Endocrine Flashcards
Sources of glucose in fasting state
all glucose comes from liver (and a bit from kidney)
Breakdown of glucose- Gluconeogenesis
Glucose is delivered to insulin independent tissues, brain and red blood cells
Gluconeogenesis
synthesises glucose from lactate, alanine and glycerol- reverse of glycolysis, occur in liver and kidney
Insulin levels in fasting states
Insulin levels are low
Sources of fuel for muscles
Muscle uses free fatty acids for fuel
Physiological changes after feeding
Rising glucose (5-10 min after eating) stimulates insulin secretion and suppresses glucagon
40% of ingested glucose goes to liver and 60% to periphery, mostly muscle
Ingested glucose helps to replenish glycogen stores both in liver and muscle
High insulin and glucose levels suppress lipolysis and levels of non-esterified fatty acids (NEFA or FFA) fall
Site of insulin and glucagon secretion
Islet of Langerhans of the pancreas
Cell that secrete insulin
Beta cells of islet of Langerhans
Cell that secrete glucagon
Alpha cells of islet of Langerhans
Paracrine crosstalk
between alpha and beta cells is physiological, ie local insulin release inhibits glucagon an effect lost in diabetes
Action of Insulin
Supresses hepatic glucose output
-Glycogenolysis
-Gluconeogenesis
Increases glucose uptake into insulin sensitive tissues (muscle, fat)
Suppresses
-Lipolysis
-Breakdown of muscle
Action of Glucagon
Increases hepatic glucose output
-Glycogenolysis
-Gluconeogenesis
Reduce peripheral glucose uptake
Stimulate peripheral release of gluconeogenic precursors (glycerol, AAs)
-Lipolysis
-Muscle glycogenolysis and breakdown
Diabetes mellitus
A chronic disorder of carbohydrate metabolism characterised by hyperglycaemia
Type 1 DM- presentations
Typically childhood
Commonly present DKA
Polydipsia, Polyuria, Sudden unexplained weight loss
Acute hyperglycaemia morbidity
If untreated leads to acute metabolic emergencies diabetic ketoacidosis (DKA) and hyperosmolar coma (Hyperosmolar Hyperglycaemic State )
Chronic hyperglycaemia morbidity
Leads to tissue complications (macrovascular and microvascular)
Side effects of DM treatment
Hypoglycaemia- can be fatal
Diseases associated with DM
Stroke
CV disease
Diabetic retinopathy (vision loss), nephropathy, neuropathy (leading to lower extremity loss)
DM diagnosis and investigation- symptomatic
Raised plasma glucose detected once-
fasting>7mmol/L
random>11.1 mmol/L
DM diagnosis and investigation- asymptomatic
Raised plasma glucose detected on two separate occasions-
fasting>7mmol/L
random>11.1 mmol/L
or oral glucose tolerance test- fasting>7mmol/L
2 hours after taking glucose >11.1 mmol/L
Pathogenesis of Type 1 diabetes
Autoimmune disease causing destruction of beat cells. No insulin production, cells cannot take glucose from blood and use it for fuel.
Cell think body is in fasting state, so has no glucose supply. Levels of glucose keep rising leads in to hyperglycaemia
Type 1 diabetes- failure of insulin secretion
-Continued breakdown of liver glycogen
-Unrestrained lipolysis and skeletal muscle breakdown providing gluconeogenic precursors
-Inappropriate increase in hepatic glucose output and suppression of peripheral glucose uptake
Type 1 diabetes- Failure to treat with insulin
Severe insulin deficiency due to autoimmune destruction of the cell lead to hyperglycaemia
DKA initial management
ABC if unconscious
Replace fluid loss with IV 0.9% saline slowly to avoid cerebral oedema
Replace deficient insulin with insulin (to inhibit ketone production)+ glucose (to prevent hypoglycaemia)
Treat hypokalaemia as a result of therapy if necessary
Treat underlying triggers
Why can insulin treatment for DKA cause hypokalaemia?
Insulin decreases potassium levels in the blood by redistributing K+ into the cells via increased sodium-potassium pump activity causing low serum K+ levels— HYPOKALAEMIA
Dangers of hypokalaemia
Low levels of K+ can cause arrythmia, weakness (as the heart and muscles can struggle to contract)
Complications of DKA treatment
Cerebral Oedema- due to rapid dilution of high conc salt in blood with IV fluids. This leads to water moving into tissues causing swelling, swelling in the brain can be cause coma/ fatal due to skull being an enclosed space
DKA pathophysiology
- Absence of insulin+
unrestrained production of glucose + decreased peripheral glucose uptake - Hyperglycaemia+ osmotic diuresis+ dehydration
- Peripheral lipolysis, increase free fatty acids, oxidised to acetyl CoA, increased ketone= acidosis
DKA diagnosis
Hyperglycaemia (blood glucose >11 mmol/L)
Ketosis (blood ketones> 3 mmol/L)
Acidosis (pH<7.3)
Type 2 diabetes aetiology
Impaired Insulin Secretion and Insulin Resistance
Type 2 diabetes- impaired insulin action
Reduced muscle and fat uptake after eating
Failure to suppress lipolysis and high circulating FFAs
Abnormally high glucose output after a meal
Pathogenesis of Type 2 Diabetes- chronic hyperglycaemia
Excessive glucose production, more blood in blood, hyperglycaemia, glycosuria
Pathogenesis of Type 2 Diabetes- muscle/fat insulin resistance
Impaired glucose clearance, less glucose in peripheral tissues, hyperglycaemia, glycosuria
Glycosuria
the presence of reducing sugars in the urine
Principles of treatment of diabetes
Control of symptoms
Prevention of acute emergencies, ketoacidosis, hyperglycaemic hyperosmolar states
Identification and prevention of long-term microvascular complications
Sulphonylureas
work mainly by stimulating beta cells in the pancreas to make more insulin (e.g gliclazide, glibenclamide)
Thiazolidinediones
Activate genes concerned with glucose uptake and utilisation and lipid metabolism
Improve insulin sensitivity (e.g pioglitazone - ACTOS)
GLP-1 action
stimulating glucose-dependent insulin release from the pancreatic islets, slows gastric emptying, inhibit inappropriate post-meal glucagon release, and reduce food intake
Metformin (biguanide)
Best treatment for type 2 diabetes
Reduces rate of gluconeogenesis, so hepatic glucose output decreases, this increases insulin sensitivity
No impact on insulin secretion/ induce hypoglycaemia/ predispose weight gain
Type 1 Diabetes
Autoimmune condition (β-cell damage) with genetic component
Profound insulin deficiency
Type 2 Diabetes
Insulin resistance
Impaired insulin secretion and progressive β-cell damage but initially continued insulin secretion
Excessive hepatic glucose output
Increased counter-regulatory hormones including glucagon
Modern insulin therapy in T1D
Separation of basal from bolus insulin to mimic physiology
T1D treatment-Basal insulin
control blood glucose in between meals and particularly during the night
Given once or twice a day
T1D treatment-Bolus insulin
Pre-meal rapid acting boluses adjusted according to pre-meal glucose and carbohydrate content of food to cover meals
T1D treatment-Basal vs Bolus insulin
Basal- base level of insulin
Bolus- simulates insulin increase after eating
T2D- needing insulin duration of diabetes
Year 0- 0% needing insulin
Year 5- 20% needing insulin
Year 10- 50% needing insulins
Basal insulin in type 2 diabetes- Pros
Simple for the patient, adjusts insulin themselves, based on fasting glucose measurements
Carries on with oral therapy, combination therapy is common
Less risk of hypoglycaemia at night
Basal insulin in type 2 diabetes- Cons
Doesn’t cover meals
Best used with long-acting insulin analogues which are considered expensive
Limited role for pre-mixed insulin in diabetes- pros
Both basal and prandial components in a single insulin preparation
Can cover insulin requirements through most of the day
Limited role for pre-mixed insulin in diabetes- cons
Not physiological
Requires consistent meal and exercise pattern
Cannot separately titrate individual insulin compononents
Limited role for pre-mixed insulin in diabetes- risks
Increased risk for nocturnal hypoglycaemia2,3
Increased risk for fasting hyperglycaemia if basal component does not last long enough
Best treatment for T1D
Intensive basal-bolus insulin therapy
Hypoglycaemia
low blood glucose levels
Level 1 (alert level) hypoglycaemia
Plasma glucose <3.9 mmol/l (70 mg/dl) and no symptoms
Level 2 (serious biochemical) hypoglycaemia
Plasma glucose <3.0 mmol/l 55 mg/dl)
Non-severe symptomatic hypoglycaemia
Patient has symptoms but can self-treat and cognitive function is mildly impaired
Severe symptomatic hypoglycaemia (Level 3)
Patient has impaired cognitive function sufficient to require external help to recover
Hypoglycaemia- pathophysiology brain
Cognitive dysfunction
Blackouts, seizures, comas, Psychological effects
Hypoglycaemia- pathophysiology heart
Increased risk of myocardial ischaemia, Cardiac arrhythmias
Hypoglycaemia- pathophysiology musculoskeletal
Falls, accidents, driving accidents, Fractures, Dislocations
Hypoglycaemia- pathophysiology heart
Inflammation, Blood coagulation abnormalities, Haemodynamic changes, Endothelial dysfunction
Common hypoglycaemia symptoms- autonomic
Trembling, palpitations, sweating, anxiety, hunger
Common hypoglycaemia symptoms- neuroglycopenic
difficulty concentrating, confusion, weakness, drowsiness, dizziness, vision changes, difficulty speaking
Common hypoglycaemia symptoms- non specific
Nausea, headache
Treatment of non severe hypoglycaemia
Carbohydrate
Normal physiological responses preventing hypoglycaemia at 4.6 mmol/L
Inhibition of endogenous insulin secretion
Normal physiological responses preventing hypoglycaemia at 3.8 mmol/L
Glucagon
Normal physiological responses preventing hypoglycaemia at 3.6 mmol/L
Adrenaline
Impaired response to hypoglycaemia
No glycogen release, adrenaline is released at 2.5 mmol/L
Altered thresholds lead to impaired awareness and increased risk of severe hypoglycaemia
Causes of hypoglycaemia
Long duration of diabetes, Tight glycaemic control with repeated episodes of non severe hypoglycaemia, increased age, use of drugs, sleeping, increased physical activity
Screening for risk of severe hypoglycaemia
Low HbA1c ; high pre-treatment HbA1c in T2DM
Long duration of diabetes
A history of previous hypoglycaemia
Impaired awareness of hypoglycaemia (IAH)*
Recent episodes of severe hypoglycaemia
Daily insulin dosage >0.85 U/kg/day
Physically active (e.g. athlete)
Impaired renal and/or liver function
Strategies to prevent hypoglycaemia- patient education
Discuss hypoglycaemia risk factors and treatment with patients on insulin or sulphonylureas
Educate patients and caregivers on how to recognize and treat hypoglycaemia
Instruct patients to report hypo episodes to their doctor/educator
Treatment of hypoglycaemia
Recognize, confirm, treat, retest, eat
Treatment of hypoglycaemia- recognize
Recognize symptoms so they can be treated as soon as they occur
Treatment of hypoglycaemia- Confirm
Confirm the need for treatment if possible (blood glucose <3.9 mmol/l is the alert value)
Treatment of hypoglycaemia- Treat
Treat with 15g fast-acting carbohydrate to relieve symptoms
Treatment of hypoglycaemia- Retest
Retest in 15 minutes to ensure blood glucose >4.0 mmol/l and re-treat (see above) if needed
Treatment of hypoglycaemia- Eat
Eat a long-acting carbohydrate to prevent recurrence of symptoms
Complications of DM- microvascular
Peripheral Neuropathy, Retinopathy, Nephropathy
Complications of DM- macrovascular
Stroke, hypertension, peripheral artery disease, coronary artery disease
Parathyroid hormone action- bone
increased bone resorption
inhibits osteoblast activity and stimulates osteoclast activity leading to bone breakdown and calcium release
Parathyroid hormone action- kidney
Increased Ca2+ reabsorption and 1 α - hydroxylation of 25-OH vit D, decreased phosphate reabsorption
Parathyroid hormone action- small intestine
No direct effect on small intestine however increase Ca2+ absorption because of increased 1,25 (OH) 2 vit D
PTH response to decreased serum calcium
Decreased serum Ca2+ detected, increased in PTH causes increased Bone resorption and Ca2+ reabsorption in the kidney.
PTH causes decrease of phosphate in the kidneys causing increased urinary phosphate excretion and decrease serum phosphate, resulting in increased 1,25-(OH)2 vit D so increased Ca2+ absorption from the small intestine
Ca2+ homeostasis is an example of +ive or -ive feedback
negative feedback
Does PTH have big or small changes to small changes in serum Ca2+
small changes in serum calcium result in big changes in PTH
Importance of maintenance of serum Ca2+
Functioning of nerves and muscles
Hypocalcaemia
Low levels of low ionised calcium in the blood
Corrected calcium equation
corrected calcium =
total serum calcium + 0.02 * (40 – serum albumin)
Consequences of Hypocalcaemia
Paraesthesia
* Muscle spas (Hands and feet, Larynx, Premature labour)
* Seizures
* Basal ganglia calcification
* Cataracts
* ECG abnormalities- Long QT interval
Chvostek’s Sign
Tap over the facial nerve
Look for spasm of facial muscles
Trousseau’s Sign
Inflate the blood pressure cuff to 20 mm Hg above systolic for 5 minutes
Causes of Hypocalcaemia
Vitamin D inadequacy or vitamin D resistance.
Hypoparathyroidism following surgery.
Hypoparathyroidism owing to autoimmune disease or genetic causes.
Renal disease or end-stage liver disease causing vitamin D inadequacy
Hypoparathyroidism
diminished concentration of PTH in the blood, which causes deficiencies of calcium and phosphorus compounds in the blood
Hypoparathyroidism causes
- Syndromes
- Genetic
- Surgical
- Radiation
- Autoimmune
- Infiltration
- Magnesium deficiency
Hypoparathyroidism pathology
Decreased renal Ca2+ reabsorption (increased Ca2+ excretion), increased renal phosphate reabsorption (increased serum phosphate), decreased bone resorption, decreased formation of 1,25(OH)2D (decreased intestinal Ca2+ absorption)
OVERALL DECREASED SERUM Ca2+
Pseudohypoparathyroidism
Resistance to parathyroid hormone
Pseudohypoparathyroidism symptoms
- Short stature
- Obesity
- Round facies
- Mild learning difficulties
- Subcutaneous ossification
- Short fourth metacarpals
- Other hormone resistance
Pseudohypoparathyroidism cause
Type 1 Albright hereditary osteodystrophy
– mutation with deficient Gα subunit
Pseudohypoparathyroidism pathology
= PTH resistance
So if Ca2+ decreases, there is no increased bone resorption or no Ca2+ reabsorption/ absorption
Hypercalcaemia
High levels of low ionised calcium in the blood
Hypercalcaemia- reason for false readings
- Tourniquet on for too long
- Sample old and haemolysed
Hypercalcaemia: Symptoms
- Thirst, polyuria
- Nausea
- Constipation
- Confusion > coma
Hypercalcaemia: Consequences
- Renal stones
- ECG abnormalities- Short QT
Causes of hypercalcaemia
- Malignancy- bone mets, myeloma, PTHrP, lymphoma
- Primary hyperparathyroidism
- Thiazides
- Thyrotoxicosis
- Sarcoidosis
- Familial hypocalciuric / benign hypercalcaemia
- Immobilisation
- Milk-alkali
- Adrenal insufficiency
- Pheochromocytoma
Most common causes of hypercalcaemia
Malignancy
Primary hyperparathyroidism
Consequences of Primary Hyperparathyroidism
- Bones
-Osteitis fibrosa cystica - Osteoporosis
- Kidney stones
- Psychic groans
- confusion
- Abdominal moans
- Constipation
- Acute pancreatitis
Consequences of Primary Hyperparathyroidism rhyme
Bones, Stones, Groans, Moans
Primary Hyperparathyroidism pathology
Increased PTH leads to increased bone resorption, renal Ca2+ reabsorption, Ca2+ absorption
HYPERCALCAEMIA
Blood supply of anterior pituitary
The anterior pituitary has no arterial blood supply but receives blood through a portal venous circulation from the hypothalamus
Regulation of the pituitary
Growth, thyroid, puberty + fertility, steroids
Location of pituitary gland
Sella turcica
Structures at risk of enlarged pituitary gland
Optic chiasm, contents of cavernous sinus (CN III, CN IV, V1, V2, CN VI + internal carotid artery)
Thyroid axis
Hypothalamus produces TRH, causes pituitary gland to release TSH, causes thyroid to produce T4 +T3. T4 + T3 causes negative feedback loop and decrease in TRH and TSH production
Pituitary problem impact on thyroid axis
TSH, T4 and T3 are low and TRH is high
Gonadal Axis
Hypothalamus produces GnRH, causes pituitary gland to release LH and FSH, causes testes/ ovaries to produce testosterone/ oestrogen. Testosterone/ oestrogen causes negative feedback loop and decrease in GnRH, LH and FSH production
HPA Axis
Hypothalamus produces CRH, causes pituitary gland to release ACTH, causes adrenal glands to produce cortisol. Cortisol causes negative feedback loop and decrease in CRH and ATCH.
GH / IGF-I AXIS
Hypothalamus produces GHRH to simulate release of GH from the pituitary gland or SMS to inhibit GH release. GH acts on liver and produces IGF-I. IGF-I causes negative feedback loop.
Diseases of the pituitary
- Benign pituitary adenoma
- Craniopharyngioma
- Trauma
- Apoplexy / Sheehans
- Sarcoid / TB
Craniopharyngioma
Epithelial tumours located near pituitary gland, extending to involve the hypothalamus, optic chiasm, cranial nerves, third ventricle, and major blood vessels
What’s the difference between a craniopharyngioma and a pituitary adenoma?
Craniopharyngiomas and pituitary adenomas can both affect hormone function.
-Pituitary adenomas come from your pituitary gland
-craniopharyngiomas are located near that gland
Causes of Presentation of pituitary gland tumour
Pressure on local structure, pressure on normal pituitary and functioning tumours
Symptoms causes by pituitary tumour pressing on local structures
- Bitemporal hemianopia
- Headaches (stretching dura or hydrocephalus)
- Carinal nerve palsy and temporal lobe epilepsy
Prolactinomas symptoms
- More common in women
- Present with galactorrhoea/ amenorrhoea/ infertility
- Loss of libido
- Visual field defect
Amenorrhoea
absence of menstrual periods
Galactorrhoea
a milky nipple discharge unrelated to the usual milk production of breastfeeding
Prolactinomas treatment
Treatment dopamine agonist eg Cabergoline or bromocriptine
Prolactinomas- 1st line investigations
Elevated serum prolactin
Pituitary MRI
Prolactinomas
Noncancerous tumour of the pituitary gland. This tumour causes the pituitary gland to make too much prolactin
Acromegaly
Hormonal disorder that develops when your pituitary gland produces too much growth hormone during adulthood
At which stage does pitiuarty tumours cause Acromegaly, not Gigantism
Fusion of the long bone epiphysis
Cushing syndrome
disorder that occurs when your body makes too much of the hormone cortisol over a long period of time
Cushing syndrome symptoms
Weight gain in the trunk+ face, with thin arms and legs.
A fatty lump between the shoulders
Pink or purple stretch marks
Thin, frail skin that bruises easily
Slow wound healing
Acne
Most common causes of Cushing syndrome
long-term, high-dose use of the cortisol-like glucocorticoids
Do benign pituitary tumours affect anterior or posterior pituitary
Anterior pituitary
Definitive signs of female puberty
Menarche – first menstrual bleeding
Definitive signs of male puberty
First ejaculation, often nocturnal
Secondary sexual characteristics that occur at puberty- female
Ovarian oestrogens regulate the growth of breast and female genitalia
Ovarian and adrenal androgens control pubic and axillary hair
Secondary sexual characteristics that occur at puberty- male
Testicular androgens
–External genitalia and pubic hair growth
–enlargement of larynx and laryngeal muscles voice deepening
Tanner stages
Scale of physical development based on external primary and secondary sex characteristics
Adrenarche
developmentally programmed peri-pubertal activation of adrenal androgen production
Pubarche
Most pronounced clinical result of adrenarche
* Result of androgen action on the pilosebaceous unit transforming vellus hair into terminal hair in hair-growth prone parts of the skin
PRECOCIOUS PUBERTY
when children’s bodies begin to change into adult bodies too soon
True PRECOCIOUS PUBERTY
Early activation of all of the HPG axis, 90% female
True PRECOCIOUS PUBERTY differential diagnosis
Brain tumour, especially in boys
PRECOCIOUS PSEUDOPUBERTY
GnRH-independent and occurs due to excess production of sex hormones either from the gonads, the adrenal glands or secreting tumours, HPG axis is not active
PRECOCIOUS PUBERTY – TREATMENT
Treatment with GnRH super agonist to suppress pulsatility of GnRH secretion
Causes of True Precocious Puberty
Idiopathic, CNS tumour/disorder, secondary central precocious puberty, psychosocial
Causes of Precocious Pseudo-Puberty
Increases androgen secretion, gonadotropin secreting tumour, ovarian cyst
Indication of delayed puberty
Girls- lack of breast development by 13
Boys- lack of testicular enlargement by age 14
CONSTITUTIONAL DELAY OF GROWTH AND PUPERTY (CDGP)
Children experience delayed puberty compared to their peers of similar age associated with a delay in the pubertal growth spurt
CONSTITUTIONAL DELAY OF GROWTH AND PUPERTY RFs
Family history of delayed puberty, congenital pituitary abnormalities, gene mutations, malnutrition, congenital and acquired gonadal abnormalities
Primary Hypogonadism
Testis/ovaries fail
-Hypergonadotropic and Hypogonadism
-Testosterone/ oestrogen go down, lack of feedback, FSH and LH go up
Secondary/Tertiary Hypogonadism
Hypothalamus/ Pituitary fail
-Hypogonadotropic and Hypogonadism
- FSH and LH go down, no response to feedback feedback, Testosterone/ oestrogen go down
Klinefelter’s syndrome
Affects males, 47,XXY Primary hypogonadism
Turner’s syndrome
Affects girls, 45,X0, Hypergonadotropic hypogonadism
Turner’s syndrome- characteristics
Short stature, Short neck with a webbed appearance, low hairline at the back of the neck, low-set ears, hands and feet that are swollen or puffy at birth, and soft nails that turn upward
Klinefelter’s syndrome- characteristics
- Azoospermia, Gynaecomastia
- Reduced secondary sexual hair
- Osteoporosis
- Tall stature
- Reduced IQ in 40%
- 20-fold increased risk of breast cancer
Hormone replacement therapy- female puberty
Low doses of (Ethinyl estradiol (tablet) or Oestrogen (tablets, transdermal)) and gradual increasing doses to provide time for pubertal growth until full adult dose is achieved, then progesterone is added
Where is vasopressin and oxytocin made and where is it released from?
Made in PVN (paraventricular nucleus) and SON (supraoptic nucleus) transported to the posterior pituitary in the axoplasm of the neurons
Osmoreceptors
maintain the osmolality of the blood through a coordinated set of neuroendocrine, autonomic, and behavioral feedbacks
Arginine Vasopressin (AVP or ADH) release controlled by
osmoreceptors in hypothalamus - day to day
baroreceptors in brainstem and great vessels - emergency
ECF ions
large amounts of sodium, chloride, and bicarbonate ions
ICF ions
potassium, magnesium and phosphate ions
Sodium concentration ([Na+]) and ECF osmolarity
considered together because sodium ions comprise the majority of the solute in the extracellular compartment
Water balance is regulated by a feedback loop: water excess
Ingestion of water, decrease Plasma osmolality, increase in cellular hydration, decrease in thirst, vasopressin secretion + water intake, increase in urine excretion, decrease in total body water
Water balance is regulated by a feedback loop: water deficit
Water loss, increase Plasma osmolality, decrease in cellular hydration, increase in thirst, vasopressin secretion + water intake, decrease in urine excretion, increase in total body water
Under normal conditions what mediates variable water excretion by the kidneys
Vasopressin
Osmolality
Concentration in plasma (mOsmol/kg), number of (not size of) particle
Serum osmolality equation
serum osmolality = 2(Na) + glucose/18 + Urea/2.8
AVP deficiency (cranial diabetes insipidus)
Lack of vasopressin, uncommon not life threating
AVP resistance (nephrogenic diabetes insipidus)
Resistance to action of vasopressin, uncommon not life threating
Syndrome of anti-diuretic hormone secretion – SIAD
Too much vasopressin release when it should not be released, common, and can be life threatening
AVP deficiency and resistance symptoms
polyuria (wee), polydipsia (excess thirst), no glycosuria (decreased glucose in urine)
AVP deficiency and resistance investigations
Measure urine volume - unlikely if urine volume <3L/day
Check renal function and serum calcium
AVP deficiency and resistance- diagnostic investigation
Water deprivation test
AVP resistance (nephrogenic DI) causes
Genetic disorders,
-acquired: either reduction in medullary concentrating gradient or antagonism of effects of AVP
AVP deficiency (Cranial DI) causes
Damage to the hypothalamus or pituitary gland – ie after an infection, operation, brain tumour or head injury
Or genetic/ idiopathic (often autoimmune)
Management of AVP deficiency (Cranial DI)
Treat underlying condition, desmopressin, high activity at V2 receptor
Management of AVP resistance (Nephrogenic DI)
-try and avoid precipitating drugs
-congenital DI - very difficult
free access to water
very high dose desmopressin
Hyponatraemia
serum sodium < 135 mmol/l
Biochemically serve hyponatremia
serum sodium < 125 mmol/l
Normal serum sodium
135-144mmol
Moderate symptoms of Hyponatraemia
Headache
Irritability
Nausea / vomiting
Mental slowing
Unstable gait / falls
Confusion / delirium
Disorientation
Severe symptoms of Hyponatraemia
Stupor / coma
Convulsions
Respiratory arrest
Hyponatremia and the brain
The brain undergoes volume adaptation in response to gradual-onset hyponatraemia
Acute or chronic hyponatremia
Acute < 48 hours
Chronic > 48 hours
Aetiology of hyponatremia
Hypovolaemic
Euvolemic (blood)
Hypervolaemic
General Hyponatraemia treatments
Stop hypotonic fluids- fluid restriction
Review drug card – long list - PPI etc.
Hyponatraemia causes- dehydration + low urine Na+< 20mmol/l
Vomiting and diarrhoea
Burns
Pancreatitis
Sodium depletion after diuretics
Saline replacement
Hyponatraemia causes- dehydration + high urine Na+>40 mmol/l
Diuretics
Addison’s (or occasionally pituitary failure)
Cerebral salt wasting
Salt wasting nephropathy
Saline replacement
Hyponatraemia causes- fluid overload
Cirrhosis of liver/liver failure
CCF
Inappropriate IV fluids
Fluid restrict
SIAD - syndrome of antidiuresis
Too much AVP, when it should not be being secreted
SIAD- causes
Malignancy, primary brain injury (meningitis, bleed), drugs, infections
Biochemistry of SIAD - syndrome of antidiuresis
Low osmolality
Plasma sodium is low
Urine is inappropriately concentrated
Water retention - ECF volume increased mildly
Increase GRF - less Na reabsorption in PCT
thus - urine Na+ usually >30mmol/l
normal thyroid and adrenal function
Treatment goals of SIAD
allow/facilitate increase in serum Na+
treat any underlying condition
in acute setting - daily U+E - hospital
in chronic setting - weekly to monthly U+E - hospital/GP
Most common causes of hyperthyroidism
Graves diseases
Toxic multinodular goitre
Toxic adenoma
Goitre
Palpable & visible thyroid enlargement
Commonly sporadic or autoimmune
Name a disease that is Endemic in iodine deficient areas
Goitre
SPORADIC NON-TOXIC GOITRE
Commonest endocrine disorder
An enlargement of the thyroid gland in a euthyroid subject living in an iodine-sufficient area
3 mechanisms for Hyperthyroidism
a. overproduction thyroid hormone
b. leakage of preformed hormone from thyroid
c. ingestion of excess thyroid hormone
Hyperthyroidism
excess of thyroid hormones in blood
DRUG INDUCED HYPERTHYROIDISM
Iodine
Amiodarone (antiarrhythmic drug)
Lithium
Radiocontrast agents
CLINICAL FEATURES of hyperthyroidism
Weight loss
Tachycardia +/ AF
Hyperphagia (very hungry)
Anxiety
Tremor
Heat intolerance
Sweating
Diarrhoea
Lid lag + stare
Menstrual disturbance
GRAVES’ SPECIFIC clinical features
Diffuse goitre
Thyroid eye disease (infiltrative)
Pretibial myxoedema
Acropachy
Investigations of hyperthyroidism
Thyroid function tests to confirm biochemical hyperthyroidism
Diagnosis of underlying cause important because treatment varies
Clinical history, physical signs usually sufficient for diagnosis
Investigations of primary hyperthyroidism- thyroid functions test
Increase free T4 + T3
Suppressed TSH
Investigations of secondary hyperthyroidism- thyroid functions test
Increase free T4 +T3
But inappropriately high TSH
If thyroid function test shows high T4+T3, but low TSH, what is the likely diagnosis
Graves disease- thyroid function test
Graves disease
Immune system disorder that results in the overproduction of thyroid hormones (hyperthyroidism)
Thyroiditis
Inflammation of the thyroid gland
Treatment for destructive thyroiditis
Antithyroid drugs (course or long-term)
Radioiodine 131I
Surgery (partial, subtotal thyroidectomy)
Thionamides
Drug class that decreases synthesis of new thyroid hormone
SIDE EFFECTS OF THIONAMIDES
Generally well tolerated
Common side effect:
rash
Less common:
arthralgia
hepatitis
neuritis
thrombocytopenia
vasculitis
Dangerous side effect of thionamides
AGRANULOCYTOSIS (destruction of WBCs)
Radioiodine mechanism
Emission of beta particles results in ionization of thyroid cells
Direct damage to DNA and enzymes
Indirect damage via free radicals
Surgical treatment for graves disease and multinodular goitre
Near total thyroidectomy for Graves’ disease and multinodular goitre
Surgical treatment for toxic adenoma
Near total thyroidectomy / lobectomy for toxic adenoma
HYPOTHYROIDISM
Thyroid hormones levels abnormally low
3 types of hypothyroidism
PRIMARY (>99%)
- absence / dysfunction thyroid gland
- most cases due to Hashimoto’s thyroiditis
SECONDARY / TERTIARY
- pituitary / hypothalamic dysfunction
Causes of primary HYPOTHYROIDISM - ADULT
Hashimoto’s thyroiditis
131I therapy
Thyroidectomy
Postpartum thyroiditis
Drugs
Thyroiditides
Iodine deficiency
Thyroid hormone resistance
Postpartum thyroiditis
Transient phenomenon observed following pregnancy
May cause hyper/hypothyroidism
Often misdiagnosed as postpartum depression
Hashimoto’s thyroiditis
Autoimmune thyroiditis that produces atrophic changes with regeneration, leading to goitre formation
More common in late middle aged women
Common cause of hypothyrodism
Causes secondary/tertiary HYPOTHYROIDISM - ADULT
Pituitary disease
Hypothalamic disease
Clinical features of hypothyroidism
Fatigue
Wt gain
Cold intolerance
Constipation
Menstrual disturbance
Muscle cramps
Slow cerebration
Dry, rough skin
Periorbital oedema
Delayed muscle reflexes
Carotenaemia
Oedema
Investigation for primary hypothyroidism
high TSH (most sensitive marker)
usually low free T4 + T3
Investigations for SECONDARY/TERTIARY HYPOTHYROIDISM
TSH inappropriately low for reduced T4 / T3 levels
Investigation for Hasimoto’s
T4/ T3 may be low/normal in mild hypothyroidism positive titre of TPO antibodies in Hashimoto’s
Treatment for hypothyroidism
Replacement therapy- synthetic L-thyroxine (T4)
Human chorionic gonadotrophin hormone (hCG)
hormone produced by the placenta during pregnancy.
It helps thicken uterine lining to support a growing embryo and stops menstruation
Metabolic Changes in pregnancy
Increased erythropoetin, cortisol, noradrenaline
High cardiac output
Plasma volume expansion
High cholesterol and triglycerides
Pro thrombotic and inflammatory state
Insulin resistance
Gestational Syndrome
specific to being pregnant
Gestational Syndrome examples
Pre-Eclampsia
Gestational Diabetes
Obstetric cholestasis
Gestational Thyrotoxicosis
Transient Diabetes Insipidus
Lipid disorders
Postnatal depression
Postpartum thyroiditis
Postnatal autoimmune disease
Paternal Disease
Thyroid gland development
Foetal thyroid follicles and thyroxine synthesis occurs at 10 weeks
Axis matures at 15-20 weeks
Maternal T4 0-12 weeks regulates neurogenesis, migration and differentiation then foetal T4
What week does Fetal thyroid follicles and thyroxine synthesis occur
Week 10
What weeks does the fetal thyroid axis mature
Weeks 15-20
Hypothyroidism in pregnancy signs and symptoms
Weight gain, cold intolerance, poor concentration, poor sleep pattern, dry skin, constipation, tiredness
Symptoms can predate pregnancy
Prevalence of hypothyroidism during pregnancy
2-3%
hCG and Thyroxine
hCG can bind to the TSH receptors present in thyroid tissue and act like a weak form of TSH to cause the thyroid to produce and release more T3 and T4
Do expecting mother with hypothyroidism need an increase or decrease in thyroxine dosage
Increase as hCG acts of a weak form of TSH causing competition at the receptors
Target screening for hypothyroidism
Age >30
BMI >40
Miscarriage preterm labour
Personal or family history
Goitre
Anti TPO
Type 1 DM
Head and neck irradiation
Amiodarone, Lithium or contrast use
Craniopharyngioma
Arise from squamous epithelial remnants of Rathke’s pouch
Benign tumour although infiltrates surrounding structures (pituitary gland and the hypothalamus)
LIMITS (not targets) for NA+ rise for hyponatremia treatment
High risk- <8mmol/l in any 24 hour period
Normal- <10-12mmol/l in any 24 hour period
SIAD - management
-Diagnose and treat underlying condition
-fluid restriction <1L/24 hour
-sometimes demeclocycline/ vaptan (vasopressin receptor antagonist)
Risk factor for Osmotic Demyelination Syndrome
Serum Na+ <105mmol/L
Hypokalaemia
Chronic excess alcohol
Malnutrition
Advanced Liver disease
>18mmol/L Na+ increase in 48 hour
Risk of improper therapy for hyponatraemia
Rapid correction of the hypotonic state leads to central pontine myelinolysis (osmotic demyelination syndrome)
Central pontine myelinolysis (Osmotic demyelination syndrome)
Massive demyelination of descending axons
May take up to 2 weeks to manifest
Management of acute severe symptomatic hyponatraemia
- iv 150ml of 3% Saline or equivalent over 20 mins
- Check serum Na+
- Repeat twice twice until 5mmol/L increase Na+
- After 5mmol/L increase
Stop hypertonic saline
Establish diagnosis
Na+ 6 hourly for 1st 24 hours
Limit increase to 10mmol/l first 24 hour
Craniopharyngioma peak ages
5 to 14 years; 50 to 74 years
Craniopharyngioma symptoms
Raised ICP, visual disturbances, growth failure, pituitary hormone deficiency, weight increase
Rathke’s pouch
gives rise to the anterior pituitary during week 4
Rathke’s Cyst
Derived from remnants of Rathke’s pouch
Single layer of epithelial cells with mucoid, cellular, or serous components in cyst fluid
Rathke’s Cyst symptoms
Mostly asymptomatic and small
Present with headache and amenorrhoea, hypopituitarism and hydrocephalus
Meningioma symptoms
Associated with visual disturbance and endocrine dysfunction
Usually present with loss of visual acuity, endocrine dysfunction and visual field defects
Lymphocytic Hypophysitis
Inflammation of the pituitary gland due to an autoimmune reaction
Non-Functioning Pituitary Adenoma (NFPA) or Silent Pituitary Adenoma (SPA)
benign anterior pituitary tumour not associated with clinical evidence of hormonal hypersecretion
Non-Functioning Pituitary Adenoma
begin tumour can cause visual disturbances, headaches
Non-Functioning Tumours
No specific test but absence of hormone secretion
* Test normal pituitary function
Non-Functioning Tumours treatment
Trans-sphenoidal surgery if threatening eyesight or progressively increasing in size
Testing Pituitary Function- guiding principle
If the peripheral target organ is working normally the pituitary is working
Thyroid function test- Primary Hypothyroid
Raised TSH low Ft4
Thyroid function test-Hypopituitary
Hypopituitary - Low Ft4 with normal or low TSH
Thyroid function test- Graves disease (toxic)
Suppressed TSH high Ft4
Thyroid function test- TSHoma- functioning tumour of pituitary (very rare)
High Ft4 with normal or high TSH
Thyroid function test- Hormone resistance
High Ft4 with normal or high TSH
Gonadal function test- male- Primary Hypogonadism
Low T raised LH/FSH
Gonadal function test-male- Hypopituitary
Low T normal or low LH/FSH
Gonadal function test-male- Anabolic use
Low T and suppressed LH
Gonadal function test-female- Before puberty
Oestradiol very low/undectable with low LH and FSH although FSH slightly higher than LH
Gonadal function test-female- Puberty
Pulsatile LH increases and oestradiol increases
Gonadal function test-female- Post menarche
Monthly menstrual cycle with LH/FSH, mid-cycle surge in LH and FSH and levels of oestradiol increase through cycle
Gonadal function test-female- Primary ovarian failure (includes menopause)
High LH and FSH with FSH greater than LH and low oestradiol
Gonadal function test-female- Hypopituitary
Oligo or amenorrhoea with low oestradiol and normal or low LH and FSH
How to test HPA axis
Measure cortisol and synacthen at 0900h
HPA function test- Primary AI
Low cortisol, high ACTH, poor response to Synacthen
HPA function test- Hypopituitarism
Low cortisol, low or normal ACTH, poor response to synacthen
When is GH levels highest and lowest?
GH is secreted in pulses with greatest pulse at night and low or undetectable levels between pulses
Affects of obesity on GH
Low in obesity
Affects of Age on GH
falls with age
Testing GH/IGF1 axis
Measure: IGF-I and GH stimulation test
-Insulin stress test
-Glucagon test
How to measure prolactin testing
Measure prolactin or cannulated prolactin (3 samples over an hour to exclude stress of venepuncture)
Prolactin may be raised as a result of
Stress
Drugs: antipsychotics
Stalk pressure
Prolactinoma
Measure for pituitary disease
Measure Ft4
Measure 0900h fasted T and LH/FSH in pituitary disease
Investigation of Vasopressin Deficiency/ Resistance
water deprivation test
Hypertonic Saline Stimulation Test
Water deprivation test
assess the ability of the patient to concentrate urine when fluids are withheld. Water deprivation should normally cause increased secretion of ADH, resulting in smaller volumes of concentrated urine.
Hypertonic Saline Stimulation Test
technique for distinguishing partial diabetes insipidus from psychogenic polydipsia, and for the diagnosis of complex disorders of osmoreceptor and posterior pituitary function
Dynamic Testing
assess the dynamic responses of hormonal and metabolic axes. These tests may involve: Stimulation of a hormonal axis by releasing hormones or other agents e.g. Synacthen to stimulate release of cortisol from adrenal glands
Preferred imaging study for the pituitary
MRI
Why is MRI the Preferred imaging study for the pituitary
Better visualization of soft tissues and vascular structures than CT
No exposure to ionizing radiation
Microparticulate
any particle in a micrometer scale are used as drug delivery systems. They offer higher therapeutic and diagnostic performance
Thyroxine replacement
Aim to achieve levels to mid to upper half of reference range
Higher doses usually required in patients on oestrogens or in pregnancy
Growth hormone replacement
Aiming for mid-range IGF1 levels, lower doses in older people
Improves lipid profiles, body composition and bone mineral density
Testosterone replacement
Improve bone mineral density, libido, sexual function, energy levels and sense of well being, muscle mass and reduce fat
Oestrogen Replacement
Alleviate flushes and night sweats; improve vaginal atrophy
Reduce risk of cardiovascular disease, osteoporosis and mortality
Desmopressin replacement therapy
Adjust according to symptoms
Monitor sodium levels
-Low Ft4 with normal or low TSH
-Low T normal or low LH/FSH
-Low cortisol, low or normal ACTH, poor response to synacthen
Hypothyroidism measurement
Hypothyroidism measurement
-Low Ft4 with normal or low TSH
-Low T normal or low LH/FSH
-Low cortisol, low or normal ACTH, poor response to synacthen
Acromegaly mean duration of symptoms
8 years
Acromegaly mean age at diagnosis
44 years
Acromegaly Co-morbidities
Cerebrovascular events, headaches, arthritis, insulin-resistant diabetes, sleep apnoea, CVD, hypertension
Acromegaly presenting clinical symptoms
Acral enlargement
Arthralgias
Maxillofacial changes
Excessive sweating
Headache
Hypogonadal symptoms
Criteria for diagnosis of acromegaly
Acromegaly excluded if:
random GH <0.4 ng/ml and normal IGF-I
If either abnormal proceed to:
75 gm Glucose tolerance test (GTT)
Acromegaly excluded if:
IGF-I normal
and
GTT nadir GH <1 ng/ml
Options for treatment of acromegaly
Pituitary surgery
Medical therapy
Radiotherapy
Two important determinants of success of surgery for acromegaly
size of tumour (hence importance of finding early)
surgeon
Medical therapy for acromegaly
Dopamine agonists – cabergoline
Somatostatin analogues
Growth Hormomne receptor antagonist
Mainstay of acromegaly therapy
Pituitary surgery mainstay of therapy
Prolactinoma
Noncancerous tumour of the pituitary gland
Produces prolactin
High prolactin levels
Reduces the production of the hormones oestrogen and testosterone
Anovulation (prevent release of eggs) in females
Decreased sperm production
Bone loss (osteoporosis)
Clinical features of Prolactinoma- local effects of tumour
Headache
Visual field defect (bi-temporal hemianopia)
CSF leak (rare)
Any pituitary tumour local effect clinical features
Headache
Visual field defect (bi-temporal hemianopia)
CSF leak (rare)
Clinical features of Prolactinoma- effect of prolactin
menstrual irregularity/ amenorrhoea
infertility galactorrhoea
low libido
low testosterone in men
Hyperprolactinaemia
high prolactin levels
Hyperprolactinaemia causes
Macroprolactinoma
Microprolactinoma
Non functioning pituitary tumour – compression of pituitary stalk – prolactin <4000 mIU/L
Antidopaminergic drugs
Other causes: stress, hypothyroidism, PCOS, drugs, renal failure, chest wall injury
Management of prolactinoma vs other pituitary tumour
Unlike other pituitary tumours management is medical rather than surgery
Clinical presentation of newly diagnosed
Type 1 diabetes- common
2-6 weeks of Polyuria, polydipsia, weight loss, ketonuria (high levels of ketone in urine)
Differences between Type 1 and Type 2 diabetes
Type 1-immune-mediated, idiopathic, insulin insufficient, younger people
Type 2- insulin resistance with inadequate insulin secretion, result of lifestyle, older people
Epidemiology of Type 1 diabetes
5-10% of all cases of diabetes, typically present in childhood, however can present later in life
Diabetic ketoacidosis (DKA)
metabolic emergency in which hyperglycaemia us associated with a metabolic acidosis due to greatly raised ketone levels
Diabetic ketoacidosis- ketone levels vs normal
> 3mmol/L vs <0.6mmol/L
Diabetic ketoacidosis- clinical features
Prostration (state of extreme physical exhaustion, weakness or collapse), dehydration, nausea, vomiting
Occasionally- abdominal pain +/ confusion
Diabetic ketoacidosis investigation results
Ketonemia (>3mmol/L), high blood glucose (>11mmol/L), bicarbonate <15mmol/L +/ venous pH<7.3
Diabetic ketoacidosis- treatment
Replacement of fluid/ electrolytes lost, restoration of the acid-base balance, insulin replacement, treat underlying cause
Diabetic ketoacidosis- pathophysiology- increased glucose
Increase glucose due to insulin deficiency >
hyperglycaemia + glycosuria >
osmotic diuresis >
fluid and electrolyte depletion>
renal hypoperfusion >
impaired excretion of ketones + H+
Diabetic ketoacidosis- pathophysiology- increased ketones
Increase ketones as a result of uncontrolled ketogenesis in the liver due to insulin deficiency > acidosis > vomiting > fluid and electrolyte depletion > renal hypoperfusion > impaired excretion of ketones + H+
Aims of treatment of Type 1 diabetes
Prevention of diabetes emergencies (ie hypoglycaemia, DKA), Treatment of hyperglycaemic symptoms
Minimise risk of long term complications by screening and control of hyperglycaemia
Treatment options in Type 1 diabetes
Insulin replacement- pump or injection
Islet cell transplant
Monogenic diabetes mellitus (MODY- maturity-onset diabetes of the young)
caused by single gene mutation, dominantly inherited, which predominantly affects beta cell function, non-insulin dependence
Monogenic vs type 1 diabetes
Type 1- doesn’t present before 6 months, immune cell mediated
Monogenic- can affect infants from birth, single genetic cause
When to consider monogenic diabetes
<6 months, patient presenting with early onset diabetes an affected parent, evidence of non-insulin dependence
Secondary diabetes subdivisions
secondary to genetic defects beta cell function or insulin action, exocrine pancreatic disease, endocrine disease, drugs/chemicals, infection
C peptide
Not present in synthetic insulin, longer half life than insulin, type 1 diabetes c-peptide is negative as result of complete destruction of beta cells
Will C-peptide persist or disappear with type 1 diabetes?
C-peptide will not be present with type 1 diabetes as beta cell are destroyed but will persist for type 1, monogenetic or secondary
Secondary diabetes to genetic defects of beta cell function
monogenic diabetes, glucokinase/hepatic nuclear factor mutations, neonatal diabetes, mitochondrial diabetes
Secondary diabetes to exocrine pancreatic disease causes
Chronic pancreatic (alcohol abuse, alters secretions leads to blocked ducts), haemochromatosis (genetic, excess iron deposited), pancreatic trauma, CF, neoplasia,
Secondary diabetes to endocrine causes
Acromegaly, Cushing’s syndrome, pheochromocytoma
Due to insulin resistance
Secondary diabetes to acromegaly
insulin resistance due to excess GH simulating gluconeogenesis and lipolysis, causing hyperglycemia and elevated free fatty acid levels
Secondary diabetes to Cushing’s syndrome
Excess glucocorticoid leads to reduced glucose uptake and increased gluconeogenesis so increase increased insulin resistance
Secondary diabetes to Pheochromocytoma
Catecholamines excess leads to increase gluconeogenesis and decrease glucose uptake leading to insulin resistance
Secondary to drug induced diabetes
Glucocorticoids- increase insulin resistance
thiazides/ protease inhibitors/ antipsychotic- not fully understood
Pharmacological name for cortisol
hydrocortisone
Cortisol rising to peak times
Starts rising at 3 am to peak shortly before waking up
Cortisol decline period
From wake up to 7pm
Cortisol quiescent period
7pm-3am
Adrenal insufficiency (AI) causes
Primary- Addison’s disease
Secondary- hypopituitarism
Tertiary- suppression of HPA (steroids)
Addison’s disease
Primary adrenal insufficiency- intrinsic diseases that affect the cortex of the adrenal glands, causing impairment in the synthesis and secretion of all steroids
Addison’s disease- Causes
Adrenal destruction
Autoimmune- most common
Infections, mets, haemorrhagic infection, surgical removal
Secondary adrenal insufficiency
Occurs when the pituitary gland doesn’t make enough of the hormone ACTH
0900 Cortisol and AI- investigations
− Cortisol > 450-500 nmol/l AI unlikely
− Cortisol < 100 nmol/l AI likely
ACTH and AI- investigations
− ACTH > 22 pmol/l primary
− ACTH < 5 pmol/l secondary
Renin / Aldo and AI- investigations
− Elevated renin in primary
Synacthen Test
uses synacthen to test how well the adrenal glands make cortisol
− 250ug IV, measure after 0’ & 30’
− > 450-550 nmol/l AI unlikely
Management- Adrenal Crisis
Bloods- cortisol +ATCH
Hydrocortisone 100mg IV/IM/SC
Treatment of Adrenal insufficiency (AI)
Glucocorticoid/ Mineralocorticoid/ Androgen Replacement
Sick Day Rules- Adrenal insufficiency (AI)
Always carry 10 x 10mg tablets hydrocortisone
* If unwell with fever or flu like illness double dose of steroids
* If in doubt double dose of steroids
* If vomiting or increasingly unwell take emergency injection
of hydrocortisone 100mg IM (SC)
* If unable to have injection take hydrocortisone 20mg 6
hourly and repeat if vomit
* Go to emergency room / ring ambulance
Most common complication of type 2 diabetes
Cardiorenal- CVD and CKD
Aims of type 2 DM treatment
Manage blood glucose
Reduce risk of CVD, CKD, microvascular complications
Weight reduction- (increased PA, decreases dietary fat)
HbA1c
average blood glucose levels for the last 2-3 months
Diabetic complications that risk increases with mean HbA1c
Diabetic retinopathy, nephropathy, Serve non-proliferative/ proliferative DR, neuropathy, microalbuminuria
Treatment options for controlling excess blood glucose in type 2 diabetes
Sensitise body to insulin- metformin and pioglitazone
Replace insulin- insulin injections/pumps
Secrete more insulin- sulphonylureas, DPP-4 inhibitors, GLP-1 receptor agonist
Initial pharmaceutical therapy for Type 2 DM
Metformin
Incretins
They stimulate pancreatic β-cells after meals, to secrete insulin i.e. glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)
Sodium glucose co-transporter 2 inhibitor (SGLT-2i)
Current treatments are act as insulin secretagogues or sensitisers
Kidney key role in glucose homeostasis-glucose reabsorption
SGLT-2i limitations
Higher risk of infection, more common in women and more often mycotic than bacterial
Diabetic Complications
Diabetic retinopathy, stroke, CVD, Diabetic nephropathy, peripheral vascular disease, DPN (Diabetic peripheral neuropathy)
Diabetic Neuropathy
uncontrolled high blood sugar damages nerves and interferes with their ability to send signals, leading to diabetic neuropathy
Clinical consequences of Diabetic Neuropathy
painful neuropathic symptoms, autonomic neuropathy and insensitivity that results in foot ulceration and amputation
Diabetic Peripheral Neuropathy (DPN) and CVD
alarming association between DPN and cardiovascular disease
Does DPN commonly cause pain
Painful symptoms are present in about a third, however pain can disabling
Does DPN commonly cause significant motor deficits
No, Significant motor deficit is not common
Treatment of Diabetic Painful neuropathy
Good glycaemic control
Medications to manage Neuralgia - ie
Tricyclic antidepressants / SSRIs
Anticonvulsants
Opioids
IV lignocaine
Capsaicin
Transcutaneous nerve stimulation / acupuncture / spinal cord stimulators
Psychological interventions / hypnosis
Diabetic Foot Ulceration (DFU)
Foot ulceration occurs in 15% of people with DM during their lifetime, Lower limb amputations X 15 in people with DM2
Cause of diabetic amputation- common pathway
Neuropathy (damage to the nerves that serve the lower limbs and hands)/ vascular disease (affects the larger vessels of the lower limbs) > trauma >ulcer > failure to heal > infection> amputation
Will most people with neuropathy be aware if they are having any problems with their feet
most people with neuropathy are insensate (due to sensory nerve damage) and will not be aware of a problem
IMPORTANT TO GET PATIENT TO REMOVE SHOE
Euvolemia
the state or condition of having the normal volume of blood or fluids in the body
Satiety
The physiological feeling of no hunger
Location where most of the appetite regulation in the brain
Hypothalamus
Graves disease- thyroid function test
If thyroid function test shows high T4+T3, but low TSH, what is the likely diagnosis
T4/ T3 may be low/normal in mild hypothyroidism positive titre of TPO antibodies in Hashimoto’s
Investigation for Hasimoto’s
Hyperosmolar hyperglycaemic state
Most common in T2DM
Characterised by profound hyperglycaemia, hyperosmolality and volume depletion in the absence of significant ketoacidosis
Hyperosmolar hyperglycaemic state cause
Often triggered after infection or acute illness (commonly MI, sepsis + stroke)
Hyperosmolar hyperglycaemic state- symptoms
Dehydration
Acute cognitive impairment
Polyuria, polydipsia, and weight loss
Weakness
Signs of the underlying cause (commonly MI, sepsis + stroke)
Hyperosmolar hyperglycaemic state- 1st order investigations
bloods- glucose (high), ketones (-ive or low), U+E, venous blood gas, serum osmolality (high)
ECG- for cardiac precipitants
Hyperosmolar hyperglycaemic state- treatment
Urgent IV fluids (with K+ replacement if needed)
Insulin
Identify/ treat underlying cause
Monitor biochemical markers
Monitor and treat complications
Hyperosmolar hyperglycaemic state- complications
cerebral oedema and central pontine myelinolysis
fluid overload
Subacute thyroiditis (De Quervain’s thyroiditis)
inflammation of the thyroid characterised by a triphasic course of transient hyperthyroidism (up to 6 weeks), hypothyroidism (upto 6 months), followed by a return to euthyroidism
Subacute thyroiditis (De Quervain’s thyroiditis)- aetiology
Presumed to be viral or autoimmune
Subacute thyroiditis (De Quervain’s thyroiditis)-
Hyperthyroid- supportive (NSAIDs, if unresponsive corticosteroids)
Hypothyroid- generally don’t require thyroid replacement therapy
Most return to normal thyroid function (90%) but some need long term levothyroxine therapy
Thyroid storm
happens when your thyroid gland releases a large amount of thyroid hormone in a short amount of time
Medical emergency
Thyroid storm causes
typically develops in untreated or partially treated hyperthyroidism conditions (ie graves’ disease)
After radioactive iodine therapy because of release of stores of thyroid hormone
Thyroid storm presentation
volume depletion, congestive heart failure, confusion, nausea and vomiting, and extreme agitation
Thyroid storm- treatment
high-dose antithyroid drugs, corticosteroids, beta-blockers, iodine solution with supportive care
Thyroid- storm investigations
Elevated T3, T4
Supressed TSH
Shouldn’t wait before treatment
Thyroid cancer types
Papillary (60%)- younger pts
Follicular (<25%)- middle age
Medullary (5%)- may produce calcitonin
Lymphoma (5%)
Thyroid cancer- common treatment
Total thyroidectomy
Iodine ablation
Node clearance
Thyroid cancer symptoms
Growing lump on thyroid
Hoarse voice
Sore throat
Difficult swallowing or breathing
Pain in front of neck (pressing)
Carcinoid tumour
a rare cancer of the neuroendocrine system
Typically found on bowels or appendix
Carcinoid syndrome
collection of symptoms of carcinoid tumour – usually one that has spread to the liver – releases hormones such as serotonin into the bloodstream
Carcinoid syndrome- signs and symptoms
Bronchoconstriction, paroxysmal flushing (esp in upper body), diarrhoea, congestive cardiac failure
Carcinoid syndrome- diagnosis
elevated levels of urinary 5-hydroxyindoleacetic acid (waste product that comes from the breakdown of serotonin by the liver)
Carcinoid syndrome- treatment
Surgery resection (radio+/radiotherapy if surgery not effective)
Management of symptoms
Serotonin syndrome
excess serotonin in the CNS, resulting from the therapeutic use or overdose of serotonergic drugs
Serotonin syndrome- triad of clinical features
neuromuscular excitation, autonomic effects, and altered mental status
Serotonin syndrome- treatment
cessation of offending medication(s) or dose reduction- if mild/ moderate
emergency supportive care if severe
Primary aldosteronism (Conn’s syndrome)
Aldosterone production exceeds the body’s requirements and is relatively autonomous with regard to RAAS
Most common specifically treatable/ curable form of HTN
Primary aldosteronism (Conn’s syndrome)- key diagnostic factors
HTN
RFs- family history of primary aldosteronism, of early onset of hypertension and/or stroke
Primary aldosteronism (Conn’s syndrome)- 1st order investigation
Aldosterone/renin ratio- most reliable screening tool- elevated aldosterone: renin
Primary aldosteronism (Conn’s syndrome)- diagnostic test
Fludrocortisone suppression test- most reliable
Saline infusion testing + Oral salt loading are alternatives
Primary aldosteronism (Conn’s syndrome)- treatment
Surgery- (unilateral) laparoscopic adrenalectomy
Aldosterone antagonists
Hyperkalaemia
too much K+ in blood
Serum potassium value >6.0 mmol/L
Hypokalaemia
too little K+ in blood
serum potassium level <3.5 mmol/L
Hyperkalaemia- common causes
-High intake of potassium in the setting of decreased renal excretion
-Extracellular redistribution of potassium from intracellular locations
Hyperkalaemia- acute manifestations
muscle weakness
ECG changes (life treating arrhythmia)
Hyperkalaemia- ECG changes
Peaked T waves and bradycardia
P wave flattening
PR prolongation
Wide QRS complex
Hyperkalaemia- ECG changes- pathophysiology
Increased extracellular potassium reduces myocardial excitability, with depression of both pace making and conducting tissues.
Hyperkalaemia- common differentials
Chronic kidney disease
Diabetic ketoacidosis/hyperosmolar hyperglycaemic state
Potassium supplementation with underlying renal dysfunction
Drug induced
Hypokalaemia- common causes
urinary or GI losses
Hypokalaemia- acute manifestations
muscle weakness and ECG changes
Hypokalaemia- prolonged manifestations
rhabdomyolysis (destruction of striated muscle cells), renal abnormalities, and cardiac arrhythmias
Hypokalaemia- ECG changes
T wave inversion
St depression
Prominent U waves
Hypokalaemia- ECG- Push-pull effect
Hypokalaemia creates the illusion that the T wave is “pushed down”, with resultant T-wave flattening/inversion, ST depression, and prominent U waves
Hyperkalaemia- ECG- Push-pull effect
In hyperkalaemia, the T wave is “pulled upwards”, creating tall “tented” T waves, and stretching the remainder of the ECG to cause P wave flattening, PR prolongation, and QRS widening
Hypokalaemia- common differentials
Vomiting, severe diarrhoea, eating disorders, alcoholism, drug induced, primary aldosteronism, DKA, Hyperosmolar hyperglycaemic state, Exercising in a hot climate
Stress response in critical illness
Parathyroid hormone
Normally secreted in response to low Ca2+ from parathyroid glands, controlled by a -ve feedback loop via Ca2+ levels
Parathyroid hormone- action
-Increase osteoclast activity producing PO(4)3- and Ca2+
-Increase Ca2+ and decrease PO(4)3- reabsorption in the kidneys
-Increased active 1,25 dihydroxy-vitamin D3
Parathyroid hormone- overall action
Increased Ca2+
Decrease PO(4)3-
Hyperparathyroidism
Too much parathyroid hormone
3 types- primary, secondary, tertiary
Primary hyperparathyroidism
Parathyroid gland produces too much Parathyroid hormone
Primary hyperparathyroidism- causes
-80% solitary adenoma
-20% hyperplasia
- <0.5% parathyroid cancer
Primary hyperparathyroidism- presentation
Often asymptomatic
Signs relate to- hypercalcaemia, increased bone resorption or HTN
Hypercalcaemia- signs
Weak, tired, depressed, thirsty, dehydrated-but-polyuric
Also renal stones, abo pain, pancreatitis, ulcers
Increased bone resorption- signs
Bone pain, fractures, osteopenia, osteoporosis
Primary hyperparathyroidism- diagnostic test
Increased serum Ca2+ and inappropriate elevation of PTH
Primary hyperparathyroidism- Indications for surgery
Symptomatic
Or asymptomatic with <50 yrs, vry serum Ca2+, low eGFR, osteoporosis, lumbar spine, total hip, femoral neck, or distal third of radius, and/or vertebral fracture
Primary hyperparathyroidism- definitive treatment
Parathyroidectomy
Primary hyperparathyroidism- treatment for asymptomatic with no surgical indications
Monitoring- serum Ca2+, BMD T-score, lumbar spine, fracture scan
Vitamin D supplementation for those deficient
Secondary hyperparathyroidism
elevation of PTH secondary to hypocalcaemia
Secondary hyperparathyroidism- causes
Vit D deficiency, chronic renal failure
Secondary hyperparathyroidism and chronic renal failure
Defect in the activation of vitamin D in the kidneys due to chronic kidney disease leads to hypocalcaemia, resulting in compensatory PTH production causing secondary hyperparathyroidism
Secondary hyperparathyroidism- diagnostic test
Low serum Ca+, Elevated (appropriately) PTH
Secondary hyperparathyroidism- treatment
Correct underlying cause
Phosphate binders, Vit D, cinacalcet if needed
Chvostek’s sign
Tapping on the face just anterior to the ear and seeing a twitching of muscles around the mouth. Seen in most hypocalcaemic states. Demonstrates neuromuscular excitability.
Trousseau’s sign
Inflating blood-pressure cuff above diastolic for about 3 minutes causes muscular flexion of the wrist, hyperextension of the fingers, and flexion of the thumb. Seen in most hypocalcaemic states. Demonstrates neuromuscular excitability.
What do Chvostek’s and Trousseau’s sign represent
Hypocalcaemia Demonstrates neuromuscular excitability.
Tertiary hyperparathyroidism
High Ca2+ and very high PTH (inappropriately)
Occurs in chronic renal failure
Tertiary hyperparathyroidism- pathophysiology
Occurs after prolong secondary hyperparathyroidism, causing gland to act autonomously having under gone hyperplasic or adenomatous change
This causes increased Ca2+ from very increased PTH secretion by feedback control
