Top Tips: Hypothyroidism

Dr Roger Henderson Offers Nine Top Tips for GPs on the Investigation, Diagnosis, and Treatment of Hypothyroidism

Hypothyroidism is an increasingly prevalent condition in the UK: in the adult population, cases of treated hypothyroidism increased from 1.4 million to 2.2 million (2.3% to 3.5% of adults) between 2005 and 2014, and are projected to rise to 2.9 million (4.2%) by 2025.¹ The condition is more prevalent in women—spontaneous hypothyroidism is around 10 times more common in women than men—and in people with obesity or White ethnicity.^1,2 Its prevalence increases with age, and in women it often occurs during the menopause.^2–4 

In around 95% of cases, a person will have primary hypothyroidism, which can be overt (the person has an elevated thyroid-stimulating hormone [TSH] level and a low free thyroxine [FT4] level) or subclinical (their TSH level is high, but their FT4 level is normal).⁵ However, in some cases, the hypothyroidism can be secondary to another condition, such as a pituitary or hypothalamic disorder.⁵ Subclinical hypothyroidism is estimated to be present in up to 10% of the UK population.^2,6 

Currently, national guidelines on the management of hypothyroidism include NICE Guideline 145, Thyroid disease: assessment and management,⁷ which was published in 2019, and the British Thyroid Association (BTA) statement on the management of primary hypothyroidism, which was issued in 2015.⁶ NICE’s Clinical Knowledge Summary provides another point of reference for primary care clinicians,⁸ and international guidance is available from the European Thyroid Association (ETA) and the American Thyroid Association (ATA).^9–11 A number of guidelines specifically on hypothyroidism and pregnancy have also been published.^12–14

Although this guidance is readily available, questions can still arise in practice about the optimal treatment of people with hypothyroidism. Here, I provide nine practical tips for clinicians when diagnosing and managing hypothyroidism in primary care.

1. Remember the Common Causes of Hypothyroidism

The most common cause of primary hypothyroidism worldwide is dietary iodine deficiency.⁹ However, in iodine-sufficient areas such as the UK, the most common cause is chronic autoimmune thyroiditis (also known as Hashimoto's disease).^9,15 Like hypothyroidism, Hashimoto’s disease affects women around 10 times more frequently than men, with a peak incidence of diagnosis between the ages of 30 and 50 years.¹⁶ In addition, an estimated 5–8% of postpartum women will develop postpartum thyroiditis, which is precipitated by a postpartum immunological rebound and leads to transient primary hypothyroidism.^4,17

Less commonly, primary hypothyroidism can be caused by damage to the thyroid gland as part of another treatment, such as a thyroidectomy, radiotherapy for head and neck cancer, or radioiodine therapy for Graves' disease or a nodular goitre.¹⁸ Drugs can also cause hypothyroidism, including:^15,18,19

• lithium, which affects the production and release of thyroid hormones
• amiodarone, which contains iodine and also affects thyroid hormone production
• anti-epileptic drugs, such as sodium valproate
• tetracyclines.

2. Know How to Assess a Person with Suspected Hypothyroidism

When taking a history in relation to hypothyroidism, clinicians should ask about:²⁰

• the typical symptoms of hypothyroidism (see Box 1²¹)
• current or recent pregnancy or nonthyroidal illness
• what drugs the person has taken recently, if any
• risk factors for hypothyroidism, such as:
  • a family history of thyroid, autoimmune, or hypothalamic–pituitary disease
  • a personal history of Turner syndrome, Down’s syndrome, or autoimmune disorders
  • iodine deficiency
  • any previous surgery to the neck or thyroid, radiotherapy to the head or neck, or radioiodine treatment
• causes of secondary hypothyroidism, including head trauma, recent surgery, or a history of brain cancer.

Clinicians should examine the patient for signs and complications of hypothyroidism (see Box 1²¹), such as goitre (thyroid enlargement) and thyroid nodules, as well as signs of other autoimmune disorders, such as type 1 diabetes, Addison’s disease, coeliac disease, pernicious anaemia, or vitiligo.²⁰ It is important to remember that a hard, irregular goitre or nodule may indicate malignancy, and that thyroid pain can indicate subacute thyroiditis.²⁰

3. Order the Appropriate Thyroid Function Tests in an Initial Diagnostic Workup

There are a number of different tests used to investigate thyroid function, so it is important to know what information each test provides and when it is most appropriate to use it.

Serum TSH Test

A serum TSH test is the most informative test for investigating and diagnosing potential hypothyroidism in primary care.^6,7,20,22 Reference ranges for serum TSH vary by laboratory, but a typical normal range is around 0.4–4.0 mU/l.²³ Serum TSH will be elevated in most cases of hypothyroidism, although it may only be mildly raised in subclinical disease, and can remain normal when secondary hypothyroidism is caused by pituitary disease.²³

Serum FT4 Test

Definitive diagnosis of hypothyroidism relies on testing for FT4 as well as TSH because the level of FT4 is low in overt primary hypothyroidism, but normal in subclinical hypothyroidism.^2,6,15 Hence, in line with NICE guidance, a serum FT4 test is also indicated if:^7,20

• disorders other than primary hypothyroidism, notably pituitary disease, are suspected
• the patient’s initial serum TSH test returns results above the reference range, as FT4 testing will help to quantify the degree of hypothyroidism (primary or subclinical).

Auto-Antibody Test

Although auto-antibody testing is unnecessary for the diagnosis of hypothyroidism, it can be useful in certain scenarios. The key auto-antibody test, for anti-thyroid peroxidase antibodies (TPOAbs), identifies autoimmune primary hypothyroidism, in which the TPOAb level will almost always be elevated.^9,20,23 TPOAb testing can also be considered for pregnant women, particularly if their TSH level is elevated, as well as for people with suspected subclinical hypothyroidism in whom a positive TPOAb is predictive of progression to overt hypothyroidism.²⁰

Other Tests

Because people with hypothyroidism are at higher risk of anaemia than those without it, it is sensible to measure full blood count and serum B12 in patients with suspected hypothyroidism, particularly in those who present with nonspecific fatigue or other symptoms of anaemia.^20,24,25 It may also be advisable to check the patient’s lipid levels, as their total cholesterol and low-density lipoprotein may be elevated in hypothyroidism.^20,26 NICE also suggests testing glycated haemoglobin (HbA_1c) and coeliac serology where indicated.²⁰

4. Be Aware that Many Conditions Can Mimic Hypothyroidism

The signs and symptoms of hypothyroidism are nonspecific, and a wide range of acute and chronic nonthyroidal conditions can lead to abnormal thyroid function tests (TFTs) and present similarly to hypothyroidism.^15,27 With acute illness in particular, a person’s TSH level can be normal then rise during recovery.²⁷ 

Endocrine, autoimmune, and haematological conditions can also present like hypothyroidism, with examples including type 1 diabetes, Addison's disease, coeliac disease, rheumatoid arthritis, anaemia, and multiple myeloma.²⁷ Other key differential diagnoses to consider include postviral syndromes, chronic fatigue syndrome, fibromyalgia, and obstructive sleep apnoea, which may be missed as a diagnosis unless specifically considered.²⁷ In older people, symptoms of dementia can mimic those of hypothyroidism, and in menopausal women, symptoms of thyroid dysfunction may be mistaken for those of the menopause.^3,7,27

5. Understand that Untreated Hypothyroidism Can Have Significant Complications

Hypothyroidism has a number of complications, listed in Box 2, including impaired quality of life, dyslipidaemia, stroke, subfertility, cognitive impairment, and—rarely—myxoedema coma.²⁶ Myxoedema coma is a life-threatening emergency, usually caused by untreated severe hypothyroidism or poor compliance to treatment and precipitated by the sudden onset of another condition, such as heart failure, sepsis, or stroke.^26,28 It may present with lethargy, bradycardia, hypothermia, seizures, or coma.²⁶ 

6. Consider Admission, Referral, or Specialist Advice in Certain Situations

If serious complications are suspected, such as myxoedema coma, emergency admission must be arranged.^26,29 Clinicians should also discuss the patient with, and arrange referral to, an endocrinologist as a matter of urgency if there is a suspicion of secondary hypothyroidism.²⁹ Other reasons for referring a patient to, or seeking advice from, an endocrinologist include:²⁹

• suspected subacute thyroiditis
• structural changes to the thyroid
• the patient is planning a pregnancy
• suspected associated endocrine disease (such as Addison’s disease)
• drug treatment, such as with amiodarone or lithium, or another potential underlying cause of hypothyroidism.

Clinicians should also ask for specialist advice when TFT results are difficult to interpret, such as if a patient has both low TSH and low FT4 levels.²⁹ If malignancy is suspected, the patient should be referred as normal using the local cancer referral pathway.^29–31

7. Treat Overt Primary Hypothyroidism with Levothyroxine in Primary Care

Levothyroxine (LT4) is the standard option for treating hypothyroidism if specialist referral is not required.^6,10,29 There is insufficient evidence to support the use of 'natural' (porcine) thyroid extracts or liothyronine over LT4 monotherapy, so they should not be offered.^7,10,29 In general, treatment should be based on the following principles:^29,32 

• the dosage is individually targeted to a patient’s clinical response and TFT results—remember that, even if TFTs are within the normal range, adaptations to LT4 therapy may still improve symptoms for some people
• treatment is monitored regularly to avoid under- and overtreatment.

When commencing treatment with LT4, clinicians should advise patients to take it on an empty stomach in the morning before other food or medication.^29,32 Patients will likely benefit from knowing that symptoms may lag behind treatment changes for several weeks or months.²⁹

Dosage

For adults aged under 65 years with primary hypothyroidism and no history of cardiovascular disease (CVD), NICE recommends starting LT4 at a daily dose of 1.6 mcg/kg of bodyweight, rounded to the nearest 25 mcg, and adjusting this incrementally according to patient response.^7,32,33 For patients who are aged 65 years or over or who have a history of CVD, an initial daily dose of 25–50 mcg is recommended, to be adjusted in steps of 25 mcg every 4 weeks according to response.^7,32,33

Individual summaries of product characteristics (SPCs) on the Electronic Medicines Compendium recommend slightly different regimens, so it may be worth consulting these SPCs when prescribing. In general, for adults aged under 50 years, the initial dosage is 50–100 mcg once daily, adjusted in steps of 50 mcg every 3–4 weeks according to response.^34–36 The maintenance dosage is 100–200 mcg/day.^34–36 For patients over 50 years of age:^34–36

• without CVD—initial dosage should not exceed 50 mcg/day, and should be adjusted by 50 mcg every 3–4 weeks to a maintenance dosage of up to 50–200 mcg/day
• with CVD—25 mcg daily (or 50 mcg on alternate days) is an appropriate initial dosage, to be increased in 25 mcg increments every 4 weeks to a maintenance dosage of 50–200 mcg/day.

Subclinical Disease

Patients with subclinical hypothyroidism may also benefit from LT4 therapy, and NICE recommends considering offering it if a patient has a TSH level greater than 10 mU/l and an FT4 level within the reference range on two occasions, 3 months apart.³⁷ Clinicians may also wish to consider a 6-month trial of LT4 therapy in symptomatic adults aged under 65 years if their TSH level is above the reference range but lower than 10 mU/l and their FT4 level is within the reference range.³⁷

8. Monitor TSH Levels at Appropriate Intervals, and Adjust Therapy Accordingly

Reviewing a patient’s serum TSH level is vital for monitoring the response to LT4 treatment and guiding any necessary adjustments, but the guidelines differ slightly in their recommendations. NICE recommends measuring TSH every 3 months initially to guide therapy, then every 12 months once the patient is stable with a normal TSH level.^7,29 In contrast, the BTA recommends measuring TSH every 6–8 weeks, progressing to every 4–6 months once it is stable, then ultimately to once a year.⁶ Regardless of the chosen interval, it is worth bearing in mind that—because LT4 has a relatively long half-life of approximately 1 week—it takes around 4–6 weeks for it to reach steady-state levels after an adjustment.¹⁰

Subclinical Hypothyroidism

If a person has untreated subclinical hypothyroidism, NICE recommends measuring their TSH and FT4 levels annually if they have features suggestive of underlying thyroid disease, or once every 2–3 years if not.^7,37

Pregnant Women

Pregnancy increases a person’s thyroid hormone requirements, so the TSH level of pregnant women on LT4 therapy should be measured every 4–6 weeks until midgestation, then at least once in each of the second and third trimesters.^10,12 Normal TSH reference ranges differ for pregnant women, and laboratories should have established trimester-specific reference ranges for the local area.^10,12–14 Regardless, women with primary hypothyroidism who are pregnant or planning a pregnancy should be referred to an endocrinology specialist for management.^29,38

9. Advise Patients that the Prognosis is Typically Excellent, but that Good Compliance is Essential

Spontaneous remission of primary hypothyroidism without treatment is rare, and people with primary hypothyroidism typically require lifelong treatment.³⁹ Nevertheless, the prognosis is generally excellent for hypothyroidism that is properly treated with LT4 therapy, as this usually allows for full physical and psychological recovery.^39,40 Indeed, studies have shown that patients with hypothyroidism who are treated to within the normal range of TSH have better long-term health outcomes than those with concentrations outside of it.⁴¹ Even so, it is worth noting that up to 10% of patients may remain symptomatic after more than 6 months of treatment, even if their TFT results have returned to normal.³⁹ 

For people with subclinical hypothyroidism, the risk of progression to overt hypothyroidism is around 2–5% for each year that it persists.^39,42 However, the ETA estimates that thyroid function normalises in 6–35% of people with untreated subclinical hypothyroidism, depending on a person’s initial TSH levels, thyroid autoantibody status, and the way in which their condition is monitored.^11,39

Patients may benefit from being signposted to sources of information about hypothyroidism and thyroid function in general, particularly from the British Thyroid Foundation, the NHS website, and the Patient website.²⁹

Summary

Hypothyroidism can be a difficult diagnosis to reach, as the symptoms of the condition are generally nonspecific and can often mimic other conditions. However, with appropriate history taking, examination, and investigation, primary care practitioners can effectively identify and treat people with this disease, easing their symptoms and improving their quality of life.

Figure 1: Algorithm for Monitoring, Referring, and Treating SCH