Goitre and Graves Disease
General appearance
What is the differential diagnosis of a central neck mass?
What is the differential diagnosis of proptosis
What investigations would you perform?
What are the causes of painful thyroid swelling?
What are the clinical signs of hypothyroidism?
What is the mechanism behind orbital oedema in grave's disease?
What are the eye findings in grave's disease?
- Overweight versus underweight
- Obvious exophthalmos
- Alopecia
- Eye-brow wasting
- Presence of goitre
- Presence of thyroidectomy scar
- Movement of goitre with swallowing
- No movement with tongue protrusion (compared to thyroglossal cyst)
- Stridor
- Cerebellar ataxia - hypothyroidism
- Onycholysis
- Thyroid acropachy (like clubbing, but caused by subperiosteal new bone formation)
- Palmar erythema
- Diaphoresis
- Dry skin
- Cold to touch/ warm to touch
- Tachycardia vs bradycardia
- Atrial fibrillation
- Hypertension
- Fine tremor
- Carpal tunnel syndrome
- Proximal myopathy
- Proptosis
- Exophthalmos
- Lid lag
- Lid retraction
- Thinning of eyebrows
- Congestive oculopathy
- Diplopia
- Decreased visual acuity
- Horner’s syndrome
- Goitre
- Red skin overlying goitre in grave’s disease (Maranon’s sign)
- Pemberton’s sign
- Tracheal deviation
- Cervical lymphadenopathy
- Movement of mass with swallowing
- Thyrotoxic bruit
- Pleural effusion
- Pre-tibial myxoedema
- Reflexes - impaired relaxation phase of deep tendon refflexes
What is the differential diagnosis of a central neck mass?
- Multinodular goitre
- Diffuse goitre
- Lymphoma
- Thyroid cancer
- Thyroglossal cyst
- Lymphadenopathy
- Carotid artery aneurysm
- Branchial abnormalities (cysts, sinuses and fistulae)
What is the differential diagnosis of proptosis
- Graves orbitopathy
- Cavernous sinus thrombosis
- Fistula between the carotid artery and the cavenous sinus
- Retro-orbital tumour (lymphoma etc)
- Abscess
What investigations would you perform?
- Most pertinent investigations would be TFTs to determine functional status
- Thyroid antibodies, especially anti TPO, anti TG, TRAB (for graves)
- Thyroid ultrasound
- Thyroid nuclear medicine scan (to determine if lesion is hot or cold)
- FNA if indicated (look at cytology for risk features, if follicular, need to go to surgery because a follicular malignancy can only be diagnosed if there is vascular or capsular extension)
What are the causes of painful thyroid swelling?
- Infective thyroiditis – usually suppurative
- Subacute granulomatous thyroiditis
- Radiation thyroiditis
- Compare this to painless swelling which is hashimoto’s or lymphocytic thyroiditis, post-partum thyroiditis, graves disease, iodine deficiency, diffuse multinodular goitre, thyroid cysts
What are the clinical signs of hypothyroidism?
- Slow, slurred speech
- Bradykinetic walk
- Overweight
- Hoarse, croaking voice
- Bradycardia
- Subcutaneous oedema owing to deposition of glycosaminoglycan in the dermal layer
- Periorbital swelling
- Proximal myopathy
What is the mechanism behind orbital oedema in grave's disease?
- infiltration of glycosaminoglycans into the extra-ocular muscles causes a raised orbital pressure
- This then causes obstruction on the superior ophthalmic vein, leading to congestion and subsequent oedema
- Conjunctival oedema is manifested as chemosis
What are the eye findings in grave's disease?
- peri-orbital oedema
- chemosis due to orbital compression
- proptosis
- exopthalmos (defined only when you see inferior sclerae when eye is in neutral position)
- exposure keratitis
- opthalmoplegia with diplopia (especially to inferior rectus and medial rectus muscles)
- decreased visual acuity and relative afferent pupillary defect
- lid lag
- lid retraction (due to sympathetic hyperactivity as a result of over-activity of muller's muscle)
Acromegaly
Dermatological manifestations
What is the unique association with skin tags in patients with acromegaly?
What is the medical work-up of a patient suspected to have acromegaly?
How do you treat acromegaly?
- sweating is an important sign as it suggests that the disease process is active
- doughy, thickened skin, best felt over the dorsum of the hand
- enlarged pores
- skin tags, known as molluscum fibrosum, around the axillae
- acanthosis nigricans
- thickened and hardened nails
- hypertrichosis
- large spade like hands with spatulate fingers
- Coarse facial feaures
- facial wrinkles
- frontal bossing
- enlargement of the nose
- prognathism - overbite
- macroglossia
- gynecomastia
- bitemporal hemianopia (seen in 10%)
- optic atrophy, angioid streaks which are red, brown, grey streaks larger than the diameter of the retinal veins that appear to emanate from optic disc
- carpal tunnel syndrome
- hypertension
- cardiomegaly and congestive cardiac failure
- diabetes
- arthropathy
- look for evidence of pituitary insufficiency
What is the unique association with skin tags in patients with acromegaly?
- presence of skin tags are known to correlate with presence of colonic polyps
What is the medical work-up of a patient suspected to have acromegaly?
- Hormonal
- IGF-1, lab specific and age corrected, no variation with meals, but false positives and negatives exist
- OGTT --> 75g load, then GH every 30min for 2h, normal response is to suppress and will be <1ng/ml, in acromegaly can inc, dec or no change but will NOT suppress <1ng/ml
- Don’t ever do random GH level
- Structural --> MRI
- Assess end-organ damage --> ECHO, ECG, visual fields, sleep study, other pit hormones, colonoscopy
How do you treat acromegaly?
- Surgical first --> transphenoidal, with 24hr post-op GH <1ng/ml 98% predictive of cure, low mortality 1%
- Medical --> somatostatin receptor ligands: longer acting, inhibit GH secretion, octreotide, lantreotide, pasireotide.
- Ideal to have high affinity for subtype 5 receptor which is what pasireotide does. SE = gallstones/ sludge
- New Rx = pegvisomant --> prevents dimerization of GH R --> prevents IGF-1 production, use in addition to uncontrolled GH release in somatostatin Rx pts
- Dopamine agonists cabergoline and bromocriptine can be used as they suppress GH release
- Monitoring response --> difficult to assess: normalization of IGF-1 or OGTT <1ng/ml
- Follow-up --> Life long f/u, aggressive Rx of metabolic RF, GH level is the single most important determinant of mortality in acromegaly
Cushing's examination
General inspection
Difference between cushing's syndrome and cushing's disease
What are the major causes of cushing's syndrome?
What is the diagnostic work-up for someone that you suspect has cushing's syndrome?
What is the management?
- Flat mental affect
- Moon like facies
- dorso-cervical fat pad
- supra-clavicular fat pad
- extensive pigmentation secondary to raised ACTH levels
- central/ truncal obesity with thin limbs
- Evidence of acne vulgaris
- Bitemporal hemianopia secondary to optic chiasm lesion (pituitary macroadenoma)
- telangiectasia
- acne vulgaris
- cataracts
- plethora
- fundoscopy reveals hypertensive changes
- kyphosis
- evidence of proximal myopathy
- brusing, thin skin
- hypertension on measuring blood pressure
- evidence of fungal infections
- acanthosis nigricans secondary to insulin resistance
- skin tags secondary to insulin resistance
- hirsuitism
- proximal myopathy, may also be exacerbated by hypokalaemia (as cortisol also has mineralocorticoid receptor tropism)
- pitting oedema secondary to fluid retention
- ask to examine hip joint for evidence of avascular necrosis of the hip
- central adiposity
- violaceous striae
- evidence of bilateral adrenelectomy scars (this was a historical treatment for cushings disease prior to transphenoidal surgery) - retroperitoneal approach is the most common therefore scars at the neck
Difference between cushing's syndrome and cushing's disease
- Cushing's disease is related to hypersecretion of ACTH by a pituitary tumour
- Cushing's syndrome refers to symptoms and signs caused by states of cortisol excess
What are the major causes of cushing's syndrome?
- Most commonly exogenous steroid use
- Cushing's disease (66%)
- adrenal adenoma > ectopic ACTH > adrenal carcinoma > nodular adrenal hyperplasia
What is the diagnostic work-up for someone that you suspect has cushing's syndrome?
- First confirm hormone excess
- there are lots of difficulty and controversy
- Screening tests (1) 24hr urine free cortisol [look for >3x, if not >3x then need to re-test] (2) late night cortisol = loss of diurnal variation (3) overnight dexamethasone suppression test = impaired corticosteroid negative feedback + dexamethasone does not interfere with assay
- Confirmatory tests [can repeat or do two diff ones as per MKSAP] (1) 24hr urine cortisol (2) o/n DM suppression test [give 1mg 2300, take cortisol 0800, suppress to <50]
- Differentiate cause:
- Plasma ACTH [low --> adrenal; high --> pituitary, ectopic, v high --> ectopic]
- High dose DMS test --> suppresses cushings disease ~ >90% supression, not ectopic ACTH. However, suppression does occur in 10 - 25% of patients with ectopic ACTH secretion.
- Dexamethasone infusion test --> as above
- Petrosal sampling, basal and after CRH. If 1.5:1 grad pre, then 3:1 post CRH, then pit source, may lateralise. Especially if there is diagnostic uncertainty
- Localise: MRI, CXR, CT adrenals
What is the management?
- If adrenal --> surgery
- Pituitary --> surgery + replacement therapy VS pasireotide
- Ectopic --> Sx if possible, consider adrenelectomy, also medical Rx: ketoconazole
Panhypopituitarism
Clinical findings:
What are the causes of hypopituitarism?
Comment on the relative potencies of the glucocorticoid preparations
How would you manage a patient with pan-hypopituitarism prior to surgery?
- Case is usually a secondary hypopituitarism, either secondary to a non secreting adenoma or surgical resection
- Evidence of local mass effect
- bi-temporal hemianopia
- unlikely to have papilloedema
- decrease in visual acuity
- always ask for formal perimetry
- tumour may extend to the cavernous sinus affecting nerves III, IV, V(1 and 2), VI
- Evidence of lack of hormone
- ACTH and corticosteroid lack: postural hypotension as glucocorticoids help maintain vascular tone, pale dry 'alabaster skin' because of the inability to tan due to lack of MSH (from POMC --> MSH + ACTH)
- TSH deficiency: evidence of hypothyroidism
- gonadotropin deficiency: decrease in secondary sexual characteristics with decrease in muscle bulk, loss of axillary hair etc
- Evidence of previous hormone excess prior to surgery
- GH excess with acromegaly
- Cushing's disease
- prolactinoma with galactorrhoea
What are the causes of hypopituitarism?
- Vascular: pituitary infarction, shehans syndrome, pituitary apoplexy
- Infection/ Inflammation: brain abscess, IgG4 related disease, ipilumimab induced hypophysitis
- Trauma
- Auto-immune: auto-immune hypophysitis
- Metabolic: nil
- Idiopathic/ Iatrogenic: post surgery/ radiotherapy/ drugs such as ipilumimab
- Neoplastic: pituitary mass
- Degenerative
- Congenital: empty sella syndrome
Comment on the relative potencies of the glucocorticoid preparations
- Comes in 5 preparations: hydrocortisone, cortisone, prednisolone, dexamethasone, fludrocortisone
- Highest potency = dexamethasone, fludrocortisone has highest mineralocorticoid potency
- Prednisone has 4x potency of hydrocortisone, therefore 5mg pred = 20mg hydrocort
- Dexa has 30 – 40x potency of hydrocort, 30mg of hydrocort = 0.75mg dex
How would you manage a patient with pan-hypopituitarism prior to surgery?
- Minor Sx --> usual AM dose
- Major Sx --> usual AM dose + 100mg prior to Sx + 50 TDS for 24hrs + taper 50% each day
- Double HC dose if unwell [however tell patient 3 x 3 rule, triple dose for three days], if v unwell, increase 3-4x, parental treatment if there is nausea or vomiting