Endo Flashcards
Adrenal gland - general anatomy and hormones
a. Adrenal medulla -> adrenaline
b. Adrenal cortex
i. Zona glomerulosa (15%) > aldosterone
ii. Zona fasciulata (75%) > cortisol (+ androgens)
iii. Zona reticularis (15%) > androgens
- Steroid biosynthesis
a. Cholesterol is the starting substrate for all steroid biosynthesis
b. Circulating plasma lipoproteins provide most cholesterol for adrenal cortex hormone production
Cholesterol imported into mitochondria, catalysed to pregnenolone, which diffuses out and enters ER
f. Subsequent reactions dependent on the zone of the adrenal cortex
g. ZONA GLOMERULOSA
i. Outer zone 15% cortical width
ii. Controlled by ECF concentration of K+ and AngII
iii. Pregnenolone progesterone 11-deoxycorticosterone aldosterone
h. ZONA FASCICULATA
i. Middle zone 75% cortical width
ii. Controlled by ACTH
iii. Pregnenolone 17-hydroxypregnenolone + 17-hydroxyprotesterone 11-deoxycortisol cortisol
i. ZONA RETICULARIS
i. Inner zone width an integrated structure – 10% cortical width
ii. Controlled by ACTH and other mechanisms
iii. 17-hydroxypregnenolone dehydroepiandrosterone (DHEA) androgen
iv. Androgen covered in other tissues to testosterone and estrogens
Glucocorticoids - regulation and receptors
a. Regulation
i. SUMMARY: Hypothalamus corticotrophin releasing hormone anterior pituitary adrenocorticotrophic hormone (ACTH) adrenal cortex cortisol
iii. Normal diurnal rhythm of cortisol secretion is caused by varying amplitudes of ACTH pulses
1. Highest at waking, low in the late afternoon + evening, lowest while asleep
vi. Inhibition
1. Cortisol (negative feedback)
a. Negative feedback exerted by cortisol on secretion of ACTH, CRH and AVP
b. Receptor
i. ACTH acts on G protein coupled receptor to activate adenylate cyclase and increase levels of cyclic adenosine monophosphate; MC2R accessory protein (MRAP) is required for ACTH to stimulate corticosteroid production mutation results in glucocorticoid deficiency
c. ACTH – action
i. Activates enzymes that convert cholesterol to pregnenolone in adrenal cortex– rate limiting step for all adrenocortical hormone production
ii. NOTE: ACTH trophic to zona fascicularis and zona reticularis
Cortisol - effects
i. Metabolic effects
1. Hyperglycaemia
a. Increased hepatic gluconeogenesis
b. Increased resistance to insulin
2. Stimulates glycogen synthetase activity and reduces glycogen breakdown (protects against long term starvation)
3. Enhances lipolysis
4. Catabolic effect on protein metabolism
ii. Haematological
1. Decrease lymphocytes/eosinophils/monocytes
2. Decrease B and T cell function
3. Increase apoptosis
4. Anti-inflammatory
iii. Circulatory and renal effects
1. Positive inotropic effect on the heart
2. Permissive effect on actions of epinephrine and norepinephrine
iv. Endocrine
1. Decrease growth
2. Increase bone resorption
3. Increase adrenal androgens
v. Immunologic
1. Major role in immune regulation
vi. Skin/bone
1. Inhibit fibroblasts bruising and poor wound healing
2. Decreasing serum calcium osteoporosis
vii. CNS = psychosis
viii. CVS = increase CO
Mineralocorticoids - regulation and action
a. Regulation
i. Stimulants
1. AngII (most powerful)
2. ACTH
3. Hyperkalaemia
ii. Inhibition = ANP
iii. Steps
1. Decreased intravascular volume JGA renin
2. Renin cleaves angiotensin (renin substrate; produced by the liver) to produce AngI
3. AngI cleaved by angiotensin-converting enzyme (ACE) in the lungs to produce AngII
4. AngII also cleaved to produce AngIII
5. AngII and AngIII = potent stimulators of aldosterone secretion
b. Action = maintain intravascular volume
i. ↑ expression of epithelial sodium channel in the collecting duct ↑ Na+ re-absorption and K+ excretion ↑ blood volume and BP
ii. Stimulation of ATPase pump ↑ H+ excretion ↑ blood pH
Adrenal androgens - regulation and action
a. Regulation
i. Poorly understood
b. Action
i. Contribute to adrenarche (sexual maturation caused by DHEA and DHEAS occurs at 6-8 years = adrenarche)
ii. Males <2% androgens are adrenal, 50% in females
Adrenal medulla - products/metabolites/actions
- Products
a. Dopamine
b. Norepinephrine
c. Epinephrine - Metabolites
a. Metabolites of catecholamines are secreted in the urine - -methoxy-4-hydroxmandelic acid + metanephrines + normetanephrine
i. Used to detect phaeochromocytomas and neuroblastomas - Action
a. Epinephrine + norepinephrine both raise MAP
b. Only epinephrine positive inotropic agent increases cardiac output
Renin-Angiotensin-Aldosterone system - general
- Function – maintain fluid and electrolyte homeostasis
- Renin
a. Produced in the juxtaglomerular cells within the afferent arteriole entering the renal glomerulus (storage and release)
b. Triggers
i. Baroreceptors – decreased pressure = increased release
ii. B adrenergic receptors – SNS results = increase release
iii. Macula densa cells – sense concentration NaCl, increased NaCl concentration = increase release
c. Inhibitors
i. ANP and BNP in response to cardiac stretch – counteract fluid retention - Pathway
a. Angiotensinogen produced in liver
b. Renin produced in kidney converts
i. Angiotensinogen to Angiotensin 1
c. Angiotensin converting enzyme (ACE) produced in lungs converts
i. Angiotensin 1 into Angiotensin 2
ii. This step occurs in lungs, but also heart, brain, vessels - Actions of AngII
a. Renal
i. Vasoconstriction of the efferent»_space; afferent arteriole to increase resorption + decrease renal blood flow
ii. Increased resorption of sodium and therefore water
b. Extra-renal
i. Vasoconstriction systemic - SNS activation
ii. Thirst
iii. ADH release – water retention
iv. Aldosterone release – sodium resorption + potassium secretion
v. Heart remodeling
Tests of the HPA (hypothalamic-pituitary-adrenal) axis - static
a. Cortisol
i. Measured at 0800 in the morning = time of normal peak
ii. Can confirm hypocortisolism
iii. Does NOT distinguish between primary adrenal failure, ACTH deficiency, or enzymatic defect in biosynthesis of cortisol
b. Salivary cortisol
i. Done at midnight = time of normal nadir
ii. Validated as a screen for diagnosis of Cushing’s syndrome in children
iii. NOT well studied for diagnosis of adrenal insufficiency
c. ACTH level
i. In patients with low 0800 cortisol levels the ACTH concentration determines whether it is more likely to be primary or central
ii. Extremely elevated ACTH level in the setting of low morning cortisol level supports diagnosis of primary adrenal failure or resistance to ACTH
d. Mineralocorticoid status
i. Electrolytes = hyponatraemia and hyperkalaemia in deficiency
ii. Elevated plasma renin activity (PRA) or direct renin
e. Adrenal androgens = DHEA, DHEAS
f. Urinary steroids
Tests of the HPA (hypothalamic-pituitary-adrenal) axis - dynamic
a. ACTH stimulation test
i. Determine response of adrenal cortex to ACTH
ii. Cortisol measured at 60 and 120 minutes following IV infusion of synthetic ACTH
iii. Note that ACTH stimulation test does NOT help to distinguish between primary and central insufficiency – most patients with central adrenal insufficiency have subnormal cortisol response to ACTH stimulation due to chronic lack of ACTH stimulation
b. Test of ACTH secretory ability
i. Useful to confirm central adrenal insufficiency
ii. Main indication is in patients with suspected central adrenal insufficiency (low cortisol and low basal ACTH) but normal results in ACTH stimulation test
iii. Dynamic tests
1. Insulin-induced hypoglycaemia
2. Glucagon-stimulation test
3. Metyrapone test
Adrenocortical insufficiency - classification
Primary = due to inadequate function of adrenal cortex
o Deficiency of glucocorticoids AND mineralocorticoid
Investigations:
i. ↓ cortisol
ii. ↑ ACTH – usually 2x ULN
iii. Fasting hypoglycaemia
iv. Evidence of mineralocorticoid deficiency – hyponatraemia, hyperkalaemia, elevated renin
v. ACTH stimulation test (NOT ALWAYS REQUIRED) – if results of static tests are not definitive, a stimulation test can be done and shows failure to 0800 cortisol level to rise with ACTH stimulation
Differentials
i. Addison’s disease
ii. Congenital adrenal hyperplasia
iii. Congenital adrenal hypoplasia
iv. Adrenoleukodystrophy
v. Adrenal haemorrhage in newborns
vi. Infections (Waterhouse Friedrichsen syndrome)
Central = due to deficient ACTH secretion
o Secondary = pituitary defect
o Tertiary = hypothalamic
o Deficiency of glucocorticoids ONLY
Investigations
i. ↓ cortisol
ii. ↓ ACTH
iii. ACTH stimulation test (‘synacthen test’) – increase in cortisol production in response to ACTH
iv. Test of ACTH secretory ability (insulin induced hypoglycaemia, glucagon stimulation, or metyrapone) – poor cortisol response to any of these tests indicates central
1. Normal in primary
2. Low response in secondary
3. Low response in tertiary WITH response to CRH
• Other
o End-organ resistance to adrenocortical hormones (ACH receptor gene mutation)
o Iatrogenic – secondary to exogenous steroids – causes central ACTH suppression
Primary ACTH deficiency - differentials
i. Addison’s disease
ii. Congenital adrenal hyperplasia
iii. Congenital adrenal hypoplasia
iv. Adrenoleukodystrophy
v. Adrenal haemorrhage in newborns
vi. Infections (Waterhouse Friedrichsen syndrome)
Adrenal crisis / acute adrenal insufficiency - background
- Background
a. Adrenal crisis = event caused by an acute relative insufficiency of adrenal hormones
b. It may be precipitated by physiological stress in a susceptible patient
c. It should be considered in patients who have a history of:
i. Known primary adrenal insufficiency
ii. Hypopituitarism (any known pituitary hormone deficit or clinical features indicating increased risk), or
iii. Previously or currently being on prolonged steroid therapy.
d. Adrenal crisis may also be first presentation of underlying disease or there may be history suggestive of chronic hypoadrenalism - Classification
a. Primary
i. Addison’s disease
ii. Congenital adrenal hyperplasia
iii. Congenital adrenal hypoplasia
iv. Adrenoleukodystrophy
v. Adrenal haemorrhage in newborns
vi. Infections (Waterhouse Friedrichsen syndrome)
b. Secondary = due to deficient ACTH secretion - Triggers
a. Serious infection or acute, major physical stress
b. Under-replaced
i. Insufficient dosage
ii. Not increasing dose in infection
iii. Persistent vomiting/diarrhoea inhibiting absorption
c. Sudden exogenous glucocorticoid withdrawal
Adrenal crisis / acute adrenal insufficiency - manifestations, investigations
- Assessment
a. Acute adrenal insufficiency occurs in both primary and secondary adrenal failure
b. Cortisol deficiency weakness, fatigue, anorexia, nausea, vomiting, hypotension and hypoglycaemia.
c. Primary adrenal hypofunction – cortisol deficiency COMBINED with mineralocorticoid deficiency
i. Mineralocorticoid deficiency hyperkalaemia and hyponatraemia, acidosis and dehydration
d. Pigmentation may be present in primary adrenal failure – ACTH excess stimulates melanocortin 1 receptor on melanocytes
e. There may be CNS signs in adrenoleukodystoprhy (ADL)
f. Summary of key findings
i. Hypotension and shock
ii. Serum electrolyte abnormalities - Hyponatraemia
- Hyperkalaemia
- Hypoglycaemia – do not be reassured by a normal BSL
- Metabolic acidosis
iii. Non-specific symptoms: anorexia, nausea, vomiting, abdominal pain, weakness, fatigue, lethargy, fever, confusion and/or coma
a. Investigations to be done in all cases of possible adrenal insufficiency / crisis:
i. Immediate blood glucose using a bedside glucometer
ii. Serum glucose, urea, sodium and potassium
iii. Arterial or capillary acid base
iv. Cortisol + 17 hydroxyprogesterone levels
1. NOTE: if unwell cortisol should be 600-1000+ therefore ‘normal’ cortisol may be
v. Renin and ACTH levels
vi. Urinary steroid profile and urinary sodium level
Adrenal crisis / acute adrenal insufficiency - treatment, prevention
- Prevention of adrenal crisis in susceptible child
a. During illness (eg. flu, fever) the usual oral dose of steroid should be tripled
i. Stress dosing of glucocorticoids
ii. Triple dose for 3 days, then double dose for 2 days, then normal dose
iii. If cannot tolerate orally IV hydrocortisone Q6hrly
b. Surgery or anaesthesia: Increased parenteral hydrocortisone should be given before surgery and general anaesthesia and ‘stress’ cover continued post-op also
i. Bolus on induction (varies depending on age 25-50-100mg <3/>3/>12)
ii. Followed by Q6H triple dose IV
iii. Taper according to clinical improvement
c. NB. Vomiting in a child who is susceptible to adrenal crisis – treat as adrenal crisis (even if otherwise well) as oral medications are not reliably absorbed - Treatment of adrenal crisis
a. IV FLUIDS
i. Maintenance = 100ml/kg/day for first 10kg body weight, 50ml/kg/day for next 10kg, 25ml/kg/day for each successive 10kg
Deficit = 100ml/kg for 10% dehydration, 60 ml/kg for 6% dehydration and 30ml/kg for 3% dehydration.
b. STEROID REPLACEMENT
i. Steroids = 50-100 mg/m2 IV - IV bolus of hydrocortisone hemisuccinate (Solu-Cortef)
- If IV access is not immediately available, give IM while establishing intravenous access
- Follow with hydrocortisone 6hourly IV
ii. Mineralocorticoids - Mineralocorticoid replacement: in patients with mineralocorticoid deficiency start fludrocortisone (Florinef) at maintenance doses (usually 0.05 - 0.1 mg daily) as soon as patient can tolerate oral fluids
- Initial correction is achieved with saline, fluids and the mineralocorticoid activity of stress dose hydrocortisone (20mg = ~ 0.1 mg Florinef)
- NB. Prednisolone has little / no mineralocorticoid activity
c. TREAT HYPOGLYCAEMIA
i. Hypoglycaemia is common in infants and small children with adrenal insufficiency.
ii. Treat with IV dextrose
d. TREAT HYPERKALAEMIA
i. This usually normalizes with fluid and electrolyte and steroid replacement
Primary adrenal insufficiency - specific features
Hyperpigmentation High ACTH Features of mineralocorticoid deficiency i. Hyponatreamia ii. Hyperkalaemia iii. High plasma renin Salt craving High plasma renin
Primary adrenal insufficiency - aetiology
a. Inherited
i. Inborn errors of steroidogenesis
ii. CAH
iii. SF-1 deficiency
iv. Disorders of LCFA metabolism- adrenoleukodystrophy/ Adrenomyeloneuropathy
v. Congenital adrenal hypoplasia
vi. Type 1 APS and type 2 APS (autoimmune polyglandular syndrome)
b. Acquired
i. Autoimmune – Addison’s
ii. Adrenal haemorrhage
iii. Infection
iv. Drugs
Primary adrenal insufficiency - manifestations, investigations
- Clinical manifestations
a. Hypoglycaemia
i. Predominant symptoms of adrenal insufficiency
ii. Often accompanied by ketosis as the body tries to use fatty acids as alternative body state
b. Hypotension/shock
i. Cortisol deficiency reduced cardiac output + vascular tone - Catecholamines such as adrenaline have decreased inotropic and pressor effects in the absence of cortisol
ii. Exacerbated by aldosterone deficiency hypovolaemia due to lack of Na+ reabsorption
c. Hyponatremia
i. Glucocorticoid deficiency increased ACTH + ADH secretion increased water resorption
ii. Mineralocorticoid deficiency reduced Na+ resorption
d. Hyperkalaemia = mineralocorticoid deficiency reduced K+ excretion
e. Bronze pigmentation = glucocorticoid deficiency ACTH and other peptide hormone produced by the ACTH precursor POMC (particularly gamma-melanocyte-stimulating hormone) bronze appearance (PRIMARY ONLY) - Investigations
a. Mineralocorticoid deficiency (PRIMARY ONLY)
i. Hyponatreamia
ii. Hyperkalaemia
iii. High plasma renin
b. Glucocorticoid deficiency
i. Hyponatraemia
ii. Hypoglycaemia
iii. Ketosis
iv. Low random cortisol levels
v. Eosinophilia, lymphocytosis
vi. High ACTH - Investigations for DDx
a. Serum 17-hydroxyprogeserone – elevated in 95% of CAH
b. Cortisol + ACTH
i. ↑ ACTH in primary ↓ ACTH in secondary
c. ACTH stimulation test - confirms diagnosis
i. Low cortisol response in primary
ii. Low/normal cortisol response if secondary – due to chronic suppression
iii. Can also be used to assess adrenal suppression in individuals on chronic steroids
d. VLCFA – elevated in ALD
e. Imaging - USS/CT/MRI – identify size and abnormality in adrenal gland
Primary adrenal insufficiency - treatment
NOT ADRENAL CRISIS
b. Long-term
i. Chronic replacement of cortisol and aldosterone
i. Hydrocortisone - 10-12mg/m2/day in 3 divided doses
1. ACTH levels may be used to monitor adequacy in primary adrenal insufficiency
a. Morning ACTH levels 3-4x the normal range are usually satisfactory
2. In CAH – levels of precursor hormones are used instead
3. Excess – weight gain, height velocity, Cushing features
4. Insufficiency – increased hyperpigmentation, hypoglycaemia, failure to thrive, raised ACTH
ii. Fludrocortisone – 50-150 mcg/day
1. Plasma renin can be used to monitor
2. Excess – hypertension, suppressed renin
3. Insufficiency – salt craving, poor weight gain, hyponatraemia, hyperkalaemia, hypotension, raised renin
Congenital adrenal hyperplasia - aetiology
21-Hydroxylase deficiency (95%)
- CYP21A2 mutations
11β-Hydroxylase deficiency (5%)
- CYP11B1 mutations
Other/Rarer: 3β-Hydroxysteroid dehydrogenase type 2 deficiency 17α-Hydroxylase deficiency P450 oxidoreductase deficiency P450 side-chain cleavage deficiency Congenital lipoid adrenal hyperplasia
Most common cause of adrenocortical insufficiency in infancy
Salt losing forms of congenital adrenal hyperplasia
Proportion of infants which develop salt losing symptoms (unable to synthesize cortisol OR aldosterone)
i. 21-hydroylase deficiency – 75%
ii. Lipoid adrenal hyperplasia – almost all
iii. 3beta-hydroxysteorid dehydrogenase – most
ADRENAL HYPOPLASIA CONGENITA (AHC) - general
a. Genetics = DAX1 mutation (located Xp21)
i. NOTE: Non-X linked = IMAGe (IUGR, skeletal abnormalities, adrenal insufficiency, genital abnormalities)
b. Pathogenesis
i. Failure of development of the definitive zone of the adrenal cortex – fetal zone may be relatively normal
ii. Adrenal insufficiency usually manifests with the fetal zone involute postnatally
c. Clinical manifestations
i. Acute primary adrenal insufficiency in the first (or second) month of life (less common)
ii. Primary adrenal insufficiency in 1st 2 years of life (most common), occasionally later in childhood or adulthood
iii. Aldosterone insufficiency may manifest prior to cortisol deficiency
iv. Males = cryptorchidism, hypogonadotropic hypogonadism
d. Contiguous gene syndrome = AHC + other syndromes
i. Developmental delay and seizures, strabismus
ii. Glycerol kinase deficiency Metabolic acidosis, hypoglycemia
iii. Duchenne muscular dystrophy
Adrenoleukodystrophy - general
a. Genetics
i. Most common form is X-linked – affects male
ii. 95% of patients have a mutation in ABCD1 gene
iii. Gene encodes a transmembrane transporter involved in the importation of very-long-chain fatty acids into peroxisomes accumulation off LCFA in adrenal cortex and brain
b. Males – 3 phenotypes
i. Childhood cerebral form = manifests between ages four and eight years
1. It initially resembles attention deficit disorder or hyperactivity
2. Progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years.
ii. Adrenomyeloneuropathy (AMN) = manifests in the late twenties as progressive paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function
1. All symptoms are progressive over decades
iii. “Addison disease only” = presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops later
c. Females = approximately 20% of females who are carriers develop neurologic manifestations that resemble AMN but have later onset (age ≥35 years) and milder disease than do affected males
d. Investigations
i. VLCFA in plasma = elevated
ii. MRI = always abnormal in boys with cerebral disease
iii. Morning cortisol and ACTH +/- Synacthen test
iv. ABCD1 gene testing
e. Treatment = BMT – only if early neurological involvement
Familial glucocorticoid deficiency - general
a. Chronic adrenal insufficiency characterised by
i. Isolated deficiency of glucocorticoids
ii. Elevated levels of ACTH
iii. Normally levels of aldosterone production – although salt-losing manifestations are present in most other forms of adrenal insufficiency occasionally occur
b. Clinical presentation
i. Hypoglycaemia
ii. Seizures
iii. Increased pigmentation
c. Genetics
i. Affects both sexes equally
ii. Inherited in autosomal recessive manner
iii. Different genes implicated
1. MRC2 – ACTH receptor
2. MRAP – protein required for signaling
Drugs causing adrenal insufficiency
a. Ketoconazole = inhibits adrenal insufficiency
Inhibition of mitochondrial cytochrome P450 enzymes (e.g., CYP11A1, CYP11B1)
b. Mitotane
c. Etomidate = general anaesthesia
Secondary/Tertiary Adrenal Insufficiency - general
Lots of causes - congenital vs acquired
- Clinical manifestations
a. ONLY manifestations of glucocorticoid deficiency (mineralocorticoids not affected) - Investigations
a. Low-dose ACTH stimulation test - Treatment
a. Iatrogenic
i. Best avoided by using the smallest effective dose for the shortest period of time
ii. Require adequate tapering dose to allow the body time to start producing its own hormone
b. Anatomic lesions of pituitary
i. Treatment indefinitely with glucocorticosteroids
Congenital adrenal hyperplasia - general background
• Family of autosomal recessive disorders of cortisol biosynthesis
• Cortisol deficiency increases secretion of ACTH adrenocortical hyperplasia and overproduction of metabolites
• Consequences depend on enzymatic step which is missing
• Combination:
1. Mineralocorticoid deficiency or excess
2. Incomplete virilisation or precocious puberty in affected males
3. Virilisation or sexual infantilism in affected females
Congenital adrenal hyperplasia - aetiology
• CYP21A2 (21 hydroxylase) deficiency (17OHP up) o 95% of adrenal steroid defects o Autosomal recessive o 1/14,000 live births o CYP21A2 chromosome 6p o Impairs 17OP to 11 deoxycortisol o Most common cause CAH
• CYP11B1 (11-beta-hydroxylase) deficiency (11deoxycortisol up)
o 5% of CAH
o Cortisol synthesis is reduced
o Excess deoxycortisone (which acts like aldosterone), adrenal androgen overproduction
o Hypertension and virilisation of affected females
• 3 Beta hydroxysteroid dehydrogenase deficiency
o Rare
o All steroid hormone synthesis impaired
o Thus deficiencies in GC, MC and active androgens
o Most present as neonates – feeding difficulties, vomiting, hypotension, hyponatremia, hyperkalemia
o Affected females may have mild virilisation – males have varying degree of failure of gonad developments from hypospadias to severe ambiguity
• CYP17 (17 alpha hydroxylase deficiency)
o Rare
o Although sufficient cortisol is not produced, large quantities of corticosterone (a steroid with both GC and MC activities) are synthesized, reducing symptoms of cortisol deficiency
o HTN
o Androgen and oestrogen synthesis are impaired – male patients have female external genitalia and a blind vagina, and affected females have primary amenorrhea and absent secondary sexual characteristics
• Congenital lipoid adrenal hyperplasia – StAR deficiency – cholesterol unable to enter metabolic pathway
o Most rare and most severe form
o All major adrenal steroids inhibited
o Adrenal glands are filled with lipid granules
o Present as neonates with adrenocortical insufficiency – poor feeding, vomiting, lethargy, hypotension, resp distress, hyponatremia, hyperkalemia, hypoglycaemia and metabolic acidosis
o Affected males have female genitalia, and affected females have normal
21-hydroxylase deficiency - key points/genetics
- Key points
a. >90% of CAH cases caused by 21-hydroxylase deficiency
b. Autosomal recessive
c. 3 main clinical phenotypes
d. Classic CAH
i. Severe salt wasting form (75%) = deficiency in both hormones
ii. Simple virilising form (25%) = less-severely affected patients are able to synthesize adequate amounts of aldosterone but have elevated levels of androgens of adrenal origin
e. Non-classic (late onset)
i. Presents later in life with signs of androgen excess WITHOUT neonatal genital ambiguity - Genetics
a. P450 enzyme hydroxylates
i. Progesterone 11-deoxycoritocsterone aldosterone
ii. 17-hydroxyprogesterone 11-deoxycortisol cortisol
b. 21-hydroxylase mediates conversion of 17-hydroxyprogesterone to 11-deoxycortisol
c. 2 steroid 21-hydroxylase genes – CYP21P and CYP21
i. CYP21 is the active gene
ii. CYP21P is 98% identical to CYP21 but is a pseudogene because of 9 different mutations
d. >90% of mutations causing 21-hydroxylase deficiency are recombinations between CY21 and CYP21P
i. 20% are deletions generated by unequal meiotic crossing over
ii. Gene conversion – caused by non-reciprocal transfer of deleterious mutations
e. Deleterious mutations in CYP21P can have different effects on enzymatic activity of CYP21
i. Completely prevent synthesis
ii. Missense mutations that yield enzymes with 1-50% of activity
f. Disease severity correlates with mutations – ie. salt wasting disease results from mutations on both alleles that completely destroy enzymatic activity
g. Closely adjacent to CYP21 is the TNX gene (encodes CT protein); patients with deletions of both have contiguous gene syndrome consisting of CAH and EDS
21-hydroxylase deficiency - pathogenesis
a. Aldosterone and cortisol deficiency
i. Both cortisol and aldosterone require 21-hydroxylation for synthesis both deficient in most severe form of disease
ii. Signs and symptoms as per adrenal crisis notes weight loss, anorexia, vomiting, dehydration, weakness, hypotension, hypoglycaemia, hyponatreamia, hyperkalaemia
iii. Typically develop in affected infants at 10-14 days of life
iv. Ineffective cortisol production compensatory elevation in ACTH adrenal cortex hyperplasia
v. Accumulation of enzyme precursors elevated levels of 17-hydroxyprogesterone + progesterone
b. Prenatal androgen excess
i. Accumulation of 17-hydroxyprogesterone shunted into pathway for androgen biosynthesis elevated levels of androstenedione converted outside the adrenal gland to testosterone
ii. FEMALES
1. Genitalia development
b. Characterised by enlargement of clitoris (may resemble a penis) and by partial or complete labial fusion (common opening with urethra – urogenital sinus)
c. Severity of virilisation is usually greatest in females with salt-losing form of 21-hydroxylase deficiency
d. The internal organs are normal, because affected females have normal ovaries and no testes and therefore do not secrete anti-mullerian hormone
2. Sexually dysmorphic behaviors
a. Elevated androgens may affect brain development
b. Girls may demonstrate aggressive play behavior, play with masculine toys
c. Women have decreased interest in maternal roles etc
iii. MALES
1. Appear normal at birth
2. Therefore diagnosis may not be made until adrenal insufficiency develops
c. Postnatal androgen excess
i. Untreated or inadequately treated children of both sexes develop additional signs of androgen excess after birth
ii. Boys with the simple virilising form often have delayed diagnosis as they appear normal
iii. Signs of androgen excess
1. Rapid somatic growth
2. Accelerated skeletal maturation – tall in childhood but premature closure of epiphyses causes growth to stop relatively early, and adult stature is stunted
3. Muscular development may be excessive
4. Pubic and axillary hair may appear
5. Acne
6. Males – penis scrotum and prostate may become enlarged, testes are usually pre-pubertal size
7. Females – clitoris further enlarged, breast and menstruation may not occur unless production of androgens is suppressed
iv. Similar but milder signs of androgen excess occur in non-classic 21-hydroxylase deficiency
1. Males and females may present with precocious pubarche and early development of pubic and axillary hair
2. Hirsutism, acne, menstrual disorders, and infertility occur
d. Adrenomedullary dysfunction
i. Development of the adrenal medulla requires exposure to the extremely high cortisol levels normally present within the adrenal gland
ii. Thus patients with classic CAH have abnormal adrenomedullary function
1. Blunted adrenaline responses
2. Decreased blood glucose
3. Lower HR with exercise
Mineralocorticoid deficiency - effects
Salt wasting
- hyponatraemia
- hyperkalaemia
- dehydration
Glucocorticoid deficiency - effects
Adrenal crisis
- shock
- hypoglycaemia
ACTH excess - effects
Pigmentation
Further stimulation of adrenal gland
Adrenal hyperplasia
21-hydroxylase deficiency - manifestations and investigations
- Clinical presentation
a. Classic CAH
i. Females with classic form (salt losing AND non-salt losing) = present with genital ambiguity - Rarely present with salt wasting if ambiguous genitalia not recognized
- Note that there are NO palpable testes
ii. Males - Salt losing = FTT, dehydration, hyponatraemia, and hyperkalaemia at 7-14 days of life (can present up to 21 days)
- Non-salt losing = present at 2-4 year of age with early virilisation (pubic hair, growth spurt, adult body odour), often very advanced bone age at presentation
b. Non-classical CAH females
i. Milder defect of glucocorticoid pathway – non-salt wasting
ii. Early pubic hair (pubarche), hirsutism, PCOS/secondary amenorrhoea
iii. May be no symptoms - Investigations
a. Electrolyte disturbance – can take 10-14 days after birth to develop
i. Hyponatreamia
ii. Hyperkalaemia
iii. Metabolic acidosis
iv. Hypoglycaemia
b. Markedly elevated 17-hydroxyprogesterone – highest in morning, lowest at night
i. Most reliably measured by taking sample 30-60 minutes after IV bolus of Cosyntropin (ACTH1-24)
c. Cortisol levels – low (normal in patients with simple virilising disease, but inappropriately low in relation to ACTH and 17-hydroxyprogesterone levels)
d. Androstenedione and testosterone – elevated in females
e. Testosterone – not elevated in males, as normal infant males have higher testosterone levels
f. Urinary 17-ketosteroids and pregnanetreiol – elevated
g. ACTH – elevated (but not often tested over 17-hydroxprogesterone)
h. Renin – elevated
i. Aldosterone – inappropriately low for level of renin
21-hydroxylase deficiency - treatment
a. Goals of treatment
i. Replace adrenal hormones = life saving
ii. Restore normal salt balance
iii. Optimise growth
b. Salt replacement
i. Particularly important for infants
c. Glucocorticoid replacement
- also suppresses excess androgen production
- often requires larger doses than other forms of adrenal insufficiency (15-20mg/m^2/d in 3 divided doses)
- double/triple dose for stress dosing
- monitor growth, puberty, bones, hormones (17OHprogesterone+adrostenedione)
- overtreatment = iatrogenic Cushings
- undertreatment = adrenal crisis and androgen excess (precocious puberty, rapid growth, advanced epiphyseal maturation, hair)
- currently growth is compromised 8-10cm overall
- can result in iatrogenic HTN
d. Fludrocortisone replacement
- normalise electrolytes, fluid balance, plasma renin
- also require higher doses (0.1-0.3mg/d in 2 divided doses)
- can often be tapered at 4-6mo of age, risk of HTN as kidneys become more sensitive
- monitor HR, BP, renin
e. Surgery
i. Highly controversial
f. Antenatal treatment (ONLY in a research setting)
i. Use of antenatal dexamethasone treatment has been increasingly used – attempting to suppress excess androgen production early in weeks of gestation
ii. Concerns regarding cognitive and developmental outcomes in those treated unnecessarily
Non Classic congenital adrenal hyperplasia - general
- Key points
- still due to 21-hydroxylase deficiency
a. Most severely affected individuals with classic CAH due to CYP21A2 deficiency present during neonatal period and early infancy with adrenal insufficiency with or without salt wasting
b. “Nonclassic,” or late-onset CYP21A2 deficiency, does not manifest with neonatal genital ambiguity; rather, it presents later in life with signs of androgen excess - Pathogenesis
a. The severity of disease relates to the degree to which the mutations compromise enzyme activity
b. In patients with the nonclassic form, enzymatic activity is reduced but sufficient to maintain normal glucocorticoid and mineralocorticoid production, at the expense of excessive androgen production - Clinical presentation
a. Present AFTER the neonatal period with signs of hyperandrogenism and WITHOUT adrenal insufficiency
b. Premature pubarche – body odour, hirsutism, pubic hair
i. Children with non-classic CYP21A2 deficiency differ from children with ordinary premature adrenarche in having advanced bone age
c. Medication-resistant cystic acne
d. Accelerated growth with tall stature
i. These children may enter puberty early, with early epiphyseal closure resulting in short stature as an adult
ii. Advanced bone age
e. Female adolescents
i. Clinical features - Acne
- Hirsutism
- Menstrual irregularity
- Low fertility rates
ii. DDx from PCOS - Non-classic CAH is uncommon in African-American individuals
- Insulin resistance may be more severe, but probably not more common in PCOS
- Polycystic ovaries on ultrasound
- Obesity more common in PCOS
11 beta hydroxylase deficiency - general
- Key points
a. Accounts for up to 5% of CAH
b. 2nd most common type of CAH
c. Results from mutation in CYP11B1 gene
d. Also results in blockage of glucocorticoid + mineralocorticoid pathways (one step further than 21-hydroxylase)
i. Adjacent CYP11B2 gene encoding aldosterone synthase is generally unaffected – able to synthesize aldosterone (Aldosterone synthase mediates the 3 final steps in the synthesis of aldosterone from deoxycorticosterone (11β-hydroxylation, 18-hydroxylation, and 18- oxidation))
- it is the absence of cortisol that drives inc ACTH and therefore inc androgens/DOC - Pathogenesis
a. Blocks conversion of:
i. DOC (deoxycorticosterone) corticosterone (which then aldosterone)
ii. 11-DOC (deoxycortisol) cortisol
b. Consequences
i. ↑ ACTH secretion
ii. ↑ levels of DOC and 11-DOC - Shunted into androgen biosynthesis in similar manner to classical CAH
- DOC has mineralocorticoid function
iii. Some corticosterone is synthesized from progesterone by the intact aldosterone synthase enzyme and has weak glucocorticoid potency – therefore unusual for patients to manifest signs of adrenal insufficiency
c. Summary
i. Excess androgens – milder than 21-hydroxyalse
ii. Excess mineralocorticoid activity (via DOC)
iii. Cortisol insufficiency (NOT adrenal insufficiency) - Clinical manifestations
a. Hypertension + hypokalaemia – characteristic
b. Female newborns – ambiguous genitalia
c. Boys – may have increased penile size
d. Children not diagnosed at birth
i. Premature adrenarche with advanced bone age - Somatic growth and bone age advance faster than idiopathic premature adrenarche
e. If untreated
i. Isosexual or contrasexual precocious puberty
ii. Hirsutism and menstrual irregularities in adolescent girls - Investigations
a. ↑ 11-Deoxycortisol and Deoxycorticosterone
b. ↓ cortisol and corticosterone
c. ↓ Renin - Differential diagnoses
a. Hypertension and hyperkalaemia – distinguishes 11OHD from 21OHD and HSD3B2 deficiency
b. Androgen excess – distinguishes 11OHD from 17OHD - Treatment
a. Hydrocortisone
b. Fludrocortisone not necessary – may even require spironolactone to antagonize the androgens and mineralocorticoids
Primary aldosteronism - general
AKA Conn syndrome
Key features
a. Excessive aldosterone secretion INDEPENDENT of RAAS
b. Rare in children but account for 5-10% of HTN in adults
c. Although usually sporadic, some familial forms
- Etiology
a. Aldosterone-secreting adenomas
i. Reported in children as young as 3.5 years
ii. More common in girls
b. Bilateral micronodular adrenocortical hyperplasia
i. Tends to occur in older children
ii. More common in males
c. Unilateral hyperplasia - Clinical manifestations
a. Often asymptomatic – hypertension detected incidentally
b. Others have severe hypertension with headache, dizziness, visual disturbance
c. Chronic hypokalaemia can lead to polyuria, nocturia, enuresis and polydipsia
d. Muscle weakness and discomfort, tetany, intermittent paralysis + growth failure affects children with severe hypokalaemia - Investigations
a. Hypokalaemia
b. Serum pH, CO2, Na+ = may be ↑
c. Serum chloride and Mg = may be ↓
d. Plasma levels of aldosterone = ↑
e. Plasma renin = ↓(suppressed)
f. Urine
i. Urine = neutral or alkaline
ii. Urinary potassium excretion = high
iii. 24 Urine aldosterone = high
g. Diagnostic test
i. Controversial diagnostic test of choice
ii. Renin and aldosterone vary based on time of day, posture, sodium intake
iii. Affected by diuretics, beta blockers, ACI, ARB, clonidine, NSAIDs
iv. Plasma aldosterone: renin = high
v. Aldosterone does NOT decrease with administration of saline solution or fludrocortisone
vi. Renin does not respond to salt and fluid restriction - DDx
a. Primary aldosteronism should be distinguished from glucocorticoid suppressible hyperaldosteronism – which can be treated with glucorticoids
b. Glucocorticoid suppressible hyperaldosteronism is diagnosed by dexamethasone suppression test - Treatment
a. Aldosterone-secreting adenoma = surgical excision
b. Bilateral adrenal hyperplasia = spironolactone or eplerenone
i. Normalise BP and potassium
Adrenocortical tumours - general
- Key points
a. Rare in childhood
b. Occur in all age groups – more commonly in children <6 years
c. 2-10% of cases – bilateral
d. Almost half of childhood adrenocortical tumours are carcinomas
e. Symptoms of endocrine hyperfunction are present in 80-90% of children
f. Tumours may be associated with hemihypertrophy
g. Also associated with other congenital defects, particularly genitourinary tract and CNS abnormalities and hamartomatous defects
h. Aldosterone secreting adenomas are a separate category from other adrenocortical tumours – very rarely malignant - Etiology
a. Familial cancer syndromes
i. Li Fraumeni = p53 tumour suppressor (TP53)
ii. Multiple endocrine neoplasia = menin (MEN1)
iii. Familial adenomatous polyposis = APC
iv. PRKAR1A gene
b. Other
i. Over-expression of IGFF2 in 80% of sporadic childhood adrenocortical tumours (also in Beckwith-Wideman syndrome – loss of imprinting of genes on this chromosome) - Clinical manifestations
a. Virilisation = most common presenting symptom in children with adrenocortical tumours 50-80%
i. Males = accelerate growth velocity and muscle development, acne, penile enlargement, precocious development of pubic and axillary air (similar to CAH)
ii. Females = masculinization of previously normal female (clitoral enlargement, growth acceleration, acne, deepening of voice, premature pubic and axillary air)
b. High oestrogens (10%) – due to over-expression of CYP19 aromatase
i. Males = gynecomastia
ii. Female = premature thelarche
c. Cushing’s syndrome = 15-40%
i. Isolated virilisation frequently occurs alone, children with adrenal tumours do not have Cushing syndrome alone - Investigations
a. Androgens elevated, often markedly (Dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), androstenedione)
b. Testosterone = increased (due to peripheral conversion)
c. Oestrone and oestradiol = elevated in patients with feminizing signs
d. Urinary 17-ketoteroids (sex steroid metabolites) = elevated
e. Imaging (USS, CT, MRI) - DDx of virilisation
i. Virilising forms of adrenal hyperplasia
ii. Exposure to androgens such as topical testosterone - Treatment
a. Surgical removal
Cushing’s syndrome
Term used to describe signs of prolonged glucocorticoid excess
Cushing’s disease
Cushing syndrome due to pituitary adenoma secreting ACTH
Cushings syndrome - key points
- Key points
a. Cushing’s syndrome – term used to describe prolonged glucocorticoid excess
b. Cushing’s disease – Cushing’s syndrome caused by a pituitary adenoma secreting ACTH
c. Caused by abnormally high blood levels of cortisol or other glucocorticoids
d. Most commonly caused by exogenous administration of glucocorticoid hormone
Most common aetiology Cushing syndrome
Cushing disease - pituitary adenoma secreting ACTH
68%
Cushing syndrome - aetiology
a. ACTH-dependent
i. Cushing disease (68%)
1. Excess ACTH secreted by pituitary adenoma bilateral adrenal hyperplasia
2. Rare in infants, most common aetiology in children >7 years
3. Usually micro-adenoma
4. Mostly sporadic
5. Syndromes associated with pituitary adenomas
a. Familial isolated pituitary adenoma syndrome
i. Mutation in the aryl hydrocarbon receptor interactive protein (AIP) gene
ii. Accounts for 2% pituitary adenomas
b. Multiple endocrine neoplasia (MEN1) – however typically prolactinomas
ii. Ectopic ACTH production (12%)
1. Uncommon in children
2. Cause = Islet cell carcinoma of the pancreas, neuroblastoma or ganglioneuroblastoma, hemangiopericytoma, Wilm’s tumour, thymic carcinoid
3. Hypertension more common in ectopic ACTH syndrome than other forms of Cushing syndrome as very high cortisol levels overwhelm 11-beta-hydroxysteroid dehydrogenase in the kidney, therefore enhanced mineralocorticoid effect
b. ACTH-independent
i. Iatrogenic
ii. Adrenal adenoma (10%)/carcinoma (10%) – primary excess cortisol production
iii. Several syndromes associated with autonomously hyperfunctioning nodules of adrenocortical tumour (rather than single adenomas or carcinomas)
1. Primary pigmented nodular adrenocortical disease (PPNAD)
a. Isolated or occurs as familial disorder with other manifestations
b. Adrenal glands are small
2. McCune-Albright syndrome = precocious puberty + fibrous dysplasia + café au lait
a. Nodular hyperplasia and adenoma formation
b. Begins in infancy
Pseudo Cushings
- alcoholism (1%)
- major depressive disorder («1%)
Cushing syndrome - manifestations
- Clinical manifestations
a. Moon facies
b. Generalised obesity in younger children, severe obesity of face + trunk compared with extremities in children
c. Adrenal tumours – signs of abnormal masculinization (hirsutism on the face or trunk, pubic hair, acne, deepening voice, enlargement of clitoris)
d. Impaired growth – results in short stature
e. Hypertension
f. Increased susceptibility to infection
g. Purplish striae on hips, abdomen and thighs
h. Pubertal development may be delayed – amenorrhoea may occur past menarche
i. Weakness, headache, emotional lability
j. Hypertension and hyperglycaemia, can result
k. Osteoporosis and pathological fractures
Fat • Central weight gain • Moon facies • Dorsal fat pad (hump) Protein • Proximal muscle wasting • Thin skin • Bruising • Striae (decrease collagen in SC tissue) CHO • Hyperglycaemia (diabetogenic) Haematological • Immune suppression • Recurrent infection • Poor wound healing Endocrine • Osteoporosis • Poor growth • Acne, hirsutism, frontal alopecia • Amenorrhoea, delayed puberty CVS • Hypertension (mineralocorticoid effect) CNS • Depression • Psychosis
+/- hyperpigmentation in ACTH excess (MSH (melanocyte stimulating hormone) from ATCH proteolysis from POMC (pro-opiomelanocortin))
+/- bitemporal hemianopia in Cushing’s disease
Cushing syndrome - investigations
Establish hypercortisolaemia
Look for cause
a. Confirm elevated cortisol levels (serum/saliva/urine)
i. Midnight cortisol level = elevated
1. Highest at 0800 and decrease to less than 50% by midnight (except in infants and young children when diurnal pattern not always established)
2. Midnight cortisol levels >4.4ug/dL
3. Serum or saliva
ii. Urinary excretion of free cortisol = elevated
1. Best measured in 24 hour urine sample and expressed as micrograms of cortisol per creatinine
iii. Low dose dexamethasone suppression test – dose of dexamethasone at 2300 > cortisol at 0800
1. Normal = <5 ug/dL (you should have suppressed cortisol production if given a big dose)
2. Elevated in Cushing’s disease (autonomous cortisol production)
b. Determining cause of elevated cortisol (dex suppression test, imaging)
i. 2 step dexamethasone suppression test – determine if ACTH dependent on independent
1. Low dose then high dose dexamethasone in 4 doses over 2 days
2. At 24 hours – low dose result
a. No suppression of cortisol confirms diagnosis Cushing’s
3. At 48hours – high dose result
- cortisol will be suppressed in ACTH dependent Cushings, as high dose dex suppresses ACTH
ii. Paired ACTH level
1. ↓ in patients with cortisol producing tumour, exogenous steroids
2. ↑ with ACTH secreting tumour (but may be normal in ACTH-secreting pituitary adenoma)
iii. CRH
1. IV bolus of CRH
2. ACTH-dependent Cushing’s = exaggerated ACTH and cortisol response
3. ACTH-independent (eg. adrenal tumour) = no increase to ACTH
c. Other
i. Glucose tolerance test – often abnormal but not diagnostic
ii. Electrolytes – usually normal
1. Potassium may be decreased in patients who have ectopic ACTH production
d. Imaging
i. CT = adrenal tumours
1. Unilateral = tumour
2. Bilateral hyperplasia = usually due to ACTH production
ii. MRI = pituitary tumours
Cushing syndrome - treatment
a. Dependent on cause
b. Pituitary adenoma (Cushing’s disease) = resection
c. Cyproheptadine (serotonin antagonist) = used in adults but rarely used in children
d. Inhibitors of adrenal steroidogenesis (metyrapone, ketoconazole, aminoglutethimide, etomidate) have been used pre-operatively
e. Mifepristone = glucocorticoid receptor antagonist, sometimes used
f. Somatostatin analogue = can inhibit ACTH secretion
g. Adrenalectomy = very rarely done
i. Results in increased ACTH and marked pigmentation if there is a pituitary adenoma – Nelson syndrome
Phaeochromocytoma - background
- Key points
a. Catecholamine secreting tumours arising from chromaffin cells
i. Produce adrenaline, noradrenaline and dopamine symptoms
b. 10% occur in children – present between 6-14 years of age
c. 80% associated with familial disorder
d. 50% malignant – require lifelong surveillance
e. Features
i. Vary in size from 1-10cm
ii. More often on the R) side than the L)
iii. In >20% adrenal tumours are bilateral – more likely if familial
iv. 30-40% tumours found in both adrenal and extra-adrenal areas or only in extra-adrenal areas
f. Location
i. Adrenal medulla (90%)
ii. Can develop anywhere along the abdominal sympathetic chain
iii. Extra-adrenal = paraganglioma - Etiology
a. Von Hippel Lindau disease
i. Retinal and CNS haemangioblastomas, renal cell carcinoma, phaeochromocytoma
ii. Germline mutation in VHL tumour suppressor gene
b. Multiple endocrine neoplasm MEN2A and MEN2B
i. Medullary thyroid cancer and parathyroid tumour, 50% develop phaeochromocytoma
ii. Mutations in RET proto-oncogene
c. Neurofibromatosis type 1 (NF1) or TS
d. Sturge-Weber syndrome
e. Ataxia-telangiectasia
Phaeochromocytoma - manifestations/investigtaions/ddx
- Clinical manifestations
a. Detected by surveillance in children with known genetic syndromes
b. Symptoms present in 50% of patients
c. Classic triad = headache, sweating, tachycardia
d. Key features
i. Hypertension – results from excessive secretion of adrenaline and noradrenaline - Paroxysmal hypertension particularly suggestive of phaeochromocytoma
- More often sustained in children
ii. Attacks of symptoms – headache, palpitations, abdominal pain, dizziness, pallor, vomiting, sweating
iii. Convulsions and other manifestations of hypertensive encephalopathy
e. Other points
i. Symptoms may be exacerbated by exercise
ii. Good appetite due to hypermetabolic state but may not gain weight
iii. Polyuria and polydipsia can occur
iv. Growth failure
v. Opthal examination – papilloedema, haemorrhages, exudate, arterial constriction
vi. Cardiomyopathy - Investigations
a. Urinary noradrenaline + metanephrines (particularly normetanephrine) + total catecholamine excretion
i. All elevated in phaeochromocytoma
ii. Children with phaeochromocytoma secrete noradrenaline in the urine (cf adults who secrete noradrenaline and adrenaline)
iii. If normal but suspicious – re-check during paroxysm
b. Plasma free catecholamines and metanephrines = elevated
c. Imaging = abdominal CT/MRI MIBG/PET if negative
d. Genetic panel = SDH panel, VHL, RET (MEN2), NF1 - DDx
a. DDx of hypertension in children
b. Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma – frequently produce catecholamines
i. Urinary levels of most catecholamines are higher in patients with phaeochromocytoma
ii. Levels of dopamine and homovanillic acid higher in neuroblastoma
Phaeochromocytoma - treatment
Surgery
- Treatment
a. Surgical excision
i. MEN2 – bilateral adrenalectomy due to the recurrence risk
ii. VHL – cortical-sparing bilateral adrenalectomy
b. Careful peri-operative management
i. Goals - Control hypertension – to avoid hypertensive crisis during surgery
- Control tachycardia
- Volume expansion
ii. Treatment - Alpha blocker (phenoxybenzamine) for 7-14 days, followed by beta blocker (propranolol) to control tachycardia 3-4 days prior to surgical resection
a. NEVER start beta blocker first – risk of worsening hypertension - High sodium diet – catecholamine-induce volume contraction and orthostasis associated with alpha adrenergic blockade
- Malignant pheochromocytoma
a. 10% malignant – paragangliomas more likely malignant
b. Histology identical for benign vs malignant
c. Diagnosis of malignant phaeochromocytoma is based on documentation of metastatic disease
i. Only accurate indicator of malignancy are the presence of metastatic disease or local invasion that precludes complete resection
d. No curative treatments for metastatic phaeochromocytoma unless the sites of disease are surgically resectable
Glucose transporters
i. Insulin independent
1. Brain = GLUT1
2. B islet cells, liver, kidney + small intestine (basolateral) = GLUT2
3. Neurons = GLUT3
4. GI tract (apical – fructose transport) + spermatocytes = GLUT5
ii. Insulin dependent
1. Skeletal muscle + adipocytes = GLUT4
Insulin - general
a. Peptide hormone
b. Half-life = ~ 6 minutes, usually cleared from circulation by 10-15 minutes
c. Insulin synthesis
i. Pre-pro-insulin = produced in the ribosome of the RER
ii. Pro-insulin = cleavage product, packaged into vesicles
iii. Insulin = cleavage product inside vesicles, results in C-peptide + insulin
d. Normal secretin of insulin
i. Pulsatile (periodicity of 9-14 minutes)
ii. Loss of pulsatility = one of the earliest signs of beta cell dysfunction
f. Insulin secretion
i. Glucose enters B cell of pancreas via GLUT-2 transporter
ii. Glucose is phosphorylated to glucose-6-phosphate by glucokinase
iii. Glucose-6-phosphate can then be metabolised to generate ATP
iv. ↑ ATP leads to closure of ATP-sensitive K channel (K-ATP)
v. Closure of channel = intracellular accumulation of potassium = depolarisation of membrane
vi. Calcium channels open
vii. Influx of calcium leads to secretion of insulin
g. Insulin receptor
i. Insulin interacts with other cells via an insulin receptor
ii. Receptor has two alpha subunits (lie OUTSIDE the cell) and two beta subunits (lie INSIDE the cell)
iii. Insulin binds to alpha subunits activates tyrosine kinase phosphorylation of insulin receptor substrates
iv. Activates a pathway that causes the cell to increase uptake of glucose via GLUT-4 transporters
h. Actions of insulin
i. Glucose transport in skeletal muscle + adipose tissue
ii. Glycogen synthesis and storage
iii. Triglyceride synthesis
iv. Na+ retention at kidneys
v. Protein synthesis
vi. Cellular uptake of K+ and amino acids
vii. ↓ glucagon release
Glucagon - general
a. Peptide hormone produced by alpha cell – has extracellular receptors
b. Opposite to insulin (counter-regulatory hormones)
c. Glucagon works with other counter-regulatory hormones – adrenaline, cortisol, growth hormone
i. All these hormones are required to counteract insulin
d. The only site of action of glucagon (clinically) is the liver
e. Stimulates the use of non-carbohydrate sources in gluconeogenesis
CHO metabolism - general
a. Glycolysis – glucose series of steps to form 2 x pyruvic acid
i. Anaerobic fermentation – occurs without oxygen – pyruvic acid to lactic acid
1. Lactic acid metabolized in liver in presence of oxygen
2. Only in some tissues, predominantly skeletal muscle, not brain
ii. Aerobic respiratory – in presence of oxygen – pyruvic acid via Kreb cycle and electron transport chain to produce carbon dioxide + water + 38ATP
1. Occurs in mitochondria
b. Glycogenolysis
i. Glycogen stored in liver (1/4), skeletal muscle (3/4), other tissues
ii. Broken down to feed glycolysis
iii. Triggered by glucagon and adrenaline
iv. Glycogen synthesized in times of CHO excess – triggered by insulin
c. Gluconeogenesis
i. Formation of glucose from FFA and AA
ii. Triggered by glucagon and adrenaline
Lipid metabolism - general
a. Lipolysis
i. Triggered by: adrenaline, noradrenaline, corticosteroids, thyroid hormone, growth hormone
ii. Triglycerides broken down into FFA + glycerol
iii. Glycerol broken down via glycolysis + anaerobic/aerobic metabolism
iv. FFA broken down via beta oxidation into acetyl CoA to feed into TCA cycle
v. Excess acetyl CoA taken to liver and undergoes ketogenesis:
1. Ketone bodies - B-hydroxybutyrate, acetoacetic acid, acetone
b. Gluconeogenesis
i. Glucose can be made from glycerol from lipolysis
c. Lipogenesis
i. Triggered by: insulin + intestinal hormones
ii. Glycolysis from excess glucose and AA/FFA via gluconeogenesis forms glycerol
iii. FFA produced from TCA cycle
iv. Form TG
Protein metabolism - general
a. Breakdown
i. Protein breakdown
1. Source of AA from breakdown cells/enzymes/food
2. Broken down into ketoacids + NH2 via deamination
3. Ketoacids enter glycolysis or TCA cycle for energy
4. NH2 transferred to liver, forms ammonia
5. Ammonia enters ornithine cycle to form urea (excreted in urine)
ii. Gluconeogenesis
1. Ketoacids produced from AA break down can enter glycolysis – reversed to form glucose
b. Synthesis
i. Triggered by insulin
ii. Non-essential AA can be synthesized from TCA cycle intermediates
iii. Essential AA from diet only
Diabetes - aetiology/subtypes
- Type I diabetes (beta cell destruction leading to deficiency)
- Type 2 diabetes (variable combinations of insulin resistance and deficiency)
- Genetic defects of beta cell function
a. Maturity onset diabetes of the young (MODY 1-6, different mutations associated with each)
b. Mitochondrial DNA mutations – includes 1 form of Wolfram syndrome, Pearson syndrome, Kearns-Sayre, diabetes mellitus, deafness
c. Wolfram syndrome – DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, deafness): WFS1-Wlframin chromosome 4p
d. Thiamine responsive megaloblastic anaemia and diabetes - Drug or chemical induced
a. Anti-rejection = cyclosporine, sirolimus
b. Glucocorticoids (with impaired insulin secretion eg. CF)
c. Many others - Diseases of exocrine pancreas
a. CF-related diabetes
b. Trauma – pancreatectomy
c. Pancreatitis – ionising radiation
d. Others - Infections
a. Congenital rubella
b. CMV
c. HUS - Variants of type 2 diabetes
a. Genetic defects of insulin action
b. Acquired defects of insulin action
i. Endocrine tumours – rare in children
c. Phaeochromocytoma
d. Cushings
e. Others – anti insulin receptor antibodies - Genetic syndromes with diabetes and insulin resistance/ insulin deficiency
a. Prader-willi syndrome
b. Down syndrome
c. Turner syndrome
d. Klinefelter syndrome
e. Others = Bardet-Biedel, Alstrom, Werner
f. IPEX
g. Celiac disease - Gestational diabetes
- Neonatal diabetes - transient, permanent
Type 1 diabetes mellitus - background
- Epidemiology
a. Most commonly presents in childhood – ¼ are adult cases
b. Most common form of diabetes in childhood
c. Bimodal distribution – peak at 4-6 years of age, and another at 10-14 years of age - Inheritability
a. 85% of newly diagnosed have NO family history
b. Risk increases with increasing amounts of affects relatives - Aetiology
a. Genetic susceptibility
i. HLADR3/DR4 + DQ2/8 - Results in 1/20 risk of T1DM compared with 1/300 population risk
- In sibling, base line risk is 1-2 %, increases if they share these HLA types
b. Other/environmental/unknown - Pathophysiology
a. Thought to start with some sort of trigger in a susceptible host
b. Leads to autoimmune destruction of beta cells primarily T cell mediated damage
c. Onset of clinical disease occurs when 90% beta cell mass is destroyed - ↑ serum glucose = glucosuria polyuria, polydipsia, fatigue
- Protein breakdown weight loss, polyphagia
- Lipolysis FA + glycerol ketones ketoacidosis
- Natural history
a. Initiation of autoimmunity
b. Preclinical autoimmunity with progressive destruction of beta cells
i. May have episodic glycosuria when stressed
ii. 80% have auto-antibodies to islet cell antigens
iii. Eventual ↓ insulin response to glucose load
c. Onset of clinical disease
d. Transient remission = honeymoon period
i. Improvement in residual beta cell function when therapy is commenced
ii. 75% have ↓ insulin requirements, <5% will not need insulin
e. Established disease
f. Complications
T1DM - manifestations and specific/eponymous phenomena
- Clinical manifestations
a. Classic triad
i. Polyuria
1. Serum glucose exceeds the renal threshold for glucose -> glycosuria
2. Glycosuria causes an osmotic diuresis and hypovolaemia
3. May present with – nocturia, bedwetting, daytime incontinence
ii. Polydipsia
1. Enhanced thirst due to increased serum osmolality from hyperglycaemia and hypovolaemia
2. Patients may often not have classic signs of dry mucous membranes or decreased skin turgor
iii. Weight loss
1. Results from hypovolaemia and increased catabolism
2. Insulin deficiency impairs glucose utilisation in skeletal muscle and increases fat and muscle breakdown
3. Initially appetite is increased, but over time children are more thirsty than hungry, and ketosis results in nausea and anorexia, contributing to weight loss
b. Other symptoms
i. Perineal candidiasis – relatively common in young children particularly girls
ii. Visual disturbance – alteration in osmotic milieu of the lens
c. Diabetic ketoacidosis
d. Silent (asymptomatic)
- Specific phenomenon
a. Dawn phenomenon
i. Early morning (2-8am) hyperglycaemia due to overnight GH secretion + ↑ insulin clearance
ii. Occurs in peri-pubertal + pubertal years, may result in sub-optimal morning insulin levels
iii. Manage with ↑ evening protophane dose
b. Somogyi phenomena
i. Rebound hyperglycaemia from late night/ early AM hypoglycaemia
ii. Due to exaggerated counter regulatory response
T1DM - ix/diagnosis/autoantibodies
a. Diagnostic criteria = one of the following
i. Fasting (>8 hours) BSL >7 mmol/L on more than one occasion
ii. Random BSL >11.1 mmol/L on more than one occasion in a patient with symptoms of hyperglycaemia
iii. BSL >11.1 two hours after oral glucose load of 1.75 g/kg (max 75g) in OGTT (rarely done)
iv. HbA1c >6.5 – not established as diagnostic for diabetes in children
b. Autoantibodies
i. Key points
1. Positivity at an early age is associated with rapid progression to clinical disease
2. The higher number of pancreatic autoantibodies and the younger the age at detection – increases risk of developing T1DM at a younger age
ii. Islet cell antibodies = present in 70-90% (1 antibody = 30% progress to DM, 2 antibodies = 70% progress to DM, 3 antibodies = 90% progress to DM)
iii. Progression of antibodies: insulin > GAD 65 > IA-2
Islet cell cytoplasmic antibodies (ICA)
• First autoantibodies discovered
• Measures a group of islet cell autoantibodies targeted against a range of islet cell proteins
• 70% in newly diagnosed T1DM and their first degree relatives
• Only a small percentage of individuals with ICA positivity will develop T1DM
Anti-insulin antibodies (IAA)
• Usually detected at T1DM diagnosis
• Present in 50% of children
• Tends to appear first – disappears with insulin therapy
• Correlates inversely with age at onset of diabetes
Anti-glutamic acid decarboxylase (anti-GAD)
• Unclear significance
• One of the most commonly detected antibodies
• 70-80% have antibody detectable at time of diagnosis
• Often present before clinical manifestations
• Remain positive for a long time after diagnosis
Anti-insulinoma protein 2 (anti-IA2)
• Appears later than insulin and GAD
• Present in 50-75% of newly diagnosed
• Considered the best predictive marker for T1DM development
Anti-zinc transporter (anti-ZNT8)
• Present in 60-80%
• Specifities of 99% and sensitivity of 70%
• Levels decrease rapidly over time
T1DM - autoimmune associations
Autoimmune thyroid disease
• 20% of patients with T1DM have positive anti-thyroid antibodies (anti-thyroid peroxidase and/or anti-thyroid globulin)
o 2-5% develop hypothyroidism
o 1% develop hyperthyroidism (much rarer, but more common than general population)
• Anti-TPO and thyroglobulin at diagnosis
• All children should be screened regularly by measuring TSH
Coeliac disease
• 7-15% of children with T1DM develop celiac disease within the first 6 years of diagnosis
• Clinical manifestations
o Unpredictable BSL
o Recurrent hypoglycaemia
o Poor glycaemic control
o Growth failure (GIT symptoms less likely)
• Anti-tTG and IgA levels
• If positive –biopsy
• If negative – re-screening two years after diagnosis and then five years after diagnosis
Adrenal disease
• <1% of children with T1DM have autoimmune adrenalitis
• 2% of children with T1DM have circulating antibodies to 21-hydroxylase
• Clinical manifestations
o Decreased insulin requirements
o Increased frequency of hypoglycaemia
Gastric autoimmunity
• Circulating antibodies to gastric parietal cells and to intrinsic factor are 2-3x more common in patients with T1DM
Vitiligo
• Prevalence in general population 0.5% - 10-20x more common in those with T1DM
• In children with T1DM prevalence of 6%
T1DM - management
a. Aims of management
i. Achieve normal physical and psychological development
ii. As little restriction on lifestyle and occupation as possible
iii. Minimize long term macrovascular and microvascular complications
b. Management principles
i. Multidisciplinary team – paediatrician, diabetes nurse educator, social worker + psychologist
ii. Three key influences on blood glucose – exercise, insulin, diet
iii. Usually 4 appointments per year
c. Lifestyle = SNAPO
i. Smoking – avoid
ii. Nutrition – CHO 50% and low GI, fat 30% with saturated <10%, protein 20%
iii. Alcohol – not recommended
iv. Physical activity – recommended with company, rescue jelly beans, and testing before, during + after
v. Obesity – avoid
d. Dietary recommendations
i. Include at least 1 low GI food at every meal and snacks
ii. Never skip meals
iii. Three major meals and 3 snacks
iv. CHO counting
1. 500 rule: Rapid acting insulin:carbohydrate ratio = 500/TDD of insulin
a. E.g. TDD 50 units. 500/50 = 10. 1 unit of insulin should cover 10g carbohydrate
2. 100 rule for corrections: 100/TDD = insulin sensitivity factor
a. E.g. TDD 50 units. 100/50 = 2. Every 1 unit of insulin will lower your BGL by 2 units
f. Regimens
i. Basal bolus = usually lantus + TDS novorapid
1. TDD of 1 unit/kg/day
2. 0.4 unit/kg as basal insulin (long acting) at 2000-2100
3. Give the remainder as rapid acting insulin in 3 equal doses before meals (0.2 U/kg before each meal)
4. Good for motivated individuals
5. Much better control, ↓risk of Dawn / Somogyi phenomenon
ii. BD = usually BD levemir + novorapid
1. TDD of 1 unit/kg/day
2. Usually commenced in children <10 years
3. Usually commenced with a total daily dose of 1 unit/kg/day
a. 2/3 TDD in morning
b. 1/3 TDD in evening
4. 2/3 intermediate acting, 1/3 short acting
iii. Insulin pump
g. Target BSLs = pre-prandial 4-8
- treat hypoglycaemia <4, ketosis >1
h. Side effects
i. Hypoglycaemia
ii. Lipohypertophy at injection sites
iii. Hypersensitivity – uncommon
iv. Insulin antibodies
v. Nearly all develop antibodies after several moths
vi. May promote unstable BSL (most = no effect)
T1DM - assessing long term control
a. HbA1c = glycosylated Hb
i. Reflects last 2-3 month control
ii. Target is 7.5, < 7 normal
iii. Falsely low = haemolytic anaemias, pure red cell aplasia, blood transfusions, anaemias associated with haemorrhage, cirrhosis, myelodysplasias, renal disease treated with EPO
b. Fructosamine = glycosylation of serum proteins
i. Reflects 1-2 week control
ii. Useful in haemoglobinopathies (HbA1c spuriously ↓/↑)
T1DM - mortality (causes)
a. DKA is the leading cause of death in children and adolescents with T1DM
b. In adults with T1DM – vascular complications, DKA and hypoglycaemia are all causes of death
T1DM - complications
- RETINOPATHY
a. Leading cause of blindness in young adults
b. Risk after 15 years (98%)
c. Associated with longer duration of diabetes and poorer glycaemic control
e. Treatment
i. Laser photocoagulation
ii. Vitrectomy – advanced eye diseases with severe vitreous haemorrhage or fibrosis
f. Diabetic maculopathy = severe macular edema manifested by impaired central vision - NEPHROPATHY
a. Earliest sign of diabetic nephropathy is increased albuminuria – defined as albumin excretion between 30-300 mg/day (20-200 mcg/min)
b. 30-40% of patients with T1DM develop ESRD
c. Treatment
i. Control of BSL
ii. Control of BP
iii. ACE-I
iv. Dietary – reduced protein - NEUROPATHY
a. Symptomatic diabetic neuropathy is uncommon in children and adolescents
b. Increases with poor glycaemic control and duration of disease
c. Peripheral neuropathy
i. Earliest evidence is distal sensory loss (distal symmetric sensorimotor polyneuropathy) affecting ‘gloves and stockings’ distribution - best detected with monofilament
d. Autonomic neuropathy
i. Includes – abnormal HR variability and BP control, pupillary adaptation to darkness, and vibratory threshold
ii. Puberty is a critical time for development of diabetic cardiac autonomic dysfunction - CEREBROVASCULAR
a. Major cause of morbidity and mortality in adults with T1DM
b. Children with T1DM have reduced LV size and decreased SV even in the absence of HTN or nephropathy
c. Dyslipidaemia, atherosclerotic changes and vascular stiffness - OTHER
a. Autoimmune diseases
b. Growth
i. Poor glycaemic control can result in poor linear growth, poor weight gain, and/or delayed skeletal and pubertal development
ii. Excessive insulin and/or caloric intake can lead to weight gain - If obesity develops, this can lead to insulin resistance, complicating diabetes management
c. Gastroparesis
i. Post-prandial antral hypomobility occurs in 30-50% of individuals with longstanding T1DM
ii. Results in N+V, abdominal pain and constipation following meals
iii. Can contribute to poor glycaemic control and early satiety
d. Necrobiosis lipoidica
i. Inflammatory skin condition associated with diabetes seen in 1-2% of children
ii. More common in those with poorer glycaemic control
iii. Asymptomatic skin lesions usually occur on the shin as oval or irregularly shaped, indurated plaques with central atrophy and yellow pigmentation
e. Limited joint mobility
i. Primarily affecting hands and feet – skin usually thick and waxy in appearance
f. Menstrual irregularity
g. Paronychia
h. Mauriac syndrome
T1DM - hypoglycaemia - general
- Key points
a. Severe hypogylcaemia most common during the night, when the glucose threshold for counter-regulatory hormone responses (sympathoadrenal) is lower less likely to wake with symptoms
b. Symptoms – correlate with sympathetic response; therefore autonomic neuropathy decreased awareness due to decrease in adrenalin response to hypoglycaemia - History – recurrent hypoglycaemia
a. Severe, moderate, mild
b. Time of day
c. Hypoglycaemic unawareness, blood glucose level where patient detects symptoms
d. HbA1c
e. Change in insulin dose, insulin type or insulin timing
f. Exclude celiac disease, Addison’s disease, autoimmune thyroiditis - Symptoms
a. Stimulation of sympathetic nervous system = anxiety, palpitations, tachycardia, pallor, perspiration, headaches, abdo pain
b. Effects on CNS = lethargy, dizziness, ataxia, weakness, confusion, personality changes, visual disturbance, unconsciousness, localized and generalized convulsions - Causes
a. Missed meal/snack
b. Vigorous exercise
c. Alcohol
d. Too much insulin - Management – Acute
a. All BSLs <4 mmol/L need to be treated regardless of the signs and symptoms
b. Give 5-10g of high GI (quick acting) carbohydrate
c. Wait 15 minutes – perform another BSL
i. If <4 mmol/L – give another 5-10g of CHO
ii. If >4 mmol – give 10-15 of low GI CHO
d. Severe hypoglycaemia
i. If BSL is <4 and child is unconscious, low GCS or having a seizure – give glucagon - 0.5ml = children <25 kg or <6 years
- 1ml = children >25kg or >6 years
ii. Takes 5-15 minutes to work
T1DM - ketosis (not DKA) - general
- Cause = missing insulin, illness
- Ketones should be checked when
a. BSL >15 mmol/L
b. Child appears unwell - Treatment required if ketones >1.0 mmol/L – dependent on BSL
BSL >15 mmol/L
• Give 10% of total daily insulin dose using rapid acting insulin (Novorapid or Humalog) immediately
o If insulin is due, add 10% of total daily insulin dose to normal insulin dose
o If insulin is not due, give 10% of total daily insulin dose as an extra injection immediately
• Check ketones in 2 hours and seek medical advice if ketones remain > 1.0 mmol/L
• Extra insulin may be required if BGL remains >15mmol/L & ketones remain > 1.0 mmol/L after 2 hours
T1DM - sick day principles
- General principles
a. Treat underlying illness, facilitate regular intake
b. Monitor BSLS 1-4 hourly, check ketones if BSL > 15
c. Do NOT omit insulin, may have to reduce dose
d. Give extra insulin if BSL > 15 + ketones (short acting only, 5-20% more) - Illnesses causing high BSLs = bacterial and viral
a. As above
b. Encourage sugar free fluids to maintain hydration - Illnesses causing low BSLs = vomiting, diarrhoea, decreased appetite
a. As above
b. Sip on sugar containing fluids
c. Mini doses of glucagon may be used to treat hypoglycaemia if unable o tolerate food or fluids
DKA - background
- Overview
a. Approximately 25% present in DKA – highest risk in toddlers and teenagers
b. DKA definition = hyperglycaemia + metabolic acidosis + ketonaemia
c. Biochemical criteria = venous gas <7.3 + blood or urinary ketones
d. Cause
i. May be first presentation for a child with previously undiagnosed diabetes
ii. OR precipitated by illness or poor compliance
e. Classifying severity
i. Mild = pH 7.2-7.3, bicarb 10-15
ii. Moderate = pH 7.1 – 7.2, bicarb 5-10
iii. Severe = pH < 7.1, bicarb < 5 - Pathogenesis
a. ↓ INSULIN (NOTE: levels also inappropriately ‘normal’)
i. ↓ glucose uptake + ↑ glucose production HYPERGLYCAEMIA glycosuria osmotic diuresis electrolyte depletion
b. ↑ LIPOLYSIS/↓ lipogenesis mobilisation of FFA/glycerol- substrates for gluconeogenesis + beta oxidation
i. Glucagon excess hepatic ketogenesis FFA converted to ketones ( hydroxybutyrate acetoacetate acetone ketonaemia and acidosis
ii. Ketone bodies - Produced by acetyl-CoA mainly in the mitochondrial matrix of liver cells when CHO are scarce energy is obtained from FFA
- Transported from the liver to the other tissues – amino acids and beta-OHB can be reconverted to acetyl-CoA to produce energy – heart + brain
- Levels of acetone lower than those of the other two types of ketone bodies – excreted in urine; acetone is responsible for ‘fruity’ odour of breath
c. Dehydration/hypovolaemia/haemoconcentration
i. ↑ cellular K, ↑ cellular Na
ii. Tissue hypoxia lactic acidosis
iii. Thrombosis
iv. ↓Renal blood flow pre-renal renal failure
v. ↓ Cerebral blood flow
DKA - manifestations/investigations
- Precipitants
a. Medication error / non-compliance (20%)
b. New diagnosis (25%)
c. Increased insulin requirement
i. Infection (30%), vomiting, injury, emotional stress, alcohol, drugs, steroids, thiazides,
d. No known precipitant (25%) - Clinical manifestations
a. Hyperglycaemia – polyuria, polydipsia
b. General – nausea, vomiting, abdominal pain
c. Acidosis – Kussmaul’s breathing, ketotic breath, decreased GCS - Assessment
a. Degree of dehydration
i. None/Mild (< 4%): no clinical signs
ii. Moderate (4-7%): easily detectable dehydration eg. reduced skin turgor, poor capillary return
iii. Severe(>7%): poor perfusion, rapid pulse, reduced blood pressure i.e. shock
b. Level of consciousness – GCS
c. Investigations
i. FBE
ii. Blood glucose
iii. UEC, CMP
iv. Blood ketones (beta-hydroxy butyrate) - Not uncommon to have levels 0.2 mmol/L
- Mild illness increases to 1.0 mmol/L
- > =3 mmol/L at risk of DKA
v. Urine ketones (acetoacetone) – not uncommon for children to have some ketones on waking
vi. Venous blood gas (including bicarbonate) - metabolic acidosis with increased anion gap
vii. Investigations for precipitating cause e.g. septic screen
viii. For all newly diagnosed patients - Insulin antibodies, GAD antibodies
- Coeliac screen (total IgA, anti-gliadin Ab, tissue transglutaminase Ab)
- Thyroid function tests (TSH and FT4)
ix. Urine = ketones, culture (if evidence if infection)
DKA - management
a. Airway / breathing
b. Supportive measures to consider if appropriate
i. Secure the airway and consider NG tube placement (to avoid aspiration) if low GCS
ii. Keep NBM
iii. X2 PIVC
iv. Supplemental O2 = give oxygen to patients with severe circulatory impairment or shock
v. Continuous cardiac monitoring (high/low K)
vi. Abx if indicated
vii. IDC = strict fluid balance
c. Fluid Requirements
i. Fluid boluses
1. Not all patients require fluid boluses (acidosis itself poor peripheral perfusion + confounds accurate assessment of dehydration)
2. Peripheral perfusion improves with Tx of acidosis (with insulin)
3. If hypoperfusion present – 10 mL/kg N. saline bolus, further bolus if CRT >2 seconds
4. Patients with DKA rarely require >20 ml/kg in total as a bolus
ii. Initial fluid replacement = normal saline + potassium
1. Adjust based on Na, K and glucose levels
iii. Ongoing fluid management
2. Aim to keep the BSL between 5-12 mmol/L
a. If BSL 12-15 add 5% dextrose
b. If BSL <5.5 or falling rapidly add 10% dextrose
c. If continues to fall despite 10% dextrose – insulin infusion should be decreased (but only if metabolic acidosis continues to improve)
4. Corrected sodium should remain stable or rise as blood glucose level falls
5. N saline + dextrose should be continued if
a. Hyponatraemia present
b. Corrected sodium fails to stabilise or rise as the BSL increases
c. Hyperosmolar and concerned about rapid shifts in osmolality
6. Fluids with a tonicity of < 0.45% saline should not be used
iv. Rehydration may be completed orally after the first 24 - 36 hours if the patient is metabolically stable (this usually coincides with insulin therapy being switched to s.c. injections)
d. Potassium
i. Patients may present with low, normal or elevated K+
ii. Potassium replacement therapy is required for treatment of DKA
1. Generally total body deficit of K+ on presentation
2. Correction of acidosis results in hypokalaemia (K+ moves into cells)
iii. Management
1. K > 5.5 mmol/L or patient anuric defer initial replacement
2. Start KCl at 40 mmol/l if body weight < 30kg, or 40-60 mmol/l if > 30 kg
a. Subsequent replacement is based on serum potassium levels
b. Potassium replacement should continue throughout i.v. fluid and insulin therapy
3. Once insulin is commenced, a repeat K+ should be taken within one hour
e. Insulin
i. Add 50 units of clear/rapid-acting insulin (Actrapid HM or Humulin R) to 49.5 ml 0.9% NaCl (1 unit/ml solution)
ii. Insulin dose
1. 0.1 units/kg/hr newly diagnosed children AND established diabetes with BSL > 15 mmol/
2. 0.05 units/kg/hour established diabetes who have had their usual insulin and whose blood glucose level is < 15 mmol/l.
iii. Adequate insulin must be continued to clear ketones and correct acidosis
1. Adjust the concentration of dextrose in the intravenous fluids, aiming to keep BSL 5-12
2. The insulin infusion can be discontinued when the child is alert and metabolically stable (pH > 7.30 and HCO3 > 15)
iv. The best time to change to s.c. insulin is just before meal time
1. Insulin infusion should only be stopped 30 minutes AFTER the first s.c. injection of rapid-acting insulin
f. Ongoing management
i. Strict fluid balance
ii. Hourly observations
iii. Hourly glucose and blood ketones measurement while on insulin infusion
iv. Re-check K+ within one hour of commencing insulin infusion
v. Venous blood gas and lab glucose 2 hourly for initial 6 hours; then 2 - 4 hourly thereafter
vi. Serum UEC 2 - 4 hourly for the initial 12 - 24 hours
viii. Nurse head up
g. Bicarbonate
i. Bicarbonate administration is not routinely recommended as it may cause paradoxical CNS acidosis
ii. Continuing acidosis indicates insufficient fluid and insulin replacement
iii. Nonetheless, in rare circumstances, some extremely sick children may benefit from cautious administration (e.g. those with pH < 7.0 +/- HCO3 < 5mmol/L who require adrenaline for BP support or those with marked hyperkalemia)
DKA - complications
a. Hyper / Hyponatraemia
i. Measured serum sodium is depressed by the dilutional effect of the hyperglycaemia
ii. To “correct” sodium concentration, use the following formula:
1. Corrected (i.e. actual) Na = measured Na + 0.3 (glucose - 5.5) mmol/l
2. i.e. 3 mmol/l of sodium to be added for every 10 mmol/l of glucose above 5.5 mmol/l.
iii. If sodium does not rise as the glucose falls during treatment or if hyponatraemia develops, it usually indicates overzealous volume correction and insufficient electrolyte replacement
1. This may place the patient at risk of cerebral oedema
b. Hypoglycaemia
i. If blood glucose falls below 4.0 mol/l and patient is still acidotic, give i.v. 10% dextrose 2-5 ml/kg as a bolus and use a 10% dextrose concentration for ongoing iv fluids (with 0.45% NaCl and K+ supplements)
ii. Do not discontinue the insulin infusion
iii. If hypoglycaemia occurred despite use of 10% dextrose in the preceding 2 or more hours, the rate of the insulin infusion may be decreased
iv. If blood glucose falls below 4.0mmol/l and most recent pH is >7.30, oral treatment for hypoglycaemia (jelly beans + 1 serve of complex carbohydrate) can be used instead of an i.v. bolus of dextrose 10%
c. Cerebral Oedema
i. Responsible for 50-60% of all T1DM related deaths
ii. 1% of DKAs affected
iii. Some degree of subclinical brain swelling is present during most episodes of diabetic ketoacidosis
iv. Clinical cerebral oedema occurs suddenly, usually between 6 and 12 hours after starting therapy
v. Mortality or severe morbidity is very high without early treatment (40-90% mortality)
vi. Prevention
1. Slow correction of fluid and biochemical abnormalities
2. Optimally, the rate of fall of blood glucose and serum osmolality should not exceed 5 mmol/L/hr, but in children there is often a quicker initial fall in glucose
3. Patients should be nursed head up
vii. Risk factors = first presentation, long history of poor control, young age (< 5 yr)
viii. Warning signs
1. No sodium rise as glucose falls, hyponatraemia during therapy, initial adjusted hypernatraemia
2. Headache, irritability, lethargy, depressed consciousness, incontinence, thermal instability.
3. Very late signs - bradycardia, increased BP and respiratory impairment (Cushing triad)
ix. Treatment
1. Mannitol
2. Reduce fluid input by 1/3 in the first instance
d. Pre-renal failure due to ATN
e. Pancreatitis
f. Electrolyte abnormality leading to arrythmia
T2DM - background
- Key points
a. Syndrome of insulin resistance + relative insulin deficiency leading to
i. ↑ hepatic glucose output
ii. ↓ muscle glucose uptake
iii. ↑ lipolysis
b. Suspect in adolescents with
i. Strong family history
ii. Phenotype of central adiposity
iii. Show other signs of insulin resistance = acanthosis nigricans, skin tags
iv. Have no insulin requirement of <0.5 units/kg/day after the partial remission (honeymoon phase)
c. Risk of T2DM in adolescents is cumulative – therefore increased suspicion if multiple risk factors - Screening for T2DM in children
a. Criteria
i. Overweight, PLUS
ii. Any 2 risk factors - Family history
- Race/ethnicity – Hispanic, Polynesian, ATSIA, Indian, Chinese
- Signs of insulin resistance = acanthosis nigricans, hypertension, dyslipidaemia, PCOS
b. Age of initiation = 10 years or at onset of puberty (whatever is earlier)
c. Frequency = every 2 years
d. Test = fasting plasma glucose test preferred - Risk factors
a. Obesity
b. Positive family history
i. Offspring of one parent with T2DM – 40%
ii. Offspring of both parents with T2DM – 60%
iii. Monozygotic twins – 90% chance
c. Racial and ethnic groups
d. Female gender – more likely than boys to develop T2DM during adolescence
e. Conditions with insulin resistance – PCOS
f. Prenatal exposures = low BW, gestational diabetes
g. Other genetic associations
i. GLUT2 defect: increased BSL, impaired secretion
ii. Glycogen synthase gene polymorphism: difficulty storing glucose as glycogen, leads to ↑ BSL, insulin resistance
T2DM - manifestations/diagnosis/investigations
- Clinical manifestations
a. Asymptomatic = 40-50%
b. Symptomatic (eg. polydipsia, polyuria) without ketonuria or acidosis = 50-70%
c. DKA = 5-15%
d. Hyperglycaemic hyperosmolar state = 5-15%
e. Associated features
i. Acanthosis nigricans – marker of insulin resistance found in 50-90% of youth with T2DM
ii. Hyperandrogenism
Diagnosis
- Hyperglycaemia in the absence of any acute physiological stress +/- presence of symptoms of hyperglycaemia
- Fasting glucose >7.0
- Randomg BGL >11.0
- Polyuria/polydipsia/weight loss/nocturia + random BGL >11.0 or HbA1c >6.5
Screen for comorbidities
- Nephropathy (UEC, urine albumin)
- Retinopathy (Dilated eye exam)
- Dyslipidaemia (fasting lipids)
- Hypertension
- NAFLD (liver USS, LFTs)
- PCOS
- Sleep apnoea
- Depression
T2DM - management
a. Goals
i. Lifestyle modification
ii. Normalization of glycaemia – target HbA1c <6.5%
iii. Management of comorbidities
b. Lifestyle
i. <10% of youth with T2DM reach glycaemic targets with lifestyle modification alone
ii. Dietary recommendations = low GI foods
iii. Exercise = moderate intensity exercise for 60 minutes/day
iv. Screen time = <2 ours/day
c. Normalization of glycaemia
i. Oral hypoglycaemics
1. Metformin
a. Metformin monotherapy is treatment of choice
b. Action
i. ↑ insulin sensitivity = ↑ insulin stimulated glucose uptake in fat and muscle
ii. ↓ hepatic glucose production
c. AE = abdominal pain, diarrhoea, lactic acidosis
d. Aids in weight loss
ii. Insulin
1. Indications
a. Required for those with HbA1c >9%
b. Severe hyperglycaemia (serum glucose > 15 mmol/L)
c. Ketosis/ketoacidosis
Other meds:
- sulphonylureas
- thiazolidinediones
- acarbose
- GLP analogues
- DPP4 inhibitors
- SLGT2 inihibitor
Manage comorbidities: HTN - 1/3 T2DM patients - lifestyle (weight loss, low salt diet, exercise) - ACE, ARB Dyslipidaemia - 2/3 patients - dietitian and dietary modification - statin Retinopathy - 10% at diagnosis, inc with time/hyperglycaemia - refer to ophthal (?laser) Nephropathy - 20% - ACE - treat HTN Depression - 15% - ref to MH
Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNS), also known as Hyperosmolar Hyperglycaemic State (HHS) - general
- Key points
a. Development of severe hyperglycaemia without significant ketosis, usually in setting of T2DM - Pathophysiology
a. Insulin deficiency (NOT absence)
i. Decreased glucose available to cells due to insulin deficiency
ii. Activation of glycogenolysis, gluconeogenesis
iii. Results in EXTREME hyperglycaemia – polyuria, polydipsia
b. Lipolysis
i. For GNG WTHOUT ketone formation due to presence of insulin
c. Dehydration ++++
i. Due to osmotic diuresis from hypoglycaemia
ii. Leads to: hypercoagulability, shock - Clinical features
a. Trigger most commonly sepsis
b. Presents late and worse prognosis than DKA
c. Extreme dehydration
d. No ketones
Altered conscious state -> HONK (hyperosmolar hyperglycaemic nonketotic coma) - Assessment and management same as DKA except-
a. Fluid resuscitation +++
b. Less insulin
c. Treat underlying cause
MODY (maturity onset diabetes of the young syndromes) - general
- Key features
a. Non-insulin dependent diabetes
b. Diagnosed at young age (<25 years)
c. Autosomal dominant
d. Lack of autoantibodies
Types 1-6
- 3 most common (HFNA1), 2 second most common (GCK)
Often a multigenerational family history - Epidemiology
a. Most common form of monogenic diabetes – accounting for 2-5% of diabetes
b. Very heterogenous – patients often misclassified as T1DM and T2DM - Genetics
a. Mutations in hepatocyte nuclear-factor alpha (HFNA1) and glucokinase (GCK) mutations are most common
b. Some family members may have the genetic defect but do not develop diabetes, unclear
c. Other patients have classic MODY phenotype but do not have identifiable mutation - Treatment
a. MODY1 and MODY3 = sulphonylurea to increase insulin secretion
b. MODY 2 = diet
MODY 2 - general
- Key points
a. Second most common form of MODY
b. Mild and non-progressive - Pathogenesis
a. Glucokinase = essential role in beta cell glucose sensing
b. Heterozygotes = mild reduction in beta cell response to glucose
i. Higher threshold for insulin release once BSL > 7 mmol/L
c. Homozygotes = complete inability to secrete insulin in response to glucose resulting in permanent neonatal diabetes - Treatment
a. Diet
b. Pharmacotherapy – sulphonylurea if required
MODY 3 - general
- Key points
a. Most common MODY
b. May have renal problems
c. Normal insulin secretion however fail to increase insulin secretion with increased plasma glucose - Pathogenesis
a. Mutation in transcription factor HNF1alpha
b. The precise mechanism by which a defect in HNF1A causes hyperglycemia is not clear - Clinical manifestations
a. Symptomatic hyperglycaemia in 20s
b. Secondary insulin resistance later develops - Treatment
a. Sulphonylureas – very sensitive and can be treated with low doses
Mitochondrial diabetes - general
- Key points
a. Rare
b. Maternal inheritance - Clinical features
a. Diabetes
b. Deafness
c. Neurological defects
CF related diabetes - general
- Epidemiology
a. 20% by 20 years - Mechanisms
a. Mainly insulin deficiency due to pancreatic insufficiency
b. Liver disease contributes to insulin resistance
c. Chronic use of steroids - Risk factors
a. Increasing age
b. Pancreatic insufficiency
c. Delta F508 homozygous
d. Female - Clinical manifestations
a. Failure weight gain, decreasing growth velocity
b. Delayed puberty
c. Plateau/deterioration in lung function - Screening
a. OGTT annually from 10years
i. 2hrs 7-11.1mmol/L = IGT
ii. 2hours >11.1mmol/L = DM
b. Can do fasting venous glucose or HbA1c to confirm
Hypogycaemia - background
- Definition
a. Hypoglycaemia is a Blood Glucose Level (BGL) low enough to cause signs and/or symptoms of impaired brain function and neurogenic response – generally BGL <3.3 mmol/L
b. Symptoms of hypogylcaemia
c. Resolution of symptoms with treatment to raise BSL - Key points
a. Prolonged or recurrent hypoglycaemia, especially when associated with symptoms and signs long term neurological damage or death
b. Hypoglycaemia is the most frequent acute complication of type 1 diabetes either due to excess insulin or illnesses causing nausea, vomiting or diarrhoea and decreased oral intake
c. Hyperinsulinism is the most common cause of persistent hypoglycaemia under 2 years
i. The presence of ketonuria and/or ketonaemia makes this diagnosis very unlikely
d. Accelerated starvation (previously known as “ketotic hypoglycaemia”) is the most common cause of hypoglycemia beyond infancy, usually presenting between 18 months to 5 years – prolonged fast usually precipitated by mild illness – documentation of low BSL with ketonuria and/or ketonaemia
e. May be an early manifestation of other serious disorders (eg. sepsis, congenital heart disease, tumours)
f. Hypogylcaemia in neonates, infants and children is almost ALWAYS a result of problems with fasting adaptation (post-prandial hypoglycaemia rare – post gastric surgery/fructose intolerance are main causes)
3. Aetiology (by age) Neonate • Hyperinsulinism • GHD • GALT Infants • Inborn errors of metabolism o Fatty acid oxidation defect o Glycogen storage disease o Galactosaemia • Hyperinsulinism • Congenital hyperinsulinism Child • Accelerated starvation • Hypopituitarism Adolescent • Insulinoma • Adrenal insufficiency
Hypoglycaemia - manifestations, history
- Clinical manifestations
a. Infant/neonatal
i. Pallor
ii. Poor feeding
iii. Hypotonia / sleepiness
iv. Jitteriness
v. Hypothermia, apnea, bradycardia
vi. Seizures
b. Neuroglycopaenic
i. Headache / Hunger
ii. Poor concentration, confusion
iii. Irritability
iv. Visual changes
v. Seizures / Stroke / Collapse
vi. Coma
c. Adrenergic
i. Diaphoresis / pallor
ii. Tachycardia / palpitations
iii. Anxiety
iv. Tremor / paresthesia - History
a. Tolerance to fasting / illness
b. Relationship to food
i. Milk products (galactosemia)
ii. Fructose e.g. juices (hereditary fructose intolerance)
iii. Protein (amino acid or organic acid disorders)
c. History of toxin ingestion – in toddlers or young children consider accidental ingestion of alcohol, oral hypoglycemic agents, aspirin, beta blockers, or toxins
d. Past history
i. Neonatal history of hypoglycemia
ii. Episodes suggestive of hypoglycemia eg. undiagnosed seizure disorder
iii. Previous gastric surgery, fundoplication (postprandial hypoglycemia)
e. Family history
i. Consanguinity
ii. Unexplained infant deaths (may be from inborn errors of metabolism)
iii. Hormonal deficiencies and hyperinsulinism
Hypoglycaemia - management
a. Raise BSL to 5-8
b. Mild to moderate
i. 10-15g fast acting CHO (125-200mL juice or soft drink, 4 jelly beans)
ii. 15g long acting (1 slice bread, 2 plain sweet biscuit or 1 fruit, 250mL milk)
iii. Monitor BSL
iv. Repeat short acting if required
c. Severe
i. IV dextrose- 2mL/kg 10% dextrose
ii. Maintenance with 5-10% dextrose – aim BSL >4mmol/L
iii. Increase rate/ repeat bolus if required – increase by 2mg/kg/min if BSL low
iv. Glucagon infusion (impairs insulin release from B islet cells)
d. Treat underlying cause
i. Diazoxide infusion (potassium sensitive ATP B islet cell channel stimulation – inhibits insulin secretion, only if KATP intact)
ii. Octreotide infusion (tachyphylaxis, impairs calcium stimulated insulin release B islet cell)
iii. Surgery
1. Indications – diffuse form unresponsive diazoxide, focal lesion
2. Diffuse = sub-total pancreatectomy (95%), focal = focal resection
Hypoglycaemia - investigations
- Investigation
a. Indications to investigate
i. Neonatal - Persistent beyond initial few days
- Glucose requirement > 10-12 mg/kg/min (even initial days)
- Babies with no identifiable risk factors (eg. mum with DM, HIE, SGA)
ii. Older infant/child - Recurrent or severe hypoglycaemia
b. Critical hypoglycaemia screen
c. Bloods = see below
d. Guthrie card = carnitine/ acylcarnitine
e. Urine = glucose, ketones, reducing substances, amino acids and organic acids
Bloods:
- critical sample at time of hypo <2.6
- ketones, lactate, FFA, carnitine/acylcarnitine, ammonia, cortisol, insuline, C-peptide, GH, amino acids, electrolytes, LFT
Controlled fast
Idiopathic Ketotic Hypogylcaemia = Accelerated Starvation - general
- Key points
a. Children 18months – 5 years
i. Pre-school years
ii. Often gone by 10years
b. Most common cause in this age group but diagnosis of exclusion
c. Impaired fasting adaptation
d. Idiopathic – mechanisms thought to not have increase in GNG in response to low glucose
e. Resolves spontaneously 7-8years age
f. Previously called ketotic hypoglycaemia but preferable NOT to use this term
g. Diagnosis of EXCLUSION - Clinical features
a. Precipitant – prolonged fasting, illness
b. Usually first thing in morning
c. Episodes unpredictable
d. Thin/small body habitus
e. Hypoglycaemia with ketones - Investigation
a. May consider doing prolonged fast
b. If can tolerate – HIGHLY unlikely to be organic cause - Diagnosis of exclusion
a. Low alanine may be present - Management
a. Avoid fasting
b. Frequent feeding high protein/CHO
Neonatal hypoglycaemia - background
- Key points
a. Neonatal hypoglycaemia = < 2.6 mmol/L
b. Incidence 1-3/1000 live births
c. 10% neonates have transient hypoglycaemia - Normal perinatal physiology
a. Transition from environment with continuous source of glucose (maternal blood) to one where glucose is in limited an intermittent supply
b. Glucose is the preferred substrate for brain metabolism, which uses most of the 5-8 mg/kg/min produced by full-term neonate
c. Glucose entry into brain cells is dependent on circulating arterial glucose (not insulin) concentration - Pathogenesis
a. Loss of continuous transport of glucose, BGL falls in health newborn during first 2 hours post-delivery to a nadir of no less than 2.2, then stabilizes by 4-6 hours to 2.5-4.5
b. Immediately post birth, plasma BGL maintained by hepatic glycogen breakdown
c. Glycogen stores used by first 8-12 hours, thereafter BGL maintained by synthesis of glucose from lactate, glycerol and amino acids
Neonatal hypoglycaemia - aetiology
a. Transient
i. Inadequate substrate/ immature function
1. Prematurity
2. SGA
3. Normal newborn
4. Increased usage – sepsis/ fever
ii. Transient hyperinsulinism
1. Maternal factors – IDM, IV glucose during labour
2. Prematurity
3. SGA, discordant twin, birth asphyxia, maternal PET – depleted stores + hyperinsulinism
4. Beckwith Wiedemann syndrome
5. Increased utilization – sepsis, fever
b. Persistent
i. Hyperinsulinism
1. K(atp) channel defect – recessive/ dominant / focal
2. Glucokinase defect (dominant)
6. Beckwith -Wiedemann syndrome
7. Sulfonyurea drugs
8. Congenital disorders of glycosylation
ii. Increased utility
1. Hypothermic
2. Anaerobic glycolysis due to reduced tissue perfusion
3. Sepsis
4. Polycythaemia
iii. Ketotic hypoglycaemia
1. Inadequate substrate
a. Prematurity/ SGA
b. MSUD, PA, MMA
2. Counter-regulatory hormone deficiency
a. Panhypopituitarism - often assoc with other midline abnormalities
b. Isolated GH deficiency
c. ACTH deficiency
d. Addison disease
3. Glycogenolysis and gluconeogenesis disorders
a. Range of disorders, usually associated with soft, massive hepatomegaly and FASTING hypoglycaemia with intact lipolysis + ketogenesis
b. G6P deficiency – GSD 1a/ 1b
c. Galactosemia
d. Hereditary fructose intolerance
iv. Fatty acid oxidation disorders
1. Short, medium, long chain fatty acid acyl-CoA dehydrogenase deficiency
2. Carnitine deficiency
3. Carnitine palmitoyltransferase deficiency
v. Other etiologies
1. Liver disease
2. Amino acid and organic acid disorders
3. Systemic disorders
Neonatal hypoglycaemia - manifestations
- Clinical manifestations
a. Frequently asymptomatic
b. In symptomatic infant
c. Neurogenic (autonomic) symptoms
i. Jitteriness
ii. Sweating
iii. Irritability
iv. Tachypnoea
v. Pallor
d. Neuroglycopenic symptoms
i. Poor suck or poor feeding
ii. Weak or high pitched cry
iii. Change in level of consciousness (lethargy, coma)
iv. Seizures
v. Hypotonia - Examination
a. Large for dates – hyperinsulinism
b. Micropenis, midline defect – hypopituitarism
c. Genital ambiguity, pigmentation – CAH
d. Blindness – septo-optic dysplasia
e. Hypotonia – FAO, GS
f. Recurrent encephalopathy – FAO
g. Jaundice – GSD III, FAO, galactosaemia
h. Hepatomegaly – GSD, GNG defect
i. Renomegaly – GSD I
j. Myopathy – GSD, FAO defect
k. Pigmentation – adrenal insufficiency
Neonatal hypoglycaemia - treatment and outcome
- Management
a. Mild to moderate – oral feeding if >1.6/1.8 asymptomatic or >2.2 if symptoms
i. Fast acting CHO – glucose gel
ii. Long acting CHO – feed +/- comp
iii. Monitor BSL
b. Severe <2.2 and symptomatic or <1.6/1.8 without symptoms
i. IV dextrose- 2mL/kg 10% dextrose
ii. Maintenance with 5-10% dextrose – aim BSL >4mmol/L
iii. If persistently low - Repeat bolus
- Increase rate of IV dextrose from 60 to 90mL/kg/day
- Increase concentration of dextrose, max 20% (>12.5% needs central line)
iv. 6-8 mg/kg/minute = substrate defect
v. >12 mg/kg/minute = hyperinsulinism
c. Specific management
i. Hyperinsulinism - Glucose
- Glucagon, diazoxide, ocreotide
- Surgery
ii. GSD/gluconeogenic defect - Continuous NG feed, corn starch
- Allopurinol (GSD I)
iii. Hypopituitarism - GH, cortisol
iv. FAO defect - Avoid fasting
- Carnitine
v. Ketotic hypoglycaemic - Nocturnal feeds
- Illness – increase CHO intake
- Protein snack, ketone monitoring
vi. Galactosaemia/ fructose intolerance - Dietary changes
- Outcome
a. Symptomatic hypoglycemia brain injury (occipital most effected)
b. Unknown what BSL or duration of low BSL leads to brain injury
c. High risk for CP, developmental delay, small head circumference
d. MCQ: Occipital lobe most vulnerable to hypogylcaemia – visuospatial impairment
Hyperinsulinaemic hypoglycaemia - background
- Key points
a. Most common cause of persistent hypoglycaemia in neonates and infancy
b. Insulin suppresses ALL mechanisms of fuel generation - glucose GNG FAO ketogenesis
c. Results in NO fuel to the brain
d. Genetic disorder with familial and sporadic forms – highly heterogenous
e. Characterised by dysregulated insulin secretion
f. BSL <2.8 + detectable insulin = HYPERINSULINISM + no ketones
i. ANY detectable insulin is inappropriate when hypoglycaemic
g. Aim of treatment BSL > 4.0 mmol/L - Pathogenesis
a. Normal relationship between plasma glucose concentration and insulin secretion is disturbed
b. Inappropriate insulin secretion during periods of hypoglycaemia
c. Disturbance of normal homeostasis caused by various mutations
d. ATP-dependent potassium (KATP) channel of beta pancreatic cells
i. Most common mutation
iii. Inactivating mutations reduce the number of KATP channels OR mean they are persistently closed resulting in depolarisation of beta cells and persistent hypersecretion of insulin
iv. CLOSURE of KATP channel results in insulin release
e. Glutamate hydrogenase gene mutation
f. Glucokinase gene mutation
Hyperinsulinaemic hypoglycaemia - manifestations, investigations
a. Macrosomic baby (or SGA/ asphyxia)
b. Early onset hypogylcaemia – often severe, recurrent
c. Glucose requirement usually > 10 mg/kg/min
d. Glycaemic response to glucagon
e. Hypoglycaemia with detectable insulin and ABSENCE of ketones + FFA (insulin suppresses normal counterregulatory response)
i. Ear crease anomaly, Exomphalos, hemihypertrophyy (BW syndrome)
a. Key investigations
i. Hypoglycaemia <2.2 mmol/L
ii. Detectable insulin (Insulin > 14 pmol/L)
iii. Absence of ketones (blood + urine)
iv. Inappropriately low FFA
Would do a critical sample screen
+/- genetic studies (e.g. if BWS suspected)
Hyperinsulinaemic hypoglycaemia - ddx
a. Exogenous insulin
b. Sulphonylurea ingestion
c. Insulinoma
d. Beckwith-Widman
e. Kabuki syndrome
f. Turner syndrome
g. Congenital disorders of glycosylation
?Transient hyperinsulinism for neonates
K-ATP mutations…
Hyperinsulinaemic hypoglycaemia - treatment
a. Aim BSL > 4.0
b. Glucose replacement
i. 2-5 mL/kg of 10% dextrose
1. Aim for GIR of 8 mg/kg/min initially
2. Increase GIR by 2 mg/kg/min if subsequent BSL low
c. Pharmacotherapy
i. Glucagon
1. 5-20 mcg/kg/ hour
2. Very effective
3. Short-term use as IV or subcut infusion
ii. Diazoxide
1. Mechanism = BLOCKS sulphonylurea receptor on beta cells OPENS KATP hyper-polarize beta cell decreases insulin release
2. Only effective if KATP intact
3. Start with 10mg/kg/day in 3 divided doses and increase as necessary; if not responding to > 20mg/kg/day, consider the patient non-responsive
4. Adverse effects
a. Most common
i. Hypertrichosis – can be severe
(excessive hair growth over and above the normal for the age, sex and race of an individual, in contrast to hirsutism, which is excess hair growth in women following a male distribution pattern)
ii. Sodium and water retention
1. Can treat with thiazide which also aid in decreased insulin
2. Usually start both together
iii. Thrombocytopaenia, leukoepnia
b. Others: advanced bone age, hyperuricaemia, decreased IgG
c. Rare but serious: ketoacidosis, heart failure, nonketotic hyperosmolar coma
iii. Octreotide
1. Mechanism = long acting somatostatin analog
2. Dose 5-30 mcg/kg
3. Opens K+ channels + inhibits insulin release; can inhibit growth hormone release
4. Only subcut/ IV, can lead to tachyphylaxis
5. Adverse effects = modest increase in risk of NEC
d. Surgical
i. Indications
1. Diffuse form unresponsive to diazoxide
2. Focal lesion
ii. Procedures
1. Diffuse = sub-total pancreatectomy (95%)
2. Focal = focal resection
Hypoglycaemia - counterregulatory hormone defects - general
- Deficiencies of ACTH/ cortisol or GH
- Hypoglycaemia in growth hormone deficiency is due to decreased lipolysis (and glycogenolysis to a lesser extent)
- Hypogylcaemia in ACTH/cortisol deficiency, hypoglycaemia results from increased insulin sensitivity, decreased GNG and increase glucose oxidation
• Congenital hypopituitarism
o May have associated cerebral or midline abnormalities
o Septo-optic dysplasia
o Micropenis in boys with GH deficiency
o Some forms related to transcription factor mutations – PROP1, SOX2, SOX3, LHX3, LHX4
• Acquired hypopituitarism
o Post-infections, haemorrhage
o Older children – post surgery, irradiation, infiltration
• Primary adrenal insufficiency
o Newborn = CAH, congenital adrenal hypoplasia
o Older child = Addison’s, ADL, TB, haemorrhage e
Glycogen storage disorders - general
• Glycogen storage disorders (GSD) due to AR mutation in genes involved in glycogenolysis
• Key features
o Hepatomegaly (soft, often massive)
o Hypoglycaemia with fasting
Usually presents in later infancy as inter-feed interval increases or during intercurrent illnesses
o Lipolysis ad ketogenesis intact
LESS symptomatic than HI as alternative fuel available
• Types
o GSD1a
Impairment of both glycogenolysis and GNG – early hypoglycaemia can occur
GNG defect causes lactic acidosis
Completely dependent on exogenous glucose
Kidney involvement – RTA, microalbuminuria
o GSDIII
Associated with muscle weakness, cardiomyopathy, hypotonia
o GSD VI and IX – milder phenotypes
o GSD 0
Defect in glycogen synthesis
Fasting hypoglycaemia and postprandial hyperglycaemia
CHO – lipolysis in liver – elevated lactate
Defects of gluconeogenesis - general
a. Include
i. Galactosaemia
ii. Hereditary fructose intolerance – fructose 1,6-diphosphatase deficiency
iii. PEPCK deficiency
iv. Pyruvate kinase deficiency
b. Features
i. Glycogenolysis remains intact
ii. Later onset – hypoglycaemia occurs in the setting of fasting or intercurrent illness
iii. Positive glucagon response in the fed but not the fasted state
iv. Keto and lactic acidosis, hyperuricaemia, hyperlipidaemia
v. Hepatomegaly (lipid as opposed to glycogen)
Fatty acid oxidation defects - general
a. Errors in pathway of
i. Fatty acid uptake and activation
ii. Mitochondrial oxidation
b. Defects in
i. Carnitine synthesis, CPT1 and 2 (transporters)
ii. Acetyl-CoA dehydrogenase – SCAD, MCAD, LCAD
iii. HMG-CoA lyase
c. Features
i. Delayed onset – after infancy – phenotype varies according to level of mutation
ii. Often unmasked by fasting/ intercurrent illness
iii. Skeletal and cardiac muscle and liver – target organs
1. Myopathy, cardiomyopathy
2. Hepatic failure
iv. Encephalopathy – Reye like syndrome
d. Investigations
i. Low or absent ketones
ii. Diagnosis – urinary organic acids, carnitine profiles
Galactosaemia - general
a. Clinical features
i. Neonatal onset
ii. Post-prandial hypoglycaemia
iii. Neonatal cholestasis, diarrhoea
b. Investigations
i. Non-ketotic
ii. Urine reducing substance +ve
iii. Increased galactose-1-P
iv. Low galactose-1 phosphate uridyl transferase (GALT) level
Hereditary fructose intolerance - general
a. Clinical features
i. Onset after weaning
ii. Deficiency of fructose 1-phosphate aldolase (inhibits hepatic GNG)
iii. RTA, cholestasis, FTT
b. Investigations
i. Non-ketotic
ii. Urine reducing substance +ve
iii. Hypo after fructose load
Neonatal hyperglycaemia - background
- Pathogenesis
a. Hyperglycaemia typically occurs when infants cannot adapt to a parenteral glucose infusion by decreasing endogenous glucose production or increasing peripheral glucose uptake
i. Usually associated with prematurity or sepsis
b. Hyperglycaemia is more common in preterm infants compared with term infants, multifactorial
i. Poor insulin response
ii. Incomplete suppression of glucose production
iii. Increased secretion of counter regulatory hormones associated with stress - Aetiology
a. Parenteral administration of glucose
b. Prematurity
c. Sepsis
d. Stress = counter-regulatory hormones (adrenaline, cortisol)
e. Drugs
f. Neonatal diabetes mellitus
Neonatal diabetes mellitus - background
- Epidemiology
a. Incidence of 1/500,000 births - Definition
a. Persistent hyperglycaemia in the first months of life that lasts for >2 weeks
b. Requires insulin for management - Clinical presentation
a. Weight loss
b. Volume depletion
c. Hyperglycaemia
d. Glucosuria +/- ketonuria/ketoacidosis
Can be permanent or transient
Permanent neonatal diabetes mellitus - general
- Etiology
a. >50% have a permanent form primarily due to mutations in ATP-sensitive K+ channel
ii. Diagnosis made in the first 2 months of life
iii. Infants are SGA, but exhibit postnatal catchup with insulin therapy
iv. Other features = neurological abnormalities including severe developmental delay, epilepsy, muscle weakness, and dysmorphic features (DEND syndrome = dev delay, epilepsy, neonatal diabetes)
v. Treatment = oral sulphonylurea (insulin previously used) - Pathogenesis
a. Activating mutations increase the number of open KATP channels at the plasma cell
b. Results in hyperpolarization of the beta cells – preventing the release of insulin
c. NOTE: inactivating mutations result in hyperinsulinaemic hypoglycaemia of infancy
Transient neonatal diabetes mellitus - general
- Key points
a. Appears within the first few weeks of life but is transient
b. Affected infants go into remission within a few months
c. Possible relapse to permanent - Clinical manifestations
a. Hyperglycaemia (may have initial hypoglycaemia due to SGA)
b. Dehydration
c. FTT - Management
a. Supportive
b. Insulin
c. Can get late onset T1DM
Infant of diabetic mother - background
- Key points
a. Maternal diabetes
i. Pre-gestational –T1DM, T2DM (1.8%)
ii. Gestational (7.5%)
b. Adequate glycaemic control before and during pregnancy critical to improve outcome
c. Mortality
i. Fetal mortality rate higher than non-diabetic mothers – especially after 32 weeks
ii. Fetal loss throughout pregnancy associated with poorly controlled maternal diabetes and congenital abnormalities
iii. Neonatal mortality rate >5x than infants of non-diabetic mothers (higher at all gestational ages + BW)
d. Maternal risks
i. Polyhydramnios
ii. Pyelonephritis
iii. Pre-eclampsia
iv. Preterm labour
v. Chronic hypertension - FETAL
a. Maternal hyperglycaemia during first trimester and conception major birth defects + spontaneous abortions
b. Diabetic fetopathy occurs in 2nd and 3rd trimesters
c. Fetal hyperglycaemia
i. Stimulates glycogen storage in the liver, increased activity of hepatic enzymes involved in lipid synthesis and accumulation of adipose tissue contribute to long-term metabolic outcomes
d. Fetal hyperinsulinaemia
i. Elevated insulin elevated metabolic rate increased oxygen consumption + fetal hypoxia
ii. Consequences = increased mortality, metabolic acidosis, alterations in fetal iron distribution, polycythaemia, impaired lung maturation
iii. Follow-on effect of above - Increased catecholamine production hypertension and cardiac hypertrophy
- Increased fetal red cell mass + iron redistribution iron deficiency in developing organs, contributing to cardiomyopathy and neurodevelopment
iv. Contributes to impaired or delayed lung maturation
e. Macrosomia
i. Excessive nutrients delivered from poorly controlled diabetic mother causes increased fetal growth, particularly of insulin-sensitive tissues (liver, muscle, cardiac muscle, SC fat)
Infant of diabetic mother - neonatal effects
a. Congenital anomalies
i. Risk of 5-6%, increases to 10-12% in mothers requiring insulin
ii. Congenital malformations account for 50% of deaths in IDM
iii. Risk can be reduced by strict glycaemic control during the pre- and peri-conceptual time
iv. Most (2/3) involve CNS and CVS
1. Cardiovascular malformations (3-9%) = TGA, DORV, VSD, truncus arteriosus, tricuspid atresia, PDA
2. Anencephaly and spina bifida
3. Flexion contractures of limbs, vertebral anomalies
4. Small left colon = rare condition which presents as transient inability to pass meconium [most cases occur in IDM]
b. Prematurity
c. Perinatal asphyxia
i. Macrosomia failure to progress and shoulder dystocia
ii. Cardiomyopathy
d. Macrosomia = >90th centile on population-appropriate growth weight or >4000g
i. Increases risk of birth injury = shoulder dystocia (1/3 of IDM with macrosomia), brachial plxus injury, clavicular or humeral fractures, perinatal asphyxia, cephalhaematoma, subdural haemorrhage, or facial palsy
ii. Subsequently more likely to have hyperbilirubinaemia, hypoglycaemia, acidosis, respiratory distress, shoulder dystocia and brachial plexus injury
e. Respiratory distress
i. RDS more likely as IDMs are more likely to be premature and maternal hyperglycaemia delays surfactant production
ii. Other causes of RDS = TTN, cardiomyopathy
f. Metabolic complications
i. Hypoglycaemia = occurs in 25%
1. Caused by persistent hyperinsulinaemia – lasts for 2-4 days
5. Mechanism: Maternal hyperglycaemia foetal hyperglycaemia foetal hyperinsulinaemia
ii. Hypocalcaemia
1. Lowest calcium occurs 24-72 hours after birth
2. Usually asymptomatic and resolves without treatment
iii. HypoMg
1. Transient and asymptomatic, usually not treated
g. Haematological complications – polycythaemia, hyperviscosity
i. Chronic neonatal hypoxia results in increased EPO
ii. Polycythaemia hyperviscosity syndrome vascular sludging, ischaemia and infarction
iii. Higher rate of renal vein thrombosis
h. Low iron stores
i. Hyperbilirubinaemia
j. Cardiomyopathy
i. Increased risk of transient hypertrophic cardiomyopathy
ii. Most prominent change is thickening of the interventricular septum
iii. Usually asymptomatic
- LONG TERM
a. Diabetes
b. Obesity and impaired glucose metabolism
c. Impaired neurodevelopment
Infant of diabetic mother - treatment
a. Maternal
i. Close monitoring
ii. Aim for strict BSL control
b. Neonatal
i. Initiate feeding within 1 hour
ii. Screen glucose test within 30 minutes of first feed
iii. Gavage feeding with breast milk or formula
iv. IV glucose as needed
Factors controlling appetite
- Hypothalamus
a. Lateral nuclei of hypothalamus = hunger when stimulated
b. Ventromedial nuclei = satiety
c. Arcuate nuclei = where GI / adipose hormones converge to regulate food intake - Central neurotransmitters
a. Anorexigenic = POMC neurons produce alpha- MSH + CART
b. Orexigenic neurons = produce neuropeptide Y + AGRP - Short term players (less of a role in weight gain)
a. Vagus nerve – stretch of GIT inhibits appetite
b. CCK released from enteroendocrine cells duodenum and jejunum in response to fat and protein inhibits appetite, promotes bile/pancreatic enzyme secretion
c. Peptide YY released from neuroendocrine cells ileum/colon in response to fat inhibits appetite
d. GLP released from pancreases in response to GI filling inhibits appetite
e. Ghrelin released from parietal oxyntic cells of stomach + intestine, rise during fasting stimulates hunger and GH secretion - Long term factors = LEPTIN
a. Peptide hormone in adipose tissue, signals satiety and appetite suppression
b. ↑ adipose = ↑ leptin
c. Acts via NPY, alpha-MSH receptors to decrease their usual orixogenic behaviour
d. Stimulates POMC neurons to increase release of alpha-MSH (counteracts NPY action)
e. ↑ metabolic rate and energy expenditure
f. ↓ insulin secretion
g. NOTE: can have leptin resistance and abnormalities in signaling in hypothalamus resulting in monogenic obesity (melanocortin 4 receptor)
POMC deficiency - general
Proopiomelanocortin (POMC)
Precursor of ACTH, melanin, lipocortin, endorphin
Obesity (no appetite inhibition)
Pallor, red hair (no melanin)
Adrenal insufficiency (no ACTH)
Obesity - background
- Diagnosis
a. Age < 2 years = sex-specific weight for length is >97.7th centile on WHO charts
b. Age > 2 years = BMI and CDC normative BMI centiles
i. Overweight = BMI 85th to 95th centile
ii. Obese = BMI > 95th centile
iii. Extreme obesity = BMI >120% of 95th centile or >35 kg/m2
c. Other
i. Age >6 years = waist to height ratio used as adjunct to BMI - Waist-to-height ratio of > 0.5 predicts cardiovascular risk in children
- Half of height regardless of height
d. NOTE: Height + weight in obesity
i. A young child might exhibit high weight and high height because linear growth can increase early in childhood if a child consumes excess energy
ii. At some point, the weight percentile exceeds the height percentile and the child’s BMI climbs into the obese range
iii. Exogenous obesity drives linear height, so most obese children are tall for their age most endocrine and genetic causes of obesity are associated with short stature
- Investigation
a. No routine laboratory investigations
b. Comorbidities should be assessed
c. Genetic obesity syndromes – indications for testing
i. Extreme early onset obesity (<5 years of age)
ii. Clinical features of genetic obesity syndromes – Hyperphagia
iii. Family history of extreme obesity - Tracking
a. Many, but not all, obese children will become obese adults
b. The likelihood of persistence of childhood obesity into adulthood (sometimes called “tracking”) is related to
i. Age
ii. Parental obesity
iii. Severity of obesity
iv. BMI trajectory during childhood - Red flags for underlying cause
a. Short stature
b. Abnormal physical signs
c. Developmental disability
d. Visual disturbance or headache (tumor)
Obesity - aetiology
- Aetiology (genes+environment)
a. Genetic 40-80% of variance in BMI
i. Genetics accounts for 70-80% for body composition particularly in early years
b. Environmental
i. Decreased exercise
ii. Decreased physical activity + increased sedentary activity
iii. Energy dense food
iv. Increased portion size - Medical causes of obesity = <5%
a. Genetic
i. Many and rare eg. POMC deficiency
b. Syndromic
i. Alstrom-Hallgren syndrome
ii. Carpenter syndrome
iii. Cohen syndrome
iv. Bardet-Beidl syndrome
v. Prader-Willi syndrome
c. Endocrine (more likely to be short)
i. Hypothyroidism
ii. Cushing syndrome
iii. PCOS
iv. GH deficiency
v. Pseudohypoparathyroidism
vi. Insulinoma
vii. Hypothalamic tumour / dysfunction
d. Fat baby syndromes
i. Prader Willi syndrome (big baby, hypotonia, small hands and feet)
ii. Beckwith Wiedermann (macrosomia, hypoglycaemia, omphalocele, macroglossia)
iii. Sotos (macrosomia, macrocephaly, large hands and feet)
iv. Weaver (macrosomia, accelerated skeletal maturation, camptodactyly)
v. Laurence-Moon/ Bardt-Biedel (obesity/ retinal pigmentation/ polydactylyl)
Obesity - treatment
- Prevention of obesity
a. Dietary and activity education
b. Healthy eating habits
c. At least 20 minutes, optimally 60 minutes, of vigorous physical activity at least 5 days per week to improve metabolic health and reduce the likelihood of developing obesity
d. Healthy sleep patterns
e. Avoid technology-related screen time
f. Involve the entire family
g. Breastfeeding of infants - Intervention principles
a. Family based lifestyle interventions
b. Long term behavioural change
c. Long term diet change
d. Increase exercise and decrease sedentary behaviour
e. Referral for multidisciplinary assessment - The simple 6
a. CHOOSE WATER AS YOUR MAIN DRINK
b. EAT BREAKFAST EACH DAY
c. EAT TOGETHER ONCE A DAY AS A FAMILY WITHOUT THE TV BEING ON
d. LIMIT SNACKS
e. SPEND 60 MINS OUTSIDE EVERY DAY PLAYING OR BEING PHYSICALLY ACTIVE
f. LIMIT SCREEN TIME TO LESS THAN 2 HOURS PER DAY - Treatment
a. Lifestyle =diet, exercise
b. Pharmacotherapy – rarely used in children
i. Metformin only in insulin resistance – shown in adults to delay progression to T1DM - Often used in adolecsents
ii. Orlistat = lipase inhibitor - Results in diarrhoea
- Weight loss
- Not commonly used
c. Bariatric surgery – rarely used in children
i. The earlier – higher complication rate
ii. Move to delay surgery until later in adolescence or early adulthood
d. BEST = multidisciplinary team
i. Hold BMI to hold centile while child grows
Obesity comorbidities - endocrine
a. Diabetes/ Insulin resistance
i. Prediabetes = moderate abnormalities in fasting glucose, glucose tolerance, or HbA1c
ii. Fasting glucose and HbA1c are typically used for screening
iii. NO validated test for measuring insulin resistance
iv. In one study – 4% of adolescents with BMI >95th centile had asymptomatic T2DM
v. Early diagnosis imperative as aggressive treatment can slow development of complications
b. Metabolic syndrome
i. ‘Metabolic syndrome’ is a term used to describe the clustering of metabolic risk factors for T2DM and atherosclerotic cardiovascular disease in adults
c. Hyperandrogenism in females
i. Adolescent girls with obesity are at an increased risk of hyperandrogenism and early onset PCOS (resulting in menstrual abnormalities
ii. Diagnosis can be difficult to establish during adolescence
d. Abnormalities in growth and development
i. Obesity in children and adolescents may be accompanied by accelerated linear growth and bone age
e. Other
i. Pubertal advancement
ii. Menstrual abnormalities
iii. Reduced GH secretion + increased clearance
Obesity comorbidities - cardiovascular
a. Obesity and children and adolescence linked with cardiovascular changes that are linked to increased cardiovascular risk in adulthood
b. Hypertension = increased in obesity, correlates with the severity of obesity
c. Dyslipidaemia = increased in obesity, particularly if central fat distribution
d. Cardiac structure + function = associate with findings similar to seen in adults; increased LV mass etc.
e. Coronary artery disease = increasing evidence suggests an association between obesity during childhood and cardiovascular disease during adulthood
Obesity comorbidities - GI
a. NAFLD
i. Obesity is associated with a clinical spectrum of liver abnormalities collectively known as NAFLD
ii. 40% of obese children have fatty liver
iii. 10% have mildly elevated serum aminotransferase concentrations – caused by NAFLD
iv. Most common cause of liver disease in children
v. Abnormalities include
1. Steatosis = increased liver fat without inflammation
2. Non-alcoholic steatohepatitis (NASH) = increased liver fat with inflammation
vi. Diagnosis
1. Most patients asymptomatic – some have RUQ or abdominal discomfort
2. Elevation in transaminases, ALP an GGT
3. Imaging (USS) can confirm fatty liver – increased echogenicity
4. NO firm diagnostic criteria
vii. Treatment = weight loss
b. Cholelithasis
i. Obesity is the most common cause of gallstones in children without predisposing conditions (eg. haemolytic anaemia, history of TPN)
ii. One study found 10% of obese adolescents had gallstones
iii. Risk for gallstones increases with BMI
iv. Signs and symptoms are non-specific
v. USS is the test of choice
Most common cause of liver disease in children
NAFLD
i. Obesity is associated with a clinical spectrum of liver abnormalities collectively known as NAFLD
ii. 40% of obese children have fatty liver
iii. 10% have mildly elevated serum aminotransferase concentrations – caused by NAFLD
v. Abnormalities include
1. Steatosis = increased liver fat without inflammation
2. Non-alcoholic steatohepatitis (NASH) = increased liver fat with inflammation
vi. Diagnosis
1. Most patients asymptomatic – some have RUQ or abdominal discomfort
2. Elevation in transaminases, ALP an GGT
3. Imaging (USS) can confirm fatty liver – increased echogenicity
4. NO firm diagnostic criteria
vii. Treatment = weight loss
Most common cause of gallstones in children without predisposing conditions
Obesity
Obesity comorbidities - pulmonary
a. OSA = prevalence of OSA increased in obese children and adolescents
b. Obesity hypoventilation syndrome
i. Key criteria
1. Extreme obesity
2. Alveolar hypoventilation during wakefulness
ii. More commonly, children and adolescents have hypoventilation during sleep in the absence of obstructive defect – perhaps due to restrictive ventilatory defect caused by obesity
c. Asthma
Obesity comorbidities - orthopaedic
a. SUFE
i. Displacement of the capital femoral epiphysis from the femoral neck through the physeal plate
ii. Typically occurs in adolescence, obesity is a significant risk factor
iii. Require orthopaedic management
b. Tibia vara (Blount disease)
i. Progressive bowed legs and tibial torsion
ii. Results from inhibited growth of the medial proximal tibial growth plate due to excessive weight baring
iii. Tibia vara associated with obesity
c. Fracture
i. More susceptible to fracture – reduced bone mass when adjusted for body size
Obesity comorbitidies - neuro/derm/psychosocial
- NEUROLOGIC
a. Idiopathic intracranial hypertension
i. Risk increases with severe obesity - DERMATOLOGICAL
a. Intertrigo
b. Furunculosis
c. Hidradenitis suppurative = inflammatory nodules or deep fluctuant cysts in the interiginous skin of the axilla and groin
d. Acanthosis nigricans
e. Stirae densiae = mechanical factors - PSYCHOSOCIAL
a. Teasing, discrimination, secondary disordered eating, poor self esteem, risk of depression
Most common cause of infertility in women
PCOS
PCOS - background
- Key points
a. Most common cause of infertility in women
b. Frequently manifests in adolescent
c. Characterised by ovulatory dysfunction and hyperandrogenism
d. Lifelong implications with increased risk of metabolic syndrome, T2DM, and possibly CVD and endometrial carcinoma - Features
a. Cutaneous signs of hyperandrogenism (eg. hirsutism, moderate-severe acne)
b. Menstrual irregularity (eg oligo- or amenorrhoea, or irregular bleeding)
c. Polycystic ovaries (one or both)
d. Obesity and insulin resistance - Diagnosis
a. Abnormal uterine bleeding pattern
i. Abnormal for age or gynaecological age
ii. Persistent symptoms for 1-2 years
b. Evidence of hyperandrogenism
i. Persistent testosterone elevation above adult norms – best evidence
ii. Moderate-severe hirsutism is clinical evidence of hyperandrogenism
iii. Moderate-severe inflammatory acne vulgaris – indication to test for hyperandrogenism
PCOS - manifestations, investigations
- Clinical manifestations
a. Cutaneous manifestations of hyperandrogenism
i. Hirsutism = sexual hair in a male pattern
ii. Acne
iii. Other characteristics of hyperandrogenaemia = seborrhoea, hyperhidrosis, hidradenitis suppurativa
iv. Frank virilisation is UNUSUAL in PCOS
b. Ovarian findings
i. Anovulation
ii. Polycystic ovaries
c. Associated metabolic features
i. Obesity - Present in 50% of patients with PCOS
- PCOS is the most common obesity-related endocrine syndrome in females
ii. Manifestations of insulin resistance - Metabolic features of insulin resistance are common in adolescents with PCOS
- Clinical manifestations of insulin resistance
a. Acanthosis nigricans
b. Metabolic syndrome
c. Sleep disordered breathing
d. NAFLD - Investigations
a. Blood tests
i. 75g OGTT with insulin levels
ii. Fasting lipids
iii. Testosterone = elevated in PCOS
iv. SHBG
v. Free androgen index
vi. 17-OH-P = screening test for non-classical CAH secondary to 21-hydroxylase deficiency
vii. DHEA = markedly elevated in adrenal tumour or cortisol reductase deficiency
viii. FSH, LH
ix. TSH
x. Prolactin
b. Pelvic USS
PCOS - differentials
a. Physiological adolescent anovulation
b. Virilising congenital adrenal hyperplasia
i. Non-classical ‘late onset’ CAH is the second most common cause of androgen excess in adolescence
ii. 3ß-hydroxysteroid dehydrogenase (3ß-HSD)
4. Investigations
a. DHEAS level very elevated
b. 17-hydroxypregnenolone elevation >10 SD above mean
c. ACTH stimulation test
d. Molecular testing
iii. 11ß-hydroxylase
c. Related congenital disorders of adrenal steroid metabolism or action
i. Cortisone reductase deficiency
ii. Apparent DHEA sulfotransferase deficiency
d. Cushings syndrome
e. Virilising tumours of adrenals or ovaries
i. >50% malignant
ii. Usually cause rapid onset of virilising symptoms including hirsutism, temporal hair recession, increased muscle bulk, voice deepening, clitoremegaly without genital ambiguity
iii. Substantial minority are mildly hyperandrogenic and indolent in onset and mimic PCOS
f. Ovarian steroidogenic block
g. Hyperprolactinaemia
h. Insulin-resistance disorders
i. Acromegaly
j. Thyroid dysfunction
k. Drugs = anabolic steroids
PCOS - treatment
a. Treatment is primarily directed against the major clinical manifestations
b. Pharmacological
i. Oral contraceptive pill
1. 1st line treatment is usually estrogen-progestin combined oral contraceptive pill (COC) – corrects both menstrual abnormalities and hyperandrogenaemia
2. Progestin component inhibits endometrial proliferation preventing hyperplasia and reducing the risk of associated carcinoma
3. Estrogen component reduces androgen excess corrects menstrual abnormalities and improves hirsutism and acne (takes 3-6 months)
ii. Anti-androgen
1. If hirsutism is not adequately controlled by cosmetic and COC treatment – anti-androgen can be added
iii. Insulin sensitiser
1. Improve ovulation in half of cases and modestly reduce androgen levels
2. Not as effective as COC in controlling menstrual cyclicity or hirsutism
3. Metformin is suggested if abnormal glucose tolerance or lipid abnormalities of the metabolic syndrome that cannot be normalised by weight loss
c. Non-pharmacological = lifestyle, weight loss
i. Lifestyle modification is first line for overweight and obesity
ii. Improves menstrual regularity, acanthosis nigricans, and hyperandrogenism
C-peptide - elevated/decreased
• Elevated
o Insulinoma
o Sulfonylurea intoxication
o Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
o Insulin resistance states eg. obesity, Cushings
o Chronic kidney disease
• Decreased
o Type 1 diabetes mellitus
o Exogenous insulin injection (factitious)
o Hypoglycemia due to insulin-like growth factor secreting tumor
o Insulin-independent hypoglycemia
Alcoholic ketoacidosis - general
- Situation
a. Acute on chronic alcoholic who has a binge
b. Then fasted, no oral intake
c. +/- vomiting
d. Usually not diabetic - Pathophysiology = ETOH + fasting
a. Fasting
i. Glycogenolysis / gluconeogenesis / lipolysis
ii. Decreased insulin, increase glucagon
iii. Insulin deficiency = lipolysis and ketone formation
b. ETOH
i. Metabolized in liver ETOH acetylaldehyde acetate, with NAD+ as cofactor (NAD NADH+ + H+)
ii. Ratio of NADH/NAD+ rises
iii. Result = inhibition of gluconeogenesis (requires NAD+), favors production of B-hydroybutyrate over acetoacetate build up of ketones - Investigations
a. BSL – low, normal, high
b. Ketones – elevated
c. Osmolarity – high
d. UEC/CMP – Mg often low
e. VBG – mixed metabolic acidosis (ketones) + metabolic alkalosis (vomiting) - Management
a. Glucose/insulin infusion
Gonads - products of ducts (mesonephric, etc)
i. Females
1. Gonads ovaries
2. Paramesonephric (Mullerian) ducts fallopian tubes, uterus, and upper vagina
3. Mesonephric (Wolfian) ducts persist in vestigial form
4. External genitalia
a. Genital tubercle clitoris
b. Genital swellings, labia majora
c. Genital folds labia minora
ii. Males
1. Gonads testes
2. Mesonephric (Wolfian) ducts epididymis, vas deferens, seminal vesicles + ejaculatory ducts
3. Paramesonephric (Mullerian) ducts regresses
4. External genitalia
a. Genital swellings fuse scrotum
b. Genital folds elongate and fuse shaft of penis and penile urethra
c. Genital tubercule glans penis
d. Prostatic buds develop in the wall of the proximal urethra and elongate to form testes
e. Testicular descent occurs in latter part of gestation
Gonads - normal development
a. Key points
i. All embryos start with bipotential gonads, Mullerian and Wolffian ducts
ii. For the first 6 weeks of human gestation the two sexes develop in an identical fashion
iii. Determination of the indifferent gonad into ovary or testis begins at 6 weeks following secretion of hormones by the fetal testes (ovary is usually silent)
iv. Further features of the urogenital tract are completed by 12 weeks in males and slightly later in females
v. Sex specific hormones from the gonads influence sexual differentiation
c. Males
i. Sex-determining region of Y chromosome (SRY) – directs development of gonads into testes
1. By 8-9 weeks have identifiable testes
2. Y chromosome is ESSENTIAL for testicular development
ii. Hormones – 3 important
1. Anti-Mullerian hormone (= Mullerian Inhibiting Hormone/ Mullerian Inhibiting Substance)
a. Produced by Sertoli cells of the fetal testis
b. Causes regression of the Mullerian ducts results in internal genital development
c. If low levels in male = mullerian structures can remain
2. Testosterone
a. Produced by fetal testes (Leydig cells)
b. Stimulates Wolffian duct differentiation into epididymis, vasa deferentia, seminal vesicles and ejaculatory ducts
c. Initially controlled by placental hCG and later by LH (produced by pituitary)
3. Dihydrotestosterone (potent testosterone)
a. Formed by 5-alpha reductase acting on testosterone
b. Regulates development of prostate and external genitalia – complete by 12th week
d. Females (essentially lack everything above)
iv. If male development is not initiated – ovarian development will occur around week 10
1. Need absence of SRY, testosterone and AMH
Hypogonadotropic hypogonadism - differentials
- Genetic
a. KAL-1, FGFR1, GnHR, DAX- - Organic
a. Tumours
i. Craniopharyngiomas
ii. Germinomas, meningiomas, gliomas, astrocytomas
b. Post head trauma
c. Cranial irradiation
d. Multiple pituitary hormone deficiency
e. Isolated gonadotrophin deficiency (without anosmia) - Syndromal
a. CHARGE
b. Prader-Willi
c. Kallman
d. Bardet-Biedl - Chronic disorders
a. Chronic systemic disease – IBD, renal failure, CF
b. Malnutrition + AN
c. Hypothyroidism, hyperprolactinaemia, poorly controlled diabetes, Cushing’s disease
Isolated gonadotropin deficiency - general
- Key points
a. Cause of hypogonadotropic hypogonadism
b. Occurs in males and females
c. Classification
i. 60% anosmia or hyposmia = Kallman syndrome
ii. 40% normal smell = normosmic IGD - Genetics
a. Sporadic or due to mutation in KAL1 gene (Xp22.3) or KAL2 - Clinical manifestations
a. Anosmia or hyposmia or normal smell
b. Absent or partial puberty - Genetics
a. Isolated gonadotropin deficiency (= hypogonadotropic hypogonadism without anosmia)
i. Specific genetic defect is not found in most cases
b. Kallman syndrome
i. Autosomal (dominant or recessive) in 85%
ii. X-linked 15% - Mutation in KAL1 gene
- Leads to failure of olfactory axons and GnRH expressing neurons to migrate from their common origin in the olfactory placode to the brain
- Investigations
a. In persons with IGD: typically, normal-appearing hypothalamus and pituitary on MRI exam
b. In persons with KS: typically, aplasia or hypoplasia of the olfactory bulbs/sulci/tracts
Hypergonadotropic hypogonadism, males - general
Primary hypogonadism, i.e. issue in gonads
- Etiology
a. Congenital
i. FSH and LH resistance
ii. Mutations in steroid synthetic pathways
iii. Gonadal dysgenesis
iv. Klinefelter syndrome
v. Noonan syndrome (PTPN-11 gene mutation in many cases)
vi. Cystic fibrosis (infertility)
b. Acquired
i. Cryptorchidism (some cases)
ii. Vanishing testes
iii. Chemotherapy
iv. Radiation
v. Infection (eg. mumps)
vi. Infarction (testicular torsion)
vii. Trauma - Clinical Manifestations
a. Primary hypogonadism suspected at birth if testes and penis small
b. Often not noticed or diagnosed until puberty when secondary sex characteristics fail to develop
i. Facial, pubic and axillary hair is scant or absent
ii. Neither acne nor regression of scalp hair
iii. Voice remains high pitched
iv. Penis and scrotum remain infantile
v. Fat accumulates in the hips and buttocks, sometimes the abdomen and breasts
c. Epiphyses close later than normal – therefore have long extremities
i. Arm span may be several inches longer than height
ii. Upper segment «< lower segment = eunuchoid - Ie. the ratio of upper to lower segment is <0.9
- Diagnosis
a. Hormone levels
i. ↓ Serum total testosterone level – measured in morning (maximum at 0800)
ii. ↑ FSH and LH
iii. hCG stimulation test – only small or no rise in testosterone level
iv. ↑ AMH – secreted by Sertoli cells and usually suppressed by testosterone
Klinefelter Syndrome - general
• 47,XXY – most common sex chromosome disorder in humans
• Prevalence of 1/500
• Key features
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
o Primary hypogonadism – small, firm testes, decreased virilisation, small phallus, hypospadias, cryptorchidism
o Growth – tall, legs > trunk
Clinical impairments become more severe with additional chromosomes
XX males - general
- 46,XX males – translocation of Y material including sex determining region (SRY) to the X chromosome during paternal meiosis
- Essentially gives same phenotype as Klinefelter:
Klinefelter:
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
o Primary hypogonadism – small, firm testes, decreased virilisation, small phallus, hypospadias, cryptorchidism
o Growth – tall, legs > trunk
Hypogonadotropic hypogonadism, males - general
Ie secondary hypogonadism (problem not with gonads)
- Key points
a. Deficiency of LH or FSH or both
b. Primary defect either in the anterior pituitary OR hypothalamus
c. Hypothalamic aetiology result in deficiencies of GnRH
d. Usually recognized due to marked pubertal delay - Etiology
a. Congenital
i. Genetic defects - Kallman syndrome
- Normosmic hypogonadotropic hypogonadism
ii. Other genetic disorders associated with hypogonadotropic hypogonadism - Eg. Leptin gene, leptin receptor, DAX1, SF-1
iii. Inherited syndromes - Prada Willi
- Bardet-Biedl
- Laurence-Moon-Biedl
- Alstrom
iv. Isolated HH (hypogonadotropic hypogonadism) at pituitary level
v. Multiple pituitary hormone deficiencies - Septooptic dysplasia
- Other disorders of pituitary organogenesis
vi. Idiopathic
b. Acquired
i. Anorexia
ii. Drug use
iii. Malnutrition
iv. Chronic illness especially Crohn’s disease
v. Hyperprolactinaemia
vi. Pituitary tumours
vii. Pituitary infarction
viii. Infiltrative disorders (eg. histiocytosis)
ix. Haemosiderosis and haemochromatosis
x. Radiation - Clinical manifestations
a. Absent or partial puberty in adolescents at presentation
b. Incomplete sexual maturation on examination - Investigations
a. ↓ Serum total testosterone level – measured in morning (maximum at 0800)
b. ↓ FSH and LH (inappropriately low) - Treatment
a. Usually managed with testosterone
b. Sometimes treatment with gonadotropins
