Endocrinology Flashcards
List the causes of primary amenorrhoea
Never had a period
3 causes
> Genitourinary abnormalities
> > Congenital absence of uterus, cervix or vagina
> Rokitansky syndrome
> Androgen insensitivity syndrome
> Chromosomal abnormalities
> Turner’s syndrome
> Secondary hypogonadism (pituitary/hypothalamic causes)
> > Kallmann syndrome
Pituitary disease
Hypothalamic amenorrhoea
List the causes of secondary amenorrhoea
No periods for 6 months
> Uterine
> Ashermans syndrome - adhesions in the uterus preventing normal menstruation
> Ovarian
> PCOS
> Premature ovarian failure
> Pituitary
> Prolactinoma
> Pituitary tumour
> Hypothalamic
> Weight loss
> Stress
> Drugs e.g. opiates
> Other
> Psychological: pregnancy, lactation
> Iatrogenic: OCP
> Thyroid dysfunction
> Hyperandrogenism
» Cushing’s syndrome
» CAH
» Adrenal or ovarian tumour
Define hirsutism and list its causes
Excess hair growth in a male pattern due to increased androgens and increased skin sensitivity due to androgens
Causes
> Ovarian
> PCOS
> Androgen-secreting tumour
> Adrenal
> Congenital adrenal hypertrophy
> Androgen secreting tumour
> Idiopathic
> Normal investigations
Describe the clinical presentation and investigations used to diagnose PCOS
Clinical presentation
> Anovulation
» Amenorrhoea/oligomenorrhoea
> Hyperandrogenism
> Hirsutism
> Acne
> Alopecia
> Investigations
> Confirm profile of PCOS
» Testosterone, androstenedione, DHEAs
» SHBG
» FSH/LH
> > Assess for other features
> Type 2 diabetes
> Abnormal lipids
> > Exclude other pathologies
Describe the pathophysiology of PCOS
> Elevated LH:FSH ratio; 2:1 is diagnostic
> Increased androgen production from theca cells under influence of LH
> Decreased sex hormone binding globulin (SHBG); free testosterone is biologicall active - hyperandrogenism, hyperinsulinaemia
> Insulin resistance
> Insulin stimulates theca cells, reduces hepatic production of SHBG and increases circulating androgens
Describe the treatment of PCOS
COCP – Dianette ideal
> Ovarian androgen suppression
Corticosteroids
> Adrenal androgen suppression
Spironolactone, cyproterone acetate
> Androgen receptor antagonist
Finasteride
> 5 alpha reductase inhibitor
Metformin
> Insulin sensitiser
» Give if at high risk of diabetes
Eflornithine
> Topical inhibitor
Weight loss
> Diet & lifestyle changes
Define hypoglycaemia and list associated symptoms
People with diabetes – plasma glucose <4 mmol/L
People without diabetes – plasma glucose <2.5 mmol/L with symptoms
Hypoglycaemic symptoms
> Autonomic
> Sweating
> Palpitations
> Pallor
> Tremors
> Nausea
> Irritability
> Hunger
> Neuroglycopaenic (later)
> Inability to concentrate
> Confusion
> Drowsiness
> Personality change
> Slurred speech
> Incoordination
> Weakness
> Dizziness
> Vision impairment
> Headache
> Seizures
> Coma
Describe the causes of hypoglycaemia
Excess insulin
> Erroneous injection of insulin or deliberate overdose
Increased sensitivity to insulin
> Exercise and weight loss
Reduced carbohydrate intake/increased metabolic demand
> Irregular or missed meal
> Malabsorption e.g. coeliac
> Eating disorder
Reduced ability to detect hypoglycaemia
> Impaired awareness, dementia, older age
> Long duration T1DM / insulin-treated T2DM
> Sleep
Reduced gluconeogenesis and glycogen reserves
> Alcohol
> CKD or advanced liver disease
Describe the management of hypoglycaemia
Biochemical or symptomatic hypoglycaemia – self-treated
> All glucose levels <4.0 mmol/l are treated – 4 is the floor
> Oral fast-acting carbohydrate (10-15g) is taken as glucose drink or tablets or confectionery
> Do not omit basal insulin
Severe – external help required
> IV 75 mL 20% dextrose over 15 mins + 15g
OR IM glucagon (1mg)
> If patient is conscious and able to swallow
> Oral refined glucose as drinks (25g) or sweets OR apply glucose gel/jam/honey to buccal mucosa
Describe Whipple’s triad
Symptoms consistent with hypoglycaemia
Low plasma glucose concentration
Relief of those symptoms after the plasma glucose level is raised
Describe the investigations for hypoglycaemia
Post-prandial
> Mixed meal test up to 5 hours
Patient fasts overnight
Have a mixed meal – usually similar to what the patient said caused symptoms i.e., measured quantity of ice cream
Take blood every 30 minutes for approx. 5 hours
Observe for hypo signs/symptoms
72h fast
> Complete at plasma glucose 2.5 mmol/L with symptoms, 72h elapsed or if plasma glucose is <3 if Whipple’s triad has previously been documented
Bloods
> Glucose
> Insulin
> C peptide
> SU screen
> Beta hydroxybutyrate (low in insulinoma)
> Pro-insulin low with exogenous insulin
> Insulin antibodies
Endogenous hyperinsulinaemic hypoglycaemia
> Localising studies: CT / MRI of pancreas, endoscopic ultrasound (EUS)
> Arterial calcium stimulation: distinguishes focal (insulinoma) from diffuse disease (nesidioblastosis / islet cell hypertrophy)
> If negative imaging, injection of calcium gluconate into gastroduodenal, splenic and superior mesenteric arteries with sampling of hepatic venous insulin levels (double or tripling of basal insulin concentrations)
List causes of spontaneous hypoglycaemia
Pancreatic
> Insulinoma
> Non-insulinoma pancreatogenic hypoglycaemia (NIPH) - Nesidioblastosis
> MEN1
Non-islet cell tumour hypoglycaemia
> IGF-II secreting tumours
» Mesenchymal tumours
» Carcinomas of the liver, stomach and adrenals
> Lymphoma, myeloma, leukaemias
Metastatic cancer
Autoimmune hypoglycaemia
> Autoimmune insulin syndrome
> Anti-insulin receptor
Reactive hypoglycaemia
> Post-gastric surgery
> Alcohol provoked reactive hypoglycaemia
Drug-induced
> Hypoglycaemic drugs
> Beta blockers
> Heparin
> Trimethoprim
Organ failure
> Severe liver disease
> End-stage renal disease and renal dialysis
> Congestive cardiac failure
Endocrine disease
> Hypopituitarism
> Adrenal failure
> Hypothyroidism
Inborn errors of metabolism
Miscellaneous
> Sepsis
> Starvation
> Anorexia nervosa
> Total parenteral nutrition
> Severe excessive exercise
Describe the physiological regulation of calcium
PTH
> Secreted in response to low free calcium
> Causes
» Bone resorption
» Reabsorption of calcium from renal tubules
» Activation of vitamin D
» Increased urinary excretion of phosphate
1,25 OH vitamin D
> Absorption of calcium from GI tract (duodenum, jejunum)
Calcitonin
> Produced by medullary C cells (parafollicular) in thyroid gland
> Inhibits bone resorption by osteoclasts
List the symptoms of hypercalcaemia
Neuro
> Lethargy
> Confusion
> Irritability
> Depression
> Coma
MSK
> Bone pain
> Muscle weakness
> Osteopenia / osteoporosis
GI
> Anorexia
> Nausea
> Constipation
> Abdominal pain
> May be secondary to pancreatitis or peptic ulcers
Renal
> Thirst
> Polyuria
> Renal calcium deposition
> Lead to renal calculi formation and nephrocalcinosis
Cardiac
> Arrhythmias – shortened QTc interval; tachycardia
Describe how the severity of hypercalcaemia is assessed
2.20-2.60 mmol/L
> Normal range of corrected calcium
<3.0 mmol/L
> Often asymptomatic
3.0-3.5 mmol/L
> May be symptomatic, prompt treatment is indicated
> 3.5 mmol/L
Urgent correction
Describe the causes of hypercalcaemia
Detectable / high PTH: PTH-dependent causes
> Primary hyperparathyroidism
> > Adenoma of parathyroid gland
> Increased bone resorption and GI absorption
> Raised calcium and PTH
> > Hyperplasia
> Tertiary hyperparathyroidism – renal failure
> Familial hypocalciuric hypercalcaemia (FHH)
> High calcium detected by parathyroid gland as normal so patient has normal detectable PTH
Undetectable PTH: PTH-independent causes
> Secondary hyperparathyroidism - malignancy
> > PTH-related peptide, similar to PTH, will raise calcium levels
> Raised calcium but PTH will be suppressed
> Lung, breast and multiple myeloma are commonest tumours
> Also seen in bone metastases due to direct osteolysis
Rarer causes
> Drugs – thiazides
> Endocrine – thyrotoxicosis, Addison’s
> Bone – immobilisation
> Vitamin D excess
> Granulomatous disorders – sarcoidosis, tuberculosis
> Lymphomas
> Iatrogenic vitamin D metabolite excess
> Renal
> Recovery from rhabdomyolysis
> Diuretic phase of renal failure
Describe the management of hypercalcaemia
Conservative
> Adequate hydration – IV 0.9% NaCl
> Bisphosphonates e.g. zolendronic acid – reduce bone resorption
> Glucocorticoids – reduce vitamin D production
> If PTH-dependent
> Calcimimetics e.g. cinacalcet – reduce PTH production
> Calcitonin – increases calcium excretion
Surgical - parathyroidectomy
Describe the anatomy of the adrenal gland
3 main layers
> Capsule
> Cortex (GFR)
> > Zona glomerulosa: mineralocorticoids – aldosterone
> > Zona fasciculata: glucocorticoids - cortisol
> > Zona reticularis: androgens – androstenedione, DHEA
> Medulla : chromaffin cells – catecholamines e.g. adrenaline, noradrenaline
Describe the function of aldosterone
Activation of mineralocorticoid receptor on epithelial surface of renal tubule cells in cortical collecting duct (CCD)
Activation of sodium channel (ENaC) allowing sodium retention
Potassium is excreted to maintain electrochemical neutrality
Describe the regulation of cortisol production
CRH secreted from hypothalamus in response to low plasma cortisol
CRH stimulates ACTH release from anterior pituitary
ACTH stimulates cortisol production from zona fasciculata
Describe the signs and symptoms of Cushing’s syndrome
Signs and symptoms
> Weight gain
Hirsutism
Psychiatric – euphoria, depression, psychotic symptoms
Proximal myopathy
Moon face with red (plethoric) cheeks
Hypertension
Bruising
Striae (red/purple)
Describe the investigations used to diagnose Cushing’s syndrome
Establish cortisol excess
> Dexamethasone suppression testing
> Failure to suppress plasma cortisol
> 24h urinary free cortisol – elevated
> Late night salivary cortisol – elevated
Causes
> ACTH-dependent (ACTH normal/high)
» Pituitary adenoma – Cushing’s disease
» Ectopic ACTH
» Ectopic CRH
> ACTH-independent (ACTH undetectable)
> Adrenal adenoma
> Adrenal carcinoma
> Nodular hyperplasia
> Iatrogenic – prolonged high dose steroid therapy
Describe the management of Cushing’s syndrome
Surgical
> Transphenoidal pituitary surgery
> Laparoscopic adrenalectomy
> Removal of ACTH source
Medical
> Metyrapone/ketoconazole - inhibit cortisol production (short-term measure)
Describe the causes and clinical features of primary adrenal insufficiency
Inadequate adrenocortical function
Primary insufficiency - Addison’s disease, autoimmune destruction
Clinical features
> Anorexia, weight loss
> Fatigue / lethargy
> Dizziness and low BP
> Abdominal pain, vomiting, diarrhoea
> Skin pigmentation
Describe how Addison’s disease is diagnosed
Biochemistry
> Low sodium, high potassium
> Hypoglycaemia
Short synACTHen test
> Measure plasma cortisol before and 30 minutes after IV ACTH injection
Increased renin, decreased aldosterone
Adrenal autoantibodies
Describe the pathophysiology, clinical features and treatment of congenital adrenal hyperplasia
AR disorder - range of genetic disorders relating to defects in steroidogenic genes
Insufficient aldosterone and cortisol production
Increased drive to produce cortisol and aldosterone, increased ACTH
> Leads to increased DHEA
Most common – CYP21 (21-alpha-hydroxylase)
Female - ambiguous genitalia
Males - adrenal crisis – hypotension, hyponatraemia; early virilisation
Treatment
> Mineralocorticoid and glucocorticoid replacement
Describe late onset CAH, including clinical features and diagnosis
Partial 21-alpha-hydroxylase deficiency
Maintain cortisol within normal range
Increased ACTH drive leads to increased 17OHP and adrenal androgens
Clinical features
> Oligomenorrhoea
> Hirsutism
> Reduced fertility
Diagnosis - synacthen test with 17-hydroxyprogesterone (17-OHP)
Describe primary aldosteronism including its presentation, diagnosis and management
Commonest secondary cause of hypertension
> 40% adenoma; 60% bilateral hyperplasia
> Hypokalaemia present in <50% of cases
Aldosterone-renin ratio (ARR) best screening tool
Investigations
> Confirm aldosterone excess
> Stop beta blockers and MR antagonists
> Saline suppression test (should suppress aldosterone)
Management
> Surgical
> Unilateral laparoscopic adrenalectomy
» Only if adrenal adenoma
» Cure of hypokalaemia and in 30-70% cases, hypertension
> Medical
> Use MR antagonists – spironolactone or eplerenone
Describe the symptoms, causes and management of a phaeochromocytoma
Tumour of adrenal medulla
Symptoms/signs
> Hypertension – intermittent in 50%
> Episodes of headache, palpitations, pallor and sweating
> Tremor, anxiety
> Nausea, vomiting
> Chest or abdominal pain
> Crises last 15 mins (often well in between crises)
Causes
> 25% associated with genetic condition
> MEN – multiple endocrine neoplasia
> VHL – Von Hippel Lindau
> SDHB & SDHD mutations (succinate dehydrogenase)
>Neurofibromatosis
> 15-20% malignant
> 80-85% benign
Management
> Alpha blockade initially
» Phenoxybenzamine or doxazosin
> Then beta blocker if tachycardic
> Labetalol or bisoprolol
> Encourage salt intake
> Surgical removal
Describe adrenal incidentalomas
Incidentally discovered adrenal lesion
Discovered through diagnostic imaging for unrelated condition, without prior suspicion of tumour/disease
2 types
> Malignancy
> Size <4 cm
> Lipid rich
> Adenoma rapid washout on dynamic scan
> Functional
> Produce aldosterone, cortisol, androgens, catecholamines…
Describe the production of testosterone
Steroid hormone produced in Leydig cells
Circulates bound to SHBG and albumin
Free testosterone is active
Activated to more potent form in target tissues
> Converted to dihydrotestosterone by 5-alpha-reductase
Describe the production of testosterone
Steroid hormone produced in Leydig cells
Circulates bound to SHBG and albumin
Free testosterone is active
Activated to more potent form in target tissues
> Converted to dihydrotestosterone by 5-alpha-reductase
Describe the effects of testosterone on the body
Growth
> Sex organs
> Skeletal muscle
> Epiphyseal plate
> Larynx growth
> Secondary sexual characteristics
> Erythropoiesis
> Behaviour
Adult
> Muscle mass
> Mood
> Bone mass
> Libido
> Body shape
Fertility
> Erectile function
> Spermatogenesis
Describe the endocrine control of gonadal function
GnRH released from hypothalamus acts on anterior pituitary
> LH and FSH released from anterior pituitary
LH acts on Leydig cells to produce testosterone
FSH acts on Sertoli cells to aid spermatogenesis
> Sertoli cells also form the blood-testis barrier, remove damaged spermatocytes and secrete androgen-binding protein
Negative feedback loop regulation
Describe the clinical features associated with male hypogonadism
Child / young adult
> Slow growth in teens
> No pubertal growth spurt
> Lack of secondary sexual development
Adult
> Low mood
> Poor libido
> Erectile dysfunction
> Hot flashes / sweats
> Poor muscle bulk / power
> Poor energy
> Sparse body / facial hair
> Gynaecomastia
> Gynoid weight gain
> Short phallus / reduced testicular volumes
> Low trauma fractures
Describe the different types of male hypogonadism
Primary hypogonadism
> Hypergonadotrophic hypogonadism
> LH/FSH high + low testosterone
Secondary hypogonadism
> Hypogonadotrophic hypogonadism – hypothalamus or pituitary problem
> LH / FSH normal or low + low testosterone
> > Causes
> > > Pituitary disease e.g. tumour, pituitary surgery or radiotherapy
Head injury
Isolated LH/FSH deficiency – Kallmann’s syndrome
Functional hypothalamic hypogonadism (exercise, weight changes, stress)
Describe Kallman’s syndrome, including pathophysiology and diagnosis
Commonest form of isolated gonadotrophin deficiency
Pathophysiology
> Failure of cell migration of GnRH cells to hypothalamus
> Associated with aplasia/hypoplasia of olfactory lobes – giving anosmia or hyposmia
> May be associated with deafness, renal agenesis, cleft lip/palate
Diagnosis
> Anosmia
> Low testosterone, LH/FSH
> Normal pituitary MRI but absent olfactory bulb may be seen
Genetics
> Most commonly isolated gene mutation
» X-linked – absence of KAL gene (KAL1)
» Autosomal dominant (KAL2)
» Autosomal recessive (KAL3)
Describe Klinefelter’s syndrome including clinical features, diagnosis and treatment
Most common genetic cause of male hypogonadism
Karyotype - 47, XXY or 47, XXY mosaicism
Clinical features
> Delayed puberty
> Reduced testicular volumes
> Reduced secondary male sexual characteristics
> Persistent gynaecomastia
> Azoospermia
> Behavioural issues / learning difficulties
> Psychological support + fertility counselling
> Elevated LH/FSH but seminiferous tubules regress and Leydig cells do not function normally
Low testosterone
Treatment
> Androgen replacement therapy (IM or topical)
> > Side-effects
> Mood issues – aggression/behaviour change
> Libido issues
> Increased haematocrit/polycythaemia
> Development of lower urinary tract symptoms, prostatic enlargement
> Acne
> Gynaecomastia
> Fertility treatment
> hCG
> Recombinant FSH & LH
> GnRH pumps
State the normal and hyponatraemic ranges of sodium
Normal range – 135-145 mmol/L
Serum Na < 135 mmol/L - hyponatraemia
Define pseudohyponatraemia and how it may be ruled out as a differential
Measure serum osmolality (mOsm/kg) & compare to calculated osmolarity (mOsm/L)
Calculated osmolarity = [2xNa] + Urea + Glucose
Measured = calculated means true hyponatraemia
If not, pseudohyponatraemia – check lipid profile and total protein
Osmolality
- Low - < 275 mOsm/kg of H2O
- Normal/high - 275-290 mOsm/kg of H2O
> Exclude
» Hyperglycaemia
» Hyperlipidaemia
» Hyperproteinaemia
List reasons to suspect a pheochromocytoma/ paraganglioma
SHDB/D = suxate dehydrogenase
List medications which may cause falsely elevated free plasma metanephrines/urine fractionated metanephrines
Summarise primary, secondary and tertiary hyperparathyroidism
