Endocrinology Flashcards
Define acromegaly.
Constellation of signs and symptoms caused by hypersecretion of GH in adults. (Excess GH before puberty results in giantism).
Explain the aetiology / risk factors of acromegaly.
- GH-secreting pituitary adenoma
- Rare: Excess GHRH results in somatotroph hyperplasia from hypothalamic ganglioneuroma, bronchial carcinoid or pancreatic tumours
Risk Factors:
- GPR101 over-expression
- Multiple endocrine neoplasia Type 1 Syndrome
- Isolated familial acromegaly
- McCune-Albright’s Syndrome
Summarise the epidemiology of acromegaly.
Rare
5 in 1 million
40-50 yrs
Recognise the presenting symptoms of acromegaly.
- Gradual progression of symptoms over many years - often only detectable on serial photographs
- Rings and shoes becoming tight
- Increased sweating
- Headache
- Carpal tunnel syndrome
- Symptoms of hypopituitarism - e.g. hypogonadism, hypothyroidism, hypoadrenalism
- Visual disturbances - caused by optic chiasm compression = bitemporal hemianopia
- Hyperprolactinaemia - irregular periods, reduced libido, impotence
Recognise the signs of acromegaly.
Hands
- Enlarged spade-like hands with thick greasy skin
- Carpel tunnel syndrome signs
- Pre-mature osteoarthritis - arthritis also affects other large joints, temporomandibular joint
Face
- Prominent eyebrow ridge (frontal bossing) and cheeks
- Broad nose bridge
- Prominent nasolabial folds
- Thick lips
- Increased gap between teeth
- Large tongue
- Prognathism
- Husky resonant voice - thickening vocal cords
Visual Field Loss
- Bitemporal superior quadrantanopia progressing to bitemporal hemianopia
- Due to pituitary tumour compressing optic chiasm
Neck
- Multi-nodular goitre
Feet
- Enlarged
Identify appropriate investigations for acromegaly and interpret the results.
- Serum IGF-1
- Oral glucose tolerance test
- Pituitary function tests
- MRI brain
Serum IGF-1
- Screening test
- GH stimulates IGF-1 secretion
- IGF-1 varies with age and increased in pregnancy and puberty
Oral GTT
- Failure of suppression of GH after 75g oral glucose load
- False-positive results in anorexia nervosa, Wilson’s disease, opiate addiction
Pituitary Function Tests
- 9am cortisol, free T4 and TSH, LH, FSH, testosterone in men) and prolactin (hypopituitarism test)
MRI
- To image the pituitary tumour and effect on the optic chiasm
Generate a management plan for acromegaly.
- Surgical - trans-sphenoidal hypophysectomy
- Radiotherapy - adjunctive
- Medical - if surgery contra-indicated or refused
SC Somatostatin Analogues - e.g. octreotide, lanreotide
- SE: Abdominal pain, steatorrhoea glucose intolerance, gallstones, irritation at injection site
Oral Dopamine Agonists - e.g. bromocriptine, cabergoline
- SE: N&V, constipation, postural hypotension (increase dose gradually and take during meals), psychosis (rare)
GH Antagonists - e.g. pegvisomant
- Monitoring - GH and IGF-1 levels, pituitary function tests, echocardiography, regular colonoscopy, blood glucose
Identify the possible complications of acromegaly and its management.
- Cardiomyopathy
- Hypertension
- Obstructive sleep apnoea
- Hyperprolactinaemia - 30%
- Hypercalcaemia
- Hyperphosphataemia
- Renal stones
- DM
- Hypertriglyceridaemia
- Psychosis - due to dopamine agonist therapy
Complications of Surgery:
- Nasoseptal perforation
- Hypopituitarism
- Adenoma recurrence
- CSF leak
- Infection - meninges, sphenoid sinus
Summarise the prognosis for patients with acromegaly.
Good if early diagnosis and treatment
Physical changes are irreversible
Define adrenal insufficiency.
Deficiency of adrenal cortical hormones - e.g. mineralcorticoids, glucocorticoids and androgens.
Explain the aetiology / risk factors of adrenal insufficiency.
- Primary (Addison’s Disease) - autoimmune >70%
- Infections - TB, meningococcal septicaemia (Waterhouse-Friderichsen Syndrome), CMV (HIV patients), histoplasmosis
- Infiltration - metastasis (e.g. lung, breast, melanoma), lymphomas, amyloidosis
- Infarction - secondary to thrombophilia
- Inherited - adrenoleukodystrophy, ACTH receptor mutation
NB: Adrenoleukodystrophy - X-linked inherited disease characterized by adrenal atrophy and demyelination.
- Surgical - after bilateral adrenalectomy
- Secondary - pituitary or hypothalamic disease
- Iatrogenic - sudden cessation of long-term steroid therapy
Summarise the epidemiology of adrenal insufficiency.
Most common cause is iatrogenic - sudden cessation of long-term steroid therapy.
Primary cause is rare - 8 in 1 million
Recognise the presenting symptoms of adrenal insufficiency.
Chronic
- Non-specific vague symptoms
- Dizziness
- Anorexia
- Weight loss
- Diarrhoea
- Vomiting
- Abdominal pain
- Lethargy
- Weakness
- Depression
Acute
- Acute adrenal insufficiency with major haemodynamic collapse often precipitated by stress - e.g. infection or surgery
Recognise the signs of adrenal insufficiency on physical examination.
- Postural hypotension
- Increased pigmentation - generalized but more on buccal mucosa, scars, skin creases, nails, pressure points (due to melanocytes being stimulated by increased ACTH levels)
- Loss of body hair in women - androgen deficiency
- Associated autoimmune conditions - e.g. vitiligo
- Addisonian Crisis - hypotensive shock, tachycardia, pale, cold, clammy, oliguria
Identify appropriate investigations for adrenal insufficiency and interpret the results.
- Confirm Diagnosis
- Identify level of defect ACTH.
- Identify cause.
- Investigations in Addisonian Crisis.
Confirm Diagnosis:
- 9am serum cortisol <100nmol/L = adrenal insufficiency
- > 550nmol/L - unlikely adrenal insufficiency
- between 100-500nmol/L - conduct short ACTH stimulation test (Synacthen test)
- Synacthen test - IM 250ug tetracosactrin given, cortisol at 30 min <550nmol/L = adrenal failure
Identify Level of ACTH Defect
- High in primary disease
- Low in secondary disease
- Long Synacthen test - 1mg tetracosactrin given, measure cortisol at 0, 30, 60, 90 and 120 mins, then at 4,6,8,12,24h
- No increase after 6 = primary adrenal insufficiency
Identfiy the Cause:
- Autoantibodies - against 21-hydroxylase
- Abdominal CT / MRI
- Adrenal biopsy for microscopy, culture PCR depending on suspected cause
- Check TFTs
Investigations in Addisonian Crisis:
- FBC - neutrophilia
- U&E - increase urea, low Na, high K
- ESR or CRP - acute infection increased
- Ca2+ - increase
- Glucose - low
- Blood cultures
- Urinalysis
- Culture and sensitivity - UTI may be trigger
- CXR - identify cause (e.g. TB, carcinoma) or precipitant of crisis (e.g. infection)
Generate a management plan for adrenal insufficiency.
Addisonian Crisis:
- Rapid IV fluid rehydration - 0.9% saline, 1L over 30-60min, 2-4L in 12-24h
- 50ml of 50% dextrose to correct hypoglycaemia
- IV 200mg hydrocortisone bolus followed by 100mg 6 hourly until BP stable
- Treat precipitating cause - e.g. antibiotics for infection
- Monitor temperature, pulse, respiratory rate, BP, sat O2, urine output
Chronic
- Replacement of glucocorticoids with hydrocortisone - TDS
- Replacement of mineralocorticoids with fludrocortisone
- Hydrocortisone dose needs to be increased during acute illness or stress
- If associated with hypothyroidism, give hydrocortisone before thyroxine to avoid precipitating an Addisonian crisis
Advice
- Steroid warning card
- Medic alert bracelet
- Emergency hydrocortisone ampoule
- Patient education
Identify the possible complications of adrenal insufficiency and its management.
- Hyperkalaemia
- Death during Addisonian crisis
Summarise the prognosis for patients with adrenal insufficiency.
- Adrenal function rarely recovers, but normal life expectancy can be expected if treated
- Type I (autosomal recessive disorder caused by mutations in AIRE gene which encodes of nuclear transcription factor) - Addison’s disease, chronic mucocutaneous candidiasis, hypoparathyroidism
- Type II (Schmidt’s Syndrome) - Addison’s disease, T1DM, hypothyroidism, hypogonadism
Define carcinoid syndrome.
Constellation of symptoms caused by systemic release of humeral factors - e.g. biogenic amines, polypeptides, prostaglandins - from carcinoid tumours
Explain the aetiology / risk factors of carcinoid syndrome.
- Slow-growing neuroendocrine tumours
- Mostly derived from serotonin-producing enterochromaffin cells
- Produce secretory products - e.g. serotonin, histamine, tachykinins, kallikrein and prostaglandin
- Classified as fore, mid or hind-gut tumours
Common Sites
- Appendix - usually benign, non-secretory
- Rectum - usually benign, non-secretory
- Other parts of large intestine
- Stomach
- Thymus
- Bronchus
- Hormones released into portal circulation metabolised in liver
- Symptoms do not usually appear until hepatic metastases - secretion of tumour products into hepatic veins
- Symptoms do not usually appear until release into the systemic circulation from bronchial or extensive retroperitoneal tumours
Summarise the epidemiology of carcinoid syndrome.
75-80% patients with carcinoid syndrome have small bowel carcinoids
1 in 1 million UK annual incidnece
Asymptomatic - common, may be incidental finding after rectal biopsy or appendectomy
10% patients with multiple endocrine neoplasia (MEN) Type 1 have carcinoid tumours
Recognise the symptoms of carcinoid syndrome.
- Paroxysmal flushing
- Diarrhoea
- Crampy abdominal pain
- Wheeze
- Sweating
- Palpitations
Recognise the signs of carcinoid syndrome on examination.
- Facial flushing
- Telangiectasia - widened venules caused thread-like red lines or patterns on the skin
- Wheeze
- Tricuspid stenosis or regurgitation
- Pulmonary stenosis
- Nodular hepatomegaly in metastatic disease
- Carcinoid crisis - profound flushing, bronchospasm, tachycardia, fluctuating blood pressure
Identify the appropriate investigations for carcinoid syndrome and interpret the results.
- 24h urine collection - 5-HIAA levels (false positive if high diet in bananas, avocados, caffeine, paracetamol)
- Blood - plasma chromogranin A & B, fasting gut hormones
- CT or MRI scan - localizes tumour
- Radioisotope Scan - radiolabelled somatostatin analogue (e.g. indium-111 octreotide) helps localise tumours
- Investigations for MEN-1
5-HIAA - metabolite of serotonin
Define Cushing’s Syndrome.
Syndrome associated with chronic inappropriate elevation of free circulating cortisol.
Explain the aetiology / risk factors of Cushing’s Syndrome.
ACTH-dependent = 80%
- Excess ACTH secreted from pituitary adenoma - Cushing’s Disease (80%)
- ATCH secreted from ectopic source - e.g. small-cell lung carcinoma, pulmonary carcinoid tumours (20%)
ACTH-Independent (20%)
- Excess cortisol secreted from benign adrenal adenoma (60%)
- Excess cortisol secreted from adrenal carcinoma (40%)
RARE:
ACTH-Independent micro- or macro-nodular adrenal hyperplasia.
Summarise the epidemiology of Cushing’s Syndrome.
2-4 per 10 million per year
May be more common
Endogenous Cushing’s Syndrome more common in females
Peak incidence 20-40 years
Recognise the presenting symptoms of Cushing’s Syndrome.
- Weight gain
- Fatigue
- Muscle weakness
- Myalgia
- Thin skin
- Easy bruising
- Poor wound healing
- Fractures - due to osteoporosis
- Hirsutism
- Acne
- Frontal balding
- Oligo or amenorrhoea
- Depression
- Psychosis
Recognise the signs of Cushing’s Syndrome on physical examination.
- Facial fullness
- Facial plethora
- Interscapular fat pad
- Proximal muscle weakness
- Thin skin
- Bruises
- Central obesity
- Pink / purple striae on abdomen, breast and thighs
- Kyphosis - due to vertebral fracture
- Poorly healing wounds
- Hirsutism
- Acne
- Frontal balding
- Hypertension
- Ankle oedema - salt and water retention as a result of mineralocorticoid effect of excess cortisol
- Pigmentation in ACTH-dependent cases
Identify appropriate investigations for Cushing’s Syndrome and interpret the results.
- Blood
- High-Sensitivity Tests
- Tests to Determine Underlying Cause
Bloods
- Non-specific changes - e.g. hypokalaemia (especially in ectopic), increased glucose
Initial High-Sensitivity Test
- Urinary free cortisol (2-3 24h urine collections)
- Late-night salivary cortisol
- Overnight dexamethasone suppression test
- Low dose dexamethasone suppression test (LDDST) - give 0.5mg dexamethasone orally every 6h for 48h, Cushing’s = fails to suppress serum cortisol below 50nmol/L 48h after 1st dose
Tests to Detemine the Underlying Cause:
- ACTH-independent (adrenal adenoma / carcinoma) - Low plasma ACTH, CT or MRI of adrenals
- ACTH-independent (pituitary adenoma) - High plasma ACTH, pituitary MRI, high-dose dexamethasone suppression test, infeior petrosal sinus sampling - Cushings = central:peripheral ratio of venous ACTH >2:1 or >3:1 after CRH
- ACTH-dependent (ectopic) - if suspect lung cancer then do CXR, sputum cytology, bronchoscopy, CT scan.
ACTH-dependent (ectopic) - if suspect carcinoid tumours then do radiolabelled octreotide scans as express somatostatin receptors
Generate a management plan for Cushing’s Syndrome.
Iatrogenic
- Discontinue administration, lower steroid dose or use alternative steroid-sparing agent if possible
Medical
- Pre-operative or if unfit for surgery
- Inhibition of cortisol synthesis with Metyrapone or Ketoconazole
- Treat osteoporosis
- Provide physiotherapy for muscle weakness
Surgical
- Pituitary adenoma - trans-sphenoidal adenoma resection (hydrocortisone replaced until pituitary recovery)
- Adrenal adenoma/carcinoma - removel plus adjuvant therapy with Mitotane for adrenal carcinoma
- Ectopic ACTH production - direct at tumour
Radiotherapy
- If not cured and have persistent hypercortisolaemia after transphenoidal resection of tumour
- Stereotactic radiotherapy provides less irradiation to surrounding tissues
Refractory Cases
- Bilateral adrenalectomy
Identify the possible complications of Cushing’s Syndrome and its management.
- DM
- Osteoporosis
- HTN
- Pre-disposition to infections
Surgical Complications:
- CSF leakage
- Meningitis
- Sphenoid sinusitis
- Hypopituitarism
Radiotherapy Complications:
- Hypopituitarism
- Radionecrosis
- Small increased risk of second intracranial tumours and stroke
Bilateral Adrenalectomy Complications:
- Nelson’s Syndrome - locally aggressive pituitary tumour causing skin pigmentation due to excessive ACTH secretion
Summarise the prognosis for patients with Cushing’s Syndrome.
5-year survival rate - 50%
Depression persists for many years following successful treatment
Define diabetes insipidus.
A disorder of inadequate secretion of or insensitivity to vasopressin (ADH) leading to hypotonic polyruria.
Explain the aetiology / risk factors of diabetes insipidus.
Failure of ADH secretion by posterior pituitary = CENTRAL / CRANIAL
Causes of CRANIAL:
- Idiopathic
- Tumours - e.g. pituitary tumour
- Infiltrative - e.g. sarcoidosis
- Infection - e.g. meningitis
- Vascular - e.g. aneurysms, Sheehan Syndrome
- Trauma - e.g. head injury, neurosurgery, DIDMOAD
DIDMOAD (Wolfram’s Syndrome) - DI, DM, optic atrophy, deafness (autosomal recessive with incomplete penetrance - WFS1, ZCD21 with products being a transmembrane protein expression in pancreatic B-cells & neurons)
Insensitivity of collecting duct to ASDH = NEPHROGENIC
- Aquaporins fail to activate
- Luminal membrane of collecting duct remains impermeable to water
- Large volume hypotonic urine
- Polydipsia
Causes of NEPHROGENIC:
- Idiopathic
- Drugs - e.g. lithium
- Post-obstructive uropathy
- Pyelonephritis
- Pregnancy
- Osmotic diuresis - e.g. DM
Summarise the epidemiology of diabetes insipidus.
Depends on aetiology
Mean age of onset 24 yrs
Recognise the presenting symptoms of diabetes insipidus.
- Polyruria
- Nocturia
- Polydipsia
- Enuresis
- Sleep disturbances
- Other symptoms depend on aetiology
Recognise the signs of diabetes insipidus on physical examination.
- Cranial diabetes insipidus has few signs if patients drink adequate fluids
- Urine output >3L in 24h
- Fluid intake < fluid output
- Signs of dehydration - e.g. tachycardia, reduced tissue turgor, postural hypotension, dry mucous membranes
- Signs of cause - e.g. visual field defect if pituitary tumour
Identify appropriate investigations for diabetes insipidus and interpret the results.
- Blood - U&E, Ca2+, Na+ rise due to dehydration, increased plasma osmolality, reduced urine osmolality
- Water deprivation test - restrict for 8h, plasma and urine osmolality measured every hour over 8h, weight patient every hour to monitor dehydration, stop test if fall in bodyweight is >3%, give desmopressin (2ug IM) after 8h and measure urine osmolality
NORMAL
- Water restriction causes rise in plasma osmolality
- Increase ADH secretion
- Increase water reabsorption in collecting ducts
- Increase urine osmolality >600mosmol/kg
Diabetes Insipidus
- No ADH secretion
- Urine unable to be concentrated by collecting ducts
- Reduced urine osmolality <400mosmol/kg
- Cranial - after desmopressin, increase in urine osmolality by 50%
- Nephrogenic, after desmopressin, increase in urin osmolality by <45%
Generate a management plan for diabetes insipidus.
- Treat identified cause
CRANIAL:
- Desmopressin (vasopressin analogue) 10ug/day
- Chlorpropamide or carbamazepine potentiate residual vasopressin in mild disease
NEPHROGENIC:
- Sodium and/or protein restriction helps polyuria
- Thiazide diuretics
Identify the possible complications of diabetes insipidus and its management.
- Hypernatraemic dehydration
- Excess desmopressin therapy may cause hyponatraemia
Summarise the prognosis for patients with diabetes insipidus.
Variable depending on cause
Cranial - transient following head trauma
Cure of cranial or nephrogenic may be possible if remove cause - e.g tumour resection, drug discontinuation
Define dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia).
Elevation of one or more plasma lipid fractions.
Explain the aetiology / risk factors of dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia).
LDL accummulates in the intima of systemic arteries.
Taken up by LDLR on macrophage = foam cell.
HDL is a shuttle in periphery for transport of cholesterol esters back to the liver –> cardioprotective
Primary - molecular genetic basis, some unknown
- Familial hypercholesterolaemia - reduced functional hepatic LDLR
- Familial hypertriglyceridaemia - unknown, autosomal dominant
- Hypertriglyceridaemia - lipoprotein lipase or apo-CII deficiency
- Familial combined hyperlipidaemia - unknown
- Remnant hyperlipidaemia - apo-E2 genotype inheritance, accumulation of LDL remnants
Secondary - subdivided depending on abnormality
- HIGH CHOLESTEROL - hypothyroidism, nephrotic syndrome, cholestatic liver disease, anorexia nervosa
- HIGH TRIGLYCERIDES - diabetes, drugs (e.g. B-blockers, thiazides, oestrogens), alcohol, obesty, chronic renal disease, hepatocellular disease
Summarise the epidemiology of dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia).
50% of UK population have a cholesterol level high enough to be a risk for CHD.
Recognise the presenting symptoms of dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia).
- Asymptomatic
- Symptoms of complications
Ask about other CVS risk factors:
- Diabetes
- Smoking
- Hypertension
- Family history
Recognise the signs of dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia) on physical examination.
Usually normal - examine for secondary causes.
Lipid deposits:
- Xanthelasmas - around eyes
- Corneal arcus
- Tendons xanthomas - e.g. extensor tendons of the hands, Achilles, patella
- Tuberous xanthomas on knees and elbows
- Xanthomas in palmar creases - in remnant hyperlipidaemia
- Eruptive xanthomas and lipidaemia retinalis (pale retinal vessels) - severe hypertriglyceridaemia
Signs of Complications:
- Reduced peripheral pulses
- Carotid bruits
- CVD risks
- High BP
Identify appropriate investigations for dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia) and interpret the results.
- Bloods
- Cardiovascular Risk Assessment
Bloods
- Fasting lipid profile
- Exclude secondary causes - e.g. glucose, TFT, LFT, U&E
CVD Risk Assessment
- Algorithms
- E.g. Framingham risk equation, QRISK, ASSIGN`
Generate a management plan for dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia).
Treat secondary causes.
Advice
- Exercise
- Lose weight
- Control BP
- Control diabetes
- Low alcohol
- Dietary modification
Lipid-lowering Drugs
- Primary prevention - if multiple risk factors + no atherosclerosis + risk CHD >20% in 10 years
- Secondary prevention - if established atherosclerosis (e.g. CHD, CAD, AA)
- Target: total cholesterol <4mmol/L, LDL <2mmol/L
Drugs for HIGH Total Cholesterol or HIGH LDL:
- HMG-CoA Reductase Inhibitors - potently lowers mortality and CVS morbidity is demonstrated in numerous trials - high dose recommended as first line - e.g. 40mg simvastatin
- Ezetimibe - inhibits cholesterol absorption in gut, used if statin not tolerated or as adjunctive agent
Drugs for HIGH Triglycerides:
- Fibrates - stimulates lipoprotein lipase activity via specific transcription factors
- Fish oil - rich in omega-3 marine triglycerides, not recommended as can aggravate
Others:
- Anion-exchange resins - e.g. colestyramine, colestipol - binds bile acids and reduces reabsorption, increases hepatic cholesterol conversion to bile acids, increases LDLR on hepatocytes
- Nicotinic acid - reduced hepatic VLDL release, reduces TG, reduces cholesterol, increases HDL, bad side effectes (PG-mediated vasodilation, flushing, dizziness, palpitations), increases glucose and urate.
Identify the possible complications of dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia) and its management.
- CAD
- MI
- PVD
- Stroke
- Hypertriglyceridaemia –> pancreatitis and retinal vein thrombosis
- Complications of treatment - statins –> myositis
Summarise the prognosis for patients with dyslipidaema (hypercholesterolaemia & hypertriglyceridaemia).
Depends on early diagnosis, treatment of hyperlipidaemia and control of other CVS risk factors.
Lipid-lowering agents –> ?Reduce cerebrovascular accidents
Define Graves’ disease.
An autoimmune thyroid condition associated with hyperthyroidism.
Explain the aetiology / risk factors of Graves’ disease.
Circulating IgG autoantibodies bind to and activate G-protein-couples thyrotropin receptors. Causes smooth thyroid enlargement and increased T3 production and react with orbital autoangitens.
Risk Factors:
- Family history autoimmune thyroid disease
- Female sex
- Tobacco use
- High iodine intake
Triggers:
- Stress
- Infection
- Childbirth
Summarise the epidemiology of Graves’ diesease.
F:M 9:1
0.5% prevalence - 2/3rd cases of hyperthyroidism.
40-60yrs - younger if maternal family history
Recognise the presenting symptoms of Graves’ disease.
- Heat intolerance
- Sweating
- Weight loss
- Palpitations
- Tremor
- Irritability
- Diarrhoea
- Increased appetite
- Labile emotions
- Oligomenorrhoea
- Infertility
- Psychosis
- Chorea
- Panic
- Itch
- Alopecia
- Urticaria
Recognise the signs of Graves’ disease on physical examination.
- Diffuse goitre
- Orbitopathy - exophthalmos
- Tremor
- Pretibial myxoedema - oedematous swellings above lateral malleoli
- Thyroid acropachy - extreme manifestation, with clubbing, painful finger, toe swelling and periosteal reaction in limb bones
- Tachycardia
- Pulse fast / irregular - AF, SVT, VT rare
- Warm moist skin
- Palmar erythema
- Thin hair
- Lid lag
- Lid retraction - exposure of sclera above iris
- Causing stare
- Thyroid nodules
- Bruit
Identify appropriate investigations for Graves’ disease and interpret the results.
- Serum TSH
- Serum free or total T4
- Serum free or total T3
- Calculation of total T3/T4 or FT3/FT4 ratio
- T3 resin uptake (T3RU)
- Free T4 index
- Radioactive iodine (I-131, I-123) or technetium-99 (Tc-99) uptake
- Thyroid isotope scan
- TSH receptor natibodies (TRAb)
- Thyroid ultrasound
- CT or MRI scan of orbit
- Skin biopsy
Define hyperparathyroidism.
Primary - Increased secretion of parathyroid hormone (PTH) unrelated to plasma calcium concentration
Secondary - Increased secretion of PTH secondary to hypocalcaemia.
Tertiary - Autonomous PTH secretion following chronic secondary hyperparathyroidism.
Explain the aetiology / risk factors of hyperparathyroidism.
Primary
- Parathyroid gland adenoma or hyperplasia
- Rarely parathyroid carcinoma (2%) - may be associated with multiple endocrine neoplasias (MEN)
(80% single adenoma, 18% multiple adenomas / hyperplasia)
Secondary
- Chronic renal failure
- Vitamin D deficiency
Summarise the epidemiology of hyperparathyroidism.
Primary
- 5 in 100,000
- Twice as common in females
- 40-60 yrs peak incidence
Recognise the presenting symptoms of hyperparathyroidism.
Primary
- Mild hypercalcaemia
- Asymptomatic
Hypercalcaemia
- Polyuria
- Polydipsia
- Renal calculi
- Bone pain
- Abdominal pain
- Nausea
- Constipation
- Psychological depression
- Lethargy
Secondary
- Symptoms and signs of hypocalcaemia and underlying cause - e.g. osteomalacia, chronic renal failure, Vitamin D deficiency
Recognise the signs of hyperparathyroidism on physical examination.
Primary
- Mild hypercalcaemia
- Asymptomatic
Hypercalcaemia
- Polyuria
- Polydipsia
- Renal calculi
- Bone pain
- Abdominal pain
- Nausea
- Constipation
- Psychological depression
- Lethargy
Secondary
- Symptoms and signs of hypocalcaemia and underlying cause - e.g. osteomalacia, chronic renal failure, Vitamin D deficiency
Identify appropriate investigations for hyperparathyroidism and interpret the results.
- Bloods
- Urine
- Renal Ultrasound
- Radiographs
- Preoperative localization
Bloods
- U&E - increased in primary and tertiary, reduced or normal in secondary
- Serum calcium - increased in primary and tertiary, reduced or normal in secondary
- Phosphate - reduced in primary and tertiary, increased in secondary
- Albumin - calculate corrected calcium
- High AlkPhos
- Vit D (low in secondary)
- PTH levels - patients with parathyroid carcinomas more likely to have marked hypercalcaemia with high serum PTH levels
Primary
- Hypercholraemic acidosis - normal anion gap
- Caused by PTH inhibition of renal tubular reabsorption of bicarbonate
Urine
- Differential - familial hypocalciuric hypercalcaemia (FHH)
- In patients with high or inappropriately normal PTH levels, measure Ca2+: creatinine ratio to differentiate
- Primary hyperparathyroidism = ratio > 0.01
- FHH (familial hypocalciuric hypercalcaemia) = ratio < 0.01
Ca2+:Creatinine
- Urine calcium mmol/L x Plasma creatinine umol/L / 1000
- Plasma calcium mmol x Urine creatinine mmol/L
- 24h urine collection sent for creatinine clearance and calcium measurement
Renal Ultrasound
- At baseline
- Look for renal calculi
Radiographs
- Subperiosteal erosions of phalanges
- Brown tumours - osteolucent bone defects
- Diffuse porotic mottling of skull caused by demineralization - pepper pot skull
- Sclerosis of superior and inferior vertebral margins with central demineralization - rugger jersey spine
- Renal calculi / nephrocalcinosis
Preoperative Localization
- Ultrasound of neck and technetium sestamibi scan
Generate a management plan for hyperparathyroidism.
PRIMARY
Acute Hypercalcaemia:
- IV fluids - 4-6 in first 24h
Conservative Management:
- If patients don’t meet surgical criteria
- Avoid factors that exacerbate hypercalcaemia - e.g. thiazide diuretics
- Maintain adequate hydration - 6-8 glasses of water per day
- Moderate calcium and vitamin D intake
Surgical:
- Subtotal parathyroidectomy
- Total parathyroidectomy in MEN1
Surgical Indications:
- Symptomatic patients or asymptomatics with ABCDE
- A = Age <50 yrs
- B = Bone mineral density T-score <2.5
- C = Calculi (renal stones), Creatinine clearance reduced by 30%
- D = Difficult to do follow up periodically
- E = Elevated serum calcium >0.25mmol/L above upper limit of normal or 24h urinary calcium >10mmol
SECONDARY
- Treat underlying renal failure
- Calcium and Vitamin D supplements
Summarise the prognosis for patients with hyperparathyroidism.
Primary
- Surgery curative for benign disease
Secondary or Tertiary
- As for chronic renal failure
Define female hypogonadism.
Characterised by impairment of ovarian function.
Explain the aetiology /risk factors of female hypogonadism.
PRIMARY HYPOGONADISM - hypergonadotrophic.
Gonadal dysgenesis
- Chromosomal abnormalities - e.g. Turner’s Syndrome
- FMR1 gene pre-mutation carriers (CGG repeats of between 55 and 200)
Gonadal Damage
- Autoimmune
- Iatrogenic - e.g. chemotherapy, radiotherapy, surgery
SECONDARY HYPOGONADISM - hypogonadotrophic
Functional
- Stress
- Weight loss
- Excessive exercise
- Eating disorders - e.g. anorexia nervosa, bulimia
Pituitary / Hypothalamic Tumours and Infiltrative Lesions
- Pituitary adenomas
- Craniopharyngiomas
- Haemochromatosis
Hyperprolactinaemia
- Prolactinomas
- Tumours causing pituitary stalk compression
Congenital GnRH Deficiency
- Kallmann’s Syndrome
- Idiopathic
Summarise the epidemiology of female hypogonadism.
Secondary hypogonadism - due to ovulation and amenorrhoea, than primary hypogonadism
Turners - 1.5% conceptions, 10% spontaneous abortions, 1 in 2000-2500 live births.
Recognize the presenting symptoms of female hypogonadism.
- Night sweats
- Hot flush
- Vaginal dryness
- Dyspareunia
- Reduced libido
- Infertility
- Symptoms of underlying cause
Recognize the signs of female hypogonadism on physical examination.
PRE-PUBERTAL HYPOGONADISM
- Delayed puberty - primary amenorrhoea, absent breast development, no secondary sexual characteristics
- Eunuchoid proportions - e.g. long legs, increased arm span for height
POST-PUBERTAL HYPOGONADISM
- Regression of secondary sexual characteristics - e.g. loss of secondary sexual hair, breast atrophy
- Perioral and periorbital fine facial wrinkles
SIGNS OF UNDERLYING CAUSE / ASSOCIATED CONDITIONS
- Hypothalamic / Pituitary Disease - visual field defects
- Kallmann’s Syndrome - anosmia
- Turner’s Syndrome- short stature, low posterior hairline, high arched palate, widely spaced nipples, wide carrying angle, short fourth and fifth metacarpals, congenital lymphoedema
- Patients with Autoimmune Primary Ovarian Failure - signs of other autoimmune diseases - e.g. hyperpigmentation in Addison’s Disease or vitiligo
Identify appropriate investigations for female hypogonadism and interpret the results.
- Low serum oestradiol
- Serum FSH and LH - high in primary (due to -ve feedback), low or inappropriately normal in secondary
- Investigations to determine aetiology
PRIMARY
- Karyotype - chromosomal abnormalities, complete or partial deletion of X Chromosome in Turner’s, presence of Y chromosome
- Pelvic imaging - US or MRI, if primary amenorrhoea to determine presence / absence of uterus, vagina, vaginal or cervical outlet obstruction (Mullerian agenesis, androgen insensitivity, transverse vaginal septum, imperforate hymen)
- Unexplained premature ovarian failure - screen for pre-mutation in FMR1 gene after counseling & consent
SECONDARY
- Pituitary function tests - 9am cortisol, TFTs, prolactin
- Visual field testing
- Hypothalamic-pituitary MRI
- Smell tests for anosmia
- Serum transferrin saturation if hereditary haemochromatosis
INVESTIGATION OF ASSOCIATED CONDITIONS
- Turner’s - periodic echocardiography and cardiology follow up, renal US
- Autoimmune oophoritis - evaluate for autoimmune adrenal insufficiency (measure 21-hydroxylase antibodies, ACTH stimulation test if positive)
Define male hypogonadism.
A syndrome of reduced testosterone production, sperm production or both.
Explain the aetiology / risk factors of male hypogonadism.
PRIMARY HYPOGONADISM - hypergonadotrophic
Gonadal Dysgenesis
- Klinefelter’s Syndrome (XXY)
- Undescended testes - cryptochidism
Gonadal Damage
- Infection - e.g mumps
- Torsion
- Trauma
- Autoimmune
- Iatrogenic - e.g. chemotherapy, surgery, radiation
Rare Causes
- Defects in enzymes involved in testosterone synthesis
- Myotonic dystrophy
SECONDARY HYPOGONADISM - hypogonadotrophic
Pituitary / Hypothalamic Lesions
GnRH Deficiency
- Kallmann’s Syndrome
- Idiopathic
Hyperprolactinaemia
Systemic / Chronic Diseases
Rare Causes
- Genetic mutations
- Prader-Willi Syndrome - loss of critical region on Chr15 causing obesity, short stature, small hands, almond-shaped eyes, learning difficulties / postnatal hypotonia
- Laurence-Moon-Biedl Syndrome - obesity, polydactyly, retinitis pigmentosa, learning difficulty
Summarise the epidemiology of male hypogonadism.
- 30-40% male infertility cases = Primary Hypogonadism
- 1-2% male infertility = Secondary Hypogonadism
- 10-20% male infertility = disorders of sperm transprot
- 40-50% male infertility = non-classifiable
- Klinefelter’s Syndrome - 1 in 500-1000 live births
Recognize the presenting symptoms of male hypogonadism.
- Delayed puberty
- Reduced libido
- Impotence
- Infertility
- Symptoms of underlying cause
Klinefelter’s Syndrome
- Intellectual dysfunction
- Behavioural abnormalities that cause difficulty in social interactions
Recognise the signs of male hypogonadism on physical examination.
- Measure testicular volume using Prader’s orchidometer - ellipsoids of different sizes (normal = 15-25ml)
PRE-PUBERTAL HYPOGONADISM
- Signs of delayed puberty - e.g. high-pitched voice, reduced pubic/axillary/facial hair, small or undescended testes, small phallus
- Gynaecomastia
- Eunuchoid proportions - arm span > height, lower segment > upper segment - due to delayed fusion of the epiphyses and continued growth of long bones
- Features of underlying cause - e.g. cryptorchidism, anosmia in Kallmann’s Syndrome
POST-PUBERTAL HYPOGONADISM
- Reduced pubic / axillary / facial hair
- Soft and small testes
- Gynaecomastia
- Fine perioral wrinkles
- Features of underlying cause - e.g. visual field defects due to a pituitary tumour, signs of chronic / systemic illness
Identify appropriate investigations for male hypogonadism and interpret the results.
- Calculate serum free testosterone - serum total testosterone, SHBG and albumin
- LH, FSH
PRIMARY
- Low testosterone
- High LH & FSH (due to -ve feedback)
SECONDARY
- Low testosterone
- Low or inappropriately normal LH & FSH
Determine level of defect:
PRIMARY
- Karyotype - to exclude Klinefelter’s Syndrome
SECONDARY
- Pituitary function tests - 9am cortisol, TFTs, prolactin
- MRI hypothalamic-pituitary area
- Visual field testing
- Smell tests for anosmia
- Iron studies - ferritin, transferrin saturation (if hereditary hemochromatosis)
Define hypopituitarism.
Deficiency of one or more of the hormones secreted by the anterior pituitary.
PAN-hypopituitarism - deficiency of ALL pituitary hormones.
Explain the aetiology / risk factors of hypopituitarism.
Pituitary Masses
- Pituitary adenomas
- Parapituitary tumours - e.g. craniopharyngioma, meningioma, glioma, metastases
- Cysts - e.g. arachnoid cyst, Rathke’s cleft cyst
Pituitary Trama
- Radiation
- Surgery
- Skull base fracture
Hypothalamus (Functional)
- Anorexia
- Starvation
- Over-exercise
Infiltration
- TB
- Sarcoidosis
- Haemochromatosis
- Histiocytosis X
Vascular
- Pituitary apoplexy
- Sheehan’s Syndrome
Infection
- Meningitis
- Encephalitis
- Syphilis
- Fungal abscess
Genetic Mutations
- Pit-1 gene
- Prop-1 gene
Summarise the epidemiology of hypopituitarism.
Pituitary Adenoma
- Annual incidence - 1 in 100,000
- Prevalence - 9 in 100,000
Recognize the presenting symptoms of hypopituitarism.
- Symptoms or signs depending on aetioogy - e.g. bitermporal hemianopia is due to pituitary mass
- Symptoms and signs according to type of hormone deficiency
Hormones & Features
GH
- Children - short stature (<3rd centile or not in keeping with parental height)
- Adults - low mood, fatigue, reduced exercise capacity/muscle strength, increased abdominal fat mass
LH / FSH
- Delayed puberty
- Female - loss of secondary sexual hair, breast atrophy, menstrual irregularities, dyspareunia, reduced libido, infertility
- Males - loss of secondary sexual hair, gynecomastia, small or soft testes, reduced libido, impotence
ACTH
- See adrenal insufficiency
TSH
- See hypothyroidism
Prolactin
- Absence of lactation - in Sheehan’s Syndrome
Pituitary Apoplexy - life-threatening hypopituitarism with headache, visual loss, cranial nerve palsies = haemorrhage or infarction of pituitary tumour
Sheehan’s Syndrome - pituitary infarction, haemorrhage and necrosis following post-partum haemorrhage
Recognize the signs of hypopituitarism on physical examination.
- Symptoms or signs depending on aetioogy - e.g. bitermporal hemianopia is due to pituitary mass
- Symptoms and signs according to type of hormone deficiency
Hormones & Features
GH
- Children - short stature (<3rd centile or not in keeping with parental height)
- Adults - low mood, fatigue, reduced exercise capacity/muscle strength, increased abdominal fat mass
LH / FSH
- Delayed puberty
- Female - loss of secondary sexual hair, breast atrophy, menstrual irregularities, dyspareunia, reduced libido, infertility
- Males - loss of secondary sexual hair, gynecomastia, small or soft testes, reduced libido, impotence
ACTH
- See adrenal insufficiency
TSH
- See hypothyroidism
Prolactin
- Absence of lactation - in Sheehan’s Syndrome
Pituitary Apoplexy - life-threatening hypopituitarism with headache, visual loss, cranial nerve palsies = haemorrhage or infarction of pituitary tumour
Sheehan’s Syndrome - pituitary infarction, haemorrhage and necrosis following post-partum haemorrhage
Identify appropriate investigations for hypopituitarism and interpret the results.
Pituitary Function Tests:
Basal Tests
- 9am Cortisol
- LH
- FSH
- Testosterone
- Oestradiol
- IGF-1
- Prolactin
- Free T4
- TSH
Dynamic Tests
- Insulin-induced hypoglycaemia (give IV 0.15U/kg insulin) - contraindicated in epilepsy, IHD, hypoadrenalism
- Peak GH and cortisol response to insulin-induced hypoglycaemia = <20mU/L GH, <550nmol/L Cortisol
- Short Synacthen Test
- MRI or CT of brain
- Visual field testing
Generate a management plan for hypopituitarism.
Hormone Replacement
Hydrocortisone
- 20mg in morning
- 10mg in evening
- Double oral dose for febrile illness
- IM hydrocortisone at times of surgery
- MedicAlert bracelet and steroid card
L-Thyroxine
- Approx 100ug daily
- Take after hydrocortisone to avoid Addisonian crisis
Sex Hormones
- Male - testosterone
- Female - oestrogen with/without progesterone
Growth Hormone
- SC 1.2unit / day in adults
- Children require specialist supervision
Posterior Pituitary Deficiency
- Due to damage to pituitary stalk
- Desmopressin - vasopressin analogue 10-20ug / day intranasally
Identify the possible complications of hypopituitarism and its management.
- Adrenal crisis
- Hypoglycaemia
- Myxoedema coma
- Infertility
- Osteoporosis
- Dwarfism - children
Complications of Pituitary Mass
- Optic chiasm compression
- Hydrocephalus - 3rd ventricular compression
- Temporal lobe epilepsy
Summarise the prognosis for patients with hypopituitarism.
Good with lifelong hormone replacement
Define hypothyroidism.
The clinical syndrome resulting from insufficient secretion of thyroid hormones.
Explain the aetiology / risk factors of hypothyroidism.
PRIMARY - reduced thyroid hormone production
Acquired
- Autoimmune - Hashimoto’s Thyroiditis (cellular and antibody-mediated)
- Iatrogenic - e.g. post-surgery, radioiodine, medication for hyperthyroidism
- Severe iodine deficiency or iodine excess (Wolff-Chaikoff Effect)
- Thyroiditis
Congenital
- Thyroid dysgenesis
- Inherited defects in thyroid hormone biosynthesis
SECONDARY
- Pituitary or hypothalamic disease - e.g. tumours
- Results in low TSH or TRH and reduced stimulation of thyroid hormone production
Summarise the epidemiology of hypothyroidism.
Frequency 0.1-2% of adults
F:M 6:1
Age onset - >40 years, but can occur at any age
Iodine deficiency see in mountainous areas
Recognise the presenting symptoms of hypothyroidism.
Insidious onset
- Cold intolerance
- Lethargy
- Weight gain
- Constipation
- Dry skin
- Hair loss
- Hoarse voice
- Mental slowness
- Depression
- Dementia
- Cramps
- Ataxia
- Paraesthesia
- Menstrual disturbances - irregular cycles, menorrhagia
- History of surgery or radioiodine therapy for hyperthyroidism
- Family or personal history of other autoimmune conditions - e.g. Addison’s disease, T1DM, pernicious anaemia, premature ovarian failure
- Myxoedema coma - severe hypothyroidism in elderly –> hypothermia, hypoventilation, hyponatremia, heart failure, confusion, coma
