antagonist e.g. tolvaptan
Which drugs do not affect renin aldosterone testing?
verapamil
Hydralazine
Prazosin
What are the effects of propanolol in Tx of Hyperthyroidism?
Reduces sympathetic activity
Decreases peripheral conversion of T4-T3
DPP-4 inhibitors: MOA Indication AE benefits
Sitagliptin Linagliptin Alogliptin Saxagliptin Vildagliptin
MOA:
Inhibit dipeptidyl peptidase‑4 (DPP‑4) thereby increasing the concentration of the incretin hormones glucagon-like peptide‑1 and glucose-dependent insulinotropic polypeptide; glucose-dependent insulin secretion is increased and glucagon production reduced.
Indication:
T2DM
AE:
Nausea
Pancreatitis-rare
Reduce dose if Cr
GLP inhibitors: MOA Indication AE benefits
Exenatide
Liraglutide
MOA:
Analogues of glucagon-like peptide‑1 (an incretin)
Increase glucose-dependent insulin secretion and suppress inappropriate glucagon secretion.
Delay gastric emptying, which slows glucose absorption, and decrease appetite.
Indication:
T2DM
AE: N/V in 50% of ppl D/Constipation GORD Dyspepsia Pancreatitis rare
Benefits:
Weight loss
No hypos unless with sulfonylurea/insulin
Sulfonylurea.
MOA
Indication
AE
Gliclazide
Glibenclamide
Glimepiride
Glipizide
MOA:
Increase pancreatic insulin secretion; may decrease insulin resistance
Indication:
T2DM
AE:
hypoglycaemia (risk is increased by advanced age, renal or hepatic impairment and interacting drugs)
WEIGHT GAIN
Acarbose.
MOA
Indication
AE
Delays intestinal absorption of carbohydrates by inhibiting alpha-glucosidase enzymes in the small intestine; reduces postprandial hyperglycaemia.
Indication:
T2DM
AE:
flatulence, diarrhoea, abdominal pain and distension
Ileus
Hepatotoxicty
In hypoglycaemia:
Give glucose; do not give sucrose (cane sugar) as its absorption will be delayed.
Thiazolidinediones:
MOA
Indication
AE
Pioglitazone
Rosiglitazone
MOA:
PPAR-y (peroxisome proliferator-activated receptor gamma) inhibitor
- which regulates genes involved in lipid and glucose metabolism.
- Increase the sensitivity of peripheral tissues to insulin; decrease hepatic glucose output
Indication:
T2DM with or without metformin, sulfonylurea
AE:
peripheral oedema, weight gain, headache, dizziness, arthralgia, decrease in haemoglobin and haematocrit
HF, pul oedema, macula oedema
HypoNa: Urine osmo > 100 Urine Na>30 Hypovolaemic Causes?
Vomiting Primary adrenal insifficiency Renal salt wasting Cerebral salt wasting Occult diuretics
Calcitonin.
MOA
Indications
Antagonises effect of PTH to reduce osteoclast function.
Increases renal excretion of Ca, Ph, K, Mg by decreasing renal tubular absorption.
Indications:
Hypercalcaemia
Pagets
Post menopausal OP
What is Etidronate?
A bisphosphonate derivative.
Indication:
Tx of sympotamtic Pagets disease
AE:
Increase risk of defective mineralisation of newly formed bone at higher doses.
Insulin resistance and CAD is independent of total cholesterol. T/F
True
Sick euthyroid.
What are the levels of TSH, T3 and T4.
Tx
A transient hypothyroid state due to illness.
TSH can be low, normal or high (TSH unlikely to be high otherwise hypothyroidism)
T3 low
T4 low
Low free T4 associated with bad prognosis
Tx:
Tx infection
TSH Resolves within 8 weeks.
What is the most common biochemical abnormality associated with obesity?
Raised serum C-peptide
What antibodies are elevated in:
Hashimotos
Graves
Hashimotos:
anti–thyroid peroxidase (anti-TPO) antibodies, antithyroglobulin antibodies
Graves:
Anti-TSH receptor antibodies
- thyroid-stimulating immunoglobulins [TSIs]
- thyrotropin-binding inhibitory immunoglobulins [TBIIs]
In a strong FHX of AI disease, which thyroid ab predicts the risk of developing hypothyroidism?
anti-TPO antibody titers assesses future risk of developing hypothyroidism
In the Ax of Grave’s disease, when is the radioidoine uptake study contraindicated?
In pregnancy and breastfeeding
Thyroglobulin (stores thyroid hormone in thyroid glan). Measurement is useful in which conditions?
Elevated in:
Thyroid cancer
Hyperthyroid
Destructive thyroiditis
Decreased in:
Factiticious ingestion
Calcitonin is secreted by the C cells of the thyroid. It is a marker of?
tumor marker in patients with a history of medullary thyroid cancer
Recmommended for patients with:
- thyroid nodules who are at higher risk for medullary thyroid cancer, such as those with a positive family history of medullary thyroid cancer, with features of multiple endocrine neoplasia type 2 (MEN2)
- thyroid biopsy results suggestive of medullary thyroid cancer
Radioactive iodine uptake scan. What diseases are associated with the following:
Diffuse
Focal
Low
Diffuse (correlates with endogenous production of thyroid):
Grave’s
Focal uptake:
toxic multinodular goiter or
toxic adenoma
Low uptake: subacute silent or postpartum thyroiditis or exposure to exogenous thyroid hormones,
Grave’s disease:
3 Treatment options
Three options.
Medications:
antithyroid drugs methimazole and propylthiouracil.
1st choice - Methimazole is the first choice because of its increased potency, once-daily dosing regimen, and lower incidence of serious adverse effects (mainly hepatic).
Propylthiouracil is used in women in the first trimester of pregnancy (because of the teratogenicity of methimazole).
Radioactive iodine ablation:
Success in greater than 90% of pts
AE uncommon, can have transient anterior neck pain or tenderness from radiation thyroiditis.
Exacerbation of the thyrotoxic state for several weeks can occur because of the release of preformed hormone.
Expected outcome is hypothyroidism in which thyroid hormone replacement is commenced.
Thyroidectomy:
Preferred in pts with Grave’s opthalmopathy
radioactive iodine treatment has been associated with (at least transient) worsening of Graves ophthalmopathy, its use is not recommended in patients with severe Graves ophthalmopathy.
Methimazole
Propylthiouracil
AE?
Drug rashes are common and occur in 5-10%.
Methimazole:
Mild reversible cholestatic pattern
Propylthiouracil:
elevated aminotransferase levels and a higher rate of serious hepatic injury
Methimazole preferred due to less side affects.
Toxic multinodular goitre and toxic adenoma:
Cause
Examination
Ix
Cause:
Activating somatic mutation in the TSH receptor gene, which leads to autonomy of function and secretion of excess T4 and T3 from the nodule(s) affected.
Recent iodine exposure from contrast dye used in CT scans and angiographic procedures (such as cardiac catheterization), can induce thyrotoxicosis in patients with preexisting autonomy of thyroid function (Jod-Basedow phenomenon).
Examination:
Presents with thyrotoxicosis
One or more palpable nodule(s) or overall gland enlargement
Ix:
Often isolated T3 toxicosis
TSHr mutation
Radioactive iodine uptake scan
- toxic mulit-nodular goitre: patchy uptake of radioactive iodine that is increased in autonomous regions and reduced outside those areas
- toxic adenoma: will reveal a solitary overactive (“hot”) nodule with suppression of the rest of the gland
Thyroid US to exclude cancer and need for Bx
Tx:
A multinodular goiter associated with hyperthyroidism can be treated with either radioactive iodine or surgery depending on multiple factors, including the size of the thyroid gland, evidence of obstructiondyspnea, or local symptoms suggestive of cervical venous obstruction.
Toxic adenoma:
Radioactive iodine ablation is the treatment of choice.
Surgical removal of the involved lobe (in patients with toxic adenoma) and total thyroidectomy (in patients with toxic multinodular goiter) is usually offered to those whose gland is not sufficiently avid for the radioactive iodine to result in ablation or who have proven thyroid cancer by biopsy.
Antithyroid drugs modulate thyroid hormone production in toxic multinodular goiter and toxic adenoma and thus must be administered continuously to control hyperthyroidism
Destructive Thyroiditis involves transient destruction of thyroid tissue, which disrupts follicles and causes the release of preformed thyroid hormone into the circulation.
What are the 3 causes?
Ix?
Tx?
subacute (de Quervain), silent, and postpartum thyroiditis
Subacute:
most commonly occurs after a viral infection and usually involves severe thyroid and neck pain; fever, fatigue, malaise, anorexia, and myalgia are common
Ix: Low TSH High T4 and T3 High CRP, ESR Classic course of approximately 6 weeks of thyrotoxicosis, a shorter period of euthyroidism, 4 to 6 weeks of hypothyroidism, and then restoration of euthyroidism.
Tx: Levothyroxine for hypothyroid period
Silent:
Painless
Anti-microsomial antibodies may be present
Post partum:
Painless autoimmune thyroiditis and can occur up to 12 months after parturition
Tx:
Propanolol
NSAIDs 1st line for pain
Steroids for severe pain
No role for antithyroid medication.
What are the 2 forms of amiodarone induced thyroiditis?
Other causes of drug induced thyroiditis?
Type 1:
Iodine-induced hyperthyroidism
- more common in iodine-deficient geographic areas in patients with multinodular goiter and is treated with antithyroid agents
Type 2:
destructive thyroiditis
occurs in iodine-sufficient regions, such as the United States, and is treated with corticosteroid therapy
Often can overlap.
Tx with antithyroid hormones and corticosteroids. If no improvement, then thyroidectomy.
Other drugs:
Lithium
interferon alfa
interleukin-2
Sub clinical hyperthyroidism:
When to begin Tx?
TSH level is less than 0.1 microunit/mL (0.1 milliunit/L).
Esp in pts >=65 years, have tachyarrhythmias or heart disease, are postmenopausal with low bone mass, or are markedly symptomatic.
Tx with methimazole.
Post menopausal women with TSH
Hypothyroidism:
Causes
Hashimoto’s most common cause
Iatrogenic - iodine ablation, external beam radiation to the thyroid bed, or surgical removal of the thyroid gland.
Ix: High TSH low T4 Anti TPO and/or thyroglobulin abs US thyroid gland if palpable goitre. Radioactive uptake scan not useful.
Tx:
Levothyroxine (T4)
- take on empty stomach 1 hour before or 2 to 3 hours after intake of food or calcium- or iron-containing supplements
Subclinical hypothyroidism. When to Tx?
TSH level > 10 microunits/mL (10 milliunits/L).
Levothyroxine therapy also can be considered for patients who are markedly symptomatic, have a goiter, are pregnant or are planning to become pregnant, or have positive anti–TPO antibodies
RF for thyroid cancer
age less than 20 or greater than 60 years
male gender
previous head or neck irradiation
a family history of thyroid (especially medullary) cancer, rapid nodule growth, and hoarseness
Ix:
TSH
If suppressed, free T4 and radioactive iodine uptake scan
Thyroid cancers.
3 Most common.
Papillary (85%), follicular (10%), and medullary (4%).
Medullary
Medullary thyroid cancer typically is characterized by plasmacytoid, spindle, round, or polygonal cells on biopsy. All patients with medullary thyroid cancer should have RET proto-oncogene sequencing after other appropriate evaluation, including measurement of plasma free metanephrine and normetanephrine levels to detect or exclude the presence of a pheochromocytoma
Medullary Cancer:
Disease Associations
Histo
Ix
Component of MEN2A and can be associated with hyperparathyroidism with hypercalcemia and hypertension due to a pheochromocytoma.
Histo:
Medullary thyroid cancer typically is characterized by plasmacytoid, spindle, round, or polygonal cells on biopsy.
Ix:
All patients with medullary thyroid cancer should have RET proto-oncogene sequencing after other appropriate evaluation, including measurement of plasma free metanephrine and normetanephrine levels to detect or exclude the presence of a pheochromocytoma
Thyroid cancer staging and Tx.
Younger than 45 years:
stage I disease includes thyroid cancer of any size, with or without cervical lymph node involvement and without distant spread;
stage II refers to patients who have distant spread of disease
45 y or older:
stage I thyroid cancer denotes tumors 2 cm or less in size without local invasion or positive cervical lymph nodes
stage II denotes tumors greater than 2 cm but no more than 4 cm in size without local invasion or positive cervical lymph nodes, stage III denotes tumors larger than 4 cm in size with slight local invasion with or without cervical lymph node involvement,
stage IV denotes thyroid cancer that either has invaded nearby neck structures or superior mediastinal lymph nodes or may or may not have invaded local tissues or lymph nodes but has spread to distant sites.
Tx:
combination of thyroidectomy, radioactive iodine therapy, and suppression of TSH secretion with levothyroxine therapy.
Radioactive iodine therapy frequently is administered for stage III and IV disease, especially with lymph node involvement, to decrease the risk of recurrence and death.
What happens to thyroid hormones in pregnancy?
Oestrogen increases TGB (thyroxine binding globulin) which increases T4 and T3 levels.
Increase dose of thyroxine 30-50% at start or pregnancy.
TSH levels decrease during 1st trimester due to BHCG stimulating thyroid hormone production and normalise by 16 weeks gestation.
What is the goal of TSH in pregnancy?
1st trimerster: 0.1 to 2.5 microunits/mL
2nd and 3rd: 0.1 to 3
Thyroid storm. Cause Precipitations Tx Mortality rate
Cause:
Thyroid storm most commonly occurs in Graves disease and has a higher frequency in younger women, but it also can be due to a toxic adenoma or multinodular goiter
Precipitations:
surgery, infection, trauma, parturition, acute iodine exposure, radioactive iodine (131I) therapy, or ingestion of medications, including salicylates and pseudoephedrine
Can occur due to long standing untreated hyperthyroidism, TMG or toxic adenoma
Tx:
propylthiouracil or methimazole), iodine solution, high-dose IV corticosteroids, β-blockers, and (rarely) lithium are used for treatment.
Mortality rates are 15-20%.
Myxoedema coma:
Cause
Cause:
history of hypothyroidism, thyroidectomy, or radioactive iodine therapy
Presentation:
mental status changes, 80% of pt.
hypothermia, 34.4 degrees. Lower levels associated with a worse prognosis.
Ix:
Low levels of everything, bradycardia, hypoglycaemia, hyponatraemia, hypoventilation -> hypercapnea
Tx:
Intravenous levothyroxine.
concurrent treatment with high-dose glucocorticoids (such as hydrocortisone) until adrenal insufficiency excluded and adrenal function normal.
Growth hormone deficiency.
Cause.
Ix
Tx
Genetic
- short stature
Acquired:
Pituitary deficiency due to Structural sellar or suprasellar lesion that has been treated with neurosurgical intervention and/or cranial irradiation.
Ix:
Low growth hormone level after insulin tolerance test is the most SPECIFIC test.
Insulin used to induce hypoglycaemia, should increase GH.
low serum insulin-like growth factor 1 (IGF-1) level.
Tx:
GH replacement in patients with other pituitary deficiencies
What is the most common pituitary deficiency associated with a structural sellar or suprasellar lesion that has been treated with neurosurgical intervention and/or cranial irradiation?
Growth hormone deficiency
Primary polydipsia (aka psychogenic polydipsia). Cause Ix Water deprivation test Desmopressin test
Primary increase in H2O intake.
Water excretion is appropriate for intake.
Polyuria > 3L/d
Cause:
Psychiatric illnesses
Phenothiazine-> dry mouth
Hypothalamic lesions affecting thirst cenre in sarcoidsoisis
Ix:
Plasma Na =500
No response to desmopressin as endogenous release is intact.
Central Diabetes insipidous (polyuria): Cause Ix Water deprivation test Desmopressin test
(Normal Na, will concentrate urine osmo in response to water deprivation and Desmopressin/ADH)
Due to deficient secretion of ADH.
Polyuria > 3L/d
Cause:
- Idiopathic 30-50%
- Trauma/Nsx
- Tumour e.g. lumg, lymphoma, leukemia
- Hypoxic encephalopathy
- Post SVT ?ANP
Ix:
Na normal and Urine osmo >600 will exclude DI
Central DI:
Na > 142, urine osmo
Nephrogenic DI: Cause Ix Water deprivation test Desmopressin test
(Na normal, urine osmo will not concentrate more than 300 and no response to desmopressin/ADH)
normal ADH secretion but varying degrees of renal resistance to its water retaining effect.
Polyuria >3L/d
Cause: Lithium main cause Hypercalcaemia Children - X-linked mutation in AVPR2 gene encoding ADH receptor V2 and AD/AR aquaporin-2 water gene.
Ix:
Na> 142
Urine osmo
Primary hyperparathyroidism:
Cause
Most common cause of hypercalacaemia in outpt setting.
Solitary parathyroid adenoma is the cause of 75-80%
Indications for Sx in asymptomatic patients:
Increase in serum Ca >=1 mg/dL
Cr Cl
Hypercalcaemia:
Causes parathyroid vs. non parathyroid
Parathyroid: Primary hyperparathyroidism Parathyroid adenoma(s) Parathyroid hyperplasia Parathyroid carcinoma Familial hypocalciuric hypercalcemia Lithium therapy–associated hypercalcemia Tertiary hyperparathyroidism
Non-parathyroid: Malignancy-associated hypercalcemia - 1,25-Dihydroxyvitamin D (B-cell lymphoma) - PTH-related protein (squamous cell carcinoma, adenocarcinoma of the breast or ovary, renal cell carcinoma, transitional cell carcinoma, T-cell lymphoma, islet cell neoplasms, myeloma) Granulomatous - sarcoid, Tb Hyperthyroid, adrenal insufficiency Drugs - thiazide Increased plasma protein e.g. MM
What has the greatest effect on peak bone mass?
Genetic factors
Periodic parlaysis associated with Graves?
Due to transient hypokalaemia
Often following high carb meal or severe exercise
Young, Male Asian predisposed.
Insulinoma. Ix findings?
Insulin > 100 pmol/L
C peptide >250 pmol/L
hypoglycaemia
Exogenous insulin. Ix findings?
Insulin high
C-peptide
Familial hypocalciuric hypercalcemia (FHH).
AD
Inactivating mutation of CASR gene.
Presentation:
Asymptomatic
Stable
FHx
Ix:
High serum Ca
Normal to mildly elevated PTH
Low urine Ca excretion
Tx:
No intervention
recognised to prevent unnecessary parathyroidectomy.
Vitamin D def. Recommended level?
> 50-75 nmol/L
If
Familial MEN1 consist of?
three Ps
Pituitary
Parathyroid
Pancreas
Growth hormone tumour.
Ix
Tx
Presentation:
frontal bossing; prognathism, with dental malocclusion and increased spacing between the teeth; enlargement of the nose, lips, and tongue; skin tags; arthritis; carpal tunnel syndrome; sleep apnea; and excess sweating
Ix:
Elevated insulin-like growth factor 1 level in the setting of signs or symptoms of growth hormone excess is consistent with acromegaly
Tx:
1st line:
Transphenoidal Sx
Post Sx with resiudal disease:
Somatostatin e.g. octreotide OR
Dopamine agonist
NAGMA.
Normal Range
Causes
Normal AG 8-16
Causes:
RTA
Carbonic anhydrase inhibitors
Severe diarrhoea
Uereto-enterostomy
drainage of pancreatic or biliary secretion
small bowel fistula
Addition of HCl or NH4Cl
What is the primary method by which PTH increases serum Calcium?
Increase bone resorption.
Bones
- increase bone resoprtion
- increase Ca and PO4 resrption
In Kidneys
- increase Ca absoprtion
- increase 1-hydroxylase
- increase phosphate excretion
GUT
- increase Vit D
- increase Ca absorption
Hormone profile in pregnancy?
Low FSH, LH
Very high levels of Oestrogen
Increases prolactin
Mild increase testosterone
Primary ovarian failure hormone profile?
Decreased FSH
Decreased oestrogen
what is the most monogenetic cause for obesity?
MC4-R mutation
