Clinical Topic A-Z Clinical Speciality

Hypothyroidism

Hypothyroidism
D007037Hypothyroidism
Endocrine and metabolic
2011-02-07Last revised in February 2011

Hypothyroidism - Summary

Hypothyroidism is the clinical consequence of deficient secretion by the thyroid gland. It is a common condition that often presents with non-specific symptoms.

It may be classified on the basis of:

The time of onset — congenital or acquired.

The level of endocrine dysfunction — primary (thyroid gland) or secondary (central — pituitary or hypothalamic dysfunction).

Severity — overt or subclinical.

Overt hypothyroidism is diagnosed by a serum thyroid-stimulating hormone (TSH) concentration above the normal reference range (the TSH concentration is almost always greater than 10 mU/L in overt hypothyroidism) and a serum free thyroxine (FT4) concentration below the reference range. Clinical features of hypothyroidism may be absent or present.

Subclinical hypothyroidism is diagnosed by a TSH concentration above the reference range with an FT4 concentration within the reference range, confirmed on repeat testing after at least 3 months. Clinical features of hypothyroidism are usually absent.

In the UK, hypothyroidism is usually due to autoimmune hypothyroidism or thyroid damage after surgery or radioactive iodine therapy.

Overt hypothyroidism has a prevalence of 1.9% in women and 0.1% in men.

Subclinical hypothyroidism has a prevalence of about 8% in women and 3% in men in an iodine-replete population, such as the UK.

Complications include:

Impaired quality of life due to presence of hypothyroid symptoms.

Pregnancy complications in women who are undiagnosed or inadequately treated (including for subclinical hypothyroidism): impaired psychomotor and cognitive development in the infant, higher incidence of miscarriage, stillbirth, pre-eclampsia, prematurity, low fetal birthweight, placental abruption, maternal anaemia, postpartum haemorrhage (due to uterine atony), maternal cardiac dysfunction, congenital abnormalities, and congenital hypothyroidism

Myxoedema coma is a rare complication.

Symptoms develop insidiously over several years, are often non-specific, and may go unrecognized. The following symptoms have the greatest discriminating ability between people with hypothyroidism and those who are euthyroid:

Current or increased constipation.

Current or increasingly hoarse voice.

Current deep voice.

Feeling colder.

Puffier eyes.

Weaker muscles.

Clinical signs may be absent.

The following should be looked for:

Deep voice or hoarseness.

Slowed movements.

Slowly relaxing tendon reflexes (such as prolonged ankle reflex time), and sometimes ataxia.

Dry, coarse, pale, or yellowish skin (due to carotene accumulation).

Periorbital oedema, proptosis, conjunctival injection and oedema, restrictive extraocular myopathy, and exposure keratitis. Sparse coarse hair.

Generalized myxoedema (non-pitting oedema).

Hypothermia.

Bradycardia, heart failure, pleural effusion.

Goitre. The goitre of Hashimoto's thyroiditis is of variable size, is often firm and irregular, and may rarely be painful. The goitre of subacute (de Quervain's) thyroiditis is usually tender to touch and diffuse, but may be hard or asymmetrical.

Overt hypothyroidism should be treated with levothyroxine. All people who are stable on levothyroxine require at least annual measurement of serum thyroid-stimulating hormone.

In people with overt or subclinical hypothyroidism, at diagnosis of pregnancy, the levothyroxine dose should be immediately increased and the TSH and FT4 levels checked while waiting for referral to a specialist.

Have I got the right topic?

192months3060monthsBoth

This CKS topic covers the management of hypothyroidism in adults.

This CKS topic does not cover the management of children with hypothyroidism; thyroid autoimmunity without hypothyroidism; or other thyroid disorders, such as thyroid cancer.

There is a separate CKS topic on Hyperthyroidism. There is also a separate CKS topic which deals with the assessment of thyroid lumps — see Neck lump.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary healthcare.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in February 2011

June 2013 — minor update. The 2013 QOF options for local implementation have been added to this topic [BMA and NHS Employers, 2013].

March 2012 — minor update. The 2012/2013 QOF indicators have been added to this topic [BMA and NHS Employers, 2012]. Issued in April 2012.

November 2010 to February 2011 — topic updated. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. There are no major changes to the recommendations.

Previous changes

April 2009 — updated to include the indicators related to hypothyroidism in the Quality and Outcomes Framework (QOF) of the General Medical Services (GMS) contract in the Goals and outcome measures section, and additional referral criteria from the consensus statement The diagnosis and management of primary hypothyroidism from the Royal College of Physicians in association with a number of other healthcare bodies. Issued in May 2009.

December 2006 to March 2007 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

The primary care management of subclinical hypothyroidism is described in detail as well as the management of hypothyroidism in women who are pregnant, planning a pregnancy, or who are postpartum.

October 2005 — minor update. Separate scenario created for the management of subclinical hypothyroidism. Issued in November 2005.

August 2004 — reviewed. Validated in November 2004 and issued in February 2005.

August 2001 — reviewed. Validated in November 2001 and issued in April 2002.

December 1998 — written. Validated in March 1999 and issued in May 1999.

Update

New evidence

Evidence-based guidelines

Evidence-based guidelines since the last revision of this topic:

Brenta, G., Vaisman, M., Sgarbi, J.A., et al. (2013) Clinical practice guidelines for the management of hypothyroidism. Arquivos brasileiros de endocrinologia e metabologia 57(4), 265-291. [Abstract] [Free Full-text (pdf)]

De Groot, L., Abalovich, M., Alexander, E.K., et al. (2012) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 97(8), 2543-2565. [Abstract] [Free Full-text (pdf)]

HTAs (Health Technology Assessments)

No new HTAs since 1 September 2010.

Economic appraisals

No new economic appraisals relevant to England since 1 September 2010.

Systematic reviews and meta-analyses

No new systematic review or meta-analysis since 1 September 2010.

Primary evidence

No new randomized controlled trials published in the major journals since 1 September 2010.

Observational studies published since the last revision of this topic:

Selmer, C., Olesen, J.B., Hansen, M.L., et al. (2012) The spectrum of thyroid disease and risk of new onset atrial fibrillation: a large population cohort study. BMJ 345, e7895. [Abstract] [Free Full-text]

New policies

No new national policies or guidelines since 1 September 2010.

New safety alerts

No new safety alerts since 1 September 2010.

Changes in product availability

No changes in product availability since 1 September 2010.

Goals and outcome measures

Goals

To support primary healthcare professionals:

To make an early diagnosis of hypothyroidism

To offer appropriate initial and subsequent management

To relieve symptoms

To refer the person with hypothyroidism, when appropriate, to other healthcare professionals

QOF indicators

Table 1 . Indicators related to hypothyroidism in the Quality and Outcomes Framework (QOF) of the General Medical Services (GMS) contract.
Indicator Points Payment stages
THY001 The contractor establishes and maintains a register of patients with hypothyroidism who are currently treated with levothyroxine 1
THY002 The percentage of patients with hypothyroidism, on the register, with thyroid function tests recorded in the preceding 12 months 6 50–90%
Data from: [BMA and NHS Employers, 2013]

Background information

Definition

What is it?

Hypothyroidism is the clinical consequence of deficient secretion by the thyroid gland. It is a common condition that often presents with non-specific symptoms.

It may be classified on the basis of:

The time of onset — congenital or acquired.

The level of endocrine dysfunction — primary (thyroid gland) or secondary (central — pituitary or hypothalamic dysfunction).

Severity — overt or subclinical.

Overt hypothyroidism is diagnosed by a serum thyroid-stimulating hormone (TSH) concentration above the normal reference range (the TSH concentration is almost always greater than 10 mU/L in overt hypothyroidism) and a serum free thyroxine (FT4) concentration below the reference range, see Table 1 [BTA et al, 2006]. Clinical features of hypothyroidism may be absent or present.

Subclinical hypothyroidism is diagnosed by a TSH concentration above the reference range with an FT4 concentration within the reference range, confirmed on repeat testing after at least 3 months, see Table 1 [Surks et al, 2004; BTA et al, 2006]. Clinical features of hypothyroidism are usually absent.

Causes

What causes it?

Worldwide, iodine deficiency is the most common cause of hypothyroidism, but is a rare cause in the UK [Weetman, 2003].

In the UK, hypothyroidism is usually due to autoimmune hypothyroidism or thyroid damage after surgery or radioactive iodine therapy [Weetman, 2003].

Causes of primary hypothyroidism

Autoimmune thyroiditis

This the most common cause of acquired hypothyroidism [Biondi and Cooper, 2008].

It may be associated with a goitre (Hashimoto's thyroiditis) or occur without a goitre (atrophic thyroiditis or primary myxoedema) [Weetman, 2003].

Injury to the thyroid gland

Thyroidectomy or other neck surgery, radioactive iodine therapy, or external radiotherapy [Weetman, 2003; Singer, 2005].

The incidence of hypothyroidism after non-thyroid surgery and/or external radiation of the neck in people with non-thyroid head and neck cancer (including lymphoma) can be as high as 50% within the first year of treatment, particularly in people who have surgery followed by high-dose radiotherapy. The effect is dose dependent, the onset is gradual, and subclinical hypothyroidism can be present for many years before development of overt disease [BTA et al, 2006].

Drug adverse effects

Iodine and iodine-containing medications, such as amiodarone.

Lithium [Weetman, 2003; Biondi and Cooper, 2008].

Interferon [Weetman, 2003].

Sunitinib (used in the treatment of advanced or metastatic renal cell carcinoma and gastrointestinal stromal tumours) [Desai et al, 2006].

Sorafenib (used in the treatment of advanced or metastatic renal cell carcinoma and hepatocellular carcinoma).

Tamoxifen and adjuvant chemotherapy for breast cancer may be associated with transient changes in thyroid-stimulating hormone levels [Anker et al, 1998; Kumar et al, 2004].

Overtreatment with antithyroid drugs [Weetman, 2003].

Thyroiditis

Subacute (de Quervain's) thyroiditis.

Silent thyroiditis.

Postpartum thyroiditis [Weetman, 2003].

Thyroid infiltration

Amyloidosis.

Sarcoidosis.

Haemochromatosis.

Scleroderma.

Primary thyroid lymphoma [Weetman, 2003; Singer, 2005].

Congenital hypothyroidism

Owing to absence or poor development of the thyroid gland, the presence of an ectopic hypoplastic gland [Weetman, 2003], or the absence of enzymes required for thyroid hormone synthesis and iodide transfer.

Causes of secondary (central) hypothyroidism [Weetman, 2003]

Pituitary underactivity

Pituitary tumour.

Pituitary surgery, radiotherapy, or trauma.

Infarction.

Sheehan's syndrome (postpartum pituitary necrosis).

Infiltrative disorders.

Isolated TSH deficiency or inactivity

Hypothalamic disease

Tumours.

Hypothalamic surgery, radiotherapy, or trauma.

Infiltrative disease.

Idiopathic hypothalamic disease.

Drugs

Bexarotene (an antineoplastic drug, used to treat skin manifestations of cutaneous T-cell lymphoma refractory to previous systemic treatment) and other retinoids.

Prevalence

How common is it?

Overt hypothyroidism:

Has a prevalence of 1.9% in women and 0.1% in men [Tunbridge et al, 1977].

Has an annual incidence of 0.4% in women and 0.06% in men [Vanderpump et al, 1995].

Has a prevalence of 0.5–5.0% in men and women older than 60 years of age, being more prevalent in women [Mariotti et al, 1995].

Subclinical hypothyroidism:

Has a prevalence of about 8% in women and 3% in men in an iodine-replete population, such as the UK [Vanderpump et al, 1995].

Has a prevalence of about 10% in women older than 55–60 years of age [DTB, 1998].

Has a prevalence of 5–20% in men and women older than 60 years of age, from different studies [Mariotti et al, 1995].

In pregnancy:

The incidence of overt hypothyroidism is approximately 0.3–0.5% [Reid et al, 2010].

The incidence of subclinical hypothyroidism is approximately 3–5% [Reid et al, 2010].

Congenital hypothyroidism:

Occurs in 1 per 4000 live births [Vaidya and Pearce, 2008].

Complications

What are the complications?

Impaired quality of life due to presence of hypothyroid symptoms.

Possible increase in cardiovascular risk, particularly if the person is younger than 65 years of age [Hak et al, 2000; Surks et al, 2004; Mariotti and Cambuli, 2007; Razvi et al, 2008; Rodondi et al, 2010].

Pregnancy complications in women who are undiagnosed or inadequately treated (including for subclinical hypothyroidism)

Impaired psychomotor and cognitive development in the infant [Morreale de Escobar et al, 2000].

Higher incidence of miscarriage, stillbirth, pre-eclampsia, prematurity, low fetal birthweight, placental abruption, maternal anaemia, postpartum haemorrhage (due to uterine atony), maternal cardiac dysfunction, congenital abnormalities, and congenital hypothyroidism [McGregor, 1996; Pearce and Stagnaro-Green, 2010; Reid et al, 2010].

Neurological complications, including deafness and focal neurology.

Myxoedema coma is a rare complication [Weetman, 2003]

In addition to the usual features of hypothyroidism, it presents with hypothermia (as low as 23°C), coma, and sometimes seizures.

The person is usually elderly and either has undiagnosed disease or is poorly adherent to treatment.

There is usually a precipitant, such as chest infection, heart failure, stroke, blood loss, exposure to cold, or drugs that depress respiration.

Prognosis

What is the prognosis?

Subclinical hypothyroidism

The rate of progression to clinically overt hypothyroidism:

Is 2.6% each year if thyroid antibodies are absent.

Is 4.3% each year if thyroid antibodies are present.

Is more likely if the thyroid-stimulating hormone (TSH) level is higher, especially if it is greater than 10 mU/L [Fatourechi, 2009].

The cumulative rate of progression in women with subclinical hypothyroidism who have both a raised TSH and thyroid antibodies is about 50% over 20 years [Vanderpump et al, 1995; Vanderpump, 2003].

Overt hypothyroidism

When taken properly, levothyroxine treatment restores normal health and lifespan [Weetman, 2003]. Note: a minority of people continue to experience symptoms more than 6 months after normalizing thyroid function tests on thyroxine. It remains controversial whether this relates to their thyroid axis or coincident psychological morbidity [Saravanan et al, 2002].

Spontaneous remission is rare and may be due to a spontaneous decrease in TSH receptor-blocking antibody concentrations [Weetman, 2003].

The mortality rate is 50% in myxoedema coma (rare), even with intensive treatment [Weetman, 2003].

Postpartum thyroiditis

Up to 30% of women with postpartum thyroiditis and thyroid antibodies later develop permanent hypothyroidism [Premawardhana et al, 2000].

Subacute (de Quervain's) thyroiditis

Relapse, usually within the first year, occurs in 10–20% of people [Weetman, 2003]. Some sources quote different proportions.

Diagnosis

Diagnosis of hypothyroidism

History

What features in the history suggest hypothyroidism?

Symptoms develop insidiously over several years, are often non-specific, and may go unrecognized.

The likelihood of overt hypothyroidism rises with increasing numbers of symptoms, particularly symptoms that have changed in the previous year.

Symptoms:

Have a low sensitivity for a diagnosis of hypothyroidism — the absence of a specific symptom does not rule out hypothyroidism.

Have poor positive predictive values — there are many false-positive individual symptoms.

Have a heightened suspicion for investigation in pregnancy — if such symptoms as constipation, weight gain, or fatigue predate the pregnancy, or are particularly troublesome, have a low threshold for investigation of thyroid function.

The following symptoms have the greatest discriminating ability between people with hypothyroidism and those who are euthyroid:

Current or increased constipation.

Current or increasingly hoarse voice.

Current deep voice.

Feeling colder.

Puffier eyes.

Weaker muscles.

Ask about other symptoms:

Deeper voice.

Drier skin.

Increasing tiredness.

More muscle cramps.

Slower thinking, poor concentration (some elderly people may present with symptoms of dementia).

Poorer memory.

Weight gain with poor appetite.

Hair loss.

Menstrual disturbance, including amenorrhoea, oligomenorrhoea, polymenorrhoea, and menorrhagia.

Paraesthesia in hands and arms (due to carpal tunnel syndrome).

Depression.

Infertility.

Decreased libido.

Hearing loss.

Prior symptoms of hyperthyroidism — thyroiditis (subacute and postpartum) commonly presents with transient symptoms of hyperthyroidism lasting for 1–4 weeks, followed by a phase of hypothyroidism lasting 4–12 weeks before thyroid function normalizes.

Thyroid pain.

Subacute (de Quervain's) thyroiditis commonly presents with thyroid pain, which often radiates to the ears.

Silent thyroiditis (usually seen as postpartum thyroiditis) presents with an absence of thyroid pain.

Unusual presentations of hypothyroidism

Hypothermia.

Congestive cardiac failure.

Pericardial and pleural effusions.

Ileus and intestinal pseudo-obstruction.

Psychosis.

Ataxia.

Coma.

Basis for recommendation

Basis for recommendation

Features in the history and unusual presentations

This information is based on expert opinion in review articles [Krassas, 2000; Roberts and Ladenson, 2004], and a textbook [Weetman, 2003].

Information on the sensitivity and specificity of symptoms is based on studies which looked at the relationship between abnormal thyroid function and symptoms [Canaris et al, 1997; Zulewski et al, 1997; Canaris et al, 2000].

Heightened suspicion for investigation in pregnancy

This recommendation is based on expert opinion in a Cochrane systematic review [Reid et al, 2010].

Examination

What examination findings suggest hypothyroidism?

Clinical signs may be absent.

Look for:

Deep voice or hoarseness.

Slowed movements.

Slowly relaxing tendon reflexes, such as prolonged ankle reflex time, and sometimes ataxia.

Dry, coarse, pale, or yellowish skin (due to carotene accumulation).

Periorbital oedema, proptosis, conjunctival injection and oedema, restrictive extraocular myopathy, and exposure keratitis. These signs are more common in Graves' disease, but can occur in 4–9% of people with chronic autoimmune thyroiditis.

Sparse coarse hair.

Generalized myxoedema (non-pitting oedema).

Hypothermia.

Bradycardia, heart failure, pleural effusion.

Galactorrhoea (due to increased prolactin levels).

Enlarged salivary glands (very rare).

Goitre. The causes of goitre are manifold. Those associated with hypothyroidism include autoimmune thyroiditis (Hashimoto's thyroiditis), thyroid hormone biosynthetic defect (for example Pendred's syndrome), destructive thyroiditis (postpartum thyroiditis, silent thyroiditis, and subacute thyroiditis), and infiltration (Riedel's thyroiditis, amyloidosis, and sarcoidosis). For further information on goitre, see the CKS topic on Neck lump.

The goitre of Hashimoto's thyroiditis is of variable size, is often firm and irregular, and may rarely be painful.

The goitre of subacute (de Quervain's) thyroiditis is usually tender to touch and diffuse, but may be hard or asymmetrical.

Systemic upset with fever:

May be present in subacute (de Quervain's) thyroiditis, but is absent in postpartum (silent) thyroiditis.

Basis for recommendation

Basis for recommendation

Features to look for on examination

Information on the features to look for on examination is based on expert opinion in a prospective cohort study [Zulewski et al, 1997], expert opinion in two cross-sectional studies [Canaris et al, 1997; Canaris et al, 2000], expert opinion in review articles [Krassas, 2000; Rehmann and Bajwa, 2004; Roberts and Ladenson, 2004], and a textbook [Weetman, 2003].

Investigations

What investigations should I do to make the diagnosis?

To make a diagnosis of hypothyroidism measure both thyroid-stimulating hormone (TSH) and free thyroxine (FT4).

Do not routinely check for thyroid peroxidase antibodies (TPO-Ab).

Indications for checking for TPO-Ab include:

Subclinical hypothyroidism where the TSH level is less than 10 mU/L.

Prior to commencement of amiodarone, interferon alfa, or lithium.

Do not routinely measure thyroglobulin antibodies (TgAb) or thyroid-stimulating hormone receptor antibodies (TSH-RAb).

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in guidelines [BTA et al, 2006] and the opinion of CKS expert reviewers.

Measurement of both thyroid-stimulating hormone (TSH) and free thyroxine (FT4)

Measurement of both TSH and FT4 should allow detection of almost all causes of thyroid dysfunction, as long as the results are correctly interpreted. Measurement of TSH alone will fail to identify some people with secondary (central) hypothyroidism.

If TSH and FT4 concentrations are both normal, hypothyroidism can confidently be excluded.

The rare exception is if the person is going from the hyperthyroid to the hypothyroid phase of thyroiditis; they may occasionally have normal thyroid test results for a few days before becoming hypothyroid.

Measurement of thyroid peroxidase antibodies (TPO-Ab) to assess for autoimmunity

The presence of TPO-Ab is a risk factor for autoimmune thyroid disorders.

TPO-Ab is present in the serum of people with a wide range of immunologically mediated thyroid disorders (for example Hashimoto's thyroiditis, Graves' disease) and in a small proportion of apparently healthy people. In most cases the presence of TPO-Ab makes no difference to management. Therefore it is not routinely recommended that TPO-Ab be tested in people with hypothyroidism.

If the person has a new diagnosis of subclinical hypothyroidism with a TSH concentration less than 10 mU/L, and they are antibody positive, they require more frequent monitoring as they have a higher risk of developing overt hypothyroidism. See TSH 10 mU/L or less.

The presence of TPO-Ab is associated with a higher risk of thyroid dysfunction developing during treatment with amiodarone, interferon alfa, or lithium.

Recommendation not to measure thyroglobulin antibodies (Tg-Ab) or thyroid-stimulating hormone receptor antibodies (TSH-RAb) routinely

Consensus recommendations from national guidelines is that measurement of Tg-Ab or TSH-RAb offers no additional clinical value.

In the UK, it is considered to be of no value to measure both TPO-Ab and Tg-Ab in non-neoplastic conditions.

Tg-Ab are found in many people with autoimmune thyroid disorders. However, in most circumstances, Tg-Ab measurements have no additional value over the measurement of TPO-Ab and need not be done if TPO-Abs are present.

The measurement of TSH-RAb is not indicated in hypothyroidism, unless there are signs of thyroid eye disease.

Interpreting the results

How do I interpret the results?

In overt hypothyroidism, the thyroid-stimulating hormone (TSH) level is above the reference range and free thyroxine (FT4) is below the reference range, see Table 1.

In subclinical hypothyroidism, the TSH level is raised and FT4 is normal. Make the diagnosis only after a confirmatory result on repeat testing within 3–6 months, except in pregnancy where treatment should be started immediately and the woman referred to a specialist, see Scenario: Preconception or pregnant, for further information.

In secondary hypothyroidism (pituitary or hypothalamic disease), the TSH level is low or 'normal' and FT4 is low. See Scenario: Suspected secondary hypothyroidism for advice on management.

It can be difficult to interpret test results in people on amiodarone or lithium; see misleading TSH results for further information.

In the transient hypothyroid stage of subacute or postpartum thyroiditis, the TSH level is raised and FT4 is low. However, a thyrotoxic pattern may be seen in the early stage — see Suspecting subacute or postpartum thyroiditis.

Reference ranges

What are the typical reference ranges for thyroid function tests?

Reference ranges vary between laboratories.

Reference ranges vary in each trimester of pregnancy.

UK guidelines on thyroid function tests give examples of typical ranges in non-pregnant adults.

Table 1 . Typical serum reference ranges in adults*
Serum measure Reference range
Thyroid-stimulating hormone (TSH) 0.4–4.5 mU/L
Free thyroxine (FT4) 9.0–25 picomol/L
Free triiodothyronine (FT3) 3.5–7.8 picomol/L
Total thyroxine (TT4) 60–160 nanomol/L
Total triiodothyronine (TT3) 1.2–2.6 nanomol/L
* Excluding pregnant women and people taking medication known to interact with levothyroxine or alter hormone levels (for example amiodarone).
Source: [BTA et al, 2006]

Misleading TSH results

Misleading TSH results

Thyroid-stimulating hormone (TSH) results may be misleading during stabilization of treatment, and in pregnancy, non-thyroidal illness, post-thyroiditis, hypopituitarism, and during treatment with drugs that affect the function or action of thyroid hormones. Discussion with an endocrinologist may be appropriate in these circumstances.

In the first trimester of pregnancy, a TSH concentration less than 0.10 mU/L may be found in up to 3% of women.

Trimester-related reference ranges should be applied for TSH and for total and free thyroxine (FT4).

Measurement of both FT4 and TSH is recommended to determine the appropriate treatment in the following situations:

During the early months of treatment for hyperthyroidism. TSH may remain suppressed, and thus results may be misleading, when hypothyroidism has been induced during the early weeks or months after treatment of hyperthyroidism (owing to delayed recovery of the previously suppressed TSH). At that stage, measurement of FT4 is the more sensitive indicator of thyroid failure. However, once the hypothalamic-pituitary-thyroid axis has recovered, measurement of TSH is more meaningful.

Recent adjustment in levothyroxine dosage with failure to reach a steady state, particularly in people with poor adherence to treatment. Some people take excessive doses in the days before a clinic visit. These people can be identified by finding both increased TSH and FT4 concentrations. Measurement of TSH alone would be likely to lead to a recommendation for increasing the daily dose of levothyroxine. Adherence to the previous drug regimen is all that is required.

After an episode of thyroiditis.

During the early weeks of levothyroxine therapy. It may take 3 months or more for the TSH concentration to normalize after prolonged hypothyroidism.

Hypopituitarism. A normal TSH concentration is found in about half of people with central hypothyroidism. FT4 concentrations are usually low, and in occasional cases of hypopituitarism, an increased TSH concentration may be seen.

Non-thyroidal illnesses (the sick euthyroid syndrome). People with any of a wide range of chronic or acute non-thyroidal illnesses may have abnormalities in thyroid function tests even though they are clinically euthyroid:

In most of these people, the TSH concentration will be normal and thus provides the best guide of thyroid status.

In some people, TSH concentrations may be low in the acute phase and may increase modestly and transiently into the hypothyroid range on recovery.

Total triiodothyronine and free triiodothyronine (FT3) concentrations usually decrease as a result of impaired tissue uptake of T4 and impaired conversion of T4 to T3. Total thyroxine and FT4 levels may also be outside the reference range.

Acute psychiatric disturbance and clinical depression. Unless clinically indicated, caution is required in the investigation of thyroid function, because non-thyroidal illness and medication that affect thyroid function tests are common and may prompt inappropriate intervention.

Hospitalized people. In hospitalized people, an increased TSH concentration is as likely to be associated with recovery from illness as to be due to hypothyroidism. Isolated alterations in serum TSH concentrations, either low (0.1 mU/L to 0.3 mU/L) or slightly raised (5 mU/L to 20 mU/L), occur in about 15% of such people owing to alterations in TSH secretion caused by non-thyroidal illness or drugs.

End-organ resistance. Certain people with end-organ resistance to thyroid hormones may present with abnormal thyroid function. Some may have high concentrations of thyroid hormone but normal TSH, whilst others will have increased thyroid hormones with a modestly increased TSH. The major differential diagnosis is a TSH-secreting pituitary tumour (after assay interferences have been excluded). Both of these conditions are very rare.

People taking amiodarone

During the first 3 months of treatment, the TSH concentration may increase transiently, particularly in people receiving higher doses. The TSH concentration tends to be normal in people receiving long-term treatment.

The thyroid hormone profile may be altered, but without thyroid dysfunction. People taking amiodarone for more than 3 months frequently have increased FT4, decreased FT3 and normal TSH concentrations, even though they remain euthyroid.

Other drug treatment. Other drugs may interfere with TSH secretion or the production, secretion, transport, and metabolism of thyroid hormones. Some drugs modify thyroid status whilst others produce abnormal thyroid function test results in otherwise euthyroid people.

High-dose glucocorticoids, high-dose dopamine, and potent opioids (for example tramadol) inhibit TSH release and therefore may decrease the TSH concentration.

Propranolol may decrease the T3 concentration and increase the TSH concentration.

Phenytoin, carbamazepine, furosemide, and salicylate compete with thyroid hormone binding to serum binding proteins and may increase the total thyroxine and FT4 concentration. Phenytoin can also cause a slight decrease in FT4 without affecting TSH. Carbamazepine very rarely causes decreased FT4 with an increased TSH.

TSH may also be elevated in the following situations:

During recovery from destructive thyroiditis, including post-viral subacute thyroiditis and postpartum thyroiditis.

Untreated primary adrenal insufficiency. Prescribing thyroxine in this situation may precipitate an adrenal crisis.

Renal failure.

Exposure to cold temperatures.

Basis for recommendation

Basis for recommendation

The recommendations on interpretation of results are based on expert opinion in a textbook [Longmore et al, 2001], review articles [Harjai and Licata, 1997; Lazarus, 1998; Kleiner et al, 1999], and the opinion of CKS expert reviewers.

The data on the typical reference ranges for thyroid function tests are taken from guidelines produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006].

The information on misleading TSH results is based on expert opinion in guidelines [Bogazzi et al, 2001; Roberts and Ladenson, 2004; Surks et al, 2004; BTA et al, 2006], information from the manufacturer's Summaries of Product Characteristics (www.medicines.org.uk), and expert opinion from CKS reviewers.

Other laboratory tests

What other laboratory tests may be abnormal in people with hypothyroidism?

Abnormalities in other laboratory tests may sometimes be due to hypothyroidism.

Normocytic normochromic anaemia or mild macrocytosis.

Increased cholesterol.

Low sodium.

Increased serum prolactin.

Elevated creatine phosphokinase.

Abnormal clotting screen (if hypothyroidism has caused von Willebrand syndrome).

Basis for recommendation

Basis for recommendation

The information on laboratory tests which may be abnormal in hypothyroidism is based on expert opinion in a review article [Roberts and Ladenson, 2004].

The information that cholesterol may be increased in hypothyroidism is based on expert opinion in a study [Diekman et al, 1995].

Suspecting subacute or postpartum thyroiditis

When should I suspect subacute or postpartum thyroiditis?

Suspect thyroiditis in someone who presents with transient thyroid dysfunction — the most common sequence is a brief thyrotoxic phase (1–4 weeks) followed by a hypothyroid phase (4–12 weeks), which usually resolves spontaneously.

Subacute (de Quervain's) thyroiditis

May present with:

Thyroid pain.

Systemic upset with fever.

A small, tender goitre which may be diffuse or asymmetrical.

A history of prodromal viral infection symptoms several weeks earlier.

Postpartum (silent) thyroiditis

May present within 2–6 months after delivery, with:

Non-specific symptoms, such as tiredness, anxiety, or depression.

Painless thyroid, often with no goitre.

No systemic upset or fever.

Basis for recommendation

Basis for recommendation

The information on the natural history of thyroiditis is based on expert opinion in a textbook [Weetman, 2003].

Subacute (de Quervain's) thyroiditis

Symptoms are based on expert opinion in a textbook [Weetman, 2003].

Hypothyroidism may follow the hyperthyroid phase of subacute thyroiditis in up to 50% of people and lasts for 4–12 weeks [Weetman, 2003; Lingvay, 2005].

Symptoms of hypothyroidism are usually mild or moderate, but hypothyroidism may become permanent in 5–10% of people [Lingvay, 2005].

Suspecting secondary hypothyroidism

When should I suspect secondary hypothyroidism?

Suspect secondary hypothyroidism if:

Thyroid function tests are suggestive of secondary hypothyroidism.

There are features of hypopituitarism (such as hypogonadism or adrenal failure).

The person is taking bexarotene.

Basis for recommendation

Basis for recommendation

This recommendation is based on expert opinion in textbooks [Longmore et al, 2001; Weetman, 2003].

Management

Management

Scenario: Screening of asymptomatic people : covers which groups of asymptomatic people to test for hypothyroidism and what tests to use.

Scenario: Subclinical hypothyroidism : covers the management of subclinical hypothyroidism and criteria for referral.

Scenario: Overt hypothyroidism : covers the management of overt hypothyroidism and criteria for referral.

Scenario: Preconception or pregnant : covers the management of women planning a pregnancy or who are pregnant, who have preexisting subclinical or overt hypothyroidism, or are newly diagnosed with subclinical or overt hypothyroidism.

Scenario: Postpartum : covers the management of women following delivery with subclinical hypothyroidism, overt hypothyroidism, or who develop postpartum thyroiditis.

Scenario: Amiodarone or lithium treatment : covers the management of someone who develops hypothyroidism whilst being treated with amiodarone or lithium.

Scenario: Suspected secondary hypothyroidism : covers the management of someone with suspected secondary hypothyroidism.

Scenario: Screening of asymptomatic people

Scenario: Screening of people asymptomatic of hypothyroidism

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Who to screen

Who should I screen for hypothyroidism?

Routine testing of asymptomatic people for hypothyroidism is not recommended, but targeted testing is recommended for certain groups with the following conditions. Measuring thyroid-stimulating hormone (TSH) is sufficient unless stated otherwise.

Goitre

At initial presentation.

At the earliest opportunity in women who are pregnant or planning pregnancy.

At 6–8 weeks postpartum (or after miscarriage or termination of pregnancy).

Type 1 diabetes

At initial presentation, then annually.

At the earliest opportunity in women who are pregnant or planning pregnancy — measure TSH, free thyroxine (FT4), and thyroid peroxidase antibody (TPO-Ab) prior to conception, at booking when pregnant, and at 6–8 weeks postpartum (or after miscarriage or termination of pregnancy).

Type 2 diabetes

At initial presentation.

Atrial fibrillation

At initial presentation.

Osteoporosis

At initial presentation.

Dyslipidaemia

At initial presentation.

Radioactive iodine or surgery for hyperthyroidism

At 4–8 weeks post-treatment, then every 3 months for up to 1 year, and annually thereafter.

Previous neck irradiation or surgery involving the thyroid gland for head and neck cancer, including lymphoma.

Annually.

Family history of thyroid disease

At the earliest opportunity in women who are pregnant or planning pregnancy.

Personal history of thyroid disease

At the earliest opportunity in women who are pregnant or planning pregnancy.

History of thyroid lobectomy

At the earliest opportunity in women who are pregnant or planning a pregnancy.

History of autoimmune thyroid disease

At the earliest opportunity in women who are pregnant or planning pregnancy.

At 6–8 weeks postpartum (or after miscarriage or termination of pregnancy).

Women with other autoimmune disorders

At the earliest opportunity in women who are pregnant or planning a pregnancy.

At baseline and annually in Addison's disease.

Have a low threshold for testing in other autoimmune disorders.

Known to be thyroid antibody positive

At the earliest opportunity in women who are pregnant or planning pregnancy.

During pregnancy.

At 6–8 weeks and 6 months postpartum (or after miscarriage or termination of pregnancy).

Down's or Turner's syndrome

Annually.

Non-specific symptoms that may suggest thyroiditis

At 6–8 weeks postpartum (or after miscarriage or termination of pregnancy).

History of postpartum thyroiditis

At the earliest opportunity in women who are pregnant or planning pregnancy.

At 6–8 weeks postpartum (or after miscarriage or termination of pregnancy).

Annually.

Subfertility, abnormal menstrual cycle, or miscarriage

At initial presentation.

Personal history of preterm birth or recurrent miscarriage

Consider measuring TSH, FT4, and TPO-Ab.

Taking amiodarone, lithium, sunitinib, sorafenib, or interferon alpha

At baseline and every 6 months.

If amiodarone is stopped, monitoring should continue for a further 12 months.

Postpartum depression

At presentation.

Basis for recommendation

Basis for recommendation

These recommendations are based on a UK consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006]. The strength of evidence supporting the recommendations is expert opinion alone.

The guideline recommends carrying out thyroid function tests in asymptomatic people only if they are at high risk of having or developing hypothyroidism.

If the person has type 1 diabetes mellitus, postpartum thyroiditis, Down's syndrome, or Turner's syndrome, there is a high risk of developing autoimmune hypothyroidism.

If the person has had radioactive iodine or surgery for hyperthyroidism, or neck irradiation or surgery (involving the thyroid gland) for head and neck cancer (including lymphoma), they are at high risk of thyroid dysfunction. Surveillance after radioactive iodine treatment is largely targeted at detecting hypothyroidism, as recurrence of hyperthyroidism is rare.

Routine screening for thyroid disorders in the general adult population is not recommended for the following reasons:

Indiscriminate use of thyroid-stimulating hormone (TSH) levels as a screening test is not effective. The greater the clinical suspicion of hypothyroidism, the more useful the TSH value [Vanderpump et al, 1996; Bandolier, 1997; Weetman, 1997; US Preventive Services Task force, 2004].

The number of new cases that will occur annually is low.

TSH levels may be affected by non-thyroidal illness.

If subclinical hypothyroidism is detected, there is uncertainty about the benefits of treatment.

These recommendations are also based on expert opinion in guidelines produced by the Endocrine Society [Abalovich et al, 2007], and expert opinion in a review article [Vaidya and Pearce, 2008].

The recommendation to consider measuring TSH, free thyroxine, and antithyroid antibodies in women who are pregnant or planning pregnancy, if they have a personal history of preterm birth or recurrent miscarriage, is based on expert opinion in a Cochrane review [Reid et al, 2010].

There is some evidence that women with antithyroid antibodies have an increased risk of miscarriage and preterm birth.

The recommendation to carry out baseline and 6-monthly TSH measurements in people taking amiodarone, lithium, sunitinib, sorafenib, or interferon alpha is because thyroid dysfunction is a recognized adverse effect of these drugs [Micromedex, 2010].

Scenario: Subclinical hypothyroidism

Scenario: Subclinical hypothyroidism (not pregnant or planning a pregnancy)

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TSH 10 mU/L or less

How should I manage someone with subclinical hypothyroidism who has a thyroid-stimulating hormone (TSH) level of 10 mU/L or less?

Confirm by repeat testing of thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels, with the addition of measurement of thyroid peroxidase antibodies (TPO-Ab), 3–6 months after the original result.

Levothyroxine treatment is not routinely recommended.

Consider offering levothyroxine treatment if:

The person has a goitre.

Their TSH level is rising.

The woman is pregnant or planning pregnancy (see Scenario: Preconception or pregnant).

Consider offering a trial of treatment if the person has symptoms compatible with hypothyroidism.

Prescribe treatment for a sufficient length of time to be able to judge whether there is symptomatic benefit, see Prescribing information.

Only continue treatment if there is a clear improvement in symptoms.

If treatment is continued, once stable, measure TSH annually and alter the levothyroxine dose to maintain the TSH level within the reference range.

If treatment is not offered, it is still necessary to monitor thyroid function to detect progression to overt hypothyroidism.

If the person has serum TPO-Abs, measure serum TSH and FT4 annually, or earlier if symptoms develop.

Otherwise, measure serum TSH and FT4 approximately every 3 years, or earlier if symptoms develop.

Basis for recommendation

Basis for recommendation

These recommendations are based on a consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006]. They are based on evidence from well conducted, non-randomized clinical trials and expert opinion.

The recommendation to test for thyroid peroxidase antibodies (TPO-Ab) once only, in addition to measuring thyroid-stimulating hormone (TSH) and free thyroxine (FT4) 3–6 months after initial testing, is based on the view of CKS and a CKS expert reviewer, that it would seem sensible to do so as antibody status influences the decision on monitoring frequency.

In women with raised serum TSH and positive antithyroid antibodies, the annual risk of developing overt hypothyroidism is approximately 5% [Vanderpump et al, 1995].

Treatment is not generally recommended because:

A significant number of people with subclinical hypothyroidism will not progress to overt hypothyroidism. See Prognosis for more information.

When TSH is elevated but less than 10 mU/L, no consistent evidence supports an association with symptoms, secondary biochemical abnormalities (hyperlipidaemia), cardiac dysfunction, or other cardiac events [Surks et al, 2004; Jorde et al, 2006; Roberts et al, 2006].

Evidence from relatively small studies indicates that levothyroxine replacement therapy for subclinical hypothyroidism does not result in improved survival or decreased cardiovascular morbidity, improved health-related quality of life, or improved symptoms [Surks et al, 2004; Villar et al, 2007].

No evidence supports the benefit of routine early treatment with levothyroxine in non-pregnant adults with a serum TSH concentration above the reference range but less than 10 mU/L [Cooper et al, 1984; Jaeschke et al, 1996; Monzani et al, 2001; Kong et al, 2002; Jorde et al, 2006].

It is recognized, however, that some people with TSH levels between 4.5 mU/L and 10 mU/L have symptoms compatible with hypothyroidism [Surks et al, 2004]. Therefore, clinicians and patients may decide on a trial of levothyroxine while monitoring for an improvement in symptoms.

There is no clear guidance available on the dose and duration of levothyroxine to use in this situation.

The dose of levothyroxine should be titrated until the TSH level is within the reference range, and given for a sufficient length of time to judge whether or not there is any clinical benefit (usually several months).

Continuation of treatment should be dependent on clear symptomatic benefit, but this may be very difficult to judge as some people may have a placebo effect.

For general information on levothyroxine dose, drug monitoring, and how to assess response to treatment, see Prescribing information.

TSH greater than 10 mU/L

How should I manage someone with subclinical hypothyroidism who has a thyroid-stimulating hormone (TSH) greater than 10 mU/L?

If the thyroid-stimulating hormone (TSH) concentration is greater than 10 mU/L and this finding is confirmed on repeated testing (at least 3 months later), commence treatment with levothyroxine.

Expert opinion differs as to the circumstances in which treatment would not be recommended. Therefore, seek specialist advice if the person:

Is very elderly.

Has just started taking amiodarone.

Has features suggestive of transient thyroiditis (viral or postpartum).

Has unstable cardiac disease.

For information on starting doses and titration, see Prescribing information.

Basis for recommendation

Basis for recommendation

This recommendation is based on a UK consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006]. The evidence supporting the above recommendation is based on well-conducted but non-randomized clinical trials and expert opinion.

Treatment is recommended because although no conclusive evidence shows that treatment will improve symptoms (see Subclinical hypothyroidism), there is evidence that these people may progress to overt hypothyroidism and deterioration in hyperlipidaemia over time.

In women with raised thyroid-stimulating hormone (TSH) levels alone, the annual risk of developing overt hypothyroidism is 2.6%. One third will become hypothyroid within 20 years [Vanderpump et al, 1995].

A TSH level greater than 10 mU/L may be associated with increased risk of coronary heart disease events and coronary heart disease mortality, although causality has not been established [Rodondi et al, 2010].

Referral

When should I refer a person with subclinical hypothyroidism?

Seek specialist advice or refer people with subclinical hypothyroidism if any of the following apply:

Subacute thyroiditis (de Quervain's thyroiditis) is suspected.

They are younger than 16 years of age.

They have particular management problems (for example severe ischaemic heart disease, or being treated with amiodarone or lithium).

They feel worse during treatment, as they may have undiagnosed Addison's disease.

There is any evidence of pituitary disease.

The thyroid-stimulating hormone level remains persistently increased despite receiving a full dose of levothyroxine — suspect poor adherence, drug interactions, or malabsorption (for example owing to coeliac disease).

The person is pregnant.

Symptoms do not improve despite appropriate thyroxine treatment (that is, thyroid function tests are now within the reference ranges), to investigate for a non-thyroid cause of the symptoms.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion [Vanderpump et al, 1996], a consensus statement from the Royal College of Physicians in association with other healthcare bodies [RCP, 2009], and a review article [Vaidya and Pearce, 2008].

Scenario: Overt hypothyroidism

Scenario: Overt hypothyroidism (not pregnant or planning a pregnancy)

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Treatment

How should I treat someone with overt hypothyroidism?

Treat overt hypothyroidism with levothyroxine.

Do not use triiodothyronine (T3) in combination with levothyroxine.

All people who are stable on levothyroxine require at least annual measurement of serum thyroid-stimulating hormone:

To check adherence.

To ensure that the dosage of levothyroxine is still correct.

For information on levothyroxine dose, drug monitoring, and how to assess response to treatment, see Prescribing information.

Basis for recommendation

Basis for recommendation

These recommendations are based on a UK consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006]. The evidence supporting the above recommendations is based on well conducted but non-randomized clinical trials and expert opinion.

The recommendation not to use triiodothyronine (T3) in combination with levothyroxine is based on a UK consensus statement produced by the Royal College of Physicians in association with other healthcare bodies [RCP, 2009], and a UK consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006]. There is no consistent evidence to recommend the use of combined therapy with levothyroxine and triiodothyronine in preference to levothyroxine alone, and there are potential risks from combination therapy, such as osteoporosis and arrhythmias [RCP, 2009].

Referral

When should I refer a person with overt hypothyroidism?

Seek specialist advice or refer people with hypothyroidism if any of the following apply:

Subacute thyroiditis (de Quervain's thyroiditis) is suspected.

They are younger than 16 years of age.

They have particular management problems (for example severe ischaemic heart disease, or being treated with amiodarone or lithium).

They feel worse during treatment, as they may have undiagnosed Addison's disease.

There is any evidence of pituitary disease.

The thyroid-stimulating hormone level remains persistently increased despite receiving a full dose of levothyroxine — suspect poor adherence, drug interactions, or malabsorption (for example owing to coeliac disease).

The woman is pregnant.

They have continuing symptoms despite appropriate thyroxine treatment (that is, thyroid function tests are now within the reference ranges), to investigate for a non-thyroid cause of the symptoms.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion [Vanderpump et al, 1996], a consensus statement from the Royal College of Physicians in association with other healthcare bodies [RCP, 2009], and a review article [Vaidya and Pearce, 2008].

Scenario: Preconception or pregnant

Scenario: Subclinical or overt hypothyroidism in the prenatal or antenatal period

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Pre-existing subclinical hypothyroidism

How should I manage a woman with pre-existing subclinical hypothyroidism who is pregnant or planning a pregnancy?

Check thyroid function tests before conception if they have not been done in the past 6 months.

Advise women planning a pregnancy to consult their GP as soon as they think they may be pregnant.

For women with known subclinical hypothyroidism who are already receiving levothyroxine treatment (perhaps because their thyroid-stimulating hormone [TSH] concentration was greater than 10 mU/L):

At confirmation of pregnancy, immediately increase the levothyroxine dose, and perform thyroid function tests while awaiting referral to a specialist:

The dose should be increased usually by adding at least 25–50 micrograms levothyroxine; the size of the initial increase in dose will depend on the dose the woman is already taking and the TSH and free thyroxine (FT4) concentrations.

Aim for a TSH concentration in the low-normal range (0.4 mU/L to 2.0 mU/L) and an FT4 concentration in the upper reference range.

If there is any uncertainty about what dose to prescribe, seek immediate specialist advice so that there is no delay in the woman receiving an adequate dose of levothyroxine.

Monitor TSH and FT4 levels:

Every 4 weeks during titration of levothyroxine.

Every 4 weeks during the first trimester, and again at 16 weeks and at 28 weeks of gestation, in a woman who is on a stable dose of levothyroxine.

More frequent tests may be appropriate on specialist advice.

All women with subclinical hypothyroidism who are pregnant or planning a pregnancy and are not receiving levothyroxine treatment should be started on levothyroxine therapy while waiting for referral to a specialist. Management is the same as for women with a new diagnosis of subclinical hypothyroidism who are pregnant or planning a pregnancy.

Basis for recommendation

Basis for recommendation

These recommendations are based on information from a consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006]; expert opinion in a guideline produced by the Endocrine Society [Abalovich et al, 2007]; expert opinion in a learning module [Edwards and Vanderpump, 2007]; and the opinion of CKS expert reviewers. Some of the evidence to support these recommendations is based on observational studies.

In women with hypothyroidism, the need for levothyroxine is increased in pregnancy by 30–50% above the preconception dosage, and absorption of levothyroxine may be diminished, therefore it is important to increase the dose quickly in women already on levothyroxine [BTA et al, 2006; Abalovich et al, 2007; Reid et al, 2010].

There is evidence of increased fetal loss, and psychomotor and IQ deficits, in infants born to mothers with undiagnosed or inadequately treated hypothyroidism (including subclinical hypothyroidism) [Casey et al, 2005].

The increase in the levothyroxine dose is necessary to maintain normal serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels for the gestational age [BTA et al, 2006].

The recommendations on monitoring of thyroid function (TSH and FT4 levels) are based on expert opinion in guidelines [BTA et al, 2006].

New diagnosis of subclinical hypothyroidism

How should I manage a woman with a new diagnosis of subclinical hypothyroidism who is pregnant or planning a pregnancy?

All women with a new diagnosis of subclinical hypothyroidism who are pregnant or planning a pregnancy should be started on levothyroxine therapy while waiting for referral to a specialist.

Follow local specialist advice regarding the dose, as experts recommend different starting doses (varying from 25 micrograms to 100 micrograms to be taken each morning).

Monitor thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels:

Every 4 weeks during titration of levothyroxine.

Every 4 weeks during the first trimester, and again at 16 weeks and at 28 weeks of gestation, in a woman who is on a stable dose of levothyroxine.

More frequent tests may be appropriate on specialist advice.

Aim for a TSH concentration in the low-normal range (0.4–2.0 mU/L) and an FT4 concentration in the upper reference range.

Basis for recommendation

Basis for recommendation

These recommendations are based on information from a consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006]; expert opinion in a guideline produced by the Endocrine Society [Abalovich et al, 2007]; expert opinion in a learning module [Edwards and Vanderpump, 2007]; and the opinion of CKS expert reviewers. Some of the evidence to support these recommendations is based on observational studies.

In women with hypothyroidism, the need for levothyroxine is increased in pregnancy by 30–50% above the preconception dosage, and absorption of levothyroxine may be diminished; therefore, it is important to increase the dose quickly in women already on levothyroxine [BTA et al, 2006; Abalovich et al, 2007; Reid et al, 2010].

There is evidence of increased fetal loss, and psychomotor and IQ deficits, in infants born to mothers with undiagnosed or inadequately treated hypothyroidism (including subclinical hypothyroidism) [Casey et al, 2005].

The increase in the levothyroxine dose is necessary to maintain normal serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels for the gestational age [BTA et al, 2006].

The recommendations on monitoring of thyroid function (TSH and FT4 levels) are based on expert opinion in guidelines [BTA et al, 2006].

Pre-existing overt hypothyroidism

How should I manage a woman with pre-existing overt hypothyroidism who is pregnant or planning a pregnancy?

Check thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels before conception if possible, to check adequacy of treatment and to make sure the woman is stable and understands the importance of adherence to levothyroxine.

If the woman has a history of Graves' disease, refer her to an endocrinologist for evaluation.

Advise the woman to consult her GP as soon as she thinks she may be pregnant.

At diagnosis of pregnancy, immediately increase the levothyroxine dose and check TSH and FT4 levels while waiting for referral to a specialist:

The dose should be increased usually by adding at least 25–50 micrograms levothyroxine; the size of the initial increase in dose will depend on the dose the woman is already taking and the TSH and FT4 concentrations. A 30–50% increase in dosage may be required. If there is any uncertainty about what dose to prescribe, seek immediate specialist advice so that there is no delay in the woman receiving an adequate dose of levothyroxine.

Check TSH and FT4 levels every 4 weeks until stabilized, aiming for a TSH concentration in the low-normal range (0.4–2.0 mU/L) and an FT4 concentration in the upper reference range.

Monitor TSH and FT4 levels:

Every 4 weeks during titration of levothyroxine.

Every 4 weeks during the first trimester, and again at 16 weeks and at 28 weeks of gestation, in a woman who is on a stable dose of levothyroxine.

More frequent tests may be appropriate on specialist advice.

Basis for recommendation

Basis for recommendation

These recommendations are based on a UK consensus guideline produced by the Association for Clinical Biochemistry, British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006], and expert opinion in a guideline produced by the Endocrine Society [Abalovich et al, 2007].

In women with hypothyroidism, the need for levothyroxine is increased in pregnancy by 30–50% above the preconception dosage, and absorption of levothyroxine may be diminished; therefore, it is important to increase the dose quickly in women already on levothyroxine [BTA et al, 2006; Abalovich et al, 2007; Reid et al, 2010].

There is evidence of increased fetal loss and IQ and psychomotor deficits in infants born to mothers with undiagnosed or inadequately treated hypothyroidism [Haddow et al, 1999; Pop et al, 1999; Casey et al, 2005].

The increase in the levothyroxine dose is necessary to maintain normal serum TSH and FT4 for the gestational age. A TSH concentration of 0.4 mU/L to 2.0 mU/L is normal for pregnancy [BTA et al, 2006].

Monitoring of thyroid function tests at least once in each trimester aims to detect inadequately treated hypothyroidism, thereby reducing the risk of long-term adverse effects on the psychomotor and auditory systems of the neonate.

The recommendation to refer women with a history of Graves' disease to an endocrinologist for evaluation is based on guidelines developed by the European Thyroid Association [Laurberg et al, 1998]; expert opinion in a clinical practice guideline on the investigation and management of primary thyroid dysfunction produced by the Thyroid Working Group, a multidisciplinary team composed of family physicians, laboratory specialists, and endocrinologists [Alberta Medical Association, 2008]; and expert opinion in a review article [Brent, 2008].

New diagnosis of overt hypothyroidism

How should I manage a woman with a new diagnosis of overt hypothyroidism who is pregnant or planning a pregnancy?

If the woman is planning a pregnancy and is newly diagnosed with overt hypothyroidism:

Start treatment (see prescribing information for information on how to do this), and advise delaying conception until she is stabilized on thyroxine replacement therapy.

Advise her to consult her GP as soon as she thinks she may be pregnant, because her thyroid-stimulating hormone (TSH) levels will need to be checked and her levothyroxine dose increased.

If the woman is pregnant and is newly diagnosed with overt hypothyroidism:

Start treatment with levothyroxine immediately; see prescribing information. There should be no delay in starting treatment.

Refer for further management.

The target TSH concentration in pregnancy is 0.4 mU/L to 2.0 mU/L, depending on trimester-specific normal TSH ranges.

Basis for recommendation

Basis for recommendation

These recommendations are based on a UK consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006], and expert opinion in a guideline produced by the Endocrine Society [Abalovich et al, 2007].

The need for levothyroxine is increased in pregnancy in women with hypothyroidism, and absorption of levothyroxine may be diminished. It is therefore important to intervene quickly [BTA et al, 2006].

There is evidence of increased fetal loss and IQ deficits in infants born to mothers with undiagnosed or inadequately treated hypothyroidism [Haddow et al, 1999; Pop et al, 1999; Casey et al, 2005].

The increase in the levothyroxine dose is necessary to maintain normal serum thyroid-stimulating hormone and free thyroxine levels for the gestational age [BTA et al, 2006].

Scenario: Postpartum

Scenario: Subclinical or overt hypothyroidism in the postpartum period

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Subclinical hypothyroidism

How should I manage a postpartum woman with subclinical hypothyroidism which existed pre-pregnancy or developed during pregnancy?

If continuing levothyroxine, reduce to the pre-pregnancy dose.

If stopping levothyroxine, monitor thyroid-stimulating hormone levels at 1, 3, and 6 months after the birth, then annually.

Basis for recommendation

Basis for recommendation

This recommendation is based on expert opinion in a guideline produced by the Endocrine Society [Abalovich et al, 2007] and the opinion of CKS expert reviewers. Thyroid function often alters markedly in the 12 months postpartum and may return to normal.

Overt hypothyroidism

How should I manage a postpartum woman with overt hypothyroidism which existed pre-pregnancy or developed during pregnancy?

A management plan for the adjustment of levothyroxine during the postpartum period may be provided by the specialist team supervising care during pregnancy. In the absence of a management plan:

In women with overt hypothyroidism which existed pre-pregnancy:

Reduce levothyroxine to the pre-pregnancy dose in the immediate postpartum period.

Recheck serum thyroid-stimulating hormone (TSH) levels 6–8 weeks postpartum.

In women with overt hypothyroidism which developed during pregnancy:

Reduce the levothyroxine dose by 25–50 micrograms in the immediate postpartum period.

Recheck serum TSH levels 6 weeks postpartum, then every 2–3 months, reducing the dose of levothyroxine by 25 micrograms until the thyroid-stimulating hormone levels are within the reference range.

Basis for recommendation

Basis for recommendation

The recommendations on the postpartum management of women with overt hypothyroidism which existed prior to pregnancy, or developed during pregnancy, are based on a consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006], a guideline produced by the Endocrine Society [Abalovich et al, 2007], and the opinion of CKS expert reviewers.

In women with hypothyroidism existing before pregnancy, after delivery levels of thyroid hormones and thyroid-stimulating hormone normally return to the pre-pregnant state, and therefore the dose of levothyroxine can usually be reduced to pre-pregnancy levels [BTA et al, 2006; Abalovich et al, 2007].

Postpartum thyroiditis

How should I manage a woman with suspected postpartum thyroiditis?

If a woman has clinical features suggestive of postpartum thyroiditis, measure thyroid-stimulating hormone (TSH) and serum thyroxine (FT4) (ideally 6–8 weeks after delivery):

If initial thyroid function tests show a thyrotoxic pattern:

Refer to a specialist for further tests to differentiate postpartum thyroiditis from Graves' disease.

If the diagnosis is postpartum thyroiditis, treatment is not required, but thyroid function should be monitored to detect onset of hypothyroidism.

If initial thyroid function tests show a hypothyroid pattern and the woman is symptomatic, or planning a subsequent pregnancy:

Seek specialist advice regarding initiation of levothyroxine treatment.

If initial thyroid function tests show a hypothyroid pattern, the woman is asymptomatic, and not planning a subsequent pregnancy:

Seek specialist advice on whether to initiate levothyroxine treatment.

If untreated, recheck TSH and T4 levels in 4–8 weeks.

Check TSH annually in women with a history of postpartum thyroiditis.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion [Vanderpump et al, 1996; BTA et al, 2006].

The recommendations on the management of women who are hypothyroid are based on expert opinion in a guideline produced by the Endocrine Society [Abalovich et al, 2007].

The recommendation to measure thyroid-stimulating hormone annually in women with a history of postpartum thyroiditis is based on expert opinion in a guideline produced by the Endocrine Society [Abalovich et al, 2007].

Women with a history of postpartum thyroiditis have a markedly increased risk of developing permanent primary hypothyroidism in the 5–10 year period after the episode of postpartum thyroiditis.

Scenario: Amiodarone or lithium treatment

Scenario: Amiodarone- or lithium-induced hypothyroidism

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Management

How should I manage someone with amiodarone- or lithium-induced hypothyroidism?

If the person has amiodarone-induced hypothyroidism:

Refer to endocrinology if a goitre or nodules are detected.

There is no need to stop amiodarone therapy.

Start levothyroxine replacement therapy (see prescribing information).

Assess thyroid-stimulating hormone (TSH) levels after 4–6 weeks. Aim to achieve a normal concentration of TSH.

Aim to keep serum free thyroxine (FT4) concentrations in either the upper end of the normal range or slightly above the normal range (as seen in euthyroid people who receive amiodarone).

Thyroid function tests may return to normal if amiodarone is discontinued.

Monitor TSH levels and reduce or stop the dose of levothyroxine as appropriate.

If the person has lithium-induced hypothyroidism:

Refer to endocrinology if a goitre or nodules are detected.

Do not stop lithium therapy.

Start levothyroxine replacement therapy (see Prescribing information).

Aim to achieve normal concentrations of TSH.

Aim to keep FT4 concentrations in either the upper end of the normal range or slightly above the normal range.

Thyroid function tests usually return to normal if lithium is discontinued.

Monitor TSH levels and reduce or stop the dose of levothyroxine as appropriate.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in a review article [Vanderpump et al, 1996]; a UK consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006]; and the opinion of CKS expert reviewers.

The recommendations on how to manage amiodarone-induced hypothyroidism are discussed in two systematic reviews [Harjai and Licata, 1997; Basaria and Cooper, 2005].

The recommendations on how to manage lithium-induced hypothyroidism are discussed in a review of the literature and guidelines for treatment for lithium-induced subclinical hypothyroidism [Kleiner et al, 1999], and a review article [Bocchetta and Loviselli, 2006].

Scenario: Suspected secondary hypothyroidism

Scenario: Suspected secondary hypothyroidism

192months3060monthsBoth

Management

How should I manage suspected secondary hypothyroidism?

If secondary hypothyroidism is suspected, refer urgently to an endocrinologist for investigation into the underlying cause and other hormone deficiencies.

Basis for recommendation

Basis for recommendation

This recommendation is based on what CKS believes is good practice and the opinion of a CKS expert reviewer.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Cautions

Who should use levothyroxine with caution?

People with adrenal insufficiency — start corticosteroid therapy before starting levothyroxine.

People aged over 50 years — slower dose titration is recommended.

People with cardiovascular disorders, particularly ischaemic heart disease or arrhythmias — slower dose titration is recommended.

People with diabetes — levothyroxine treatment can increase blood glucose levels, although this is rarely clinically significant. The dose of glucose-lowering drugs may need to be adjusted.

Basis for recommendation

This information is based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010]:

People with adrenal insufficiency may react to levothyroxine treatment, so the manufacturer advises that corticosteroid therapy should be started before levothyroxine treatment.

A lower start dose and slower titration is recommended for people over the age of 50 years or people with ischaemic heart disease because over-treatment with levothyroxine can cause anginal pain and arrhythmias.

CKS expert reviewers commented that levothyroxine rarely causes a clinically significant increase in blood glucose levels.

Pregnancy and breastfeeding

Can levothyroxine be used during pregnancy and breastfeeding?

Pregnancy — treatment of maternal hypothyroidism with levothyroxine is essential during pregnancy. Serum thyroid-stimulating hormone should be monitored carefully to prevent both under- and over-treatment with levothyroxine. See Scenario: Preconception or pregnant for further information on dose adjustment and monitoring during pregnancy.

Breastfeeding — treatment of maternal hypothyroidism is essential to allow lactation. The amount of levothyroxine present in breast milk is too small to affect the result of tests for neonatal hypothyroidism.

Basis for recommendation

Pregnancy

Both maternal and fetal hypothyroidism are known to have serious adverse effects on the fetus [BTA et al, 2006; Abalovich et al, 2007]. See Harms of hypothyroidism in pregnancy for further information.

Breastfeeding

Adequate thyroid hormone serum levels are required for normal lactation [LactMed, 2010].

The amount of levothyroxine present in breast milk is very small (estimated to be about 1% of the dose an infant with hypothyroidism would need) [Schaefer et al, 2007]. This amount does not influence the thyroid function of a healthy infant and, therefore, is also too small to affect tests for neonatal hypothyroidism.

Interactions

What clinically important drug interactions with levothyroxine should I be aware of?

Warfarin — people taking warfarin who are subsequently given levothyroxine will need a warfarin dose reduction as they become euthyroid. The anticoagulant effect is altered by thyroid function, and cases of bleeding have occurred. Monitor the INR (for example, weekly) and adjust the dose of warfarin accordingly.

Oral glucose-lowering drugs — levothyroxine treatment can increase blood glucose levels (although this is rarely clinically significant). The dose of oral glucose-lowering drugs may need to be adjusted.

Digoxin — people with hypothyroidism are more sensitive to the effects of digoxin, and lower digoxin doses may be needed. However, as the person becomes euthyroid, the digoxin dose will need to be increased. Monitor heart rate and digoxin levels as necessary.

Theophylline and aminophylline — people with hypothyroidism metabolize theophylline more slowly, and a lower dose may be needed. However, as the person becomes euthyroid, larger doses may be needed.

The absorption of levothyroxine can be reduced (resulting in clinical or subclinical hypothyroidism) by the following drugs:

Calcium, iron, antacids, anion-exchange resins (such as colestyramine and colesevelam) — where possible, advise the person to leave at least 2–4 hours after taking their levothyroxine dose before taking these medicines.

If it is difficult to separate the doses by a reasonable interval (for example with orlistat), it may be prudent to monitor thyroid-stimulating hormone (TSH) levels after starting or stopping the interacting drug, to ensure that an effective dose of levothyroxine is being used.

The following drugs may increase levothyroxine requirements. It may be prudent to monitor TSH levels 2–3 months after starting, stopping, or changing doses of these drugs:

Oral hormone replacement therapy (HRT). Transdermal HRT is not expected to interact.

Oral contraceptives.

Protease inhibitors.

Amiodarone

In general, amiodarone can be continued if the person develops hypothyroidism. However, careful monitoring is needed. For further information, see Scenario: Amiodarone or lithium treatment.

Specialist referral for amiodarone-induced hyperthyroidism is recommended, as management may be complex and involve further investigations.

Lithium

In general, lithium can be continued if the person develops hypothyroidism. However, careful monitoring is needed. For further information, see Scenario: Amiodarone or lithium treatment.

For lithium-induced hyperthyroidism, the individual should be referred to an endocrinologist if thyroid-stimulating hormone (TSH) concentrations are repeatedly abnormal, or goitre or nodules are detected.

Enzyme-inducing drugs — there are isolated case reports of reduced effects of levothyroxine in people taking liver enzyme-inducing drugs (such as carbamazepine, barbiturates, phenytoin, rifampicin). However, the clinical impact of this potential interaction seems to be small.

Basis for recommendation

These recommendations are based on information from Stockley's drug interactions [Baxter, 2010], the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 2010], and guidelines from the British Thyroid Association [BTA et al, 2006].

Start dose and titration

How should I start and titrate levothyroxine?

The treatment target is a thyroid-stimulating hormone (TSH) level within the reference range (typically 0.4–4.5 mU/L).

If the person is younger than 50 years of age:

Start with a dose of 50 micrograms to 100 micrograms once a day (taken before breakfast).

Higher start doses may be used if the person is post-thyroidectomy.

Adjust the dose by 25 micrograms to 50 micrograms every 2–3 months according, to TSH levels.

If the person is older than 50 years of age, or has cardiovascular disease:

Start with a dose of 25 micrograms once a day (taken before breakfast).

Adjust the dose by 25 micrograms every 2–3 months, according to TSH levels.

Most people will become clinically euthyroid with a maintenance dose of levothyroxine 75 micrograms to 150 micrograms each morning.

If the person does not feel well with TSH in the upper half of the reference range (2.5–4.5 mU/L), then it is reasonable to aim for a TSH in the lower reference range (0.4–2.5 mU/L). For example, by increasing the levothyroxine dose by 25 micrograms daily or on alternate days.

Failure of higher doses (such as 200 micrograms or more) to normalize TSH levels may be associated with poor adherence (intermittent dosing) or undiagnosed malabsorption syndromes, such as coeliac disease.

Pregnant women should be referred for specialist management. See Scenario: Preconception or pregnant for further information on dosage and monitoring during pregnancy.

Basis for recommendation

Start doses and titration schedule

Theses recommendations are based on guidelines from the British Thyroid Association [BTA et al, 2006] and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010].

A lower start and titration dose is recommended if the person is older than 50 years of age and has cardiovascular disease in order to reduce the risk of over-titration and cardiac adverse effects.

High maintenance doses

The recommendation that poor compliance or malabsorption may be the underlying reason for high levothyroxine doses failing to normalize TSH levels is based on expert opinion from two case history reports [d'Estève-Bonetti et al, 2002; McDermott et al, 2005].

Dose timing

Levothyroxine is given as a once daily dose in the morning, preferably before breakfast [ABPI Medicines Compendium, 2010].

A recent randomized controlled trial (RCT) suggested that TSH levels are suppressed more by bedtime dosing of levothyroxine than by morning dosing, although quality of life measures were unaffected [Bolk et al, 2010]. This RCT has multiple methodological problems. It is, therefore, not possible to determine whether morning or evening dosing with levothyroxine has a clinically significant effect on TSH levels and symptoms of hypothyroidism.

Monitoring

How should I monitor someone taking levothyroxine?

Aim to make the person feel well, and achieve a serum thyroid-stimulating hormone (TSH) concentration that is within the reference range (typically 0.4–4.5 mU/L).

The minimum period for TSH levels to stabilize after a change in levothyroxine dose is 2 months.

Check TSH levels 2–3 months after each dose increase, to determine whether further dose titration is needed.

If the TSH level is within the reference range (typically 0.4–4.5 mU/L), the dose is adequate.

If the TSH level is below the reference range or is undetectable:

Titrate the levothyroxine dose down in 25-microgram steps until the TSH level is within the reference range.

This may be difficult in some people who have an apparent psychological benefit and general feeling of well-being when their TSH concentration is undetectable. Titrating down by 25 micrograms in each instance may make this reduction possible.

If the TSH is elevated, titrate the levothyroxine dose up in 25 microgram to 50 microgram increments until the TSH is within the reference range.

Some people will continue to feel unwell even when receiving adequate levothyroxine therapy and with their TSH and free thyroxine (FT4) concentrations within the reference range. Dose increases are not recommended.

Once stabilized, TSH only can be checked annually. However:

Both TSH and FT4 should be measured in clinical situations where the pituitary–thyroid axis is not intact or is unstable, or if non-adherence or malabsorption is suspected (for example, high doses of levothyroxine fail to reduce TSH into the reference range).

If the person has permanent secondary (central) hypothyroidism, TSH measurement is valueless and FT4 alone should be used for monitoring.

Pregnant women should be referred for specialist management. However, whilst awaiting specialist advice, aim for a TSH in the low to normal range (0.4–2.0 mU/L).

Basis for recommendation

These recommendations are from a UK consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006].

Expert opinion from this group is that TSH levels take 2–3 months to stabilize following a change in levothyroxine dose [BTA et al, 2006].

Once stabilized, annual TSH measurement is recommended because levothyroxine requirements can change with ageing [BTA et al, 2006].

Long-term overtreatment with levothyroxine (leading to a hyperthyroid state) may cause iatrogenic hyperthyroidism that could lead to long-term bone mass loss (especially in elderly women) [Faber and Galløe, 1994; Uzzan et al, 1996] or atrial fibrillation (especially in elderly people) [Sawin et al, 1994].

Some people continue to feel unwell even when receiving adequate levothyroxine therapy and with their TSH and free thyroxine (FT4) concentrations within the reference range. It remains controversial whether this relates to their thyroid axis or coincident psychological morbidity. There is no trial evidence that increasing the levothyroxine dose will improve psychological or cognitive symptoms in these people. Rather, a lack of benefit has been demonstrated from giving levothyroxine to euthyroid people with these symptoms [Pollock et al, 2001; Walsh et al, 2006].

Adverse effects

What adverse effects should I be aware of, and how should I manage them?

Long-term treatment with thyroxine titrated to achieve a thyroid-stimulating hormone (TSH) concentration within the reference range is not known to be associated with adverse effects.

Adverse effects are due to excessive doses (which may occur if the initial increase in metabolism [from upward dose titration] is too rapid) and correspond to symptoms of hyperthyroidism, but they usually disappear after dose reduction or withdrawal of treatment.

The most common adverse effects affect the following systems:

Heart: arrhythmias, anginal pain.

Central nervous system: headache, hyperactivity, sweating, tremor, heat intolerance.

Gastrointestinal tract: diarrhoea, excessive weight loss, vomiting.

Musculoskeletal system: muscle cramps, muscle weakness.

Long-term over-treatment with levothyroxine (leading to a hyperthyroid state) may cause iatrogenic hyperthyroidism that could lead to long-term bone mass loss (especially in elderly women) or atrial fibrillation (especially in elderly people).

It is, therefore, important that TSH is measured 2–3 months after dose titration, and annually once the person has stabilized to ensure that TSH levels are detectable (> 0.1 mU/L) and are preferably within the reference range (typically 0.4–0.45 mU/L).

Basis for recommendation

This information is based on a UK consensus guideline produced by the Association for Clinical Biochemistry, the British Thyroid Association, and the British Thyroid Foundation [BTA et al, 2006], and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010].

For further information on long-term adverse effects of over-treatment, see the Supporting evidence section on Adverse effects.

Evidence

Evidence

Supporting evidence

This section summarizes the evidence that supports the recommendations about the primary care treatment of hypothyroidism.

Subclinical hypothyroidism and risk of CVD

Evidence on the association between subclinical hypothyroidism and the risk of developing cardiovascular disease

Pooled data from cohort studies suggest that subclinical hypothyroidism may be associated with an increased risk of coronary heart disease (CHD) and cardiovascular mortality, but this finding is not statistically significant. Analysis of only the most robust studies weakens this association. Subgroup analysis suggests that the risk may be greatest in people younger than 65 years of age.

A systematic review (search date: to September 2010) identified 11 prospective cohort studies that assessed the relationship between subclinical hypothyroidism, coronary heart disease, and mortality [Rodondi et al, 2010].

Description of included studies

Participants were mostly middle-aged or older men and women. Follow up ranged from 2.5 years to 20 years.

In the pooled population of 55,287 people (3450 with subclinical hypothyroidism), there were 4470 CHD events and 2168 deaths.

Individual participant data were pooled for the analysis.

Some of the individuals received thyroxine therapy during the follow-up period.

Results

The hazard ratio (HR) for CHD events associated with subclinical hypothyroidism was 1.18 (95% CI 0.99 to 1.42).

HR for CHD mortality associated with subclinical hypothyroidism was 1.14 (95% CI 0.99 to 1.32).

The risk for CHD associated with subclinical hypothyroidism seemed to be higher in younger participants, but the number of outcomes in this age group was small, and there was no significant trend in CHD risk across age groups.

Comment

Analysis of all studies suggests that subclinical hypothyroidism may be associated with an increased risk of CHD and cardiovascular mortality. However, the studies were of varying quality and the I2 test indicated some inconsistency. In addition, the confidence intervals were all wide, and crossed 1 (statistically not significant). When only data from higher-quality studies were pooled, the relative risk of CHD was lower (closer to 1).

Harms of hypothyroidism in pregnancy

Evidence on the harms of untreated hypothyroidism in pregnancy

There is evidence of increased fetal loss, impaired psychomotor development, and IQ deficits in infants born to mothers with undiagnosed or inadequately treated hypothyroidism.

A cohort of 220 healthy children born after uncomplicated pregnancies and deliveries were assessed at 10 months of age for neurodevelopment using a validated infant development scale [Pop et al, 1999].

Children of women with low serum free thyroxine (FT4) concentrations (below the 10th percentile at 12 weeks' gestation) had significantly lower development scores, compared with children of mothers with higher FT4 values: t-test, mean difference 7.4 (95% CI 1.1 to 13.9).

An FT4 concentration below the 10th percentile at 12 weeks' gestation was a significant risk factor for impaired psychomotor development (relative risk [RR] 5.8, 95% CI 1.3 to 12.6).

A lower maternal FT4 concentration at 12 weeks' gestation was associated with impaired psychomotor development at 10 months of age.

Low maternal serum FT4 during early pregnancy may be an important risk factor for impaired infant development.

Thyroid-stimulating hormone (TSH) was measured from serum samples of 25,216 pregnant women to investigate whether undiagnosed hypothyroidism in pregnancy is associated with adverse cognitive outcome in school-age offspring [Haddow et al, 1999]:

Sixty-two women had a TSH concentration in at least the 98th percentile and low thyroxine concentrations. This group was matched to 124 women with normal values. Their children, who were 7–9 years of age and did not have hypothyroidism as newborns, underwent 15 intellectual tests.

The children of the 62 women with low thyroxine performed slightly less well on all 15 tests than did the matched control children (most differences did not reach statistical significance). The mean IQ was 103 versus 107 (p = 0.06), and 15% versus 5% of children had an IQ less than 85 (p = 0.08).

Undiagnosed hypothyroidism in pregnant women was found to be associated with reduced intellectual ability in their children.

Pregnant women with subclinical hypothyroidism were retrospectively identified from hospital thyroid screening records [Casey et al, 2005]. Their pregnancies were followed up, and pregnancy outcomes were compared with those in pregnant women with normal TSH values:

Of 25,756 pregnant women who were screened, 404 (2.3%) were considered to have subclinical hypothyroidism.

Pregnancies in women with subclinical hypothyroidism were three times more likely to be complicated by placental abruption (RR 3.0, 95% CI 1.1 to 8.2).

Preterm birth (delivery at or before 34 weeks' gestation) was almost two-fold higher in women with subclinical hypothyroidism (RR 1.8, 95% CI 1.1 to 2.9).

Because the women with subclinical hypothyroidism were older, maternal age may have been a confounding factor.

The IQ scores of the offspring of women with subclinical hypothyroidism may be related to the effects of prematurity.

Pregnant women with TSH levels of 5.0 mIU/L or less were prospectively followed up [Negro et al, 2010].

The rate of spontaneous pregnancy loss was significantly lower in the euthyroid group (3.6%; 127 of 3481) compared with the subclinical hypothyroidism group (6.1%; 39 of 642), p = 0.006.

There was no difference between groups in the rate of preterm delivery: 4.7% of euthyroid women compared with 5.1% of women with subclinical hypothyroidism p > 0.05.

There were no differences in maternal age, pregnancy history or thyroid function tests between groups.

Levothyroxine

Levothyroxine

Subclinical hypothyroidism

Evidence on the effect of levothyroxine treatment in subclinical hypothyroidism

Data are insufficient to determine whether levothyroxine replacement has any clinically important effects on cholesterol levels, left ventricular dysfunction, or cardiovascular morbidity or mortality. The available data suggest that levothyroxine replacement does not improve symptoms, mood, or quality of life in people with subclinical hypothyroidism.

A Cochrane systematic review (search date: to May 2006) identified 12 randomized controlled trials (RCTs) that compared the efficacy of treatment with levothyroxine with placebo or no treatment in adults with subclinical hypothyroidism [Villar et al, 2007].

Description of included trials

The thyroid-stimulating hormone (TSH) level was less than 15 mU/L in three studies, less than 12 mU/L in three studies, less than 10 mU/L in three studies, and up to 32 mU/L or 55 mU/L in three studies.

Five studies included people without a known history of thyroid disease, four studies included people that had subclinical hypothyroidism following treatment for autoimmune thyroiditis, and in two studies subclinical hypothyroidism was caused by Hashimoto's thyroiditis.

Study durations ranged from 6 months to 14 months.

The total size of the study population was relatively small, comprising 350 people.

Results

No RCTs assessed the effect of levothyroxine on cardiovascular morbidity or mortality.

Seven small RCTs found no statistically significant improvement in symptoms, mood, and quality of life. Only one study showed a statistically significant improvement in cognitive function.

Six small RCTs assessed the effect of levothyroxine on serum lipid levels. There was a trend towards a reduction in total cholesterol and lower density lipoprotein (LDL) cholesterol levels with levothyroxine treatment when the data were analysed using the final mean levels. However, if the data were analysed by change from baseline, there was no significant difference between levothyroxine and placebo.

Three RCTs found that restoration of euthyroidism seemed to improve left ventricular dysfunction. However, these studies included people with high serum TSH and with previous thyroid disease.

A previous systematic review (search date: to May 1999) pooled data from 13 trials (both controlled and uncontrolled) that assessed the effect of levothyroxine therapy on serum lipoproteins in 247 people with mild thyroid failure [Danese et al, 2000]:

Description of included trials

Two studies were parallel group RCTs, one was a crossover RCT, and 10 were uncontrolled single-group studies.

All studies enrolled at least 75% women. Mean age ranged from 32–71 years of age. Two studies enrolled people who were inadequately treated with levothyroxine. Two enrolled people with either cardiovascular disease or hypercholesterolaemia. Three studies did not adequately characterize the selection of participants, and six studies predominantly consisted of people with a history of ablative therapy for hyperthyroidism.

Results

In people with a history of overt hypothyroidism whose levothyroxine dose was not sufficient to normalize serum TSH, the change in serum cholesterol was much greater (–0.44 mmol/L [95% CI –0.18 to –0.70 mmol/L]) than in people with subclinical hypothyroidism (–0.14 mmol/L [95% CI –0.01 to –0.28 mmol/L]).

No details were given about the number of people and the type of trials within each of these subgroups, but the heterogeneity within the studies that enrolled people with subclinical hypothyroidism (p = 0.07) suggested that additional factors might be associated with the change in serum cholesterol concentrations in this group.

Comment

Most of the studies in this review were not RCTs. Some attempted to assess diet, exercise, weight change, and medications which may have influenced lipid concentrations. There was potential for publication bias. It is not known whether the apparent small reduction in cholesterol concentrations is clinically significant.

Overt hypothyroidism

Evidence on the effect of levothyroxine treatment in overt hypothyroidism

CKS found no systematic reviews or randomized controlled trials comparing levothyroxine with placebo. However, there is consensus that levothyroxine treatment is beneficial.

Investigating the effectiveness of levothyroxine in a placebo-controlled trial would not be considered ethical.

Levothyroxine plus liothyronine

Evidence on combined treatment with levothyroxine plus liothyronine

Combined levothyroxine and liothyronine treatment does not clinically improve well-being, cognitive function, or quality of life compared with levothyroxine alone.

A recent systematic review (search date: to August 2008) identified 10 randomized double-blind trials that compared levothyroxine alone with combined levothyroxine plus liothyronine for the treatment of hypothyroidism [Chao et al, 2009].

Description of included studies

Six studies were crossover design and four were parallel studies.

The doses and ratios used for combination treatment varied greatly between and within trials.

The degree of hypothyroidism was generally not specified.

Study sample sizes were small (most studies included between 20 and 110 participants). Only one study had a large sample size (697 participants).

Study duration ranged from 5 weeks to 15 weeks.

Results

No statistically significant differences were found between levothyroxine alone and combined treatment for biochemical variables, mood states, clinical variables, adverse effects, and drop-out rates.

However, combined levothyroxine and liothyronine treatment showed a statistically significant improvement in cognitive performance compared to thyroxine alone: weighted mean difference –0.49, 95% CI –0.90 to –0.008. However, this is not a clinically significant difference.

Authors' conclusions

Combined levothyroxine and liothyronine treatment does not clinically improve well-being, cognitive function, or quality of life compared with thyroxine alone.

Three further small randomized controlled trials (RCTs) have been published since this systematic review:

One parallel group RCT (71 participants) found that combined therapy did not improve the well-being compared with levothyroxine alone [Valizadeh et al, 2009].

One small crossover study (59 participants) found that replacing part of the usual levothyroxine dose with liothyronine for 3 months improved scores on quality of life, depression, and anxiety scales compared with levothyroxine alone [Nygaard et al, 2009].

A genetic sub-analysis of the largest RCT (552 participants) raised the possibility that a subgroup of people with reduced deiodinase activity may benefit from combined levothyroxine and liothyronine therapy, but this requires confirmation [Panicker et al, 2009].

Dose timing

Evidence on morning dosing compared with bedtime dosing

The only available randomized controlled trial (RCT) has multiple methodological problems. It is, therefore, not possible to determine whether morning or evening dosing with levothyroxine has a clinically significant effect on TSH levels and symptoms of hypothyroidism.

One randomized controlled trial (RCT) compared thyroid-stimulating hormone (TSH) levels after morning administration of levothyroxine with TSH levels after bedtime administration of levothyroxine [Bolk et al, 2010].

Description of study characteristics

One hundred and five consecutive patients whose levothyroxine requirements had been stable for at least 6 months were randomized to one capsule of levothyroxine in the morning and one placebo capsule at bedtime, or one placebo capsule in the morning and one capsule of levothyroxine at bedtime.

Participants were given a similar dose as before trial entry.

Treatment schedules were switched after 3 months.

Evaluable data were available for 90 participants. (The authors' power calculation estimated that a sample size of 75 patients would give at least 80% power to detect a significant difference of 1 mIU/L between morning and bedtime administration.)

However, the median levothyroxine dose in the group that received morning levothyroxine first was higher than in the group that received bedtime levothyroxine first: 125 micrograms compared with 100 micrograms.

In addition, the mean baseline TSH level was lower in the group that received morning levothyroxine first: 1.5 mIU/L in the morning group compared with 3.3 mIU/L in the bedtime group.

Results

Morning intake first: TSH levels increased in the first 6 weeks, and then reduced slightly (still above baseline) by 12 weeks. Following cross-over at week 12 to bedtime dosing, TSH levels continued to reduce to baseline levels.

Bedtime intake first: TSH levels reduced in the first 6 weeks, and then increased slightly (still below baseline) by 12 weeks. Following cross-over at week 12 to morning dosing, TSH levels continued to increase to baseline levels.

The 36-item Short Form Health Survey, Hospital Anxiety and Depression Scale, and 20–item Multidimensional Fatigue Inventory showed no differences in scores between the periods of morning or bedtime intake.

Authors' conclusions

Levothyroxine taken at bedtime significantly improved thyroid hormone levels but not quality of life variables.

Comments

This study has multiple methodological weaknesses which limit the conclusions that can be drawn from it.

The method of randomization was not described.

The study groups did not have similar baseline characteristics,. not controlled for.

The duration of the cross-over period is arguably inadequate. It can take up to 3 months for the TSH level to stabilise following dose adjustment.

The increase in TSH levels after 6 weeks treatment in the group assigned to morning intake first is unexpected and a cause for concern. (Since levothyroxine dosing is traditionally given in the morning, TSH levels would be expected to remain similar to baseline levels if the dose given was unchanged.)

Adverse effects

Evidence on long-term adverse effects

The risk of atrial fibrillation is related to reduced serum thyroid-stimulating hormone (TSH) and not to treatment with levothyroxine itself, although excessively high doses of levothyroxine may make people more vulnerable.

A suppressed TSH level (0.03 mU/L or less) is associated with an increased risk of osteoporotic fracture. However, a low TSH level (0.04 mU/L to 0.4 mU/L) is not associated with an increased risk of osteoporotic fracture.

Atrial fibrillation

The risk of atrial fibrillation is related to reduced serum thyroid-stimulating hormone (TSH) and not to treatment with levothyroxine itself, although excessively high doses of levothyroxine may make people more vulnerable.

CKS found no systematic reviews or randomized controlled trials that evaluated the relationship between serum TSH and atrial fibrillation.

A cohort study (2007 participants at least 60 years of age without atrial fibrillation) examined whether low serum TSH was associated with an increased risk of atrial fibrillation [Sawin et al, 1994]:

Methods

The study cohort was all the members of the original Framingham Heart Study who were 60 years of age or older at the time of the fifteenth follow-up visit in 1978–1980.

Serum TSH and electrocardiograms were performed at baseline. Atrial fibrillation could be diagnosed by electrocardiogram (ECG) at the intervening 2-year follow-up visits, or during any intervening hospitalizations.

Duration of follow up: 10 years.

Results

Low serum TSH (0.1 mU/L or less) was associated with an increased risk of atrial fibrillation (diagnosed by ECG).

Incidence of atrial fibrillation: 28 per 1000 person-years with low TSH compared with 11 per 1000 person-years with normal TSH (p = 0.005); event rate: 13/61 (21.3%) people with low TSH values compared with 133/1576 (8.4%) people with normal TSH; relative risk adjusted for other known risk factors 3.1, 95% CI 1.7 to 5.5.

Exclusion of people who received levothyroxine therapy (36/61 with a low TSH concentration and 46/1576 with a normal TSH concentration) did not affect the relative risk.

Authors' conclusions

Atrial fibrillation is related to reduced serum TSH. Subclinical hyperthyroidism can occur spontaneously or in association with levothyroxine therapy. Among people who are receiving levothyroxine therapy and have low serum TSH concentrations, the risk of atrial fibrillation can be lessened by avoiding excessively high doses.

A cross-sectional study (5860 participants 65 years of age or older) also examined whether low serum TSH was associated with an increased risk of atrial fibrillation [Gammage et al, 2007].

Methods

People with known thyroid dysfunction were excluded.

Participants were identified (method not described) and investigated in primary care with thyroid function tests and a resting ECG.

Logistic regression was used to analyse the data for associations.

Results

Atrial fibrillation was present in 4.7% (260/5519) of euthyroid people (normal serum TSH) and in 9.5% (12/126) people with subclinical hyperthyroidism (normal FT4 and FT3; serum TSH lower than 0.4 mU/L). The difference was statistically significant (p < 0.001).

Serum free T4 (FT4) concentration was significantly associated with atrial fibrillation. The association was independent of age and sex. The results were presented graphically and show that the higher the FT4 level, the greater the prevalence of atrial fibrillation, and that the higher the FT4 level, the greater the increase in prevalence of atrial fibrillation for a unit increase in serum FT4. Results of significance tests were not reported.

Bone mass

A suppressed TSH level (0.03 mU/L or less) is associated with an increased risk of osteoporotic fracture. However, a low TSH level (0.04 mU/L to 0.4 mU/L) is not associated with an increased risk of osteoporotic fracture.

A systematic review (search date: to 1992) identified 13 cross-sectional studies (441 premenopausal and 317 postmenopausal women with prolonged subclinical hypothyroidism) that assessed any change in bone mass with levothyroxine use [Faber and Galløe, 1994].

Description of included trials

Studies were included if they contained a control group.

Premenopausal women were taking an average of 164 micrograms of levothyroxine daily for an average of 8.5 years.

Postmenopausal women were taking an average of 171 micrograms of levothyroxine daily for an average of 9.9 years.

About half of the women studied had thyroid cancer.

Results

In premenopausal women treated with levothyroxine for an average of 8.5 years, no significant difference was found between levothyroxine and controls in bone mass (–2.67% change in bone mass, 95% CI –1.58% to –6.92%, p < 0.15).

In postmenopausal women treated with levothyroxine for an average of 9.9 years, a significant difference was found between levothyroxine and controls in bone mass (–9.02% change in bone mass, 95% CI –2.36% to –15.7%, p < 0.007).

Comments

Individual studies had small samples and different durations and doses of levothyroxine were used.

It is unclear whether the results translate into a clinically significant effect in terms of patient-orientated outcomes (such as osteoporosis and increased risk of fractures).

The women in the control group had some degree of annual loss of bone anyway.

It was not stated whether any women were taking hormone replacement therapy, and if so what effect this may have had on the data.

Trials measured the change in bone mass at the distal forearm, femoral neck, and lumbar spine, but it is questionable whether these are equivalent and whether the rate of change in one location differs to that in another.

The three individual areas of measurement did not differ significantly, but only when the data were pooled.

Some trials included people with thyroid cancer. Because these people often have calcitonin deficiency, confounding may have occurred.

Most of the subsequently published trials (January 1994 to October 2010) that investigated whether there was an association between levothyroxine use and low bone mass were methodologically flawed, with small numbers of participants, and use of surrogate outcome measures as a marker of potential osteoporosis. CKS identified only one trial with sufficient participant numbers that used osteoporotic fracture as an outcome measure, and this is discussed below:

A population-based cohort study (all people in Tayside, Scotland, taking levothyroxine; 17,684 participants) assessed the relationship between serum TSH concentrations and morbidity from cardiovascular disease and fractures [Flynn et al, 2010].

Methods

Data from the TEARS dataset (anonymized records linked from all dispensed prescriptions, the regional thyroid follow-up register, the radioactive iodine database, all biochemistry results performed in the region, and all hospital admission data for thyroid operations) were linked with ICD codes from clinical records and electronic death certificates.

The TEARS dataset covered the period from 1993 to 2001.

Participants' time-weighted TSH scores were assigned to one of four groups: suppressed (0.03 mU/L or less), low (0.04 mU/L to 0.4 mU/L), normal (0.4 mU/L to 4.0 mU/L), or high (> 4.0 mU/L).

Results

Median duration of follow up was 4.5 years; 85.9% of participants were women (mean 60.3 years of age) and 14.1% of participants were men (mean 61.8 years of age).

There were 2144 episodes of cardiovascular disease, 367 of dysrhythmias, and 562 osteoporotic fractures.

Of all people taking levothyroxine, 61.7% had a normal TSH, 11.2% had a high TSH, 6.1% had a suppressed TSH, and 21.1% had a low TSH.

For people with a high TSH, adjusted hazard ratios (HRs) were increased for cardiovascular disease (HR 1.95, 95% CI 1.73 to 2.21), dysrhythmias (HR 1.80, 95% CI 1.33 to 2.44), and osteoporotic fractures (HR 1.83, 95% CI 1.41 to 2.37) compared with people with normal TSH.

For people with suppressed TSH, adjusted HRs were also increased for cardiovascular disease (HR 1.37, 95% CI 1.17 to 1.60), dysrhythmias (HR 1.60, 95% CI 1.10 to 2.33), and osteoporotic fractures (HR 2.02, 95% CI 1.55 to 2.62) compared with people with normal TSH.

People with low TSH did not have an increased risk of cardiovascular disease (HR 1.1, 95% CI 0.99 to 1.12), dysrhythmias (HR 1.13, 95% CI 0.88 to 1.47), or osteoporotic fractures (HR 1.13, 95% CI 0.92 to 1.39).

Authors' conclusions

People with a high or suppressed TSH had an increased risk of cardiovascular disease, dysrhythmias, and fractures. People with a low but unsuppressed TSH did not. It may be safe for people treated with levothyroxine to have a low but not suppressed serum TSH concentration.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of Hypothyroidism, with additional searches for evidence in the following areas:

Association between treatment with levothyroxine and osteoporosis

Association between treatment with levothyroxine and atrial fibrillation

Relationship between hypothyroidism and cardiovascular disease

The search excluded children.

Search dates

January 2007 – September 2010

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Hypothyroidism/, hypothyroidism.tw.

exp Thyroxine/, levothyroxine.tw., L-thyroxine.tw.

exp Osteoporosis/, osteoporosis.tw., exp Bone Diseases, Metabolic/, osteopenia.tw., low bone-mineral density.tw.

exp Atrial Fibrillation/, atrial fibrillation.tw.

exp Cardiovascular Diseases/, cardiovascular disease.tw., exp Coronary Disease/, coronary heart disease.tw., ischaemic heart disease.tw., ischemic heart disease.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

NICE Evidence

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Royal Australian College of General Practitioners

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

BMJ Clinical Evidence

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

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