Endocrinology Flashcards
MEN syndromes
Men 1 - Pituatory adenoma, parathyroid hyperplasia, pancreatic tumours - P’s!
Men 2a - Parathyroid hyperplasia, Medullary thyroid malignancies, pheochromocytoma - associated with RET gene gain of function mutation (loss of function Hirshsprung)
Men 2b - Mucosal neuromas, Marfans, Parathyroid Hyperplasia, Pheochromocytoma
PCOS diagnosis
- Androgen Excess
- Oligomenorrhoea
- > 12 cysts per ovary of > 2mm, with one ovary > 10ml
Hormones
- High LH
- High Testosterone
- High/Normal oestrogen
- High LH:FSH ratio
MODY
Mature onset Diabetes of the young
Monogenic diabetes; result from mutations or changes in a single gene; presents with strong family history of diabetes
- MODY 1 - least common, due to HFN4
- MODY 2 - GCK mutation, results in mildly high fasting glucose without complications. Only require treatment in pregnancy
- MODY 3 - HFNA1 mutation, most common, sensitive to sulphonylureas
Vitamin D pathway
7-dehydrocholesterol -> Vitamin D3 (cholecalciferol) via UV -> 25-hydroxyvitamin D3 in liver -> 1, 25 hydroxyvitamin D3 (calcitriol) via 1-alpha hydroxylase at kidney.
1-alpha hydroxylase in kidney is inhabited by FGF-23 during Klotho deficiency in CKD
Familial Hypocalcuric hypercalcaemia
Calcium receptor in parathyroid gland requires higher levels of calcium to down regulate PTH
PTH levels will be normal at high calcium levels
PTH will continue to reabsorb calcium from kidneys
- High Calcium
- Normal PTH
- Low urinary calcium
- Urine Ca:CR ratio calculated with Hammersmith equation
- Surgery contraindicated
Addison’s disease
- Primary adrenal insufficiency
- Congenital; 21 hydroxylase deficiency
- Autoimmune; 21-hydroxylase antibodies
- High ACTH with tanned skin
- No response with short synacthen
- Low cortisol
- Hypoaldosteronism, high K+, low Na+
- High Renin
- Loss of sex characteristics
- Associated with autoimmune polyglandular syndrome
Deiodinase inhibitors
Amiodarone, Steroids, Propanolol
Block conversion of T4 to T3
Turners syndrome
XO genotype
Primary ammenorhoea & poor breast development
Short stature
Bicupsid aortic valve - requires surveillance
Autoimmune thyroiditis
Auditory dysfunction
Metabolic syndrome
Horseshoe kidney
Acromegaly investigations
IGF-1 level (has long half life and decreased variation in comparison to GH)
High growth hormone & IGF-1 during Glucose Tolerance test
Pituitary MRI
PTH action at kidney, bone & gut
Kidney * PTH = Phosphaturia*
- Decreased calcium excretion
- Increased phosphate excretion
- Increase 1-alpha-hydroxylase activity
Gut
- Increased calcium and phosphate resorption
Bone
- Remodelling by binding PTH receptors at osteoblasts (osteoclasts lack PTH receptors)
- Upregulates RANK ligand which in turn stimulates osteoclasts (indirect activation of osteoclasts)
But if pulsatile exposure to PTH i.e with Teriparatide this will increase osteoblasts and help with osteoporosis!
PTH - Calcium curve shifts
Familial Hypocalcuric hypercalcaemia - shifts RIGHT
Autosomal dominant hypocalcaemia - shifts LEFT
Cinacalcet- shifts curve to left
Indications for surgery in primary hyperparathyroidism
Serum calcium > 2.80
BMD T score < 2.5 or fragility fracture (strongest indication!)
Age < 50
eGFR < 60
24 hour urinary calcium > 10mmol
FGF-23
Secreted by Osteoclasts
Driven by ‘Klotho deficiency’
Causes phosphate wasting by 2 mechanisms;
- Inhibits 1-alpha-hydroxylase to decrease formation of 1,25-hydroxyvitamin D & downregulates PO4 absorption at GIT
- Induces phosphate excretion in kidneys via NPT2a sodium-potassium cotransporter
- High FGF-23 leads to hypophosphataemia and rickets
Whipples Triad
- Hypoglycaemia below 3.1
- Neuroglycopenic symptoms
- Resolution of symptoms with glucose ingestion
Thiazolidinediones
Sensitise insulin via PPAR activation which makes cells more dependent on glucose with increased peripheral uptake
Increased risk of CVD, bladder malignancy and fractures
i.e. Rosiglitazone
Note: fenofibrate are also PPAR activators
Production testosterone in males
GnRH pulsing -> LH -> Leydig cells -> testosterone
- testosterone -> oestradiol via Aromatase
- testosterone -> dihydrotestosterone via 5-alpha reductase
- testosterone acts at Sertoli cells with FSH to induce spermatogenesis
Decreased SHBG
- Hypothyroidism
- Glucocorticoids
- Nephrotic syndrome
- Growth hormone excess
- Obesity
- Insulin resistance
Associated with increased free testosterone
Liver derangement with Graves Rx
- Carbimazole = cholestatic
- PTU = hePaTocellUlar
Adiponectin
Released by adipose tissue in states of decreased body fat (levels inversely related to body fat)
Will be LOW in obesity
- decreasing catabolism of fats and increasing insulin resistance
- Low adiponectin levels predict diabetes in Pima Indians
Physiology of appetite
Orexegenic - Ghrelin acting at Neuropeptide Y neutron in hypothalamus to release Agouti-related peptid and Orexin. Agouti-related peptide competitively binds MC4 receptors to increase hunger
Anorexigenic - Leptin binds to POMC neurons at the hypothalamus to release Alpha-MSH which competitively binds to MC4 receptors to decrease hunger, along with inhibiting Agouti-related peptide release (Leptin = Less)
Hormones that stimulate appetite
Easier to remember the hormones that stimulate appetite (only 3);
- Ghrelin
- Neuropeptide Y
- Agouti-related peptide
The rest inhibit appetite!
Actions of GLP1 agonists
- Increases beta cell number and therefore production of insulin via GLU2
- Inhibits production of glucagon
- Suppresses appetite
- Slows gastric emptying
GLP-1 is usually inhibited by DPP-4 (which is why DPP-4 inhibitors work i.e. Linagliptin)
Congenital adrenal hyperplasia
Due to 21-hydroxylase deficiency which prevents aldosterone and cortisol production -> shunts 17-hydroxyprogesterone to testosterone
Common in patients with bilateral adrenal lesions
Can cause ambiguous genitalia in females
Layers of adrenal gland
Adrenal Cortex (GFR)
Zona glomerulosa- aldosterone
Zona fasciculata- cortisol
Zona reticularis- DHEA, Androstenedione
Adrenal Medulla
Adrenaline
Noradrenaline
Dopamine
Indications for Inferior petrosal sinus sampling
Confirmatory test for ACTH dependent cushings where pituitary adenoma is < 6mm.
- If ACTH central:peripheral > 2:1 then for pituitary surgery
- If ACTH central:peripheral < 2:1 then consider ectopic ACTH production i.e. lung cancer
Jon Basedow Effect
Ingestion of Iodine causes Hyperthyroidism in glands that are not under pituitary control i.e. Graves, TMG, Endemic goitres
Effect seen in Type 1 amiodarone induced thyroiditis where iodine overload causes hyperthyroid in abnormal glands
Wolff Chaikoff effect
Ingestion of Iodine load causes hypothyroidism as a means of autoregulation
Normal thyroid glands will overcome this - “escape”, but those with autoimmune thyroiditis will not overcome this hypothyroidism (fail to escape phenomenon)
Type 1 Amiodarone induced thyroiditis
- Occurs within weeks of ingestion
- Hyperthyroidism due to iodine load
- Occurs in abnormal glands (Jod Basedow effect)
- Increased vascularity on USS
- Treated with Carbimazole
Type 2 Amiodarone induced thyrotoxicosis
- Occurs within years of ingestion
- Destructive thyroiditis causing release of pre-formed thyroid hormone
- Occurs in normal glands
- Normal vascularity on USS
- Raised thyroglobulin and IL6
- Treat with steroids
Features of Thyroid malignancy on USS
Irregular margins
Cervical lymphadenopathy
Absence of Halo sign
Hypoechogenicity
Solid lesion
Intranodular vascularity
Taller than wide
> 1cm
Determine TiRAD score
Indication for FNA in thyroid nodule
TIRADS 1-2 No FNA
TIRADS 3 > 2.5cm
TIRADS 4-6 > 1.5cm
TIRADS 7 > 1cm
If FNA positive;
Total thyroidectomy is required for all primary tumour of >1cm or if extranodal extension or metastases present
Any nodule > 4cm requires lobectomy regardless of features or biopsy result
Types of thyroid malignancy
Papillary - 80%, young females, Familial adenomatous polyposis Hx, monitor thyroglobulin
Follicular - 10% , monitor thyroglobulin
Medullary - cancer of parafollicular cells, associated with MEN2a, secrete calcitonin. Poor prognosis with mets.
Anaplastic - non-responsive to treatment and aggressive. Very poor prognosis.
Sick Euthyroid
Inhibition of deiodinase and therefore conversion T4 to T3
- Reduces T3
- Increases reverse T3 (unclear clinical significance)
- Normal T4 and TSH
- T4 and TSH can decrease in severe illness
In recovery, TSH transiently rises to 10 - if TSH rebound > 10, likely patient has underlying hypothyroidism
Management of thyroid malignancy
TIRADS score
- FNA if > 1cm and suspicious
- Lobectomy for any lesion > 4cm, even if FNA negative
- Thryoidectomy
- Any lesion > 4cm
- Malignant lesion > 1cm - Post-op radio iodine therapy - to help with monitoring of reoccurance
- TSH suppression with thyroxine (aim to suppressive TSH with thyroxine doses above physiological levels)
- Monitor Thyroglobulin or Calcitonin
If suppressing TSH with Thyroxine - may need to give recombinant human TSH to stimulate thyroglobulin and monitor levels
High T3, T4 and TSH
TSH secreting pituitary adenoma
MOA Carbimazole
Prodrug converted to Methimazole
Inhibits iodination of thyroglobulin by blocking thyroid peroxidase
Side effects
- Agranulocytosis
- CholestatiC picture (PTU = HePaTic)
- Teratogenic; scalp defects
- GI upset
- Rash
Teriparatide
Binds PTH receptor
- PTH will act anabolically at intermitted dosing
- Only anabolic agent for the treatment of severe osteoporosis, (rest are anti-remodelling agents)
Used for treatment not prevention
Thiazide diuretic and calcium
Block sodium-chloride co-transporter resorption & subsequently up regulates sodium-calcium transporter leading to hypercalcaemia
- hypercalcaemia
- hypokalaemia
Reason for Hyponatraemia in primary adrenal insufficiency
- Increased CRH which stimulates ADH
- Hypoaldosterone
Amiodarone effects on Thyroid
- Decreases conversion T4 to T3, with decreased negative feedback on TSH resulting in high TSH and T4 with low T3
-Wolff Chaikoff effect; Ingestion causes Hypothyroidism due to autregulatory negative feedback - T1 AT - Jon Basedow effect; increased iodine causes hyperthyroidism
- T2 AT - Release of stored T3 and T4 due to inflammation
Thyroid hormone changes in pregnancy
- Decreased TSH with rising HcG in first trimester (inverse relationship)
- Increased thyroxine binding globulin & mobilisation of T3 and T4 (stimulated by high oestrogen state and decreased hepatic clearance)
- Increased Iodine requirements (and potential for goitre if not adequate)
- Ensure measurement of TRAB in pregnant patients with graves to stratify risk of neonatal hyperthyroidism
- Treat hyperthyroidism with PTU in first trimester (hepatotoxicity), then Carbimazole in second and third (scalp defects)
Indications for treatment of subclinical hypothyroidism
- Pregnancy
- TSH level > 10
Kallmans syndrome
Dominant X-linked disorder
Lack of GnRH causing inadequate LH and FSH -> Low testosterone and oestrogen
- Small testes or small breasts
- Primary amenorrhoea in females
- Anosmia due to aplasia of olfactory bulb
- In men and women who desire fertility, replacement of LH and FSH is necessary as alternative as exogenous testosterone and oestrogen suppresses spermatogenous and ovulation
- Can have mild cognitive impairment
BSL targets in pregnancy
Fasting and pre-prandial 4.0–5.5mmol/L
Post-prandial less than 8.0mmol/L at 1h or less than 7mmol/L at 2h
Mechanism SGLT2 inhibitors
Block SGLT2 on the apical membrane of proximal tubule cells to decrease glucose resorption
- Reduces HbA1c%
- Mild reduction BP
- Reduces CVS events
- Mild weight loss
- Reduced uric acid
- Reduced microalbuminuria
SGLT2 side effects
- Euglycaemic ketoacidosis
- UTI
- Increased risk amputations
- Increased risk atypical fractures
- Dehydration
Investigations for Cushings Syndrome
- 24 hour urinary cortisol
- ACTH (+/- dexmethasone high or low dose - but not recommended anymore!)
- Imaging
Vitamin D synthesis
-7-dehydrocholesterol to cholecalciferol (Vitamin D3) via UV light, or Vitamin D3 directly from diet
-Cholecalciferol to calcidiol (25 hydroxyvitamin D) in liver
-Calcidiol to calcitriol in kidneys (1.25 hydroxyvitamin D) via 1 alpha-hydroxylate
Bound testosterone and Oestrogen
60% bound to SHBG
40% bound to Albumin
< 2% free
Changes in SHBG
Increased SHBG - less free androgens
Ageing
Hyperthyroidism
Liver disease
HIV
Oestrogen
Phenytoin
Tamoxifen
Decreased SHBG - more free androgens
Obesity -> weight loss improves PCOS
Insulin resistance
Hypothyroidsim
GH excess
Steroids
Androgens or progestins
Nephrotic syndrome
NAGMA
ABCD
•Addisons (adrenal insufficiency)
•Bicarbonate loss (GI or Renal)
•Chloride excess
•Diuretics (Acetazolamide)
Post-exercise hypoglycaemia in diabetics
- Decrease long-acting insulin
- Consume carbs pre-bed post-exercise
- Ensure BSL > 7 pre-bed
Diagnosis and Rx Acromegaly
inadequate suppression GH and IGF-1 with GTT
Rx Octreotide (somatostatin analogue), Pegvisomant (GH receptor antagonist) or Cabergoline
Somatostatin has negative feedback on GH release
Cinacalcet MOA
Calcium mimetic to negatively feedback on PTH
Drugs inducing hyperprolactin
- Antipsychotics ie. respiradone
- Anti-emetics - Metaclopramide/Domperidone
- Antidepressants - TCAs, MAOi’s
- Analgesia - Opioids
- Anti-hypertensives - Verapamil, Methyldopa
Genetic factors of obesity
Low adiponectin
MC4-r mutations
Leptin and Ghrelin
Leptin reduces appetite by releasing MSH- alpha from POMC to act at MC4-receptors. Also inhibits Ghrelin release.
Ghrelin increases appetite by releasing Agouti-related peptide via Neuropeptide Y to act on MC4-R receptors. Increased levels in Prader WIlli syndrome.
Congenital Adrenal Hyperplasia
- Due to 21 hydroxylase deficiency
- Shunts to form testosterone instead of aldosterone and cortisol
- High levels of hydroxyprogesterone
- Often results in bilateral adrenal lesions
- Most common cause of ambigous genitalia
- Low cortisol
- Low aldosterone
- High Testosterone
Hormone changes pregnancy
Increased beta-HCG
Increased T3 & 4, but Increased Thyroid binding globulin with decreased free T3/4
Decreased TSH in first trimester but will start to increase with B-HcG decline
Increased oestrogen and testosterone
Decreased LH & FSH
Increased prolactin
Secondary hyperaldosteronism
- High Renin
Ddx; - Renal Artery stenosis
- Aortic coarctation
- Reninoma
- Gitelmans syndrome - mimics thiazide in grown-ups
- Barters syndrome - mimics loop diuretics in Babies
Primary hyperaldosteronism
- Aldosterone secreting Adenoma (Conns syndrome)
Acarbose MOA
Glucosidase inhibitor to reduce saccharine breakdown & resorption at GI tract
MUDPILES
Causes of anion gap metabolic acidosis
MUDPILES
Methanol
Uraemia
DKA
Paracetamol overdose
Isoniazid
Lactic acidosis
EtOH
Salicylates
Causes NAGMA
USED CAR
- Utero-enterostomy
- Small bowel fistula, pancreatic fistula
- Extra Chloride
- Diarrhoa
- Carboic anhydrase inhibitors (Acetazolamide - prevents resorption HCO3)
- Addisons disease
- RTA
