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Selenium supplementation for Hashimoto's thyroiditis

  1. Esther J van Zuuren1,*,
  2. Amira Y Albusta2,
  3. Zbys Fedorowicz3,
  4. Ben Carter4,
  5. Hanno Pijl5

Editorial Group: Cochrane Metabolic and Endocrine Disorders Group

Published Online: 6 JUN 2013

Assessed as up-to-date: 2 OCT 2012

DOI: 10.1002/14651858.CD010223.pub2


How to Cite

van Zuuren EJ, Albusta AY, Fedorowicz Z, Carter B, Pijl H. Selenium supplementation for Hashimoto's thyroiditis. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010223. DOI: 10.1002/14651858.CD010223.pub2.

Author Information

  1. 1

    Leiden University Medical Center, Department of Dermatology, Leiden, Netherlands

  2. 2

    AMA International University of Bahrain, College of Medicine, Manama, Bahrain

  3. 3

    The Cochrane Collaboration, UKCC (Bahrain Branch), Awali, Bahrain

  4. 4

    Cardiff University School of Medicine, Institute of Primary Care & Public Health, Cardiff, UK

  5. 5

    Leiden University Medical Centre, Department of Endocrinology, Leiden, Netherlands

*Esther J van Zuuren, Department of Dermatology, Leiden University Medical Center, PO Box 9600, B1-Q, Leiden, 2300 RC, Netherlands. E.J.van_Zuuren@lumc.nl.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 6 JUN 2013

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Characteristics of included studies [ordered by study ID]
Karanikas 2008

MethodsParallel randomised controlled clinical trial.

Randomisation ratio: 1:1.

Superiority design.


ParticipantsInclusion criteria:

  • LT4 substitution.
  • Positivity for anti-TPOAb.
  • Negativity for anti-thyrotropin (TSH) receptor antibodies.
  • Thyroid ultrasound imaging suggestive of chronic thyroiditis (typical hypoechogenicity).
  • Otherwise healthy participants.


Exclusion criteria:

  • Clinical history of hyperthyroidism.
  • Drugs known to induce thyroid dysfunction (cytokines, lithium, amiodarone).
  • Pregnancy in the last 12 months before enrolment.
  • No history of rheumatoid diseases.
  • No further treatment such as over-the-counter vitamins or trace elements or corticoid or anti-inflammatory therapy.


Diagnostic criteria:

  • Positivity for anti-TPOAb.
  • Thyroid ultrasound imaging suggestive of chronic thyroiditis (typical hypoechogenicity).


InterventionsNumber of study centres: 1,

Treatment before study: LT4 substitution.

Titration period: not reported.

Intervention: LT4 + 200 μg sodium selenite once a day during 3 months.
Control: LT4 + placebo once a day during 3 months.


OutcomesOutcomes reported in abstract of publication:

  • FT4, TSH, anti-TPOAb.
  • Plasma Se.
  • Intracellular cytokine evaluation in CD4+ and CD8+ T cells of peripheral blood mononuclear cells.


  • Subjective well-being of participants.


Study detailsRun-in period: not reported.

Study terminated before regular end: no.


Publication detailsLanguage of publication: English.

Commercial / non-commercial / other funding: not reported.

Publication status: full article.


Stated aim for studyQuote from publication (page 8): "The aim of our study was to evaluate the immunological benefit of Se administration in unselected AIT patients and thus address the question whether Se administration should generally be recommended for AIT patients".


NotesAbbreviations: AIT: auto-immune thyroiditis; CD4+/8+: cluster of differentiation 4/8; FT4: free thyroxine; LT4: levothyroxine; Se: selenium; TSH: thyroid-stimulating hormone; TPOAb: thyroid peroxidase antibodies.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuote (page 8): "Enrolled patients were randomized into two groups according to their initial TPOAb titer, age, and supposed duration of the disease"

Comment: randomisation seems to be based on prognostic factors, with no mention of stratified randomisation
After email contact: no further details; see Appendix 10

Allocation concealment (selection bias)Unclear riskComment: the method used to conceal the allocation sequence, that is, to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment, was not reported
Comment: information was insufficient to permit a clear judgement

Blinding of participants and personnel (performance bias)
Objective outcomes
Unclear riskQuote (page 9): "..blinded.."

Comment: the report did not provide sufficient detail about the specific measures used to blind study participants and personnel from knowledge of which intervention a participant received, to permit a clear judgement

Blinding of participants and personnel (performance bias)
Subjective outcomes
Unclear riskQuote (page 9): "..blinded.."

Comment: the report did not provide sufficient detail about the measures used to blind study participants and personnel from knowledge of which intervention a participant received, to permit a clear judgement

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote (page 9): "..blinded.."

Comment: the report did not provide sufficient detail about the measures used to blind study personnel from knowledge of which intervention a participant received; however, as all objective outcomes were based on blood tests, this is unlikely to have introduced bias into the outcome assessment; we judged this as having low risk of bias

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskQuote (page 9): "..blinded.."

Comment: the method used to blind the assessment of subjective outcomes by participants was not described; information was insufficient to permit a clear judgement

Incomplete outcome data (attrition bias)
Subjective outcomes
Low riskComment: intention-to-treat analysis

Comment: we judged this as having low risk of bias

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComment: as only means were reported, it was unclear whether all participants were entered into the analysis

Comment: information in the report was insufficient to permit a clear judgement

Selective reporting (reporting bias)Low riskThe protocol for the study was not available, but the prespecified outcomes and those mentioned in the methods section appear to have been reported

Comment: we judged this as having low risk of bias

Other biasLow riskComment: the study appears to be free from other sources of bias

Krysiak 2011

MethodsParallel randomised controlled clinical trial.

Randomisation ratio: 1:1:1:1.

Superiority design.


ParticipantsInclusion criteria:

  • Females between 18 and 60 years.
  • Positive anti-TPOAb > 100 U/mL.
  • Reduced echogenicity of the thyroid parenchyma on thyroid ultrasonography.
  • Euthyroid function (TSH < 4.0 mU/L, normal values for FT4 and FT3).
  • Medically stable.
  • In the judgement of the investigators, otherwise acceptable for entry on the basis of the findings of medical history, physical examination and routine laboratory tests.
  • Only individuals with newly diagnosed and previously untreated Hashimoto’s thyroiditis were included.


Exclusion criteria:

  • Any acute and chronic inflammatory processes.
  • Other auto-immune disorders.
  • Positive serum antibodies against TSH receptor.
  • Current treatment with thyroid hormones.
  • Concomitant treatment with drugs that may affect inflammatory processes in the vascular wall.
  • Concomitant treatment with other drugs known to affect thyroid hormones or to interact with levothyroxine and selenomethionine.
  • BMI > 40 kg/m2.
  • Turner or Down syndrome.
  • Any form of coronary artery disease.
  • Moderate or severe arterial hypertension (ESC/ESH grade 2 or 3).
  • Symptomatic congestive heart failure.
  • Diabetes, impaired glucose tolerance or impaired fasting glucose.
  • Impaired renal or hepatic function.
  • Pregnancy or lactation.
  • Poor patient compliance.


Diagnostic criteria:

  • Positive antibodies (> 100 U/mL) against thyroid peroxidase (TPOAb).
  • Reduced echogenicity of the thyroid parenchyma on thyroid ultrasonography.
  • Euthyroid function (TSH < 4.0 mU/L, normal values for FT4 and FT3).


InterventionsNumber of study centres: 1.

Treatment before study: no treatment.

Titration period: not reported.

Intervention 1: levothyroxine sodium 0.5 μg/kg once a day for participants with TSH levels below 1.0 mIU/mL, 0.75 μg/kg once a day for individuals with TSH levels between 1.0 and 2.0 mIU/mL, and 1 μg/kg for participants with a TSH above 2.0 mIU/mL during 6 months.

Intervention 2: selenomethionine once a day 200 μg during 6 months.

Intervention 3: combination of interventions 1 and 2 once daily during 6 months.

Control: placebo during 6 months.


OutcomesOutcomes reported in abstract of publication:
The primary endpoint was to evaluate monocyte- and lymphocyte-suppressing as well as systemic anti-inflammatory effects of levothyroxine, selenomethionine or their combination using a panel of inflammatory markers: tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, monocyte chemotactic protein (MCP)-1, IL-2, interferon-γ and high-sensitivity C-reactive protein (hsCRP).


Study detailsRun-in period: not reported.

Study terminated before regular end: no.


Publication detailsLanguage of publication: English.

Non-commercial funding: quote (page 2214): "This work was supported by the scientific Grant 2 P05F 03629 of the Committee of Scientific Research".

Publication status: full article.


Stated aim for studyQuote from publication: "Our objective was to compare the effect of levothyroxine and selenomethionine on monocyte and lymphocyte cytokine release and systemic inflammation in patients with Hashimoto’s thyroiditis".


NotesAbbreviations: BMI: body mass index; ESC/ESH: European Society of Cardiology/European Society of Hypertension; FT3: free triiodothyronine; FT4: free thyroxine; LT: levothyroxine; TPOAb: thyroid peroxidase antibodies; TSH: thyroid-stimulating hormone.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote (page 2207): "The included patients were randomised in a double-blind manner to receive…"

Comment: insufficient detail was reported about the method used to generate the allocation sequence to allow a clear assessment of whether it would produce comparable groups

After email contact: a computer random number generator was used

Comment: probably done

Allocation concealment (selection bias)Low riskComment: the method used to conceal the allocation sequence, that is, to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment, was not reported
Comment: information was insufficient to permit a clear judgement

After email contact: quote: ".. two other persons to help us with allocation procedure and drug distribution (based on the results of allocation). During all visits, both investigators were unaware of a record number and an identity card number, receiving patient documentation not containing these data."

Comment: reasonable attempts have been made to conceal the allocation; see Appendix 10

Blinding of participants and personnel (performance bias)
Objective outcomes
Unclear riskQuote (page 2207): "…in a double blind manner.."

Comment: the report did not provide sufficient detail about the specific measures used to blind study participants and personnel from knowledge of which intervention a participant received to permit a clear judgement

After email contact: quote: "The names of drugs had not been placed on the packages or on the drugs. However, levothyroxine, selenomethionine and placebo were stored on different shelves but the same for each drug. Although the participants were not informed about this, theoretically, they may see from which shelves they received their drugs"

Comment: risk of bias remains unclear; see Appendix 10

Blinding of participants and personnel (performance bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes were reported

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote (page 2207): "A person performing laboratory assays was unaware of patient’s personal data, clinical status, treatment group, and study sequence."

Comment: the report did not provide sufficient detail about the measures used to blind study personnel from knowledge of which intervention a participant received; however, as all the objective outcomes were based on blood tests, this is unlikely to have introduced bias into the outcome assessment; we judged this as having low risk of bias

After email contact: quote: "The person helping us to perform laboratory assays (a technician) worked in another building and received samples which had previously been coded to protect patient identity."

Comment: outcomes were investigator assessed; unlikely blinding could be broken; see Appendix 10

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskQuote (page 2208): "Only data of individuals who completed the study were included in the final analyses" and (page 2209) "Only the data of 165 subjects who completed the study were included in the final analyses"

Comment: reasons reported

Comment: although this was a per-protocol analysis, the low and balanced number of drop-outs was unlikely to introduce bias

Selective reporting (reporting bias)Low riskComment: the protocol for the study was not available, but the pre-specified outcomes and those mentioned in the methods section appear to have been reported

Comment: we judged this as having low risk of bias

Other biasLow riskComment: the study appears to be free from other sources of bias

Negro 2007

MethodsParallel randomised controlled clinical trial.

Randomisation ratio: 1:1.

Superiority design.


ParticipantsInclusion criteria:

  • Euthyroid, anti-TPOAb-positive pregnant women.


Exclusion criteria:

  • Thyroid dysfunction.
  • Treated with drugs that interfere with thyroid function.


Diagnostic criteria:

  • Anti-TPOAb titers of more than 100 kIU/L were considered positive.
  • Thyroid ultrasound.


InterventionsNumber of study centres: 2.

Treatment before study: no treatment.

Titration period: not reported.

Intervention: selenomethionine 200 μg once a day from 12 weeks' gestation until 12 months after delivery.

Control: placebo once a day from 12 weeks' gestation until 12 months after delivery.


OutcomesOutcomes reported in abstract of publication:

Prevalence of post-partum thyroid disease and hypothyroidism:

  • Se status.
  • Thyroid ultrasound.
  • TSH and FT4.
  • Anti-TPOAb.


Study detailsRun-in period: not reported.

Study terminated before regular end: no.


Publication detailsLanguage of publication: English.

Commercial / non-commercial / other funding: no.

Publication status: full article.


Stated aim for studyQuote from publication (page 1263): "We examined whether Se supplementation, during and after pregnancy, influences the thyroidal auto-immune pattern and function".


NotesAbbreviations: FT4: free thyroxine; Se: selenium; TSH: thyroid-stimulating hormone; TPOAb: thyroid peroxidase antibodies.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote (page 1264): "TPOAb(+) pregnant women with were randomly divided into two groups". "A computer program was used to randomly assign the TPOAb(+) patients to either group S1 or group S0"

Comment: this was probably done

Allocation concealment (selection bias)Low riskQuote (page 1264): "A sealed opaque envelope was assigned to each patient; only the doctor who treated the patient, and who did not participate in any subsequent phase of the study, knew to which group the patient was assigned"

Comment: the report provides sufficient detail and reassurance that participants and investigators enrolling participants could not foresee the upcoming assignment; this was probably done

Blinding of participants and personnel (performance bias)
Objective outcomes
Unclear riskComment: no report on any blinding

Comment: we judged this as having unclear risk of bias

Blinding of participants and personnel (performance bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes

Blinding of outcome assessment (detection bias)
Objective outcomes
High riskComment: no reporting on any blinding; outcome assessment was not blinded

Comment: although the objective outcomes were blood test results and thyroid ultrasound findings, a potentially high risk of bias cannot be excluded

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes

Incomplete outcome data (attrition bias)
Objective outcomes
Low riskComment: 8/85 in the S1 group and 10/84 in the S0 group dropped out; reasons stated; per-protocol analysis

Comment: although the analysis was per-protocol, the low number of well balanced drop-outs across both groups posed a low risk of bias

Selective reporting (reporting bias)Unclear riskComment: the protocol for the study was not available, but the pre-specified outcomes and those mentioned in the methods section appear to have been reported; however, the FT4 values were incompletely reported

Comment: the potential risk of bias was unclear

Other biasLow riskComment: the study appears to be free from other sources of bias

Turker 2006

MethodsParallel randomised controlled clinical trial.

Randomisation ratio: 1:1.

Superiority design.


ParticipantsInclusion criteria:

  • Females with known AIT and elevated serum anti-TPOAb (> 100 IU/mL) and/or anti-TgAb (> 188 IU/mL).


Exclusion criteria:

  • Using treatment with corticosteroids, vitamins, trace elements or antidepressive/antipsychotic drugs.


Diagnostic criteria:

Elevated serum anti-TPOAb (> 100 IU/mL) and/or anti-TgAb (> 188 IU/mL).


InterventionsNumber of study centres: 2.

Treatment before study: not reported.

Titration period: not reported.

Intervention: LT4 + 200 μg + L-selenomethionine once a day during 3 months.

Control: LT4 + placebo once a day during 3 months.


OutcomesOutcomes reported in abstract of publication:

  • Serum TSH.
  • FT3, FT4.
  • Anti-TPOAb and anti-TgAb levels.


Study detailsRun-in period: not reported.

Study terminated before regular end: no.


Publication detailsLanguage of publication: English.

Commercial / non-commercial / other funding: no.

Publication status: full article.


Stated aim for studyQuote from publication (page 152): "1: To test the effect of 200 mg L-selenomethionine/day therapy in a larger group to determine the parameters that may affect success rates. 2: To observe the dose–response curves by shifting doses (200–100 mg/day) after saturation of tissues with a high dose (200 mg/day) of Se for 3 months, which may exclude any doubt about the Se status of the tissue stores, instead of subjective measurements of the serum Se levels. 3: Finally, to follow the long-term effects of therapy".


NotesAfter 3 months, the Se group (S2) was split into 2 groups. Group S22 went on taking L-selenomethionine 200 μg/day, while others (group S21) lowered the dose to 100 μg/day. Then after another 3 months, 12 participants in group S22 (group S222) went on taking L-selenomethionine 200 μg/day, while 12 participants in group S21 (S212) increased the dose to 200 μg/day.

In the absence of a wash-out period, we considered only data from the first 3 months.

Abbreviations: AIT: auto-immune thyroiditis; FT3: free triiodothyronine; FT4: free thyroxine; LT4: levothyroxine; Se: selenium; TgAb: thyroglobulin antibodies; TSH: thyroid-stimulating hormone; TPOAb: thyroid peroxidase antibodies.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskQuote (page 152): "Patients were randomized into two groups according to their initial serum TPOAb and TSH concentrations and ages to exclude any difference in serum TPOAb and TSH levels or age."

Comment: randomisation seems to be based on prognostic factors, and no mention is made of stratified randomisation

Allocation concealment (selection bias)Unclear riskComment: the method used to conceal the allocation sequence, that is, to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment, was not reported
Comment: information was insufficient to permit a clear judgement

Blinding of participants and personnel (performance bias)
Objective outcomes
Unclear riskQuote (page 151): "We conducted a blinded, prospective study"

Comment: the report did not provide sufficient detail about the measures used to blind study personnel from knowledge of which intervention a participant received; we judged this as having unclear risk of bias

Blinding of participants and personnel (performance bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes

Blinding of outcome assessment (detection bias)
Objective outcomes
Low riskQuote (page 151): "We conducted a blinded, prospective study"

Comment: the report did not provide sufficient detail about the measures used to blind study personnel from knowledge of which intervention a participant received; however, all objective outcomes were based on blood tests, and this is unlikely to have introduced bias into the outcome assessment; therefore, we judged this as having low risk of bias

Blinding of outcome assessment (detection bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes

Incomplete outcome data (attrition bias)
Subjective outcomes
Unclear riskComment: not applicable; no subjective outcomes

Incomplete outcome data (attrition bias)
Objective outcomes
Unclear riskComment: as only means were reported, it was unclear whether all participants were entered into the analysis

Comment: information in the report was insufficient to permit a clear judgement

Selective reporting (reporting bias)Low riskComment: the protocol for the study was not available, but the pre-specified outcomes and those mentioned in the methods section appear to have been reported

Comment: we judged this as having low risk of bias

Other biasLow riskComment: this study appears to be free from other sources of bias

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Balázs 2008The full text reveals that this appeared to be a CCT.

Contempré 1992The full text reveals that this appeared to be a CCT.

Duntas 2003Email contact revealed that this appeared to be a quasi-randomised trial; see Appendix 10.

Gärtner 2002Email contact revealed that this appeared to be a quasi-randomised trial; see Appendix 10.

Gärtner 2003Email contact revealed that this appeared to be a quasi-randomised trial; see Appendix 10.

Nacamulli 2010Email contact revealed that this appeared to be a quasi-randomised trial; see Appendix 10.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Krysiak 2012

MethodsParallel randomised controlled clinical trial.

Randomisation ratio: 1:1:1:1.

Superiority design.

ParticipantsInclusion criteria:

  • Euthyroid women, aged between 18 and 65 years, with recently diagnosed and previously untreated Hashimoto’s thyroiditis.
  • Positive antibodies (> 100 U/mL) against thyroid peroxidase (anti-TPOAb).
  • Reduced echogenicity of the thyroid parenchyma on thyroid ultrasonography.
  • Serum TSH less than 4.0 mU/L.
  • Plasma levels of FT4 and FT3 within the reference range.


Exclusion criteria:

  • Any acute and chronic inflammatory processes.
  • Other auto-immune disorders.
  • Positive serum antibodies against TSH receptor.
  • Current treatment with thyroid hormones.
  • Concomitant treatment with drugs that may affect inflammatory processes in the vascular wall.
  • Concomitant treatment with other drugs known to affect thyroid hormones or to interact with levothyroxine and selenomethionine.
  • Body mass index (BMI) above 40 kg/m2.
  • Turner or Down syndrome.
  • Any form of coronary artery disease.
  • Moderate or severe arterial hypertension (ESC/ESH grade 2 or 3).
  • Symptomatic congestive heart failure.
  • Diabetes, impaired glucose tolerance or impaired fasting glucose.
  • Impaired renal or hepatic function.
  • Pregnancy or lactation.
  • Inadequate patient compliance.


Diagnostic criteria:

  • Anti-TPOAb > 100 U/mL.
  • Euthyroid function (TSH < 4.0 mU/L, normal values for FT4 and FT3.)
  • Reduced echogenicity of the thyroid parenchyma on thyroid ultrasonography.

InterventionsNumber of study centres: 1.

Treatment before study: no treatment.

Titration period: not reported.

Intervention 1: levothyroxine sodium 0.5 μg/kg once a day for participants with TSH levels below 1.0 mIU/mL, 0.75 μg/kg once a day for individuals with TSH levels between 1.0 and 2.0 mIU/mL and 1 μg/kg for participants with a TSH above 2.0 mIU/mL during 6 months.

Intervention 2: selenomethionine once a day 200 μg during 6 months.

Intervention 3: combination of interventions 1 and 2 once daily during 6 months.

Control: placebo during 6 months.

OutcomesOutcomes reported in abstract of publication:

The prothrombin time ratio, the activated partial thromboplastin time, and plasma levels/activities of fibrinogen, factor VII, von Willebrand factor, factor X and plasminogen activator inhibitor-1 (PAI-1).

Study detailsRun-in period: not reported.

Study terminated before regular end: no.

Publication detailsLanguage of publication: English.

Non-commercial funding: quote (page 980): "This work was supported by the scientific grant No. 2 P05F 036 29 of the Committee of Scientific Research".

Publication status: full article.

Stated aim of studyQuote from publication: "To investigate for the first time whether levothyroxine and selenomethionine, administered alone or in combination, affect coagulation and fibrinolysis in Hashimoto’s thyroiditis patients with normal thyroid function tests"

NotesAbbreviations: ESC/ESH: European Society of Cardiology/European Society of Hypertension; FT3: free triiodothyronine; FT4: free thyroxine; LT: levothyroxine; Se: selenium; TgAb: thyroglobulin antibodies; TPOAb: thyroid peroxidase antibodies; TSH: thyroid-stimulating hormone.

 
Characteristics of ongoing studies [ordered by study ID]
EudraCT2007-001107-38

Trial name or titleDescription of study: dose-finding study to investigate efficacy and tolerability of 6-month oral treatment with selenium in participants with auto-immune thyroiditis; prospective, controlled parallel-group study with Cefasel versus placebo; double-blind, randomised clinical multicentre study of phase II with four treatment groups.

MethodsAllocation: randomised.

Endpoint classification: dose-finding study.

Intervention model: active- and placebo-controlled, parallel-group.

Masking: double-blind.

Primary purpose: quote: "The main objective is to evaluate the optimal dose with the best efficacy of a 6-month oral treatment with 100 µg, 200 µg and 300 µg selenium daily compared with placebo concerning the auto-immune process and the function of the thyroid gland in patients with auto-immune thyroiditis".

ParticipantsCondition: auto-immune thyroiditis (Hashimoto's thyroiditis).

Enrollment: 200.

Inclusion criteria:

  • Mature ambulant patient at the age of 18 to 80 years.
  • Participants who have given their signed declaration of consent and data protection declaration.
  • Thyroid peroxidase (TPO) antibody titre at least tenfold above the normal range or at least fivefold above the normal range and positive finding on sonography (diffuse reduced echogenicity of the tissue).
  • Basal TSH < 4.5 mIU/L and FT4 within normal range.


Exclusion criteria:

  • Previous and concomitant therapy not permitted.
  • Basedow's disease.
  • Further manifestations of pluriglandular insufficiency syndrome with the exception of vitiligo.
  • Indication of thyroid functional autonomies.
  • Manifest hypothyroidism, defined by basal TSH above normal range for the respective method and FT4 below normal range.
  • Previous radioiodine therapy or operation on the thyroid.
  • Suspicion of a malignant tumour of the thyroid gland on sonography.
  • Indication of malassimilation.
  • Intolerance against any excipient of Cefasel 100 µg.
  • Females in the child-bearing years without appropriate contraception.
  • Pregnancy (present or planned) or lactation.
  • Present malignant disease (current or within the past 5 years without recurrence).
  • Severe somatopathic, neurological and/or psychiatric disease.
  • Patients who do not agree to the transmission of their pseudonymous data within the liability of documentation and notification.
  • Participation in another clinical trial (parallel or within the previous 6 months).
  • Participation in the same clinical trial.
  • History of alcohol and/or drug of abuse.
  • Patients who are unable to understand the nature, scope and possible impact of the study or considered to be non-compliant concerning drug intake or study activities.
  • Planned move or holidays during the course of the study so that not all study visits can be followed.
  • Insufficient knowledge of language (German-written and spoken).

InterventionsIntervention(s): 100 µg, 200 µg and 300 µg selenium daily.

Control(s): placebo.

OutcomesPrimary outcome:

Difference in concentrations of anti-TPO antibodies after 6-month therapy with selenium relative to baseline for treatment groups given 100 µg, 200 µg and 300 µg compared with placebo.

Secondary outcomes:

  • Concentrations of TSH, FT3 and FT4 evaluated analogously to the primary endpoint.
  • The ratio of participants developing during the course of the study with hypothyroidism requiring treatment (TSH > 10 mIU/L, FT4 in normal range or TSH above and FT4 below normal range).
  • Quality of life and sonographic results.

Starting dateStudy start date: 26-05-2008.

Study completion date: 18-04-2012.

Contact informationResponsible party/principal investigator: Cefak KG, Germany.

Study identifierEudraCT: 2007-001107-38.

Official titleDose-finding study to investigate efficacy and tolerability of 6-month oral treatment with selenium in participants with auto-immune thyroiditis: prospective, controlled parallel-group study with Cefasel versus placebo-double-blind, randomised, clinical multicentre study of phase II with four treatment groups.

Stated purpose of studyQuote: "The main objective is to evaluate the optimal dose with the best efficacy of a 6-month oral treatment with 100 µg, 200 µg and 300 µg selenium daily compared to placebo concerning the auto-immune process and the function of the thyroid gland in patients with auto-immune thyroiditis"

NotesWebsite accessed 5-11-2012.

Abbreviations: FT3: free triiodothyronine; FT4: free thyroxine; TSH: thyroid-stimulating hormone.

ISRCTN26633557

Trial name or titleDescription of study: selenium supplementation in euthyroid participants with thyroid peroxidase antibodies.

MethodsAllocation: randomised.

Endpoint classification: efficacy study.

Intervention model: placebo-controlled, parallel-group

Masking: double-blind.

Primary purpose: not reported.

ParticipantsCondition: euthyroid with thyroid peroxidase antibodies.

Enrollment: 150.

Inclusion criteria:

  • Thyroid peroxidase (TPO) antibodies greater than 100 kU/L.
  • Thyroid-stimulating hormone (TSH) 0.4 to 4.0 mE/L.
  • Free thyroxine (FT4) 10 to 23 pmol/L.
  • Triiodothyronine (T3) 1.30 to 2.70 nmol/L.
  • Female sex.


Exclusion criteria:

  • Use of multivitamin tablets containing selenium in the month preceding inclusion.
  • Drug or alcohol abuse.
  • No informed consent.

InterventionsIntervention(s): selenium supplementation.

Control(s): placebo.

OutcomesPrimary outcomes:

  • Change in anti-TPO antibody concentration.
  • Difference in TSH level.


Secondary outcomes:

  • Development of subclinical or overt hypothyroidism.
  • Quality-of-life estimation.

Starting dateStudy start date: 01-08-2005.

Study completion date: 31-07-2007.

Contact informationResponsible party/principal investigator:

Dr S.A. Eskes

Academic Medical Centre
Department of Endocrinology
P.O. Box 22660

1105 AZ Amsterdam, The Netherlands

s.eskes@sfg.nl

Study identifierISRCTN26633557.

Official titleSelenium supplementation in euthyroid patients with thyroid peroxidase antibodies.

Stated purpose of studyNot reported.

NotesWebsite accessed 5-11-2012

NCT01465867

Trial name or titleDescription of study: selenium supplementation in pregnancy (Serena).

MethodsAllocation: randomised.

Endpoint classification: interventional study.

Intervention model: parallel.

Masking: double-blind.

Primary purpose: prevention.

ParticipantsCondition: euthyroid women with auto-immune thyroiditis.

Enrollment: 150.

Inclusion criteria:

  • Pregnant women with 4 to 8 ± 2 weeks of gestation.
  • Women in whom embryo transfer is expected within 60 days.
  • Euthyroid women (0.4 μIU/mL < TSH < 2.7 μIU/mL), positive for anti-TPOAb and/or anti-TgAb, not assuming LT4 replacement.
  • Euthyroid women (0.4 μIU/mL < TSH < 2.7 μIU/mL), positive for anti-TPOAb and/or anti-TgAb under LT4 replacement (to maintain TSH within the control range).
  • Women with TSH > 2.7 μIU/mL positive for anti-TPOAb and/or anti-TgAb, not assuming LT4 replacement (requiring the beginning of LT4 replacement).
  • Women with TSH > 2.7 μIU/mL positive for anti-TPOAb and/or anti-TgAb, under LT4 replacement (requiring an adjustment in LT4 replacement).


Exclusion criteria:

  • Use of antidepressive/psychotic drugs, amiodarone, propranolol, lithium, cytokines.
  • History of hyperthyroidism positive anti-thyrotropin antibodies.
  • Known fetal anomaly.
  • Known infection (pelvic inflammatory disease, human immunodeficiency virus, hepatitis C virus) and mola hydatidosas.
  • Chronic renal failure.
  • Uncontrolled hypertension.
  • Uterine malformation.
  • History of medical or metabolic complication such as heart disease or diabetes.

InterventionsIntervention(s):

  • Selenium.
  • Selenium + L-Thyroxine (LT4).


Control(s):

  • Sugar pill placebo.
  • Sugar pill placebo + L-Thyroxine (LT4).

OutcomesPrimary outcomes:

  • Changes in anti-TPOAb and/or anti-TgAb.


Secondary outcomes:

  • Changes in thyroid volume and echogenicity.
  • Changes in thyroid hormones (TSH, FT4, FT3).
  • Evaluation of maternal risks.
  • Pre-eclampsia.
  • Evaluation of Infant risks.
  • Changes in of quality of life.
  • Evaluation of health services.
  • Changes in the selenium-dependent anti-oxidant enzyme glutathione peroxidase.
  • Changes in implantation and pregnancy rates.

Starting dateStudy start date: not yet recruiting.

Study completion date: February 2015.

Contact informationResponsible party/principal investigator:

Andrea M. Isidori, University of Roma La Sapienza

Department of Experimental Medicine, Section of Clinical Pathophysiology and Endocrinology, "Sapienza" University of Rome

andrea.isidori@uniroma1.it

Study identifierNCT NUMBER: NCT01465867.

Official titleSelenium supplementation treatment in euthyroid pregnant women with auto-immune thyroid disease: effects on obstetrical complications.

Stated purpose of studyQuote: "to establish the effect of Se supplementation in euthyroid women with AIT (pregnant and in whom embryo transfer is expected within 60 days) on Ab trend, thyroid function and structure, implantation rates, pregnancy rates, pregnancy outcome and numbers of obstetrical, fetal and neonatal complications".

NotesAbbreviations: FT3: free triiodothyronine; FT4: free thyroxine; HCV: hepatitis C virus; HIV: human immunodeficiency virus; LT4: levothyroxine; PID: pelvic inflammatory disease; TgAb: thyroglobulin antibodies; TSH: thyroid-stimulating hormone; TPOAb: thyroid peroxidase antibodies.

 
Comparison 1. Selenomethionine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Anti-TPO antibody levels2Mean Difference (IV, Random, 95% CI)Subtotals only

    1.1 1700 IU/mL levels at baseline
185Mean Difference (IV, Random, 95% CI)-917.0 [-1029.16, -804.84]

    1.2 600 IU/mL at baseline
1169Mean Difference (IV, Random, 95% CI)-345.0 [-358.79, -331.21]

 
Summary of findings for the main comparison. Selenium (+LT4) compared to placebo (+LT4) for participants with Hashimoto's thyroiditis

Selenium (+LT4) compared with placebo (+LT4) for participants with Hashimoto's thyroiditis

Patient or population: participants with Hashimoto's thyroiditis.
Settings: hospital outpatient department.
Intervention: selenium (+ levothyroxine)a.
Comparison: placebo (+ levothyroxine).

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Placebo (+ levothyroxine)Selenium
(+ levothyroxine)

Change from baseline in health-related quality of lifeSee commentSee commentNot estimableSee commentSee commentNot reported in any study

Change from baseline in assessment of symptoms such as mood, fatigue and muscle weakness
Short-Form Health Survey
Follow-up: mean 3 months
167 per 1000778 per 1000
(268 to 1000)
RR 4.67
(1.61 to 13.5)
36
(1 study)
⊕⊕⊕⊝
lowb,c,d

Proportion of participants reporting an adverse event
Follow-up: mean 5 months
RR 2.71
(0.29 to 25.66)
258
(3 studiese)
⊕⊕⊝⊝
lowb
Participants in placebo group counted twice (same participants in both comparisons)

Change from baseline in serum levels of anti-thyroid peroxidase antibodies
Decrease from 1508 to 25 IU/L
Follow-up: mean 4.5 months
See commentSee commentNot estimable252
(4 studiese)
⊕⊕⊝⊝
lowb
Data could not be pooled because of substantial clinical heterogeneity of participants, interventions and controls

Change from baseline in LT4 replacement dosage at end of studySee commentSee commentNot estimableSee commentSee commentNot reported in any study

Economic costsSee commentSee commentNot estimableSee commentSee commentNot reported in any study

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio.

GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: 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.
Very low quality: We are very uncertain about the estimate.

 aKaranikas 2008 and Turker 2006 included levothyroxine in both treatment arms. Krysiak 2011 included levothyroxine in one arm combined with selenium.
bRandomisation was probably based on prognostic factors, and no mention was made of stratified randomisation.
cWide confidence interval.
dRR 4.67.
eOne study provided two comparisons.
 
Table 1. Glossary of terms

TermExplanation

Auto-antigenUsually a normal protein or complex of proteins (sometimes deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)) that is recognised by the immune system of patients suffering from a specific auto-immune disease.

AntibodyProduced by immune cells, B cells, to identify and neutralise foreign objects such as bacteria and viruses. The antibody recognises a unique part of the foreign target, called an antigen; this might also be an auto-antigen.

AtherosclerosisA condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol.

BiosynthesisAn enzyme-catalysed process in cells of living organisms by which substrates are converted to more complex products.

CytokinesSmall protein molecules, secreted by several types of cells to stimulate other cells.

CD4+ T-helper cellsA subgroup of T-cell lymphocytes, a type of white blood cell that plays an important role in the immune system, particularly the adaptive immune system.

CD8+ cytotoxic T cellsA subgroup of T-cell lymphocytes that induce the death of cells infected with viruses (and other pathogens) or otherwise damaged or dysfunctional.

DyslipidaemiaHigh cholesterol or fat levels in the blood.

GoitreA swelling in the thyroid gland.

GPx4Phospholipid hydroperoxide glutathione peroxidase, a selenoprotein enzyme.

GPxGlutathione peroxidase, a selenoprotein enzyme that has an antioxidant function.

HomeostasisA state of balanced levels of the molecule in the human body.

HyperglycaemiaHigh glucose levels in the blood.

IFN-γInterferon-gamma; a cytokine or type II interferon that is critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumour control. Aberrant IFN-γ expression is associated with a number of auto-inflammatory and auto-immune diseases.

LDLLow-density lipoproteins or 'bad' cholesterol.

MacrophageA type of immune cell that differentiates from monocytes in tissue and phagocytises (engulfs) foreign materials.

PancreatitisInflammation of the pancreas.

Rheumatoid arthritisA chronic, systemic inflammatory disorder that may affect many tissues and organs but principally attacks flexible (synovial) joints.

SelenoproteinSelenium incorporated into proteins.

StrokeA condition of impaired blood supply to the brain resulting in rapid loss of brain function(s).

ThyrocyteThyroid gland epithelial cells.

VitiligoAn auto-immune disorder that affects the skin, causing loss of pigment.

 
Table 2. Overview of study populations

CharacteristicIntervention(s) and comparator(s)[N] Screened/eligible[N] Randomised[N] Safety[N] ITT[N] Finishing study[%] Randomised finishing studyFollow-upa

Karanikas 2008I: LT4 + 200 μg sodium selenite3618----3 months

C: LT4 + placebo18----3 months

total:36----3 months

Krysiak 2011I1: Levothyroxine sodium-42-N/A41986 months

I2: Selenomethionine 200 μg43-N/A42986 months

I3: Levothyroxine sodium
+ selenomethionine 200 μg
43-N/A42986 months

C1: Placebo42-N/A40956 months

total:170165N/A165976 months

Negro 2007I: 200 μg selenomethionine222785--7791from 12 weeks' gestation to12 months' post partum

C: Placebo84--7488

total:169--15189

Turker 2006I: LT4 + 200 μg + L-selenomethionine-48----3 months

C: LT4 + placebo40----3 months

total:88----3 months

Total All interventions 279-

All controls 184-

All interventions and controls 463-

 aDuration of intervention and/or follow-up under randomised conditions until end of study.
- = not reported.
ITT: intention-to-treat; N/A: not applicable.
 
Table 3. Research recommendations based on a gap in the evidence of the effects of selenium for Hashimoto's thyroiditis

Core elementsIssues to considerStatus of research for this review

Evidence (E)What is the current state of the evidence?This systematic review identified one randomised controlled trial (RCT). Incomplete evidence of efficacy and safety of selenium for Hashimoto's thyroiditis.

Population (P)Diagnosis, disease stage, co-morbidity, risk factors, gender, age, ethnic group, specific inclusion or exclusion criteria, clinical settingInclusion criteria:

  • Hashimoto's thyroiditis as diagnosed by a physician and supported by serum levels of anti-TPOAb and anti-TgAb above the normal level of the laboratory's normal ranges.


Exclusion criteria:

  • Clinical history of hyperthyroidism.
  • Any acute and chronic inflammatory processes.
  • Drugs known to induce thyroid dysfunction (cytokines, lithium, amiodarone).
  • Concomitant treatment with drugs that may affect inflammatory processes in the vascular wall.
  • Pregnancy in the last 12 month before enrolment.
  • No further treatment such as over-the-counter vitamins or trace elements or corticoid or anti-inflammatory therapy.

Intervention (I)Type, frequency, dose, duration, prognostic factorSelenium 100 µg or 200 µg supplementation (sodium selenite or selenomethionine) plus titrated LT4 to maintain basal TSH within normal range for at least 3 months.

Comparison (C)Type, frequency, dose, duration, prognostic factor
  • No control plus titrated LT4 to maintain basal TSH within normal range for at least 3 months.


  • Placebo tablets plus titrated LT4 to maintain basal TSH within normal range for at least 3 months.

Outcome (O)Which clinical or patient-related outcomes will the researcher need to measure, improve, influence or accomplish? Which methods of measurement should be used?Primary outcomes  

  • Change from baseline in HRQoL assessed using any validated quality-of-life instrument at end of study.
  • Change from baseline in symptoms such as mood, fatigue and muscle weakness assessed using any validated instrument at end of study.
  • Proportions of participants reporting an adverse event throughout the study period.


Secondary outcomes  

  • Change from baseline in serum levels of anti-thyroid peroxidase antibodies at end of study.
  • Change from baseline in LT4 replacement dosage at end of study.
  • Economic costs.

Time Stamp (T)Date of literature search or recommendation1 November 2012

Study TypeWhat is the most appropriate study design to address the proposed question?
  • RCT (adequately powered/multi-centred).
  • Methods: concealment of allocation sequence.
  • Blinding: blinding of participants, trialists and outcomes assessors.
  • Setting: hospital/university.