Hypothyroidism is a common condition affecting T3 and T4 (the thyroid hormones).
🏃♀️ Physiology
Before we take a look at the pathophysiology, let’s recap our normal thyroid physiology:
The thyroid gland is a butterfly-shape gland in the anterior neck and it produces and stores thyroid hormones. At a cellular level, the thyroid gland is made up of follicles, these are multiple epithelial cells which form a ring. In the lumen of these follicle rings there is a protein-rich reservoir of enzymes and substances required to make the thyroid hormones.
The function of the thyroid hormones is vast. They regulate metabolism by acting on nuclear receptors and stimulating metabolic pathways. They essentially increase the metabolism, so high levels increase metabolism while low levels decrease the metabolism.
Some of the processes they increase include:
- Basal metabolic rate
- Gluconeogenesis
- Glyocgenolysis
- Protein synthesis
- Lipogenesis
- Thermogenesis
Let’s take a look at how thyroid hormones are synthesised:
It is a 6 step process (ATE ICE):
- Active transport - iodide is actively transported into the follicular cell by the Sodium-Iodide transporter (NIS).
- Thyroglobulin - is secreted into secretory vesicles. It contains plenty of tyrosine and ribosomes.
- Exocytosis - of thyroglobulin into the lumen of the follicle. Thyroglobulin acts as the scaffolding for thyroid hormone synthesis.
- Iodination - of thyroglobulin by the enzyme thyroperoxidase. The iodide binds to the tyrosine molecules to form either monoiodotyrosine (MIT) or diiodotyrosine (DIT).
- Coupling - of MIT and DIT = triiodothyronine (T3) and coupling of DIT and DIT = tetraiodothyronine (i.e. thyroxine) [T4].
- Endocytosis - of this iodinated thyroglobulin back into the cell. Lysosomes break down the thyroglobulin scaffold to recycle the amino acids while the T3 and T4 are stored for release.
T3 and T4 are fat soluble and are carried by plasma proteins (albumin and thyronine binding globulin). T3 is more potent but has a shorter half-life. T4 is deiodinated into the more active T3 by the enzyme deiodinase.
Lastly, let’s recap the HPT (hypothalamic-pituitary-thyroid) axis:
- The hypothalamus detects low plasma concentrations of T3 and T4. It then releases thyrotropin-releasing hormone (TRH) into the hypophyses portal system.
- TRH binds to receptors on thyrotrophic cells on the anterior pituitary, these thyrotroph cells release thyroid stimulating hormone (TSH) into our systemic circulation.
- TSH binds to the TSH receptor on the basolateral membrane of the follicular cells. This causes the release of thyroid hormones.
🔢 Classification
- Congenital hypothyroidism occurs when a child is born with an underactive thyroid (1 in 3000 births). It may be due dysgenesis (underdeveloped thyroid) or may be due to dyshormonogenesis (developed gland but it does not produce enough of the hormone). Babies may present as being floppy with hypotonia, macroglossia, an umbilical hernia, reduced feeding and constipation.
- We can divide acquired hypothyroidism into primary and secondary based on the level of the axis affected:
This makes up 95% of the cases. It occurs when the thyroid gland is unable to produce thyroid hormones due to iodine deficiency or abnormalities of the gland itself.
It can be broken down into overt vs subclinical:
- Overt hypothyroidism - TSH levels are raised and T4 is below the normal range.
- Hashimotos thyroiditis - most common in the developed world.
- Subacute (De Quervains’) thyroiditis
- Riedel thyroiditis
- Postpartum thyroiditis (lymphocytic thyroiditis)
- Infiltrative disorders - such as haemochromatosis, amyloidosis, sarcoidosis, malignancy.
- Radioiodine treatment and thyroidectomy
- Dietary iodine deficiency - most common in the developing world.
- Drugs
- Subclinical - TSH levels are raised and T4 is within the normal range.
This is when the issue lies in the pituitary or hypothalamus, leaving the thyroid understimulated.
- Pituitary or hypothalamic failure - again may be due tumours, surgery, trauma, radiotherapy, infection, infiltrative disorders, drugs, Sheehan’s syndrome (postpartum pituitary necrosis).
😷 Presentation
Due to the large number of effects thyroid hormone has on the body, symptoms may present in a variety of ways:
- General symptoms
- Weight gain
- Lethargy and fatigue
- Cold intolerance
- 💆♂️ Head and neck symptoms
- Macroglossia - with Downs syndrome.
- Puffy face
- Loss of lateral third of the eyebrow (Hertoghe’s sign)
- Goitre
- Reinke’s oedema - laryngeal oedema leading to hoarse voice
- 🧴 Dermatological symptoms
- Dry skin (anhydrosis)
- Cold skin
- Non-pitting oedema
- Dry course hair
- Hertoghe’s sign
- Sparse pubic hair
- Yellow tinge
- 🫀 Cardiac symptoms
- Bradycardia
- Cardiomegaly
- First degree atrioventricular block
- 🧠 Neurological symptoms
- Carpal tunnel syndrome - due to deposition of mucopolysaccharides on the median nerve.
- Decreased deep tendon reflexes
- Cerebellar ataxia
- Peripheral neuropathy
- Proximal myopathy - a symmetrical weakness of proximal upper and/or lower limbs associated with hypothyroidism.
- Gynaecological symptoms
- Menorrhagia
- Gastrointestinal symptoms
- Constipation
- Poor appetite
A chronic autoimmune thyroiditis leading to hypothyroidism. However, there may be transient thyrotoxicosis in the acute phase of the disorder.
It is 10x more common in women. Peak incidence occurs in ages 30-50 years. It is most common in the developed world (“iodine-sufficient” areas).
😷 Presentation
Features of hypothyroidism. If a goitre is present it is non-tender.
The antibodies present include:
- ⭐️ Anti-thyroperoxidase (anti-TPO) antibodies
- Anti-thyroglobulin (anti-Tg) antibodies
- Anti-TSH receptor (anti-TSHR) antibodies - although these are most commonly associated with hyperthyroidism.
It is associated with other autoimmune disorders such as coeliac disease, T1DM, vitiligo, Addison’s disease pernicious anaemia and also MALT lymphoma.
This affects about 3 in 100 women after pregnancy. It is a sort of transient Hashimoto’s thyroiditis in that it has an initial thyrotoxicosis phase and anti-TPO antibodies are present in about 90% of patients.
There are 3 stages in postpartum thyroiditis:
- Thyrotoxicosis phase - may be treated using propranolol for symptom control but not usually treated with anti-thyroid medications.
- Hypothyroidism - treated with levothyroxine.
- Normal thyroid function
Another chronic form of thyroiditis. It is now believed to be a manifestation of IgG4-related disease which has multi-organ involvement (pancreas, liver, kidney, salivary glands). In Riedel’s there is replacement of the thyroid par enchyma by fibrotic tissue.
Its hallmarks are fibrosis of the thyroid gland and infiltration by IgG4-secreting plasma cells.
⭐️ It is associated with a painless goitre.
Also known as subacute granulomatous thyroiditis. It is believed to follow a viral infection (such as mumps or flu) and typically presents with hyperthyroidism in its acute phase but cases hypothyroidism in its chronic phase.
It has 4 typical phases:
- ⭐️ Hyperthyroid phase - presents with a painful goitre and raised ESR. Lasts 3-6 weeks.
- Euthyroid phase - normal thyroid levels. Lasts 1-3 weeks.
- Hypothyroidism phase - lasts weeks-months.
- Euthyroid recovery - a return to normal function and structure of the thyroid.
🔍 Investigations
- Thyroid scintigraphy - it shows globally reduced uptake of iodine-131.
- ESR
🧰 Management
Most patients require no treatment.
The thyroid pain may respond to NSAIDs.
Steroids may be used in severe cases, especially if hypothyroidism develops.
Some common drugs to remember that may cause hypothyroidism include:
- Amiodarone - Wolff-Chaikoff effect. This is an autoregulatory phenomenon where T4 production is inhibited as a result of excessive circulating iodine levels.
- Lithium
- Carbimazole
- Sodium valproate and other anti-epileptic drugs.
- Iron/calcium carbonate tablets can reduce the absorption of levothyroxine - should be given 4 hours apart.
This is when the TSH value is raised but the T3 and T4 values are normal. The patient does not feel the symptoms of hypothyroidism but they are at risk of progressing into overt hypothyroidism (2-5% chance annually). If they have autoantibodies, this risk increases.
Tha management will be discussed below.
🔍 Investigations
Investigations include:
- ⭐️ TFTs - this includes:
- TSH level
- Free T4 (FT4) level
- Serum TPO antibodies (TPOAb) - this is if autoimmune hypothyroidism is suspected.
- ESR - this will be raised in De Quervain’s.
If malignancy is suspected → ultrasound of the neck may be done.
💡 Response to treatment is measured by using the TSH level as FT4 fluctuates more and is less reliable.
🧰 Management
Management can be divided into management of overt hypothyroidism and subclinical hypothyroidism:
🏆 Levothyroxine
The starting dose should be lower in elderly patients and those with ischaemic heart disease - 25mcg OD starting dose, slowly titrated.
All other patients should be started on a dose 50-100mcg OD.
Pregnant women should have their dose increased by 25-50mcg.
TFTs should be rechecked after 2-3 months, and every time the thyroxine dose is changed it should be rechecked after 2-3 months.
The aim with treatment is to normalise the TSH value.
⚠️ Patients on iron, calcium carbonate supplementation should take their levothyroxine at least 4 hours apart as it reduces the absorption. It is advised to take levothyroxine on an empty stomach before food or other medication.
Adverse effects of thyroxine therapy:
- Hyperthyroidism
- Osteoporosis
- Worsening angina
- Atrial fibrillation
Not all patients with subclinical hypothyroidism require treatment. The management is dependent on the level of TSH:
- TSH >10mU/L and FT4 in normal range on 2 separate occasions, 3 months apart:
- TSH between 5.5 - 10mU/L and FT4 in normal range on 2 separate occasions 3 months apart:
- If <65 years old and symptomatic - consider a 6 month trial of levothyroxine.
- In elderly - watch and wait.
- If asymptomatic - repeat TFTs in 6 months.
Consider offering levothyroxine.
Central hypothyroidsm needs to be managed by treating the underlying condition.
🚨 Complications
- Myxoedema coma - extreme manifestation of (usually untreated) hypothyroidism. It is a form of decompensated hypothyroidism in which the adaptations of the body to untreated hypothyroidism fail to maintain homoeostasis and become overwhelmed by hypothermia, infection or other precipitating factors. These adaptations include peripheral vasoconstriction to maintain core body temperature. This process of adaptation and eventually failing function, affects all organs, including the brain, heart, lungs, kidney and gastrointestinal tract. Hypothermia, hyporeflexia, bradycardia and seizures → myxoedema coma.
- ITU/HDU care
- ⭐️ IV T3/T4
- ⭐️ IV hydrocortisone - 50-100mg
- Mechanical ventilation and oxygen - if hypoventilation
- IV fluids - to correct hypovolaemia
- Correct hypothermia
- Correct hypoglycaemia
- Treat any heart failure
Management of myxoedema coma includes: