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.
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Increase in plasma volume:
Pregnancy causes an increase in plasma volume, which dilutes plasma proteins like albumin and TBG. Since levothyroxine is highly protein-bound, a decrease in protein binding may increase the free fraction of the drug in plasma, potentially altering its distribution. However, the effect on levothyroxine’s overall volume of distribution might be minimal because of its high affinity for binding proteins.
Increased cardiac output:
Increased perfusion rate to the liver and kidneys can lead to increased clearance. But levothyroxine is predominantly metabolized in the liver through deiodination rather than by liver blood flow-dependent processes. This means that even with increased hepatic perfusion, the metabolism rate may not significantly change since it depends more on enzyme activity than blood flow. And levothyroxine has a long half-life and is highly protein-bound, which moderates any rapid changes in its pharmacokinetics. This means the increase in cardiac output may have a limited impact on its overall clearance.
Increased activity of enzymes CYP3A4 and CYP2D6:
This increased enzyme activity may lead to enhanced hepatic metabolism of drugs primarily metabolised by these enzymes. However, since levothyroxine metabolism primarily involves deiodination rather than CYP-mediated pathways, this change is unlikely to significantly impact its clearance.
Clearance: 0.056 L/h
Enzyme increases in pregnancy - so more metabolism - so may need a higher dose or dose reduction as increased enzyme can increase metabolite
Increased level of enzyme may cause the level of active form increase (prodrug)
What does the thyroid gland do?
Secretes 2 iodinated hormones:
- tetra-iodothyronine ( thyroxine, T4)
- to-iodothyronine (T3)
Hormones are responsible for maintenance, growth and develop of all body tissues
Regulates metabolism
Synthesis of thyroid hormone ATE ICE
• Active transport - lodine into follicular cells via active transport sodium-lodide symporter (NIS) (powered by sodium -potassium ATPase pump)
• Thyroglobulin - Tyrosine rich protein formed in follicular ribosomes
• Exocytosis of thyroglobulin into follicular lumen (stored as colloid)
• Iodination of thyroglobulin - lodine binds to benzene ring of thyroglobulin (enzyme Thyroid peroxidase) to form monoiodotyrosine (MIT) and diodotyrosine (DIT). (After oxidation of iodide so they can attach)
• Coupling of MIT and DIT = T3, DIT and DIT = T4
• Endocytosis of iodinated thyroglobulin back into follicular cells. Proteolysis removes thyroglobulin - free T3 and T4 released.
Potency of T3 and T4
• T3 more potent (more biologically active)
• T3 more affinity for thyroid receptor complex (hence greater potency)
• T4 more prevalent (20:1) - T4 converted to T3 (and inactive reverse T3) by 5’-deiodinase at target tissue - so considered a prohormone
• T4 has a longer half life (6-7 days) than T3 (24-36hrs)
Transport of T3 and T4 to target cells
Via Protein binding
• Thyroxine-binding globulin TBG - 75%
• Albumin - 15%
• Free T3 and T4 - physiologically active as able to enter cells
Affect of thyroid hormones on target tissues
Metabolism: increase in body heat
Growth: regulation of cell proliferation
Cardiovascular: activates sympathetic nervous system : increase in heart rate, cardiac output and respiratory rate
Musculoskeletal skeletal : stimulates bone resorbtion
Describe the feedback mechanism
Negative feedback
Stimulus eg feeling cold detected by hypothalamus in brain
Release of TRH
This stimulates anterior pituitary to release TSH (thyroid stimulating hormone)
When these levels rise, T3 and T4 production rises
Once these levels detected in blood, body signals hypothalamus to stop release of TRH and TSH
Hypothyroidism causes
Primary:
Failure of thyroid gland: autoimmune, drug induced, postpartum, iodine deficiency
Secondary:
Disease of hypothalamus, hypopituitarism - not enough TSH
Peripheral: insensitivity to thyroid hormones
Hypothyroidism symptoms
Fatigue
Dry skin
Puffy face & eyes
Muscle pain abs weariness
Depression
Weight gain (with decreased appetite)
Constipation
Hypothyroidism diagnosis
Increased TSH
Primary hypothyroidism: decreased T4 so increases TSH as body trying to produce more
Subclinical hypothyroidism: increased TSH but normal T4 (can develop thyroid issues). Look at TSH value (treat if above 10). Can be asymptomatic.
Primary hypothyroidism treatment + monitoring + counselling
Levothyroxine (synthetic T4)
- under 65 + no heart disease history: 1.6mcg/kg (nearest 25mcg)
- 65+/heart disease: initially 25-50mcg then titrated
Monitoring
- TSH every 3 months until stabilised (2 reading within range 3 months apart)
Once daily
Take 1hr before breakfast and meds (maximises absorption)
Doses increased in pregnancy due to more thyroxine binding globulins (NICE)
Caution in those with cardiovascular complications
Counselling: life treatment, timing ( avoiding other drugs, caffeine etc), monitoring, medical exemption for prescription
Hyperthyroidism vs thyrotoxicosis
• Hyperthyroidism = Increased synthesis and secretion of thyroid hormone in the thyroid gland
• Thyrotoxicosis = Clinical syndrome which results when too much circulating thyroid hormone. Prevalence is 2% in women and 0.2% in men
• Thyrotoxicosis can occur without hyperthyroidism. Can be due to increased ingestion of thyroid hormone or excess release of stored thyroid hormone eg thyroiditis or drugs
• Knowing the cause of the condition can be difficult but mav affect the management - if transient treat symptomatically - liaise with secondary care.
Hyperthyroidism causes
• Grave’s disease (75%
Autoimmune condition which results in the
production of thyroid receptor antibodies (TRABs)
which mimic the effect of TSH on TSH receptor = more thyroid hormone = more circulating T3 / T4
more prevalent in women than men
• Thyroid nodules 20%
Multinodular Goitre which produces T3/T4
•Thyroiditis
Usuallv selt- limiting. Inflammation causes destruction of thyroid tissue and leakage of stored T3/T4
• Drug Induced eg Amiodarone (contains iodine)
• Adenona
• Smoking
• Family history of thyroid disorders
Hyperthyroidism symptoms
Warm,moist skin
Insomnia
Weight loss (despite increased appetite)
Fine motor tremor
Thirst
Palpitations, anxiety, agitation
Hyperthyroidism diagnosis
Primary hyperthyroidism: high free T4, so low TSH
Subclinical hyperthyroidism: thyroid levels on range, but TSH still dropped
Hyperthyroidism treatment
Specialist initiated (referral to endocrinologist)
Anti thyroid drugs + symptomatic management eg beta blockers whilst waiting assessment
Antithyroid drugs : thionamides (inhibit peroxidase)
Baseline tests required: FBC & LFTs
Carbimazole (precursor of methimazole) 1st line: 15-40mg once daily until euthyroid (usually 4-8 weeks) (in range) then reduce to 5-15mg daily. Reduce gradually then stop (usually 12-18 months)
Not 1st line: • Propylthiouracil (PTU) given if:
- Reaction to carbimazole
- Pregnant/breastfeeding in next 6 month
- History of pancreatitis
Also inhibits deiodination of T4 to T3)
• Dose: 200-400mg daily in divided doses until euthyroid, then reduce gradually to 50-150mg Daily in divided doses
Carbimazole warning & who shouldn’t take
Contraceptive required
Pancreatitis history
- Very infrequently acute pancreatitis reported with carbimazole use
- If occurs stop treatment immediatelv and do not restart (re-exposure to carbimazole can cause life threatening acute pancreatitis)
1st trimester pregnancy
Congenital malformations (craniofacial, defects of abdominal wall/GI tract)
- especially if used in first trimester or taken at does of more than 15mg.
- Highly effective contraception during carbimazole treatment in women of child bearing age
Side effects of Carbimazole & propylthioracil
Agranulocytosis - carbimazole and propylthioracil (5 in 1000 patients)
• Bone marrow suppression
• Reduction in white cell count can lead to infection
• Report signs of infection eg sore throat, fever
• Treatment needs to be stopped promptly if evidence of neutropenia
• Hepatotoxicity:
- Carbimazole - 1 per 250 patients
- Propylthiouracil - 1 per 37 patients
Treatment regimes with antithyroid medication
Not for pregnancy due to risk of higher doses
• Titration -block regime: dose adjusted regularly based on free thyroid levels. Titrate to the lowest possible dose to maintain euthyroid.
• Block and replace regime: Block synthesis of thyroid hormone and then monitor free thyroid levels (FT4) and add in levothyroxine when
FT4 in reference range
•Radioactive Iodine - 1s line for grave’s disease unless malignancy suspected, active thyroid eye disease or pregnancy/planning pregnancy in next 4-6months.
- Damages DNA, leads to thyroid cell death and therefore a reduction in thyroid function - life long hypothyroidism
- Not in pregnancy/breastfeeding
• Surgery - Total or partial thyroidectomy
Invasive and expensive results in life- long hypothyroidism (Levo for rest of lives)
Monitoring for antithyroid drug treatment
• Do not monitor FBC or LFTs whilst taking antithyroid drugs unless suspicion of agranulocytosis or liver damage (eg yellowing of eyes m, sore throats, fevers)
• During: TSH and FT4/FT3 every 6 wks until in range, then TSH every 3 months until treatment stopped
• After : TSH within 8 weeks, then every 3 months for a year. Then once a year.
