Thyroid 🏃🏻♀️ Flashcards
Review the available national guidelines and other evidence, consider whether Ummi is suitable to begin treatment? What monitoring should be put in place if treatment is started?
Ummi has subclinical hypothyroidism, characterised by elevated TSH levels with normal free T4, and symptoms of hypothyroidism, such as unexplained tiredness and swollen ankles.
TSH 5.2: Less than 10.Don’t recommend LT4. Repeat test every 3 months. Above 10 start treatment. (Full blood count)
Levothyroxine 100mcg daily
What were the possible differential diagnoses in this case and how did you rule these out? (consider what signs symptoms were not present to rule these conditions out).
Iron deficiency anaemia
Fatigue and tiredness are common symptoms of anaemia.
Ummi’s haemoglobin (Hb) level of 120 g/L is within the normal range for females, though on the lower side. Her ferritin level (25 ng/mL) is also within the lower end of normal but not low enough to confirm anaemia as the primary cause.
Depression
Ummi appears to be low in mood, which could be contributing to her fatigue.
While low mood is noted, it’s not severe enough to be diagnosed as depression without further clinical assessment. Hypothyroidism could be contributing to her mood symptoms, making it a more likely cause.
Heart Failure or Cardiovascular Issues
Swollen ankles could indicate fluid retention, which is often seen in cardiovascular issues.
Her blood pressure (120/80 mmHg) is within an acceptable range. No other signs, such as shortness of breath or chest pain, were noted. Additionally, her ECG and eGFR are within normal limits, which suggests no immediate cardiovascular concerns.
Chronic Kidney Disease (CKD)
Swollen ankles can also be a sign of fluid retention related to kidney issues.
Her creatinine (75 μmol/L) and eGFR (>90 mL/min/1.73 m²) are normal, ruling out significant kidney dysfunction.
Primary Hypothyroidism
The patient displays symptoms of hypothyroidism.
The patient’s free T4 levels are staying the same and within range, and they are not decreasing as they would in primary hypothyroidism.
Bradycardia
The patient has a heart rate that is less than 60 bpm (53 bpm), and she is also experiencing swelling or oedema in the lower extremities.
The patient is not hypotensive, which rules out bradycardia as the cause of her symptoms.
The patient returns in 6 months as they are now planning for a family with their partner. Are there any changes to treatment that you need to consider and why? She is currently euthyroid with a dose of levothyroxine 50 mcg daily.
Increased Dose Requirement:
Higher doses of levothyroxine are needed during pregnancy, especially in the first 12 weeks, to support the baby’s metabolic, growth, and developmental needs. (Baby doesn’t produce own thyroxine until around 12 weeks)
Increased thyroxine-binding globulins (TBG) during pregnancy reduce free T4 levels.
Dose Adjustment:
Increase levothyroxine dose by 25 mcg daily upon confirmation of pregnancy.
Alternatively, double the dose on two specific days of the week to achieve the same weekly increase.
Increase to 75mcg
Thyroid Function Monitoring:
Regular thyroid function tests are recommended during pregnancy, particularly TSH levels.
Target TSH range: 0.3 to 2.5 mU/L to ensure appropriate hormone levels for both mother and baby.
Post-Delivery Screening for baby:
A heel prick test can detect thyroid disorders in the newborn.
Identify the physiological changes occurring in pregnancy that can affect the pharmacokinetics of drugs: focus on factors that will affect (i) volume of distribution, and (ii) clearance.
Volume of distribution: (water ,fat, protein, cardiac output)
Total body water increase = increased volume of distribution for hydrophilic drugs, which results in lower plasma concentrations.
Maternal body fat expands by approximately 4kg, which increases the volume of distribution for lipophilic drugs - lipophilic drugs can accumulate in adipose tissue which can delay the release into circulation.
There is an increase in plasma volume. This dilutes plasma proteins (eg albumin) and therefore there can be a decrease in plasma protein binding. The unbound fraction of the drug increases and thus this physiological change can increase distribution.
Cardiac output changes as need to supply blood to foetus so volume of distribution increases.
Clearance:
Increased cardiac output can increase perfusion to the liver and kidneys, increasing the clearance of the drugs through hepatic and renal pathways. Not all drugs- only drugs with high extraction from the liver.
Increased renal blood flow and glomerular filtration rate increases the clearance of drugs that are primarily cleared via the kidneys. As a result , these drugs may require dose adjustments to maintain therapeutic levels due to the shortened half life.
Increased activity of enzymes CYP3A4 and CYP2D6. This increases the hepatic metabolism and clearance of some drugs. Decreased activity of enzymes CYP1A2 and CYP2C19. This inhibition occurs primarily due to hormone levels during pregnancy and this reduces the metabolism and clearance for relevant drugs that they metabolise.
Summarise the distribution and elimination processes of levothyroxine. Select two of the physiological changes identified in Q4, and comment on whether you expect these to have an effect on the volume of distribution and clearance of levothyroxine.
Distribution:
Small volume of distribution (around 11L) as not distributed into adipose tissues
Binds HIGHLY to plasma proteins, primarily thyroxine-binding globulin (TBG), transthyretin, and albumin. (More than 99%)
Only small fraction (~0.03%) remains as free T4, which is active form responsible for physiological effects.
Widely distributed in tissues, including liver, kidneys, and peripheral tissues where T4 is converted to the active T3 form.
As it’s a hydrophilic drug and resides mainly in plasma and extra cellular fluid and during pregnancy blood volume and extra cellular volume increase, apparent volume of distribution increases for this drug. As it doesn’t reside in adipose tissue, increase in fat has minimal effect.
Renal changes don’t effect the volume of distribution much as it depends more on blood volume and extra cellular fluid. Relies on protein binding target than renal filtration.
Pregnancy increases blood volume so increase in thyroxine binding globulins (TBG) levels, which can also slightly increase apparent volume of distribution. Effect is minimal compared to changes in clearance.
Elimination:
Key enzyme:
Iodothyronine Deiodinase
Converts T4 (levothyroxine) (prodrug) into:
T3 (triiodothyronine): The biologically active form. (Metabolite )
Reverse T3 (rT3): An inactive metabolite.
This process occurs in peripheral tissues such as the liver, kidneys, and muscles. Increase enzymes in pregnancy therefore more t3 so may need to reduce dose as more metabolite
Liver Enzymes:
Phase II Metabolism: Conjugation of levothyroxine occurs in the liver through glucuronidation and sulfation, making the drug water-soluble for excretion.
Very slowly eliminated
Clearance 0.056L/h
Half-life: ~6–7 days in healthy adults, shorter (~3–4 days) in hyperthyroid patients, and longer (~9–10 days) in hypothyroid patients.
Primarily metabolized in the liver through deiodination, converting T4 to T3 (active) or reverse T3 (inactive).
Excreted mainly via the bile into the feces, with a smaller proportion excreted in the urine.
