Endocrinology Flashcards
If a patient with hypercalcaemia has an elevated PTH what is the most likely diagnosis?
Primary (or tertiary) hyperparathyroidism
If a patient with hypercalcaemia has a normal PTH level, what diagnoses do you have to consider?
Primary hyperparthyroidism
Tertiary hyperparathyroidism
Familial hypocalciuric hypercalcaemia
In a patient with hypercalcaemia and a low (or low normal) PTH, what further investigations should you undertake?
PTHrp
25-hydroxyvitamin D (25[OH]D, calcidiol)
1,25-dihydroxyvitamin D (calcitriol)
TFTs
Consider multiple myeloma screen
Consider vitamin A level
What does an elevated 25-hydroxyvitamin D (25[OH]D, calcidiol) level in the setting of hypercalcaemia Indicate?
Vitamin D intoxication
What next tests should you order in a patient with hypercalcaemia, a low PTH and elevated levels of 1,25-dihydroxyvitamin D (calcitriol)
Chest imaging to look for evidence of granulomatous disease (eg sarcoidosis) or malignancy (eg lymphoma)
What biochemical markers are consistent with hypercalcaemia of malignancy?
Hypercalcaemia (usually greater elevation that in hyperparathyroidism)
Low or low-normal PTH
Elevated PTHrP
Low calcitriol level
What biochemical markers are consistent with hypercalcaemia of malignancy?
Hypercalcaemia (usually greater elevation that in hyperparathyroidism)
Low or low-normal PTH
Elevated PTHrP
Low calcitriol level
In hypercalcaemia, what 3 disorders are associated with hypocalciuria?
Familial hypocalciuric hypercalcaemia
Thiazide diuretics
Milk-alkali syndrome
If evaluation for hypercalcaemia does not suggest primary hyperparathyroidism, hypercalcaemia of malignancy or vitamin D intoxication (ie low PTH, low PTHrP, low or normal calcitriol level), what other conditions are most likely?
Conditions associated with unsuspected stimulation of bone resorption including:
multiple myeloma
thyrotoxicosis
immobilization
vitamin A toxicity
Or unrecognized calcium intake in the face of renal insufficiency (as in the milk-alkali syndrome)
What is the milk-alkali syndrome?
The milk-alkali syndrome consists of the triad of:
hypercalcemia +
metabolic alkalosis +
acute kidney injury
associated with the ingestion of large amounts of calcium and absorbable alkali
What is osmotic demyelination syndrome and when does it occur?
Occurs with overly rapid correction of SEVERE (<120mmol/L)
CHRONIC (ie >2 days)
HYPOTONIC
hyponatraemia
Almost exclusively occurs in those with serum sodiums less than 120 (and majority less than 105)
Other risk factors (including for patients who develop ODS at less severe degrees of hyponatraemia and slower rates of correction) include:
- alcohol use disorder
- malnutrition
- liver disease
- hypokalaemia
- hypophosphataemia
What is the pathophysiology of osmotic demyelination syndrome?
In response to systemic serum hypotonicity (the serum sodium concentration is the primary determinant of serum tonicity) water flows across the blood-brain barrier thereby increasing brain water content and causing brain cells (primarily astrocytes) to swell (ie cerebral oedema). These cells surround brain capillaries and protect neurons from swelling via a cell-to-cell transfer of cellular solutes and water.
However the brain adapts almost immediately (adaptation is completed within 2 days) to return brain volume toward normal by:
Firstly, the initial cerebral oedema raises interstitial hydraulic pressure which creates a gradient forcing interstitial sodium and water out of the brain and into CSF,
Secondly, astrocytes lose intracellular solutes (osmlytes incl potassium, amino acids such as glutamine/glutamate etc) thereby shedding excess water so it has the same tonicity as plasma
Because of this adaption, hyponatraemia that develops over more than 2-3 days is not associated with severe brain swelling and is therefore less likely to be complicated by seizures, coma and brain herniation.
HOWEVER once the brain has adapted to the hypotonicity (ie patients without acute hyponatraemia), the rate of correction of hyponatraemia becomes important - overly rapid correction in patients with chronic hyponatraemia may lead to ODS.
The exact pathogenesis of ODS is incompletely understood.
It is thought that in ODS, rapid correction of hyponatraemia (which increases serum sodium and therefore serum tonicity) causes excess water to flow out of the brain (across BBB) to the systemic circulation but the reuptake of osmolytes into brain cells occurs more slowly - this results in an acute fall in brain cell volume which causes direct injury to astrocytes/oligodendrocytes that are crucial for normal myelination and maintenance of BBB. As well, the initial movement of potassium and sodium back into brain cells leads to an increase in cell cation concentration BEFORE the organic osmolytes can be replaced which leads to protein aggregation, DNA fragmentation and apoptosis leading astrocytes and oligodendrocytes to die in regions of the brain affected by demylelination.
The end result is that ODS causes demyelination, often diffusely of which central pontine involvement may or may not be present
Patients with hyponatraemia >120mmol can rarely suffer ODS - under what two clinical situations can this occur?
1) Patients with severe liver disease and moderate hyponatraemia whose sodium levels increase after liver transplantation
2) Patients with AVP disorders (formerly diabetes insipidus) who develop moderate hyponatraemia as complication of desmopressin therapy then have desmopressin discontinued
What is the maximum rate of sodium correction you should not exceed in a patient with risk factors for ODS?
You should not exceed 6 to 8 mmol/L in any 24-hour period
Goal 4-6mmol/L
When do symptoms of ODS typically occur?
Delayed for 2-6 days after overly rapid correction of serum sodium has occurred
What are the main symptoms of ODS?
Dysarthria, dysphagia, weakness (para- or quadri-paresis), behavioural disturbances, movement disorders, seizures, lethargy, confusion, coma
Is MRI-documented demyelination in ODS reversible?
No - frequently irreversible
What are the main clinical features of patients with ODS affecting the pons?
Speech dysfunction (occurs early and persists) incl mutism
- corticospinal signs (hyperreflexia + bilateral babinski sign)
- corticobulbar signs (brisk jaw jerk)
- swallowing dysfunction (leading to aspiration pneumonia/resp failure)
- increased muscle tone
- facial weakness
- primitive reflexes
What are the key clinical features of extra-pontine involvement in ODS?
A parkinsonian picture with choreoathetosis or dystonia that responds to dopaminergic treatment
- psychiatric disturbances
- catatonia
- postural limb tremor
- myoclonic jerks
How is ODS diagnosed and what are the limitations in diagnosis?
Suspect in all patients with risk factors and consistent clinical manifestations if overly rapid correction of hyponatraemia within last week
MRI-brain is best (CT less reliable but an option if MRI unavailable
BUT MRI may not become positive for as long as 4 weeks after disease onset - thus an initial negative radiologic study
How do you prevent ODS?
In patients with risk factors:
- monitor sodium every 2-3 hours and avoid correcting sodium by more than 6-8mmol/d
- monitor urine output to detect water diuresis
If water diuresis occurs can adopt:
- proactive strategy - give desmopressin + hypertonic saline
- reactive strategy - give desmopressin or 5% dextrose in water
- rescue strategy - give desmopressin
How do you treat ODS/
Lower serum sodium to level below 48hr target using
- desmopressin
- dextrose 5% in water
Consider immune-modulating therapy incl steroids, plasmapharesis, IVIG
Supportive cares
What are the main adverse effects of overt hypothyroidism in pregnancy?
Increased risk of:
- miscarriage
- stillbirth
- premature delivery
- low birth weight
- lower IQ in offspring
If a woman with pre-existing hypothyroidism becomes pregnant, what dose adjustment to their thyroxine is typically required?
Typically need to increase dose by about 30% during pregnancy
Do you routinely need a thyroid USS in hypothyroidism or hyperthyroidism?
No unless palpable nodule
Is there any evidence that treating subclinical hypothyroidism in pregnancy (despite its association with adverse pregnancy outcomes such as miscarriage) improves pregnancy loss or preterm delivery OR improves fertility in those attempting natural conception?
No - insufficient evidence at present
HOWEVER, if attempting ART then thyroxine is recommended aiming to achieve target of <2.5mU/L
What is the most frequent reason for hyperthyroidism in pregnancy?
Gestational thyrotoxicosis (bHCG stimulate thyroid hormone secretion)
- usually occurs in 1st trimester as hCG peaks at 7-11weeks
- 1-3% incidence rate
- usually assoc with higher hCG eg hyperemesis, multiple gestation, hydatiform mole, choriocarcinoma
- usually treat with short-term beta-blockers for symptomatic mx NOT anti-thyroid drugs
What are the risks of maternal Graves’ disease on foetal/neonatal outcomes?
Increased risk of foetal/neonatal thyroid disease (hypo- or hyper-thyroidism) + central hypothyroidism
Therefore, requires serial USS monitoring to detect foetal hyperthyroidms eg IUGR, foetal goitre, tachycardia, CCF, accelerated bone maturation, foetal hydrops
Risk relates to the fact that TSH receptor antibodies cross the placenta
For women with Graves’ disease, what testing should be done during pregnancy?
Serum TRAb in early pregnancy
- if positive then repeat testing at 18-22 weeks (including if on antithyroid drugs)
- if elevated at 18-22 weeks then should repeat again at 30-33
Note serum TRAb > 3x ULN indicates high risk of foetal thyrotoxicosis
If a pregnant women with Graves’ disease is on antithyroid drugs and TRAb become undetectable on testing during pregnancy - what should be done about their antithyroid drugs and why?
Could consider reducing or withdrawing antithyroid drugs to protect from foetal hypothyroidism and goitre
Why should you check thyroid function in neonates of women with Graves’ disease?
Because after birth, any antithyroid drug medication is cleared more rapidly from the neonate than TRAb so the baby may become hyperthyroid
What is the preferred antithyroid drug in pregnancy?
PTU - 1st trimester - why? lower risk of birth defects
Note antithyroid drugs cross placenta and tend to be more potent in foetus than in mother (i.e. if mother is euthyroid, foetus is often overtreated/at risk of goitre or hypothyroidsm)
Therefore aim is to use smallest dose possible (or even discontinue in second half of pregnancy) aiming for FT4 values at or just above pregnancy-specific ULN
What is the common time-course for post-partum thyroiditis?
50% isolated hypothyroidism - occurs 3-12 months post-partum - treat with thyroxine if symptomatic, breastfeeding or actively attempting pregnancy otherwise monitor
- note 10-20% will develop permanent hypothyroidism - risk greater if positive antibodies and higher TSH
20% biphasic
30% isolated hyperthyroidism - occurs 2-6 months post-partum -> treat symptomatically with beta-blockers and continue to monitor with 4-6 weekly TSH to assess for development of hypothyroidism
What are the differentiating features between post-partum thyroiditis and Graves’ disease?
Graves disease = positive TSH receptor antibodies + eye disease + increased uptake on thyroid uptake scan
Postpartum thyroiditis = negative TSH receptor antibodies + elevated T4:T3 ratio + no eye disease + suppressed thyroid uptake on scan
Explain the physiological negative feedback loop in thyroid function?
Negative feedback primarily occurs via T3 which is predominantly deiodinated by type 2 peripheral deiodinase locally in tissues
How tightly is thyroid hormone protein bound?
99% protein bound
- TBG
- transthyretin
- albumin
