Abstract
Introduction
Hypothyroidism is six times more common in women, affecting up to 40 in 10,000 each year (compared with 6/10,000 men).
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for clinical (overt) hypothyroidism? What are the effects of treatments for subclinical hypothyroidism? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found nine studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: levothyroxine, and levothyroxine plus liothyronine.
Key Points
Primary hypothyroidism is defined as low levels of blood thyroid hormone due to destruction of the thyroid gland. This destruction is usually caused by autoimmunity or an intervention such as surgery, radioiodine, or radiation.
It can be classified as clinical (overt) when diagnosed by characteristic clinical features, raised levels of thyroid stimulating hormone (TSH), and reduced levels of T4; or subclinical when serum TSH is raised, but serum T4 is normal, and there are no symptoms of thyroid dysfunction.
Hypothyroidism is 6 times more common in women, affecting up to 40 in 10,000 each year (compared with 6/10,000 men).
There is consensus that levothyroxine is effective in treating clinical (overt) hypothyroidism, but evidence is sparse.
Treatment can lead to hyperthyroidism, reduction of bone mass in postmenopausal women, and increased risk of atrial fibrillation if the person is over-treated.
We found no evidence from RCTs that levothyroxine plus liothyronine improves symptoms more than levothyroxine alone.
We don't know how effective levothyroxine is in treating people with subclinical hypothyroidism, as trials have been too small to detect any clinically relevant improvements in outcomes.
Clinical context
About this condition
Definition
Hypothyroidism is characterised by low levels of blood thyroid hormone. Clinical (overt) hypothyroidism is diagnosed on the basis of characteristic clinical features (e.g., mental slowing, depression, dementia, weight gain, constipation, dry skin, hair loss, cold intolerance, hoarse voice, irregular menstruation, infertility, muscle stiffness and pain, bradycardia, hypercholesterolaemia) and a serum TSH above and T4 (and or T3) below the reference range. A number of guidelines quote serum TSH as 5–10 mU/l as mild, and >10 mU/I as severe hypothyroidism. Subclinical hypothyroidism is a biochemical diagnosis with findings of a serum TSH above the reference range and serum T4 (and/or T3) within the reference range. Primary hypothyroidism occurs after destruction of the thyroid gland because of autoimmunity (the most common cause), or medical intervention such as surgery, radioiodine, and radiation. Secondary hypothyroidism occurs after pituitary or hypothalamic damage, and is caused by insufficient production caused by pituitary or hypothalamic hypofunction. Secondary hypothyroidism is not covered in this review. Euthyroid sick syndrome is diagnosed when tri-iodothyronine (T3) levels are low, serum T4 is low, and TSH levels are normal or low. Euthyroid sick syndrome is not covered in this review.
Incidence/ Prevalence
Hypothyroidism is more common in women than in men (in the UK, female:male ratio of 6:1). One study (2779 people in the UK with a median age of 58 years) found that the incidence of clinical (overt) hypothyroidism was 40 in 10,000 women a year and 6 in 10,000 men a year. The prevalence was 9.3% in women and 1.3% in men.[1] In areas with high iodine intake, the incidence of hypothyroidism can be higher than in areas with normal or low iodine intake. In Denmark, where there is moderate iodine insufficiency, the overall incidence of hypothyroidism is 1.4 in 10,000 a year, increasing to 8 in 10,000 a year in people over 70 years.[2] The incidence of subclinical hypothyroidism increases with age. Up to 10% of women over the age of 60 years have subclinical hypothyroidism (evaluated from data from the Netherlands and US).[3] [4]
Aetiology/ Risk factors
Primary thyroid gland failure can occur as a result of chronic autoimmune thyroiditis, radioactive iodine treatment, or thyroidectomy. Other causes include drug adverse effects (e.g., amiodarone and lithium), transient hypothyroidism due to silent thyroiditis, subacute thyroiditis, or postnatal thyroiditis.
Prognosis
In people with subclinical hypothyroidism, the risk of developing clinical (overt) hypothyroidism is described in the UK Whickham survey (25 years' follow-up; for women: OR 8, 95% CI 3 to 20; for men: OR 44, 95% CI 19 to 104; if both a raised TSH and positive antithyroid antibodies were present; for women: OR 38, 95% CI 22 to 65; for men: OR 173, 95% CI 81 to 370). For women, the survey found an annual risk of 4.3% a year (if both raised serum TSH and antithyroid antibodies were present) and 2.6% a year (if raised serum TSH was present alone); the minimum number of people with raised TSH and antithyroid antibodies who would need treating to prevent this progression to clinical (overt) hypothyroidism in one person over 5 years is 5 to 8.[1] Cardiovascular disease: A large cross-sectional study (25,862 people with serum TSH between 5.1–10.0 mU/L) found significantly higher mean total cholesterol concentrations in people who were hypothyroid compared with people who were euthyroid (5.8 mmol/L v 5.6 mmol/L).[3] Another study (124 elderly women with subclinical hypothyroidism, 931 women who were euthyroid) found a significantly increased risk of MI in women with subclinical hypothyroidism (OR 2.3, 95% CI 1.3 to 4.0) and of aortic atherosclerosis (OR 1.7, 95% CI 1.1 to 2.6).[4] Mental health: Subclinical hypothyroidism is associated with depression.[5] People with subclinical hypothyroidism may have depression that is refractory to both antidepressant drugs and thyroid hormone alone. Memory impairment, hysteria, anxiety, somatic complaints, and depressive features without depression have been described in people with subclinical hypothyroidism.[6]
Aims of intervention
To eliminate the symptoms of hypothyroidism and maximise quality of life.
Outcomes
Symptom severity; quality of life; cognitive function (evaluated by cognitive function tests, memory tests, reaction time, self-rating mood scales, and depression scores); cardiac function (evaluated by electrocardiogram, ejection fraction measured by echocardiography); changes in body composition (measured by osteodensitometry or bioimpedance measurements); prevention of progression from subclinical to overt hypothyroidism; and adverse effects of treatments (bone mass, fracture rate, CVD [episodes of atrial fibrillation and ischaemic events]; development of hyperthyroidism).
Methods
Clinical Evidence search and appraisal July 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to July 2013, Embase 1980 to July 2013, and The Cochrane Database of Systematic Reviews 2013, issue 7 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) Database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews of RCTs in the English language, at least single-blinded, and containing at least 20 individuals (at least 10 per arm) of whom at least 80% were followed up for a minimum of 6 weeks from randomisation. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table.
GRADE Evaluation of interventions for Hypothyroidism (primary).
| Important outcomes | Cardiac function, Changes in body composition, Cognitive function, Prevention of progression from subclinical to overt hypothyroidism, Quality of life, Symptom severity | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments for clinical (overt) hypothyroidism? | |||||||||
| at least 6 (at least 465) | Symptom severity | Levothyroxine (L-thyroxine) plus liothyronine versus levothyroxine alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for multiple/different regimens used |
| 8 (538) | Quality of life | Levothyroxine (L-thyroxine) plus liothyronine versus levothyroxine alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for multiple/different regimens used |
| 12 (at least 705) | Cognitive function | Levothyroxine (L-thyroxine) plus liothyronine versus levothyroxine alone | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for multiple/different regimens used |
| 2 (95) | Changes in body composition | Levothyroxine (L-thyroxine) plus liothyronine versus levothyroxine alone | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| What are the effects of treatments for subclinical hypothyroidism? | |||||||||
| at least 4 (at least 164) | Symptom severity | Levothyroxine replacement versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and unclear outcome measures |
| 5 (315) | Cognitive function | Levothyroxine replacement versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for incomplete reporting and unclear outcome measures |
| 2 (65) | Quality of life | Levothyroxine replacement versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality point deducted for sparse data and incomplete reporting of results |
| 1 (unclear, but <95) | Prevention of progression from subclinical to overt hypothyroidism | Levothyroxine replacement versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- T3
is used as an abbreviation for endogenous tri-iodothyronine in medical and biochemical reports.
- T4
is used as an abbreviation for endogenous thyroxine in medical and biochemical reports.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
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