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
Describe the concept of extracellular hypertonicity
Hyponatraemia due to osmotic effect of hyperglycaemia
Na does not require specific treatment
Corrected Na may be calculated
> Corrected Na = [Glu/4] + measured Na
Describe the 3 states of true hyponatraemia and how to assess the volume status of a patient
Assess volume status of patient
> Pulse
> BP – postural drop
> Urine output / fluid status
> JVP
> Ascite, oedema
3 states
Hypervolaemic – Na and H2O excess; hypotonic
> Urine Na > 20 - acute or chronic renal failure
> Urine Na < 20 - hepatic failure, nephrotic syndrome
Euvolaemic - H2O excess; excessive intake or impaired excretion
> Urine Na > 20
> Urine osmolality <100 – H2O intoxication
> Urine osmolality > 100 – SIADH
Causes
> Glucocorticoid deficiency
> Renal failure
> Hypothyroidism
Hypovolaemic - Na depletion
> Urine Na > 20 - renal losses, diuretic excess, mineralocorticoid deficiency, salt-losing nephropathy
> Urine Na < 20 - extra-renal losses, vomiting, diarrhoea, burns
Describe SIADH and its causes
Common cause of low Na
Excessive ADH release but patient’s volume is normal - ICF and ECF expanded but no oedema
Inappropriately high urine osmolality (>100 mmol/Kg)
Urine sodium high >20 mmol/L
Diagnosis of exclusion
> Normal renal function
> Normal thyroid function
> Normal adrenal function
> Not on diuretics
Causes
> Pulmonary infections and lesions
> Carcinoma
> CNS disorders
> AIDS
> Post-op pain or stress
> Vomiting
> Drugs: amitryptiline & other TCAs, fluoxetine
Describe the treatment of SIADH
Volume status
> Hypovolaemic - isotonic saline
> Hypervolaemic - salt and fluid restriction; loop diuretics
> Euvolaemic - free water restriction
Aim
> Increase Na gradually & achieve >120 mmol/L gradually
> If symptomatic may use hypertonic saline (3%)
Pharmacological treatment
> Demeclocycline
» Vasopressin antagonist
» Functional diabetes insipidus (side-effect)
> Aquaretics
> AVP receptor antagonists (vaptins)
> Induce a Na and water diuresis
List the symptoms of diabetes
Polyuria
Nocturia
Polydypsia
Thirst, dry mouth
Weight loss
Tiredness, fatigue, lethargy
Pruritus vulvae, balanitis (genital candidiasis)
Blurring of vision
Nausea
Headache
Hyperphagia – predilection for sweet foods
Mood change – irritability, difficulty in concentration, apathy
Describe the diagnostic criteria for diabetes
Fasting plasma glucose - >=7.0 mmol/L
Random (or 2 hour post 75g glucose load) plasma glucose of >=11.1 mmol/L
One abnormal value diagnostic if symptomatic, 2 if asymptomatic
HbA1c >=6.5% or 48 mmol/mol
Diabetes should not be diagnosed on the basis of glycosuria or capillary glucose
Describe the classification of diabetes
Type 1 diabetes
> Immune pathogenesis; severe insulin deficiency
Type 2 diabetes
> Combination of insulin resistance and insulin deficiency
Other specific types
> Genetic defects of beta cell function – monogenic diabetes
> Genetic defects of insulin action e.g. lipodystrophies
> Pancreatic disease
> Excess endogenous production of hormonal antagonists to insulin
> Growth hormone – acromegaly
> Glucocorticoids – Cushing’s syndrome
> Glucagon – glucagonoma
> Catecholamines – phaeochromocytoma
> Thyroid hormones – thyrotoxicosis
> Drug-induced: glucocorticoids, thiazide diuretics, HIV drugs, immune checkpoint inhibitors
> Genetic syndromes: Down syndrome, Klinefelter’s…
> Gestational diabetes
Describe the causes, features and management of pancreatic diabetes
Causes
> Pancreatectomy
> Pancreatitis
> Haemochromatosis
> Carcinoma
> Cystic fibrosis
Risk of hypos higher than T1DM due to loss of alpha cells that produce glucagon
Main features
> History of cause (sometimes alcohol history), exocrine dysfunction
> Ketones or acidotic
> C-peptide low but often detectable
> Pancreatic autoantibodies negative
Management: sulphonylurea +/- insulin
Describe the cause of monogenic diabetes, its clinical features and management
Cause: change in a single gene – monogenic; autosomal dominant inheritance
> HNF1-A responsible for 70% of MODY
Clinical features
> <25 yrs onset
> C-peptide not usually very low
> Pancreatic autoantibodies negative
> Runs in families from one generation to next
Management
> Diet
> Oral antihyperglycaemic agents (OHAs)
> Insulin
Describe the pathogenesis of type 1 DM
Chronic, progressive metabolic disorder characterised by hyperglycaemia and absence of insulin secretion
Results from autoimmune destruction of insulin-producing beta cells in the islets of Langerhans
Genetic susceptibility + environmental triggers lead to development of type 1 DM
Triggers may include
> Viral infections especially enterovirus
> Dietary toxins – exposure to cow’s milk at an early age
> Vitamin D deficiency
> Hygiene hypothesis
> Immune checkpoint inhibitors
> Markers of autoimmune process
> Anti-GAD
> Anti-IA-2
> Anti-ZnT8
Describe the clinical use of C peptide
C peptide is secreted in equimolar concentrations to endogenous insulin
Useful marker of endogenous insulin secretion – not a constituent of synthetic insulin
Levels
> <200 pmol/L - severe endogenous insulin deficiency
» T1DM, pancreatic diabetes and MODY
» May be >200 pmol/L in T1DM “honeymoon”
> > 900 pmol/L - increased insulin secretion related to insulin resistance
T2DM but can be lower if some insulin deficiency
> Can be overlap in different types of diabetes
> Can be <600 pmol/L in T2DM if marked hyperglycaemia due to glucotoxicity
Describe glucose monitoring
Capillary glucose
Continuous glucose monitoring (CGM)
> Tiny sensor inserted under skin to measure interstitial glucose
> Last up to 2 weeks
> Creates an Ambulatory Glucose Profile (AGP)
> Gives estimated HbA1c, target glucose range, high and low thresholds
> Intermittently scanned (flash) or isCGM – every 15 mins
> Real-time or rtCGM – every 5 minutes
> Correlates well with blood glucose but 10-15 minute lag
> Trend arrows and alarms
FreeStyle Libre Device – Flash Glucose Monitoring
> 14 days
> Measures interstitial glucose every minute
> Doesn’t interrupt insulin flow
> Best for trends
> Low and high glucose alarms
State the glucose targets diabetic patients should be aiming for
HbA1c <53 mmol/L
Before breakfast: 5.5-7 mmol/L
Before other meals: 4.5-7.5 mmol/L
Before bed: 6.5-8 mmol/L
Aim for glucose to rise <2 mmol/L 2h post-bolus
Describe the regimes used in insulin delivery
Basal bolus
> Intermittent injections, 4x daily
> Basal insulin 1x daily (night)
> Bolus 2x daily – rapid acting insulin with meals
> Resembles physiological insulin release
BD mix regime
> Mixed insulin (1/3 fast acting, 2/3 long acting)
> Requires eating same type of food at same time every day + no exercise or adjustment of routine
> Fewer injections but less physiological
Insulin pumps or continuous subcutaneous insulin infusion (CSII)
> Electronic device containing plastic cartridge of insulin
> Rapid acting insulin only e.g. Novorapid
> Delivers multiple basal rates + multiple boluses
Sensor augmented pump system
> Sensor measures interstitial glucose continuously
> Target range set on smartphone app
> Tells insulin pump how much insulin to deliver
> Still have to input calorie count to calculate bolus insulin
Describe the causes and main biochemical features of diabetic ketoacidosis
Causes
> At diagnosis when replacement not started
> Underlying illness
> Infections like COVID-19, pneumonia, UTI
> MI & CVA
> Discontinuation of insulin (accidental or deliberate)
> Inadequate insulin delivery - error in admin, pump failure…
> Drugs : SGLT2i, steroid, cocaine
Hyperglycaemia: >11 mmol/L or known diabetes
Hyperketonaemia: >=3.0 mmol/L on fingerprick testing, ketonuria – more than 2+ on urine dipstick
Metabolic acidosis: venous bicarbonate <15 mmol/L, venous pH <7.3, H+ >50 nmol/l
Describe the management of DKA and HHS
Continue basal insulin
Give fluids (1L 0.9% NaCl over 1 hour) & potassium chloride (KCl)
> Insulin drives potassium into cells
> Risk of hypokalaemia & cardiac arrhythmia
Give further insulin AFTER fluids
Describe the biochemical features of hyperglycaemic hyperosmolar state (HHS)
Hyperglycaemia: >30 mmol/L
Hyperosmolality: >320 mOsm/kg
Without significant ketonaemia (<3 mmol/L) OR ketonuria (<3+ on urine dipstick) OR metabolic acidosis (venous bicarbonate >15 mmol/L, venous pH >7.3 (H+ < 50 nmol/L) )
Compare DKA and HHS
DKA
- Type 1 DM; <65y
- Short history
- No residual insulin
- Hyperglycaemia and dehydration
- Acidosis
- Patient alert
- Abdominal pain
HHS
- Type 2 DM; >65y
- Insidious history
- Residual insulin
- Severe hyperglycaemia and profound dehydration
- No acidosis
- Patient drowsy
- Abdo pain uncommon
Describe gastroparesis as a complication of diabetes
Presents with bloating, indigestion, smelly burps
Associated with hyperglycaemia
Presents with morning nausea
Early satiety due to abnormal and delayed gastric emptying
Describe the pathogenesis of type 2 DM
Prevalence rises with increasing levels of obesity (BMI > 30) and age
Genetic predisposition combined with weight gain leads to dyslipidaemia
Insulin resistance causes hyperinsulineaemia
> Found in pre-diabetes and early diabetes states
This can result in hypertension, impaired glucose tolerance and impaired fasting glucose
Eventually hyperglycaemia arises, leading to early and then late diabete
Describe the goals of type 2 DM treatment as well as biomedical targets for patients
Reducing rates of microvascular complications
> Retinopathy, nephropathy, foot disease (ulceration)
> Glycaemic control required
Reducing rates of macrovascular complications
> MI, stroke, heart failure, peripheral vascular disease
> Glycaemic control & managing conventional CV risk factors (smoking, BP, cholesterol)
Biomedical targets
HbA1c - 7% or 53 mmol/mol
BP - <130/80 ; ACEI or ARB, CCB or thiazide diuretic
Cholesterol - statin if aged >40, <5 once started
Healthy body weight
List treatments for T2DM
- Lifestyle changes: diet, exercise
- Metformin
- Sulphonylureas e.g. gliclazide
- Thiazolidinediones (pioglitazone))
- SGLT2 inhibitors e.g. canagliflozin
- Insulin
- DPP-4 inhibitors e.g. sitagliptin
- GLP-1 receptor agonists e.g. liraglutide
Describe the mechanism of action, dosage, benefits and side-effects of metformin
Mechanism of action
> Suppresses hepatic gluconeogenesis
> Reduces glucose output from liver
> Increases peripheral insulin sensitivity, increasing glucose uptake and utilisation
> Increase AMPK activity
Dosage: 500mg once daily, increase by 500mg until max of 2g
Benefits
> Weight reduction
> Low hypo risk
> CV benefit
> Extensive experience
Side-effects
> GI side effects e.g. diarrhoea, bloating, nausea
> Vitamin B12 deficiency
> Cannot use if eGFR <30
> Small risk of lactic acidosis
Describe the mechanism of action, dosage, benefits and side-effects of sulphonylureas
Mechanism of action
> Close potassium channel in beta cells stimulating release of stored insulin
> Increased cellular glucose uptake and glycogenesis
> Reduces gluconeogenesis
Benefits
> High efficacy
> Extensive experience
Side-effects
> No CV benefit
> Weight gain
> High hypo risk
> Caution in CKD
Describe the mechanism of action, dosage, benefits and side-effects of thiazolidinediones
Mechanism of action
> PPAR-gamma receptor antagonists
> Increase sensitivity of fat, muscles and liver to endogenous and exogenous insulin
Benefits
> CV protection
> Low hypo risk
Side-effects
> Weight gain
> Fluid retention
> Fractures
Describe the mechanism of action, dosage, benefits and side-effects of insulin
Mechanism of action
> Increase glucose uptake and utilisation in skeletal muscle
> Reduced hepatic output, increased glycogenesis
> Decreased lipolysis
> Decreased gluconeogenesis
Benefits
> High efficacy
> Extensive experience
Side-effects
> High hypo risk
> No CV benefit
> Weight gain
Describe the mechanism of action, dosage, benefits and side-effects of DPP-4 inhibitors
Mechanism of action
> Inhibit DPP-4 and enhance effects of endogenous incretins (GLP-1)
> Increase glucose-mediated insulin secretion, suppress glucagon secretion
Benefits
> Low/moderate efficacy
> Low hypo risk
> Few adverse events
Side-effects
> Weight neutral
> No CV benefit
> Reduce dose in CKD
Describe the mechanism of action, dosage, benefits and side-effects of GLP-1 receptor antagonists
Mechanism of action
> Increased glucose-mediated insulin secretion
> Suppresses glucagon secretion
> Increases satiety and suppresses appetite
Benefits
> High efficacy
> CV benefit
> Low hypo risk
> Weight loss
Side-effects
> Injected
> GI side effects
> Uncertain safety regarding pancreas
Describe the mechanism of action, dosage, benefits and side-effects of SGLT2 inhibitors
Mechanism of action
> Inhibit SGLT2 in proximal convoluted tubule of the kidney
> Decrease renal reabsorption of glucose
Benefits
> Moderate efficacy
> CV benefit
> Renal benefit
> Weight loss
> Low hypo risk
Side-effects
> Risk of GU infections
> Small risk of hypovolaemia/DKA
Briefly outline the SIGN prescribing guidelines for type 2 diabetes
1st line
> Metformin
> Sometimes SU
2nd line
> 2 agents
> Add SU, flozin, gliptin, glitazone
3rd line
> 3 agents
> Add any of the above OR start injectable therapy with GLP-1 agonist or insulin
4th line
> 4 agents from above list
Describe prescribing considerations in the elderly, in renal disease and heart failure
Elderly
> Polypharmacy with risk of drug interactions
> Increased likelihood of ADRs
> Decrease in eGFR
> Increased likelihood of hypoglycaemia
Renal disease
> Stop metformin when eGFR <30
> Caution with SUs due to hypo risk
> Dose reduction required for some tides and gliptins
> SGLT2 inhibitors less effective at glucose lowering in CKD
> Renal protection – dapagliflozin indicated for CKD
Heart failure
> May use metformin in chronic heart failure but withhold during acute episodes
> Stop or do not initiate glitazone
> Flozins improved outcomes for heart failure with & without diabetes
Describe thyroid hormone synthesis
Sodium iodine symporter in the luminal membrane takes in and traps iodide from plasma
Iodide secreted through pendrin into colloid and oxidised, becoming iodine
> Target of anti-thyroid drugs
Iodine binds to tyrosine residues on thyroglobulin
Process of organification catalysed by thyroid peroxidase
Results in formation of T4 and T3
TSH stimulates exocytosis of T3 and T4
> T4 – inactive hormone secreted in greater amounts
> T3 – active form
> Converted from T4 by deiodinases in body tissues
> Acts at a nuclear receptor
> Acts on thyroid response elements in gene promoters
> Stimulates/inhibits mRNA and hence protein production
Thyroid hormones circulate in plasma bound to transthyretin, thyroid binding globulin and albumin
List functions of thyroid hormones
> Metabolism, growth and development
Developmental
Lungs
CNS – myelin, axonal growth
Bone – chondrocytes
Teeth, hair, dermis
CV effects: increased CO, HR, SV, SBP
Stimulates bone turnover
Increases speed of muscle contraction
Stimulates gut motility
Increases glucose usage and glycogenolysis
Describe the causes of hyperthyroidism
> Autoimmune - Grave’s disease
> TSHoma – pituitary tumour
> Other hormones acting as TSH – HCG
> Often with hyperemesis gravidarum
> Transient thyrotoxicosis
> Requires fluid treatment not thyroid drugs
> Thyroid adenoma
> De Quervain’s thyroiditis – viral trigger
> Excess administration of thyroxine
> Toxic multinodular goitre
> Pregnancy
> Drugs: amiodarone, iodine , thyroxine
List symptoms of hyperthyroidism
Classical of thyrotoxicosis
Anxiety
Weight loss
Tremor
Heat intolerance
Sweating
Diarrhoea
Tachycardia, AF, warm peripheries
Hypertension
Palpitations
Describe amiodarone thyroid disease
Type 1 – autoimmune thyrotoxicosis
> Antibody negative
> Treatment – high dose carbimazole
Type 2 – destructive thyroiditis
> Antibody positive
> Treatment – glucocorticoids +/- ATDs
Causes hypo or hyperthyroidism
Amiodarone-induced thyrotoxicosis
> Contains iodine
> Half-life is between 90-120 days, at least 3 months to wear off
Describe the thyroid conditions caused by iodine
Jod-Basedow phenomenon
> Iodine deplete areas of the world
> Move to area of high iodine prevalence, result in transient iodine-induced hyperthyroidism
> Lasts 2-12 weeks
> Symptomatic treatment e.g. beta-blockers
Wolff-Chaikoff effect
> Iodine-induced hypothyroidism
> Excess iodine transiently inhibits iodide organification
> 10 day duration
> Used for acute treatment of severe thyrotoxicosis – thyroid storm
» Fever and CVS instability
» Untreated thyroid disease
Describe the treatment of hyperthyroidism
Beta-blockeres
Carbimazole 40 mg daily
> Can cause aplasia cutis in pregnancy
Propylthiouracil (PTU) given in pregnancy
Both inhibit iodine organification by thyroid peroxidase
Side-effects
> Rash / urticaria
> Arthralgia
> Agranulocytosis
> Liver damage in PTU
131I – radioactive iodine
Describe thyroid eye disease
Exophthalmos (proptosis), diplopia
Lid lag and retraction
Graves’ ophthalmopathy
> Grittiness and redness
> Conjunctival oedema – chemosis
> Periorbital oedema
> Ophthalmoplegia
> Optic neuropathy
Describe non-eye signs of thyroid disease
Pretibial myxoedema - Rare
Thyroid acropachy
> Club-like fingers
> All 5 digits are enlarged and swollen
> Periosteitis or periosteal reactions present
> Very rare
List causes of hypothyroidism
Autoimmune thyroiditis
> Hashimoto’s thyroiditis
» Destruction of the thyroid gland (anti thyroid peroxidase (TPO) antimicrosomal antibody)
> Silent
> Post-partum
Viral (often painful)
Thyroidectomy
Following radio-iodine therapy
Drug-induced: amiodarone, lithium, sunitinib
Pituitary disease (hypopituitarism)
> Secondary hypothyroidism
Severe iodine deficiency
Inborn errors – congenital hypothyroidism
> Causes
» Thyroid dysgenesis (85%) - TSH receptor
» Dyshormonogenesis
»> Thyroid peroxidase
»> Thyroglobulin
»> Sodium iodide symporter
»> Pendrin (Pendred syndrome)
Maternal thyroid disease
> Neonatal hypothyroidism
List the presentation of neonatal hypothyroidism
Cretinism
Coarse facial features
Macroglossia
Large fontanelles
Umbilical hernia
Mottled, cool and dry skin
Developmental delay
Pallor
Myxoedema
Goitre
List signs and symptoms and treatment of hypothyroidism
Symptoms
> Weight gain
> Depression
> Lethargy
> Constipation
> Cold intolerance
> Poor concentration
> Hoarseness
> Menorrhagia
Signs
> Bradycardia
> Goitre
> Dry skin
> Coarse thin hair
> Anaemia
> Slow relaxing reflexes
Treatment - Levothyroxine (L thyroxine – T4)
Describe thyroid nodules, their investigation and treatment
Common, potential thyroid cancers
Investigations
> Ultrasound
> Fine needle aspiration biopsy
Thyroid tumours
> Follicular cell
> Benign adenoma
> Papillary cancer
> Follicular cancer
> Anaplastic cancer
> Poorly differentiated
> C cell
> Medullary cancer
Treatment
> Fine needle aspiration of nodules
> Surgery
> Therapeutic radioiodine
> Suppression of TSH if TSH-dependent
> Monitoring of thyroglobulin
List the different types of insulin preparations
Rapid – Novorapid
Short-acting – Humulin S, Actrapid
Intermediate – Insulatard, Humulin I
Long-acting – Lantus, Levemir
Rapid acting-intermediate mixture – Humalog Mix 25
> 25% rapid acting insulin
Short acting-intermediate mixture – Humulin M3
List features of thyroid storm
Fever
Marked tachycardia
Heart failure
Tremor
Nausea and vomiting
Diarrhoea
Dehydration
Restlessness
Extreme agitation
Delirium
Coma
Describe the education given to diabetic patients
Glucose / ketone monitoring
Insulin administration
> Rotate administration site to avoid lipodystrophy
Carbohydrate counting and insulin management
Sick day rules
> Check blood glucose and ketones
> Sip sugar-free fluids
> Continue taking basal insulin + bolus insulin if necessary
Hypoglycaemia
Driving regulations
> Check blood glucose before driving
> If hypoglycaemic, eat and wait 45 mins then re-check
> If long drive - check blood glucose every 2 hours
> Check frequency of hypoglycaemia, retinopathy?, awareness of hypoglycaemia, diabetic control
> Do they drive for a living?
> Alert DVLA
Exercise & alcohol
Pregnancy
Targets
Complications
DAFNE – dose adjustment for normal eating
Describe autoimmune polyendocrine syndrome type 2
Triad of Addison’s, autoimmune thyroiditis, and T1DM
More common in females
Presents in adulthood
Polygenic
- HLA DQ/DR allele association
Associations with
- pernicious anemia
- primary hypogonadism
- myasthenia gravis
- coelic disease
- alopecia
- stiff man syndrome
Discuss why signs of mineralocorticoid excess and cortisol excess is a red flag
The adrenal hormones are similar molecularly – as a consequence cortisol and aldosterone can activate the same receptors – both have affinity for the receptors
Cortisol is made at greater conc than aldosterone in health – why doesn’t it just override the aldosterone and give us all hypertension – the reason this doesn’t happen is due to 11BHSD (11 beta hydroxysteroid dehydrogenase) (enzyme) being co-located on the MR – this changes cortisol to the inactive cortisone – prevents cortisol from illicitly activating the MR
Overwhelming/huge levels of cortisol overwhelms the 11 BHSD allow cortisol to illicitly activate the MR and give signs of cortisol excess and mineralocorticoid excess – big red flag (sounds like cortisol coming from an ectopic ATCH – rather than pituitary adenoma or adrenal lump – as the levels are too high)
- ATCH should be done for diagnosis
State how to differentiate gynacomastia from normal fatty tissue due to obesity
- Gynecomastia will have harder tissue around the nipple compared to just fat
List reasons to suspect a pheochromocytoma/ paraganglioma
SHDB/D = suxate dehydrogenase
State biochemical testing for pheochromocytoma/ paraganglioma
measurement of free plasma metanephrines or measurement of urine fractionated metanephrines
List medications which may cause falsely elevated free plasma metanephrines/urine fractionated metanephrines
State the pharmacological treatment of prolactinoma and the potential mental health side effect
Prolactinoma is treated with dopamine agonists (cabergoline)
- Can be associated with mood disorders particularly impulsive disorders
State the effects of metformin
- suppresses hepatic gluconeogenesis, reducing glucose output from the liver
- increases peripheral insulin sensitivity, increasing glucose uptake and utilisation
- increases AMPK activity
List conditions which cause lower than expected HbA1c (looks like better control)
Decreases RBC lifespan
Sickle-cell anaemia
GP6D deficiency
Hereditary spherocytosis
Haemodialysis
List conditions which cause higher than expected HbA1c (looks like worse control)
Increases RBC lifespan
Vitamin B12/folic acid deficiency
Iron-deficiency anaemia
Splenectomy
List test results in the diagnosis of diabetes if a) symptomatic b) asymptomatic
If symptomatic one of the following results is sufficient:
If asymptomatic need two results required from different days:
Random blood glucose= above 11.1mmol/l
Fasting plasma glucose= above 7mmol/l
2 hour glucose tolerance= above 11.1mmol/l
HbA1C= above 48mmol/mol (6.5%)
List symptoms of DKA
DKA is Deadly
Delirium/pyschosis
Kussmaul breathing
Abdominal pain/nausea/vomiting
Dehydration
Summarise primary, secondary and tertiary hyperparathyroidism
Discuss Rotterdam diagnostic criteria
Rotterdam diagnostic criteria
Assuming that other causes have been excluded, PCOS can be diagnosed if two of the following are present:
Polycystic ovaries (>12 cysts seen on imaging or ovarian volume >10 cubic cm)
Oligo-/anovulation
Clinical or biochemical features of hyperandrogenism
