Teaching Clinic - Hypothyroidism Flashcards
Where is T3 and T4 from?
• All the T4 in the circulation is derived from thyroid secretion whereas only 20% to 30% of circulating T3 is of thyroidal origin
• Normal mean daily T4 secretion is between 100 and 125 nmol (80 - 100 ug) which is entirely derived from the thyroid
• At least 2/3 of daily mean T3 production is derived from peripheral conversion of T4
• In situations of environmental iodine deficiency or diseases causing a lowered intrathyroidal iodine pool, thyroidal secretion of T3 is increased
Thyroid function test and what is the most important hormone tested?
- Approx 99.98% T4 and approx 99.7% of T3 bound to specific plasma proteins (TBG, TBPA and albumin)
- Log/linear inverse relationship between serum TSH and free T4 concentration produced by -ve feedback inhibition of TSH secretion by thyroid hormones
- If free T4 is slight lowered, TSH will be increased greatly (TSH is very sensitive)
What is used to screen for primary thyroid dysfunction? What are the limitation of using TSH as a screening test?
TSH is used to screen for primary thyroid dysfunction
Limitations:
Assume that hypothalamic pituitary function is intact and normal
Assume that patient’s thyroid status is stable
What thyroid test should be used for patients with stable vs unstable thyroid status?
STABLE thyroid status:
- TSH more sensitive indicator of thyroid status than FT4
UNSTABLE thyroid status:
- FT4 is a more reliable indicator of thyroid status than TSH
How to classify hypothyroidism based on TSH and T4?
Hypothyroidism in adults: S/S
Slow relaxation phase in reflexes
Risk factor of hypothyroidism
Case 1
Secondary amenorrhoea for 8 months to private gynaecologist
No visual disturbance
Mild weight loss = intentional (ACEi) vs unintentional
Weight gain = rapid -> thinking Cushing’s; (PCOS)
Hyperprolactinemia
Hypothalamic problems
Pituitary problems
Thyroid problems
Medications which may interfere with hormonal cycle (HRT)
R/O pregnancy
Menarche 12, regular cycle
Uncomplicated pregnancy at 28
Barrier method for contraceptives
PMH: nil
DH: Nil
FH: mother ?hx of thyroid problem
Private blood tests in gynaecologist showed prolactin 1080 mIU/L
What are the pathological DDx for hyperprolactinemia?
- Drugs-induced - first thing to r/o:
a. Dopamine: anti-psychotics, antiemetics, H2, methyldopa
b. Antiemetics: metoclopramide, cimetidine, domperidone
c. Others: estrogen - Prolactinoma
- Stalk effect
- Renal failure (decreased prolactin clearance)
- Hypothyroidism
- Chest trauma
- Physiological: Pregnancy / lactation
How do we take a non-stress prolactin level?
Take the blood 15 minutes after putting needle in as prolactin may be raised during stress
This is important as venipuncture may cause stress = increase in prolactin
Aetiology of hyperprolactinemia
● Pulse 68, SR
● Dry skin
● No galactorrhea
● Small firm goiter
Ix
● PRL raised 1100 mIU/1 (up to 500)
● Thyroid function
○ Elevated TSH
○ Low T4
What type of hypothyroidism is this? What could be the cause?
How do we diagnose hypothyroidism?
Dx of HypoT
● Elevated TSH and low fT4 suggest primary hypoT
● Check anti-TPO and anti-Tg Ab
● USG is NOT required in absence of additional clinical indications (goiter or palpable nodule)
● Thyroid scan is NOT useful and not necessarily: primarily used in hyperthyroidism
What is Hashimoto Thyroiditis?
- Leading cause of hypothyroidism in iodine sufficient areas
- Autoimmune
- M/F 1:15
- May present with or w/o goitre, usually painless
- Thyroid Ab titres usually measurable
- Histology: Diffuse lymphocytic infiltration with lymphoid follicles, plasma cells and disruption of thyroid follicles
- May be associated with other autoimmune diseases
What is thyroperoxidase autoantibody?
Initially described as anti-microsomal autoantibody
• TPO is involved in thyroid hormone synthesis at the apical pole of the follicular cell
• The most sensitive test for detecting autoimmune thyroid disease
• Present in >95% of subjects with Hashimoto’s thyroiditis and around 85% subjects with Graves’ disease
What is thyroglobulin autoantibody (TgAb)?
What is the function of TRAb (thyroid releasing antibody)?
What is the treatment of hypothyroidism?
Levothyroxine
Generally first-line:
- Low cost
- Dose consistency
- Low risk of allergic reactions
- Potentially fewer cardiac adverse effects than T3 production
Life-long replacement with thyroid hormones
Exceptions: transient hypothyroidism due to subacute thyroiditis and drug-induced hypothyroidism
- Plasma half-life of T4 is ~7 days, once daily dosing results in a steady state being reached in about 6 weeks
Practical tips on giving thyroxine replacement
Practical tips on giving thyroxine replacement
• Typical full replacement doses in adults are 1.6 mcg/kg/day
• Lower starting doses (25-50 mcg/day) might be used in older individuals, those with mild hypothyroidism or those with untreated cardiovascular disease
• T4 primarily absorbed in jejunum
• About 70% of the dose administered is absorbed on an empty stomach
• Should be taken on an empty stomach about 30 minutes before breakfast
• Bioavailability can vary between different brands of T4 formulations
• Calcium, iron, antacids, proton pump inhibitors, anticonvulsants, rifampicin increase T4 requirement by different mechanisms (absorption or metabolism)
When taking calcium, separate the timing for 4 hours as it may affect absorption of T4
Hypothyroid patient with thyroxine replacement
BW = 60 kg
Started T4 at 100 mcg daily
How will you monitor her treatment response?
Monitoring of T4 Replacement (T4 half life is 7 days)
* Adequacy of treatment monitored by TSH
* Measure FT4, TSH 4-6 weeks after commencing treatment and monitor and titrate T4 dose until a normal TSH is reached.
E.g. increase T4 dose by 12.5025ug/day if TSH remains above target
* Aim to keep TSH 0.5 to 2.5 - 3 mlU/I.
* Stable patients, measure TSH and FT4 annually.
Hypothyroid patient with thyroxine replacement
Thyroid function normalised and remained normal for 2-3 years
Recent blood tests showed
TSH 15 mIU/L (N: 0.35-4.8)
FT4 12 pmol/L (N: 12-23)
What happened? What are the common reasons for abnormal TSH levels on a previously stable dosage of thyroid hormone?
Common reasons for abnormal TSH levels on a previously stable dosage of thyroid hormone
* Non-adherence to thyroid hormone regime
* Decreased absorption of thyroid hormone
* Taking thyroid hormone with food
* Taking thyroid hormone ≤4 hours of calcium, iron, soy products, or aluminum-containing antacids
* Given medication that decreases absorption of thyroid hormone e.g. cholestyramine, colestipol, orlistat, or sucralfate
* Significant weight change
* Pregnancy
* Changing in the formulation of thyroid hormone replacement
* Started on medications e.g. some anti-epileptics
Hypothyroid patient on thyroxine replacement. Patient is pregnant, what do you need to monitor and manage?
Issues around pregnancy
* Goal of preconception TSH: lower reference limit to 2.5mlU/L
* Early dosage adjustment: preemptively increase T4 dose by 30% and inform their clinicians promptly upon confirmation of pregnancy
* Typical strategy: increasing dose from once daily to nine doses per week (doubling the daily dose two days each week)
* Regular monitoring of TFT every 4 weeks with dosage adjustment
* For women during pregnancy: aim
* TSH <2.5mlU/L (1st trimester)
* TSH <3.0mlU/L (2nd-3rd trimester)
* Return to pre-pregnancy dosage of T4 after delivery
Case 2:
● 45/M non-smoker, non-drinker
● Referred by GP because of impotence
● Diagnosed T2DM for 7mo
● FBG 11 mmol/L, HbA1c 8.5
- Investigations
- WBC 11.951 ; ANC 8.76 T
- LRFT, CaP04, RG unremarkable
- ESR 88 mm/hT; CRP 7.6 ng/mLT
- CXR clear; XR neck - no abnormal soft tissue or gas density
- Blood culture, urine culture and NPA for resp virus all negative
- TSH 0.1 mIU/L (N: 0.35 - 4.8)
- fT 26 pmol/L (N: 12 - 23)
- What was the likely clinical diagnosis? What further investigation may support your diagnosis?
Biochemical picture: Primary hyperthyroidism
Is it from increased production from thyroid or due to increased release of pre-formed thyroid hormones due to thyroid destruction?
Technetium thyroid scan: Primary increase in synthesis (toxic nodule, TMG, Grave’s (diffuse increase vascularity on U/S), destructive thyrotoxicosis (no increase in vascularity on U/S)
What is subacute thyroiditis?
Painless thyroiditis DDx
- Hashimoto thyroiditis
- Atrophic thyroiditis - Atrophic thyroid
- Post-partum thyroiditis
- Variable prognosis depending on residual thyroid reserve
How does the thyroid hormone change along with subacute thyroiditis?
What is subclinical hypothyroidism?
Subclinical hypothyroidism
• High TSH with normal fT4 levels
• Investigations: thyroid antibodies
• Management in non-pregnant adults
• Assess lipid levels and hypothyroid symptoms
• Regular TFT monitoring
• Start T4 replacement if persistent TSH >10 mlU/L
When do we treat hypothyroidism?
Normal TSH: no need for intervention
TSH >10 mIU/L: treat with T4
Case 3:
48/F non-smoker
Presented to A&E with ankle swelling for several months
Mild shortness of breath on exertion; no chest pain
Malaise and lethargy; generalised aches and pains in muscles
● DH: Adalat retard 20 mg qd (nifedipine)
● FH: brother has IHD
● PMHx: HT x 1 year, hyperthyroidism x 15 years treated with RAI
○ Ask hypothyroidism hx
PE
● P 58/min, SR, BP 100/70
● JVP not elevated
● Apex displaced lateral 2 cm
● HSDNO, chest clear
● Bilateral ankle edema
ECG: Sinus bradycardia
CXR: cardiomegaly
Creatinine kinase 1080 u/L
What is the approach to elevated creatinine kinase?
- Heavy exertion recently
- Fall
- Intramuscular injection
- Hypothyroid myopathy (CK is elevated)
- Inflammatory myositis (far-fetched)
Check troponin T to rule out cardiac disease (causes elevated CK)
What are the DDx for generalised aches and pains in muscles?
Patient with Hx of radioiodine
Blood test
TSH 88 mIU/L (N: 0.35-4.8)
fT4 5 pmol/L (N: 12-23)
What is the Dx? What should be done?
Post-radioiodine hypothyroidism
Started thyroxine replacement
Post-radioactive hypothyroidism
Transient: 3.5 to 28%
Pre anti 10 to 15% in first 2 years, then around 3% per year
Requires long-term follow-up
Post-thyroidectomy hypothyroidism
- What are considerations in the management plan?
Do you just check T4 replacement?
Post-op parathyroidism: (Calcium phosphate)
Patients with differentiated cancer of thyroid, we try to suppress T4 so they have a lower chance of recurrence (clarify TSH target, whether they need T4 suppressive therapy?)
Case 4
• M/45; non-smoker and non-drinker
• Referred by private practitioner for erectile dysfunction
• Type 2 diabetes dx 7 months ago: FG 11 mmol/L, HbA1c 8.5%
Test testosterone (gonadal status)
HbA1c 7.4%
LH 0.3 mIU/L, FSH 0.5 mIU/L, Testosterone 5 mmol/L (N: 10-35)
Defect is in hypothalamus
Pituitary / hypothalamus is abnormal
If high LH, FSH = gonads are abnormal
TSH, fT4, central hypothyroidism, 9 am cortisol level (50) = low
Short synacthen test
Baseline ACTH 6 pg/mL
Cortisol = 30 mmol/L (0’); 75 nmol/L (30’); 100 nmol/L (60’)
What is the cause of this hormonal profile? What are the likely MRI findings?
Hypopituitarism
MRI: empty sella (due to damage from RT)
Post-radiotherapy Hypopituitarism
- Treatment
- Monitoring
Commenced on cortisol, thyroxine & testosterone replacement
Start cortisol replacement first before thyroxine!!!!
- Rate of turnover of cortisol is decreased in hypothyroidism because of reduction in 11 beta hydroxysteroid dehydrogenase activity = may precipitate adrenal crisis if you do it the other way round (exaggerate cortisol insufficiency)
Monitor T4, don’t monitor TSH since the pituitary is gone (aim T4 to mid-level or even higher)
Case 5
M/74
Admitted for non-specific dizziness in the recent few months, worsened in the recent 1-2 weeks
Blood test on admission
- Na 111 mmol/L
- K 3.8 mmol/L
- Cr 83 umol/L
How do you approach the investigation of hyponatremia?
R/O triggers
Volume status: Hypervolemic then treat
Plasma Osm and urine Osm
Want to r/o hypocortisol and hypoACTH
Pseudohyponatremia:
- Hypertriglyceridemia
- Hyperlipidemia
- High protein
Rule out:
- GI causes, e.g. vomiting / diarrhoea
- Renal causes, e.g. diuretics
Clinically euvolemic
Plasma osmo 235; urine Osm 542; urine Na 32 mmol/L
9am cortisol 37 nmol/L
TSH 0.51 mIU/LL (N: 0.35-4.8), fT4 9.5 pmol/L (N: 12-23)
What Ix should be done?
LH, FSH, Testosterone, Prolactin, Cushingoid, acromegaly
MRI pituitary
What was seen on MRI pituitary
Tenting of optic chiasm
Suprasellar extension
Pituitary macroadenoma
Do a visual field perimetry = bitemporal hemianopia
What is non-thyroidal illness syndrome (NITS)?
Case 6
• F/65
• CA vulva (melanoma) requiring radical vulvectomy and lymph node dissection
• Put on nivolumab since Dec 2023
• Baseline TSH, T4 normal
• Developed fever, tachycardia and painful neck swelling in the same month
What Ix to do?
Thyroid scan
Case 6
* F/65
* CA vulva (melanoma) requiring radical vulvectomy and lymph node dissection
* Put on nivolumab since Dec 2023
* Baseline TSH, T4 normal
* Developed fever, tachycardia and painful neck swelling in the same month
What is the possible cause?
Thyroid will be destroyed by immune-checkpoint inhibitors –> destructive thyroiditis (with presentation of mostly hypothyroidism, some having preceding transient thyrotoxic phase)
Could lead to hypophysitis
ICI = upregulates T-cell response
Classes of ICI
Classes of ICl
• First FDA approval in 2011: ipilimumab for melanoma
• Anti-cytotoxic T lymphocyte antigen 4 (anti-CTLA4):
ipilimumab
• Anti-programmed cell death-1
(anti-PD-1): nivolumab, pembrolizumab
What causes immune related adverse events
Traditional cytotoxic chemotherapy or molecular target therapies rarely cause endocrine dysfunction
Thyroiditis, hypophysitis, DM, primary adrenal insufficiency, hypoparathyroidism
Most commonly thyroid and pituitary:
- Rich vascularisation: more suspecitivle to contact with activated T lymphocytes
- Direct expression of CTLA-4 in the pituitary or of PD-1/PD-L1 in the thyroid
How to differentiate between thyroiditis and Graves’ disease
Anti-TSHR (Only in graves)
Technetium-99m thyroid scan (increased uptake = graves, decreased uptake = thyroiditis)
Presence of thyroid eye disease (Only in graves)
Why will there be increased endocrine IRAEs?
More and more cancers
More patients are prescribed immune-checkpoint inhibitors
Routine monitoring for endocrine IRAEs
- Glucose (immune-checkpoint associated DM), electrolytes (Na, K, Ca), TSH, fT4, 8-9 am coristol
- At baseline
- Every drug infusion for 6 months
- Every 2-3 months for next 6 months
- Every 6 months thereafter
- Clinical investigation of symptoms suggestive of endocrine IRAEs
Central hypothyroidism: common causes
- Pituitary adenoma
- Infiltrative disease
- Radiotherapy
- Immune-checkpoint inhibitors
In primary hyperthyroidism how can technetium thyroid scan be used to differentiate the cause?
