Endocrine - Level 3 Flashcards
Physiology of PTH secretion?
o PTH secreted in response to low Ca2+ levels
o By 4 parathyroid glands situated posterior to thyroid
Control of PTH secretion?
o Negative feedback via Ca2+ levels
Actions of PTH?
o Increased osteoclast activity releasing Ca and PO4 from bones
o Increased Ca and decreased PO4 resorption in kidney
o Active 1, 25-dihydroxy-vitamin D production is increased
OVerall effect of PTH?
Raise Ca, lower PO4
Definition of hypoparathyroidism? - Congenital and Acquired?
- Hypoparathyroidism = low Ca, high PO4 and low (or inappropriately normal) PTH
o Congenital = gland failure, low secretion of PTH
o Acquired = Radiation, surgery (thyroidectomy, parathyroidectomy), hypomagnesaemia (Mg required for PTH secretion)
Definition of pseudo-hypoparathyroidism?
- Pseudohypoparathyroidism = low Ca, high PO4 with high PTH (PTH resistance)
Causes of congenital hypoparathyroidism?
Autoimmune destruction of glands – autoimmune polyglandular syndrome
• Type 1 – mutation of auto immuneregulator gene on c21
o Features: Addison’s, chronic candiasis, hypoparathyroidism, hypogonadism, pernicious anaemia, vitiligo, alopecia
• Type 2
o Features: Addison’s, T1DM, coeliac disease, hypothyroidism, hypogonadism, pernicious anaemia, vitiligo, alopecia
DiGeorge Syndrome
• CATCH22
• Cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcaemia c22q11 deletion
Kenny-Caffey syndrome, Kearns-Sayre syndrome, Sanjad-Sakati syndrome, Defect in calcium-sensing receptor gene/PTH gene
Causes of acquired hypoparathyroidism?
Post-neck surgery (thyroid, parathyroid, laryngeal, oesophageal)
Accidental damage, removal
Radiation
Chemotherapy
Alcohol
Infiltration of parathyroid glands (iron, copper)
Magnesium deficiency
Symptoms of hypocalcaemia?
- Muscle, bone and abdominal pain
SPASMODIC
o Spasms (carpopedal spasms = Trousseau’s sign)
o Perioral paraesthesia (face, fingers, toes)
o Anxious, irritable, irrational
o Seizures (grand mal)
o Muscle tone increased in smooth muscle (colic, wheeze, dysphagia)
o Orientation impaired (confused)
o Dermatitis
o Impetigo herpetiformis
o Chvotek’s sign (corner of mouth twitches when facial nerve tapped over parotid), cataract, cardiomyopathy
Blood tests performed in hypoparathyroidism? ECG findings in hypocalcaemia?
- Bloods o Bone profile – low Ca, high PO4, PTH PTH – low in primary and secondary PTH – high in pseudohypoparathyroidism o Serum Mg (may be low) o U&Es o Vitamin D levels o Others: TFTs, ACTH, Fe, Copper
- ECG
o Prolonged QT interval
Other investigations to consider in hypoparathyroidism?
o 24-hour urine calcium – usually low o Renal US o Brain MRI o Echocardiogram Cardiac abnormalities (DiGeorge)
Emergency treatment in hypoparathyroidism?
o If hypocalcaemia severe (<1.88mmol)
IV calcium gluconate (90mg) then infusion
Continuous ECG monitoring
o IF hypomagnesaemia
IV Magnesium sulphate 1g QDS
Acute asymptomatic or chronic treatment in hypoparathyroidism?
o Calcium and vitamin D supplements
Oral calcium carbonate 500-1000mg BDS/TDS
Oral calcitriol (vitD) 0.25-1mcg BDS
If inadequate – PTH hormone 50mcg SC OD
Thiazide diuretic reduces urinary calcium
o Magnesium supplements (if low)
Magnesium oxide 400mg oral BDS
Monitoring in hypoparathyroidism?
o Regular - serum Ca, albumin, phosphate and U&Es
o Urine calcium
o Renal imaging
Dietary advice in hypoparathyroidism?
o Rich in calcium and vitamin D
Complications in hypoparathyroidism?
o Laryngospasm o Muscle cramps, tetany, seizures o QT prolongation – syncope, arrhythmias o Renal stones o Stunted growth, malformed teeth
How common is thyroid cancer?
- Most common endocrine malignancy
- 1% of all malignancies
- Women
Risk factors of thyroid cancer?
o Exposure to ionising radiation (especially papillary) o History of thyroid goitre o Thyroid nodule o Thyroiditis o FHx of thyroid cancer o Females o Asians o Cowden’s syndrome o FAP
Types of thyroid cancer?
o Papillary (60%) o Follicular (25%) o Medullary (5%) o Anaplastic (5%) o Lymphoma (5%) o Hurthle Cell Carcinoma
Characteristics of papillary thyroid cancer?
Often younger patients 35-40
3x women
Spread – lymph nodes, lung (jugulo-diagastric node metastasis is called lateral aberrant thyroid)
Characteristics of follicular thyroid cancer?
Occur in middle age, 3x women
Well-differentiated
Spreads – early via blood (bone, lungs)
Characteristics of medullary thyroid cancer?
Parafollicular calcitonin-producing C cells of thyroid
Sporadic (80%) or part of MEN syndrome
May produce calcitonin
Do not concentrate iodine
Characteristics of anaplastic thyroid cancer?
From follicular cells but poor differentiation
Rare, elderly with poor response to treatment
Most aggressive cancer
Characteristics of lymphoma thyroid cancer?
Women more common
Mostly non-Hodgkins lymphoma
May present with dysphagia or stridor
Characteristics of Hurthle Cell carcinoma thyroid cancer?
Females
Symptoms of thyroid cancer?
- May be asymptomatic lump
- Thyroid nodule
o Hard, fixed, enlarging
o Non-tender on palpation - Hoarseness with goitre
- Cervical lymphadenopathy
Investigations in thyroid cancer?
o Bloods - TFTs (mainly euthyroid), calcitonin for MTC
o US of thyroid gland - Hypoechogenicity, microcalcifications, irregular borders, solid
o Fine-needle aspiration cytology - Any thyroid nodule >1cm and <1cm if suspicious US
o 123I radionucleotide imaging
o CT/MRI to detect local/regional lymph node spread
Staging in thyroid cancer?
o 1
<45 – any T, any N and M0
>45 – T1, N0, M0
o 2
<45 – any T, any N, M1
>45 – T2, N0, M0
o 3
T3, N0, M0 or T1-3, N1, M0
o 4
T4, or any M1 tumours
Guidelines for referral of thyroid lump?
o Referral within 2 weeks to thyroid surgeon or endocrinologist if:
Unexplained thyroid lump
Unexplained voice changes with goitre
Cervical lymphadenopathy
Painless thyroid mass, rapidly increasing in size over weeks
o Non-urgent referral if:
Thyroid nodules and abnormal TFTs
Hx of sudden onset pain in lump
Specialist management of papillary, follicular and Hurthle Cell thyroid cancer?
Total thyroidectomy +/- node excision +/- radioiodine (131I) ablation
Levothyroxine (to supress TSH)
Specialist management of medullary Cell thyroid cancer?
Total Thyroidectomy + node clearance + Levothyroxine
2nd line - Vandetanib
Specialist management of lymphoma Cell thyroid cancer?
Chemoradiotherapy (CDVP + external beam radiotherapy)
Specialist management of anaplastic Cell thyroid cancer?
Total thyroidectomy/Palliative Excision + Chemoradiotherapy
Levothyroxine (suppress TSH)
Follow up of thyroid cancer?
o TFTs after 3 months
o Annual – neck US, TFTs, CT scan
Complications of thyroid surgery?
laryngeal nerve palsy, hypoparathyroidism
Prognosis of thyroid cancer?
o 10-year survival 90% in differentiated cancers
o 5-year survival in anaplastic is 5%
Definition of toxic multinodular goitre?
Plummer’s disease
o Multiple autonomously functioning nodules, resulting in hyperthyroidism
o Function independently to TSH and almost always benign
How common is multinodular goitre?
- Most common goitre in UK
- Common in elderly
Risk factors for a multinodular goitre?
o Iodine deficiency
o >40
o Head and neck radiation
o Female
Symptoms of multinodular goitre?
- Thyroid lump – many nodules o Often asymptomatic, may be seen by mirror or family o Usually irregular - Occasionally pain - May have dysphagia, stridor
Symptoms if toxic multinodular goitre?
o Malaise, fever
o Thyroid pain
o Hyperactivity, insomnia, irritability, anxiety, palpitations
o Heat intolerance, sweating
o Increased appetite, weight loss, diarrhoea
o Infertility, oligomenorrhoea, amenorrhoea
o Reduced libido
Investigations in multinodular goitre?
- TFTs
o Euthyroid
o Hyperthyroid – toxic multinodular goitre - Specialist investigations:
o USS of thyroid
o FNA cytology
o CT/MRI if cancer
Management of thyroid lumps in primary care - referral?
o Referral within 2 weeks to thyroid surgeon or endocrinologist if:
Unexplained thyroid lump
Unexplained voice changes with goitre
Cervical lymphadenopathy
Painless thyroid mass, rapidly increasing in size over weeks
o Non-urgent referral to thyroid surgeon or endocrinologist if:
Thyroid nodules and abnormal TFTs
Hx of sudden onset pain in lump
Management of toxic multinodular goitre?
Radioactive iodine
• Pre-treatment with thiamazole/propylthiouracil
Surgery
• 1st line if mass effect occurring
Definition of toxic nodule?
o Autonomously functioning nodules, resulting in hyperthyroidism
o Function independently to TSH and almost always benign
Types of toxic nodule?
o May be cystic, colloid, adenomatous, hyperplastic or cancerous
Causes of toxic nodule?
o Iodine deficiency (worldwide) o Hashimoto’s thyroiditis and Grave’s disease (UK) o Drugs – lithium, amiodarone o Pregnancy o Menopause
Symptoms of toxic nodule?
- Thyroid lump o Asymptomatic mostly - Pain - Compression of trachea - If toxic, signs of hyperthyroidism o Malaise, fever o Thyroid pain o Hyperactivity, insomnia, irritability, anxiety, palpitations o Heat intolerance, sweating o Increased appetite, weight loss, diarrhoea o Infertility, oligomenorrhoea, amenorrhoea o Reduced libido
Investgiations of toxic nodule?
- TFTs o Simple goitre – normal TFTs o Toxic nodule – abnormal TFTs (TSH suppressed) - Specialist tests: o USS o FNA cytology o CT/MRI
Referral of people with thyroid lump in primary care?
- Referral within 2 weeks to thyroid surgeon or endocrinologist if:
o Unexplained thyroid lump
o Unexplained voice changes with goitre
o Cervical lymphadenopathy
o Painless thyroid mass, rapidly increasing in size over weeks - Non-urgent referral to thyroid surgeon or endocrinologist if:
o Thyroid nodules and abnormal TFTs
o Hx of sudden onset pain in lump
Management of toxic nodule?
o Radioactive iodine (I-131)
Pre-treatment thiamazole
o 2nd line - Subtotal Thyroidectomy
1st line if mass effect
Definition of goitre?
- Enlargement of the thyroid gland
- May be multi-nodular or single nodules
Types of goitre - diffuse smooth?
Grave’s disease
Hashimoto’s thyroiditis
Iodine deficiency
Lithium, amiodarone
Types of goitre - nodular goitre?
Multinodular
Single nodule (cyst, adenoma, cancer)
Definition of de Quervain’s thyroiditis?
Subacute granulomatous thyroiditis
Inflammation of thyroid
Triphasic course:
• Transient thyrotoxicosis, then hypothyroidism followed by euthyroidism
Aetiology of de Quervain’s thyroiditis?
Viral – following URTI (influenza, adenovirus, mumps, coxsackie)
Pathology of de Quervain’s thyroiditis?
Thyrotoxicosis due to follicular damage and release of preformed hormone
Symptoms and signs of de Quervain’s thyroiditis?
o Symptoms
Thyroid pain, migratory, fever, palpitations, malaise, tremor, heat intolerance
o Signs
Enlarged, firm, painful thyroid
Investigations of de Quervain’s thyroiditis?
TFTs – TSH low, T3/4 elevated
CRP/ESR – raised
US
Nuclear uptake low
Management of de Quervain’s thyroiditis?
Thyrotoxicosis phase - self-limiting, BB and NSAIDs for symptom control, if severe then prednisolone
Hypothyroid – may need levothyroxine
Description of Hashimoto’s thyroiditis?
Destruction of thyroid cells by lymphocytes and plasma cells – bind and block TSH receptor
Destructive thyroiditis with release of thyroid hormone and transient thyrotoxicosis, followed by hypothyroid phase – inadequate production and secretion of hormones
Epidemiology of Hashimoto’s thyroiditis?
Women 20x
Aetiology of Hashimoto’s thyroiditis?
HLA-DR3/5
Symptoms of Hashimoto’s thyroiditis?
Enlarged thyroid, dyspnoea and dysphagia if large enough Rarely, early – hyperthyroid symptoms Hypothyroid more common • Fatigue, constipation, dry skin and weight gain. • Cold intolerance. • Slowed movement and loss of energy. • Decreased sweating. • Mild nerve deafness. • Peripheral neuropathy. • Menstrual irregularities (typically menorrhagia). • Depression, dementia and memory loss. • Hair loss from an autoimmune process
Investigations of Hashimoto’s thyroiditis?
TFTs – TSH raised
Anti-TPO and anti-Tg antibodies
Thyroid US
Management of Hashimoto’s thyroiditis?
As hypothyroidism
• Life-long levothyroxine
Surgery for large, obstructive goitres
Definition of postpartum thyroiditis?
o Autoimmune disorder with hyperthyroidism followed by hypothyroidism within 1 year of delivery
Symptoms of postpartum thyroiditis?
Symptoms of hypothyroidism
Painless, typically 2-6 months after delivery
Investigations of postpartum thyroiditis?
TFTs – high TSH, low T3/4 in hypothyroidism
Anti-TPO and anti-Tg positive
Management of postpartum thyroiditis?
Refer to endocrinologist
Monitor hypothyroid phase every 4-6 weeks for 6 months, treat if symptomatic
• Levothyroxine for 6-12 months, withdraw over 4 weeks
Annual TFTs to screen for thyroid problems
Definition of Riedel’s thyroiditis?
Very rare, sclerosing disease
Replacement of thyroid parenchyma with dense fibrous tissue, extends beyond thyroid capsule into surrounding structures of neck
Females 3x
Symptoms and signs of Riedel’s thyroiditis?
Painless lump in neck, dyspnoea, stridor
Woody-hard, symmetrical fixed thyroid gland
Hypothyroidism usually
Management of Riedel’s thyroiditis?
Surgery if pressure symptoms
What hormones are produced by anterior pituitary gland?
GH (growth in tissues, especially bones and muscles)
FSH (oestrogen secretion and follicular development, sperm production)/LH (production of oestrogen and testosterone)
PRL (breast milk production)
TSH (activates thyroid for metabolism)
ACTH (stimulates adrenal glands to produce cortisol and other hormones)
What hormones are produced by posterior pituitary gland?
Oxytocin (stimulate release of breast milk and contraction of uterus in labour)
ADH (conserve water and prevent dehydration)
Definition of hypopituitarism?
o Inability of pituitary gland to provide enough hormones
o Usually chronic and lifelong
Definition of panhypopituitarism?
deficiency of all anterior hormones
Risk factors of hypopituitarism?
o Pituitary tumours/apoplexy/surgery
o Traumatic brain injury
o Hypothalamic disease
Causes of hypopituitarism - hypothalamic?
Kallman’s syndrome (congenital hypogonadotropic hypogonadism)
Tumour
Meningitis, encephalitis, TB
Stroke & SAH)
Causes of hypopituitarism - pituitary stalk?
Trauma
Surgery
Craniopharyngioma, meningioma, glioma
Carotid artery aneurysm
Causes of hypopituitarism - Pituitary?
Adenomas
Irradiation
Inflammation
Infiltration (haemochromatosis, amyloid, sarcoidosis, metastases)
Ischaemia (pituitary apoplexy, DIC, Sheehan’s syndrome)
Symptoms of GH deficiency in hypopituitarism?
Central obesity Atherosclerosis Dry, wrinkly skin Low strength/balance/wellbeing/exercise ability Low cardiac output/glucose Osteoporosis Children – failure to thrive
Symptoms of FSH/LH deficiency in hypopituitarism?
Males – erectile dysfunction, decreased libido/muscle bulk, hypogonadism (less hair, small testes, low ejaculate volume, low spermatogenesis)
Females – Oligo/Amernorrhoea, low fertility/libido, breast atrophy, osteoporosis, psyparenunia
Symptoms of TSH deficiency in hypopituitarism?
Hypothyroid picture
Symptoms of ACTH deficiency in hypopituitarism?
Adrenal insufficiency/Addison’s picture
• Acute – weakness, dizziness, N&V, fever, shock
• Chronic – fatigue, pallor, anorexia, weight loss
• Hypoglycaemia, hypotension, anaemia
NO INCREASED SKIN PIGMENTATION AS LOW ACTH
Symptoms of Prolactin deficiency in hypopituitarism?
Absent lactation
Symptoms of ADH deficiency in hypopituitarism?
(Diabetes Insipidus)
Polyuria, polydipsia, hypernatraemia
Bloods performed in hypopituitarism?
o FBC
o U&Es
o TFTs
o Glucose
Hormone profile done in hypopituitarism?
o TFTs, prolactin, gonadotrophins, testosterone and cortisol
o Triple Stimulation of GnRH, TRH and insulin
Measure gonadotrophins, TSH, GH, glucose and cortisol
Other tests performed in hypopituitarism?
o Synacthen Test (ACTH administered and cortisol measured – low)
o Insulin Tolerance Test (adrenal and GH axis)
o Water deprivation test (for DI)
- Imaging
o MRI
Management of acute hypopituitarism?
o IV fluids
o If apoplexy – IV hydrocortisone and surgical decompression
Management of chronic hypopituitarism?
o Treat underlying cause if possible
Management of ACTH deficiency in hypopituitarism?
Oral hydrocortisone
Carry steroid card, alert bracelet
Sick day dosing according to Addison’s rules
Management of TSH deficiency in hypopituitarism?
Levothyroxine after corrected ACTH (provoke adrenal crisis)
Management of Gonadotrophin (FSH/LH) deficiency in hypopituitarism?
Females
• Fertility not desired – oestrogens (with progesterone if uterus – prevent unopposed oestrogen) – patches or pill
• Fertility desired – Gonadotrophins
Males
• Fertility not desired – Testosterone gel, patches, buccal tablets
• Fertility desired – Gonadotrophins
Management of GH deficiency in hypopituitarism?
Recombinant somatropin
Management of ADH deficiency in hypopituitarism?
Desmopressin
Location of pituitary gland?
structure attached to base of brain behind the nose, protected by sphenoid bone
Classification of pituitary tumours?
o <1cm diameter – microadenoma
o >1cm diameter – macroadenoma
Epidemiology of pituitary tumours?
- 10% of intracranial tumours
- Almost always benign adenomas – most common
- In children, prolactinoma most common
Types of pituitary tumours?
o Chromophobe – 70% - many non-secretory, some cause hypopituitarism, half produce prolactin, few produce ACTH, GH. Local pressure effect in 30%
o Acidophil – 15% - secrete GH or PRL
o Basophil – 15% - secrete ACTH
Classes of pituitary tumours?
o Non-functioning adenoma o Prolactinoma o GH-secreting o ACTH-secreting o TSH-secreting o LH/FSH-secreting
Associations of pituitary tumours?
o MEN1 – endocrine cancer syndrome characterised by tumours in parathyroid gland, endocrine gastroenteropancreatic tract (gastrinoma, insulinoma) and anterior pituitary (prolactinomas)
Local effects of pituitary tumours?
o Headache
Retro-orbital or bitemporal
Worse on waking
If large, hydrocephalus
o Visual field defects
Bitemporal hemianopia (heteronymous) – compression of optic chiasm
Cranial nerve 3, 4 & 6 palsies
o Hypothalamic dysfunction of temperature, sleep, appetite, thirst
Hypopituitarism effects of pituitary tumours?
o Low LH/FSH Infertility Oligo/amenorrhoea Decreased libido, muscle bulk Erectile dysfunction
o Low GH Central obesity Atherosclerosis Worse strength, balance, wellbeing, glucose Impaired growth in children
o Low TSH
Hypothyroidism
o Low ACTH
Lean, tanned, tired, anorexia, dizzy, nausea, vomiting
Hormonal secretion symptoms of pituitary tumours?
o Acromegaly – GH
o Galactorrhoea – PRL
o Cushing’s - ACTH
o Thyrotoxicosis - TSH
Investigations to perform in pituitary tumours?
- Visual Fields
- Pituitary Function Tests
o Prolactin – PRL
o GH - IGF-1, insulin tolerance test
o ACTH - cortisol, Synacthen test
o LH/FSH, testosterone, estradiol
o TRH-stimulation test - MRI with gadolinium
o Infra- and supra-stellar extension
o Vessel lateral to pituitary gland is internal carotid artery
Management of pituitary adenoma?
o Observation
If microadenoma & asymptomatic
Hormone replacement as necessary
o Surgery
Endoscopic transsphenoidal pituitary adenoma resection
Hormone replacement as needed
o Drugs
Bromocriptine (1st-line prolactin-secreting adenoma)
Somatostatin analogues (GH-secreting adenomas)
o Radiotherapy
Residual or recurrent adenomas
Prognosis of pituitary tumours?
o Remission in up to 90% of patients with microadenoma, 50% in macroadenoma
Compications of pituitary tumours?
o Pituitary Apoplexy – sudden-onset hypopituitarism caused by infarction of pituitary adenoma
Sx – Mass effect, collapse, acute onset headache, meningism, low GCS
Rx – urgent hydrocortisone, fluid balance and cabergoline (dopamine agonist if prolactinoma) +/- surgery
Adrenal gland made up of what two parts?
Cortex
Medulla
Zones of cortex of adrenal gland and what hormones produced?
Zona Glomerulosa – secretes mineralocorticoids (aldosterone)
Zona Fasciculata – secretes glucocorticoids (cortisol)
Zona Reticularis – Secretes androgens
What hormones produced by medulla of adrenal gland?
Secretes catecholamines (adrenaline, noradrenaline, dopamine)
Definition of phaeochromocytoma?
o Catecholamine-producing tumours in adrenal medulla
o Arise from sympathetic paraganglia cells (phaeochrome bodies), collections of chromaffin cells in the adrenal medulla
Rule of phaeochromocytoma?
10% malignant 10% extra-adrenal 10% bilateral 10% familial • Hereditary cancer syndromes – thyroid, MEN-2a and 2b, neurofibromatosis, VHL syndrome
Where are phaeochromocytoma usually found?
- Usually found in adrenal medulla
- Extra-adrenal tumours are rare - paragangliomas – aortic bifurcation (organs of Zuckerkandl)
Symptoms of phaeochromocytoma and what precipitates them?
- Symptoms precipitated by straining, exercise, stress, abdominal pressure, surgery or drugs (BB, IV contrast, TCAs)
- Triad:
o Episodic headache
o Sweating
o Tachycardia
Signs of phaeochromocytoma?
o Heart – hypertension, postural hypotension, tachycardia, palpitations, dyspnoea, faints, angina, MI
o CNS – Headache, visual disorder, dizzy, tremor, numbness, fits, Horner’s, CNS haemorrhage
o Psychological – anxiety, confusion
o Gut – D&V, abdominal pain
o Other – sweating, heat intolerance, pallor, pyrexia, backache
Investigations of phaeochromocytoma?
- BP
- Bloods
o FBC – Raised Hb, High WCC
o Glucose - raised - 3 x 24-hour urines for metadrenalines, creatinine, total catecholamines, vanillylmandelic acid (VMA)
o Clonidine suppression test if borderline
Imaging of phaeochromocytoma?
o Abdominal CT
o Meta-iodobenzylguanidine (MIBG)scan (look for extra-adrenal tumours)
Treatment of phaeochromocytoma?
o Surgical resection of tumour
Alpha-blockade 7-10 days pre-op (phenoxybenzamine)
B-blocker if heart disease or tachycardic (always after alpha blocker)
Consult anaesthetist
o Post-op
24h urine total catecholamines, VMA and metadrenalines 2 weeks post-op
Monitor BP
Emergency management of phaeochromocytoma?
o Get help
o ICU
o Short-acting Alpha blocker IV – phentolamine 2-5mg – repeat to maintain safe BP
o When BP controlled:
o Long-acting Alpha-blocker PO phenoxybenzamine 10mg/24h (can be increased)
Up dose until BP controlled and no postural hypotension
Alternative Alpha1 blocker is doxazocin
o B1-blocker given to control tachycardia or myocardial ischaemia
o Surgery
Elective 4-6 weeks after to allow full alpha-blockade and volume expansion
Definition of Cushing’s syndrome?
- Prolonged exposure to elevated levels of endogenous/exogenous glucocorticoids
- Loss of normal feedback mechanisms of HPA axis and loss of circadian rhythm of cortisol
Causes of Cushing’s syndrome - ACTH dependent?
Excessive ACTH from pituitary (Cushing’s disease)
• Bilateral adrenal hyperplasia – most common 80%
Ectopic ACTH-producing tumour
• Small cell lung cancer and carcinoid tumours
Causes of Cushing’s syndrome - ACTH independent?
Adrenal adenoma
Adrenal carcinomas
Excess glucocorticoid administration
Symptoms of Cushing’s syndrome?
o Weight gain
o Mood change (depression, lethargy, irritability, psychosis)
o Proximal weakness
o Gonadal dysfunction (irregular menses, hirsutism, erectile dysfunction)
o Acne
o Recurrent Achilles tendon rupture
Signs of Cushing’s syndrome?
o Central obesity o Plethoric, moon face o Buffalo neck o Supraclavicular fat distribution o Skin and muscle atrophy o Bruising o Purple abdominal striae o Osteoporosis o Hypertension o DM o Infection prone o Poor wound healing
Bloods in Cushing’s syndrome?
Raised WCC
Confirmation of Cushing’s syndrome?
24-hour urinary free cortisol
3 collections
Diagnosed if 2 or more collections measure cortisol excretion >3x upper normal limit
1mg overnight dexamethasone suppression test
Ingested at 11pm and serum cortisol measures at 8am
Late-night salivary cortisol
Determining cause of Cushing’s syndrome?
o Plasma ACTH
If raised – high-dose dexamethasone suppression test (8mg)
• Inferior petrosal sinus sampling
Low plasma ACTH with high cortisol = ACTH-independent Cushing’s syndrome
High ACTH with high cortisol = ACTH-dependent Cushing’s syndrome
o MRI of pituitary
o Chest and abdomen CT
Management of Cushing’s syndrome - iatrogenic?
o Stop steroids if possible
Management of Cushing’s syndrome - Cushing’s disease?
o Removal of pituitary adenoma
Management of Cushing’s syndrome - Adrenal adenoma/carcinoma?
o Adrenalectomy (radiotherapy & adrenolytic if carcinoma)
Management of Cushing’s syndrome - ectopic ACTH?
o Surgery if local tumour
o Metyrapone, ketoconazole and fluconazole decreased cortisol secretion
Complications of Cushing’s syndrome?
- Metabolic syndrome
- Hypertension
- DM
- Obesity
- Hyperlipidaemia
- Osteoporosis
- Coagulopathy
- Impaired immunity
Definition of congenital adrenal hyperplasia?
- Autosomal recessive disorders of cortisol biosynthesis
- Inadequate cortisol production leads to raised ACTH, adrenal hyperplasia and overproduction of androgenic precursors (particularly 17OH-progesterone) – leads to increased testosterone, decreased cortisol and aldosterone
Epidemiology of congenital adrenal hyperplasia?
- 1 in 5000 births and commoner in consanguineous marriages
Causes of congenital adrenal hyperplasia?
- 21-hydroxylase deficiency cause of about 95% of cases
- Characterised by cortisol deficiency, with or without aldosterone deficiency and androgen excess
- May be family history of neonatal death
Symptoms and signs of congenital adrenal hyperplasia?
- In infant females, virilisation of external genitalia, clitoral hypertrophy and fusion of labia
- In infant male, penis may be enlarged and scrotum small and hyperpigmented
- Other signs
• Male pattern bladness
• Infertility
• Irregular menses
• Short stature
• PCOS
• Precocious puberty - Salt loss adrenal crisis
• Present 1-3 weeks old, vomiting, weight loss, hypotension and floppiness, circulatory collapse
Investigations of congenital adrenal hyperplasia?
- Biochemical screening can be performed
- Raised 17 alpha-hydroxyprogesterone in blood is diagnostic
- In salt losers:
• Low plasma sodium, high plasma potassium, metabolic acidosis and hypoglycaemia - Pelvic USS to demonstrate uterus
- Corticotropin stimulation test
- Karyotyping
Management of congenital adrenal hyperplasia - medical and surgical?
- Multidisciplinary team assessment needed
- Birth registration must be delayed until sex is known
- Medical therapy
• Lifelong glucocorticoids (hydrocortisone) to supress ACTH levels
• Mineralocorticoids (fludrocortisone), saline, glucose if salt loss adrenal crisis
Double dose of steroids if ill or having surgery
• Monitoring of growth, skeletal maturity and 17 alpha-hydroxyprogesterone - Surgery
• Reconstruction of clitoris and vaginoplasty
Definition of hyperaldosteronism?
- Excessive levels of aldosterone
o Act at distal renal tubule, promoting sodium and water retention and excretion of potassium
Risk factors of hyperaldosteronism?
o FHx of PA or early hypertension
Types of hyperaldosteronism?
o Primary – excess production of aldosterone, independent of renin-angiotensin system, causing high Na, and water retention and low renin
o Secondary – High renin levels from low renal perfusion
Causes of primary hyperaldosteronism?
Adrenal Adenoma (Conn’s syndrome) – 80%
Bilateral Adrenal hyperplasia (BAH) – 15%
• Cells become hyperplastic, excessive secretion of aldosterone
Familial Hyperaldosteronism
Adrenal Carcinoma
Glucocorticoid remediable aldosteronism (GRA)
Causes of secondary hyperaldosteronism?
Renal artery stenosis Accelerated hypertension Diuretics CCF Hepatic failure Nephrotic syndrome Bartter’s syndrome
Symptoms of hyperaldosteronism?
o Often asymptomatic o Hypokalaemia symptoms: Muscle weakness Hypotonia Hyporeflexia Cramps Tetany Palpitations Light-headedness Constipation Polyuria, polydipsia
Signs of hyperaldosteronism?
o Hypertension
o Hypokalaemia
o Metabolic alkalosis
o Sodium normal or high end of normal
Investigations performed in hyperaldosteronism?
- BP
- Bloods (off diuretics for >4 weeks, off BB and CCB for 2 weeks, stop steroids, potassium, laxatvies)
- Urine
o 24-hour urinary aldosterone – raised in primary
Specific bloods done in hyperaldosteronism?
- Bloods (off diuretics for >4 weeks, off BB and CCB for 2 weeks, stop steroids, potassium, laxatvies)
o U&E – hypokalaemia, sodium (normal or high end of normal)
o Hormone Profiles (measure 9am lying and 12pm standing)
Renin activity
• If normal or high – excludes primary hyperaldosteronism - refer
• If low – aldosterone levels and refer to specialist
Aldosterone levels
On lying and standing
• If reduced aldosterone and cortisol on standing – Conn’s syndrome
• If increased aldosterone and reduced cortisol - BAH
Further tests done in hyperaldosteronism?
Fludrocortisone suppression test & Oral salt loading
ECG – arrhythmias
CT 1st line (MRI)
o Locate cause
Adrenal vein sampling
o If one side has higher aldosterone, adenoma likely and surgical excision indicated
Genetic Testing for GRA
Management of Conn’s syndrome in hyperaldosteronism?
Aldosterone antagonists (spironolactone) 4 weeks before surgery
Surgery
• Adrenalectomy – laparoscopic
Post-op aldosterone antagonists if PA after surgery
Management of BAH in hyperaldosteronism?
Aldosterone antagonists (amiloride, spironolactone, eplerenone)
Management of GRA in hyperaldosteronism?
Dexamethasone 4-weeks
If BP still high – spironolactone
Management of adrenal carcinoma in hyperaldosteronism?
Surgery
Post-operative adrenolytics (Mitotane)
Complications of hyperaldosteronism?
o CVD and stroke as a result of hypertension
Definition of hypoaldosteronism??
- Decreased levels of aldosterone – produced by adrenals
Causes of hypoaldosteronism??
o Primary
Addison’s disease
Congenital adrenal hyperplasia
Aldosterone synthase deficiency
o Secondary
Secondary adrenal insufficiency
Disease of pituitary or hypothalamus
Steroids
Symptoms and signs of hypoaldosteronism??
- Hyperkalaemia
- Metabolic acidosis
- Hypotension
- Renal tubular acidosis
Investigations of hypoaldosteronism??
- Bloods
o U&E – hyperkalaemia
o Aldosterone
o Renin - Interpretation
o Low aldosterone with high renin = primary hypoaldosteronism
o Low aldosterone and low renin = secondary hypoaldosteronism
Diagnostic investigations in hypoaldosteronism?
o Saline suppression test (Salt loading)
o Fludrocortisone suppression test
o CT scan
Management of hypoaldosteronism??
- Fludrocortisone +/- glucocorticoid replacement
Definition of hirsutism?
o Excess growth of terminal hair in androgen-dependent areas (faces, chest, linea alba, lower back, buttocks and anterior thighs)
Terminal hair = dark, thick and coarse
Vellus hair = soft, fine and unpigmented (NOT HIRSUTISM)
o Due to increased androgen production, increased sensitivity or both
How common is hirsutism?
- 5-15% of women of reproductive age
Causes of hirsutism?
o PCOS (70%)
o Idiopathic
o Congenital adrenal hyperplasia
o Ovarian or adrenal tumour (secreting androgens)
o Acromegaly
o Drugs – anabolic steroids, danazol, metoclopramide, methyldopa, sodium valproate
o Menopausal Women
Symptoms of hirsutism?
- Excess terminal hair in masculine pattern
- In androgen-secreting tumour/CAH - signs of virilisation (hair loss from scalp, voice deepen, increased muscle bulk, clitoromegaly)
Diagnosis of hirsutism?
o Excessive terminal hair in face, chest, linea alba, lower back, buttocks and anterior thighs
o Assess severity with hair growth and extent of impact on QoL
Assessment of underlying causes in hirsutism?
o PCOS – oligomenorrhoea/amenorrhoea, infertility, acne, hair loss on scalp, central obesity, acanthosis nigricans
o Androgen-secreting tumour – sudden onset, rapid progression, masses in abdomen/pelvis
o Cushing’s syndrome – facial weight gain/neck/torso, easy bruising, stretch marks, proximal muscle weakness
o Drugs
Further assessment in hirsutism - mild and no PCOS?
o No further investigations
Further assessment in hirsutism - moderate/severe hirsutism and no PCOS?
o Early morning plasma testosterone level (day 4-10 of cycle)
If >4 – referral
Further assessment in hirsutism - high risk of CAH?
o Early morning 17-hydroxyprogesterone levels
If elevated - referral
What is hypertrichosis?
o Excessive hair growth in generalised pattern (not due to excess androgens)
o Can be congenital (Hurler’s syndrome, trisomy 18, fetal alcohol), hypothyroidism, porphyrias, anorexia, malnutrition, ciclosporin, phenytoin, hydrocortisone
When to refer within 2 weeks to endocrinologist in hirsutism?
Sudden onset, rapid progression, severe, signs of virilisation (hair loss from scalp, voice deepen, increased muscle bulk, clitoromegaly)
When to refer to endocrinologist?
Serum testosterone >4 (urgently if >6)
17-hydroxyprogesterone elevated
Management of hirsutism - general measures if no referral needed?
o Weight loss o Hair reduction/removal (not on NHS) Shaving Waxing Bleaching Specialist clinic • Electrolysis • Laser photoepilation
Management of hirsutism - if mild?
reassure and advise no additional treatment
Management of hirsutism - if moderate/severe?
Facial hirsutism – Topical eflornithine
• If no benefit in 4 months – stop and refer to endocrinologist
• DO NOT PRESCRIBE IF PREGNANT, BREASTFEEDING or <19
All other women (pre-menopausal)
• Dianette (co-cyprindiol)
o Stop 3-4 months after hirsutism completely resolved
• Yasmin COCP
• If not worked after 6 months – refer to endocrinologist for specialist treatments
Management of hirsutism - Specialist treatments?
For hirsutism • Anti-androgens (high-dose cyproterone acetate, spironolactone and flutamide) • Finasteride • Metformin, pioglitazone • Goserelin, leuprorelin
For infertility – clomiphene
Description of hyperglycaemic hyperosmolar state (HHS)?
- Typically, those with Type 2 DM
- Develops over days/weeks and is more common in elderly
- Characterised by high glucose levels (>35mmol/L), high blood osmolarity (>340mosmol/kg) and lack of urinary ketones
- No switch to ketone metabolism as basal insulin secretion sufficient but insufficient to reduce blood glucose
Risk factors of hyperglycaemic hyperosmolar state (HHS)?
o Older o Dementia o Sedative drugs o Heatwaves o Immunocompromised
Causes of hyperglycaemic hyperosmolar state (HHS)?
o Infection o Infarction o Insufficient diabetic therapy o Intercurrent illness o Dehydration o Drugs Diuretics, Beta-blockers, CCB, Anti-psychotics, steroids, alcohol, cocaine, MDMA
Symptoms of hyperglycaemic hyperosmolar state (HHS)?
o Onset over days or weeks
o Dehydration – thirst, polydipsia, polyuria, decreased skin turgor, dry mouth, hypotension, tachycardia
o GI – nausea, vomiting, abdominal pain
o Hyperventilation – (resp compensation for metabolic acidosis) Deep rapid (Kussmaul breathing) and smell of acetone on breath
o Altered conscious state, focal neurological deficits
Diagnosis of hyperglycaemic hyperosmolar state (HHS)?
o Severe hyperglycaemia (>30mmol/L)
o Marked serum hyperosmolarity (>320mosmol/kg)
o WITHOUT Ketones (<3mmol/L)
Tests of hyperglycaemic hyperosmolar state (HHS)?
o Urinalysis – glycosuria o BM - >30mmol/L o Bloods – FBC, CRP, U&Es, blood glucose, osmolarity (>320mmol/L) o ABG o Blood cultures (if infection) o CXR o ECG
ABCDE approach in hyperglycaemic hyperosmolar state (HHS)?
o Secure airway if GCS low
o 2 large-bore cannulas
o High flow O2 if needed
Initial management of hyperglycaemic hyperosmolar state (HHS)?
LMWH prophylaxis
0.9% saline IVI over 48h, typically 8-15L for 70kg adult
Replace K+ when urine produced (Monitor UO hourly, add K when >30mL/h, check U&E hourly initially and replace as require, continuous ECG monitoring)
• 3.5-5.5mmol/L – 40mmol KCl/litre of IV fluid
• <3.5mmol/L – ICU/HDU help
Insulin IV (low dose – 0.05u/kg/hour) If BG not falling by 5mmol/L/h with rehydration
Keep glucose at 10-15mmol/L to avoid cerebral oedema
Look for cause (MI, drugs, bowel infarct)
Consider NG tube and urinary catheter
Admission to ICU/HDY or acute medical admissions
Monitoring of hyperglycaemic hyperosmolar state (HHS)?
o At least hourly: Capillary blood glucose Vital signs Fluid balance Level of consciousness ECG and K+
Complications of hyperglycaemic hyperosmolar state (HHS)?
o Ischaemia o VTE o ARDS o DIC o Cerebral Oedema
Description of diabetes insipidus?
- Passage of large volumes (>3L/day) of dilute urine due to impaired water reabsorption by kidney
- Due to reduced ADH secretion from posterior pituitary (cranial DI) or impaired response by kidney to ADH (nephrogenic DI)
Physiology of diabetes insipidus?
o ADH synthesised in hypothalamus and transported to posterior pituitary
o Released into circulation, governed by plasma osmolarity
o Failure causes inability to concentrate urine in distal renal tubules
Causes of cranial diabetes insipidus?
Idiopathic (<50%) Congenital - DIDMOAD – diabetes insipidus, diabetes mellitus, optic atrophy and deafness (Wolfram’s syndrome) Tumour - Craniopharyngoma, metastases, pituitary tumour Trauma Hypophysectomy Autoimmune hypophysitis Histiocyte sarcoidosis Haemorrhage Meningoencephalitis
Causes of nephrogenic diabetes insipidus?
Inherited Metabolic • Low potassium • High calcium Drugs • Lithium CKD Post-obstructive uropathy Pregnancy
Symptoms of diabetes insipidus?
o Polyuria
o Nocturia
o Polydipsia – uncontrollable and all-consuming
o Dehydration
o Symptoms of hypernatraemia -Lethargy, thirst, weakness, confusion, fits
Signs of diabetes insipidus?
o Dehydration
o Enlarged bladder
Blood tests of diabetes insipidus?
o U&Es - Raised Na
o Glucose
o Ca
o Serum osmolarity - raised
Further test performed to confirm diabetes insipidus?
24-hour urine collection to measure urine volume
o Urine osmolarity – reduced
o Urine:plasma osmolarity ratio <2:1
Diagnostic test of diabetes insipidus?
8-hour Water Deprivation Test
o Tests whether kidneys continue to produce dilute urine despite dehydration and localise the cause
Describe procedure of 8-hour water deprivation test in diabetes insipidus?
Free fluids until 07:30. Light breakfast at 06:30, no tea, no coffee, no smoking
Stage 1
• Fluid deprivation (0-8h), start at 08:00
• Empty bladder, then no drinks and only dry food
• Weigh hourly (if >3% then urgent serum osmolarity)
o If >300mOsmol/kg – proceed to stage 2
o If <300 – continue test
• Collect urine every 2h, measure volume and osmolarity
• Venous osmolarity every 4h
• Stop after 8h if urine >600 (normal)
Stage 2 (Differentiating cranial from nephrogenic)
• Proceed if urine still dilute (<600)
• Desmopressin 2ug IM – drink water if want
• Urine osmolarity for next 4h
Interpretation of diabetes insipidus 8-hour water deprivation test?
Cranial DI – urine os <300 & after desmopressin >800
Nephrogenic DI – urine os <300 & after desmopressin <300
Primary polydipsia – urine os >800 & after desmopressin >800
Normal – urine os >600 in stage 1 and U:P >2
Management of cranial DI?
o MRI head to find cause
o Desmopressin (synthetic analogue of ADH)
Watch out for hyponatraemia
o Test anterior pituitary function
Management of nephrogenic DI?
o Treat cause
o If persistent – Bendroflumethiazide 5mg PO/24h & Desmopressin
Emergency management of diabetes insipidus?
o Urgent plasma U&E and serum & urine osmolarities
o Monitor urine output
o U&E BDS
o IVI to maintain fluid with urine output
o If hypernatraemia – 0.9% saline to reduce <12mmol/L per day
o Desmopressin 2ug IM
Physiology of sodium control?
- Sodium concentration maintained by ADH (vasopressin) secretion, RAAS system and renal handling of sodium
Definition of syndrome of inappropriate ADH secretion?
inappropriate ADH secretion from posterior pituitary or ectopic source despite low serum osmolarity
o Euvolaemic, hypotonic hyponatraemia
Causes of SIADH?
o Malignancy – lung small-cell, pancreas, prostate, thymus, lymphoma
o CNS Disorders – meningoencephalitis, abscess, stroke, SAH, SDH, head injury, GBS, SLE, vasculitis
o Chest – TB, pneumonia, abscess, aspergillosis, small-cell cancer
o Endocrine – hypothyroidism
o Drugs – thiazide diuretics, PPIs, opiates, SSRIs, psychotropics, cytotoxic
o Other – porphyria, major surgery, HIV
Symptoms and signs of SIADH?
- Anorexia, headache, nausea, vomiting, lethargy
- Personality change, muscle cramps, weakness,, confusion
- Drowsiness
- Euvolaemia
Bloods in SIADH?
o Hyponatraemia (Na <135mmol/L)
o Potassium normal
o TFTs – exclude hypothyroidism
Assessment of volume status in SIADH?
- Assess volume status, urine Na/osmolarity
o Concentrated Urine (Na>30mmol/L and osmolarity >100mosmol/kg)
o Low plasma osmolarity (<280mosmol/kg)
o In absence of hypovolaemia, oedema or diuretics
Test to find cause of SIADH?
o CT chest/abdomen/pelvis to exclude malignancy
Management of SIADH - mild?
Stop offending medications Treat Cause Fluid restriction • Calculate Furst formule (urine Na + K/serum Na) o <0.5 – 1L fluid restriction o 0.5-1 – 0.5L fluid restriction o >1.0 – do not fluid restrict
Management of SIADH - severe acute and chronic?
Specialist advice (demeclocycline/tolvaptan)
Acute
• IV hypertonic saline
• Fluid restriction
• Furosemide if fluid overload risk
Chronic • IV hypertonic saline • Tolvaptan • Furosemide if fluid overload risk • Demeclocycline
