Endocrinology Flashcards
What is adrenal insufficiency?
Adrenal glands don’t produce enough hormones (cortisol +/- aldosterone)
What hormones control the release of cortisol and aldosterone from the adrenal glands?
Hypothalamus secretes CRH -> pituitary gland secretes ACTH -> release of cortisol from adrenal glands
Renin produced by kidneys -> RAAS system -> end product is aldosterone production from adrenal gland
Primary adrenal insufficiency
Labs (cortisol, aldosterone, renin, ACTH, CRH, Na, K)
Causes
Presentation
Tx
Problem with ADRENAL GLAND itself
- > low in cortisol and aldosterone
- high plasma renin activity
- > high ACTH and CRH
- > hyponatraeamia, hyperkalaemia
Causes
- Most common cause in developed world is autoimmune destruction (incr levels of serum anti-adrenal Ab (anti 21 hydroxylase) = Addisons disease
- Infection [Tb (most common cause worldwide), HIV, fungal]
- Bilateral adrenal metastases
- Bilateral adrenal infarction, haemmhorage (caused by meningococcaemia = waterhouse-friedrichson syndrome)
- Congenital adrenal hyperplasia (most common cause in infancy)
- Drugs
- Adrenoleukodystrophy - peroxisomal disorder; incr serum VLCFA
Presentation
- Hyperpigmentation of skin creases, oral mucosa due to excess ACTH
- Salt craving due to low aldosterone
- Signs of hypopituitarism
Tx - long term replacement of cortisol (hydrocort) and aldosterone (fludrocort)
Secondary adrenal insufficiency
Labs (cortisol, aldosterone, renin, ACTH, CRH)
Causes
Presentation
Results from insufficient production of ACTH from pituitary
- Low ACTH and cortisol
- Normal aldosterone (no problem w adrenals)
- High CRH (positive feedback)
Causes
- Panhypopituitarism (trauma or tumour within pituitary or compression by another tumour in vicinity)
- OR isolated ACTH deficiency (autoimmune, genetic disorders, medications)
Presentation
- headaches
- visual abnormalities
- signs of hypopituitarism
Tertiary adrenal insufficiency
What is it
Causes
Presentation
Insufficiency of CRH secretion from hypothalamus
- Low CRH, ACTH
- Low cortisol
- Normal aldosterone
Causes
- Sudden withdrawal of chronic GC therapy
- Removal of ACTH secreting tumour
- -> 1 and 2 are caused by sudden removal of high levels of EXOGENOUS circulating GC where neg feedback loop was suppressing CRH release from hypothalamus - takes a while for this neg feedback to resolve and for the hypothalamus to begin eleasing CRH again.
Other causes directly impacting hypothalamus:
- Head trauma
- Intracranial tumours
Presentation
- headaches
- visual abnormalities
- hypoglycaemia
+/- signs of panhypopituitarism
Adrenal crisis presentation
Triggered by some sort of stressor (infx/illness, surgery, trauma) in setting of adrenal insufficiency
Acute:
Hypotension, shock
Vomiting
Abdo pain
Fever
Drowsiness, Coma
Chronic:
- fatigue
- anorexia
- nausea and vomiting
- LOW/FTT
- postural hypotension and salt craving
- abdo, muscle, joint pain
IX
- metabolic acidosis
- hyperkalaemia and hyponatraemia
- hypoglycaemia
Tx
- Immediately give IV fluids (20ml/kg) and stat dose IV hydrocort followed by q6-8hrly dosing hydrocort until no longer acutely unwell
+/- IV dextrose if hypoglycaemic
Note- hyperkalaemia normally resolves with fluid and steroid tx
Investigation/diagnosis of adrenal insufficiency - what investigations would you order?
- Morning serum cortisol level to confirm diagnosis of adrenal insufficiency
a) LOW: confirms diagnosis -> proceed to measure serum ACTH levels (high: primary AI vs low: secondary/tertiary AI)
b) HIGH: excludes
c) Intermediate: proceed to ACTH stimulation test - ACTH stimulation test (involves administering synthetic ACTH ‘cosyntropin’ and measuring serum cortisol levels before and after)
- > if cortisol levels are normal before and after = AI excluded
- > If levels are low before and low after = primary AI
- > if levels are low before but increase after = secondary/tertiary - To distinguish between sec and tertiary
- CRH stimulation test (inject CRH then measure ACTH)
- > no rise in ACTH: secondary
- > Rise in ACTH: tertiary
Signs of panhypopituitarism
Presentation:
TSH: fatigue, lassitude, cold intolerance, constipation
GH: short stature, hypoglycaemia
ACTH : hypoglycaemia, vomiting, malaise
Aldosterone: Diabetes insipidus (polyuria, polydipsia, dehydration)
GH: Growth failure/short stature/FTT
LH, FSH: delayed puberty, Decr libido, Amenorrhoea
Adrenoleukodystrophy
Neurometabolic condition
Predominantly affects males age 4-8yo
VLCFA accumulate in CNS -> neurodev regression and adrenal cortex -> adrenal insufficiency
Presentation:
- Initially resembles ADHD
- Progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms
- often have impaired adrenal function at the time of neurological sx onset
- Lead to total disability within six months to two years
Female carriers
- 20% develop mild-to-moderate spastic paraparesis in middle age or later usually w normal adrenal function
Ix
- incr serum levels VLCFA
- MRI: T2 enhancement in Pareto-occipital regions
- adrenal tests
- genetic testing (mutation in ABCD1 gene)
Mx
- Life long hydrocort tx
- HSCT is an option for boys and adolescents in early stages of sx who have evidence of brain involvement on MRI
Congenital adrenal hyperplasia
What is it
What is the most common cause
Classical presentation
Ix/diagnosis
Congenital cause of primary adrenal insufficiency
Deficiency in enzymes involved in adrenal steroid synthesis pathways
-> 21-hydroxylase deficiency is most common cause (X-linked); salt wasting form
-> 11 beta hydroxylase deficiency is more rare
-> normal converts progresterone to aldosterone and cortisol precursor (get deficiency of these)
-> instead shunts it down androgen pathway so end up with EXCESSIVE androgen production)
Ix
- Decr cortisol and aldosterone
- Incr ACTH
- -> Cells in adrenal gland proliferate in compensatory response, resulting in adrenal gland hyperplasia and excess androgen precursors (testosterone +/- DHEA)
Sx -
21 hydroxylase deficiency: Presents in neonatal period
Signs of adrenal crisis (often in first 1-2 weeks)
- Salt wasting (hyponatraemia, hyperkalaemia, dehydration)
- GC deficiency (adrenal crisis; shock, hypoglycaemia)
- ACTH excess (hyperpigmentation)
Note: 11beta hydroxylase deficiency is characterised by incr levels of MC so get HTN and hyperNa and hypoK and adrenal crisis is much rarer
- Sx of androgen excess (both forms)
- -> Females: genital ambiguity (external masculinisation)
- Ambiguous genitalia (b/l undescended testes)
- Enlarged clitoris
- Early puberty
- Advanced bone age, tall stature
- Acne
- Hirsutism
- -> Males: *more likely to be diagnosed late *as appear normal at birth (may have hyper pigmented scrotum or enlarged phallus)
- dx often not made until signs of adrenal insufficiency in first 1-2 weeks (shock, dehydration, hypoNa, hyperK) or much later with precocious puberty/tall stature/adv bone age, skin pigmentation, HTN, hirsutism, acne
Ix
- NST
- Reduced levels of 21 hydroxylase, aldosterone, cortisol
- Increased levels of testosterone, androstenedione, ACTH, renin
- Elevated serum levels 17 hydroxyprogresterone (progest -> 17 hydroxyprogesterone -> 21 hydroxylase -> cortisol)
- HypoNa, HyperK, hypoglycaemia
Mx
- Hydrocortisone (synthetic cortisol) and fludrocortisone (synthetic aldosterone) daily
Cushing syndrome
Causes
Presentation
Endocrine disorder characterised by increased serum cortisol levels
Causes
#1a Exogenous GC (medication) - most common
#1b Pituitary adenoma ('cushings disease') secreting ACTH - most common -\> b/l adrenal hyperplasia
#2 Adrenal adenoma/carcinoma producing excess cortisol
#3 ectopic tissue excreting excess ACTH (neuroblastoma, Wilms) - v rare
Presentation
- Round, full moon shaped face
- Truncal obesity
- Skin thinning, striae, easy bruising
- Osteoporosis -> fractures
- Impaired growth -> short stature
- Muscle wasting, thin extremities
- Buffalo hump
- HTN
- Hyperglycaemia -> DM
- Decr immunity (incr infections particularly fungal)
- Menstrual irregularity
- Psychiatric disturbances
Investigation of cushing’s syndrome
- diagnosis and investigative pathway for aetiology
Step 1: Diagnosis
- Exclude iatrogenic (excess GC medication)
Need 2x neg results:
a) Late night (midnight) salivary cortisol test (should be low at midnight and high in morning; in cushings will be high at midnight)
Or
b) 24hr urinary free cortisol level (anything >3x ULN)
c) Overnight dex suppression test (low dose)
Step 2: underlying cause
Serum ACTH levels
a) If low = ACTH independent (ie cushings not due to excess ACTH, likely adrenal source)
b) If high = ACTH dependent (either pituitary adenoma=cushing disease or ectopic ACTH secretion ie not from pituitary)
Distinguish with HIGH DOSE dex suppression test (giving high dose dex should suppress ACTH release if coming from pituitary, but will not if coming from elsewhere)
–> If low = pituitary/cushing disease
–> if high (not suppressed) = ectopic ACTH secretion (not from pituitary)
OR can distinguish with the CRH stimulation test
- Administer IV CRH
- Measure serum ACTH and cortisol levels 45min post infection
–> Incr ACTH and cortisol = Cushing’s disease
–> No rise = ectopic ACTH secretion
If cushing’s disease confirmed:
-> MRI head to confirm location of pituitary adenoma
If ectopic ACTH secretion:
-> CT or MRI of CAP to determine tumour location, stage
If ACTH independent
- > Exclude iatrogenic GC
- > Abdo CT to identify ?adrenal mass
Features of benign vs malignant adrenal masses
More often benign adrenal adenoma
RF for malignant adrenal carcinoma:
- Age <10, >50
- Androgen excess in females (acne, deep voice, hirsutism)
CT: malignant more likely to have areas of haemorrhage, necrosis, calcification
Type 1 DM
- pathophys
- sx/presentation
- Ix
Pathophys:
Autoimmune pancreatic destruction (beta islet of langerhans cells)
- Often Ab against glutamic acid decarboxylase and Ab against islet cells (80% have ICA)
- Results in low insulin production -> glucose can’t be taken up into cells (‘starving in a sea of glucose’)
Sx appear when 90% of pancreatic islet cells have been destroyed:
- 2 peaks: 3-6yo; 10-14yo
- Presents with DKA
- Acute onset polyuria, polydipsia, polyphagia, glycosuria
- LOW
- Severe dehydration
- Abdo pain, N&V
- Ketotic (fruity) breath and kaussmal breathing
Ix
- Elevated GAD Ab
- Elevated IA2 Ab
- Decr C-peptide levels (reflects insulin deficiency)
Type 2 DM
- pathophys
- sx/presentation
- Ix
Insulin RESISTANCE
- Tissues aren’t taking up glucose despite normal insulin levels
- Beta cells of pancreas begin by producing more insulin to compensate -> eventually get ‘tired’ and beta cells die off -> then get decreased insulin production
RF
>45
Family hx
BMI > 25
Sedentary lifestyle
CV risk factors (HTN)
Presentation
- Polydipsia (secondary to dehydration)
- Polyuria (water follows excess glucose in urine)
- Polyphagia
- Unexplained LOW
Ix -
- Fasting glucose test
- OGTT
- Random glucose test
- HBA1c (% of glycated Hb in blood ie fraction of RBCs that have glucose stuck to them) > 6.5%
- incr c peptide levels (reflects high insulin leve;s_
Mx - basal bolus insulin
Chronic problems of DM
Persistent hyperglycaemia can damage
- vessels (arteriolosclerosis)
- nerves
- Diabetic retinopathy
- Diabetic nephropathy
- Peripheral and autonomic neuropathy
- Peripheral vascular disease
- > foot ulcers
Metformin
- Class
- MOA
- CI and S/E
Is a biguanide
Actions
- Increases insulin sensitivity and thus incr glucose uptake into tissues
- Promotes weight loss
- Doesn’t cause hypos
SE: nausea, diarrhoea, lactic acidosis
B12 deficiency -> macrocytic anaemia
CI: Chronic renal failure and heart failure (due to SE of lactic acidosis)
DKA
Causes
Presentation
Complications
Definition
1) Hyperglycaemia (and glycosuria)
-> BSL >11 (or fasting >7)
2) Metabolic Acidosis
-> pH <7.3 or bicarb <15
3) Ketonaemia (and ketonuria)
+/- high anion gap
Other ix
- HyperK initially -> risk of hypoK with insulin tx as K is pushed back into cells
- HypoNa
Causes
- First presentation T1DM
- Inadequate insulin
- Illness (incr insulin requirements)
Presentation:
- Dehydration
- Kussmaul respiration (deep, rapid breathing)
- Ketotic breathing (sweet and fuirty smelling)
- Abdo pain
- N&V
- Polyuria, polydipsia
- Mental status changes (delirium, psychosis, decr GCS) if cerebral oedema develops (hypoNa)
On first presentation do hypoglycaemia screen
Mgmt
Mild, tolerating oral intake:
- Give novorapid S/C (1unit/kg/day)
- Oral rehydration
- Recheck BSc, ketones 1 hr
Mod-severe:
- IV insulin infusion
- IV fluids (corrects dehydration)
- IV K if <5.5 (as insulin causes K uptake from blood into cells and can cause further hypokalaemia)
+/- IV bicarb if ph <7 or evidence of poor cardiac contractility
- regular monitoring of fluid balance, vitals, neuro obs, VBG/ketones, UEC (Na and K derangement), CMP (phosphate can drop)
Hypoglycaemia
Definition
Causes
- In DM-
- Non DM: transient vs persistent
BGL < 3.3 (<2.6 in infant)
Causes
In DM:
- Insulin (too much or not eating enough)
- Sulfonylureas
- Infection
- Too much exercise
Others:
Transient
- Prem, IUGR (decr liver glycogen and muscle protein and fat to use as substrate)
- Infant of diabetic mother (hyperinsulinism)
Persistent:
- Hyperinsulinism
- Insulinomas (insulin secreting tumours)
- Beckwith Wiedmann syndrome
- Persistent hyperinsulinaemic hypoglycaemia of infancy - Endocrine
- GH deficiency
- Hypopituitarism
- Adrenal insufficiency (ACTH, adrenaline deficiency, addison disease) - Substrate deficiency
- Eating disorder
- Ketotic hypoglycaemia (now ‘accelerated starvation’; essentially substrate decency) - METABOLIC
- Glycogen storage disorder
- Fatty acid oxidation defect
- Organic academia
- Carb metabolism disorder (galactosaemia, hereditary fructose intolerance, fructosaemia)
Sx (autonomic system activation)
- palpitations
- sweating
- shaking
- nausea
- hunger
- At extreme - confusion, seizure, coma
Mx
Give rapid oral glucose or soft drink/juice/milk feed followed by carb (bread or banana)
if comatose - give IV 10% dextrose 2ml/kg or IM glucagon
Features of diabetic retinopathy on fundoscopy
Cotton wool spots
Flare haemorrhages
Microaneurysms
Diabetic Nephropathy
Histological features
what is the earliest sign?
Nodular glomerulosclerosis
Histology:
Kimmelstiel-wilson nodules (clumps of hyaline material in arterioles)
Microalbuminaenuria is earliest sign -> can progress to CKD
Insulin tx in diabetes
- Long-acting insulin first, nocte (detemir or glargine)
-> adjust dose depending on morning fasting BSL - Add doses of rapid insulin throughout day, building to ‘basal bolus scheme’
= administer short-acting insulin 3 x day, before breakfast, lunch, dinner with nocte long-acting insulin
= measure BSL before each meal and before administering insulin
OR can give 2x doses pre-mix insulin/day (before breakfast and before dinner)
What do you give if cerebral oedema suspected in child w DKA
Mannitol (no NOT wait for CNS imaging, give immediately)
Causes of hypoglycaemia in the adolescent (non DM related)
Insulinoma
Adrenal insufficiency
eating disorder
Causes of hypoglycaemia in the child
Accelerated starvation (previously known as “ketotic hypoglycaemia”) hypopituitarism growth hormone deficiency
Causes of hypoglycaemia in neonate to 2 yo age group
Congenital hyperinsulinism (most common cause of persistent hypoglycaemia \<2 yrs) Inborn errors of metabolism Congenital hormone deficiencies (eg growth hormone deficiency)
Causes of hypoglycaemia in neonates
Causes of incr metabolic rate
- Prematurity
- IUGR
- Perinatal asphyxia
- Hypothermia
- Sepsis
- Resp distress
GDM
Macrosomia
Syndrome (eg Beckwith-Wiedemann)
Pancreatic dysfunction
Sx of hypoglycaemia in newborns (<48 hrs)
Apnoea, hypotonia, jitteriness, poor feeding, high pitched cry
1st presentation hypoglycaemia workup investigations
Take bloods whilst patient is hypoglycaemic (before giving tx)
- Plasma glucose
- Ketones (beta hydroxybutyrate)
- FFA - FA oxidation defect
- Insulin and C-peptide
- Lactate - metabolic, sepsis
- Ammonia - metabolic
- Cortisol (deficiency)
- Carnitine/acylcarnitine - FA oxidation defect
- Amino acids - metabolic
- Electrolytes
- LFTs
- GH (deficiency)
What cofactors are essential for the krebs cycle?
NAD+ (niacin)
Thiamine
Rickets
What is it?
Causes
Presentation
Ix
Tx
Soft bones/failure in mineralisation of growing bone
Can be caused by deficiency of Ca, Phosphate or vitamin D (most common) which leads to bone…
- softening
- impaired growth
- malformations
Causes
- Inadequate vit D intake
- Prem
- BF infants (esp to mothers w low vit D)
- Malnutrition
- Malabsorption
- Inadequate sunlight exposure (esp dark skinned) - Impaired metabolism of vit D to active form
- liver or renal disease
- phenytoin (metabolises vit D) - Incr excretion of Phosphate
- Familial hypoPh Rickes
- Fanconi syndrome (RTA)
Presentation
- bone, joint pain
- prox muscle weakness
- bone fragility and incr risk fractures
- genu varum (bowing of legs w knock knees)
- prominent frontal bone/frontal bossing
- rachitic rosary (bumps along chest from bulbous enlargement of costochondral jxn)
- harrison groove or sulcus, pigeon chest
- protruding abdomen
- craniotabes (demineralized area or softening of the skull)
- large fontanelle w delayed closure fontanelle
Ix
- Ca, Ph
- High PTH
- High ALP
- 25 OH D3 and 1,25 OH D3 depend on cause
- Xray L wrist (or L knee if <2yo)
Tx
- Vitamin D supplementation (calceriferol if nutritional; calcitriol if renal disease)
- Treat underlying cause
Bone mineralisation
Osteoblasts Build bones - secrete osteoid which is made of type 1 collagen (framework)
Then have deposition of ca and Ph within the framework
Requires enzyme ALP to carry out this process
Vitamin D formation
Vitamin D
- ingested in food (cholecalciferol = vitamin D3 and Vitamin D2)
- created in skin in response to UV exposure (7 dehydrocholesterol to vitamin D3)
Liver
- via 25 hydroxylase -> 25-hydroxy-vitamin D
Kidneys
via 1 alpha hydroxylase -> 1,25 hydroxy-vitamin D (=active form = Calcitriol)
Role of calcitriol (Active vitamin D)
Increases serum Ca, Ph levels
Incr renal tubular reabsorption Ca2+
Incr intestinal absorption Ca2+ and Phosphate
Stimulates bone mineralisation
Suppresses PTH release from parathyroid gland
PTH - role of
Released from parathyroid in response to low Ca levels
Results in: incr plasma Ca and decr plasma Ph
- Stimulates resorption of Ca and Ph from bone into blood
(Incr Ca, decr serum Ph) - Boosts 1 alpha hydroxylase activity -> formation of more active vitamin D in kidneys
- Incr gut absorption of Ca
- Incr reabsorption of Ca from kidneys but incr urinary excretion of Ph
Causes of vitamin D deficiency
Intestinal malabsorption
- celiac, chrons disease
Decr sunlite/UV light exposure
Medications
- Phenytoin (competes for liver hydroxylase enzymes so reduces formation of active vit D)
Liver and Kidney disease (can’t form active vitamin D)
Xray findings of rickets
Widened epiphyseal plate
Incr joint space
Metaphyseal cupping and fraying
Metaphyseal fraying
Bowing of legs
Subperiosteal haemhorrages
+/- subperiosteal erosions, cysts, fractures, osteopenia if severe
Sx of hypothyroidism
Lethargy
LOA, weight gain (reduced metabolic weight)
Proximal muscle weakness (myopathy)
Constipation (reduced GI motility)
Dry skin(reduced secretion from sweat, sebacious glands)
Cool skin (vasoconstriction)
Brittle nails
Cold intolerance
Myxedema (‘puffy’ appearance due to water retention)
Goitre
Menorrhagia, low libido, infertility
Bradycardia, low CO, dyspnoea
Low mood
TFTs of hypothyroidism
Low T3 and T4
TSH levels vary
- High w primary cause
- Low/N w secondary cause
Production of thyroid hormones
Hypothalamus detects low levels of Thyroid hormones and releases TRH
- > Anterior pituitary thyrotropes produce TSH
- > stimulates thyroid gland follicles to convert thyroglobulin to iodine-containing T3 and T4 (T4 is ultimately converted to T3 which is the active form)
Role of thyroid hormones
T3 (active form) does the following:
- Incr cardiac output
- Stimulates bone resorption
- Activates SNS
- Sweat and sebacious gland secretions
- Hair follicle growth
- Skin fibroblasts
3 types of hypothyroidism
Primary
- thyroid gland isn’t making enough thyroid hormone
- pituitary incr TSH production
Secondary
- damage to pituitary -> decr TSH release
Tertiary
- damage to hypothalamus -> decr CRH -> decr TSH release
What is the most common cause of hypothyroid in developed countries?
Hashimoto thyroiditis
Hashimoto thyroiditis
Autoimmune condition
- Antibodies against thyroglobulin and thyroid peroxidase (anti-TG and anti-TPO)
= Type 4 T cell mediated HS reaction
Genetics:
- HLA-DR3,4,5 positive
Thyroid responds to autoimmune damage by undergoing hypertrophy and hyperplasia -> GOITRE formation
Thyroid scan: patchy uptake
On histology: Hurthle cells and lymphoid aggregates with germinal centre (Due to lymphoid infiltration)
Tx - thyroxine
De Quervain thyroiditis
Inflammatory condition following flu-like illness
Self-limiting
3 phases
- hyperthyroidism
- hypothyroidism
- return to normal function
Histology
- neutrophils, destruction of thyriod follicles
- granulomas surrounding follicles
OE - jaw pain and tender thyroid.
Ix - high ESR
What is cretinism
This is congenital hypothyroidism
Causes of congenital hypothyroidism
80% Thyroid dysgenesis (abnormally formed)
- > Aplasia 1/3
- > Ectopic 2/3
20% Dyshormonogenic goitre - inborn error of thyroid hormone production
-> ex: Pendred syndrome: goitre, SNHL, hypothyroidism
2% Transient disease = Ab-mediated maternal hypothyroidism (placental transfer of maternal anti-TRab antibodies due to maternal autoimmune disease, or due to antithyroid drugs)
Other Iodine deficiency (in countries without iron fortification of foods)
Transient hypothyroixinaemia
- 50% of prom infants due to immature HPA
- corrects over 4-8 weeks
- no tx required
- normal TSH, low FT4
Presentation of congenital hypothyroidism
6 Ps:
Pot-bellied
Pale
Prolongued jaundice (unconjugated; may be first sx)
Puffy-faced
Protruding umbilicus (umbi hernia)
Protuberant tongue (macroglossia)
Poor brain development (ID by 3-6mo)
Other -
Hypotonia
FTT, feeding difficulty
Constipation
LARGE FONTANELLES
Dry skin
Apnoeas
Bradycardia
Causes of central hypothyroidism
Ie Secondary -
- > anterior pituitary tumour
- > infarction that damages pituitary gland
- > leads to decr TSH production
Tertiary (damage to hypothalamus)
- trauma
- tumour
- > decreased TRH production
Treatment of hypothyroidism
Replacement of thyroid hormone (levothyroxine)
Types of hyperthyroidism
Primary - thyroid gland is secreting too many thyroid hormones
Secondary (pituitary gland secreting too much TSH)
Primary hyperthyroidism
- causes
- ix
Causes
- graves disease most common (95%)
- toxic multinodular goitre
- thyroiditis
- triggered by iodine- IV contrast
TSH low
T3, T4 high
Radioactive iodine uptake test and thyroid scan can distinguish between causes
Graves disease
Pathophy
Related genes
Features
Histology
Autoimmune
- Anti-TRAb antibodies (anti-TSH receptor Ab) ->
- Type II HS reaction: antibodies bind to the TSH receptor and result in production of thyroid hormones
- In neonatal form it is due to maternal transfer of Ab and this is only transient, lasts 6-12 weeks
Genes:
- HLA DW3
- HLA B8
Features:
Diffuse toxic goitre
Exopthalmous
Pretibial myxedema
Sx of hyperthyroidism
Hisitology
- Tall and crowded follicular epithelial cells with scallopped colloid (consumption of colloid)
Thyroid scan
- Diffuse b/l symmetrical increased uptake
Toxic multinodular goitre
Cuase of hyperthyroidism
BENIGN
One or more throid follicles starts to grow bigger and produces lots of Thyroid hormone independent of TSH regulation
Focal patches of hyperfunctioing cells with lots of colloid inside
‘hot nodules’ - incr activity on radioactive iodine uptake tests
Sx of hyperthyroidism
Metabolic:
Heat intolerance
Incr sweating
Tremor
GI
Increased appetite
LOW
Diarrhoea
Skin/hair:
Warm, moist skin
Fine, fibriable hair
Nail bed separation
MSK:
Graves opthalmopathy
Osteoporosis
Thyrotoxic myopathy (prox muscle weakness)
Reproductive:
Oligomenorrhoea,
amenorrhea, low libido, infertility
Gynaecomastia in males
Cardiac:
Tachycardia, HTN, chest pain, dyspnoea
Cardiomegaly
Arrhythmias (AF-rare)
Restlessness, anxiety, insomnia
Thyroid storm
cause
features
tx
Can worsen during acute stress (infx, trauma, surgery)
Fever
Tachyarrhythmia, HTN
Restlesness, delirium, agitation, coma, death if not rapidly treated
Tx
- IV PTU
- IV propanolol
Tx of hyperthyroidism
Beta blockers (propanolol)
Methimazole or Propothiouracil = ‘PTU’ (inhibits thyroid peroxidase, thus decr thyroid hormone synthesis)
Prednisolone (inhibits T4 to T3 conversion)
Potassium Iodide (lugol solution) decr thyroid hormone synthesis and decr vascularisation in thyroid
May need thyroidectomy
Secondary causes of hyperthyroidism
Often pituitary adenoma secreting excess TSH
High levels HCG (structurally similar to TSH so bind to the TSH receptor and stimulate it)
- > IE in first trimester of pregnancy
- > HSG-secreting germ cell tumours of testicles or ovaries
T3, T4 high
TSH high or normal
Effect of dopamine on HPA axis
Dopamine inhibits prolactin release
What hormones does the posterior pituitary release and what triggers their release
Hormones produced in herring bodies
- ADH/vasopressin
- Oxytocin
Release triggered by neuronal signals from hypothalamus
Hormones released into systemic circulation
Ectopic thytoid
Thyroid in wrong location
Panhypopituitarism as a cause for hypothyroidism, is this detected on the NST?
Due to a central or secondary cause
-> LOW TSH -> Low T4
*not picked up on NST as low TSH (NST detects elevated TSH)
Thyroid agenesis
Total lack of thyroid tissue -> low T3/T4, high TSH
LH and FSH
Triggered by GnRH from hypothal
FSH
- M: binds to Sertoli cells -> sperm development
- F: binds to Glomerulosa cells -> testosterone to oestrogen conversion
LH
- M: binds to Leydig cells -> testosterone product
- F: binds to Ovarian cells -> steroidogenesis
TSH
what triggers vs inhibits its release
What is its action
Triggered by TRH from hypothal
Inhibited by somtatostatin, dopamine and GC
Bind to receptor on thyroid follicular cells to cause release of T3, T4 (via activation of adenylyl cyclase)
Prolactin
Triggered by serotonin, ACh, opiates, estrogens from hypothalamus
Inhibited by dopamine
Acts on
- breast -> lactation (high levels during neonatal period)
- uterus -> cessation of menses during puerperium
Glycogenolysis
Breakdown glycogen (liver and muscle) to glucose
Glycogenesis
Formation of glycogen (stored form of glucose in liver, muscles)
What forms is vitamin D given as a supplement
Cholecalciferol (vitamin D3) -> goes to liver -> kidney
Calcitriol (1,25 dihydroxy vitamin D) given to kids with CKD as this is the active form (doesn’t require metabolism by kidneys)
What do TSH and gonadotropins have in common?
Contains same alpha subunit as LH and FSH and HCG (differentiated based on beta subunit)
GH release pathway
HPA axis
Effects
Stimulation
Inhibition
Hypothalamus -> release of GHRH -> acts on pituitary to stimulate GH release from anterior pituitary
Pulsitile release, small peaks with big gaps in between during day and larger peaks with smaller gaps between during sleep
- *Effects**
- increase bsl
- incr uptake of aa into muscle -> cell proliferation
- Diabetogenic (more glucose produced in liver -> IGF production -> incr growth and inhibits further GH release from pituitary)
- Growth stimulated via GH binding to receptors -> IGF1 release -> long bone growth
- *Stimulation**
- stress/illness/trauma
- exercise
- hypoglycaemia
- starvation
- adrenaline/NA
- sleep
- protein intake (incr muscle mass)
- sex steroids
- *Inhibition**
- hyperglycaemia
- obesity
Features of hypogonadotrophic hypogonadism
Low testosterone and low FSH, LH, sex steroids
Microphallus, cryptorchidism (undesc testes)
What is the main cause of persistent hypoglycaemia in infancy/neonatal period?
causes (2)
Ix features
Hyperinsulinaemia hypoglycaemia of infancy
2 main genetic causes
- K ATP channel defect
- glucokinase defect
Hypoglycaemia <2.2
Detectable insulin (>14)
Absence of ketones
Inappropriately low FFA
Functions of ADH
What inhibits release
Osmolality maintenance
Insertion of aquaporin 2 into collecting ducts of kidneys to cause water reabsorption and concentration of urine
Release inhibited by NA
hyponatraemia in dka
what causes this and how do you correct for this?
depressed level due to the dilution effect of the hyperglycaemia
Need to ‘corrected sodium’ = measured Na + 0.3 (glucose - 5.5)
Metformin
MOI
SE
Biguanide
Increases insulin sensitivity
SE - GI upset
Weight loss
Where does the pituitary gland sit anatomically?
Inferior to hypothalamus, in the sella turnica below optic chiasm
- > anterior pituitary arises from Rathke’s pouch (dorsal outpouching from roof of oral cavity), signals from hypothalamus via portal vessels
- > posterior pituitary arises from neural ectoderm, signals frmo hypothalamus via neuronal axons
Diabetes Insipidus Ix and tx
how to distinguish between central vs peripheral cause?
Ix
1) Urine osmolality and specific gravity (low) -> lots and lots of very dilute urine as unable to concentrate urine properly
2. High serum osmolality, often w hyperNa
3a) Water deprivation test: DI (urine osmolality will remain low) vs other cause of polydipsia (urine will concentrate)
3b) Desmopression/ADH analogue: if central cause, urine will concentrate/osmolality will increase; if nephrogenic, urine osmolality will stay low/only incr slightly.
Tx
- Neonates: primarily fluid tx due to incr volume requirement
- Treat underlying cause if reversible
- If central cause: desmopressin infusion
- If nephrogenic: thiazides, carbamazepine and cloramphenicol to sensitise tubules
What hormones does the anterior pituitary release and what triggers their release?
- ACTH and MSH
- GH
- LH, FSH
- TSH
- Prolactin
What is the most common cause of permanent congenital hypothyroidism?
Thyroid dysgenesis (includes ectopia, hypoplasia, aplasia)
Sporadic aetiology
Sometimes associated with cardiac and renal anomalies
What is the Wolff Chaikoff effect?
Autoregulatory phenomenon, whereby a large amount of ingested iodine acutely INHIBITS thyroid hormone synthesis within the follicular cells, irrespective of the serum level of thyroid-stimulating hormone (TSH)
Results in
- HIGH TSH
- Low T3, T4
Dyshormonogenesis as cause for congenital hypothyroidism
How common
Technician scan
Causes
- Defects of synthesis of thyroid hormones
- 15% of congenital hypothyroidism (2nd most common cause)
- GOITRE most always present
- incr uptake on technician scan (except is low w/ iodine transport defects)
Caused by defects in:
- most common is thyroid peroxidase ‘organification’ (required to incorperate iodine to tyrosine)
- iodine transport
- thyroglobulin
- Deiodination
Technetium 99 scan
- causes of…
1. absent or reduced thyroid uptake
2. ectopic thyroid tissue
3. increased uptake
- absent/reduced uptake:
- agenesis
- maternal thyroid blocking Ab
- Infants with iodine trapping/iodine transport defects
- maternal lithium use in pregnancy (lithium competes for uptake) - ectopic thyoid tissue (form of dysgenesis)
- Incr uptake
- dyshormogenesis
- excessive iodine exposure
Prolactin
Prolactin triggered by serotonin, ACh, opiates, estrogens from hypothalamus
Inhibited by dopamine
Growth hormone deficiency
causes
presentation
ix
Congenital or acquired causes of low GH
Presents w growth failure and delayed bone age
Ix
- Low IGF-1
- Low IGFBP-3
- Confirmed with GH provocation test
- MRI to exclude central causes (hypothal/pituitary tumours such as craniopharyngioma)
Layers of adrenal cortex and what they secrete
Capsule (outer most) -> ‘G F R’
SALTY 1. Zona Glomerulosa ->
mineralocorticoids (aldosterone - salty)
- regulated by RAAS
SWEET 2. Zona Fasciculata -> glucocorticoids (cortisol - sweet)
- regulated by CRH -> ACTH
SEX 3. Zona Reticularis -> androgens (DHEA, androstenodione - sex)
- regulated by CRH -> ACTH
- Medulla -> catecholamines (adrenaline)
How can the pigmentation in Addison’s disease be explained?
ACTH is cleaved from POMC
MSH (melanocyte stimulating hormone) is also cleaved from POMC
In Addisons you have decr cortisol, but increased levels of ACTH as compensation.
Hyperpigmentation is caused by overproduction of POMC, resulting in incr levels of ACTH and MSH. High levels of circulating ACTH also cross-react with the melanocortin 1 receptor on the surface of dermal melanocytes.
What are genetic syndromes causing shortness?
Turners (45XO)
Achondroplasia (dominant)
Down’s
Prader Willi
Noonan
Russel-Silver
Features of hypogonadotrophic hypogonadism
Low FSH, LH, sex steroids (testosterone etc)
Microphallus, cryptorchidism (undesc testes)
Arm span and upper: lower segment ratios
and impact on assessment of growth
Arm span: height should be 1: 1 at all ages
- > Abnormal in Marfans/Klinefelters/dwarfism
- > Arm span < height = skeletal abnormalities
Upper (crown to pubic symphysis)
Lower (pubic symphysis to ground)
RATIO CHANGES W AGE
- > 1.7:1 as a neonate
- > 1.4:1 4-5 years
- > 1:1 at 10-12 years
- > Proportionate = familial short stature
Functions of ADH
What inhibits release
Osmolality maintenance
Insertion of aquaporin 2 into colleceting ducts of kidneys to cause water reabsorption and concentration of urine
Release inhibited by NA
Short stature:
Definition
Causes
- Most common causes
- Equal reduction in height/HC/weight
- Height more affected
- Weight more affected
- GENDER
- > Most common cause in boys vs girls
- > Most common cause in girls vs boys
Height < 2 SD below the mean OR < 2nd centile
Growth velocity <25th centile
- Most common cause is familial short stature (short parents)
- Constitutional growth delay (delayed bone age and delayed puberty w family history) - common in boys
- Equal reduction in height/HC/weight =
- > TORCH
- > Chromosomal (Turners, Downs, Noonans, Prader-Wili, Bloom, Russel-Silver syndromes)
- > Chronic illness (any form of chronic illness = Coeliac, CF, renal failure etc) - Height more affected =
- > Endocrine (Hypothyroid, GH deficiency, Cushing syndrome)
- > Skeletal dysplasia (achondroplasia, hypochondroplasia) - Weight more affected = malnutrition/psychosocial deprivation (think of tall skinny child with big head)
GENDER
Girls with short stature = turners XO until proven otherwise
Boys with short stature = commonly physiological
Pituitary adenoma
presentation
Secretory and no secretory forms
- Secretory (65-70% tumours) - excess hormone secretion (prolactin, GH, cortisol; tends to be only one hormone depending on cell of origin)
- Non secretory can present w sx due to mass effect (headaches, bitempral hemianopia)
Craniopharyngoma presentation
Where does it arise from? What does it look like on MRI?
Most common supratentorial tumour (5-10% childhood brain tumours; 50% occur under 20yo)
Arises from rathkes pouch
Often large, cystic and CALCIFIED
Presents w
- Mean age 8yo
- Headache
- Bitemporal hemianopia (compression optic chiasm)
- Hydrocephalus (bulging fontanelle, nausea/morning headache w vomiting, sun set eyes, seizures)
- Deficiency in hormone production can lead to endocrine abnormalities
- -> Growth slowing (hypothyroidism, GH deficiency)
- -> Pubertal delay
- -> Diabetes insipidus due to low aldosterone
- -> Addisonian crisis
Central vs nephrogenic diabetes Insipidus
Central: Insufficient ADH production from posterior pituitary gland
Nephrogenic: Renal insensitivity to ADH (less common, more severe)
-> polyuria and polydipsia -> dehydration, weight loss/FTT, collapse (particularly in babies)
Central causes
- Idiopathic
- Tumours (craniopharyngioma, optic glioma, germinoma, LCH)
- infiltrative (LCH, sarcoid, haem malignancy)
- Infective (listeria in newborns; TB meningitis)
- Trauma (surgery, rdiotx, asphyxia, IVH)
OR peripheral/nephrogenic causes
- Resistance to ADH
- Genetic (mutation V2 receptor; defective Aquaporin 2 gene)
- RTA
- HyperCa -> nephrocalcinosis
- Hypokalaemia if severe and prolonged
What thyroid conditions does NST detect?
Detects HIGH TSH (and therefore low T4) = Primary thyroid conditions
Examples
- Thyroid dysgenesis (85% cases)
- Dyshormonogenesis (errors in thyroxine synthesis -15% cases)
- TSH resistance (v rare)
- Iodine deficiency and excess
- Maternal Ab-mediated hypothyroidism (very rare)
Does NOT detect central hypothyridism (as TSH is normal/low)
What is the most common cause of permanent congenital hypothyroidism?
Thyroid dysgenesis (includes ectopia, hypoplasia, aplasia)
Sporadic aetiology
Sometimes associated with cardiac and renal anomalies
Dyshormonogenesis as cause for congenital hypothyroidism
How common
Technician scan
Causes
- Defects of synthesis of thyroid hormones
- 15% of congenital hypothyroidism (2nd most common cause)
- GOITRE most always present
- incr uptake on technician scan (except is low w/ iodine transport defects)
Caused by defects in:
- most common is thyroid peroxidase ‘organification’ (required to incorperate iodine to tyrosine)
- iodine transport
- thyroglobulin
- Deiodination
Main factors driving growth at each of the following phases of life
- Fetal
- Infancy
- Childhood
- Puberty
- Fetal
- placental nutrient supply
- mother’s size - Infancy (first 3 yrs)
- Nutrition (GH independent) - Childhood
- GH-dependent
- Nutrition
- Thyroid hormone
- Vitamin D
- Steroids - Puberty
- Sex hormones and GH
Age range of growth spurts in girls and boys and how does this relate to timing of puberty and menarche
Growth spurts age range
- Girls: 9-15 (peak 11-13); preceded by breast bud development (first sign of puberty in girls)
- Boys: 11-17 (peak 13-15); preceded by testicular enlargement (first sign of puberty in boys)
In girls menarche occurs AFTER the pubertal growth spurt ie menarche onset occurs once they’ve reached their final height
Once patient has reached puberty, they have reached their max height and in girls always precedes menarche
Effect of craniospinal irradiation on growth and mechanism for this
Short stature
-> reduction in spinal growth mediated by reduced levels of GH
Endocrine abnormalities common after radiotx to pituitary hypothalamic axis
-> can get GH, TSH, ACTH, GnRH deficiencies (in that order)
Can also get central precocious puberty as well as ACTH deficiency and GH deficiency
What are genetic syndromes that cause tallness?
Fragile X
Kleinfelters 47XXY
marfans*
homocysteinuria*
ehlos danlos syndrome*
*Also cause primary osteoporosis
What are genetic syndromes causing shortness?
Turners (45XO)
Achondroplasia (dominant)
Normal weight loss/gain after birth
- Weight loss in first few days 5-10% of birth weight
- Return to birth weight 7-10 days of age (or 10-14 d if preterm); ~3.5kg
- Double birth weight by 4-5mo (7kg)
- Triple BW at 1yr (~10kg)
