Endocrine Flashcards
Diabetics who do NOT benefit from intensive HbA1c control
Patients with recurrent hypos
Patients with macrovascular complications
Young children <13 y.o
Drug to avoid in LADA
SGLT2 –> DKA
% beta cell reduction at diagnosis of T2DM
50%
Insulin secretion phases
First phase: peak 2-4 minutes, nadir 10-15 minutes
second phase: plateaus at 2-3 hours
Which insulin phase response is lost in DM
First phase response lost in both DM1 and 2 - evidenced by impaired post-prandial hyperglycaemia (OGTT)
Cells that secrete GLP-1
L cells in the jejunum/ileum
Effects of GLP-1
Stimulate insulin secretion
Suppress glucagon secretion
Slows gastric emptying
Improves insulin sensitivity
Decreases food intake
Effects of DPP4
Increase endogenous incretin levels
Lower HbA1c by 0.5-1%
Weight neutral
CV neutral
GLP-RA
Supraphysiologic incretin effect
Weight loss
Improved CV and renal benefits
-Decreased CV events but not decreased CV death
Where is filtered glucose reabsorbed
90% in S1 proximal tubule
SGLT2-i
Act on Na+/glucose co-transporter in PT
Genital candida affects 10%
Benefits in HFpEF and HFrEF in those with and without DM
Fewer renal outcomes
Appetite suppressant signals
PYY, CCK, GLP-1, amylin, insulin, leptin
Appetite stimulating signals
Ghrelin, Neuropeptide Y, AgRP
Most effective measure for weight loss
Gastric bypass and banding - only interventions which show benefit beyond 2 years
Diabetic nephropathy
1 cause of ESRF
Tubulointerstitial fibrosis postulated to be the major determinant of progression
Hypertension best predictor of CKD in T2DM
Proteinuria and CKD independent risk factors for CVD
Diabetic retinopathy
1 cause of blindness in 20-74y.o
Non proliferative - VA normal
Proliferative - neovascularisation and macula oedema
Treatment of diabetic retinopathy
Fenofibrate has some benefit
Laser
Anti-VEGF agents
Vitreo-retinal therapy
Diabetic neuropathy
15% lifetime risk of amputation
Most commonly causes a distal symmetric polyneuropathy
Loss of 10g monofilament and decreased vibration predict ulcers
Features of cardiac autonomic neuropathy
Resting tachycardia
Postural hypotension
Greatest risk factor for diabetic foot disease
Previous ulceration or amputationM
Management of peripheral neuropathy in diabetes
TCA first line
Gabapentin
Pregabalin
Factor which has the biggest benefit for macrovascular DM complications
reducing systolic BP
then LDL
then HbA1c
Goal BP in DM
<140/80, or <130 if high stroke risk
Conditions associated with DM
Psoriasis
Osteoporosis and fracture risk
Depression
Dementia
Malignancy (liver, pancreas, endometrium, colon, breast, bladder)
PCOS
Malignancy which DM is protective for
Prostate
T1DM antibodies
Anti-GAD (most specific)
Anti-islet cell
Anti-insulin
Anti-ZnT8
C peptide levels in DM
Low in DM1
Normal or high in DM2
Features of CAH
Increased ACTH leads to hyperpigmentation and adrenal enlargement
Abnormal external genitalia
Signs of hyperandrogegism: increased growth, acne, hirsutism, premature pubarche, menstural irregularities and PCOS. Premature balding and infertility in males
Defect in CAH
Mutation in the gene encoding for 21-hydroxylase - usually converts adrenal precursors into aldosterone, cortisol. Instead covered to DHEA and testosterone. Autosomal recessive
Serum cortisol measurement vs urine and saliva cortisol measurement
Serum measures total cortisol, others measure free cortisol
Cortisol binding globulin
90% of cortisol is bound to CBG
Factors that increase CBG
Pregnancy, oestrogen, hyperthyroidismF
Factors that decrease CBG
Inflammation/acute illness, hypothyroid, protein deficiency, liver cirrhosis, CBG gene mutations
Causes of primary adrenal insufficiency
Autoimmune
Infection (mycobacteria)
Tumours
Bleeding
Bilateral adrenalectomy
Infiltrative (sarcoid, haemochromatosis)
Genetic (CAH)
Meds (ketoconazole, fluconazole, checkpoint inhibitors)
Causes of secondary adrenal insufficiency
Pituitary tumours
Iatrogenic (Surgery, RTx)
Trauma/vascular
Diagnosis of adrenal insufficiency
- Early morning cortisol <80 (check ACTH too)
- Short synacthen test
Consider insulin tolerance test for ACTH reserve - Adrenal CT if primary suspected (increased ACTH and increased renin)
Rationale for checking for concurrent hypocortisolism when hypothyroidism is diagnosed
Can co-exist in autoimmune polyglandular syndrome - and if thyroxine is commenced it can precipitate a life threatening adrenal crisis because thyroxine accelerates metabolic clearance of cortisol
Adrenoleukodystrophy
X-linked recessive
2 phenotypes
a) cerebral ALD - childhood - dementia, blindness, quadriplegia
b) adrenomyeloneuropathy - spasticity, distal polyneuropathy, young men
Diagnosis with elevated serum very long chain fatty acids
Screen any young man with adrenal insufficiency
Adrenal insufficiency treatment
Primary: Hydrocortisone AND fludrocortisone and consider DHEA
Secondary: hydrocortisone only
Addisons presentation
Weakness, fatigue, anorexia, N/V, salt craving
exam: hypotension, dehydration, hyperpigmentation
Bloods: hyponatraemia, hyperkalaemia, metabolic acidosis, decreased BGL
Presentation of Cushing’s disease
Hyperpigmentation, easy bruising, thin skin, spinal osteoporosis
Treatment of Cushing’s disease
Surgery
If surgery non-curative - medical osilodrostat
Workup for Cushing’s syndrome
Perform 2 of 3 to confirm hypercortisolism
24 hr urine cortisol
overnight 1mg DST
late night salivary cortisol
Then do ACTH to see if dependent or independent
If ACTH dependent
1. High dose DST
2. Consider MRI pituitary
3. BIPPS (unless adenoma >6mm and suppression with high dose DST - then straight to surgery). Central to peripheral ACTH >2 consistent with Cushing’s disease
4. GATATE imaging to localise if ectopic ACTH suspected
Potassium in ectopic ACTH
Very low as very high glucocorticoid excess overwhelms capacity of 11-betahydroxylase enzyme and therefore mineralocorticoid receptors ARE affected. Not affected in Cushing’s disease.
Low renin, high aldosterone
Primary hyperaldosteronism (conns, hyperplasia)
high renin, high aldosterone
secondary hyperaldosteronism (renal artery stenosis, diuretics)
low renin, low aldosterone
mineralocorticoid excess (exogenous, Cushings, licorice)
Workup for hyperaldosteronism
- normalise K+
- liberal salt intake
- stop offending meds (spiro etc)
- ARR
- If elevated, confirm with saline infusion testing
- if Aldo not suppressed –> adrenal CT to exclude carcinoma
- adrenal vein sampling
Management of unilateral adrenal hyperplasia causing hyperaldosteronism
Unilateral adrenalectomy first line
Spiro, amiloride, eplerenone 2nd line
Management of bilateral adrenal hyperplasia causing hyperaldosteronism
Spiro, amiloride, eplerenone first line
-Monitor renin, if remains low, increase dose
unilateral adrenalectomy second line
Glucocorticoid remediable hyperaldosteronism
Familial hyperaldosteronism type 1
Rare autosomal dominant condition
Aldosterone receptors responsive to ACTH
Causes arterial hypertension at a young age (rather than 3rd-6th decade in Conn’s/hyperplasia)
Suspect if strong FHx of death due to CVA
Phaeochromocytoma presentation
Triad of headache, palpitations, sweating
Genes in phaechromocytoma
Genetic link 50% of the time
MEN2
vHL
NF-1
Features of malignancy in phaeochromocytoma
> 5cm
Extra-adrenal
SDHB
Dopaminergic subtype
High Ki-67
Testing in phaeochromocytoma
Plasma metanephrines
Genetic testing
Ga-DOTATE-PET
Management of phaeochromocytoma
Surgery with alpha blockade (get BP <130/80) then beta-blockade if tachycardia
Chemo and RTx
Klinefelters syndrome
47 XXY
Most common cause of primary hypogonadism
Tall stature, small testes
Effects of testosterone replacement in hypogonadism
Improves sexual function, energy, osteoporosis, Hb, muscle mass, decreased fat mass
Does not improve spermatogenesis as this is dependent on FSH/LH
Conditions associated with increased SHBG
Ageing
cirrhosis
hyperthyroidism
anticonvulsants
oestrogen
HIV
Conditions associated with low SHBG
Moderate obesity
Nephrotic syndrome
Hypothyroidism
Glucocorticoids
Acromegaly
DM
Raloxifene effect on fracture risk
Decreased vertebral but not non-vertebral fractures
Bisphosphonates effect ono fracture risk
Decreases both vertebral and non-vertebral fractures
Atypical femoral fractures
Associated with bisphosphonate use, as well as steroids and PPIs
More common in Asian women
Management
-Stop bisphosphonate
-If unstable operate
-If stable and no pain - WBAT and monitor with MRI
-If stable and pain - nail fixation
PTH effect on bone
Continuous PTH = bone resorption
Intermitten PTH = anabolic
Teriparatide
Recombinant PTH
For patients with severe osteoporosis and recurrent fractures despite anti-resorptive
Osteomalacia presentation
Bone pain, stress fractures, myopathy (waddling gait)
Osteomalacia pathophysiology
Renal phosphate wasting
FGF23 regulates urinary phosphate
Iron deficiency and IV iron replacement both cause increased FGF23 and therefore decreased serum phosphate
X-linked hypophosphataemic rickets
PHEX gene
Pain, stiffness, gait abnormalities
Poor dental condition, short stature, hearing loss
Pseudofractures are common (femur, hands/feet)
X-linked hypophosphataemic rickets treatment
Burosumab - Anti-FGF23 Ab
Paget’s disease pathophys
Primarily increases osteoclast activity
(osteoblasts activity also Increased)
Greatly increased bone turnover leading to abnormal bone, overgrowth and severe pain
Paget’s disease presentation
Bone pain
Deformity
OA of adjacent joints
Fractures
Spinal stenosis
Paget’s disease treatment
Bisophosphonates (zoledronic acid 5mg once yearly)
Calcitonin
Analgesics
Surgery
Causes of PTH dependent hypercalcaemia
Hyperparathyroidism (primary or tertiary)
Abnormality of CaSR (FHH, autoimmune)
Causes of PTH independent hypercalcaemia
Cancer (myeloma, PTHrP, osteolytic mets)
Increased calcitriol (sarcoid/granulomatous disease)
Excess GI calcium absorption (milk-alkali syndrome)
Endocrine (thyrotoxicosis, phaeo, Addisons)
Immobilisation
Medications that cause hypercalcaemia
lithium
thiazide
calcitriol
calcium carbonate
antacids
Indications for surgery in asymptomatic primary hyperparathyroidism
Serum Ca >0.25mmol/ ULN
CrCL <60ml/min
Urinary Ca >400mg/day (and/or nephrocalcinosis)
BMD T-score <-2.5 or vertebral fracture
Age <50
If non-surgical give bisphosphonate to reduce fracture risk
Graves disease antibody
TSHr auto-antibody
Graves disease associations
Fhx of autoimmune thyroid disease
Recent iodine exposure
Postpartum state
Graves disease features
Thyrotoxicosis, diffuse goitre, eye signs, pre-tibial myxoedema
Graves disease management
Beta-blocker for symptoms
1. Thionamides (carbimazole or PTU)
2. radioactive iodine
3. Surgery
Thionamides and their side effects
Carbimazole and PTU
Titrate dose to TSH
Treat for at least 12-18 months, 50% change of long-term remission
most relapses occur within 6 months of drug cessation
SE: Rash, LFT derangement, neutropenia, pANCA vasculitis
Radioactive iodine and its side effects
Safe except in young women and those with significant eye disease
Takes months to work
Usually causes hypothyroidism
Thyroid surgery and side effects
Damage to parathyroid
Graves can recur in thyroid remnant
PTU mechanism of actions, serious side effects and pregnancy safety
Blocks conversion of T4 to T3
Can be associated rarely with fulminant inflammatory hepatitis
Safer than carbimazole in first trimester
Enters breast milk but safe if <300mg/day
Carbimazole mechanism of action
Inhibits uptake of iodine by the thyroid
Can cause non-threatening cholestasis
Enters breast milk, but safe if <30mg/day
Risk factors for progression of Graves ophthalmolpathy
Smoking
Radioactive iodine therapy
Iatrogenic hypothyroidism
Management of Graves ophthalmopathy
Mild: selenium
Mod-sever: IV steroids +/- mycophenolate
Sight threatening: IV steroids and if poor response after two weeks then surgical decompression
How to adjust thyroxine dose going into pregnancy
Increase by 1.3x
Thyroiditis features
TENDER
low tc99 uptake
Use propranolol and NSAIDs/steroids
PTU and carbimazole don’t work
Treating amiodarone thyrotoxicosis
Cease + give thionamide + steroid
Colestyramine if persistent _ serious
Surgery if no response
radioactive iodine not useful
Lithium effect on thyroid
Hypothyroid
Anti-CTLA4 effect on thyroid
Hypophysitis and central hypothyroidism (5%)
thyroiditis (2%)
Anti-PDL1 effect on thyroid
Thyroiditis (4%)
Central hypothyroidism (<1%)
Alemtuzumab effect on thyroid
Anti-CD52
Graves disease is common (15%!!!!)
When to treat subclinical hypothyroidism
TSH >10
Pre-conception/early pregnancy
When to treat subclinical hyperthyroidism
TSH <0.1
Co-existing AF/osteoporosis
Symptoms of thyrotoxicosis
Lenvatinib
Iodine refractory, progressive thyroid cancer not appropriate for surgery
Markers for recurrent disease in follicular thyroid ca and medullary thyroid ca
Follicular = thyroglobulin
Medullary = calcitonin
How to investigate for ACTH deficiency and how to replace
Insulin tolerance test - check cortisol response
Treat with glucocorticoid (Dex) does not need mineralocorticoid replacement
How to investigate for LH/FSH deficiency and how to replace if low
Diagnose based on low testosterone or amenorrhoea accompanied by low or normal LH/FSH
Treat with testosterone or OCP/HRT unless there is a history of prostate or breast cancer
For fertility use hCG for men or ovulation induction with FSH/hCG
How to investigate for GH deficiency and how to replace if low
Insuline tolerance test or glucagon stimulation test
Treat with daily s/c growth hormone
Features of prolactinoma
Hypogonadism (infertility, amenorrhoea)
Breast tenderness and discharge
High serum PRL
Why exclude hypothyroidism when high prolactin is found
TRH stimulates prolactin release
Prolactinoma management
Bromocriptine or cabergoline with aim to normalise prolactin
May withdraw treatment after 2-4 years if prolactin is normal and tumour has involuted >50% and is >5mm from optic chasm
60% will not recur within 5 years though lifelong follow-up needed
Features and diagnosis of acromegaly
Elevated IGF-1 (not GH) in the setting of acral enlargement, diabetes, osteoarthritis, sleep apnoea, hypertension
Thyroid cancer most common cancer associated with acromegaly
Management of acromegaly
Surgery first line
Can trial somatostatin receptor agonist (octreotide, lanreotide) prior to surgery
Surgical cure = normal IGF1 and GH suppression after OGTT
Elevated IGF-1 post surgery for acromegaly
Aim to normalise IGF1 to reduce risk of death
Dopamine agonist first line, then octreotide, then pegvisomant
Side effects of octreotide, lanreotide, pasireotide
Gallstones, abdominal pains
Pasireotide may cause diabetes
Craniopharyngoma presentation
Diabetes insipidus
Hyperphagia
Ant. pituitary deficiencies with increased prolactin
Craniopharyngoma mutation
Some carry BRAF mutations that respond to dabrafenib
Pituitary apoplexy presentation
Sudden headache +/- neuropraxia
Pituitary apoplexy management
IV steroid (4mg dex or 50mg hydrocort QID)
Imaging
Surgery if CN palsy present
GH deficiency presentation
Emotional and physical fatigue
Contraindications to GH replacement
Concurrent active malignancy or severe diabetic retinopathy
Diagnosis of diabetes insipidus
Water deprivation test to induce post >300 to see if urine Osm >500-600
or
hypertonic saline infusion to induce Na+ >150mmol to assess plasma copeptin
Copeptin >4.9 = primary polydipsia
Copeptin <4.9 = central DI
Management of diabetes insipidus
Tolvaptain or conivaptain
Carney syndrome
PPKARA1A mutation
Spotty skin pigmentation, myxomas, testicular, adrenal and/or pituitary adenomas or hyperplasia
T4 half life
T3 half life
TSH half life
T4 half life 7 days
T3 half life 10 hours
TSH half life 30 minutes
Receptor implicated in Graves orbitopathy
IGF-1
Medication targeting IGF-1 receptor in graves orbitopathy
Teprotumumab
