Endocrine Flashcards
Define diabetes.
metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with metabolic disturbances leading to defect in secretion and/or action of insulin
What are the symptoms of diabetes?
- glycosuria (energy source depletion) = tired, weak, weight loss, difficulty concentrating
- glycosuria (osmotic diuresis) = polyuria, polydipsia, thirst, dry mucous membranes, postural hypotension
- glucose shifts (swollen ocular lenses) = blurred vision
- ketone production = N&V, abdo pain, heavy breathing, acetone breath, coma, drowsiness
- complications = microvascular, macrovascular, neuropathy, infection
How is diabetes diagnosed?
fasting glucose > 7.0 mmol/L random > 11.1 mmol/L HbA1c 6.5% or 48 mmol/mol one is diagnostic if symptomatic 2 if asymptomatic
Name 3 investigations that you would carry out following diagnosis of diabetes.
- plasma ketones (>0.6mmol/l = T1DM)
- islet autoantibodies e.g. GAD65, IA2 = T1DM
- C peptide: secreted in equimolar conc. of insulin, marker of endogenous insulin secretion, useful 3-5 years after diagnosis
Define T1DM and briefly describe its pathogenesis.
- chronic, progressive, metabolic disorder with hyperglycaemic due to absence of insulin secretion
- autoimmune destruction of Islets of Langerhans insulin-producing beta cells
- HLA DR3/4 gene
List the genetically susceptible T1DM triggers.
viral infections - enterovirus immunisations diet - cow's milk at early age increased SE status obesity vitamin D deficiency perinatal factors - maternal age, history of preeclampsia
How does T2DM differ from T1?
T2 involves insulin resistance rather than absence with relative deficiency as a result
Maturity onset diabetes of the young is an autosomal dominant condition. Name the main gene associated with it and 3 of its main clinical features.
- HNF1-A
- often <25 years onset
- runs in families
- managed by diet, OHAs and insulin
What are the risk factors for development of gestational DM? (3)
high BMI, previous GDM, family history of DM
Women with risk factors should have OGTT at 24-28 weeks. Which values are consistent with diagnosis of GDM?
- fasting venous glucose >5.1 mmol/L
- one hour value > 10 mmol/L
- 2 hours after OGTT > 8.5 mmol/L
What disorders can lead to secondary diabetes?
- defects in beta-cell function and insulin action
- disease of exocrine pancreas e.g. pancreatitis
- endocrinopathies e.g. acromegaly, Cushing’s
- immune suppressive agents e.g. glucocorticoids
- antipsychotics
- genetic syndromes e.g. Downs
Briefly describe the mechanism by which insulin in secreted.
- GLUT2 mediate glucose entry into beta cells
- ATP production causes ATP-sensitive K+ channels close
- increases K+ leads to depolarisation of cell
- Ca2+ enter cell and trigger exocytosis of insulin and C peptide into nearby blood vessels
- released in 2 phases
Discuss the different types of insulin analogue used in the management of T1DM.
- short/rapid (bolus) e.g. novorapid
- intermediate/long (basal) e.g. Glargine (Lantus)
- mixed e.g. novomix 30
What are the benefits of using insulin pens?
- easy to transport and convenient
- less injection pain
- can be used without being noticed
What are the benefits of pump therapy?
- continuous SC insulin infusion
- better glycaemic control
- infuses insulin at basal rate with patient-activated boosts at meals
What are the disadvantages/complications with using pump therapy?
- expensive with maintenance costs
- reactions and infections at cannula site
- tube blockage
- pump malfunction
What are the 3 components of Whipple’s triad for hypoglycaemia?
- Symptoms of hypoglycaemia: autonomic/neuroglycopaenic
- Measured plasma glucose < 2.8 mmol/L
- Relief of symptoms when the glucose is raised to normal
What is the four step treatment for hypoglycaemia?
- 15-20g quick carbo e.g. dextrosol or lucozade
- 1.5-2 tubes of glucose gel
- 1mg glucagon IM
- IV glucose
What are the DVLA rules regarding patients with hypoglycaemia?
BG > 5 mmol/L - carry CHO
BG 4.5, eat before driving
If hypo - wait 1 hour before driving and for BG > 5
What 3 things are seen in diabetic ketoacidosis?
- METABOLIC ACIDOSIS - venous HCO3- < 18, H+ > 45, pH < 7.3
- PLASMA GLUCOSE > 13.9
- URINARY/PLASMA KETONES - urinary > 2, plasma > 3
Is DKA more commonly seen in T1DM or T2DM?
T1DM
Describe how untreated DKA can cause fatality in the young and in adults.
- young: cerebral oedema
- adults: severe hypokalaemia, ARDS, illness causing decompensation
Briefly describe the pathophysiology of DKA.
- absolute or relative insulin deficiency and increased stress hormones
- lipolysis: FFAs and ketogenesis
- gluconeogenesis: severe hyperglycaemia
- osmotic diuresis and acidosis: dehydration
What are the clinical features of DKA?
polyuria, polydipsia, weight loss, breathlessness (Kussmaul’s respiration), abdominal pain, leg cramps, N&V, ketone smell in breath if severe
List precipitating factors of DKA.
- acute illness: MI, trauma, pancreatitis
- new-onset DM
- insulin omission: depression, weight management
- infections
- others: steroids, pump failure, eating disorders
What is the treatment of DKA?
- IV fluid - 10% dextrose
- IV insulin
- IV potassium
- consider and treat precipitant
Describe the physiological changes seen in hyperglycaemia hyperosmolar state.
- glucose > 30 mmol/L
- serum osmolality > 320 mOsmol/L
- HCO3- > 15 mmol/L
- absence of significant ketones
Briefly discuss the pathogenesis of HHS.
- glycogenolysis and gluconeogenesis
- hyperglycaemia
- osmotic diuresis
- dehydration
What are the 3 main precipitating factors in HHS?
infection, poor compliance, drugs
How would you treat HHS?
- treat precipitant
- 0.9% NaCl - aim for a positive fluid balance of 3-6L by 12 hour
- insulin
- LWMH, foot protection
What are the complications of diabetes?
- retinopathy - annual photographic screening
- nephropathy - annual monitoring of renal function
- neuropathy/foot disease - foot ulcers, progressive neuropathy, structural change, ischaemia
- CVD - stroke, abnormal ECG, MI, claudification, high BP, absent foot pulses, keep BP < 130/80, statins
What drugs are used in the treatment of T2DM?
- metformin
- sulphonylureas
- thiazolidinediones
- SGLT2 inhibitors
- incretin-based therapy
What is the mechanism of action of metformin?
Increase the activity of AMP-dependent protein kinase (AMPK). This inhibits gluconeogenesis and reduces insulin resistance.
What are the benefits of using metformin?
weight loss, increased insulin sensitivity, improved glycaemia, improved lipid profile, improved vascular function
What type of T2DM drug is glibenclamide and how does it work?
sulphonylurea
Stimulates B cells of the pancreas to produce more insulin. Increase cellular glucose uptake and glycogenesis; reduces gluconeogenesis.
How do SGLT2 inhibitors work? Give an example.
- inhibit glucose reabsorption in PCT - decrease blood glucose and increase excretion
- dapagliflozin
Discuss the mechanism of action of incretin based therapy in T2DM.
- DPP4 inhibitors - inactivation of the inhibition of GLP1 and GIP
- increased GLP1 causes increased insulin release and decreased glucagon
Describe the symptoms of hypoglycaemia.
- autonomic: sweating, palpitations, pallor, tremor, nausea, irritability, hunger
- neuroglycopenic: inability to concentrate, confusion, drowsiness, personality change, slurred speech, weakness, dizziness, visual impairment, headache, seizure, coma
List causes of non-diabetes related hypoglycaemia.
- pancreas: insulinoma
- non-islet cell tumour: mesenchymal tumours, liver carcinomas
- autoimmune: anti-insulin receptor
- reactive hypoglycaemia: post-gastric surgery
- drug induced
- organ failure
- endocrine disease: hypopituitarism, adrenal failure, hypothyroidism
- inborn errors of metabolism
- sepsis, starvation, anorexia nervosa
What is Conn’s syndrome?
primary aldosteronism
What is the commonest secondary cause of hypertension?
primary aldosteronism
When is primary aldosteronism suspected and what other investigations need to be carried out?
- aldosterone-renin ratio >35
- saline suppression tests: 2L saline over 4 hours, aldosterone > 270 pmol/L suspicious
- stop beta blockers and MR antagonists and replace with a-blockers, verapamil, hydralazine during investigations
How is primary aldosteronism managed?
- unilateral laparoscopic adrenalectomy if unilateral: cure of hypokalaemia and most high BP
- MR antagonists e.g. spironolactone, eplerenone
What is the most common gene mutation seen in congenital adrenal hyperplasia?
CYP21 - 21a hydroxylase
Is congenital adrenal hyperplasia an autosomal dominant or recessive condition?
autosomal recessive
What are the different clinical features seen in males and females in CAH?
male: low BP, low Na+, early virilisation
female: ambiguous genitalia
How is congenital adrenal hyperplasia treated?
mineralocorticoid and glucocorticoid replacement
What are the clinical features of Cushing’s syndrome?
proximal myopathy, facial plethora, bruising, striae, hypertension, weight gain, moon face, buffalo hump, hirsutism
What are the different ACTH dependent and ACTH independent causes of Cushing’s syndrome?
- dependent: pituitary adenoma (Cushing’s disease), ectopic ACTH, ectopic CRH
- independent: adrenal adenoma, adrenal carcinoma, nodular hyperplasia
If cortisol levels are found to be increased, what tests should be carried out?
Perform 2 of:
- 24hr urinary free cortisol
- urine cortisol: creat. ratio 3x
- dexamethasone suppression test
- late night salivary cortisol
What is the management involved in Cushing’s syndrome?
short term hydrocortisone replacement
What is a phaeochromocytoma?
tumour in adrenal medulla causing increased secretion of catecholamines
What symptoms would make you think of a phaeochromocytoma?
- hypertension (intermittent in 50%)
- episodes of headache, palpitations, pallor and sweating
- tremor, anxiety, N&V, chest or abdo pain
- crises last 15 mins
What is the general treatment for a phaeochromocytoma?
- surgical resection
- preoperative treatment: alpha blockade, beta if tachycardic, encourage salt intake
What is Addison’s disease?
primary adrenal insufficiency due to autoimmune destruction
List the clinical features of Addison’s disease.
anorexia/weight loss, fatigue, abdominal pain, vomiting, diarrhoea, dizziness, low BP, skin pigmentation
How is Addison’s disease diagnosed?
- biochemistry: low Na, high K, hypoglycaemia
- short synACTHen test: measure plasma cortisol before and 30min after IV ACTH injection - normal baseline > 250 nmol/L, post > 480
- ACTH levels - very high -> skin pigmentation
- high renin, low aldosterone
- adrenal autoantibodies
What are the primary and secondary causes of adrenal insufficiency?
- primary: autoimmune, infection (TB), metastatic cancer, adrenal haemorrhage, drugs
- secondary: panhypopituitarism, isolated ACTH deficiency
- tertiary suppression: chronic high-dose glucocorticoid therapy, after cure of Cushing’s
What causes secondary aldosteronism? Name 3 processes that affect this.
defect in RAAS
heart failure, liver cirrhosis, nephrotic syndrome
Discuss the release products of the hypothalamus and how they affect the anterior pituitary.
- GHRH: release of GH from somatotrophs to multiple organs
- GnRH: release of FSH and LH from gonadotrophs to ovaries/testes
- CRH: release of ACTH from corticotrophs to adrenal cortex
- TRH: release of TSH from thyrotrophs to thyroid
- dopamine: negative feedback to prolactin from lactotrophs to breast/uterus
What does the posterior pituitary release?
- ADH - decreases water excretion
- oxytocin
What causes hypopituitarism and how is it treated?
- failure of anterior pituitary function
- multiple hormone replacement: hydrocortisone (first for cortisol), thyroxine, testosterone and oestrogen, growth hormone
- no replacement for prolactin
What leads to failure of anterior pituitary function?
tumours, radiotherapy, infarction/haemorrhage, infiltration (sarcoid), trauma
List some causes of high prolactin levels.
- prolactinomas
- lactation/pregnancy
- drugs that block dopamine e.g. antiemetics, tricyclics
- ‘stalk effect’ - due to loss of inhibitory dopamine
Discuss the different types of pituitary tumours.
- Non-functioning - commonest
- Prolactinomas
- TSHoma
What are the clinical features, investigations and treatment of non-functioning pituitary tumours?
- CF: visual field defects, headache, eye movement problems
- investigations: imaging, visual field assessment, prolactin, other pituitary hormones
- treatment: surgery, RT
What are the clinical features, investigations and treatment of prolactinomas?
- galactorrhoea, headaches, mass effect, visual field defect, amenorrhoea/erectile dysfunction
- serum prolactin > 6000, MRI pituitary
- dopamine agonists e.g. cabergoline, surgery
Discuss the impact of pregnancy in prolactinoma.
- gets bigger
- dopamine agonists are contraindicated
- monitor visual fields in macro
What causes agromegaly?
pituitary tumour secreting GH post puberty
What are the features seen in agromegaly?
sweats and headaches, alteration of facial features, increased hand and feet size, visual impairment, cardiomyopathy, increased inter-dental space
How is agromegaly diagnosed?
- glucose tolerance test: should suppress GH, agromegaly stays > 2ug/L
- measure IGF1
- MRI
Discuss the treatment of agromegaly.
- surgery
- somatostatin analogue, dopamine agonist, GH receptor agonist
- radiotherapy if residual tumour or ongoing symptoms
What are the risks associated with long exposure to increased growth hormone?
- arthropathy (reversible)
- neuropathy (intermittent anaesthesias - irreversible)
- CV disease - LV dysfunction, arrhythmias
- hypertension
- reversible upper airway obstruction
- malignancy - colonic polyps
- diabetes mellitus - reversible
What are the clinical features of diabetes insipidus and what are the differential diagnosis?
- polydipsia, polyuria
- nephrogenic diabetes insipidus or psychogenic polydipsia
What causes central diabetes insipidus?
ADH deficiency - idiopathic, trauma, pituitary tumour, pituitary surgery, pregnancy, familial
How would you diagnose diabetes insipidus?
- water deprivation test - suppress ADH release
- assess ability to concentrate urine with ADH
How is diabetes insipidus treated?
- treat underlying cause
- DDavP - synthetic ADH as spray, tablets or injection
What are the 3 component of the autoimmune polyendocrine syndrome type 2?
- addisons
- AI thyroiditis
- T1DM
What is the gene mutation associated with APS type 2?
HLA DR 3/4
List 6 conditions that are associated with APS type 2?
- pernicious anaemia
- coeliac disease
- primary hypogonadism
- alopecia
- myosthenia gravis
- stiff man syndrome
How does PCOS present?
polycystic ovarian syndrome
- anovulation - amenorrhoea, oligomenorrhoea, irregular cycles
- hyperandrogen - hirsutism, alopecia, acne
- adolescence
- metabolic abnormalities and T2DM
- increased testosterone and LH
What is primary amenorrhoea and what causes it?
- never had a period
- GU absence
- Turner’s syndrome
- secondary hypogonadism
Name some causes of secondary amenorrhoea.
- uterine - Ashermans syndrome
- ovarian - PCOS, failure
- pituitary - prolactinoma, tumour
- hypothalamus - weight, stress, drugs
Define hirsutism.
excess hair growth in a male pattern due to increased androgens and increased skin sensitivity to androgens
What are the causes of hirsutism?
PCOS, androgen secreting tumour, CAH, idiopathic
Discuss the pathophysiology of PCOS.
GONADOTROPHINS
- high LH - more LH receptors in PCOS ovaries, more theca cells, increased androgens
- low FSH - leads to continuous stimulation of follicles without ovulation, decreased conversion of androgens to oestrogens
ANDROGENS
- increased due to LH
- disordered action of enzymes
- decreased SHBG - more free testosterone
INSULIN
- increased insulin resistance
How is PCOS managed?
- lifestyle changes
- metformin: improves insulin sensitivity, decreased LH and increased testosterone, may regulate ovulatory function and hence menstruation BUT ineffective for fertility/hirsutism
- COCP: ovarian androgen suppression
- corticosteroids: adrenal androgen suppression
- spironolactone: MR antagonist
- finasteride: 5 alpha reductase inhibitor
Discuss the action of parathyroid hormone.
- to raise blood calcium
- kidneys: reabsorption of Ca from DCT
- bone: increased osteoclasts leading to Ca resorption
- gut: increased Ca absorption and stimulate vit D synthesis
What causes familial hypocalciuric hypercalcaemia?
loss of function mutation of calcium sensing receptor
Where are calcium sensing receptors found?
parathyroid gland, kidneys, thyroid (calcitonin)
Briefly describe the process by which vitamin D is produced.
- 7-dehydrocholesterol is converted to cholecalciferol in the skin by IV light
- converted to 25-hydroxycholecalciferol (storage form of vit D) in the liver
- converted to 1,25-dihydroxycholecalciferol (active form) in the kidneys
List some symptoms of hypercalcaemia.
- “stones, bones, abdominal groans, thrones and psychiatric overtones”
- confusion, depression, fatigue, coma
- shortening of QTc, bradycardia, hypertension
- polyuria, nephrogenic DI, stones, nephrocalcinosis
- muscle weakness, bone pain, osteoporosis
- anorexia, nausea, constipation, pancreatitis
Discuss the aetiology of hypercalcaemia
PTH MEDIATED
- primary hyperparathyroidism
- familial syndromes e.g. MEN1
- familial hypocalciuric hypercalcaemia
PTH INDEPENDENT
- malignancy
- granulomatous disorders
- vit D toxicity
- drugs e.g. thiazides, lithium
- adrenal insufficiency
Give 3 mechanism by which malignancy can cause hypercalcaemia.
- osteolytic metastases and myeloma
- tumour secretion of PTHrP: binds to PTH receptor - bone resorption and renal reabsorption e.g. squamous cell lung cancer, oesophageal cancer, renal cell carcinoma, breast cancer
- tumour cell production of vit D: activated macrophages e.g. lymphoma
What is the management strategy of hypercalcaemia?
Underlying cause, intravenous fluids (saline), furosemide (diuretic), calcitonin, pamidronate (bisphosphonate)
What are the causes of primary hyperparathyroidism?
isolated PT adenoma, PT hyperplasia, PT carcinoma
What conditions are associated with primary hyperparathyroidism?
- bone: osteoporosis, bony cysts
- kidneys: renal calculi, nephrocalcinosis, renal impairment
- pancreatitis
What investigations would you carry out if you suspected primary hyperparathyroidism?
- drugs, U&Es, PTH, urine Ca:creat ratio, vit D
- DEXA, renal US
- consider MEN1 or MEN2 if <40 or 1st degree relative of highPTH
Discuss the management plan for primary hyperparathyroidism.
- parathyroidectomy: if Ca >3 mmol/L, hypercalciuria, osteoporosis, <50, renal stones
- observation: if no end damage/unfit for surgery
- medicine: if not surgery e.g bisphosphonates, CaSR agonists (cinacalcet)
Give 4 causes of vitamin D deficiency.
- poor sunlight exposure: elderly, housebound, Northernisation
- malabsorption
- gastroectomy
- renal disease
What is osteomalacia and briefly describe how it develops.
- failure to ossify bones in adulthood as a result of vit D deficiency
- hypomineralisation of cortical and trabecular bone
How does osteomalacia present?
insidiously with bone pain, proximal myopathy, hypocalcaemia
What metabolic abnormalities are seen in osteomalacia?
low Ca, low P, high ALP, low vit D, high PTH
Discuss the treatment for osteomalacia.
- cholecalciferol
- restore body stores, correct metabolic disturbances, heal bone abnormalities - alfacalcidol
- i.e. active vit D
- in renal impairment and hypoparathyroidism
- higher risk of hypercalcaemia
Discuss the differences in clinical features between male hypogonadism in children and adults.
CHILD
- slow growth in teens
- no pubertal growth spurt
- small testes and phallus
ADULT
- depression/low mood/low energy
- poor libido and erectile problems
- poor muscle bulk
- sparse hair, gynaecomastia, small testes and phallus
What is hypogonadotrophic hypogonadism?
secondary hypogonadism is due to problems with either the hypothalamus or pituitary gland - deficiency in GnRH or LH/FSH
What are the causes of secondary hypogonadism?
tumour genetic syndromes, injury, cerebellar ataxia, surgery, RTx, Kallmann’s syndrome
What are the hormonal features seen in secondary hypogonadism?
low testosterone, low LH+/-FSH+/-prolactin
What is Kallmann’s syndrome?
failure of cell migration of GnRH cells to hypothalamus from olfactory placode
Describe the inheritance of Kallmann’s syndrome.
familial with variable penetration
- X linked = absence of KAL1 gene
- AD = KAL2
- AR = KAL3
List the clinical features that are associated with Kallmann’s syndrome.
- deafness (hypoplasia of olfactory lobes)
- renal agenesis
- cleft lip +/- palate
- micropenis +/- cryptorchidism
Give examples of causes of primary hypogonadism.
- complex genetic syndromes
- cryptorchidism
- adult Leydig and semineferous tubule failure e.g. trauma, chemotherapy, RTx, multisystem failure
- Klinefelter’s syndrome
What are the hormonal features of primary gonadal disease?
low testosterone, normal/high FSH/LH, normal prolactin
What is Klinefelter’s syndrome?
- commonest genetic cause of hypogonadism
- XXY sex chromosomes
- high LH and TSH - but semineferous tubules regress and Leydig cells do not function normally
Discuss the variation in phenotype in Klinefelter’s syndrome.
due to hormonal response to LH surges during puberty
- delayed puberty
- suboptimal genital development
- decreased male sexual characteristics
- persistent gynaecomastia
- azospermia
- behaviour/learning difficulties
How is Klinefelter’s syndrome managed?
androgen replacement, psychological support, fertility counselling
Discuss the management plan of male hypogonadism.
- androgen replacement e.g. oral, IM, topical
- fertility treatment e.g. HCG, recombinant LH and FSH, GnRH pumps
What are the side effects associated with androgen replacement therapy?
mood issues, libido issues, increased haemocrit, possible prostate effects, acne, sweating, gynaecomastia
List the causes of hypothyroidism.
hypopituitarism, thyroidectomy, Hastimoto’s thyroiditis, congenital
What is the treatment for hypothyroidism?
levothyroxine (T4)
What are some of the symptoms of neonatal hypothyroidism?
coarse facial features, macroglossia, umbilical hernia, dry skin, developmental delay, pallor, myxoedema, goitre
What are the causes of congenital hypothyroidism?
thyroid dysgenesis, dyshormonogenesis
What is the standard treatment for hyperthyroidism?
beta blockers, carbimazole, or radioactive iodine
Discuss the aetiology of Grave’s disease.
autoimmune, genetics (HLA, TG, thyroid receptor), environmental, immune modulating treatment
What are the causes of hyperthyroidism?
pituitary adenoma, autoimmune, thyroid adenoma, toxic multinodular goitre
What is the name given to iodine induced hyperthyroidism?
Jod Basedow phenomenon
What is the name given to iodine induced hypothyroidism?
Wolff Chaikoff effect
What are the two types of amiodarone thyroid disease and how are they treated??
- Autoimmune thyrotoxicosis - high dose carbimazole
2. Destructive thyroiditis - glucocorticoids
How are thyroid carcinomas managed?
- FNA of nodules
- surgery and therapeutic radioiodine
- monitoring of thyroidglobulin
List three associations of the RET proto-oncogene.
- familial medullary thyroid cancer
- multiple endocrine neoplasia 2 and 3
- Hirschprungs (nerves missing from intestine, constipation)
Describe the clinical manifestations of hyperthyroidism.
weight loss, tremor, heat intolerance, diarrhoea, tachycardia, hypertension, palpitations, sweating
Describe the clinical manifestations of hypothyroidism.
weight gain, constipation, cold intolerance, depression, lethargy, concentration, hoarseness, menorrhagia
