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)
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
Fragile X syndrome
inheritance/gene
presenting features
X-linked dominant, FMR1 gene mutation
Intellectual disability
Autism
‘Elven appearance’ - long narrow face, large ears, prominent forehead/jaw
Joint laxity
Large testes after puberty
Chronic otitis media
Seizures
Tremor/ataxia (late onset, >50yo)
Short stature definition
Causes
1. Equal reduction in height/HC/weight
- Height more affected
- Weight more affected
GENDER
-> Most common cause in boys vs girls
< 2 SD below the mean IE below 2.3rd centile
Equal reduction in height/HC/weight = TORCH/chromosomal
Height more affected = endocrine/skeletal dysplasia
Weight more affected = malnutrition
GENDER
Girls = turners XO until proven otherwise
Boys = commonly physiological
Physiological causes of short stature
constitutional delay of growth adn puberty
Familial short stature
Carpenter syndrome
DDx for this
Obesity
o ID
o Craniosynostosis almost always present - abnormal head shape
o Brachycephaly, polydactyly, syndactyly of feet
o Cryptorchidism, hypogonadism in males
o Umbilical hernia
ddx - bardot biedel syndrome (also has retinal dystrophy/early night blindness, renal abnormalities, DI or DM etc; doesnt have umbni herni or craniosynostosis)
Endocrine causes of short stature
Things you need to grow: vit D, Ca/Ph, GH/IGF1, Thyroid hormone, steroid/sex hormones
- Cushing’s syndrome
- Hypothyroidism
- Pseudohypoparathyroidism
- Rickets
- IGF1 (GH) deficiency
- Sexual precocity
Precocious puberty i a boy - what age is abnormal and think what until proven otherwise?
Sec sexual characteristics <9yo is abnormal
Brain tumour (hypothalamic hamartoma) until proven otherwise (ix: hCG and alpha-FP); could also be testicular tumour - choriocarcinoma etc Other - CAH, dysgerminomas
Genetics assoc w t1dm
HLADR3/DR4 + DQ2/8
Precocious puberty in a girl - who age and think what?
Sec sex characteristics <8yo or menarche <10yo is abnormal
Unlikely to be pathological
Mostly familial causes
Delayed puberty in a boy - what age and think what?
Failure of puberty onset by 14yo
Unlikely to be pathological
Most common cause is constitutional delay (short child with delayed bone age and family history)
Cause of short stature in renal failure
IGF-1 deficiency
(renal failure distorts the GH/IGF-1 axis leading to high GH and inappropriately normal/slightly low IGF-1
Cause of short stature in Turners
Short Stature Homeobox (SHOX) insufficiency
Features of constitutional delay of growth and puberty
Normal height for bone age but NOT for chronological age
(delayed bone age for chronological age)
Family history of delayed growth and/or puberty
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, ACTH and TSH deficiencies
Can also get central precocious puberty as well as ACTH deficiency and GH deficiency
BSL targets (fasting/random)
Normal
Impaired
Diabetes
Fasting:
Normal < 6
Diabetes > 7
Random or OGTT
Normal < 7.7
Diabetes > 11.1
Target BSLs for children w diabetes
Aim BSL 4-8 before meals
What does HBA1c reflect and what is target for children w diabetes?
What conditions can affect the HBA1c level ?
Reflects BSL control over past 2-3 months
Is a measure of glycated haemoglobin (sugar bound to RBCs)
Aim HBA1C < 7.5
Any condition that reduces RBC lifespan and increases turnover may falsely lower HbA1c. Examples include:
- red cell aplasia
- blood transfusion
- haemorrhage
- renal disease treated with erythropoietin
Bardet-Biedl syndrome
FEatures
Obesity onset age 2
Deafness
Retinitis pigmentosa
Polydactyly
Hypogonadism
Intelectual deficit
Hypotonia
Renal disease
Fragile X syndrome
X-linked dominant, FMR1 gene mutation
Intellectual disability
Autism
‘Elven appearance’ - long narrow face, large ears, prominent forehead/jaw
Joint laxity
Large testes after puberty
Chronic otitis media
Prader WIlli SYndrome
Mutation
loss of function of genes on chromosome 15 Imprinting defect (loss of paternal contribution)
Initial FTT the onset obesity age 2-3 with hyperphagia
Microcephaly
Short stature
Hypotonia
Learning difficulties
High-arched palate
Almond shaped eyes
Narrow hands and feet
Delayed puberty
Beckwith Widemann syndrome
Deregulation of imprinting genes on chromosome 15 (11q15.5) incl IGF2
Features
• Hemihypertrophy
• Organomegaly
• Abdo wall defects: omphalocoele, umbilical hernia
• fetal macrosomia, polyhydramnios
• Hyperinsulinemia -> Hypoglycemia and Intolerance of fasting
• Macroglossia
• Macrocephaly
• Eat pits/creases
• Tumour predisposition (Wilms, hepatoblastoma, neuroblastoma, rhabdomyosarcoma)
• Renal disease
Cohen syndrome
o Obesity onset mid childhood
o ID
o Microcephaly
o Small hands and feet with long, thin fingers and toes
o Prominent central incisors
o FTT in infancy w hypotonia
Alstrom syndrome
o Obesity onset age 2-5
o Blindness, deafness
o Chronic neuropathy
o Acanthosis nigricans
o Normal IQ
o Chronic nephropathy
Auto-antibodies in T1DM
o Anti-insulin antibodies – appears first, disappears w tx
o Anti-glutamid acid decarboxylase (GAD) – most common (70-80% at diagnosis)
o Anti insulinoma protein 2
o Islet cell antibodies
o Anti-zinc transporter
Autoimmune disease assoc w T1DM
Autoimmune thyroid disease
- Anti-TPO, Anti-thyroglobulin
Coeliac disease
- Anti-tTg
- Anti-IgA (endomysial antibodies)
- Anti-gliadin
- Diaminated gliadine peptide (DPG) IgA or IgG
Adrenal disease
- Anti 21-hydroxylase
Synthesis pathway of androgens
Where are they made?
Made in zona Reticularis (inner most layer of Adrenal cortex)
Cholesterol -> Pregnenolone
- > Progesterone or 17-hydroxypregnenolone
- > 17-hydroxyporgesterone
- > Dehydroepiandrosterone (DHEA)
- > Androgen
- > Testosterone
- > DHT (formation of ext male genitalia and prostate) via 5 alpha-reductase
->OR to Estrogen via aromatase)
Synthesis of cortisol
Where is it made?
Made in zona fasciculata in adrenal cortex
Cholesterol -> Pregnenolone
- > 17-hydroxypregnenolone + 17-hydroxyprogesterone
- > 11-deoxycortisol
- > cortisol
Synthesis of aldosterone
Where is it made?
Made in zona glomerulosa (outer most layer of adrenal cortex)
Pregnenolone
- > progesterone
- > 11-deoxycorticosterone
- > aldosterone
What is the diurnal rhythm of glucocorticoids?
Highest at waking in hte morning, low in late afternoon + evening, lowest whilst asleep
What products are made in the adrenal medulla?
Dopamine
NA
Adrenaline
Non classic CAH presentation
Present AFTER the neonatal period with signs of hyperandrogenism and WITHOUT adrenal insufficiency
Premature pubarche
Advanced bone age
Medication resistant cystic acne
Accelerated growth w tall stature
In females - hirsutism, menstrual irregularity, low fertility
DDx - PCOS
What is Conn’s syndrome?
Presentation
Ix
Causes
Tx
Primary aldosteronism
- exessive aldosterone secretion independent of RAAS
Rare in children but 5-10% of HTN in adults
Presentation
- HTN w headache, dizziness, visual disturbance
- Proximal muscle weakness (due to hypoK)
- Polyuria
- *Ix**
- High serum Na
- Low serum K
- Metabolic alkalosis
- High plasma aldosterone:renin ratio
- Reduced urine Na:K ratio
- High 24 hr urine aldosterone
- Decr renin activity
- *Causes**
- Idiopathic adrenal hyperplasia 66%
- Adrenal adenoma of zone glomerulosa secreting aldosterone 33%
- Adrenal carcinoma secreting aldosterone
- Familial Hyperaldosteronism
- *Tx**
- Pred (suppresses aldosterone release)
- Spironolactone (aldosterone antagonist, incr K and lowers BP)
- Surgery
Phaeochromocytoma
- what is it
- sx
- ix
- tx
- What genes/syndromes are associated with this tumour?
Catecholamine secreting tumour arising from chromaffin cells in adrenal medulla or along sympathetic chain
-> Secretes NA > adrenaline, dopamine
Sx are INTERMITTENT: headache, sweating, tremor, tachycardia, HTN, postural hypotension ,anxiety/panick attacks, abdo pain, dizziness, cachexia
Ix
- 24 hr urinary catecholamines (VMA and metanephrins)
- Serum catecholaemines
- MIBG (special chromatin tissue isotope scan)
- Imaging (ct/MRI, MIBG/PET)
- Genetics (NF1, MEN2, VHL or von Hippel-Lindau)
Tx
- Surgical excision
- BP control
- Tachycardia control (alpha blocker followed by beta blocker)
Gluconeogenesis
Production of glucose from breakdown of non-CHO substrates (lipids, protein)
Glycogenolysis
breakdown of glycogen to glucose (glycogen in liver broken down into glucose)
Glycogenesis
formation of glycogen (glucose taken up into liver and stored here)
Glucagon role
Increases blood glucose via:
- glycogenolysis (main action)
- gluconeogenesis
- lipolysis (minor)
Insulin effect
Decr blood glucose (aa and FFAs)
via incr glucose uptake into muslce, adipose tissue
-> lipogenesis, protein production, glycogen synthesis
Incr glucose uptake into liver -> glycogen synthesis
What cells produce glucagon
Alpha cells in pancreas
What cells produce insulin
Beta cells in pancreas
What is the role of somatostatin and where is it produced
Inhibits GH, insulin and glucagon secretion
Produced by hypothalamus and gamma cells in pancreas in response to hyperglycaemia, hypothyroidism
What organ doesn’t require insulin for glucose uptake and what channel does it involve
Brain
Glucose taken up by GLUT1 transporters, insulin independent
Screening for diabetic microvascular complications
Retinopathy
- dilated eye exam
Neuropathy (peripheral and autonomic)
- vibration
- monofilament for pressure sensation
- proprioception
Nephropathy
- Albumin: creatinine ratio (first sign in albuminuria)
Thyroid
- Serology at diagnosis
- TFTs
Celiac disease
- serology at diagnosis then annually
Hypoglycaemia in DM
Definition - BSL <4
Causes
Missed meal/snack
Exercise
alchohol
Too much insulin
Mx - treat regardless of sx
- 5-10g of quick acting carb
- -> or if decr GCS, seizure or unable to tolerate oral intake, give glucagon or IV 10% dextrose - WAIT 15 MIN -> repeat BSL
- if <4, repeat step 1. of >5, give 10-15g of long-acting carb
Ketosis
Causes
When to test for ketones?
When to treat?
Treat if ketones >1 (in serum OR urine)
Causes
- Missing insulin
- Illness
Check if
- BSL >15
- Diabetic child unwell
Treat with extra insulin
Sick day management principles for children w T1DM
Treat underlying illness
- note bacterial and viral illnesses can cause high BSLs, use sugar-free fluids for hydration
- illnesses with vomiting, diarrhoea and decr appetite can cause low BSLs -> use fluids containing sugar
Facilitate regular oral intake
Monitor BSLs every 2-4 hrs
Check ketones if BSL >15
Do NOT omit insulin, may have to reduce dose
Give extra insulin if BSL >15 + ketones (short acting only, 5-20% more)
Complications of DKA
- Acute cerebral oedema
- Cardiac arryhmias due to K imbalance
- Mucormycosis (fungal infection that starts in sinuses but can spread to brain)
Potassium changes in DKA and how does this change with treatment
- Often elevated to begin with in serum (BUT total body deficit)
- Correction of acidosis results in hypokalaemia (K+ moves into cells)
- Therefore generally K replacement therapy required
What is the corrected sodium and how do you calculate this?
Measured serum sodium is depressed by the dilutional effect of the hyperglycaemia (water moves with glucose)
-> So the actual/corrected Na will be HIGHER
Corrected (i.e. actual) Na = measured Na + 0.3 (glucose - 5.5) mmol/l
What clinical feature is a marker of insulin resistance?
- Acanthosis nigricans – marker of insulin resistance found in 50-90% of youth with T1DM
- skin tags
- alopecia
- amenorrhoea
- hirsutism
- infertility in women
MAnagement of T2DM
Aim HBA1C <6.5%
Lifestyle
- Diet, low GI foods
- Exercise 60min/day
- Screen time <2hrs/day
Medication
- Metformin is treatment of choice both in BSL mgmt and aids in weight loss
- Insulin if HBA1c >9%, BSLs >15 or ketosis
Screen for/manage complications
Hyperosmolar non-ketotic acidosis
Development of severe hyperglycaemia WITHOUT ketosis, usually in setting of T2DM
Triggered by sepsis most often
Clinical presentation
- polyuria, polydipsia
- extreme dehydration
- shock
- hypercoagulable state
Tx
- Fluid resus
- Treat underlying causes
- Similar to DKA except use less insulin
Risk factors for CF related DM
Due to pancreatic insufficiency - deficient insulin
RF
a. Increasing age
b. Pancreatic insufficient
c. Delta F508 homozygous
d. Female
Development of gonads - differentiation (males vs females)
All embryos start with bipotential gonads
- > Mullerian (ultimately become female organs)
- > Wolffian ducts (become male organs)
Testicular development requires Y chromosome (sex determining region ‘SRY’)
Differentiation between sexes begins at 6 WEEKS of gestation following secretion of hormones by fetal testes (ovary is silent)
- Anti-mullerian hormone (AMH) from Sertoli cells -> regression of mullerian structures
- Testosterone from Leydig cells -> formation of Wolffian duct structures
- Dihydrotestosterone -> development of prostate and external genitalia
Female ovarian development occurs around week 10, requires ABSENCE of SRY, testosterone and AMH.
- Mullerian duct becomes uterus, uterine tubes
- Wolffian duct degenerates
Absent or partial puberty with anosmia and cleft palate in MALE
Diagnosis
Inheritance
Cause
Other features of the condition
Kallman syndrome
- Cause of ISOLATED hypogonatropic hypogonadism (due to GnRH deficiency)
85% AD, 15% X linked
Genetic mutation in KAL1 (now called ANOS1) or KAL2 gene that leads to failure of olfactory and GnRH expressing neurons to migrate from their common origin to the brain
- > males: gynaecomastia, not much facial/chest hair, small gonads/penis
- > females: delay in breast and pubic hair development and no menstruation
Other features:
- Short stature
- Colour blindness
- Ichthyosis (dry thick scaly skin)
- Renal abnormalities (agenesis)
Features of Klinefelter syndrome
- specifically what cardiac defect is associated?
47 XXY - most common sex chromosome disorder (1/500)
Features
o Primary hypogonadism – small, firm testes, decreased virilisation, small phallus, hypospadias, cryptorchidism , gynaecomastia
o Growth – tall, legs > trunk
o Cognitive – normal intelligence, learning disability, autism, social problems
o Cardiac – 55% mitral valve prolapse
o Oncology – increased frequency of extragonadal germ cell tumour, breast cancer
Investigation of suspected hypogonadism
in MALES
- Test morning total testosterone levels
2a. if T normal/high, measure LH
- > if LH high, consider androgen insensitivity
- > if LH low, excludes hypogonadism
2b. if T low, repeat. if low again, measure LH/FSH
- > if LH high= primary hypergonadotrophic hypogonadism -> karyotype (could be turner or kleinfelters)
- > if LH, FSH low = hypogonadotropic hypogonadism
Causes of primary or ‘peripheral’ hypogonadism (or hypergonadotropic hypogonadism due to elevated FSH, LH with low testosterone)
in MALES
Congenital
- Klinfelter syndrome
- Noonan syndrome
- Cystic fibrosis
- Mutations in steroid synthesis pathway
- FSH, LH resistance
Acquired
- Chemo
- Radiation
- Infarction (testic torsion)
- Infection (mumps)
- Trauma
Primary vs secondary hypogonadism in MALES
Both have decr total testosterone levels measured at 8am
Primary (eg anorchia) - hypergonadotropic hypogonadism (defect at the gonads)
- elevated FSH, LH (from pituitary)
- low AMH (indicates no functional sertoli cells/anorchia) and low inhibin B (released from leydid cells) useful in first 2 yrs of life to determine whether there is functional testicular tissue presence (?anorchia)
- Small or no rise in testost w hCG stimulation test
Secondary/central - hypogonadotropic hypogonadism (defect at the anterior pituitary or hypothalamus)
- low FSH, LH
Causes of hypogonadotroic hypogonadism (Secondary) in MALES
Congenital
- Kallman syndrome
- Prada Willi synd
- Bardet-Biedl synd
- Alstrom synd
- Isolated HH at pituitary
- idiopathic
Acquired
- Anorexia
- Drug use
- Malnutrition
- Chronic illness (crohns)
- Hyperprolactinaemia
- Pituitary tumours
- Pituitary infarction
- Infiltrative disorders
- Haemochromatosis, haemosiderosis
- Radiation
Primary hypergonadotropc hYpergonadism in women
Definition
Sx
Causes
Ovarian failure (loss of oocytes, folliculogenesis and ovarian estrogen production, infertility) accompanied by high FSH before age 40
Hard to diagnose before puberty except in cases of turner’s syndrome (most common cause)
Sx include
- irreg menses
- infertility
- hot flushes, dry vagina, bone loss, osteoporosis
Causes
- Genetic (turners, FSH/LH resistance, steroid synthesis pathway mutations, noonan, galactosaemia, fragile X, bloom, fanconi, ataxia telangiectasia)
- Acquired (chemo, radiation, cmv/mumps)
Tx - puberty induction with transdermal estradot (oestrogen/progestone supplementation)
Galactosaemia - what is this caused by and what endocrine effect does it have?
- Inherited inborn error of metabolism affecting galactose pathway
- Most commonly due to deficiency in galactose1-phosphate uridyl transferase (GALT)
- Results in progressive ovarian fibrosis; testis spared (=> primary hypergonadotropic hypogonadism)
Definition of micropenis
Length <2.5cm
Width <0.9cm
Turners Syndrome
45XO (sporadic inheritance)
Symptoms can include …
- short stature
- recurrent otitis media
- pubertal delay/virilisation
- a wide, webbed neck
- a low or indistinct hairline in the back of the head
- swelling (lymphedema) of the hands and feet
- broad chest and widely spaced nipples
- shortened 5th metacarpal
- arms that turn out slightly at the elbow
- congenital heart defects or heart murmur
- scoliosis (curving of the spine) or other skeletal abnormalities
- kidney problems
- an underactive thyroid gland
a slightly increased risk to develop diabetes, especially if older or overweight
osteoporosis due to a lack of estrogen, (usually prevented by hormone replacement therapy)
define virilisation
the development of male physical characteristics (such as muscle bulk, body hair, and deep voice) in a female or precociously in a boy, typically as a result of excess androgen production.
Benign premature adrenarche
- Typically refers to appearance of sexual hair <8 years (girls) or <9 years (boys) – WITHOUT other evidence of maturation
- Mild form of hyperandrogenism that is a variant of normal
- Slowly progressive incomplete form of premature puberty
- Diagnosis requires biochemical demonstration of serum steroid pattern (hormones within normal range, andrenal angrogens ie DHEAS ULN/high)
- More common in girls than boys
- normal bone age
thelarche - what is this, what does it indicate and when does it typically occur?
onset of breast development (first sign of puberty onset in girls, generally 8-13yo)
Idiopathic premature thelarche
- Isolated breast development (sporadic, transient) most often appears in the first 2-3 years of life
- BENIGN condition, but may be the first sign of true or peripheral precocious puberty, or it may be caused by exogenous exposure to estrogens
- Normal growth/bone age
- Normal menarche and bone age
- Normal genitalia
- Normal ix (serum hormone concentrations, bone age, ultrasound)
How do you calculate BMI
BMI = (weightkg)/(heightcm)^2
What hormone is responsible for secondary sexual characteristics?
DHEA
Management of hypercalcaemia
What is the threshold for treatment?
Treat if > 3.5 (severe)
- Increase urinary excretion
- > Rehydration with N saline + 5% glucose (incr filtration)
- > Loop diuretics (inhibit Ca reabsorption) - Increase GI excretion with glucocorticoids
- Prevent bone resorption by inhibiting osteoclasts
- > Bisphosphonates (longer-term effects)
- > Calcitonin (acute effect)
- > Oral phosphates bind w Ca
Mcunin Albright syndrome
Triad of
Causes of tall stature
Idiopathic
- Familial (normal GV and bone age) = most common cause
- Precocious puberty (start out tall, end up short)
- Obesity
Endocrine
- Hyperthyroid
- Pituitary gigantism (GH excess)
- CAH (similar to precocious puberty - start out taller, end up short)
Syndromes
- Marfan syndrome
- Kleinfelter (XXY; low IQ)
- Triple X (low IQ)
- XYY (low IQ)
- Homocystinuria (low IQ)
Large babies/infants
- Gestational diabetes
- Beckwith Wiedemann
- Cerebral gigantism of sotos (Sotos Syndrome)
Features of Marfan Syndrome
- Arachnodactyly (long thin fingers)
- Increased arm span compared to height
- Ligament laxity
chest deformity (pacts excavatum, scoliosis) - Cardiac AR/dissection
- UPwards Subluxation lens
- High arched palate
- Osteoporosis
Definition of tall stature
What is normal growth velocity
Tall stature > 97.7th centile or velocity > 75th centile
Growth velocity
- Sensitive marker of normal vs abnormal growth progression (gold standard)
- Calculation: height difference in cm (2 measurements at least 4 months apart divided by time difference in years between the 2 measurements (eg 0.3yrs)
- Normal growth velocity:
- Crossing <2 centiles in height
- Or between 25-75th velocity centiles
- 2-6 years: ~9cm/year
- 6 years - puberty: ~6cm/year
Precocious puberty:
How does bone age compare with chronological age?
Central vs peripheral
Causes
Mx
Bone age > chronological age
= Advanced bone age (from oestrodiol)
Causes
- CENTRAL (driven by HPA axis with elevated LH and FSH)
- -> Familial (more commonly in girls)
- -> Hypothyroid
- -> Brain tumours (hypothalamic haemartomas the most common)
- -> Acquired (post sepsis, surgery, DXT, radiation)
–> Treatment with GnRH agonist ‘Lucrin/Leuprolide’ (suppresses LH, FSH release) aims to maximise max adult height (biggest benefit when started <6yo)
- PERIPHERAL (not central/HPA axis driven; low FSH and LH; driven by elevated oestrogen or testosterone or adrenal androgens)
- -> Andrenal: CAH (virilising), adrenal tumour (feminising)
- -> Gonadal: ovarian or testicular tumour (oestrogen of HCG producing)
- -> McCune-Albright syndrome (coast of maine lesion, bony fibrous dysplasia)
- -> Hypothyroid
Tx: Removal of any cysts/tumours excreting hormones; Tamoxifen (partial estrogen receptor antagonist) or Ketaconazole in boys (androgen antagnoist)
Indications for treatment with growth hormone
CI
GH deficiency
Intracranial lesion or cranial irradiation - at 12 months in remission
Turner syndrome
Prader-Willi infants <2years old (improves body composition)
Chronic renal disease
Short and slow growth (<1st centile)
CI
- Diabetes mellitus
- Risk of malignancy (downs syndrome, bloom syndrome)
- Active malignancy
What is the absorbance of Ca in the gut and what factor improves this?
20-30% absorbed via GIT
Vitamin D improves absorption
Phosphate - roles
Makes up CaPh in bone matrix
Buffer for H+
Component of DNA, RNA, aa etc
Reabsorbed in PCT
Na/Ph cotrasnporter
Regulated by PTH (increases excretion)
Ca:
Where is it reabsorbed
What is it regulated by?
Roles
- Ca-phosphate bone matrix (99%)
- muscle contraction
- enzyme activity
- blood coagulation
- releasing NT
Reabsorption
- Ca reabsorbed mostly in PCT, along with Na
- Thick ascending limb via paracellular pathway
- Intestine
Regulation
- PTH -> incr reabsorption in gut and kidneys, incr Ca bone resorption, incr vit D synthesis in kidneys
- Vit D -> incr calcium reabsorption in gut
- Calcitonin -> inhibits Ca reabsorption
Magnesium
Roles
Sites of reabsorption
Roles
- Strengthens bone matrix
- Cofactor for glucose and fat breakdown, antioxidant production, enzymes/proteins, DNA/RNA synthesis, regulation of cholesterol production
Reabsorption
30% reabsorbed in PCT
60% reabsorbed in TAL via paracellular pathway
What things can falsely elevated Ca levels?
Low pH (acidosis) Albumin
These things free Ca from being bound to protein (ie increase free ionised calcium levels which are measured)
Causes of TRUE hypercalcaemia
HIGH PTH, high Ca, low Ph: Primary hyperparathyroidism (hypoplasia or adenoma; men 1 and II)
Ectopic PTH from tumour
Low PTH, high Ca, high Ph:
Malignancy (leuk/lymph, solid tumours w mets, renal tumours, adenomas) -> releases parathyroid hormone which stimulates osteoclasts to release Ca into blood -> lytic bone lesions
Excess vitamin D -> excess Ca absorption in GIT
Medications
- thiazide diuretics: incr Ca reabsorption in distal tubule
Genetic
- Familial hypocalciuric hypercalcaemia (PTH inappropriately normal, AD, asymptomatic)
- Williams syndrome (sensitive to vitamin D)
In neonates
- fat necrosis (w birth trauma)
- Transient neonatal hyperparathyroidism (mo who are hypoparathyroid)
- Neonatal hyperparathyroidism 13q13 (inactivation of PTH receptor so hard to detect Ca levels)
Hypercaemia
- clinical signs/sx
‘Stones (renal), bones (pain), abdominal moans (peptic ulcers) and psychiatric groans (confusion, delirium, seizures)
Slows neuronal transmission:
- Sluggish reflexes
- Constipation
- Generalised muscle weakness
- Confusion, hallucination
- Seizures
Cardiac: Tachycardia, HTN, AV block, shortening of QTc, cardiac arrest
Causes hypercalciuria -> loss of fluid -> dehydration -> Ca oxalate kidney STONES
Can also cause nephrogenic DI from nephrocalcinosis
Bones: chonedrocalcinosis, subperiosteal bone erosions
Causes of true hypocalcaemia
Low PTH (hypoparathyroidism)
- -> autoimmune destruction of parathyroid gland
- -> surgical removal of parathyroid gland
- ->- DiGeorge Syndrome (hypoplastic/absent parathyroid gland)
- -> Mg deficiency (required for PTH production)
- High PTH
- -> Pseudohypoparathyroidism
- -> Rickets: Low vitamin D levels (required for GIT reabsorption), excessive urinary Ca excretion
- Kidney failure - poor reabsorption so Ca is excreted in urine
- Excess Phosphate intake (binds to Ca, precipitates in urine)
- Tissue injury (burns, rabdo, TLS)
- Acute pancreatitis (FFA bind to Ca, causing precipitation in urine)
- Too many blood transfusions (chelation of blood products binds to Ca, compound is inactive)
In neonate
- prematurity
- growth restricted
- infant of diabetic mother
- mo who is vitamin D and/or Mg deficient
- Mo who is hyperparathyroid
- Transient PTH resistance
- Transient hypoparathyroidism
- Primary hypoparathyroidism
Clinical effects of Hypocalcaemia
- Tetany
- Trousseau’s sign [tetanic spasm of hands and wrist from inflated BP cuff for 3-5mins >15mmHg above SBP; sensitive and specific (1% false positive)]
- Chovstek’s sign (facial spasm from tapping facial nerve in front of ear)
- Muscle cramps
- Parasthesias
- Abdo pain
- Periorbital tingling
- Seizures
- CV: prolonger QT, arrhythmia (torsades de pointes)
Tx hypocalcaemia
- Treat underlying cause
- Vitamin D +/- Mg supplementation
- Consider Ca supplementation
- Oral Ca carbonate or Ca gluconate if mild-moderate
- IV only if severe/sympomatic
- > IV ca gluconate or ca chloride
- > require telemetry to monitor for arrhythmias
Pseudohypoparathyroidism
Cause
Ix
Phenotype
Vs pseudopseudohypoparathyroidism
PTH resistance due to genetic defect in hormone receptor adenylate cyclase system
Is a cause of low Ca with elevated PTH and Phosphate, elevated ALP
Several types
1A- Albrights hereditary osteodystrophy (most common)
1B
1C
2
Phenotype:
- obesity, short stature, stocky with round face
- shortening of 4/5th metacarpals
- subcutaneous Ca deposits
- skeletal deformities (bowed legs, short wide phalanges)
- tetany, stridor, convulsions
- IUGR
- dev delay and ID
VS pseudopseudohypoparathuroidism
- same phenotype but NORMAL BIOCHEMICAL PARAMETERS (Ca, Ph, ALP, PTH)
Albrights hereditary osteodystrophy
What is its other name?
Genetics, causes
Ix
Assoc
Pseudohypoparathyroidism type 1A
- Most common type of pseudohypoparathyroidism
Genetics
- Autosomal dominant
- Gene mutation of GNAS1, usually sporadic, imprinting condition
Cause
- Results in PTH resistance in renal tubules
- > Ca excretion -> hypocalcaemia, high Ph
Assoc
- Also get resistance to other hormones (TSH -> hypothyroid w goitre; LH/FSH -> menstrual irregularity, reduced fertility, cryptorchidism; GnRH -> GH deficiency)
Causes of Rickets
Calcipenic: ca absorption < Ca demand
- Vitamin D deficiency (most commonly) or hereditary resistance
- Calcium deficiency (in setting of normal vit D)
Phosphopaenic: almost always caused by renal ph wasting
- Presentation: short with PROFOUND skeletal bowing
1. Genetic familial hypohosphataemic rickets (x-linked dominant) - defective prox tubular reabsorption of Ph with reduced 1,25OHD3 synthesis
2. Inadequate intake (prep, antacids)
3. Renal losses - fanconi
- distal RTA
- dent disease (similar to fanconi)
Renal fanconi
Waste Phosphate in urine -> rickets
Glycosuria
Aminoaciduria
Tubular proteinuria
Proximal RTA
Waste bicarb in urine -> acidaemia
Hypokalaemia (due to secondary hyperaldosteronism)
Causes of undervirilised 46XY (male)
- Disorders of testicular development
- Gonadal agenesis/dysgenesis
- Denys-drash syndrome (WT1 mutation)
- WAGR syndrome
- SRY gene mutation - Deficiency of testicular hormones
- CAH
- -> 3 beta hydroxysteroid dehydrogenase deficiency
- -> - 17 hydroxylase deficiency
- LH receptor mutation
- Persistent mullerian duct system - Defect in androgen action
- 5 alpha reductase mutations (normally converts testosterone to dihydrotestosterone so get DHT deficiency with excess estrogen)
- Androgen R defects (androgen insensitivity)
Causes of overvirilised 46XX (female)
- Androgen excess
- CAH
- -> 21-hydroxylase deficiency *most common cause*
- -> 11beta hydroxylase deficiency)
- Aromatase deficiency (can’t convert testosterone to oestrogen)
- GC receptor gene mutation
- Virilising ovarian or adrenal tumour
- Androgenic drugs (progesterone, danazol) - Disorders of ovarian development (hermaphroditism)
- Ovotesticular DSD (born with both ovaries and testes)
- Testicular DSD (SRY region usually on Y chromosome translocated to X chromosome resulting in male phenotype w male internal and external genitalia in a 45XX individual)
5 alpha reductase deficiency
what is it
inheritance
presentation
Cause of undervirilised XY
Dihydrotestosterone deficiency, elevated testosterone which is converted to estrogen instead of dihydrotestosterone
Have elevated testosterone and low DHT
autosomal recessive
Presentation: 46XY, bilateral testes (and internal male urogenital tract leading into blind-ending vagina)
Female external genitalia (may have clitoromegaly)
What is ovotesticular DSD
‘true hermaphroditism’
presence of both functional ovary and testis
What is testicular DSD, what causes it?
Presentation features
XX genotype
SRY region usually on Y chromosome translocated to X chromosome resulting in male phenotype w male internal and external genitalia in a 45XX individual
Features
- male external genitalia ranging from normal to ambiguous
- two testicles
- azoospermia
- absence of müllerian structures
- Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia.
- Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia.
Gender role and gender identity are reported as male.
If untreated, males with 46,XX testicular DSD experience the consequences of testosterone deficiency
Alopecia areata
- what is it
- pathophys
- associations
- An autoimmune condition characterised by a rapid and complete loss of hair in round or oval patches on the scalp and on other body sites
- Autoimmune lymphocytes react against hair follicles, all patients have autoantibodies to hair follicle antigens
- Assoc w other autoimmune conditions, atopy, nail changes, cataracts
what is a barr body?
Inactive (‘silenced’) x chromosome in a cell with more than 1 x chromosome (XX, YXX, XXX)
Inactivation occurs early in embryonic life
Idiopathic Precocious puberty
What is it characterised by?
Premature but otherwise normal appearing pubertal development in GIRLS (is as a rule almost always pathological in boys)
Girls develop breasts and have an early growth spurt (before age 8) with advanced bone age compared with chronologic age
These children have pubertal levels of FSH, LH and sex hormones.
Presentation of GH deficiency in neonates
FTT
Hypoglycaemia
Sparse hair
Prominent forehead
Delayed bone age
Micropenis
Small facies w hypo plastic nasal bridge
Delayed eruption of dentition
What is sick euthyroid syndrome
What changes occur to TSH, T3, T4
Tx
Disturbance of thyroid function in the settling of non-thyroidal illness (usually severe illness). Can also occur in fasting, chronic malnutrition and with some drugs.
Often presents with LOW T3 secondary to inhibition of thyroxine 5’ deiodinase +/- low or high T4
Low or high TSH
Tx- treat underlying illness. No indication for Thyroxine replacement.
APECED
Autoimmune polyendocrinopathy
AIRE gene
AR disorder
Type 1 presents 1st decade of life
- First presents with chronic mucocutaneous candidiasis before progressing to
- hypoparathyroidism
- Addison’s disease
Type 2 presents 2nd-3rd decade of life
- Addisons disease
- Thyroid disease
- Diabetes (T1DM)
osteogenesis imperfecta
- ‘brittle bone disease’
- 90% AD genetic disorder - lack of type 1 collagen due to mutations in COL1a1 or col1a2 genes
- 10% rare AR mutations
- Results in bones that break easily
- Sx: brittle bones, short stature, blue sclerae, loose joints, hearing loss, aortic dissection
-Tx: lifestyle changes, PT, braces, metal rods through long bones
? bisphophonates
Mechanism of action of thiazolidinediones
Bind avidly to peroxisome proliferator-activated receptor gamma in adipocytes to promote adipogenesis and fatty acid uptake (in peripheral but not visceral fat)
Increases insulin sensitivity (decr resistance)
Fanconi syndrome
What is it
What serum changes does it cause
What causes this
RTA type 2 (impaired proximal tubular function)
Bicarb wasting in urine -> serum acidosis
Also waste: Ph, glucose, uric acid and aa in urine
-> low serum levels of these compounds
Leads to rickets (phosphopenic)
Causes
- cystinosis
- wilson’s disease
- hereditary fructose intolerance
McCune-Albright syndrome (‘MAS’)
Classic triad
Pathophys/cause
Triad of
- precocious puberty
- patchy hyperpigmentaion (~irregularly outlined cafe au lait with ‘coast-of Maine’ border)
- fibrous dysplasia of bone
Other
- arrhythmias
- hepatitis
- intestinal polyps
Pathophys/cause:
Patients with ‘MAS’ have a somatic mutation of the alpha subunit of the G3 protein that activates adenylate cyclase (cAMP). This mutation leads to continued stimulation of hormone RECEPTORS
Ie have low levels of the actual hormones (ACTH, TSH, FSH, LH) but overstimulation of receptors leading to:
- > Precocious puberty
- > Gigantism
- > Cushing syndrome
- > Adrenal hyperplasia
- > Thyrotoxicosis
Presentation of glycogen storage disease in neonate
- Profound neonatal hypoglycaemia, although more often presents at three-four months of age when feeding becomes less frequent.
- Hepatomegaly is often massive
- Ketosis is usually present
- glucose requirement to maintain normoglycaemia is NOT usually elevated in these infants, with normal requirement being 4-6 mg/kg/min of glucose.
Hyperinsulinaemia
- causes
- presentation
- suspected when neonates with hypoglycaemia have an elevated glucose requirement to maintain normoglycaemia, with a requirement >8mg/kg/min being one of the diagnostic criteria
- large for GA
- mild hepatomegaly
Causes
- maternal GDM
- inherited (1/50000) - arabic, jewish descent are high risk
Fatty acid oxidation disorder
- presentation
- symptomatic hypoglycameia after prolonged period of fasting, typically presenting in infants or toddlers.
- Once glycogen is consumed, these children have an impaired ability to break down fatty acids to form ketone bodies, but no increased glucose requirement for correction.
Diazoxide
- Use
- MOA
- Mgmt of neonatal hyperinsulinaemic hypoglycaemia
- Acts to inhibit insulin release
by opening ATP-dependent potassium channels on pancreatic beta cells in the presence of ATP and Mg2+, resulting in hyperpolarization of the cell
Phases of puberty (in order) for female
- Breast development (thelarche) is usually the first sign of puberty (10–11 years)
- Appearance of pubic hair (adrenarche) 6–12 months later
- Peak height velocity occurs early (at breast stage II–III, typically between 11 and 12 years of age) in girls and always precedes menarche
The interval to menarche is usually 2–2.5 years but may be as long as 6 years
The mean age of menarche is about 12.75 years
Phases of puberty (in order) for male
- Growth of the testes (>3 mL in volume or 2.5 cm in longest diameter) and thinning of the scrotum are the first signs of puberty
- Followed by pigmentation of the scrotum and growth of the penis
- Pubic hair then appears, axillary hair usually occurs in midpuberty
- Acceleration of growth maximal at genital stage IV–V (typically between 13 and 14 yr of age
Androgen insensitivity syndrome
- 46XY with testes present
- Normal to elevated testosterone levels
- HIGH LH/FSH
- X-linked inheritance
Phenotype varies:
- Complete androgen insensitivity syndrome (CAIS)
- Typical female external genitalia - Partial androgen insensitivity syndrome (PAIS)
- Predominantly female, predominantly male, or ambiguous external genitalia - Mild androgen insensitivity syndrome (MAIS)
- Typical male external genitalia bur infertility
Williams syndrome
Features
Elfin facies
Supravalvular aortic stenosis
HTN
intellectual disability
Cocktail party manner
Hypercalcaemia and hypercalciuria thought to be due to elevated vitamin D or incr vit D sensitivity
May get nephrocalcinosis
What medication used to treat hypothyroid has SE of liver failure (and thus is not often used in children)?
PTU
Russel Silver Sydrome
Methylation defect chromosome 11
Overexpression of maternal genes
Dx - clinical +/- genetics
Prominent forehead
Triangular face
Downturned corners of mouth
Short stature/IUGR: Small with relatively large head compared w rest of body
Hemihypertrophy
Hypoglycaemia
Hypotonia
Mild dev delay
Tx - may respond to GH treatment
Pneumonic
S - small for GA
I - imprinting defect
L - triangLe shaped face
F - feeding difficulties
E - unEven (hemigypertrophy)
R - relatively large forehead
AMH deficiency in males
XY karyotype with normal male external genitalia
Perseverance of female ovarian organs as Anti-mullerian hormone (secreted by sertoli cells) -> regression of mullerian structures
In other words…
External virilization is complete but, due to AMH deficiency, müllerian ducts do not regress and coexist with testes and male excretory ducts.
What is the main stimulus for secretion of PTH
Ionised calcium level
Kleinfelter syndrome
XXY (can have XXXY)
Non disjunction of sex chromosomes in male or female foetus
Clinical features
- Tall stature
- Normal or low intelligence/learning difficulties
- Cardiac: mitral valve prolapse
- Incr risk of extragonadal germ cell tumours
- gynaecomastia
- primary hypogonadism so testicular origin (small testes/penis from puberty on, reduced virilisation)
Mx - consider testosterone replacement when LH and FSH start to rise in puberty
aromatase inhibitors to treat gynaecomastia
11 beta hydroxylase deficiency
Type of CAH (rare)
Also have decr cortisol and aldosterone
Hypertension due to build up of DOC (precursor of aldosterone, more mild form of it)
Also get hyperkalaemia
Hypoglycaemia
What is the most common cause of neonatal hyperthyroid disease?
How do these babies present
What is tx
Neonatal graves disease
- Are classically premature, born to mothers who have hx of graves disease, on anti-thyroid medications
- Due to transfer of maternal TRAb Ab across placental membrane (maternal hx graves disease) - targets TSH R (T2 HS reaction)
Presentation
- IUGR
- Goitre
- Exopthalmous
- Microcephaly
- Irritable, hyperalert
- Tachycardia, tachypnoea
- Hyperthermia/fever
- Jaundice
- HTN
- Progression to cardiac decompensation
Ix: Incr T3, T4; Decr TSH; anti-TRab antibodies
Tx
- Beta blocker
- Carbimazole or PTU
- Iodide
+/- steroids (blocks conversion of T4 to T3)
Albrights osteodystrophy
- Pseudohypoparathyroidism type 1a (PHP1a)
- Short stature
- Obesity
- Round face
- Subcutaneous ossifications (formation of bone under the skin)
- Short fingers and toes (brachydactyly) - particularly the 4th and 5th MC
What is pseudohypoparathyroidism
resistance to PTH
high levels of PTH and Ph
Low levels serum Ca and vitamin D (calcitriol)
Hypothalamic-pituitary axis: hormones secreted
Hypothalmus -> anterior pituitary -> target tissue
- GnRH -> Lh + FSH -> ovaries, testes
- GHRH -> GH -> many tissues
- Dopamine -> breasts, gonads inhibits prolactin
- TRH -> TSH -> thyroid T3, T4
- CRF -> ACTH -> adrenals cortisol
Hypothalmus -> post pituitary
- Vasopressin -> ADH -> kidneys (collecting duct)
- Oxytocin -> Oxytocin -> breasts
*Note to remember hormones released from ant pituitary: FLAT PiG
FSH
LH
ACTH
TSH
Prolactin
GH
Which tumour type is known to cause gigantism?
Pituitary MICROadenoma (ie very small, most skull X-rays are normal)
- > very rare
- > excessive GH secretion
Presentation
- > if before growth plate closure (12 girls/14 boys) -> gigantism/tall stature
- > if after growth plate closure -> acromegaly (hands, feet, face)
- deficiencies in other pituitary hormones leads to:
- > hypogonadism and delayed puberty
- > hyperprolactinaemia
- > Diabetes mellitus (GH is diabetogenic, leads to glucose production in liver)
What analogue can be used to suppress GH secretion?
Octreotide (synthetic somatostatin analogue)
Teenage girl presents with headache, nausea and vomiting and galatorrhorea. Also has not yet had her period.
What is the diagnosis?
Prolactinoma
- > most common pituitary tumour occurring in adolescnece
- > Presents in teenage girls with headache, bitemporal hemianopia, nausea, vomiting, galactorrhoea, amenorrhoea, hypogonadism, delayed puberty and hypopituitarism
Ix: prolactin level > 2000 (extremely high)
Also test for other pituitary hormones
Mx:
- Medical :
- > Bromocriptine and Cabergoline: DA agonist -> can reduce tumor size by inhibiting the synthesis and secretion of prolactin, and inhibiting angiogenesis in the surrounding tissue - Surgical excision
Order of hormone loss in hypopituitarism (ie with invasion or compression by lesion)
- GH most commonly lost first
- FSH/LH
3, TSH - ACTH
Causes of hypopituitarism
Generally deficiency in anterior pituitary hormones over posterior pit. hormones (GH > FSH/LH > TSH > ACTH)
Congenital
- Septo-optic dysplasia (HEX1 mutation/De Morsier’s)
- Kallman syndrome
- Genetic GHRH or GH deficiency’
- Holoprosencephaly, anencephaly
- Empty sella syndrome
Destructive:
- Neoplastic infiltration or compression (Craniopharyngoma, adenoma, meningioma, glioma, secondary deposits)
- Infective (Tb, meningitis, encephalitis, toxoplasmosis)
- Traumatic (post radiotx, post-op, NAI, traumatic delivery)
- Infiltrative (LCH, haemochromatosis, sarcoid)
Functional: Neglect, AN, starvation
Infant with visual impairment, nystagmus and GH deficiency
Hex1 mutation
What is this condition and what are the diagnostic features?
De Morsier’s syndrome or septo-optic dysplasia
Diagnosis requires 2/3 (req MRIB and hormone levels):
- underdevelopment of the optic nerve (optic nerve hypoplasia)
- hypopituitarism (GH 70%, severe cases may have panhypopituitarism)
- absence of the septum pellucidum (a midline part of the brain)
SiADH
- What is it
- Serum and urine ix findings
- Causes
- Cx if untreated
- Tx
Excessive ADH secretion
-> Increased renal reabsorption of water
Ix
- > Reduced serum osmolality
- > HYPONa
- > Normal-Increased urine concentration/osmolality
- > Inappropriately high urine Na
Causes
- CNS: meningitis, encephalitis, head trauma, brain abscess, asphyxia, IVH, subdural haematoma
- Infx: rotavirus, HIV, Tb
- Tumours: brain tumours, lymphoma, thymic cancers, ewing sarcoma
- Lungs: pneumonia, abscess, CF
- Metabolic: acute intermittent porphyria
- Drugs: carbamazepine, vincristine, cyclophosphamide, morphine, TCAs
Cx
- Cerebral oedema -> nausea, vomiting, irritability, seizures, coma
Tx
- Fluid restriction (2/3 maintenance)
Differentials for hyponatraemia
- Systemic dehydration (fluid loss -> hyperNa -> incr ADH secretion -> hyponatraemi)
- Salt losses
- > GIT (gastroenteritis),
- > kidneys (AIN, CRF, PCKD)
- > skin (CF) - SiADH (hypoNa, decr plasma osm, incr urine osm & Na)
- Cerebral Na loss sec to CNS disorder/trauma (due to hyper secretion ANP -> incr urine Na and output -> hypovolaemia)
- Primary polydipsia (incr water retention)
- Hyperglycaemia (fluid shift out of cell -> dilutional effect)
Relative strength of steroids
Cortisol/hydrocort = 1 (IV hydrocort, most potent) Pred = 4 (tablet, mid-potency) Dex = 25 (cream for eczema, least potent)
Roles of aldosterone
Production is stimulated by RAAS system -> stimulates CRH release from hypothalamus -> ACTH release from ant pit -> aldosterone release from adrenal gland zona glomerulosa
Function:
- Increase Na+ and water retention -> incr BP
- Lower plasma K+ concentration
- Secretion of H+ into tubules (incr serum pH)
Role of ANP
Atrial natriuretic peptide
- > Released in response to incr stretch of atrial walls (indicating high BP)
- > Acts acutely to lower BP via 3 mechanisms:
1. Increased renal excretion of salt and water
2. Vasodilation
3. Increased vascular permeability
What does the NST detect in regards to thyroid disease
What false negatives are possible
Detects high TSH as a marker for primary hypothyroidism (thyroid gland dysfunction)
DDX
- Congenital hypothyroidism
- Atrophic autoimmune thyroiditis
- Hashimoto thyroiditis
- Iodine deficiency
False negatives with
- sick euthyroid
- prematurity
- secondary or tertiary hypothyroidism (as TSH will be low)
What causes a goitre
Increased pituitary secretion of TSH in response to decr circulating levels of thyroid hormone
In Graves is due to Anti-TRAb stimulating the TSH receptor
Also infiltrative disease, inflammation/infection adn neoplasms
Role of calcitonin
Produced by C cells in thyroid gland in response to high serum Ca
Acts to LOWER serum Ca and Ph via
- Inhibits osteoclasts = incr bone mineralization
- Renal Ca excretion
- Renal Ph excretion
ECG signs of HYPOCa
Prolonged QTc
Arrhythmia (torsades de pointes)
PCOS
presentation
ix
mx
Presentation:
Adolescent girl
Acne
Menstrual irregularities or secondary amenorrhoea
Obesity
Hirsutism
Insulin resistance
USS - large polycystic ovaries
Increased circulating androgens (testosterone N/incr, LH incr, FSH decr or N)
-> High LH:FSH ratio
Mild hyperprolactinaemia
Mx
- OCP or cyproterone (anti androgen)
- Pred (pituitary ACTH suppression)
Persistent hyperinsulinaemic hypoglycaemia of infancy
- what is it?
- tx?
Developmental disorder where there are hyper plastic abnormally dispersed pancreatic beta cells resulting in inappropriately HIGH levels of plasma insulin
*REQUIRE extremely high rates/doses of glucose infusions during periods of hypoglycaemia/fasting*
Tx- diazoxide and thiazide diuretic
second line tx is w octreotide and/or glucagon
What is ketotic hypoglycaemia?
Children between 18mo-5years presenting with hypoglycaemia (+/- difficult to rouse in morning, coma, seizure) in setting of a prolonged fast/illness/missed meal
Essentially these children have low muscle mass and are unable to tolerate a fast due to low substrate availability
Ix - hypoglycaemia with appropriate ketonaemia, ketonuria, low plasma insulin
Addisons disease
Autoimmune primary adrenal insufficiency - most common cause for primary adrenal insufficiency in developed world
FT
- > low 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
MEN gene - I vs II; inheritance
Multiple endocrine neoplasia
AD gene - assoc w number of endocrine tumours
I - not as nasty. parathyroid, pituitary (prolactin, GH, ACTH), pancreas
IIa - nasty. pheochromocytoma, thyroid medullary carcinoma (nasty; prophylactic thyroidectomy if child is known to carry the gene)
IIb - same as IIa but marfanoid features + multiple neuromas
What does bone age tell you?
How do you assess the bone age?
Bone age = skeletal maturity
Tells you how far the skeleton has matured and gives you an idea of potential height and the cause of short stature
Assess bone age via LEFT HAND/WRIST XR (L Knee X-ray if <2yo)
-> Assess the number of epiphyseal centres (rate of ossification)
Compare bone age with chronological age
-> Bone age > chronological age = Advanced bone age
-> Bone age < chronological age = Delayed bone age
Delayed bone age in the ABSENCE OF PATHOLOGY = slow maturation = more potential growth
Causes of Advanced bone age
Bone age > chronological age = Advanced bone age
Causes of advanced bone age
- Growth advance
- Precocious puberty
- Excessive androgen production
- Hyperthyroid
Causes of Delayed bone age
Bone age < chronological age = Delayed bone age
Causes of Delayed bone age
- Familial delayed maturation
- Delayed puberty
- Severe illness
- Hypothyroid
- GH deficiency
Causes of delayed puberty
Failure of onset of any signs of puberty by 13 yrs (F) or 14 yrs (M)
*Most common in boys* - cause usually constitutional delay (short stature, delayed puberty, fhx)
CAUSES of Secondary (central) hypOgonadotrophic (Low LH, FSH and low testosterone)
- Constitutional/familial or sporadic
- HPA
- -> Panhypopituitarism
- -> GnRH deficiency
- -> Kallman syndrome
- -> Intracranial tumour (prolactinoma)
- Hypothyroidism
- Systemic disease
- -> Chronic disease eg: renal failure
- -> Malnutrition
- -> AN, psychosocial etc
CAUSES of Primary (peripheral) hypERgonadotrophic (High LH, FSH and low testosterone)
- Chromosomal
- -> Kleinfelter’s 47XYY (most common cause of delay and infertility in males)
- Steroid hormone enzyme deficiency
- -> CAH (3beta hydroxysteroid dehydrogenase deficiency)
- Gonadal dysgenesis
- -> Turner syndrome 45XO
- -> CF
- -> Noonan syndrome
- -> Congenital anarchia (absence of testes in phenotypic male)
- Gonadal disease
- -> Chemo/radiotherapay
- -> Trauma
- -> Torsion
- -> DXT
What is the role of Mg in Ca homeostasis
Magnesium is required for secretion as well as action of PTH
Therefore, hypomagnesaemia causes hypocalcemia refractory to correction unless magnesium is normalized.
What blood test results would indicate infertility vs pubertal failure in a child with kleinfelters?
Inertility = Sertoli cell failure:
High FSH
Due to loss of sertoli cell negative feedback
Also would have LOW inhibin B (released from sertoli cells)
Vs delayed puberty = leydid cell failure would be represented by high LH. At this stage would start testosterone supplements (monitor LH ~yearly)
How do you investigate for
- GH excess
- GH deficiency
?GH excess
- OGTT - GH should be suppressed after administration of OGTT. If it isn’t, indicates GH excess
?GH deficiency
- Look at heigh velocity as screening test - if >/= 25th centile, you can r/o growth failure
- If low, go on to do GH stimulation test (adminsiter arginine, clonidine, glucagon or insulin). If you have 2x GH peaks <5=, confirms GH deficiency
Which sex hormone is predominantly responsible for growth cessation?
Estrogen - responsible for skeletal maturation and closure of growth plates.
Deficiency of estrogen leads to prolongued growth, tall stature due to delayed closure of growth plate.
Effect of hypothyroidism on growth
Delayed bone age due to delayed maturation of bone and growth
Leads to cessation of growth and short stature
Thyroixine supplementation enables catch up growth and ability to reach predicted/target height
When should you suspect an endocrine problem in an obese child?
Differentials
Suspect endocrine when weight/obesity increasing but height static (as generally obesity drives vertical height growth as well)
DDX
- Hypothyroidism
- GH deficiency
- Cortisol excess (Cushings)
Mid parental height calculation
Significance of this
Boys: Dad height + (mums height +13cm) /2
Girls: (Dad height - 13cm) + mum’s height / 2
Child’s height should be within 8cm either side of mid parental height (if familial short stature)
Calculation and clinical significance of height velocity
Height velocity differentiates normal variant short stature from pathological short stature (slow HV)
HV = (difference in height between 2 measurements/time between measurements in months)*12
Should be calculated over 6-12mo interval of time
NORMAL HV lives within 25-75th centile
Pathological short stature has HV < 25th centile
Normal variant short stature has 2 main causes, both with NORMAL HV
- Familial short stature has normal bone age (<1 yr of CA) - final height short
- Constitutional delay of growth and developemnt has delayed bone age - final height is normal. also delayed puberty.
What fracture types raise suspicion for pathological fracture?
Vertebral fractures - common presentation of ALL
Tibial fracutres
Osteoporosis in children: reduced bone mineral content for height and weight <2 SD below mean
Causes
- CF
- IBD
- Asthma
- CP
- Epilepsy
- Coeliac disease
- Organ transplant
- Hypogonadism
