Endocrine Flashcards
Which Thyroid function test is tested at first?
TSH first, if TSH abnormal then free T4.
Thyrotoxic periodic paralysis
• Pathogenesis: thyrotoxicosis + β-adrenergic response
o Overactive Na/K ATP-ase (fig.)
o Precipitating factors: adrenaline or insulin (cause transcellular shift of K), e.g. heavy meal, exercise
• Clinical features
o Common presentation: a Chinese young male cannot stand up from chair after a heavy meal or exercise
o Proximal myopathy (LL»_space; UL) with preserved reflexes (c.f. GBS)
o No bulbar / respiratory involvement, sensory intact
o Symptoms of thyrotoxicosis (c.f. familial hypoK PP)
• Investigations:
o Bloods: electrolytes (K decrease), CPK, TFT
o ECG: hypoK (PR prolongation, ST depression, U wave)
• Management:
o HDU/ICU Monitoring: ECG, RFT
o K supplement: IV KCl in NS (not D5) / oral K, note rebound hyperK (total body K is high —> shift from cell)
o Propranolol: to blunt Na-K ATPase
o Definitive anti-thyroid treatmen
- Carefullly replace potassium
-> only small doses are needed to normalise potassium level as there is no net loss of body potassium
-> Excessive replacement may cause rebound hyperK
Differential diagnoses of sellar mass
• Pituitary adenoma (MC)
• Craniopharyngioma (benign tumor
from Rathke’s pouch, often cystic)
• Other tumors: pituitary CA (very
rare), metastatic tumor (esp. breast),
germ cell tumor, lymphoma
• Non-neoplastic mass: Rathke cleft
cyst, arachnoid cyst
Mass effects of pituitary mass
• Headache: stretching of diaphragm sellae / dura
• Visual defect: classically bitemporal hemianopia (optic chiasm), but can also be unilateral visual loss (optic nerve)
or homonymous hemianopia (optic tract)
• Diplopia: lateral extension of sellar mass into cavernous sinus
• Disconnection hyperprolactinaemia: decreased inhibition on prolactin secretion
Types and associations of pituitary of adenoma
• Microadenoma (<1cm) vs macroadenoma (≥1cm)
• Functional vs non-functional
• Associations: MEN1, MEN4, Carney complex, McCune-Albright syndrome
Pituitary microadenoma cause what?
Hormone excess:
- Hyperprolactinaemia
- galactorrhoea
- amenorrhoea
- hypogonadism - Acromegaly
- headache
- sweating
- change in shoe and ring size - Cushing’s disease
- weight gain
- bruising
- myopathy
- hypertension
- striae
- depression
Clinical features of macroadenoma
- Local complications
- headache
- visual filed defect
- disconnection hyperprolactinaemia
- diplopia (cavernous sinus involvement)
- acute infarction/expansion (pituitary apoplexy) - Hypopituitarism
- growth hormone —> lethargy
- gonadotropins —> lethargy, loss of libido, hair loss, amenorrhoea
- ACTH —> lethargy, postural hypotension, pallor, hair loss
- TSH —> lethargy
- vasopressin (ADH) —> thirst and polyuria - hormone excess
- hyperprolactinaemia
- acromegaly
- Cushing’s disease
Ix and Mx of pituitary mass
Investigations:
• Hormonal profile
o Pulsatile secretion (e.g. GH, ACTH): require dynamic testing
o Constant secretion (e.g. PRL, TSH, LH/FSH): can be directly measured (usually 9am)
• Anatomical diagnosis:
o Skull X-ray: double flooring (asymmetrical enlargement)
o MRI pituitary (T1-weighted)
o Visual field testing (perimetry)
Management of pituitary tumour:
• Non-functional microadenoma: observe with serial hormone measurement and MRI scan
• Functional / Macroadenoma / Mass effect +ve:
o Prolactinoma: medical therapy (DA agonist) (1st line) —> surgery / RT
o Others (e.g. acromegaly, Cushing’s disease): surgery (1st line) ± adjunct RT for residual tumor
What is pituitary apoplexy?
• Definition: sudden haemorrhage into pituitary gland
• Clinical features
o Increased ICP: sudden-onset excruciating headache, n/v, altered mental state, neck rigidity and photophobia
o Compression on optic pathway: visual field defect
o Involve Cavernous sinus: diplopia (CN3/4/6)
o Other neurological manifestation: extravasation of blood into SAH —> meningism
o Hypopituitarism: severe hypoNa (due to adrenal crisis/SIADH/hypothyroidism)
• Investigations
o CT/MRI pituitary for definitive diagnosis
• Management: Surgical decompression + steroid cover
o Indicated if signs of increase ICP, decrease GCS, or evidence of compression onto surrounding structures
Etiology and clinical features of Hypopituitarism
Etiology:
- tumour : Non-functioning adenoma (MC)(mass effect), craniopharyngioma (stalk effect)
- iatrogenic: hypophysectomy, post-RT
- infarction: pituitary apoplexy, Sheehan’s syndrome
- others: TB infection, empty sellar syndrome
Clinical features:
- mass effect
- hormone deficiency: usually in the order of GH> LH/FSH>ACTH>TSH
o Acute insult may cause Addisonian crisis
Ix of Hypopituitarism
• MRI pituitary & formal visual field testing
• Hormonal function assay
Adrenal —> ACTH/ LDSST —> Clinical monitor
Thyroid —> fT4/ TSH —> fT4 monitor
Gonad —> LH/FSH/E2/T —> Testosterone (measure mid-way between injection)
• Management
o Hydrocortisone 20mg/day
- Avoid nocte (risk of insomnia)
- Stress dose: double dose (risk of Addisonian crisis) be aware of DI unmasking since hydrocortisone destroy ADH
o Thyroxine 1.6mcg/kg/day
- Start AFTER hydrocortisone is given (risk of Addisonian crisis) Thyroxine destroys cortisol
o DDAVP sublingual
o Sex hormone: depend on gender & fertility wish
1. No fertility wish
-Male:
—> Testosterone (more physiological): IM Sustanon Q4 weeks (S/E: BPH, dLFT, polycythemia)
-Female:
Combined oral contraceptive pills (E+P)
- Fertility wish
-Male:
—> Gonadotropins/ GnRH (testosterone does not restore spermatogenesis)
-Female:
—> Gonadotropins/ GnRH
Etiology and clinical features of hyperprolactinaemia
Aetiology (SAQ!)
• Hypothalamic/ pituitary: pituitary tumour (non-functioning, prolactin-secreting, prolactin & GH-secreting), pituitary stalk damage (e.g. RT, trauma, tumors)
• Drug-induced: DA antagonist (e.g. metoclopramide, domperidone*), DA-depleting drugs (e.g. methyldopa)
• Systemic disorders: primary hypothyroidism (TRH), CKD, liver cirrhosis
• Physiological: pregnancy / lactation, stress, chest wall stimulation (e.g. herpes zoster)
*Domperidone in hyperprolactinaemia
• Domperidone does not cause EPSE:
not cross BBB (c.f. metoclopramide)
• Domperidone causes hyperPRL:
pituitary has no BBB
Clinical features
• Mass effect
• Galactorrhoea (F) / Gynaecomastia (M)
• Hypogonadotrophic hypogonadism:
o Male: decrease libido, decrease shaving frequency, erectile dysfunction, infertility
o Female: amenorrhoea, infertility, climacteric symptoms, decrease BMD
• Concomitant acromegaly (GH as common lineage)
Presentations varies with gender & pathology
• Pathology: prolactinoma presents earlier, non-Functioning pituitary adenoma presents late (mass effect: macroadenoma ≥ 1cm)
• Gender: female presents earlier (amenorrhoea), male presents late
Ix of hyperprolactinaemia
• Pregnancy test
• Prolactin level: PWH assay automatically ruled out macroPRL
o <500 = normal
o >1000: consider prolactinoma
o >5000: highly suggestive of macroprolactinoma
o >100,000: high-dose hook effect (false negative)
• Underlying cause:
o MRI pituitary: indicated if symptomatic / PRL > 1000 / evidence of pituitary insufficiency (e.g. hypoT4)
o RFT, LFT, TFT
• Screen other endocrine axes: IGF-1, ACTH/ cortisol, TSH/ T4, LH/ FSH/ E2/ T
Mx of hyperprolactinaemia
• Dopamine agonist (e.g. bromocriptine, cabergoline) – 1st line (decrease PRL secretion + decrease size of prolactinoma)
o Aim: to avoid long-term consequence of hypogonadism
o Indications:
- Symptomatic (regardless of serum prolactin)
- Serum prolactin >10,000
- MRI pituitary macroadenoma
- MRI pituitary microadenoma + hyperPRL
o Drug choice: cabergoline has higher efficacy, less S/E, less frequent dosing; bromocriptine in pregnancy
o Duration:
- Taper off after 2 years of normal PRL levels (for microadenoma only)
- Otherwise keep until menopause
o S/E: n/v, postural hypotension, constipation, psychosis, retroperitoneal fibrosis, cardiac valve fibrosis (TR)
o Advise contraception prn (fertility might return after PRL normalizes)
• Transsphenoidal surgery (TSS) ± adjuvant RT - 2nd line
o Indications:
- Remain symptomatic/ high PRL despite medical treatment
- DA agonist fails to shrink the tumour significantly (macroadenoma)
- Pituitary apoplexy
- Planning pregnancy
o Adjuvant RT (EBRT / stereotactic radiosurgery): if residual mass after resection and histology shows radiosensitive tumour
o Complications & management:
- Hypopituitarism: high dose IV hydrocortisone since the day of surgery
- DI —> SIADH —> DI: monitor I/O, Na, urine osmolality daily
- CSF rhinorrhoea: test fluid for beta transferrin
- Diplopia: damage to optic chiasm
• Issues in pregnancy:
o Considering conception: bromocriptine is preferred (∵shorter-acting than cabergoline)
o Consider transsphenoidal surgery before conception
o If pregnant:
- Stop bromocriptine once pregnancy is confirmed
- Monitor visual field and MRI if symptomatic —> may need to restart bromocriptine
- Stop bromocriptine after delivery (C/I in breastfeeding)
Definition, Etiology and clinical features of acromegaly
Definitions
• Acromegaly: GH excess in adults (after epiphyseal fusion)
• Gigantism: GH excess in children (before epiphyseal fusion)
Aetiology
• GH-secreting pituitary adenoma (>95%)
• Others: hypothalamic GHRH ganglioneuroma, ectopic GH (e.g. carcinoid)
Clinical features
() = signs of active acromegaly
• Mass effect: headache, visual field defect, etc
• MSK:
o Enlarged extremities (spade-like hands, carpal tunnel syndrome, OA knee)
o Facial bones (prominent supraorbital ridges, frontal bossing, prognathism / mandibular overgrowth, wide-spaced teeth)
• Skin & soft tissues: thickened skin / skin tags, hyperhidrosis (>80%), hirsutism, enlarged lips/ nose/ tongue (macroglossia), deep & hollow-sounding voice, OSA
• Organomegaly: cardiomyopathy (HT, IHD), hepatosplenomegaly, risk of CRC
• Secondary insulin resistance: IGT / DM, acanthosis nigricans
• Disease association: MEN-1, Carney complex (cardiac myxoma, spotted skin pigmentation), McCune Albright syndrome (precocious puberty, café-au-lait spots, fibrous dysplasia)
Ix, Mx of acromegaly
Investigations
• Spot IGF-1 (GH not useful: diurnal rhythm, influenced by exercise & stress, short half-life)
• Extended OGTT: gold standard
o Procedure: overnight fasting —> 75g glucose PO —> check IGF-1 at 0h & glucose + GH Q30min until 3h
o Confirm if cannot suppress GH to <2.5 mIU/L
• MRI pituitary & perimetry
• Assessment of other endocrine axes
• Screen for complications: BP, ECG, echocardiogram, colonoscopy, sleep study (if suspected OSA)
Management
• Transsphenoidal hypophysectomy – 1st line, Cx: hypopituitarism, recurrence
• ± Adjuvant RT (EBRT / SRS e.g. Gamma knife surgery): if persistent increase IGF-1
(residual adenoma after resection common); can take 10 years to effect
• Medical therapy – 2nd line
o Indications:
- Not a surgical candidate: medical comorbidities, large unresectable tumours
- Bridging for RT to take effect (may need 5-10 years)
- Dopamine agonist (PO) (D2 receptor present in adenoma, may have GH prolactin co-secreting tumor)
- E.g. Bromocriptine, Cabergoline
- S/E: n/v, postural hypotension, constipation, psychosis, retroperitoneal fibrosis - Somatostatin analogues (IM injection Q4week)
- E.g. Octreotide LAR (Sandostatin), Lanreotide, Pasireotide
- S/E: n/v, gallstone, impaired glucose tolerance (decreased insulin, esp. pasireotide) - GH receptor antagonist (SC daily) (not available in HA)
- E.g. Pegvisomant
- S/E: dLF
Monitoring:
• Clinical S/S
• Annual random GH, IGF-1
• Annual pituitary hormone profile
• Colonoscopy
• MRI pituitary (not routine)
Ix of thyroid disease
Thyroid imaging
• Radioisotope thyroid scan (123I) (Technetium-99): preferred in thyrotoxic patients with nodular thyroid
o Supersede RAIU (lower radioactive dose, higher resolution)
o Differentiate hot nodule (low malignant risk) vs cold nodule (5% malignant risk à USG for FNAC)
o C/I: pregnancy, breastfeeding
o Different uptake patterns (need to know!)
• Thyroid ultrasound +/- FNAC: preferred in euthyroid/ hypothyroid patients
o Measure size of gland
o Differentiate solid vs cystic nodule
o Facilitate FNAC
Anti-thyroid antibodies
• TSH receptor antibodies*: Graves’
• Anti-TPO, anti-thyroglobulin: Graves’, Hashimoto’s thyroiditis
Investigations for complications
Hyperthyroidism
• Bone profile: increased Ca, increased ALP (bone remodelling / CMZ-induced
cholestasis)
• RFT: decreased K (TPP)
• decreased red cell zinc
Hypothyroidism:
• CBC: macrocytic anaemia (non-megaloblastic)
• Electrolytes: hypoNa (fluid retention)
• Lipid: secondary cause of hyperlipidaemia
• CK increased: thyroid myopathy (c.f. much higher CK in rhabdomyolysis)
• Prolactin increased : due to TRH increased
Etiology of Cushing’s disease
Aetiology
• ACTH-dependent
o Pituitary (Cushing’s disease): ACTH-secreting pituitary adenoma (85% endogenous causes)
o Ectopic: ACTH-secreting tumour (e.g. SCLC, carcinoid, MTC)
• ACTH-independent
o Adrenal: hyperplasia/ adenoma/ carcinoma
o Exogenous: long-term use of exogenous glucocorticoids (MC overall)
• Pseudo-Cushing’s (hypercortisolism state): obesity, alcoholism, stress, depression, pregnancy, CYP3A4 inducers
Clinical features of Cushing’s disease
Skin:
- Moon face, buffalo hump, enlarged fat pads in SCF
- Thinning of skin, easy bruising, purplish striae (∵protein catabolism, ↓Collagen synthesis)
- Hirsutism, acne (↑ACTH —> ↑androgen)
- Hyperpigmentation (↑ACTH)
- Acanthosis nigricans (insulin resistance)
MSK:
- Proximal myopathy
- Glucocorticoid-induced osteoporosis (osteoblast inhibition, RANKL expression)
Immune:
- Immunosuppression: increased infection risk
Metabolic:
- HT (GC + MC)
- Glucose intolerance (GC)
- Central obesity (cortisol-stimulated appetite + lipogenesis + adipocyte differentiation)
- ± Hypothyroidism (cortisol suppresses TSH & inhibit peripheral deiodination)
Reproductive:
- Menstrual disturbance (F), impotence / loss of libido (M) (hypogonadism)
Psychiatric:
- Insomnia, emotional lability, psychosis
Eye:
- Glaucoma, cataract (posterior subcapsular)
Ix and Mx of Cushing’s syndrome
Ix:
1. Screening —> ONDST, 24hr UFC, LDDST/late night salivary cortisol x 2/ late night plasma cortisol
- Diagnose cushing’s if
A. 2 positive screening test +/- high pre test probability by clinical presentation
B. 24hr UFC >3-4x ULN
Exclude Cushing’s if
A. Superseded ONDST / 3 normal UFC
B. 2 normal screening test - Rule out pseudo-Cushing’s
A. LDDST+CRH: give CRH 2h after last dose of dexamethasone, measure cortisol 15 min later —> cortisol>38nmol/L = Cushing’s
B. Late night salivary cortisol - ACTH dependent / Independent
A. ACTH
B. CRH stimulation or DHEAS - ACTH independent
—> CT abdomen with fine cut
—> adrenal sampling - ATCH-dependent Cushing’s
A. MRI pituitary + CRH stimulation test(pituitary higher rise in peak ACTH & cortisol, ectopic no response)
B. IPSS (bilateral inferior petrosal sinus sampling —> indicated if MRI & CRH test equivocal: pituitary ACTH—>petrosal-to-perpheral ACTH >2 or >3/ HDDST / 8mg ONDST
Definitive treatment
Cautions
• Peri-operative steroid cover as normal HPA axis is usually suppressed
• Pre-operative antibiotics ± anticoagulation: high risk of infections & thromboembolism
• Post-operative glucocorticoid ± mineralocorticoid supplement until HPA axis returns (take around 1 year) —> Synacthen test before stopping supplements
Pituitary
• Trans-sphenoidal surgery: microadenomectomy or subtotal resection of anterior pituitary
o Post-op Day 5: check 9am cortisol to see if there is residual tumor —> require RT
o Monitor all pituitary hormones (T4, LH/FSH, GH, IGF-1, prolactin, reproductive hormones)
• Pituitary RT: if unresectable / recur / fertility desired
• Bilateral adrenalectomy if failed TSS, but need prophylactic pituitary RT to prevent Nelson’s
syndrome (negative feedback —> ↑ACTH stimulates tumor growth and pigmentation)
Ectopic:
- Workup for malignancy
• Resectable: surgical excision of tumour
• Unresectable: medical therapy
Adrenal:
- Adenoma: unilateral adrenalectomy
- Carcinoma: surgical excision ± adjuvant mitotane (adrenolytic)
Medical treatment:
• Indications in different conditions:
o Cushing’s disease: 2nd line after TSS / RT, control of hypercortisolism before surgery, persistence/recurrence
after surgery
o Ectopic ACTH: unresectable / metastatic / occult malignancy
o Adrenocortical carcinoma: adjuvant therapy to lower cortisol levels
• Drug options:
o Targeting pituitary: Somatostatin analogue (pasireotide), dopamine agonist (cabergoline), osilodrostat
o Targeting adrenal gland: Adrenal enzyme inhibitor (e.g. ketoconazole, metyrapone, mitotane),
glucocorticoid receptor blocker (e.g. mifepristone)
Course after effective therapy
• S/S of Cushing’s syndrome resolve gradually over a period of 2-12 months
• HT, osteoporosis and glucose intolerance improve but may persist
Hypertension
Differential diagnosis (SAQ!!)
• Essential hypertension (95%)
• Secondary hypertension (5%) – important!
o Renal: CKD, GN, renovascular disease (RAS, renal vein thrombosis), PCKD
o Endocrine: 1o hyperaldosteronism, Cushing’s syndrome, phaeochromocytoma, hyperthyroidism, acromegaly
o Respiratory: OSA
o Cardiac: CoA
o Drug-induced: immunosuppressant, sympathomimetic (nasal decongestant), steroid
Important questions
• Symptoms of uncontrolled hypertension: headache, visual disturbance
• Symptoms of end-organ damage: macrovascular, microvascular
• Causes of secondary hypertension
o OSA: heavy snoring, morning headache, EDS
o Renal: oliguria, haematuria, frothy urine
o Endocrine:
- Primary hyperaldosteronism (no specific S/S)
appetite
- Cushing syndrome: steroid use, proximal muscle weakness
- Phaeochromocytoma: paroxysmal headache, palpitation, sweating
- Acromegaly: headache, visual field disturbance, glove & shoe size
- Hyperthyroidism: heat intolerance, weight loss despite good appetite
Investigations
• Fundoscopy for HT retinopathy (fig.):
modified Scheie classification / “SAFE”
o Grade 1: arteriolar narrowing
o Grade 2: AV nicking (arteriole
• Other end-organ damage: ECG, CXR, RFT, CT brain
• CV risk: fasting glucose/ HbA1c, lipids
• Underlying cause: ARR, ONDST, 24h urine catecholamines, IGF-1, TFT
Hypertensive crisis
Definition
• Hypertensive emergency: BP >180/120 + evidence of new/ target organ damage (e.g. HT encephalopathy, acute MI, APO, unstable angina, aortic dissection, AKI, eclampsia)
• Hypertensive urgency: BP > 180/120 but no acute / impending target organ damage
Management of hypertensive emergency
• Admit ICU/CCU with continuous BP monitoring
• Medication:
o IV labetalol 20mg over 2 mins —> Repeat 40mg bolus if uncontrolled at 15min —> IV infusion —> PO
o IV Na nitroprusside (C/I: pregnancy)
o IV Hydralazine (C/I: AMI, aortic dissection)
• Target BP in first hour
o <140: preeclampsia/eclampsia, pheochromocytoma crisis
o <120: aortic dissection
o decreased ≤25% in 1st hour: other cases
Secondary amenorrhea
Definitions
• Primary amenorrhoea: absence of menarche by age of 15 (or by age of 13 without secondary sexual development)
• Secondary amenorrhoea: absence of menses for 6 months who previously had menses
• Oligomenorrhoea: cycle length > 6 weeks
Differential diagnosis
• Physiological: pregnancy, menopause
• Hypothalamic: Kallmann syndrome (GnRH deficiency), brain lesion
• Pituitary: hyperprolactinaemia
• Ovarian causes: PCOS, premature ovarian insufficiency (e.g. Turners, CMV, mumps)
• Anatomic causes: Asherman’s syndrome (extensive intrauterine adhesions due to instrumentation), MRKH syndrome (Mullerian duct agenesis)
Rotterdam Criteria (2 out of 3)
- Hyperandrogenism
- Menstrual irregularities
- Polycystic ovaries on ultrasonography (>12 antral follicles in one ovary and /or ovarian volume >10cm2)
Type of Diabetic mellitus
Primary
- Type 1
- autoimmune
- >85% present:
• Anti-islet cell Ab (e.g. anti- GAD (glutamic acid
decarboxylase) Ab)
• Anti-insulin Ab
- usually Young, thin
- insulin dependence
- less common in FHx
- Associated with Graves’ disease, MG, Addison’s disease, Pernicious anaemia
- High risk of DKA - Type 2
- multifactorial
- Old and fat
- late insulin deficiency and dependence
- strong FHx
- Associated with metabolic syndrome: obesity, HT, HL, PCOS, NAFLD, Hyperuricaemia, past GDM
- low risk of DKA - MODY
- monogenic AD mutation
- total 6 types
- young onset <25
- NO circulating Ab
- multigenerational FHx
- low risk of DKA
- No associations
- Mx: Type 1/3 -> sulphonylurea, Type 5/6–> insulin - Latent autoimmune diabetes in adults (LADA)
- Permanent neonatal diabetes mellitus (PNDM)
- Maternally inherited diabetes with deafness (MIDD): mitochondrial mutation, Mx: CoQ10, C/I to metformin (lactic acidosis)
Secondary cause
• Pancreatic diseases: chronic pancreatitis, CA pancreas, cystic fibrosis
• counter-regulatory hormone: acromegaly, Cushing’s syndrome, pheochromocytoma, glucagonoma
• Drug-induced: steroid, phenytoin, thiazide diuretics
• Genetic syndrome: Down’s, Klinefelter’s, Turner’s, DIDMOAD (Wolfram’s syndrome: DI, DM, optic atrophy, nerve deafness)
DM Ix, PE and diagnostic criteria
Diagnostic criteria (must know!)
American Diabetic Association (ADA) criteria: any one
• HbA1c ≥ 6.5%
• Fasting plasma glucose ≥ 7.0 mmol/L
• 2-hour post OGTT plasma glucose ≥11.1 mmol/L
• Random plasma glucose ≥11.1 mmol/L (in the
presence of classical hyperglycemic symptoms)
FamMed: Asymptomatic + 2 abnormal readings OR Symptomatic + 1 abnormal reading
*Fasting blood glucose 5.6-7 = impaired fasting glycaemia
* OGTT plasma glucose 7.8-11.1 = impaired glucose intolerance
Fasting plasma glucose
- ≥7.0
- Fasting ≥8h
2-hour post-oral glucose tolerance test (OGTT) plasma glucose
- ≥11.1
- Pre-procedure: 3 days of normal diet & activity, fast overnight
- Procedure: at 9am, drink 75g anhydrous glucose in 300mL water in 10min (free water intake in between)
- Measurement: check plasma glucose at baseline & 120min
- (C/I if initial glucose is very high: life-threatening hyperglycemia)
HbA1c
- ≥6.5%
- Glycated haemoglobin that persists throughout the life of the RBC —> mean BG level over the lifespan of RBC (~120 days)
Falsely high if rapid RBC turnover (e.g. pregnancy, haemolytic anaemia, thalassaemia major)
Inaccurate in CKD: hemodialysis, EPO treatment
Alternatives: fructosamine, glycated albumin, 1,5-anhydroglucitol, continuous glucose monitoring (CGM)
Physical examination in diabetes
1. Underlying secondary causes
- Cushingoid features
- Features of acromegaly
2. Signs of DM complications
- Measure BP, postural BP, BMI, urine dipstix
- Skin: ulcers, acanthosis nigricans, necrobiosis lipoidica diabeticorum
Foot:
- Ulcers, deformities, amputation, fungal infection
- Pes cavus, sensory loss [neuropathy]
- Capillary refill, atrophic changes, pulses [PVD]
- Ankle edema [nephropathy]
Neuro:
- Muscle atrophy, small hand muscle wasting, power [neuropathy]
Cardiac:
- Heart failure signs [CAD], carotid bruit, murmurs
Abdomen:
- Lipodystrophy due to insulin injection
Mx of DM
Management overview
• Treatment targets: Individualised glycaemic control
o HbA1c < 7% in general – stricter (6.5%) for young / short DM Hx, less stringent for elderly / advanced DM
o BP < 130/80
o Lipids: HDL >1.0 (M) or >1.3 (F), LDL <1.8 (<1.4 if Hx of CAD), TG < 1.7
• Stat with 3-6 months of lifestyle modifications (decreased HbA1c by 1-2%)
o Diet (complex carbohydrates, low fat, small frequent meals)
o Aerobic exercise
o Smoking cessation, limit alcohol intake
• Pharmacotherapy (refer to next page)
• Manage associated conditions: HT, hyperlipidaemia, obesity
• Screen & manage complications (see separate section)
Vision threatening thyroid eye disease complication
- globe subluxation
- exposure keratitis
- compressive optic neuropathy
- glaucoma
Pharmacology Mx of DM
- Metformin
- start: 500mg BD / 850mg daily (Nax: 850mg tds)
- MoA: Biguanides: decrease hepatic glucose production, increase insulin sensitivity
- oral, taken after or with food
- pros: weight neutral, used in pregnancy, few hypoglycaemia
- cons: GI (metallic taste, diarrhoea, vitamin b12 deficiency—> numbness, poor memory), Metformin induced lactic acidosis (Mx: stop Metformin, Actrapid prn, NaHCO3 prn, haemodialysis prn)
- C/I: renal imoair( C/I if GFR<30, half dose if GFR 30-45), risk of lactic acidosis: Hx, CT contrast , increased LFT, sepsis - Sulphonylurea e.g. glicazide, glipizide
- MoA: increase insulin secretion
- oral : 15-30 mins before meal
- pros: rapid
- cons: hypoglycaemia, weight gain with increase appetite
- C/I: GFR<30 - DPP4 inhibitor e.g. linagliptin
- MoA: increase incretin—> increase insulin secretion after meal
- oral
- pros: weight neutral, few hypoglycaemia
- cons: pancreatitis, pancreatic CA/ CHF - GLP1 agonist e.g. liraglutide, semaglutide
- MoA: increase insulin secretion after meal
- SC injection weekly
- pros: weight loss, cardio protective, few hypoglycaemia
- cons: GI upset, pancreatitis, medullary thyroidal CA
- C/I: renal impairment , pancreatic disease, Hx of MTC/MEN2, Hx of gallstone - Thiazolidonedione e.g. pioglitazone
- MoA: increase insulin sensitivity
- oral
- pros: useful in fatty liver, renal impairment
- cons: fluid retention, weight gain, increased fracture risk, possible CA bladder, worsen macular edema
- C/I: CHF, liver impairment, Hx of CA bladder - SGLT2 inhibitor e.g. empaglifozin
- MoA: block SGLT2 in proximal tubule —> decrease renal glucose reabsorption
- oral
- pros: few hypoglycaemia, weight loss, cardio protective , benefit in CkD, decrease BP 3-5mmHg
- cons: GU infection (vulvovaginal candidiasis, urosepsis, UTI), euglycaic DKA, postural hypotension
- C/I: T1DM, T2DM with GFR<30
Summary (First line = metformin)
• Clinical CV disease: SGLT2 inhibitor or liraglutide (GLP-1 agonist with proven CV benefits)
• HF or CKD: empagliflozin (proven CV & renal benefits)
• ESRF (eGFR <30): linagliptin / alogliptin (*excreted through liver), selected sulphonylureas (e.g. glipizide, gliclazide), GLP-1 agonist, insulin
o C/I to metformin (lactic acidosis), SGLT2i (dehydration), most sulphonylureas, other DPP4i, pioglitazone (fluid retention)
• None of above: depends on whether prefer weight loss (GLP1RA/ SGLT2i) or minimal hypoglycaemia (SGLT2i/ GLPRA, DPP4i/ TZD)
Insulin therapy of
• decreased HbA1c by 1.5-3.5%
• First-line if initial HbA1c high
• Side effects
o Weight gain
o Hypoglycaemia: monitor BG
o Lipodystrophy, lipohypertrophy: rotate injection site
Types of insulin
Types of preparations:
• Basal supplement: intermediate / long-acting insulin (e.g. NPH, glargine, determir, degludec)
• Pre-meal bolus: rapid-acting / short-acting insulin (e.g. lispro, aspart, regular)
• Pre-mixed: combination
- Rapid acting Insulin
- Aspart (Novorapid) / Insulin Lispro (Humalog)
- Prandial
- onset 10min
- duration: 3h
- admin: 15 min before meal - Short acting (regular)
- Regular human insulin (Actrapid HM) / Regular human insulin (Humulin R)
- Prandial
- onset 30min
- duration 8h
- admin: 30 mins before meal - Intermediate
- NPH (Protaphane HM) / NPH (Humulin N)
- Basal
- onset 1h
- duration 24h
- admin OD / BD - Long
- Glargine (Lantus) / Detemir (Levemir)
- Basal
- onset 3h
- duration 24h
- admin OD (OM or bedtime) - Ultra-long
- Degludec (Tresiba)
- Basal
- onset 30min
- duration 42h
- admin OD - Premixed
- 30% Novorapid + 70% NPH (NovoMix 30) / 30% Actrapid + 70% NPH (Mixtard 30HM)
- mixed
- onset 30 min
- 24h duration
- admin Novomix: 15min / Mixtard: 30min
Human insulin: can clump together (“dimerization”) and cause slow & unpredictable absorption —> insulin analogue
Initiation of insulin therapy in T2DM
Basal insulin initial dose: 0.2U/kg/day or 10U intermediate or long-acting insulin at bedtime (0.5U/kg/day in obese patients), then fasting glucose 3x/week (target H’stix 4-7)
- Multiple daily injection
- Rapid / short-acting insulin before 3 meals (increased AM dose for Dawn phenomenon (increased BG from 2am to 8am due to counter-regulatory hormones, not a/w nocturnal hypoglycemia), increased dose for main meal)
Intermediate / pre-mixed insulin at bedtime
- initial dosage: 0.3-0.5U/kg
- Preferred in : T1DM, More motivated / active patients
- pros: Most physiological, Adjust pre-meal dose by meal size
- cons: Frequent injections, Frequent H’stix: tds + nocte - BD insulin regimen
- Premixed / intermediate-acting
insulin: 2/3 dose before breakfast, 1/3 dose before dinner
- 0.3-0.5U/kg
- preferred in T2DM +daytime glycemia, Less motivated but regular lifestyle
-pros: simple
- cons: Require regular mealtime, Nocturnal hypogly —> Morning rebound hypergly (Somogyi phenomenon: Nocturnal hypoglycemia —> Rebound morning hyperglycemia due to counter-regulatory
hormones)
- oral DM drug: Keep metformin (sensitivity of
insulin —> may use lower dose) Stop sulphonylurea (hypogly) - Once daily supplementary
- Intermediate-acting insulin: Give at bedtime (night-time add on)
- 0.2 unit/kg BW
- preferred in T2DM + fasting glycemia
- pros: simple, increase patient acceptance to insulin
- cons: >0.5U/kg: weight gain,
- oral DM drug: Keep metformin, Sulphonylurea half max dose
Titration of insulin dosage
- Hyperglycemia before meal: short-acting insulin before previous meal
- Early morning hypoglycemia: decreased night insulin / have a snack before sleep
Insulin use during intercurrent illness
• Maintain calories intake
• Requirement on insulin: increased due to catabolic effect of infection, decreased due to loss of appetite
• Hstix QID, adjust insulin accordingly
• Insulin use in critically ill patients
o DKI
o Insulin pump: if fluid overload; more frequent H’stix
Perioperative management of DM
Pre-op preparation
• Investigations: standing/ lying BP, pulse, glucose, HbA1c, RFT/ electrolytes/ HCO3, ECG, urinalysis
• Target: 5-11 mmol/L
• Admit 1-2 days before major OT for DM control
Day of operation
• Well controlled: omit insulin/ OHA on day of OT (may continue if minor OT)
• Poorly controlled / On insulin / High-dose OHA: start DKI infusion Q4-6h after fasting / at least 2h before operation
o D5 500ml
o 10mmol KCl (fixed dose to avoid error)
o Insulin: add according to sliding scale
• Monitoring: Hstix & K Q1h
Post-op care
• Continue DKI infusion until stable + resume eating
o Resume insulin: give sc insulin 30 mins before off IV insulin
• Monitoring: ECG, Hstix & K Q6h
DM patients on metformin requiring
contrast
IV contrast:
RFT if no prior RFT within 12mo
• Renal function normal (i.e. eGFR ≥ 30 within 6mo / ≥ 45 within 12mo):
• Renal function normal but AKI: stop
metformin on the day —> check RFT 48h
after exam —> resume if normal
• Renal function poor: consult medical, then manage as above
IA contrast:
• Stop metformin on the day —> check
RFT 48h after exam —> resume if normal
DKI drip
Not to be confused with:
• Insulin pump: for hyperglycaemia
• DI drip: for hyperkalaemia
SGLT2 inhibitor before OT
• Stop 3 days before elective OT /
immediately before emergency OT
• Start DKI when fasting and monitor BG
• Check serum BOHB before and after OT
• Resume SGLT2i when solid oral intake
Diabetic ketoacidosis
Aetiology (6I):
insulin deficiency (T1DM), infection (e.g. chest infection, UTI), inflammation (e.g. pancreatitis), infarct (silent MI), iatrogenic (e.g. anti-psychotics, steroids, SGLT2i), ingestion (e.g. meth, cocaine)
Pathophysiology
• Hyperglycaemia: increased gluconeogenesis & glycogenolysis + decreased glucose uptake into cells (lack of insulin)
• Ketosis: absolute insulin deficiency —> lipolysis release acetyl CoA —> ketogenesis
Clinical features
• Polyuria & polydipsia
• Hypovolemia:
o Signs of dehydration (tachycardia, hypotension, dry mucous membrane)
o Decreased consciousness - correlate with degree of hyperosmolarity but not acidosis
o CVS (chest pain)
o Abdomen: vomiting usually precedes abdominal pain (c.f. surgical causes)
• K abnormalities: muscle weakness, arrhythmia
• Acidosis: Kussmaul’s breathing (deep, fast breathing pattern to compensate for HAGMA), fruity odour (acetone)
Investigations + subsequent monitoring
1. Confirm diagnosis
• Plasma & urine glucose —> monitor hourly
• Urine dipstick ± plasma ketones/BOHB
• ABG (repeat prn)
• RFT, CaPO4 ± Mg —> monitor RFT hourly until BG <14
o PseudohypoNa: ECF expansion
o HypoK / hyperK both possible: total K deficit due to K+ loss in osmotic diuresis, but serum
K may remain high due to insulin deficiency (decrease uptake into cell) & metabolic acidosis
• ± Amylase: increase even if no pancreatitis
2. Underlying cause
• ECG: hyperK (tented T wave, widened QRS), hypoK (flattened T wave, prominent U wave)
• CXR
• Septic work-up: CRP, blood & urine C/ST
• Clotting profile
Management of DKA
Principles: rehydration + insulin + K
Monitor: vitals, I/O, H’stix, ketones, RFT, ABG Q1h
1. Rehydration: improve the circulatory volume and tissue perfusion
• Resuscitation by IV NS 1-2L in first hour, then 100ml/h titrating against hydration status & urine output
o Fluid in first 12hrs should not exceed 10% BW: avoid cerebral oedema
o Give 0.45% NS if Na > 150
2. Insulin: clear the ketones, normalize
the glucose and osmolarity
• IV insulin infusion pump: to clear ketone
o Only when K > 3.5
o Dose: 0.15 IU/kg bolus, then 0.1 IU/kg/h (target BG lower 3-4/h)
o When BG ≤14: change NS to D5; and decreased insulin dosage to maintain BG 8-12, decrease monitoring to Q2-4h
o Start SC insulin (maintenance) when AG normal and resume diet, then stop IV 2h after that
- Estimate daily requirement = 70% of total dose
- Give as intermediate-acting insulin: 2/3 in morning, 1/3 in evening
3. Correct electrolyte and acid base balance
• KCl 10-20 mmol/h (if K < 5): titrate according to K level, aim K at 4-5
• NaHCO3: only if pH < 7.0
o Dosage: 50mmol (pH 6.9-7.0), 100mmol (pH < 6.9)
o Must check K & ABG
o No evidence of improving mortality, but with complications [Renal]
4. Identify and treat
• Treat hypotension and circulatory failure
precipitating cause
• Antibiotics if evidence of infection
5. Avoid complications of treatment
• Cerebral oedema:
o MC in young patients < 20y
o MOA: ?excessive rate of IV fluid infusion, rapid fall in [Na], rapid correction of hyperosmolality
o Mx: r/o hypoglycaemia, IV mannitol or hypertonic saline (3%), hyperventilation, CT brain
• Cognitive impairment (memory, attention, IQ)
• DVT: hyperviscosity state
Hyperosmolar hyperglycaemic state
Overall similar to DKA, but
• Pathophysiology:
o Hyperosmolarity
o No ketosis due to presence of small amount of insulin
• Clinical features
o Dehydration: more gradual onset, and thus more severe
o K+ depletion: less severe
o Ketosis/ acidosis absent: no Kussmaul’s breathing
o Hyperosmolality: change in mental state - more prominent
• Investigations:
o Serum urea is the best prognostic factor
• Management:
o Fluid replacement: more is required, NS or 1/2 NS if Na (to avoid hyperNa)
o Insulin: less than DKA, ~half dose (i.e. 0.05U/kg/h) – watch out for overshoot hypoglycemia
DKA vs HHS
- DKA
Plasma glucose: >14
Electrolytes: PseudohypoNa (ECF expansion), K+ depletion more severe
ABG: pH < 7.3, HCO3 < 15
Effective osmolality (2[Na]+glucose): Variable
Ketones: Moderate ketonuria (2+ on urine dipstix), Moderate ketonemia ≥3 mmol/L, High serum BOHB* - HHS
Plasma glucose: >33.3
Electrolytes: HyeprNa (dehydration), K+ depletion less severe
ABG: pH > 7.3, HCO3 > 15
Effective osmolality (2[Na]+glucose): >320
Ketones: Mild ketonuria / ketonemia
Note: DKA/HHS can cause hemichorea-hemiballism
• Investigation: CT brain (r/o subthalamic nucleus infarct)
• Management: optimize glucose control with insulin pump / DKI drip
Hypoglycaemia
Definition: blood glucose ≤ 3.9 mmol/L
Prolonged OGTT
Procedure
• Overnight fast
• PO 75g anhydrous glucose
• Check BG & insulin Q1h x 5 / when symptomatic
Clinical features
• Whipple’s triad: BG < 3.9 + Symptoms of hypoglycemia + rapid relief by glucose administration
• Sympathetic symptoms: palpitation, tachycardia, sweating, tremor - may be blunted in DM patients (Patient without: autonomic neuropathy, beta blocker, poor controlled type 1 DM)
• Neuroglycopenic symptoms (due to decreased activity of CNS): dizziness, fatigue, confusion, seizure
Investigations (taken at time of hypoglycemia)
• Plasma glucose: Confirm hypoglycemia (H’stix is not accurate)
• Plasma insulin & C-peptide
• CBC, LRFT, CRP/ESR, septic workup, cardiac enzymes (silent MI)
• HbA1c (ongoing glyceminc control)
• Urine ± plasma ketones (absent = hyperinsulinism)
• Special tests
o Urine sulphonylurea [OHA overdose]
o Prolonged fasting test [insulinoma]
o Prolonged OGTT [reactive hypoglycemia] – limited use
o Short Synacthen test + ACTH [Addison’s]
o Glucagon stimulation test [GH def.]
Aetiology
Fasting-Excessive glucose utilisation
1. Insulin administration
- high serum insulin
- low C-peptide
2. Oral hypoglycemia drugs
- high serum insulin
- high C-peptide
- History
- Urine drug screen
3. Insulinoma
- high serum insulin
- high C-peptide even during fasting
- Prolonged fast test
4. Extra-pancreatic tumours
- Retroperitoneal fibrosacroma, hepatoma —> high big IGF-2 -> suppression.GH release —> low IGFBP3 and IGF1 —> high free IGF-2 —> low hepatic glucose production + high glucose uptake by peripheral tissues
- low serum insulin
- low C-peptide
- high IGF-2
- low IGFBP3
Fasting-Diminished glucose production
5. Endocrine disease
- Adrenal insufficiency
- Pituitary insufficiency: low GH
- Short Synacthen test + ACTH
6. Liver disease e.g. cirrhosis
- low glycogen reserve
- Hx of liver disease
- LFT, USG small liver
7. Renal disease
- Uraemia: decrease liver gluconeogenesis, low appetite
- RFT
8. Autoimmune cause
- Agoonist autoAb to insulin receptor and beta cells
- Antibodies
Post prandial
9. Autoimmune cause
- Agonist Ab to insulin
- Antibodies and increase insulin but reduce C-peptide
10. Post-gastrectomy syndrome
- rapid absorption of glucose —> excessive insulin
- History, low K, low PO4
11. Alcohol related
- low gluconeogenesis
- high ketones
Management
• Resuscitation (A, B, C)
• Confirm hypoglycaemia by blood glucose (NOT H’stix), but do not delay treatment
• Conscious: 10-15g simple carbohydrates (e.g. soft drink), then carbohydrate meal
• Decreased consciousness: D50 40ml IV stat via large vein with saline flush (or D20 100ml), then D10 infusion
• Unable to obtain IV access: IM glucagon 1mg or oral glucose (after airway protection)
• Monitor BG & H’stix Q1h until stable, depending on RFT/LFT and type of drugs taken
• Manage underlying cause
o Insulinoma [SUR]:
• Exclude MEN1 (check CaPO4, PTH, prolactin, gastrin)
• Confirm Dx by prolonged fasting test and localization studies
• Mx: frequent small meals, diazoxide (300-800decrease insulin secretion, S/E: hirsutism, fluid retention), octreotide, surgical resection
o NICTH: surgical resection, increase caloric intake ± high-dose glucocorticoid / glucagon infusion / GH
Complications of DM
Pathophysiology
• Mechanisms: non-enzymatic glycation of proteins, activation of polyol pathway, formation of advanced glycated end-products (AGE), etc.
• Pathology: thickening of capillary basement membrane, increased vascular permeability
Macrovascular complications x3
1. Coronary heart disease
- Risk of MI 3-5x higher
- Leading cause of death in T2DM
- “High risk” under the risk stratification for CHD —> intensive statin therapy
2. Ischaemic stroke
- Risk of stroke 2.5x higher
3. Peripheral arterial disease
- Intermittent claudication, foot ulcer, foot gangrene
- Risk of LL amputation 15x higher
Mx:
- BP < 130/80
- LDL ≤ 1.8
- Smoking cessation
Microvascular complications x3
1. Diabetic retinopathy
Patho: increase retinal blood flow disrupts metabolism —> retinal vessels damage —> hypoxia —> compensatory neovascularisation (fragile)
Fundoscopic findings: papilledema is NOT a feature!
• Non-proliferative (NPDR): “MDS HIV”
o Microaneurysms
o Dot & blot haemorrhage (deeper than flame
haem.)
o Soft exudates (cotton wool spots) – infarcted
nerves
o Hard exudates – lipids leaked out
o Venous beading
o Intraretinal microvascular abnormalities
(IRMA)
• Proliferative (PDR):
o Neovascularization (due to VEGF)
o Vitreous haemorrhage
• Diabetic macular oedema (DME): occur at any stage
• Complications:
o Tractional retinal detachment
o Rubeosis (neovascularization at iris)
o Secondary glaucoma
Causes of visual loss in DM:
• DR: sudden (vitreous haemorrhage, retinal
detachment) vs gradual (DMO)
• CV risk factors: glaucoma, cataract, AMD
Mx:
Vitreous haemorrhage: pan-retinal
photocoagulation, vitreoretinal surgery
Secondary glaucoma: control IOP
DMO:
• Intravitreal injection, e.g. anti-
VEGF (bevacizumab), steroid
• Macular grid laser
2. Diabetic nephropathy
- Risk factors: high GFR, poor BP control, high HbA1c
Clinical features
• Glomerular hyperfiltration (0-5y): GFR
• Microalbuminuria (5-10y): 30-300mg/day albumin
• Macroalbuminuria (10-15y): > 300mg/day
• Clinical nephrotic syndrome (diabetic
glomerulosclerosis)
• Progression to ESRD (15-30y)
Renal biopsy findings: GBM thickening, mesangial expansion, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules)
Mx:
Screening: uACR since Dx (T2DM) or 5 years after Dx (T1DM)
• Normal: < 30mg/g (< 30mg/day)
CV risk factors control: ACEI/ ARB (beneficial even if normal BP), statins, smoking cessation
Glycemic control: SGLT2 inhibitors,
GLP1 agonists, insulin
ESRD: stop metformin & SGLT2i, use drugs that are not renally metabolized (glipizide, linagliptin, insulin)
3. Diabetic neuropathy
Mixed patterns can occur:
• Symmetrical sensory / sensorimotor neuropathy: length-dependent, symmetrical -> glove-and-stocking pattern —> foot ulcer, Charcot’s joint
• Asymmetrical motor neuropathy (diabetic
amyotrophy): progressive weakness and wasting of proximal muscles
• Mononeuropathy / “mononeuritis multiplex”: most commonly affect CN3, CN6, median n., femoral n., sciatic n., common peroneal n.
o DDx: subacute combined degeneration of cord due to metformin-induced B12 deficiency —> test dorsal column
• Autonomic neuropathy: CV (postural hypotension), GI (gastroparesis, alternating diarrhoea/constipation), GU (urinary retention, erectile dysfunction)
Mx:
Screening: 128 Hz tuning fork, 10g
monofilament fibre
Foot care education
- Cleanse with soap and water
- Apply topical moisteurizers
- P&O for fit athletic shoes and thick socks, avoid walking barefoot
- Treat all minor injuries & infection
Neuropathic pain: SNRI (e.g.
duloxetine), TCA (e.g. amitriptyline),
pregabalin/ gabapentin
Gastroparesis: domperidone, metoclopramide
Diabetic foot
• Multifactorial: PVD (macrovascular) + sensory neuropathy (microvascular) + autonomic neuropathy (↓sweating, microvascular) + poor glucose control (decreased wound healing) + poor footwear
• Clinical features:
o Neuropathy: paraesthesia, painless, ulcer, repeated microtrauma (cannot feel foot)
• Charcot joint (neuropathic arthropathy): rocker-bottom foot, destruction of small joints
o Ischaemia: loss of pulses, claudication, rest pain, gangrene
• Prevention: foot hygiene (see above)
• Treatment: treat infection (moisturiser + topical antibiotics), debridement of dead tissues, amputation
Other complications
• Cutaneous:
o Diabetic dermopathy: atrophic brown spots
commonly in pretibial region - “shin spots” (fig.)
o Necrobiosis lipoidica diabeticorum (fig.)
o Acanthosis nigricans
o Granuloma annulare: ring popular lesions on back of hands and feet
• Musculoskeletal:
o Juvenile cheiroarthropathy: chronic stiffness of hand due to skin contracture over joints secondary to glycosylated collagen, positive Prayer’s sign
o Dupuytren’s contracture
o Frozen shoulder (adhesive capsulitis)
• Cataracts:
o Subcapsular and senile cataracts secondary to glycosylated lens protein and increased sorbitol
Hyperthyroidism, hypothyroidism complication
Hyperthyroidism
- thyroid storm
- thyroid heart disease: AF, HF
- Osteoporosis
- Thyrotoxic periodic paralysis
Hypothyroidism
- Proximal myopathy (change in myocyte permeability), increase risk of statin myopathy
- Carpel tunnel syndrome (mucopolysaccharides deposition)
- Frozen shoulder
-Myxoedema coma: CHF, coma
- Hyperlipidaemia & complications of obesity
- Neuropsy: dementia, depression
- Cretinism (in children)
Thyroid Ix
TSH, fT4
Thyroid imaging
• Radioisotope thyroid scan (123I) (Technetium-99): preferred in thyrotoxic patients with nodular thyroid
o Supersede RAIU (lower radioactive dose, higher resolution)
o Differentiate hot nodule (low malignant risk) vs cold nodule (5% malignant risk —> USG for FNAC)
o C/I: pregnancy, breastfeeding
o Different uptake patterns
- low uptake: transient thyroiditis, extrathyroidal T4 source
- Single uptake: Toxic adenoma
- Mutiple uptake: toxic multi ocular goitre
- whole gland uptake: Graves’ disease
• Thyroid ultrasound +/- FNAC: preferred in euthyroid/ hypothyroid patients
o Measure size of gland
o Differentiate solid vs cystic nodule
o Facilitate FNAC
Anti-thyroid antibodies
• TSH receptor antibodies*: Graves’
• Anti-TPO, anti-thyroglobulin: Graves’, Hashimoto’s thyroiditis
Investigations for complications
Hyperthyroidism
• Bone profile: increased Ca, increased ALP (bone remodelling / CMZ-induced cholestasis)
• RFT: decreased K (TPP)
• decreased red cell zinc
Hypothyroidism:
• CBC: macrocytic anaemia (non-megaloblastic)
• Electrolytes: hypoNa (fluid retention)
• Lipid: 2o cause of hyperlipidaemia
• CK: thyroid myopathy (c.f. much higher CK in rhabdomyolysis)
• Prolactin increased : due to increase TRH
Ethology of thyrotoxicosis
- Graves’ disease
- Association: pernicious anaemia, Hashimoto, etc
- Specific signs:
• Graves’ ophthalmopathy (ophthalmoplegia, exophthalmos, proptosis, chemosis)
• Thyroid acropathy (clubbing)
• Pretibial myxoedema (non-pitting edema)
• Lymphoid hyperplasia (LN, spleen)
Ix:
- anti-TSH receptor
- Anto-TPO, anti-TG
- thyroid scan: diffuse uptake - Toxic solitary nodule Toxic MNG (19%)
- Most common in elderly > 60y
- Thyroid scan: focal/heterogenous uptake - Subacute thyroiditis (De Quervain’s) (5%)
- Fever, neck pain, preceded by URTI
- Phase: thyrotoxic (6-8 weeks) —>hypothyroid (6-8 weeks) —> normalised
- Management: self-limiting
• Symptomatic (propranolol, NSAID): self-limiting
• ATD not useful
• FU for possible hyperthyroidism
- Thyroid scan: decreased uptake
- Increased ESR
- Serology: all negative - Drugs
- Amiodarone, lithium: hyperthyroid or hypothyroid
- Iodine contrast (up to 18 weeks post-contrast)
- Thyroid scan - HCG (pregnancy)
- Separate reference range during pregnancy
Mx: monitor fT4 (decline after 1st trimester), no Tx required
- AVOID thyroid scan - Exogenous source
- Iatrogenic over-replacement of T4
- Slimming agents (e.g. tiratricol)
- USG Doppler: decreased flow
- Blood thyroglobulin decrease
- Stool T4 increase
Other rarer causes: TSH-producing pituitary adenoma, Hashitoxicosis, post-partum thyroiditis, struma ovarii
Amiodarone induced thyroid disease
Type 1
- pathogenesis: Iodine-induced hyperthyroidism, (Jod-Basedow phenomenon)
- background pathology: Often present: pre-existing MNG / Graves’
- Amiodarone duration: Shorter (<2 years)
- Ix: Doppler USG-high blood flow, Thyroglobulin-normal, IL-6 - normal
- Mx: stop amiodarone, High dose anti-thyroid drugs (e.g. 40-60mg CMZ) ± Short-term lithium (~4wk) to speed up recovery ± Thyroidectomy, Treat until urine iodide normalizes
Type 2
- Destructive thyroiditis (direct cytotoxicity of amiodarone)
- no background pathology
- longer amiodarone duration - (>2 year)
- Ix: Ix: Doppler USG-low blood flow, Thyroglobulin-high, IL-6 - increase
- Mx: stop amiodarone, High dose steroids 40-60mg/day (anti-inflammatory +inhibit conversion of T4 to T3) ± Short-term lithium (~4wk) ± Thyroidectomy
Amiodarone-induced hypothyroidism
• Occur in patients with pre-existing Hashimoto’s thyroiditis
• Pathology: iodine load —> failure to escape from Wolff-Chaikoff effect
• Management: T4 supplement
Mx of thyrotoxicosis
Management overview
1. Beta blockers
- Symptomatic relief of thyrotoxicosis
(Propranolol: + inhibit T4-T3 conversion)
- C/I: Asthma, COPD, heart block, thyrotoxic heart failure (cautious)
2. Anti-thyroid drugs (ATD)
- First episode of Graves’ disease / Preparation for RAI/ surgery / Pregnancy (PTU —> CMZ)
- C/I: Agranulocytosis, Baseline ANC < 0.1
3. RAI
- Graves’ disease with failed ATD
- Toxic adenoma / toxic MNG
- Complications: TPP, thyrotoxic heart
disease
- Post-thyroidectomy for CA
- C/I: Pregnancy & breastfeeding (contraception for ≥6m), Retrosternal goitre (radiation thyroiditis —> oedema), Graves’ orbitopathy: steroid cover if use inevitable, Thyroid storm: risk of transient hyperthyroidism, Iodine allergy
4. Surgery
- 4C: uncontrolled, compression, CA, cosmetic
Antithyroid drugs (ATD)
1. Carbimazole
- TPO inhibitor
- Start: 10mg BD / TDS; Max: 20mg TDS
First line except below (∵more potent, longer half-life, less hepatotoxicity, less bitter taste)
2. Propylthiouracil
- TPO inhibitor + Inhibit peripheral conversion conversion of T4 to T3
- 100-200mg TDS
- preferred when first trimester pregnant (decrease found in placenta), Thyroid storm
Onset: 6-8 weeks (t1/2 T4 7 days) —> propranolol cover + FU with TFT after 8 weeks
Efficacy:
• Graves’: long term remission in 50% —> 2nd course of ATD or RAI
• Toxic nodules/ MNG: ineffective – 100% relapse, only for control before RAI / surgery
• Thyroiditis: ineffective
Duration: 12-18 months —> another 18 months trial —> consider RAI / surgery
• Start at high dose (e.g. carbimazole 10mg TDS) and titrate down depend on TFT
• Role of TRAb level: persistently high conc. = higher risk of relapse —> continue ATD for 12 months more / consider RAI / surgery
Monitoring:
• fT4 every 8-10 weeks (reflect more the actual thyroid function c.f. TSH: with time lag)
• CBC D/C, LFT
Side effects
• Allergic reaction (5%): Mx by antihistamine, switch another ATD (50% cross-reactivity)
• Agranulocytosis (0.3%): NOT dose-related, mostly in first 3 months, caution if fever or sore throat
o Management (SAQ!)
- Discontinue all ATD —> Lifelong C/I to any ATD
- Reverse isolation, septic work-up (blood C/ST, urine dipstix & C/ST, sputum, CXR ± LP)
- Broad-spectrum antibiotics with anti-pseudomonal coverage (e.g. ceftriaxone + gentamicin)
- G-CSF
- Lithium (temporarily inhibit thyroid hormone synthesis & secretion)
- ± TFT (r/o thyroid storm), ± Blood smear / bone marrow study (r/o haematological conditions)
• Hepatotoxicity (0.1%): mostly in first 6 months
o CMZ: cholestasis
o PTU: allergic hepatitis à fulminant liver failure
• Vasculitis:
o ANCA-related vasculitis
o Drug-induced lupus
• Teratogenicity: all cross the placenta, but carbimazole is more teratogenic
o Carbimazole: aplasia cutis
o Propylthiouracil: preauricular sinus & cysts, CAKUT
Radioactive iodine (RAI/ iodine-131)
• Efficacy: long term remission in 80% —> 2nd course can be given after 6 months
• Dosage: single oral dose, based on body weight and goitre size
• Approach to RAI treatment
o Rule out pregnancy by PT (avoid pregnancy for 6 months before RAI) & iodine allergy
o Pretreatment by CMZ x 6/52 (maintain euthyroid)
o Stop 1/52 before RAI (to maximise uptake of RAI)
o Restart 1/52 after RAI till TFT normalised (risk of rebound hyperthyroidism, RAI takes ~3 months to work)
o If failed (20%): retry RAI
o If Graves’ orbitopathy but RAI indicated: start prednisolone 1 day after RAI and taper off over 6-8 weeks
• Post-treatment precautions:
o Avoid close contact with children & pregnant women for 1 week
o Contraception for ≥6 months (both males and females)
o Avoid sharing cups/ utensils
o Encourage fluid intake & frequent voiding + flush toilet twice
• Advantages:
o Rapid control of thyrotoxic symptoms within 2-3 weeks
o Obvious reduction in goitre size within 1 year
• Side effects:
Early
• Transient exacerbation of thyrotoxicosis ± thyroid storm
o Radiation thyroiditis (1 - 3 weeks): pain, Mx NSAID, steroid
o Rebound hyperthyroidism (weeks - months): Mx: carbimazole cover
• Exacerbation of ophthalmopathy
Late
• Possible permanent hypothyroidism requiring thyroxine
• ↑miscarriage rate
Thyroid eye disease / Graves’ ophthalmopathy (GO)
Pathophysiology: stimulation of fibroblasts results in
• Accumulation of GAG in EOM
• Increase in retrobulbar fat
Risk factors
• Smoking
• Elderly male
• RAI
• Unstable thyroid function (too high/ low)
Clinical features (severity is independent of thyroid status)
• Sympathetic overactivation (for ALL thyrotoxicosis): lid retraction, lid lag
• Graves’ ophthalmopathy: proptosis, diplopia, chemosis, ophthalmoplegia (most commonly IR)
• NO SPECS classification: to document severity
• Clinical activity scale (CAS): to decide treatment
Investigations: CT orbit
Management (5S)
• Smoking cessation
• Stabilise thyroid function (avoid hypothyroid)
• Symptomatic treatment: eye lubrication
• Suppress inflammation:
o High-dose IV pulse methylprednisolone (500-1000mg x 10-12 weeks)
o Immunosuppressants (e.g. MTX, MMF)
o IGF-1 receptor monoclonal body (teprotumumab): IGF-1 cross-talk with TSH-R expressing cells
• Surgical decompression / External orbital RT if deformities severe
- Sight-threatening complications: optic neuropathy (loss of colour vision as 1st sign), exposure keratopathy, globe
subluxation
Gestational thyrotoxicosis
• Pathogenesis
o Beta-subunit of hCG shares homology with beta-subunit of TSH
o Physiological rise of hCG (peak at 10-12 weeks of pregnancy) stimulates TSH-R
• Risk factors: high hCG (e.g. twin pregnancy, hyperemesis gravidarum, molar pregnancy)
• Biochemically indistinguishable from other etiologies (e.g. Graves’), distinguished by:
o Past history of thyroid disease, any thyrotoxic Sx pre-conception, any goitre, autoAb profile
o Closely monitor fT4: expect to decline after 1st trimester
• Anti-thyroid drugs are NOT indicated
Hypothyroidism
• Primary (90%)
o Autoimmune: Hashimoto’s thyroiditis
o Iatrogenic: post-ablative (RAI or thyroidectomy), drugs (amiodarone, lithium)
o Post-viral: hypothyroid phase of subacute thyroiditis
o Congenital hypothyroidism
• Secondary: pituitary/ hypothalamic lesion
o Pituitary tumor
o NPC: tumor infiltration / post-RT
o Empty sellar syndrome
Hashimoto’s thyroiditis
• Chronic lymphocytic thyroiditis, autoimmune disease a/w HLA-DR3 & DR5
• Predominant in female (7:1)
• Clinical course:
o Initial destruction of thyroid glands —> release of T4 —> Hashitoxicosis”
o Gradual thyroid function decline
• Association: Graves’, MG, T1DM, vitiligo, Addison’s
• Serology: positive anti-TPO & anti-TG
o High anti-TPO titres predict likelihood of progressing from subclinical hypoT4 to overt hypoT4
Management of hypothyroidism
Primary hypothyroidism
• L-thyroxine: 50mcg daily, then titrate against TSH
o 25mcg daily in elderly patients / IHD (worsen by increased HR)
o Higher dose (dose by ~50%) for pregnant women (maintain euthyroidism —> prevent cretinism in fetus)
o DDI: Ca, Fe, PPI / antacids, cholestyramine - separate administrations
• Monitoring: TSH at 4 weeks (reflect long-term level c.f. fT4: normalised quickly within 1 week of drug intake)
Central hypothyroidism
• Evaluate rest of anterior pituitary axis:
o Rule out concurrent adrenal insufficiency: replace hydrocortisone for 5 days before T4 (increase clearance of cortisol and thus risk of adrenal crisis)
• Monitoring: fT4 (TSH is suppressed by exogenous T4)
Thyroid storm
Thyroid storm
• Definition: acute exacerbation of thyrotoxicosis
• Aetiology: infection/ trauma/ surgery in a hyperthyroid patient
• Clinical features:
o Hypermetabolic state: extreme hyperthermia (≥ 40oC), fast AF, vomiting, diarrhea
o Altered mental state: delirium, agitation
o Multiorgan failure (key feature!): congestive heart failure, renal failure, liver failure (jaundice)
o Mortality: 30%
• Scoring system: Burch-Wartofsky Point Scale (fig.)
o ≥45 suggestive of TS; <25 unlikely TS
• Differential diagnosis:
o Infection: Sepsis, agranulocytosis (2° to anti-thyroid drugs)
o Endocrine: Phaeochromocytoma crisis
o Others: neuroleptic malignant syndrome, serotonin syndrome
• Investigations: CBC, TFT, LFT, RFT, glucose, ECG (arrhythmia)
Management of thyroid storm
• Treat underlying cause
• Monitoring: cardiac monitor, CVP, Swan Ganz, consult ICU
• Supportive treatments:
o Hyperthermia: paracetamol (NOT NSAID/salicylate: displace thyroxine from proteins —> T4 to T3 conversion), physical cooling
o Dehydration & nutrition: IV fluid (2-4 L/day), IV glucose, IV thiamine
o Heart failure: O2, digoxin / diuretics ± inotropes
o Atrial fibrillation: digoxin (do NOT give amiodarone)
• Definitive treatment:
o PTU 200mg Q4h (±via NG tube): preferred over CMZ because also inhibit T4 —> T3 peripheral conversion
- Consider lithium carbonate if C/I to ATD
o Lugol’s iodine (10 drops Q8h): Wolff-Chaikoff effect to block thyroid hormone release
- Must be given ≥1hr after PTU to avoid I- being used as substrate
o Beta-blockers: propranolol 40-80mg Q4-6h (C/I: CHF, asthma, COPD, hypoglycemia —> use diltiazem)
- Propranolol also inhibits T4 à T3 conversion
o IV hydrocortisone 100mg stat: prevent T4 —> T3 conversion + lower body temperature + treat potential adrenal insufficiency
o ± Cholestyramine: decreased enterohepatic circulation of thyroid hormones
o Consider plasmapheresis and charcoal hemoperfusion if desperate cases
Myxoedema coma
• Definition: severe hypothyroidism secondary to stressful events (e.g. trauma, infection, MI, cold exposure)
• Clinical features
o Hallmark features: decreased mental state, hypothermia
o Cardiovascular: hypotension, bradycardia, pericardial / pleural effusion, pulmonary edema
o Metabolic disturbances: hypoglycemia, hypoNa, respiratory acidosis
o Generalized oedema
• Investigations: TFT, RFT, Hstix, CPK (increased ), ACTH/ cortisol (adrenal insufficiency: overlapping S/S, thyroxine
supplement precipitates adrenal insufficiency), ECG, ABG
• Management
o Treat underlying cause e.g. empirical antibiotics
o Supportive: fluid (NS 200-300mL/h), glucose (D10) ± vasopressors
o Maintain body temperature
o Thyroid replacement: T4 200-500mcg PO stat (consider IV T3 5-20mcg BD if not PO)
o Hydrocortisone 100mg Q6h IV (until adrenal insufficiency ruled out)
Adrenal Ix
Stimulation test: to confirm adrenal insufficiency
1. Short Synacthen test (SST) / Basal ACTH
- Normal dose SST:
IM/IV Synacthen 250mcg, then measure plasma cortisol at time 0, 30, 60 min
- Low dose SST (if suspect secondary adrenal insuff.): IV Synacthen 1mcg, then measure plasma cortisol at 0 & 30 min: more sensitive but require dilution
- Physiologic response: peak > 550nmol/L
with increment > 200nmol/L
- Inappropriate response: no increase
- Fasting not required
- Can perform anytime of the day, but best in
the morning
Screening tests for Cushing’s
1. Overnight dexamethasone suppression test (ONDST) - most sensitive
- Dexamethasone 1mg PO at 11pm, then serum cortisol at 9am mane
- Normal < 50nmol/L
- Inappropriate response: response > 140nmol/L
- False positive: enzyme inducers (stop OCP ≥1wk before test)
- 24h urine free cortisol
- Collect 3 readings
- Normal < 280nmol/24h
- False negative in ESRD (decreased GFR), Incomplete collection - Low dose dexamethasone suppression test (LDDST)
- Dexamethasone 0.5mg Q6h for 2 days , then serum cortisol
- Normal < 50nmol/L - Late night salivary cortisol
- chew on cotton wool at 11pm
- Normal < 4nmol/L
- Avoid smoking and tooth brushing - Late night plasma cortisol
- Take blood at midnight
- Normal <50 nmol/L
Summary of tests
- Cushing’s syndrome
—> Diagnostic: ONDST, 24h UFC, LDDST / late night salivary cortisol / late night plasma cortisol (三中二 = diagnostic)
—> Differentiating: plasma ACTH, CRH, imaging
- Hyperaldosteronism
—> Spot ARR
—> Salt-loaded balance study
- Hyperandrogenism
—> Sex hormone profile
- Phaeochromocytoma
—> 24h urine metanephrines
—> I-123 MIBG scan
- Adrenal insufficiency
—> Cortisol/ ACTH
—> Short Synacthen test
—> ARR
- Hypogonadism
—> Sex hormone profile
Hyperaldosteronism
Aetiology
Primary (high ARR)
• Aldosterone-producing adenoma
(“Conn’s adenoma”) (40%)
• Bilateral idiopathic adrenal
hyperplasia (60%)
• Aldosterone-producing
adrenocortical carcinoma (<1%)
• Familial hyperaldosteronism* (rare)
Secondary (low ARR)
- high renin, high aldosterone
• Renal artery stenosis
• Renin-secreting tumors
• Diuretics
• Bartter / Gitelman
- low renin, low aldosterone
• Cushing’s syndrome
• Exogenous mineralocorticoids
• Syndrome of apparent mineralocorticoid
excess (AR mutation for 11β- hydroxysteroid dehydrogenase type 2)
• Liddle’s syndrome (AD mutation in
ENaC)
• Liquorice (low 11β-HSD activity)
Clinical features
• Hypertension
• Hypokalemia (<30%): fatigue, weakness, tetany, polyuria / polydipsia (nephrogenic DI)
Investigations
• Bloods: electrolytes (high normal Na), ABG (hypoK, low Cl, metabolic alkalosis)
• Urine: spot urine K
• Screening: spot plasma renin activity & aldosterone concentration
o Collect blood in the morning in a seated posture; stop MRA ± diuretics before testing [Grand round]
o Primary hyperaldosteronism: plasma renin activity <1ng/mL/hour, plasma aldosterone conc. ≥ 20 ng/dL
o Now use less aldosterone : renin ratio (ARR) [Grand round]
• Confirmatory & discriminatory: salt-loaded balance study [PWH] (alternative: fludrocortisone suppression test)
o Procedure:
- PO NaCl 1800mg TDS for 5 days (± K supplement: prevent hypoK due to Na intake)
- Admit on Day 5: confirm spot urine Na ≥100 mmol/L —> administer IV saline if inadequate
- Collect plasma renin activity & aldosterone at 9AM supine + 1PM erect
- Collect 24h urinary aldosterone
o C/I in uncontrolled HT, CHF, risk of cardiac arrhythmia
o Confirmatory: 9am plasma renin activity <1ng/mL/hour, plasma aldosterone conc. ≥ 10 ng/dL (≥277 pmol/L)
o Discriminatory by comparing 9am and 1pm sample
- BIAH: renin & aldosterone – sensitive to postural change (standing causes Ang II)
- Adenoma: paradoxical decreased renin & aldosterone – aldosterone production becomes independent of RAAS but dependent on ACTH (highest in morning, fall afterwards)
• Further discriminatory tests for unilateral vs bilateral disease [Grand round]
o Imaging – CT or MRI adrenal
o 131Iodocholesterol scintigraphy: low sensitivity for small lesions
o Adrenal venous sampling: gold standard for diagnosis
- Take blood cortisol & aldosterone from upper, middle, lower IVC, right and left adrenal veins
- Adrenal vein to IVC cortisol > 10:1 = successful cannulation
- Calculate cortisol-corrected aldosterone ratio for each adrenal vein, and divide higher to lower side to obtain ratio —> >4:1 = lateralize to higher side; <3:1 = bilateral
Management
• Primary aldosteronism:
o Adenoma: laparoscopic adrenalectomy with 4 weeks pre-op spironolactone
- Rule out concomitant Cushing’s syndrome: require peri-op steroid cover
- Post-op: stop K supplement and MRI, liberal salt intake, titrate down anti-HT
o BIAH: medical treatment (∵bilateral adrenalectomy can cause adrenal crisis)
- Mineralocorticoid receptor antagonists (MRA)
—> Spironolactone: more potent but non-selective (S/E: tender gynaecomastia, impotence)
—> Eplerenone: less potent but better tolerated
—> Newer drugs – non-steroidal MRA (e.g. esaxerenone, finerenone), aldosterone synthase inhibitors
- Amiloride: ENaC inhibitor
• Secondary hyperaldosteronism: treat underlying cause
Adrenal insufficiency
- Primary (Addison’s disease)
- Aetiology: Autoimmune adrenalitis (MC)
Infection: TB, meningococcaemia (W-F Sx)
Tumor: adrenal met, lymphoma
Congenital adrenal hyperplasia
Rarer causes: APS, XALD
- Pathophysiology: low GC, low MC, high ACTH
- S/S:
↓GC effect: weight loss, weakness, anorexia, n/v, abdominal pain, fasting hypoglycaemia
↓MC effect: hyperK
↓GC + MC: postural hypotension, hypoNa
(depletional & dilutional), salt craving
↑ACTH (~MSH): hyperpigmentation
↓Adrenal androgen: decreased body hair & libido (female)
- associated disease: primary hypothyroidism, T1DM, PA, vitiligo
- Ix:
Low 9am cortisol (c.f. random cortisol in
Addisonian crisis)
High ACTH
Short Synacthen test: cortisol <200 nmol/L
from baseline and peak ≤ 550 nmol/L
ARR (check for MC deficiency)
- Ix if inconclusive Insulin tolerance test (rare), glucagon stimulation test, CRH stimulation test
- Ix for causes: Adrenal autoantibodies (e.g. 21-
hydroxylase, 17-hydroxylase) +/- TFT, B12/fol
CT adrenals
TB workup: CXR, early morning sputum for
AFB, C/ST, PCR
- Mx: Adequate fluid replacement
Hydrocortisone 10mg BD / TDS (divided dose: mimic circadian rhythm) - monitor clinically for under/ over-replacement (no Ix available)
Fludrocortisone 0.1mg/day; monitor plasma renin ( = inadequate)
Cautions:
• Steroid card indicating they are currently on steroid replacement
• Stress dose (double dose) in stress, e.g. infection, trauma
• Admission if severe vomiting or diarrhoea (decreased oral absorption of hydrocortisone)
• Higher dose if DDI (e.g. anti-TB drugs) - Secondary / tertiary
- Aetiology: 2o: hypopituitarism (e.g. Sheehan’s Sx)
3o: long-term steroid use, brain tumour
- Pathogenesis: low GC but normal MC
- S/S: Same except:
• No skin hyperpigmentation
• No salt craving, normal K, less postural hypotension
• HypoNa only dilutional (∵SIADH-
like in GC deficiency)
- Associated disease: primary hypothyroidism, T1DM, PA, vitiligo
- Ix:
Low 9am cortisol
Low ACTH
SST: subnormal
(consider low-dose SST 1mcg)
- Ix if inconclusive: Insulin tolerance test (rare), glucagon stimulation test, CRH stimulation test
- Ix: MRI pituitary
- Mx: Adequate fluid replacement
Hydrocortisone 10mg BD / TDS (divided dose: mimic circadian rhythm) - monitor
clinically for under/ over-replacement (no Ix available)
Fludrocortisone 0.1mg/day; monitor plasma renin ( high = inadequate)
Cautions:
• Steroid card indicating they are currently on steroid replacement
• Stress dose (double dose) in stress, e.g. infection, trauma
• Admission if severe vomiting or diarrhoea (low oral absorption of hydrocortisone)
• Higher dose if DDI (e.g. anti-TB drugs)
Addisonian crisis
Risk factors
• Previously undiagnosed Addison’s disease
• Sudden compromise of adrenal function, e.g. adrenal haemorrhage
• Known Addison’s with intercurrent problem, e.g. trauma
• Long-term steroid use > 2 weeks
Clinical features
• Severe abdominal pain, n/v/ diarrhoea —> dehydration, hypotension
• Hypoglycaemia
• Electrolyte disturbance: hypoNa, hyperK
Investigations
• RFT, electrolytes, glucose
• Spot cortisol (during stress) ± ACTH
• Short Synacthen test not required (already in stress)
Management
Treat on clinical suspicion, do NOT wait for cortisol results
• IV rehydration: 4L D5 or NS at 500-1000mL/h first, then 200-300mL/h, chart I/O (cautious for fluid overload)
• Correct electrolytes
• IV hydrocortisone 100mg IV stat, then Q6h
o IV/IM 4mg dexamethasone if concerned about assay interference
• +/- Oral fludrocortisone 0.2mg daily PO, titrate to normalise K and BP
• Treat underlying cause
Steroid cover for surgery / trauma
Indications
• Supraphysiological dose of steroids (>7.5mg/day prednisolone) for >2 weeks in the past year
• Suspected adrenal / pituitary insufficiency
• Patients on steroids for uncertain dose / duration
Regimen
• Major surgery: IV 100mg hydrocortisone on call to OT + IV 50mg hydrocortisone in recovery room + 50mg Q6h
o Taper off if post-operative course smooth
o Maintain at 100mg IV Q6h if complicated by sepsis, hypotension, etc.
• Minor surgery (e.g. hernia repair): IV 100mg hydrocortisone single dose
• Superficial surgery (e.g. dental surgery): no need
Hyperandrogenism
Aetiology
• Pituitary: Cushing’s disease, hyperprolactinaemia
• Adrenal: CAH (late-onset), adrenal tumour
• Ovarian: PCOS, theca cell tumour
• Drugs: anabolic steroid, ACTH
Clinical features
• Female:
o Virilisation: hirsutism, temporal balding, deepening of voice, acne, muscle mass
o Defeminisation: loss of female secondary sex characteristics, i.e. amenorrhoea, decreased breast size, infertility
• Male:
o Reduced testicular size & spermatogenesis (inhibition of gonadotropin secretion)
o Minimal effect on hair, muscle mass
Investigations
• Androgen profile: DHEAS, testosterone
• LH/FSH (>2.5 in PCOS)
• 17-OH progesterone (CAH)
• CT adrenals and ovaries (tumour)
Management
• Correct underlying cause (e.g. discontinue causative drugs)
• Anti-androgen, e.g. spironolactone
• Surgical resection of tumour
Hypogonadism
Aetiology
• Primary: congenital (Klinefelter’s), infection (mumps orchitis), trauma
• Secondary: congenital (Kallmann’s), endocrine (Cushing’s)
Investigations
• Sex hormone: LH/ FSH, testosterone
• Semen analysis
Management: androgen replacement therapy
• S/E: acne, fluid retention, aggressiveness, BPH, OSA
• Monitor: DEXA (osteoporosis if untreated), PSA (risk of BPH/ CA prostate)
Phaeochromocytoma
Definitions
- Pheochromocytoma: catecholamine-secreting tumour derived from chromaffin cells of adrenal medulla
- Paraganglioma: tumour arising from chromaffin cells of sympathetic / parasympathetic nervous system
• Sympathetic paraganglioma: usually catecholamine-secreting (i.e. “extra-adrenal pheochromocytoma”), located
along sympathetic chain
• Parasympathetic paraganglioma: usually non-functional, located in neck / skull base
Aetiology
• Sporadic (MC)
• Familial (AD inheritance), e.g. NF1, MEN2 (RET oncogene), Von Hippel-Lindau disease, Carney triad (GIST + pulmonary chondroma + paragangliomas, due to succinate dehydrogenase gene mutation)
Clinical features
• Classic triad: paroxysmal headache, sweating, palpitations
• Other S/S: young-onset paroxysmal HT + postural hypotension (due to adrenaline action), anxiety, pallor
• Pressor response during procedures or with certain drugs (e.g. TCA, IV contrast) or food (cheese)
• 10% rule: 10% familial, 10% bilateral, 10% extra-adrenal, 10% malignant, 10% secrete adrenaline/ dopamine (c.f. 90% NA), 10% children, 10% not associated with HT, 10% recurrence
o Extra-adrenal: para-aortic (75%), urinary bladder (10%), thorax (10%), skull base / neck / pelvis (5%), organ of Zuckerkandl
o Malignant pheo: histologically and biochemically indistinguishable, defined by metastasis
• Pheochromocytoma crisis: APO, ICH
5P’s of pheo
• Pressure (HT)
• Pain (headache, chest pain)
• Palpitation
• Perspiration
• Pallor (vasoconstriction)
Investigations
Biochemical screening:
• Biopsy is NOT required: high risk of hypertensive crisis and hematoma
• 24h urine catecholamines + fractionated metanephrines (more sensitive: continuous release)
o Abnormal if >2x elevation
o False positive: stress, OSA, drugs (e.g. TCA, α agonist, levodopa —> stop 1 week)
• Plasma catecholamine / metanephrine (most specific, but need indwelling catheter >30min)
o Preferred in chronic renal failure because 24h urine sample is difficult to interpret
Imaging:
localize tumor
• Anatomical scan: CT with low-osmolar contrast / T2-MRI with gadolinium contrast
o CT: alpha blockade prior to administration of IV contrast (∵risk of HT crisis)
• Functional scan: I-123 MIBG scan (metaiodobenzylguanidine = NE analog)
• PET-CT: 68Gallium-DOTATATE for neuroendocrine tumors
Dynamic test
• Clonidine suppression test: only if strong clinical suspicion but above tests inconclusive
o C/I in pregnancy
o Procedure:
- Fast overnight —> Insert cannula 30 minutes before test —> Take bloods for Epi &
NE x2 (5 mins apart)
- Give PO clonidine 0.3mg with 250mL water
- Closely monitor BP/P Q30min for postural hypotension and bradycardia
- Take bloods for Epi & NE at 2h and 3h after clonidine
Osteoporosis
Definition
• Reduced bone mineral density (BMD) below a defined lower limit of normal (T score ≤ -2.5)
• Pathophysiology: bone remodelling cannot keep up with microtrauma, causing reduced bone mass with normal mineral-to-osteoid ratio (c.f. reduced in osteomalacia)
Aetiology
• Primary (MC): higher risk in post-menopausal female, smoking, alcohol, vit D deficiency, physical inactivity
• Secondary:
o Endocrine: DM, Cushing’s, hyperthyroidism, acromegaly
o GI: cholestasis (e.g. PBC, PSC), pancreatic insufficiency
o Pulmonary: COPD
o Renal: CKD (2° hyperPTH)
o Hemat: myeloma
o Autoimmune: IBD, AS, RA
o Drugs: corticosteroids, PPI, cyclosporine
Clinical features
• Asymptomatic (MC): incidental finding of osteopenia on X-ray
• Fragility fracture: fracture with fall from standing height
o Common sites: vertebrae (thoracic/lumbar), distal radius, hip, proximal femur
o Collapse fracture: gradual-onset height loss, kyphosis, chronic pain
Investigations
• XR spine: thinning of cortex, codfish sign (biconcave vertebra), compression fracture
• Dual energy x-ray absorptiometry (DEXA): assess BMD at lumbar spine & hip (MC sites of fracture)
o T score: no. of SD below peak bone mass of a 30-year old adult of same sex and ethnicity
- Osteopenia: T score -1.0 to -2.5
- Osteoporosis: T score ≤ -2.5
- Severe osteoporosis: T score ≤ -2.5 + at least one fragility fracture
o Z score: compared to normal individuals of same age, sex & ethnicity; used in pre-menopausal F, M < 50y
- Suspect secondary cause if Z score ≤ -2.0
o FRAX score: 10-year risk of major osteoporosis-related fracture
- Limitations: only for >40 / post-menopausal F
• Other scans: quantitative CT (volumetric bone density), trabecular bone scan (bone quality)
• Underlying causes: CBC, LRFT, CaPO4, ALP, ESR, TFT, Ig pattern
Management
Lifestyle modification
• Quit smoking & alcohol
• Weight-bearing exercise
• Ca and vit D rich diet ± supplements (to prevent 2o hyperparathyroidism)
o Calcium (1200mg/day): milk, yogurt, salmon, broccoli, orange
o Vitamin D (1000 IU/day): fortified milk, egg, fish
• Sunlight exposure
• Fall prevention and rehabilitation
Pharmacotherapy
Indications:
• Osteoporosis (T-score ≤ -2.5)
• Osteopenia (T-score -1.0 to -2.5) + FRAX score ≥ 20% for major osteoporotic fracture / ≥3% for hip fracture
• Hx of fragility fracture
Monitoring: DEXA 6 months later
- Bisphosphates
- PO alendronate (weekly) —> reassess 5 years —> taken on empty stomach in the morning + drinking plenty of water then sit up for 30 mins with no food/drinks —> C/I in renal failure, S/E in atypical fracture of femur, osteronecrosis of jaw, renal failure, hypoCa, GERD, flu-like symptoms (IV only)
- IV zoledronate (yearly) —> reassess 3 years —> high risk case (new fragility while on bisphosphates), at least 4 weeks of Ca/VitD supplement beforehand —> C/I in renal failure, S/E in atypical fracture of femur, osteronecrosis of jaw, renal failure, hypoCa, GERD, flu-like symptoms (IV only) - RANKL inhibitor
- SC Denosumab (Q6months)
- high risk case (new fragility while on bisphosphates), at least 4 weeks of Ca/VitD supplement beforehand
- OK for renal failure, S/E: similar to bisphosphates - SERM (weak anti-resorption)
- PO Raloxifene
- 8 years duration
- for post menopausal women
- S/E: risk of VTE - Calcitonin
- Nasal spray
- C/I in fish allergy - PTH analogue
- SC teriparatide (daily)
- 2 years max
- SFI: reversed for severe case (T score <-3.5)
- S/E: n/v, hyperCa, renal stones - Sclerostin inhibitor
- romosozumab
Osteomalacia
• Definition: low mineral-to-osteoid ratio after epiphyseal closure (before epiphyseal closure: rickets)
• Aetiology: vit D deficiency (malnutrition, liver disease, CKD), mineralization defect (Al, hypophosphatasia)
• Clinical features: diffuse skeletal pain, fracture
• Investigations: low CaPO4, vit D, high ALP, high PTH
• Management: vit D supplementation, PO4 supplementation (if hypophosphatasia)
Paget’s disease of bone
• Definition: chronic bone disorder characterized by excessive abnormal bone remodeling
• Bone most affected: pelvis > femur > skull > others
• Clinical features: severe bone pain, skeletal deformities, focal warmth (vasculiarity)
• Complications: high-output HF (vascularity and workload), osteosarcoma
• Investigations: CaPO4 normal, ALP, XR, bone scan
• Management: analgesia, Ca & vit D supplement, bisphosphonates
Multiple Endocrone neoplasm
MEN I (“3P”)
- Pituitary adenoma (e.g. prolactinoma, acromegaly)
- Parathyroid hyperplasia
- Pancreatic NET: gastrinoma, insulinoma, VIPoma
- Ix: MEN-1 mutation, PTH, glucose, MRI pituitary
MEN IIA (“PMP”)
- Parathyroid hyperplasia
- Medullary thyroid carcinoma
- Pheochromocytoma
Familial MTC only: variant of MEN2A
MEN IIB/III (“MMMP”)
- Mucosal neuroma
- Marfanoid body habitus
- Medullary thyroid carcinoma
- Pheochromocytoma
Ix:
- RET gain-of-function mutation
- FNAC thyroid nodule
- CT abdomen
MEN4
- Parathyroid adenoma, pituitary adenoma, reproductive tumor
- CDNK1B mutation
Autoimmune polyendocrine syndrome
Type 1: autoimmune poly-endocrinopathy- candidiasis-ectodermal dystrophy (APECED)
- AD (incomplete penetrance)
- AIRE mutation
- S/S:
Addison’s disease, T1DM
Hypoparathyroidism
Mucocutaneous candidiasis, nail dystrophy,
dental enamel hypoplasia
Type 2: Schmidt’s syndrome
- AR
- Polygenic: HLA-DR3
- S/S:
Addison’s disease, T1DM
Grave’s disease
Pernicious anaemia
MG
