Endocrine Flashcards
Diagnosis of diabetes
- Fasting BSL >7mmol/L (no caloric intake for 8hrs)
- 2hr plasma glucose >11.1 during OGTT (glucose load of 1.75g/kg, max 75g)
- Random BSL >11.1 in a pt with Sx of hyperglycemia or DKA
- HbA1c >6.5% (paediatric patients = 6.35%)
Premature thelarche
- Isolated breast development - slow progression
- Absence of other secondary sexual features
- Normal linear growth
- Normal bone age - important
- Peaks at around 2yo and again at 6-8yo
- Soy based formulas, lavender oil and tea tree oil - ??increased risk of premature thelarche
When to investigate “premature thelarche”
- Progressive secondary sexual development
- Increasing height velocity
- Accelerated bone maturation
GnRH dependent (central) precocious puberty
- Early maturation of hypothalamic-pituitary-gonadal axis
- Characterised by evidence of sustained sex steroid exposure:
- -> Accelerated linear growth
- -> Advanced bone age
- -> Progressive pubertal clinical changes
- -> Pubertal levels of FSH and LH (GnRH test: LH dominant with levels >5)
- -> Pubertal levels of oestradiol in girls, T in boys
- Ix with GnRH (leucrin) stimulation test
Causes of central precocious puberty
- Idiopathic (F>M)
- Loss of hypothalamic inhibition: structural growths
- -> Hypothalamic hamartomas - CNS tumours e.g. astrocytoma, pineal gland tumours, optic gliomas
- Acquired CNS insults e.g. CNS irradiation, hydrocephalus, subarachnoid cysts, CP, tub sclerosis
- Neurofibromatosis type 1 (optic glioma)
- Previous excess sex steroid exposure e.g. poorly controlled CAH
- Genetic e.g. gain of function mutation of kisspeptin gene, MKRN3 gene mutation (imprinting)
Treatment of central precocious puberty
- Administration of Leuprolide depot every 3mths
- GnRH analogue: provides constant serum GnRH which over-rides pulsatility of endogenous GnRH –> secondary feedback inhibition
- Effects: initially see a surge in LH/FSH, then as the GnRH receptor becomes desensitised, subsequent secondary inhibition
- Protocol: 11.25mg IM 3mthly with a review with LH level 1hr post-dose
- -> LH <2 = adequate suppression
- F/u: annual GnRH test and bone age
Long term outcomes after treatment with Leuprolide in central precocious puberty
- Height: greatest height gain seen in girls with onset of puberty <6yo (average gain 9-10cm)
- Menstrual cycles and fertility appear normal as adults
- Possible increased incidence of PCOS
McCune-Albright Syndrome
Cafe-au-lait spots
- Irregular “Coast of Maine” lesions
- Rarely cross midline
- Increases with age
Peripheral precocious puberty (cyst-related)
Polyostotic fibrous dysplasia (develops slowly over time)
- Need to continuously screen for it
Other manifestations: phosphate wasting, GH excess, Cushing’s, thyrotoxicosis, cardiac arrhythmias, cholestasis
Pathogenesis of McCune-Albright Syndrome
- Somatic mutation - not inherited
- Constitutive activation of alpha-subunit of G3 protein that activates adenylyl cyclase
- Affects signal transduction of multiple G protein coupled receptors e.g. LH, FSH, GHRH, TSH, ACTH, PTH, catecholamines etc
Causes of gonadotrophin-independent (peripheral) precocious puberty in girls
McCune Albright Syndrome Ovarian cysts Ovarian tumours Exogenous oestrogen exposure Adrenal tumours (aromatisation of T) CAH Primary hypothyroidism (TSH cross-reacts w/ LH/FSH-R) Pituitary gonadotrophin secreting tumours (rare)
Causes of gonadotrophin-independent (peripheral) precocious puberty in boys
McCune Albright Syndrome
Leydig cell tumours
HCG secreting tumours
Familial male-limited precocious puberty (LH-R mutation)
Exogenous oestrogen exposure
Adrenal tumours
CAH
Primary hypothyroidism (testicular enlargement only)
Pituitary gonadotrophin secreting tumours (rare)
What is the primary reason for short stature in Turner Syndrome?
Haploinsufficiency of SHOX gene
- SHOX gene is located at distal ends of short arms of both sex chromosomes
Risk of germ cell tumours in DSD conditions
High-risk requiring gonadectomies:
- Dysgenetic gonads (+Y) that are intra-abdominal 15-35%
- PAIS (non-scrotal) 50%
- Frasier syndrome 60%
- Denys-Drash (+Y) 40%
- Turner (+Y - mosaic?) 12% (intermediate risk)
Intermediate risk for germ cell tumours
- For monitoring +/- Bx
- 17B-HSD 28%
- Dysgenetic gonads (+Y) - unknown risk –> Bx
- PAIS (scrotal glands) - unknown risk –> Bx
When is the best time to take a cortisol level?
Early morning (+/- ACTH stimulation)
- Crucially time-dependent
- Regulated by stress and circadian rhythm
- By midnight –> minimal cortisol, by 2am –> start producing cortisol, by 6-9am –> maximal concentration should be reached
Incidence of classical CAH in female
1/28,000
When do physiological pre-pubertal gonadotrophin surges occur?
- Mid-gestation: LH/FSH levels peak, then decline/disappear by term
- Second surge between 30-100 days of life: “mini-puberty of infancy”, can utilise this opportunity for a “free” stimulation test
- If ex-premature infant, perform at CGA
“Pro-testis” factors
- SOX9 gene: influences expression of SRY
2. SRY gene: transcription factor which promotes the development of testes, Sertoli and Leydig cells
Camptomelic dysplasia
- AD, translocation w/ breakpoint at 17q24-25 or deletion of 17q
- Excess female phenotype in 46XY –> absence of SOX9 –> no SRY gene product
- CF: pierre robin sequence, short bowed limbs, dislocatable hips, 11 ribs, club feet, laryngotracheomalacia, C-spine instability
- Early neonatal death is common
Genes responsible for development of bipotential gonads
LIM1, SF1, WT1
Denys Drash Syndrome
- Missense mutation in WT1
- If 46XY, cannot express full testicular development and vice versa for 46XX
- CF: mesangial sclerosis causing early, infantile nephrotic syndrome –> early renal failure, increased risk of Wilm’s tumour (aggressive)
WNT4 deletion in 46XX
- WNT 4 is a “pro-ovary factor” that promotes development of mullerian structures
- 46XX DSD - no germ cells, ovarian failure and mullerian agenesis
Adrenal hypoplasia congenita
DAX1 deletion
Tests to consider in ovotesticular DSD/46XX testicular/46XY complete gonadal dysgenesis
i.e. “True hermaphrotidism”
Blood karyotype Scrotal skin fibroblast biopsy Gonadal biopsy - Need to identify genotype/karyotype - Usually due to mosaicism or chimerism
CAH: 21-hydroxylase deficiency
- No cortisol!
- Circulatory collapse - 80% - no aldosterone, 20% produce aldosterone
- Na wasting, hyperkalemia with acidosis - 46XX DSD: virilisation due to shunting of cholesterol by-products down androgen synthesis pathway
- 46XY: normal male genitalia
CAH: 11-beta hydroxylase deficiency
- Further down steroidogenesis pathway
1. 11-DOC = weak mineralocorticoid (excessive amts) –> high Na, hypertension
2. 46XX DSD (mild virilisation)
CAH: which enzyme deficiency causes a 46XY DSD?
- 17B-hydroxysteroid dehydrogenase: involves androgen pathway only
- 3B-hydroxysteroid dehydrogenase: able to produce DHEA, but low androstenedione; Na wasting and low cortisol
- 17a-hydroxylase: rare, HTN and hypoK with renin suppression, sex hormones cannot be synthesised correctly
- Reduced androgen production –> undervirilisation of 46XY
Differential diagnoses for an isolated micropenis
- Familial
- Idiopathic
- Hypopituitarism (assoc. undescended testes)
- Prader-Willi Syndrome
- Floppy neonate with feeding problems
Mechanism of micropenis in hypopituitarism
- Usually, there is a gonadotrophic surge in 3rd trimester, which does not occur if there is hypopituitarism
- Underdeveloped (not ambiguous!) genitalia with micropenis and undescended testes
Congenital anorchia
“Disappearing testes”
- 46XY DSD: undervirilised due to reduced testosterone production
- Possible intrauterine torsion
Antimullerian hormone defect
46XY with uterus/mullerian structures
- Normal male genitalia
- However, due to absence of AMH, mullerian structures also persisted and developed internally
- Usually presents with “herniation” and incidentally found during surgery
- Normal male phenotype after removal of mullerian structures
Investigations for isolated micropenis
Rule out hypopituitarism (MRI)
Genetic testing for Prader-Willi (if suspected clinically)
At +30 days, test for testosterone, LH, FSH levels
- If abN: further Ix for central hypogonadism (DDx: Kallman syndrome)
- If normal: counsel family, ?testosterone replacement therapy
Investigations in neonatal period for ambiguous genitalia
Neonatal period:
- USS to assess internal organs (day 1)
- Karyotype (day 1)
- Electrolytes and BSL (day 1-2)
- 17-OH (day 4+)
Day 30+:
- Testosterone, oestrogen, LH, FSH - time with “minipuberty”
- Cloacogram (pre-surgery for planning)
- At 18mo, if complex DSD suspected: laparoscopy with biopsy of internal structures, scrotal skin biopsy (fibroblasts) for chromosomes, androgen receptor studies
Management/support for DSDs
- Address Q’s regarding fertility, sexuality; avoid stereotyping/gender bias etc etc
- Medical treatment as required
- Gender surgery
- Delay constructional surgery
- Primary duty is to child
- Limited evidence of good outcome
- Base advice on evidence not personal opinion
- Excision surgery must have clear indication - Screen for malignancy: gonadectomy vs biopsy vs monitor
- Psych support
Causes of adrenal insufficiency
- Tertiary: hypothalamus
- Tumour, malformation
- Iatrogenic: high dose corticosteroid therapy - Secondary: pituitary
- CRH receptor defect, isolated ACTH def
- Panhypopit - Primary: adrenals
- Acquired vs congenital
Waterhouse-Friederichsen syndrome
Haemorrhage into adrenal glands –> acquired adrenal insufficiency
- Meningococcus septicaemia
- Stressed neonate (e.g. extreme preterm)
Natural course of autoimmune Addison’s disease
- Antibody formation against 21-OH, SCC, 17-OH
- Increasing resting plasma RENIN
- Raised afternoon ACTH
- Depressed ACTH-stimulated cortisol response
- When 90% of adrenal function depleted = disease manifestation - decreased aldosterone and cortisol
APECED Syndrome
- Mutation in AIRE gene (21q22.3) - autoimmune regulator
- Autoimmune adrenalitis, hypoparathyroidism, mucocutaneous candidiasis
Autoimmune polyendocrinopathy (APS) 2
Autoimmune adrenalitis
Autoimmune thyroiditis
T1DM (dififcult to control due to adrenal antibodies)
Other features common to APS 1 and 2
Chronic active hepatitis (cause of mortality), malabsorption, alopecia, vitiligo, pernicious anaemia and hypogonadism
Pathogenesis of hyperpigmentation in Addison’s
ACTH and MSH formed from POMC –> excess ACTH can bind cutaneous melanocortin-1 receptor
Triple A syndrome
- Adrenal insufficiency
- Alacrima
- Achalasia
- Neurological impairment with early onset dementia
Long term steroid (cortisol) replacement
Hydrocortisone:
- Suppressive dose = 10-15mg/m2/day
–> CAH: suppress androgens to reverse virilisation
- Replacement dose = 6-10mg/m2/day
–> Secondary adrenal failure (20% higher than baseline production)
- Stress (e.g. infection): 3-5 fold increase in HC dose
- Surgery: IV 100mg/m2/day on day 1 and 2
Fludrocortisone: ~0.1mg/day
Monitoring hydrocortisone dose long term in CAH patients
Monitor with height velocity and bone age
- Excessive HC: weight gain –> reduced growth velocity –> delayed bone age –> decrease dose
- Insufficient HC: continue androgen production –> increased height velocity –> increased bone age (leading to short stature) –> reduce dose
- If androgen control still poor, add fludrocortisone
Effect of pH on plasma calcium
- Low pH: increased ionised calcium
- High pH: decreased ionised calcium
Hormones that affect plasma Calcium
Increase plasma Ca:
- GH (through IGF1)
- Thyroxine
- Oestrogens
Decrease plasma Ca:
- Glucocorticoids: inhibits osteoclast formation+activity, long term - decreases protein synthesis in osteoblasts, decreases intestinal absorption of Ca, increase Ca excretion
Phosphate
- Major control of P: renal
- -> Increased excretion mediated by PTH binding to receptors in proximal tubule
- -> Reabsorption primarily occurs in proximal tubule - easily saturable process –> urinary spillover if high P
- Buffered by Ca and bone
- Gut absorption is linearly related to dietary intake
PTHrP
- Critical for normal foetal development
- -> Most important hormone in maternal-foetal Ca transfer
- -> Widely expressed in many tissues, modulator of cell growth and differentiation
- Paraneoplastic phenomena: mediator of syndrome of “humoral hypercalcemia of malignancy”
Effects of PTH
Chromosome 11, 1/2 life = 10min
Stimulated by hypocalcemia and hyperphosphatemia
Mechanism:
- Major = bone mobilisation - increased osteoclast activity
- Increased renal reabsorption at DCT, increased PO excretion
- Stimulates 1a-hydroxylase enzyme to increase Vit D hydroxylation
Effects of Vitamin D (1,25-VD)
- Major: Increased Ca and PO reabsorption in small intestine (jejunum)
- Increases osteoclast activity in bone
- Increased renal tubular reabsorption of calcium and phosphate
Major source of vitamin D
- Skin (>80%): 7 dehydrocholesterol in skin –> Vit D3 by UVB light
- Diet (10%): Vitamin D2 (ergocalciferol)
Risk factors for Rickets of Prematurity
Ca and P deficiency - def of Phos > Ca
- Prematurity (80% of Ca/P transfer in utero occurs in 3rd trim)
- BW <1000g
- Cholestatic jaundice
- Complicate neonatal course
- Prolonged TPN
- Soy formula/breast milk without fortification
- Medications: corticosteroids, diuretics
- Poor vitamin D intake
Risk factors for Vitamin D Deficiency Rickets
- Unsupplemented, prolonged breastfeeding + late weaning (BM Vit D = <25IU/L)
- Maternal Vit D deficiency
- Dark skin ethnicity
- Decreased sun exposure
- Malabsorption
- AEDs
Biochemical abnormalities in Vitamin D Deficiency Rickets
- Hypocalcemia
- N/Low phosphate –> P wasting due to PTH activity
- High PTH and ALP
- Low Vitamin D (esp 25-D = storage form)
- -> Monitor response to therapy by measuring 25-D levels
Biochemical abnormalities in Rickets of Prematurity
- Hypophosphatemia (inadequate intake/reduced in utero transfer)
- -> Appropriate renal response = low P in urine
- Calcium levels are variable (low/N/high)
- -> 1,25-D activated due to low P –> increased intestinal absorption, unable to be stored in bone (due to low P - cannot form hydroxyapetite), excreted in urine
- Normal 25-D, N/high 1,25-D (low P activates renal 1a-hydroxylase)
- High ALP (>x5-6 ULN is suggestive of diagnosis)
- -> Increased bone demineralisation
PHEX gene
Phosphate regulating endopeptidase on X chromosome
- Present predominantly in bone and teeth
- Product of PHEX gene degrades and inactivates hormone-like substances that promote phosphate excretion + impair bone mineralisation
- Indirectly inactivates FGF23
Fibroblast growth factor 23 (FGF-23)
Humoral mediator that decreases renal tubular reabsorption of phoshate and decreases activity of renal 1a-hydroxylase activity
Familial hypophosphatemic rickets
a.k.a Vitamin D resistant rickets
- X-linked mutation in PHEX gene –> increased levels of FGF-23
- Males are affected with full phenotype, affected mothers may only have fasting hypophosphatemia
- Defect in PO reabsorption (renal wasting) –> phosphaturia
- Defect in hydroxylating 25-Vit D
- CF: rickets esp lower limbs, poor growth, delayed dentition, tooth abscesses
- Ix: Low PO, Low 1,25 Vit D, normal Ca/25-Vit D/PTH, high ALP due to poor mineralisation
- Tx: oral phosphate and calcitriol
Excess 1,25-Vit D (excessive doses of calcitriol)
Hypercalcaemia –> hypercalciuria (renal reabsorption mechanism becomes saturated) –> nephrocalcinosis
Excessive phosphate supplementation
High P –> reduced Ca (increased binding, decreased 1,25-D conversion)
Stimulates PTH –> worsens bone reabsorption –> decreased mineralisation and #
Calcitonin
Produced by parafollicular cells of thyroid in response to hypercalcemia
Stimulates Ca deposition in bones
Decreases Ca absorption in intestines
Promotes Ca excretion in kidneys
Calcium-sensing receptor
- CaSR of parathyroid gland continuously senses serum ionised Ca
- Class C G-protein coupled receptor –> phosphoinositide turnover
- Rapidly adjusts PTH release for even minute changes in ionised Ca levels
- -> When active, inhibits PTH secretion
- CaSR in renal tubules has direct effect on calcium reabsorption
Biochemical defects in hypoparathyroidism
Normally, PTH: increases bone resorption –> increase Ca, increases renal PO excretion
- Low serum Ca, normal/high PO4
- Low urinary Ca
- Inappropriately normal or low PTH
- ALP low/normal
Other: calcification of basal ganglia, cataracts, long QT
Pseudohypoparathyroidism Type 1A - clinical features:
- Inactivating mutation of GNAS (maternally inherited mutation)
- TSH resistance - <2yrs, usually presents first,
- PTH resistance - presents in infancy or later
- GHrH resistance in pituitary - contributes to short stature
- FSH/LH resistance - menstrual irregularities in older girls
Other: brachydactyly 3-5th fingers, syndactyly 2-3rd toes, subcutaneous calcifications, cataracts, short stocky build with round face, flat nasal bridge and short neck, mental retardation
Pseudopseudohypoparathyroidism
Same inactivating mutation of GNAS inherited from father = Albright hereditary osteodystrophy phenotype without endocrine dysfunction
Recall: tissue-specific parental imprinting of GNAS
Vitamin D deficiency
- Based on 25-OH Vit D level
- Deficiency = <50nmol/L
- Insufficiency = 50-<75nmol/L
Treatment of Vitamin D Deficiency (acute therapy)
- Age <1mth: 1000IU (25microg) daily for 3/12
- Age 1-12mth: 3000IU (75microg) daily for 3/12
- Age >12mth: 5000IU (125microg) daily for 3/12
OR Stoss therapy (noncompliance risk): high dose of Vit D3 at beginning of winter to maintain Vit D level
- 300,000 - 500,000IU as once off dose
- Vit D3 stored in fat –> very long half life
DDx for vitamin D deficiency rickets
- Calcium deficiency
- Type 1 Vit D dependent rickets: 1-alpha hydroxylase deficiency
- Type 2 Vit D dependent rickets: mutation in vit D receptor, end-organ resistance to 1,25-OH
- Hypophosphatemic rickets
- -> X-linked
- -> RTA
- -> Hereditary hypophosphatemic rickets w/ hypercalciuria
- -> Nutritional phosphate deficiency
Primary hyperparathyroidism - causes
- Sporadic, single adenoma
- MEN (multiple endocrine neoplasia) type 1 and type 2a
- -> Type 1: hyperplasia or neoplasia of pancreas, anterior pituitary, parathyroid
- -> Type 2A: pheo, medullary thyroid carcinoma, hyperparathyroidism
- McCune-Albright Syndrome
- Familial hyperparathyroidism - jaw tumour syndrome
Investigations for hyperparathyroidism
- Bloods: Ca, P, Vit D, PTH, ALP
- CaSR mutation analysis
- USS neck
- Sestimibi nuclear medicine scan
- Other markers of MEN disease
- Check Ca levels in first degree relatives
DDx for adrenal mass with hypercalcemia
Malignancies: - Pheochromocytoma - Neuroblastoma - Adrenocortical carcinoma Non-malignant: - TB - Sarcoidosis
Causes of calcium and phosphate abnormalities in malignancy
Paraneoplastic:
- PTHrP - hypercalcemia
- -> Acts on PTH receptor, mimics PTH effect on bone and kidney, resultant hyperCa suppresses endogenous PTH secretion
- FGF23 - phosphate wasting, normal Ca
- 1a-hydroxylase activity - hypervitaminosis D –> hypercalcemia, hyperphosphatemia
Treatment of acute hypercalcemia
- ECG monitoring
- Maximise urinary Ca excretion: hydration/hyperhydration with saline and loop diuretics
- Inhibit bone resorption: bisphosphonates, calcitonin
- Glucocorticoids
- Dialysis with low Ca dialysate (last resort)
Bisphosphonates
- MOA: phosphatase resistant pyrophosphate analogue that absorb to surface of bone hydroxyapetite. Inhibits Ca release by interfering with metabolic activity of osteoclasts + cytotoxic to osteoclasts
- SE: flu-like Sx, GI symptoms, hypoCa
- In emergency: IV pamidronate 0.25-1mg/kg over 8hrs, single dose lating up to 2-4/52. Can be repeated
Calcitonin (emergency treatment)
- MOA: rapid transient lowering of Ca levels by increasing Ca renal excretion and inhibiting osteoclast activity
- Dose: 2-4U/kg subcut 6-12hrly
- SE: tachyphylaxis with repeated doses
Kenny-Caffey Syndrome
- Medullary stenosis of long bones, short stature, delayed bone age, delayed closure of fontanelles, eye abnormalities
- Idiopathic hypoparathyroidism have been found leading to episodic hypocalcemia
- AD and AR forms, mutation in TBCE gene disturbs microtubule organisation in cells
Biochemical abnormalities in Type 1 and Type 2 Vitamin D dependent rickets
- Type 1 = defect in renal 1-alpha hydroxylase –> decreased hydroxylation of 25-D to active 1, 25-D
- Low Ca/P, high ALP and PTH, normal/high 25-D, low 1,25-D - Type 2 = defect in VItamin D receptor, preventing normal physiologic response of 1,25-D
(AKA hereditary vitamin D-resistant rickets)
- Low Ca/P, high ALP and PTH, normal/high 25-D, very high 1,25-D
Biochemical defects of pseudohypoparathyroidism
- Low Ca, high PO4, high PTH, high ALP
- Other: High TSH (resistance)
Familial hypoparathyroidism (hypercalciuric hypocalcemia)
- Activating mutation of Ca-sensing receptor –> inhibits PTH secretion when hypocalcemic
- Low Ca, high PO, low PTH with high urinary Ca –> nephrocalcinosis
Familial hypocalciuric hypercalcemia
- AD, inactivating mutation of Ca-sensing receptor –> PTH secretion ongoing despite hypercalciemia
- High Ca, low PO, high PTH with low urinary Ca excretion
- Urinary Ca/Creat clearance ratio low <0.01
- Usually asymptomatic
Drugs that block peripheral conversion of T4 to T3
Propanolol
Glucocorticoids
Propylthiouracil
Amiodarone
Drugs that block the release of T3 and T4 from thyroid
Lithium
Iodine
TSH regulates…
Uptake of iodide (Na/I- co-transporter)
Endocytosis of thyroglobulin containing T3&T4
Relationship between thyroid hormone and GH
- T4 facilitates GH release from pituitary –> if hypothyroid, cannot interpret GH test rests
- T4 promotes chondrocyte hypertrophy
- GH mediates proliferation of pre-chondrocytes and stimulation of IGF-1. IGF-1 drives differentiation of pre- to chondrocytes - Low T4: slows growth and epiphyseal ossification –> thin growth plates
- High T4: accelerates epiphyseal fusion –> advances bone age
Effects of thyroid hormone
- T4/T3 increases sensitivity of target tissues to catecholamines: lipolysis, gluconeogenesis, glycogenolysis
- T3 increases B-adrenergic receptors in heart, sk muscles, adipose and lymphocytes
- Increases basal metabolic rate by increasing Na/K-ATPase activity
Half life of Thyroid hormone
7 days
Shorter at birth: 3 days
Thyroid function after birth
At birth, TSH surge which peaks at ~30min of life –> rise in T3 and T4. Falls after day 1 of life
- Adaptive mechanism to produce heat after birth as foetal thermogenesis is inhibited in utero
MOA of carbimazole and propylthiouracil
- MOA: methimazole targets thyroid peroxidase - prevents coupling and iodinating tyrosine residues on thyroglobulin –> reduces production of T3 and T4
- SE: aplastic anaemia, hepatic necrosis –> failure, crosses placental
- -> ?PTU associated with higher rates in paediatric population
- Affects foetal thyroid hormone levels –> transient neonatal hypothyroidism (<5/7) can result
What can thyroxine tablets bind with?
Soy formula and iron, therefore, crushed thyroxine (preparation for neonates) should not be mixed them
Sick euthyroid syndrome
Occurs in CRITICALLY ILL pts, can have: - Low T3 - Low/normal/high T4 - Normal TSH Low T3 occurs due to inhibition of iodothyronine B or outer -ring monodeiodinase activity and decreased rate of T3 from T4 in body tissues. No thyroid hormone replacement necessary. Fix underlying condition.
Why is carbimazole preferred over propylthiouracil?
- PTU was found to increase risk of hepatotoxicity –> hepatic failure. Do not recommend use in paediatric pts unless carbimazole cannot be tolerated
- Carbimazole can also cause an adverse effect: 18-fold increased risk of choanal atresia, crosses the placenta more readily c.f. PTU
Side effects of thionamides
Skin rash Aplastic anaemia/granulocytopenia Drug fever Nephritis SLE-like syndrome = ANCA positive vasculitis Splenomegaly
Thionamides and breastfeeding
Can continue to breast feed is the bottom line!
- PTU: crosses breast milk in only small amounts and TFTs remain normalised in babies who are breast fed
- Carbimazole: crosses breast milk readily ++, but normal TFTs, developmental and intellectual function have been reported in breast fed babies
Treatment of neonatal thyrotoxicosis: step 1
- Lugo’s iodine (5% iodine and 1% KI) 1 drop TDS - blocks T4 release and synthesis, iodine uptake
- -> Wolf Chaikoff effect - feedback suppression
- -> Cease treatment once pt asymptomatic
Treatment of neonatal thyrotoxicosis: step 2
- If tachycardic and irritable (sympathetic overstimulation), commence propanolol 1mg/kg/day
- -> Also, stops peripheral deiodination of T4 to T3
- -> Stop treatment once HR normalises
Treatment of neonatal thyrotoxicosis: step 3
- Carbimazole: to inhibit coupling of iodotyrosines, oxidation and organic binding of iodide and block synthesis of thyroxine
–> Takes several days to take effect on T4 levels
–> Monitor weekly once stable
Treatment will take ~3 days to take effect as circulating T4 has a half life of 3 days
Treatment of neonatal thyrotoxicosis: step 4
Other treatment measures:
- If cardiac failure: diuretics and digitoxin
- If severely thyrotoxic: prednisolone (2mg/kg) - prevents peripheral deiodination and compensates for hypercatabolism of glucocorticoids induced by T3/T4
- Ensure strict fluid balance and replace insensible losses
- Ensure adequate caloric intake
- Maintain normothermia
- May require sedatives
Neonatal thyrotoxicosis and cognitive function
- Associated with craniosynostosis and learning difficulties
- Microcephaly, advanced bone age may occur
- Warn of potential learning problems + delayed milestones - close monitoring during early school years
How long does it take before the adrenal gland starts to atrophy?
Depriving adrenal gland of ACTH for >2/52 causes it to atrophy –> reduced cortisol release
Risk factors for thyroid neoplasm
- History of radiation to head/neck
- Solitary nodule >1cm with fixed, hard or irregular borders
- FHx of MEN
- Rapidly growing nodule that is firm or hard
- Satellite lymph nodes
- Hoarseness or dysphagia
Which one is more likely to be malignant? Hot or cold thyroid nodules
Cold!
Cause of obesity in craniopharyngioma
- Hypothalamic damage due to tumour, surgery or radiation
GH replacement in craniopharyngioma
- Can commence GH replacement after being tumour free for 12mths
- GH does not increase the risk of tumour recurrence
Investigations for panhypopituiarism in a neonate (day 30)
- Serum ACTH, cortisol (preferably several throughout the day)
- -> Neonates do not have diurnal variation
- TSH/T4 levels
- GH level after ruling out hypothyroidism
- -> Free GH levels in a term neonate (within first few days of life): >10 reassuring, <10 strongly suggestive of GH deficiency
- LH/FSH/T/E - postnatal gonadotrophin surge
When assessing panhypopit, which test is not helpful in the immediate neonatal period?
IGF-1 and IGFBP-3 are difficult to interpret in a neonate
Cause of hypoglycemia in panhypopituitarism
- GH deficiency: antagonistic effect on insulin, influences metabolic actions such as CHO and lipid metabolism
- Hypocortisolism/ACTH deficiency
Prolonged jaundice
- Prolonged jaundice is suggestive of severe pituitary dysfunction
- Panhypopit associated with conjugated hyperbilirubinemia
- Hypothyroidism associated with unconjugated hyperbilirubinemia
Management of panhypopituitarism: order of hormone replacement
- Hydrocortisone
- Need to normalise cortisol before thyroxine replacement or precipitate Addisonian crisis
- Maintain haemodynamic stability - Thyroxine and growth hormone
- Hypothyroidism reduces cortisol clearance and reduces BMR –> reduced need for cortisol
- Thyroxine replacement increases cortisol requirement which the failing adrenals cannot provide - Sex hormones in adolescence (~12yo) if hypogonad
Treatment of hypogonadotropic hypogonadism
For pts who wish to be fertile:
- Gonadotropin treatment (e.g. HCG = LH, HMG = FSH) would stimulate development of gonads/increase testicular vol, induce T production by Leydig cells, induce spermatogenesis
Simple/practical method:
- Induce secondary sexual characteristics by giving testosterone (or oestrogen) preparation IV or PO
Kallman Syndrome
KAL gene on Xp22.3
Familial isolated gonadotropin deficiency and anosmia
Rickets
Bone malformation due to any abnormality in production or excretion of Ca and Phos –> undermineralisation of GROWTH PLATE
Mineral deficiency prevents normal process of bone mineral deposition. If mineral deficiency affects growth plates –> retarded bone age
Pattern for height velocity
- Infants grow very quickly - height velocity is not useful in this age group
- Commence monitoring height velocity at 2-3yo - Height velocity gradually declines in childhood, nadir just prior to pubertal onset
- Puberty-associated growth spurt (peak M: 10.3cm, F: 9cm) typically lasts ~2yrs
- Gradual decline in height velocity, stops at time of epiphyseal closure
Constitutional growth delay
- Short, slow growth, delayed puberty, delayed bone age
- FHx of delayed puberty often present
- Longer period of prepubertal growth, slightly smaller before puberty
- Pubertal growth spurt occurs normally, albeit at later time –> attain normal adult height as they had prolonged period of prepubertal growth
DDx for short stature
- Primary growth abnormalities
- Osteochondrodysplasias
- IUGR - Secondary growth abnormalities
- Malnutrition
- Chronic diseases e.g. GI, resp, renal disease, haematological
- Psychosocial deprivation - Chromosomal abnormalities
- Endocrine disorders
- Acquired causes that disrupt to HPA axis
- E.g. tumours, infiltrative dz, infection, trauma
- Iatrogenic: craniospinal radiation, steroid Tx - Constitutional growth delay
Endocrine causes of short stature
- Hypothyroidism (T4 facilitates GH release)
- Cushing syndrome (cortisol excess - suppress GH)
- Pseudohypoparathyroidism (poor bone mineralisation)
- Rickets (poor bone mineralisation, nutritional def)
- IGF/GH deficiency
- GH deficiency due to hypothal/pit dysfunction
- GH insensitivity
- Primary defects in IGF synthesis/transport/clearance
- IGF resistance: defects of IGF-1 receptor, post-receptor defects
Genetically inherited conditions that can cause familial short stature (short parents, short child)
- Neurofibromatosis type 1 - often assoc. w/ GH abN
- Pseudohypoparathyroidism
- Thyroid disease
- Osteochondroplasias e.g. Leri-Weill dyschondrosteosis with madelung deformity
- Renal disease
- Haematological dz e.g. thalassemias
True onset of puberty is defined by…
Boys: testicular volume >4mL
Girls: breast development
Normal upper body:lower body segment ratio
Neonate: 1.7
Childhood (4-5yrs): 1.4
Pre/pubertal (10-12yrs): 1.0
- Children grow in craniocaudal direction
Normal arm span to height ratio
1.0
Important chromosomal causes of short stature
Turner syndrome Noonan's syndrome Down syndrome Prader-Willi syndrome SHOX gene abnormalities
Intrauterine causes of growth failure
- Foetal causes: chromosomal abN, syndromes such as Russel Silver, Prader Willi Syndrome, TORCH infections
- Placental causes: impaired uteroplacental function/insufficiency
- Maternal causes: malnutrition, GDM, HTN, drugs
- Most non-dysmorphic children will catch up by age of 5, provided no underlying medical condition causing IUGR
Achondroplasia
- MC cause of genetic disproportionate short stature
- AD or de novo mutation in FGFR3 gene
- Neonates: rhizomelic shortening of limbs, macrocephaly, brachydactyly, narrow chest
- CF: face - midface retrusion and frontal bossing, hypotonia leading delayed acquisition of motor milestones (compounded by macrocephaly), trident configuration of hands, genu varus, thoracic kyphosis and exaggerated lumbar lordosis
- XR: square ilia, horizontal acetabular, narrow sacrosciatic notch, prox radiolucency of femur, diffuse metaphysial abN
- Normal life span and intelligence unless complicated by hydrocephalus or craniocervical junction compression
Causes of GH therapy failure
- Technical problems: measurement error, poor compliance, improper handling/storage/injection, incorrect dose
- Other conditions: subclinical hypothyroidism, chronic dz or poor nutritional status, glucocorticoid therapy, previous epiphyseal fusion
- Failure of GH: anti-GH antibodies (GH1 gene mutations), GH resistance syndromes, incorrect diagnosis
Endocrinopathy in Prader-Willi Syndrome
Secondary to abN in hypothalamic signalling
- GH deficiency common: GH Tx has definite benefits on linear growth + body composition, developmental milestones
- Hypogonadotropic hypogonadism with cryptoorchidism
- -> Requires pubertal induction with sex hormone replacement
- Adrenal insufficiency
- Hypothyroidism: primary and secondary
- Obesity with hyperphagia (hypothalamus related)
- Insulin resistance and T2DM high risk
DDx for disproportionate tall stature
Marfan syndrome (nil learning/behavioural problems)
Homocystinuria
Klinefelter syndrome
Investigations for short stature
- Bone age (+/- limited skeletal survey)
- Bloods:
- FBC/ESR: anaemia, infection, inflammation
- Chem20, bone chemistry: renal, malabsorption, Ca/P/Vit D disorders
- pH, HCO3: RTA
- TTG, Total IgA: coeliac disease
- TSH/T4: hypothyroidism
- IGF-1: GHD
- FSH (if <2yo or >9yo) and karyotype: Turner syndrome
- Urine pH, protein, blood: renal disease - Pituitary function testing: provocation tests
Adrenarche
- Maturational increase in adrenal androgen production - biochemically apparent at ~6yo for both M & F. Due to developmental change in pattern of adrenal response to ACTH.
- Weak adrenal androgens contribute to pubarche, sebaceous gland + apocrine gland development in “seuxal” areas of skin
- DHEA becomes predominant 17-ketosteroid in blood = marker of adrenarche
When does adrenarche and puberty become dissociated?
- Hypogonadism
- Normally, clinical manifestations of adrenarche closely follow puberty
Testosterone and DHT
- Testosterone:
- Synthesised from chol in Leydig cells and androstenedione secreted by adrenal cortex
- Maturation of wolffian duct structures, formation of male internal genitalia, increased muscle mass, development of male sex drive and libido - DHT:
- T converted to DHT by 5a-reductase in target cells
- Formation + maturation of external genitalia, enlargement of prostate and penis, facial hair, acne and temporal recession of hair line
Normal onset of puberty in F and M
Girls:
- Onset: 10.5-11yo
- Lower: 8yo
- Upper: 13yo
Boys:
- Onset: 11.5-12yo
- Lower: 9yo
- Upper: 14yo
Progression of puberty: females
Thelarche –> pubarche –> growth spurt –> menarche
- Tempo: 6-9mo per stage
- 3-6mo after thelarche –> pubarche
- Growth spurt during Tanner stage 2 and 3 (~12yo)
- Most rapid growth has occurred by menarche
- Pubertal growth: 23-28cm, height velocity average 8.3cm/yr
- Menarche ~12.9yrs, during Tanner stage 3 and 4 (2yr post thelarche)
Progression of puberty: males
Testicular enlargement (>4mL) –> pubarche –> penile growth –> growth spurt –> spermarche, facial hair
- Tempo: 9-12mo per stage
- Peak growth during 13-14yo (testicular vol 10-12mL, stage 4-5)
- Pubertal growth: 30-31cm, height velocity average 9.5cm/yr
- Axillary hair mid-puberty
Delayed puberty
- If >5yo have passed between beginning and completion of puberty
- Boys: no secondary sexual characteristics >14yo
- Girls: no secondary sexual characteristics >13yo
Bone age and precocious puberty
Bone age gives substantial information on presence of prolonged sex steroid exposure
- With progressive oestrogen exposure, bone age will be significantly higher than chronological age
- Remeber: oestrogen increases GH prod’n, leads to epiphyseal fusion and cessation of growth
Common clinical manifestations in McCune Albright Syndrome
Baltimore Study 1996
- Most common manifestation OVERALL = precocious puberty
- MC in boys: acromegaly/gigantism
- MC in girls: precocious puberty
- Associated malignancy: osteosarcomas (rare - 2%)
Investigations for gonadotropin-independent precocious puberty (peripheral) in boys
- Imaging: abdo and adrenal USS +/- CT
- Androgen profile:
- Androstenedione
- Testosterone: free testosterone
- SHBG
- DHEAS
- 17-OHP (for CAH) - Consider tumour markers: B-HCG, AFP, urinary VMA and metanephrine
Buserelin stimulation test
Buserelin is a potent GnRH agonist - produces more effective and sustained stimulation of gonadotrophs resulting in LH and FSH secretion
- Interpretation:
- -> LH and FSH <5: hypogonadotropic hypogonadism
- -> LH and FSH >10: normal pituitary axis
- -> LH and FSH 5-10: probably normal pit axis
- LH <5 has sensitivity of 100%, sepcificity 96% and PPV 89% of HH
CHARGE syndrome and hypogonadism
Mutation in CDH7 - positive regulator of neural stem cell proliferation
- Thought to have critical role in development and maintenance in GnRH neurons for regulating puberty and fertility
- Hypogonadotropic hypogonadism
Causes of hypogonadotropic hypogonadism
- Genetic: KAL-1, FGFR1, GnHR, DAX-1
- Tumours: craniopharyngioma, germinomas, meningiomas, gliomas, astrocytomas
- Post-head trauma
- Cranial irradiation
- Multiple pituitary hormone deficiency
- Syndromal: CHARGE, Prader-Willi, Laurence-Moon-Biedel, Bardet-Biedel
- Chronic dz: IBD, renal failure, malnutrition and AN, hypothyroidism, hyperprolactinemia, poorly controlled T1DM, Cushing disease
Oestrogen therapy for pubertal induction
Estradot patches = delivers 25 or 50microg/24H of oestradiol
- 1/8th of 50microg patch applied twice weekly for 6/12
- 1/4 patch applied twice weekly for 6/12
- 1/2 patch applied twice weekly for 6/12
- Whole patch
- When spotting occurs, change to COCP or Estalis, which is a continuous oestradiol and norethisterone transdermal patch
- Gradual increase in dose to prevent growth plate closure
Testosterone therapy for pubertal induction
Testosterone esters 50mg IM monthly
Increase dose 6mthly to adult dose of 250mg monthly
GH and E therapy in Turner’s Syndrome
Combinging ultra low doses oestrogen and growth hormone seem to improve height
(Prior to pubertal induction in TS, measure FSH –> if high, confirms gonadal failure)
Craniospinal radiation
- GH deficiency with poor spinal growth from radiation
2. Precocious puberty –> slowing of puberty with evolving depletion of FSH/LH –> pubertal arrest and failure
Pubertal induction in boys after chemo/radiation therapy
- Testosterone Tx alone will suppress the HPG axis –> persistence of pre-pubertal gonadotropin levels
- -> This leads to induction of puberty, but spermatogenesis remains immature
- Induction with HCG and rFSH –> effective testicular growth, spermatogenesis
Hypergonadotraphic Hypogonadism
Boys:
- Vanishing testes syndrome/congenital anorchia
- Chemotherapy/radiotherapy
- Syndromes: Noonan, Klinefelter, XX males
- Infection (e.g. mumps), torsion, trauma
- Cystic fibrosis
Girls:
- Syndromes: Turner, Noonan, XX gonadal dysgenesis, 45X/46XY gonadal dysgenesis
- Galactosaemia
- Bloom syndrome, Werner Syndrome, Fanconi anaemia, Ataxia-telangiectasia (ovarian hypoplasia)
- APECED - autoimmune ovarian failure
- Chemtherapy and radiation: streak ovaries
Hypopituitarism causing isolated ACTH deficiency
TBX19 or PCSK1
Female presentation in 3B-hydroxysteroid dehydrogenase deficiency
- 3BHSD Def –> blocks Na, cortisol and androstenedione production, DHEA still produced
- Classical: Mild virilisation, Na wasting and low cortisol; after infancy - features of adrenarche with axillary and pubic hair due to DHEA
- Non-classical: PCOS with hirsutism, acne, menstrual disorders and infertility
Female presentation in 17a-hydroxylase deficiency
- Rare
- 17aOH def: prevents pregnenolone –> 17OH-pregnenolone i.e. blocks entry into cortisol and sex steroid pathway
- HTN, hypokalemia with suppressed renin and aldosterone (feedback suppression)
- No 46XX DSD as adrenal androgen production is suppressed, but at puberty, failure of sexual development c.f. 46XY DSD
Precocity
Ask:
- What’s affected?
–> Sequential: testes/breast development with pubic hair = central precocity
–> Pubic and axillary hair, body odour, normal blood markers = premature adrenarche only
–> Is it oestrogen and testosterone effects that are not sequential/sparing gonads in boys = peripheral precocity
E.g. Girls: breast development, menses
E.g. Boys: external virilisation with penile enlargement, advanced bone age
***Remember: in this group, if bone maturation nearing pubertal age –> hypothal takes over to cause central precocity
–> Virilisation of female: at birth = CAH or maternal conditions/drugs, gonadal dysgenesis; after postnatal period, consider adrenocortical tumour
Adrenal rest testicular tumours
Occurs in boys with 3B-HSD, 21-hydroxylase deficiency or 11B-OH deficiency who have not had appropriate corticosteroid therapy
- Can develop unilateral or bilateral adrenal rest tumours
- These can regress with appropriate therapy
- Complication: infertility
Carney complex
AD inheritance
Blue naevus, cardiac and skin myxomas, sexual precocity, primary pigmented adrenocortical disease, growth hormone producing pituitary adenomas, thyroid tumours, melatonin schawnnomas
Lifetime risk of T1DM and first degree relatives
Monozygotic twin: 33-50% HLA-identical sib: 16% Father: 6-9% Sibling: 5-6% Mother: 1-4%
Antibodies associated with T1DM
Zinc transporter 8 - ZnT8A and insulinoma-associated antigen - IA-2 Ab is seen in <8yo
Glutamic acid decarboxylase - GAD Ab and IA-2 Ab is seen in adolescents
Insulin Ab = newly discovered
HLA and associated T1DM risk
High risk with HLA-DR3 and DR4
- Presence of 1 increases risk 2- to 3-fold
- Presence of both increases risk 7- to 10-fold
DKA
BSL >11
Mild: pH <7.3 or HCO3 <15, and presence of ketones (>3)
Mod: pH <7.2 or HCO3 <10, ketones
Severe: pH <7.1 or HCO3 <5, ketones
Infections associated with diabetes
Congenital rubella
CMV
Enterovirus
Genetic syndromes associated with diabetes
T21 Turner syndrome Prader-Willi syndrome Klinefelter syndrome Friedreich's ataxia Myotonic dystrophy Porphyria
Permanent neonatal diabetes
- 50-66% have an activating mutation in KCNJII gene and ABCC8 gene –> Kir6.2 and SUR1 subunits of ATP-K channel in Beta-cells
- Other mutations: homozygous GCK mutation (7p13), homozygous IPF-1 gene and mutations in insulin gene
- PC: Can be normoglycemic at birth, develops hypoglycemia between birth to 6mo (median = 5wo)
- 20% have severe phenotype = DEND syndrome (Kir6.2 mutation)
- Tx: Responds well to sulfonylurea –> great glycemic control and QoL
Which mutation causing neonatal diabetes can be less responsive to sulfonylureas?
Mutation in ABCC8 gene –> abN SUR1 subunit which is the binding site for sulfonylurea
- Variable response
Transient neonatal diabetes
- 70% have mutation in chr6p24 - paternally expressed gene with maternal gene silencing (imprinting disease)
- Overexpression of ZAC and HYMA1 genes
- Mechanisms: paternal UPD, duplication of 6p24 on paternal allele, hypomethylation of maternal allele (imprinting defect)
- PC: transient hyperglycemia, severe growth retardation, large tongue and umbilical hernia
- -> Pronounced glycosuria –> dehydration and metablic acidosis
- Tx: BD intermediate acting insulin (1-2u/kg/day)
Disease course of transient neonatal diabetes
- Remission in early infancy period with normal OGTT
- Relapse of diabetes occurs between 4-25yo
- Loss of first phase insulin secretion as seen in T2DM
- -> 50-60% of pts develop permanent diabetes
MODY
Maturity onset diabetes of the young
- Usually single gene mutation/inheritable diabetes –> defect in B-cell maturation and abnormal insulin secretion
- -> Non-ketotic as insulin secretion is still maintained, albeit at higher glycemic threshold
MODY 1
- HNF4-alpha mutation –> transcription factor involved in B-cell development and fxn
- Progressive insulin secreting defect
- PC: neonatal HYPOglycemia, progressive hyperglycemia
- Low HDL and apolipoproteins A and C –> lipid profile similar to T2DM
- Very sensitive to sulfonylurea
MODY 2
- GCK gene mutation on ch7p13 - heterozygous mutation
- Glucokinase enzyme is important in B-cell glucose sensing
- PC: stable, mild hyperglycemia with small increment increase (<4.5mmol/L) in BSL on OGTT, usually normal BMI with no microvascular complications
- Responds to sulfonylurea and insulin
MODY 3
- HNF1-alpha mutation (most common)
- Strong family history, progressive B-cell failure and thus progressing from mild to severe dz overtime
- PC: symptomatic hypoglycemia with glycosuria secondary to reduced renal reabsorption, high HDL-C
- Prone to developing microvascular complications
- Very sensitive to sulfonylureas
MODY 4
- IPF-1 gene mutation
- Necessary for pancreatic development –> homozygous mutation causes agenesis of pancreas
MODY 5
- HNF1-beta mutation
- Important = multisystem manifestations
- -> Renal cysts and other malformations, hypospadias, uterine abN, joint laxity, learning difficulties, abN LFTs
- Pancreatic atrophy with co-existing EXOcrine pancreatic insufficienty
- Does not respond to oral agents, requires insulin
Summary of MODY
- MODY 1 and 3: progressive beta cell failure, both have strong FHx and are at risk of microvascular complications. MODY 1 has low HDL and apolipoproteins, MODY 3 has high HDL and renal glycosuria, both sensitive to sulfonylureas
- MODY 2: very mild hyperglycemia in a patient with normal BMI with very low risk of microvascular Cx
- MODY 5: multisystem involvement and associated exocrine pancreatic insufficency due to pancreatic atrophy
Monitoring during pubertal induction
- 6 monthly bone age, FSH, LH
- IGF-1 for growth hormone dosing (if concurrent)
Endocrine changes seen in pts with anorexia nervosa
- Hypothalamic suppression with low gonadotrophin levels
- Pubertal regression
- Sick euthyroid syndrome
- Decelerated linear growth
- Reduced bone mineral density
- Low IGF-1 and low thyroxine levels
