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Cited by 2,938Thyroid Disorders and TreatmentsOphthalmology and Eye DisordersThyroid and Parathyroid Surgery

2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis

Open access
Ross, Douglas S., Burch, Henry B., Cooper, David S., Greenlee, M. Carol, Laurberg, Peter, Maia, Ana Luiza, Rivkees, Scott A., Samuels, Mary +3 more·2016·Thyroid®
DOI 10.1089/thy.2016.0229
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Abstract

Background: Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. Methods: The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Results: Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. Conclusions: One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

AI snapshot

Written from a shortened version of the paper’s full text (it is longer than we read).

TL;DR

This 2016 ATA guideline updates the 2011 thyrotoxicosis recommendations and provides 124 evidence-based recommendations for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. It covers Graves’ disease, toxic nodular disease, pediatric and pregnancy populations, subclinical hyperthyroidism, Graves’ orbitopathy, and miscellaneous causes using GRADE-rated evidence.

Key findings

  • The guideline developed 124 evidence-based recommendations; in the United States, hyperthyroidism prevalence is approximately 1.2% (0.5% overt and 0.7% subclinical), with Graves’ disease the most common cause.
  • For Graves’ hyperthyroidism, RAI, antithyroid drugs (ATDs), or thyroidectomy are all recommended options; RAI success in rendering patients hypothyroid depends on activity: 61% with 5.4 mCi, 69% with 8.2 mCi, 74% with 10 mCi, 81% with 15 mCi, and 86% with 15.7 mCi.
  • ATD adverse effects were reported in 13% of 667 GD patients across eight studies; minor allergic pruritus/rash occurred in 6% with MMI and 3% with PTU, while hepatocellular injury occurred in 2.7% with PTU and 0.4% with MMI. Agranulocytosis had an estimated cumulative incidence of 0.3% in 100 days among over 50,000 GD patients.
  • For toxic multinodular goiter (TMNG), retreatment risk is <1% after near-total/total thyroidectomy versus 20% after RAI, but hypothyroidism is 100% after near-total/total thyroidectomy; for toxic adenoma (TA), RAI carries a 6%–18% risk of persistent hyperthyroidism and 3%–5.5% risk of recurrence.

Methods

  • The ATA assembled an 11-member expert task force that reviewed the 2011 guidelines, performed a systematic PubMed search for primary references and reviews published after the 2011 guidelines, supplemented by focused PubMed searches, and developed recommendations based on literature and expert opinion where appropriate.
  • Recommendations were rated using the GRADE system for strength (strong or weak) and quality of evidence (high, moderate, low, or insufficient); when evidence was insufficient, the task force made a “no recommendation” statement.
  • Deliberations occurred between 2014 and 2016; consensus was used, with voting if agreement could not be reached. Topics included initial evaluation, Graves’ disease management with RAI/ATDs/surgery, TMNG/TA, pediatric and adolescent GD, pregnancy, subclinical hyperthyroidism, Graves’ orbitopathy, and other causes.

Limitations

  • Stated: the guidelines are not intended to replace clinical judgment, individual decision making, or the wishes of the patient or family; each recommendation should be evaluated in light of these elements.
  • Stated: in several instances the evidence was insufficient to recommend for or against a test or treatment, and the task force made a “no recommendation” statement; recommendations were based on literature and expert opinion where appropriate.
  • Evident from the text: this is a guideline synthesis rather than a primary study, many recommendations are weak or supported by low-quality evidence, and the evidence base is heterogeneous, with some recommendations relying on consensus or expert opinion.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1089/thy.2016.0229

Cites

659 of 659 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 952 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The importance of age as a determinant of the prevalence and severity of hyperthyroid symptoms has recently been confirmed.

    “The importance of age as a determinant of the prevalence and severity of hyperthyroid symptoms has recently been confirmed (30).”
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    Spurious free T4 elevations may occur from heterophilic antibodies or in the setting of heparin therapy, due to in vitro activation of lipoprotein lipase and release of free fatty acids that displace T4 from its binding proteins.

    “Spurious free T 4 elevations may occur from heterophilic antibodies or in the setting of heparin therapy, due to in vitro activation of lipoprotein lipase and release of free fatty acids that displace T 4 from its binding proteins.”
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  • Premisecitation

    A pituitary lesion on magnetic resonance imaging and a disproportionately high ratio of the serum level of the a-subunit of the pituitary glycoprotein hormones to TSH supports the diagnosis of a TSH-producing pituitary adenoma.

    “A pituitary lesion on magnetic resonance imaging (MRI) and a disproportionately high ratio of the serum level of the a-subunit of the pituitary glycoprotein hormones to TSH supports the diagnosis of a TSH-producing pituitary adenoma (43).”
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    Heterophilic antibodies can also cause spurious high TSH values.

    “Heterophilic antibodies can also cause spurious high TSH values, and this should be ruled out by repeating the TSH in another assay, measurement of TSH in serial dilution, or direct measurement of human anti-mouse antibodies.”
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  • Premisecitation

    Graves' disease is the most common cause of hyperthyroidism in the United States.

    “GD is the most common cause of hyperthyroidism in the United States (11,12).”
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    Premisereasoning

    The relationship between free T4 and TSH when the pituitary-thyroid axis is intact is an inverse log-linear relationship; therefore, small changes in free T4 result in large changes in serum TSH concentrations.

    “The relationship between free T 4 and TSH when the pituitary-thyroid axis is intact is an inverse log-linear relationship; therefore, small changes in free T 4 result in large changes in serum TSH concentrations.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Symptoms and signs that result from increased adrenergic stimulation include tachycardia and anxiety and may be more pronounced in younger patients and those with larger goiters.

    “Symptoms and signs that result from increased adrenergic stimulation include tachycardia and anxiety and may be more pronounced in younger patients and those with larger goiters (28).”
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    Premisenone given

    The RAIU may be low after exposure to iodinated contrast in the preceding 1-2 months or with ingestion of a diet unusually rich in iodine such as seaweed soup or kelp.

    “The RAIU may be low after exposure to iodinated contrast in the preceding 1-2 months or with ingestion of a diet unusually rich in iodine such as seaweed soup or kelp.”
    Quote in the paperSubstantial claim

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    Assays for estimating free T3 are less widely validated and less robust than those for free T4.

    “Assays for estimating free T 3 are less widely validated and less robust than those for free T 4 .”
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    Premisecitation

    Toxic nodular goiter is less common than Graves' disease, but its prevalence increases with age and in the presence of dietary iodine deficiency.

    “Although toxic nodular goiter is less common than GD, its prevalence increases with age and in the presence of dietary iodine deficiency.”
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    In mild hyperthyroidism, serum T4 and free T4 can be normal, only serum T3 may be elevated, and serum TSH will be low or undetectable.

    “In mild hyperthyroidism, serum T 4 and free T 4 can be normal, only serum T 3 may be elevated, and serum TSH will be low or undetectable.”
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    Interpretationreasoning

    These laboratory findings have been called T3-toxicosis and may represent the earliest stages of hyperthyroidism caused by Graves' disease or an autonomously functioning thyroid nodule.

    “These laboratory findings have been called ''T 3 -toxicosis'' and may represent the earliest stages of hyperthyroidism caused by GD or an autonomously functioning thyroid nodule.”
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    Premisecitation

    Subacute thyroiditis is thought to be caused by viral infection and is characterized by fever and thyroid pain.

    “Subacute thyroiditis is thought to be caused by viral infection and is characterized by fever and thyroid pain (24).”
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    Painless thyroiditis caused by lymphocytic inflammation occurs with different frequency depending on the population studied: 0.5% in Denmark, 6% in Toronto, and 22% in Wisconsin.

    “in Denmark it accounted for only 0.5% of thyrotoxic patients, but it was 6% of patients in Toronto and 22% of patients in Wisconsin (16)(17)(18).”
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    In a study using a model of a theoretical population of 100,000 enrollees in a managed care organization in the United States, the use of TRAb measurements to diagnose Graves' disease compared to RAIU measurements reduced costs by 47% and resulted in a 46% quicker diagnosis.

    “In a study using a model of a theoretical population of 100,000 enrollees in a managed care organization in the United States, the use of TRAb measurements to diagnose GD compared to RAIU measurements reduced costs by 47% and resulted in a 46% quicker diagnosis (45).”
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    • Rests on an assumption: The model of a theoretical population of 100,000 enrollees in a managed care organization in the United States is representative of clinical practice for diagnosing Graves' disease.

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    Premisecitation

    Other causes of euthyroid hyperthyroxinemia include drugs that inhibit T4 to T3 conversion, such as amiodarone or high-dose propranolol, acute psychosis, extreme high altitude, and amphetamine abuse.

    “Other causes of euthyroid hyperthyroxinemia include drugs that inhibit T 4 to T 3 conversion, such as amiodarone (23) or high-dose propranolol (31), acute psychosis (38), extreme high altitude (39), and amphetamine abuse (40).”
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    Premisecitation

    The most common causes of hyperthyroidism in the United States include Graves' disease, toxic multinodular goiter, and toxic adenoma.

    “the most common causes include Graves' disease (GD), toxic multinodular goiter (TMNG), and toxic adenoma (TA) (1).”
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    Interpretationnone given

    In a patient with a symmetrically enlarged thyroid, recent onset of orbitopathy, and moderate to severe hyperthyroidism, the diagnosis of Graves' disease is likely and further evaluation of hyperthyroidism causation is unnecessary.

    “In a patient with a symmetrically enlarged thyroid, recent onset of orbitopathy, and moderate to severe hyperthyroidism, the diagnosis of GD is likely and further evaluation of hyperthyroidism causation is unnecessary.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In one small study of 25 patients with Graves' disease, the Hyperthyroid Symptom Scale did not strongly correlate with free T4 or T3 and was inversely correlated with age.

    “in one small study of 25 patients with GD, the Hyperthyroid Symptom Scale did not strongly correlate with free T 4 or T 3 and was inversely correlated with age (28).”
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    Premisenone given

    TBG excess may occur as a hereditary X-linked trait, or it may be acquired as a result of pregnancy or estrogen administration, hepatitis, acute intermittent porphyuria or during treatment with 5-fluorouracil, perphenazine, or some narcotics.

    “TBG excess may occur as a hereditary X-linked trait, or it may be acquired as a result of pregnancy or estrogen administration, hepatitis, acute intermittent porphyuria or during treatment with 5-fluorouracil, perphenazine, or some narcotics.”
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    Premisecitation

    Euthyroid hyperthyroxinemia includes elevations in T4 binding globulin or transthyretin, abnormal albumin, abnormal transthyretin, and rarely immunoglobulins that directly bind T4 or T3.

    “These conditions include elevations in T 4 binding globulin (TBG) or transthyretin (37); the presence of an abnormal albumin which binds T 4 with high capacity (familial dysalbuminemic hyperthyroxinemia); a similarly abnormal transthyretin; and, rarely, immunoglobulins that directly bind T 4 or T 3 .”
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    Uptake is usually elevated in patients with Graves' disease and normal or high in toxic nodular goiter, unless there has been a recent exposure to iodine.

    “Uptake is usually elevated in patients with GD and normal or high in toxic nodular goiter, unless there has been a recent exposure to iodine (e.g., radiocontrast).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    In overt hyperthyroidism, serum free T4, T3, or both are elevated, and serum TSH is subnormal (usually <0.01 mU/L in a third-generation assay).

    “In overt hyperthyroidism, serum free T 4 , T 3 , or both are elevated, and serum TSH is subnormal (usually <0.01 mU/L in a third-generation assay).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Untreated or partially treated thyrotoxicosis is associated with weight loss, osteoporosis, atrial fibrillation, embolic events, muscle weakness, tremor, neuropsychiatric symptoms, and rarely cardiovascular collapse and death.

    “Untreated or partially treated thyrotoxicosis is associated with weight loss, osteoporosis, atrial fibrillation, embolic events, muscle weakness, tremor, neuropsychiatric symptoms, and rarely cardiovascular collapse and death (26,27).”
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    Premisecitation

    In immunometric assays, excess biotin displaces biotinylated antibodies and causes spuriously low results, while in competitive binding assays, excess biotin competes with biotinylated analogue and results in falsely high results.

    “In immunometric assays, frequently used to measure TSH, excess biotin displaces biotinylated antibodies and causes spuriously low results, while in competitive binding assays, frequently used to measure free T 4 , excess biotin competes with biotinylated analogue and results in falsely high results.”
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    Premisenone given

    Technetium scans result in a low range of normal uptake and high background activity, and total body radiation exposure is less than for 123I scans.

    “While technetium scans result in a low range of normal uptake and high background activity, total body radiation exposure is less than for 123 I scans; either type of scan can be useful in determining the etiology of hyperthyroidism in the presence of thyroid nodularity.”
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    The image in toxic multinodular goiter demonstrates multiple areas of focal increased and suppressed uptake.

    “The image in TMNG demonstrates multiple areas of focal increased and suppressed uptake.”
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    Premisecitation

    Once a patient is hyperthyroid and the cause is Graves' disease, the patient and physician must choose between three effective and relatively safe initial treatment options: RAI therapy, ATDs, or thyroidectomy.

    “Once it has been established that the patient is hyperthyroid and the cause is GD, the patient and physician must choose between three effective and relatively safe initial treatment options: RAI therapy, ATDs, or thyroidectomy (59).”
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    Premisecitation

    Patients with painless thyroiditis presenting within the first year after childbirth (postpartum thyroiditis) often have a personal or family history of autoimmune thyroid disease and typically have measurable serum concentrations of anti-thyroid peroxidase antibodies.

    “Patients with painless thyroiditis presenting within the first year after childbirth (postpartum thyroiditis) often have a personal or family history of autoimmune thyroid disease and typically have measurable serum concentrations of anti-thyroid peroxidase antibodies (52).”
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    Interpretationreasoning

    Because available beta-blockers lack sufficient beta-1 selectivity at recommended doses, they are generally contraindicated in patients with bronchospastic asthma.

    “Since there is not sufficient b-1 selectivity of the available b-blockers at the recommended doses, these drugs are generally contraindicated in patients with bronchospastic asthma.”
    Quote in the paperSubstantial claim

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    Premisenone given

    Subacute thyroiditis is generally painful, the gland is firm to hard on palpation, and the erythrocyte sedimentation rate is usually >50 mm/h and sometimes over 100 mm/h.

    “Subacute thyroiditis is generally painful, the gland is firm to hard on palpation, and the erythrocyte sedimentation rate is usually >50 mm/h and sometimes over 100 mm/h.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Thyroidectomy in the first and third trimesters of pregnancy is associated with teratogenic effects from anesthetic agents, increased risk of fetal loss in the first trimester, and increased risk of preterm labor in the third trimester.

    “Thyroidectomy is best avoided in the first and third trimesters of pregnancy because of teratogenic effects associated with anesthetic agents and increased risk of fetal loss in the first trimester and increased risk of preterm labor in the third.”
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    Premisecitation

    In one study, the ratio of total T3 to total T4 (ng/lg) was >20 in Graves' disease and toxic nodular goiter, and <20 in painless or postpartum thyroiditis.

    “in one study the ratio of total T 3 to total T 4 (ng/lg) was >20 in GD and toxic nodular goiter, and <20 in painless or postpartum thyroiditis (51).”
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    Premisenone given

    If TRAb is negative it does not distinguish among other etiologies, and it can be negative in very mild Graves' disease.

    “If negative it does not distinguish among other etiologies, however, and it can be negative in very mild GD.”
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    Premisecitation

    In a randomized controlled trial of MMI alone versus MMI plus a beta-adrenergic blocking agent, after 4 weeks, patients taking beta-adrenergic blockers had lower heart rates, less shortness of breath and fatigue, and improved physical functioning on the SF-36 health questionnaire.

    “In a randomized controlled trial of MMI alone versus MMI and a b-adrenergic blocking agent, after 4 weeks, patients taking b-adrenergic blockers had lower heart rates, less shortness of breath and fatigue, and improved ''physical functioning'' on the SF-36 health questionnaire (58).”
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    Premisenone given

    Doppler flow has been used to distinguish between subtypes of amiodarone-induced thyrotoxicosis and between Graves' disease and destructive thyroiditis.

    “Doppler flow has also been used to distinguish between subtypes of amiodarone-induced thyrotoxicosis (see Section [V2]) and between GD and destructive thyroiditis (see Section [W2]).”
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    Premisecitation

    Bioassays for Thyroid Stimulating Immunoglobulin specifically detect stimulating antibodies and can differentiate between the TSH-R antibody types.

    “Such assays specifically detect simulating antibodies (TSI) and can differentiate between the TSH-R antibody types.”
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    Premisecitation

    Because a hyperactive gland produces more T3 than T4, T3 will be elevated above the upper limit of normal more than T4 in thyrotoxicosis caused by hyperthyroidism, whereas T4 is elevated more than T3 in thyrotoxicosis caused by thyroiditis.

    “Because a hyperactive gland produces more T 3 than T 4 , T 3 will be elevated above the upper limit of normal more than T 4 in thyrotoxicosis caused by hyperthyroidism, whereas T 4 is elevated more than T 3 in thyrotoxicosis caused by thyroiditis (50);”
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    Premisecitation

    In patients with antithyroglobulin antibodies, measurement of fecal T4 is an alternative but not widely available approach; mean values were 1.03 nmol/g in euthyroid patients, 1.93 nmol/g in Graves' hyperthyroidism, and 12-24 nmol/g in factitious thyrotoxicosis.

    “In patients with antithyroglobulin antibodies, which interfere with thyroglobulin measurement, an alternative but not widely available approach is measurement of fecal T 4 (54); mean values were 1.03 nmol/g in euthyroid patients, 1.93 nmol/g in Graves' hyperthyroidism, and 12-24 nmol/g in factitious thyrotoxicosis.”
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    Premisenone given

    Thyroglobulin is released along with thyroid hormone in subacute, painless, and palpation thyroiditis, whereas its release is suppressed in the setting of exogenous thyroid hormone administration.

    “Thyroglobulin is released along with thyroid hormone in subacute, painless, and palpation thyroiditis (following manipulation of the thyroid gland during surgery), whereas its release is suppressed in the setting of exogenous thyroid hormone administration.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    TRAb is cost effective because if it is positive it confirms the diagnosis of the most common cause of thyrotoxicosis.

    “TRAb is cost effective because if it is positive it confirms the diagnosis of the most common cause of thyrotoxicosis.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Very high doses of beta-blockers are occasionally required to manage thyrotoxicosis symptoms and reduce heart rate to near the upper limit of normal, but low to moderate doses most often give sufficient symptom relief.

    “Occasionally, very high doses of b-blockers are required to manage symptoms of thyrotoxicosis and to reduce the heart rate to near the upper limit of normal (31), but most often low to moderate doses (Table 4) give sufficient symptom relief.”
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    Premisecitation

    In the United States, the treating physician must ensure and document that no adult member of the public is exposed to 0.5 mSv when the patient is discharged with a retained activity of 33 mCi or greater, or emits at least 7 mrem/h at 1 m.

    “In the United States, the treating physician must ensure and document that no adult member of the public is exposed to 0.5 mSv (500 milli-roentgen equivalent in man [mrem]) when the patient is discharged with a retained activity of 33 mCi (1.22 GBq) or greater, or emits ‡7 mrem/h (70 lSv/h) at 1 m.”
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    Premisecitation

    A recent meta-analysis found no increase in overall cancer risk after RAI treatment for hyperthyroidism, but a trend toward increased risk of thyroid, stomach, and kidney cancer was seen, requiring further research.

    “A recent meta-analysis found no increase in the overall cancer risk after RAI treatment for hyperthyroidism; however, a trend towards increased risk of thyroid, stomach, and kidney cancer was seen, requiring further research (98).”
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    Premisecitation

    ATD treatment itself might have a beneficial immunosuppressive role, either primarily decreasing thyroid-specific autoimmunity or secondarily ameliorating the hyperthyroid state and restoring the dysregulated immune system.

    “The treatment itself might have a beneficial immunosuppressive role, either to primarily decrease thyroid specific autoimmunity, or secondarily, by ameliorating the hyperthyroid state, which may restore the dysregulated immune system back to normal (111).”
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    Premisecitation

    One study found that experienced physicians' estimate of thyroid size is accurate compared with anatomic imaging, but other investigators have not confirmed this observation.

    “One study found that this estimate by experienced physicians is accurate compared with anatomic imaging (86); however, other investigators have not confirmed this observation (87).”
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    Premisecitation

    Transient hypothyroidism following RAI therapy can rarely occur, with subsequent complete recovery of thyroid function or recurrent hyperthyroidism.

    “Transient hypothyroidism following RAI therapy can rarely occur, with subsequent complete recovery of thyroid function or recurrent hyperthyroidism (107).”
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    Premisecitation

    In one study, if MMI was restarted 7 days after RAI, free T4 measured 3 weeks after RAI was 6% lower than at the time of RAI administration; if MMI was not restarted, free T4 values were 36% higher.

    “In one study, if MMI was restarted 7 days after RAI, the free T 4 measured 3 weeks after RAI was 6% lower than the values at the time of RAI administration, and if MMI was not restarted after RAI, the free T 4 values were 36% higher than the values at the time of RAI administration (80).”
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    Premisecitation

    Fetuses exposed to RAI after the 10th to 11th week of gestation may be born athyreotic and are also at a theoretical increased risk for reduced intelligence and/or cancer.

    “Fetuses exposed to RAI after the 10th to 11th week of gestation may be born athyreotic (101,102) and are also at a theoretical increased risk for reduced intelligence and/or cancer.”
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  • May combine two claims.

    Premisecitation

    A recent randomized controlled trial found that 38 mg of KI together with 15 mg of MMI daily resulted in better control of hyperthyroidism and fewer adverse reactions compared to 30 mg of MMI alone.

    “Indeed, a recent randomized controlled trial described the administration of 38 mg of KI together with 15 mg of MMI daily, which resulted in better control of hyperthyroidism and fewer adverse reactions compared to 30 mg of MMI given alone (121).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Over several decades, reports have indicated that pretreatment with lithium reduces the activity of RAI necessary for cure of Graves' hyperthyroidism and may prevent the thyroid hormone increase seen upon ATD withdrawal.

    “Over several decades, there have been reports that pretreatment with lithium reduces the activity of RAI necessary for cure of Graves' hyperthyroidism and may prevent the thyroid hormone increase seen upon ATD withdrawal (81)(82)(83).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [81] source

      Not checked in the free run.

    • cites [82]

      Not checked in the free run.

    • cites [83] source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The MMI dose should be targeted to the degree of thyroid dysfunction because too low a dose will not restore a euthyroid state in severe disease and an excessive dose can cause iatrogenic hypothyroidism in mild disease.

    “The dose of MMI should be targeted to the degree of thyroid dysfunction because too low a dose will not restore a euthyroid state in patients with severe disease (115) and an excessive dose can cause iatrogenic hypothyroidism in patients with mild disease (116).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [115] source

      Not checked in the free run.

    • cites [116] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The goal of RAI therapy in Graves' disease is to control hyperthyroidism by rendering the patient hypothyroid, and this treatment is very effective provided a sufficient radiation dose is deposited in the thyroid.

    “The goal of RAI therapy in GD is to control hyperthyroidism by rendering the patient hypothyroid; this treatment is very effective, provided a sufficient radiation dose is deposited in the thyroid.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A long-term increase in cardiovascular and cerebrovascular deaths has been reported after RAI therapy not resulting in hypothyroidism, as opposed to unchanged mortality in RAI-treated patients on levothyroxine therapy, reflecting the role of persistent hyperthyroidism rather than RAI therapy on mortality.

    “A long-term increase in cardiovascular and cerebrovascular deaths has been reported after RAI therapy not resulting in hypothyroidism as opposed to unchanged mortality in RAI-treated patients on levothyroxine therapy, reflecting the role of persistent hyperthyroidism as opposed to that of RAI therapy on mortality (96,97).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [96] source

      Not checked in the free run.

    • cites [97]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Once a patient of either sex is euthyroid after RAI, there is no evidence of reduced fertility, and offspring of treated patients show no congenital anomalies compared to the population at large.

    “However, once the patient (either sex) is euthyroid, there is no evidence of reduced fertility, and offspring of treated patients show no congenital anomalies compared to the population at large (100).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Block and replace therapy is not generally recommended because it has been shown to result in a higher rate of ATD side effects.

    “However, this approach is not generally recommended because it has been shown to result in a higher rate of ATD side effects (109,119).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [109] source

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    • cites [119]

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  • May combine two claims.

    Premisecitation

    In patients without adjunctive ATD, randomized controlled trials found RAI success rates of 61% with 5.4 mCi, 69% with 8.2 mCi, 74% with 10 mCi, 81% with 15 mCi, and 86% with 15.7 mCi.

    “In patients without adjunctive ATD, randomized controlled trials found 61% success with 5.4 mCi (200 MBq) (92), 69% with 8.2 mCi (302 MBq) (93), 74% with 10 mCi (370 MBq) (94), 81% with 15 mCi (555 MBq) (94), and 86% with 15.7 mCi (580 MBq) (95) RAI.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92]

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    • cites [93]

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    • cites [94]

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  • May combine two claims.

    Premisecitation

    Hypothyroidism may occur from 4 weeks after RAI, with 40% of patients hypothyroid by 8 weeks and more than 80% by 16 weeks.

    “Hypothyroidism may occur from 4 weeks on, with 40% of patients being hypothyroid by 8 weeks and >80% by 16 weeks (106).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The average age of patients developing agranulocytosis was slightly older (45 vs. 40 years), an observation that has been made by others.

    “The average age of patients developing agranulocytosis was slightly older (45 vs. 40 years), an observation that has been made by others.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the first study, a retrospective cohort analysis of over 50,000 Graves' disease patients found 55 developed agranulocytosis, of whom five had pancytopenia, for an estimated cumulative incidence of 0.3% in 100 days, with a median interval to onset of 69 days.

    “In the first study, a retrospective cohort analysis of over 50,000 GD patients, 55 developed agranulocytosis, of whom five had pancytopenia, for an estimated cumulative incidence of 0.3% in 100 days (127), with a median interval to onset of 69 days.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PTU can cause fulminant hepatic necrosis that may be fatal; liver transplantation has been necessary in some patients taking PTU.

    “In contrast, PTU can cause fulminant hepatic necrosis that may be fatal; liver transplantation has been necessary in some patients taking PTU (132).”
    • Also stated in: § Weak recommendation, low-quality evidence. · plain
      “PTU can cause fulminant hepatic necrosis that may be fatal; liver transplantation has been necessary in some patients taking PTU (326).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [132] source

      Not checked in the free run.

    • cites [326] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Eighty-nine percent of the reported patients developed agranulocytosis, and 11% developed pancytopenia or aplastic anemia.

    “Eighty-nine percent developed agranulocytosis, and 11% developed pancytopenia or aplastic anemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All 50 patients with agranulocytosis alone were successfully treated with granulocyte colony stimulating factor, steroids, or supportive care, but one of five patients with pancytopenia died.

    “All 50 patients with agranulocytosis alone were successfully treated with granulocyte colony stimulating factor, steroids, or supportive care, but one of five patients with pancytopenia died.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [127] source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Two of the three recent reports were from Japan and one from Denmark; in both countries the majority of patients are treated with MMI, so data are more limited for PTU-associated agranulocytosis.

    “Two studies were from Japan and one was from Denmark.In both countries the majority of patients are treated with MMI, so data are more limited for PTU-associated agranulocytosis.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [127] source

      Not checked in the free run.

    • cites [128] source

      Not checked in the free run.

    • cites [129] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hepatocellular injury occurred in 2.7% of patients taking PTU and 0.4% of patients taking MMI.

    “Hepatocellular injury occurred in 2.7% of patients taking PTU and 0.4% of patients taking MMI.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cutaneous reactions appeared after a median of 18-22 days of treatment, significantly earlier than transaminase elevations at a median of 28 days.

    “Cutaneous reactions appeared after a median of 18-22 days of treatment, significantly earlier than transaminase elevations (median 28 days).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The second study was based on a national database for adverse drug reactions, which may have included some patients reported in the first study.

    “The second study was based on a national database for adverse drug reactions, which may have included some patients reported in the first study (128).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The FDA issued a safety alert in 2010 regarding the use of PTU, and an analysis of FDA Medwatch data concluded that children are more susceptible to hepatotoxic reactions from PTU than are adults.

    “It is for this reason that the Food and Drug Administration (FDA) issued a safety alert in 2010 regarding the use of PTU, and an analysis of FDA Medwatch data (133) concluded that children are more susceptible to hepatotoxic reactions from PTU than are adults.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the study from Denmark, hepatotoxic reactions were not classified as cholestatic or hepatocellular, but the frequency of liver failure was similar for MMI (0.03%) and PTU (0.03%).

    “In the study from Denmark (129), hepatotoxic reactions were not classified as cholestatic or hepatocellular, but the frequency of ''liver failure'' was similar for MMI (0.03%) and PTU (0.03%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At the onset of agranulocytosis, the average MMI dose was 25 mg/d and the average PTU dose was 217 mg/d.

    “At the onset of agranulocytosis, the average MMI dose was 25 mg/d and the average PTU dose was 217 mg/d.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Of the 754 reported patients, 725 received MMI, 28 received PTU, and one received both drugs.

    “Of them, 725 patients received MMI, 28 received PTU, and one received both drugs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A total of 754 Graves' disease patients who developed ATD-induced hematologic complications were reported, for an estimated incidence of 0.1%-0.15%.

    “A total of 754 GD patients who developed ATD-induced hematologic complications were reported, for an estimated incidence of 0.1%-0.15%.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MMI hepatotoxicity has been described as typically cholestatic, but hepatocellular disease may be seen.

    “MMI hepatotoxicity has been described as typically cholestatic, but hepatocellular disease may be seen (130,131).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [130]

      Not checked in the free run.

    • cites [131]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The percentage of patients discontinuing ATD therapy was 17% in the low-dose MMI group, 29% in the high-dose MMI group, and 34% in the PTU group.

    “The percentage of patients discontinuing ATD therapy was 17% in the low-dose MMI group, 29% in the high-dose MMI group, and 34% in the PTU group (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a separate study of 449 Graves' disease patients receiving MMI or PTU, 24% developed a cutaneous reaction, 3.8% developed transaminase elevations more than 3-fold above normal, and 0.7% developed agranulocytosis with absolute neutrophil count less than 500.

    “In a separate study of 449 GD patients receiving MMI or PTU, 24% developed a cutaneous reaction, 3.8% developed transaminase elevations more than 3-fold above normal, and 0.7% developed agranulocytosis (absolute neutrophil count <500) (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PTU and rarely MMI can cause antineutrophil cytoplasmic antibody-positive small vessel vasculitis as well as drug-induced lupus.

    “PTU and rarely MMI can cause antineutrophil cytoplasmic antibody (pANCA)-positive small vessel vasculitis (137,138) as well as drug-induced lupus (139).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [137]

      Not checked in the free run.

    • cites [138]

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    • cites [139]

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  • May combine two claims.

    Premisecitation

    In 7% of patients, agranulocytosis occurred later than 4 months after starting ATD, but some of these patients had discontinued the medication for long periods and developed agranulocytosis after a second or subsequent exposure.

    “In 7% of patients, agranulocytosis occurred later than 4 months after starting ATD, but some of these patients had discontinued the medication for long periods of time and developed agranulocytosis after a second or subsequent exposure.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Seventy-two percent of patients developed agranulocytosis within 60 days of starting ATD, and 85% within 90 days.

    “Seventy-two percent developed agranulocytosis within 60 days of starting ATD, and 85% within 90 days.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among 71,379 new users of ATDs with a median follow-up of 196 days, MMI was associated with a higher rate of diagnosis of noninfectious hepatitis than PTU (0.25% vs. 0.08%), whereas cholestasis was not different (0.019% vs. 0.016%).

    “Among 71,379 new users of ATDs with a median follow-up of 196 days, MMI was associated with a higher rate of a diagnosis of noninfectious hepatitis than PTU (0.25% vs. 0.08%, respectively), whereas cholestasis was not different (0.019% vs. 0.016%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In most cases, vasculitis resolves with drug discontinuation, although immunosuppressive therapy may be necessary.

    “In most cases, the vasculitis resolves with drug discontinuation, although immunosuppressive therapy may be necessary (145).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [145] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A case report described a severe reaction to MMI consisting of rash, pruritis, and tongue and throat swelling that was successfully managed with antihistamine therapy, but this is not generally recommended because of the risk of anaphylaxis.

    “One recent case report described a more severe reaction to MMI consisting of rash, pruritis, and tongue and throat swelling that was successfully managed with antihistamine therapy, but this is not generally recommended because of the risk of anaphylaxis (162).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [162] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    Measurement of TRAb levels prior to stopping ATD therapy aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission.

    “Measurement of TRAb levels prior to stopping ATD therapy is suggested because it aids in predicting which patients can be weaned from the medication, with normal levels indicating greater chance for remission.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    There is insufficient evidence to recommend for or against routine monitoring of WBC counts in patients taking ATDs.

    “There is insufficient evidence to recommend for or against routine monitoring of WBC counts in patients taking ATDs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Higher initial doses of MMI (60-80 mg/d) do not improve remission rates and increase the risk of side effects.

    “Higher initial doses of MMI (60-80 mg/d) do not improve remission rates; they increase the risk of side effects and are not recommended (170).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ANCA-positive vasculitis is more common in patients of Asian ethnicity, and the majority of reports come from Asia.

    “ANCA-positive vasculitis is more common in patients of Asian ethnicity, and the majority of reports come from Asia (143).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [143] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Switching from one ATD to the other is safe in the case of minor side effects, although patients may develop similar side effects with the second ATD.

    “A recent study provided evidence that switching from one ATD to the other is safe in the case of minor side effects, although patients may develop similar side effects with the second ATD (123).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Typically, granulocyte myeloperoxidase is the targeted antigen of the ANCA, but antibodies to many other proteins are seen as well.

    “Typically, granulocyte myeloperoxidase is the targeted antigen of the ANCA, but antibodies to many other proteins are seen as well (142).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some patients display a gradual decline in WBC count prior to developing agranulocytosis, suggesting that monitoring might have been useful in some affected patients.

    “However, other patients did display a gradual decline in WBC count prior to developing agranulocytosis, suggesting that monitoring might have been useful in some affected patients (152).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with improving thyrotoxicosis, a rising alkaline phosphatase with normalization of other liver function does not indicate worsening hepatic toxicity because the origin of the alkaline phosphatase is from bone, not liver.

    “In patients with improving thyrotoxicosis, a rising alkaline phosphatase with normalization of other liver function does not indicate worsening hepatic toxicity (156) because the origin of the alkaline phosphatase is from bone, not liver.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the group with elevated TRAb, relapse rates approach 80%-100%, while in the group with low or undetectable TRAb, relapse rates are in the 20%-30% range.

    “In the group with elevated TRAb, relapse rates approach 80%-100%, while in the latter group, relapse rates are in the 20%-30% range (171,172).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [171] source

      Not checked in the free run.

    • cites [172] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 71 patients with an adverse event from either MMI or PTU who switched to the other ATD, 34% of patients switched to PTU and 30% of patients switched to MMI developed side effects, generally the same type as occurred on the original ATD, while the remaining patients tolerated the second ATD without complications.

    “Thirty-four percent of patients switched to PTU and 30% of patients switched to MMI developed side effects, generally the same type as occurred on the original ATD, while the remaining patients tolerated the second ATD without complications (123).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Routine monitoring of WBC counts is not likely to identify cases of agranulocytosis because the frequency is 0.2%-0.5% and the condition is usually sudden in onset.

    “Although routine monitoring of WBC counts may detect early agranulocytosis, this practice is not likely to identify cases because the frequency is quite low (0.2%-0.5%) and the condition is usually sudden in onset.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Low white blood cell counts are common in patients with Graves' disease and in African Americans, 10% of whom have a neutrophil count under 2000, and abnormal liver enzymes are frequently seen in patients with thyrotoxicosis.

    “This suggestion is made in part because low WBC counts are common in patients with GD and in African Americans [10% of whom have a neutrophil count under 2000 (148)], and abnormal liver enzymes are frequently seen in patients with thyrotoxicosis (149).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [148] source

      Not checked in the free run.

    • cites [149] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    While up to 40% of patients taking PTU develop ANCA positivity, the vast majority of such individuals do not develop clinical vasculitis.

    “While up to 40% of patients taking PTU develop ANCA positivity, the vast majority of such individuals do not develop clinical vasculitis (144).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MMI doses of 2.5-10 mg/d for a mean of 14 years were safe and effective for the control of GD in 59 patients.

    “Another study reported that MMI doses of 2.5-10 mg/d for a mean of 14 years were safe and effective for the control of GD in 59 patients (174).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [174]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A lower remission rate has been described in men, smokers (especially men), and those with large goiters (≥80 g).

    “A lower remission rate has been described in men, smokers (especially men), and those with large goiters ( ‡80 g) (165-169).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [165]

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    • cites [166]

      Not checked in the free run.

    • cites [167] source

      Not checked in the free run.

    • cites [168]

      Not checked in the free run.

    • cites [169]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In relapsed GD patients, those treated with RAI (n = 114) more often had persistent thyroid eye disease, continuing thyroid dysfunction, and experienced more weight gain compared with patients receiving long-term ATD treatment (n = 124).

    “Those patients treated with RAI (n = 114) more often had persistent thyroid eye disease, continuing thyroid dysfunction, and experienced more weight gain compared with patients receiving long-term ATD treatment (n = 124).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [175]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Significant elevations of serum transaminases to 3-fold above the upper limit of normal are seen in up to 4% of patients taking PTU, a prevalence higher than with MMI.

    “Significant elevations to 3-fold above the upper limit of normal are seen in up to 4% of patients taking PTU (155), a prevalence higher than with MMI.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with ATD-induced agranulocytosis who had at least one prior granulocyte count measured, 21% had a normal WBC count within a week and 53% within 2 weeks before developing agranulocytosis.

    “In a recent analysis of 211 patients with ATD-induced agranulocytosis who had at least one prior granulocyte count measured, 21% had a normal WBC count within a week and 53% within 2 weeks before developing agranulocytosis (128).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    There is insufficient information to recommend for or against routine monitoring of liver function tests in patients taking ATDs.

    “There is insufficient information to recommend for or against routine monitoring of liver function tests in patients taking ATDs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In patients who remain euthyroid for more than 1 year (in remission), relapses can occur years later, and some patients eventually become hypothyroid.

    “If the patient remains euthyroid for more than 1 year (i.e., they are in remission), thyroid function should be monitored at least annually because relapses can occur years later (171), and some patients eventually become hypothyroid (179).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [171] source

      Not checked in the free run.

    • cites [179] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Improved patient outcome has been shown to be independently associated with high thyroidectomy surgeon volume; average complication rates, length of hospital stay, and cost are reduced when the operation is performed by a high-volume surgeon.

    “Improved patient outcome has been shown to be independently associated with high thyroidectomy surgeon volume; specifically, average complication rates, length of hospital stay, and cost are reduced when the operation is performed by a surgeon who conducts many thyroidectomies.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [198] source

      Not checked in the free run.

    • cites [199] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Following thyroidectomy for GD in the hands of high-volume thyroid surgeons, the rate of permanent hypoparathyroidism is <2%, and permanent RLN injury occurs in <1%.

    “Following thyroidectomy for GD in the hands of high-volume thyroid surgeons, the rate of permanent hypoparathyroidism has been determined to be <2%, and permanent RLN injury occurs in <1% (201).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [201]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Surgeons who perform more than 25 thyroid surgeries per year have superior patient clinical and economic outcomes compared to those who perform fewer; complication rates are 51% higher on average when surgery is performed by low-volume surgeons.

    “Data show that surgeons who perform more than 25 thyroid surgeries per year have superior patient clinical and economic outcomes compared to those who perform fewer; complication rates are 51% higher on average when surgery is performed by low-volume surgeons (62,199,200).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [62] source

      Not checked in the free run.

    • cites [199] source

      Not checked in the free run.

    • cites [200]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a series of 162 patients with GD and 102 patients with TMNG, none of whom received SSKI preoperatively, no significant differences were observed in operative times, blood loss, or postoperative complications between the two groups; the authors concluded that omitting preoperative SSKI for GD patients does not impair patient outcomes.

    “In a recent series of 162 patients with GD and 102 patients with TMNG, none of whom received SSKI preoperatively, no significant differences were observed in operative times, blood loss, or postoperative complications between the two groups; the authors concluded that omitting preoperative SSKI for GD patients does not impair patient outcomes (183).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [183] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with negative TRAb, relapses tend to occur relatively later than those that develop in patients whose MMI is stopped when TRAb is still positive, although 5% occurred within the first 2 months in one study.

    “In patients with negative TRAb, relapses tend to occur relatively later than those that develop in patients whose MMI is stopped when TRAb is still positive (171,176), although 5% occurred within the first 2 months in one study (167).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [171] source

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    • cites [176] source

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    • cites [167] source

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  • May combine two claims.

    Premisecitation

    A significant association is seen between increasing thyroidectomy volume and improved patient outcome; the association is robust and is more pronounced with an increasing number of thyroidectomies.

    “A significant association is seen between increasing thyroidectomy volume and improved patient outcome; the association is robust and is more pronounced with an increasing number of thyroidectomies (198,199).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [198] source

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    • cites [199] source

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  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    It is unclear whether the study of omitting preoperative SSKI was adequately powered to detect a significant difference, if one existed.

    “It is also unclear whether it was adequately powered to detect a significant difference, if one existed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [183] source

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  • May combine two claims.

    Premisecitation

    A meta-analysis identified preoperative vitamin D deficiency and GD itself as risk factors for postoperative hypocalcemia.

    “A meta-analysis of risk factors for postoperative hypocalcemia identified preoperative vitamin D deficiency as a risk factor for postoperative hypocalcemia, as well as GD itself (188).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] source

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  • May combine two claims.

    Premisenone given

    Thyroid storm may be precipitated by the stress of surgery, anesthesia, or thyroid manipulation and may be prevented by pretreatment with ATDs.

    “Thyroid storm may be precipitated by the stress of surgery, anesthesia, or thyroid manipulation and may be prevented by pretreatment with ATDs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Total thyroidectomy has a nearly 0% risk of recurrence, whereas subtotal thyroidectomy may have an 8% chance of persistence or recurrence of hyperthyroidism at 5 years.

    “Total thyroidectomy has a nearly 0% risk of recurrence, whereas subtotal thyroidectomy may have an 8% chance of persistence or recurrence of hyperthyroidism at 5 years (194)(195)(196)(197).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [194]

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    • cites [195]

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    • cites [196]

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  • May combine two claims.

    Study design and conductreasoning

    The study of omitting preoperative SSKI was performed at a single high-volume institution, compared two different pathologies, and had no comparison group of patients with GD who received SSKI, so its findings may not be generalizable.

    “Given that this study was performed at a single high-volume institution, its findings may not be generalizable; comparison was made between two different pathologies, and there was no comparison group of patients with GD who received SSKI.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [183] source

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  • May combine two claims.

    Premisecitation

    Reports of escape from the beneficial effects of iodine and reports of iodine-induced hyperthyroidism in patients with nodular goiter discouraged the use of iodine in GD.

    “However, reports of escape from these beneficial effects of iodine (241) as well as reports of iodine-induced hyperthyroidism in patients with nodular goiter (242) discouraged the use of iodine in GD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [241] source

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    • cites [242] source

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  • May combine two claims.

    Premisecitation

    Iodine acutely lowers thyroid hormone concentrations by reducing hormone secretion and inhibits its own organification (the Wolff-Chaikoff effect).

    “Iodine acutely lowers thyroid hormone concentrations by reducing hormone secretion (238,239), and inhibits its own organification (the Wolff-Chaikoff effect) (240).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [238] source

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    • cites [239] source

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    • cites [240] source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The BWPS criteria include hyperpyrexia, tachycardia, arrhythmias, congestive heart failure, agitation, delirium, psychosis, stupor, coma, nausea, vomiting, diarrhea, hepatic failure, and the presence of an identified precipitant.

    “These criteria (Table 6) include hyperpyrexia, tachycardia, arrhythmias, congestive heart failure, agitation, delirium, psychosis, stupor, and coma, as well as nausea, vomiting, diarrhea, hepatic failure, and the presence of an identified precipitant (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

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  • May combine two claims.

    Premisecitation

    In a recent study including 25 patients with a clinical diagnosis of thyroid storm, the BWPS was ≥45 in 20 patients and 25-44 in the remaining five, but these latter five patients (20%) were not identified using the JTA system.

    “In a recent study including 25 patients with a clinical diagnosis of thyroid storm, the BWPS was ‡45 in 20 patients and 25-44 in the remaining five, but these latter five patients (20%) were not identified using the JTA system (226).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] source

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  • May combine two claims.

    Premisecitation

    Therapeutic measures specifically intended to decrease T4-to-T3 conversion include preferential use of PTU over MMI, glucocorticoid therapy, and beta-adrenergic blocking agents such as propranolol with selective ability to inhibit type 1 deiodinase.

    “A number of therapeutic measures are specifically intended to decrease T 4 -to-T 3 conversion, such as the preferential use of PTU over MMI (229,230), glucocorticoid therapy (231), and the use of b-adrenergic blocking agents such as propranolol, with selective ability to inhibit type 1 deiodinase (232).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [229] source

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    • cites [230] source

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    • cites [231] source

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  • Classified as probably not a substantial claim.

    Premisecitation

    The treatment strategy for thyroid storm can be broadly divided into therapy directed against thyroid hormone secretion and synthesis, measures directed against the peripheral action of thyroid hormone, reversal of systemic decompensation, treatment of the precipitating event or intercurrent illness, and definitive therapy.

    “The treatment strategy for thyroid storm can be broadly divided into (i) therapy directed against thyroid hormone secretion and synthesis; (ii) measures directed against the peripheral action of thyroid hormone at the tissue level; (iii) reversal of systemic decompensation; (iv) treatment of the precipitating event or intercurrent illness; and (v) definitive therapy (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

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  • May combine two claims.

    Premisecitation

    The appropriate dosing of L-thyroxine varies with patient body mass index and the percentage of levothyroxine absorbed from the gut.

    “The appropriate dosing of L-thyroxine will vary with patient body mass index (219), and the percentage of levothyroxine absorbed from the gut.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [219] source

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  • May combine two claims.

    Premisecitation

    Among 125 patients hospitalized with a clinical diagnosis of compensated thyrotoxicosis but not in thyroid storm, 27 (21.6%) had a BWPS ≥45, and 21 (16.8%) had a diagnosis category of either TS1 or TS2, suggesting similar rates of overdiagnosis with these two systems.

    “Importantly, in the same series, among 125 patients hospitalized with a clinical diagnosis of compensated thyrotoxicosis but not in thyroid storm, 27 (21.6%)had a BWPS ‡45, and 21 (16.8%) had a diagnosis category of either TS1 or TS2, suggesting similar rates of overdiagnosis with these two systems.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] source

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  • May combine two claims.

    Premisecitation

    Data comparing the BWPS and JTA diagnostic systems suggest an overall agreement, but a tendency toward underdiagnosis using the JTA categories of TS1 and TS2 compared to a BWPS ≥45.

    “Data comparing these two diagnostic systems suggest an overall agreement, but a tendency toward underdiagnosis using the JTA categories of TS1 and TS2, compared to a BWPS ‡45 (72,186,226,227).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [72] source

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    • cites [186]

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    • cites [226] source

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  • May combine two claims.

    Interpretationcitation

    An additional 50 patients (40%) hospitalized with a clinical diagnosis of thyrotoxicosis without thyroid storm would have been diagnosed as having impending thyroid storm by the BWPS, which reinforces that a BWPS in the 25-44 range does not supplant clinical judgment in the selection of patients for aggressive therapy.

    “However, an additional 50 patients (40%) hospitalized with a clinical diagnosis of thyrotoxicosis without thyroid storm would have been diagnosed as having impending thyroid storm by the BWPS, which reinforces that a BWPS in the 25-44 range does not supplant clinical judgment in the selection of patients for aggressive therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] source

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  • May combine two claims.

    Premisecitation

    Life-threatening thyrotoxicosis or thyroid storm is a rare disorder characterized by multisystem involvement and mortality rates in the range of 8%-25% in modern series.

    “Life-threatening thyrotoxicosis or thyroid storm is a rare disorder characterized by multisystem involvement and mortality rates in the range of 8%-25% in modern series (25,72,226,227).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [25] source

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    • cites [72] source

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    • cites [226] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The Japanese Thyroid Association (JTA) has proposed an additional empirically defined diagnostic system that uses combinations of similar clinical features to assign patients to diagnostic categories TS1 or TS2.

    “Recently, an additional empirically defined diagnostic system has been proposed by the JTA (72).The JTA system uses combinations of similar clinical features to assign patients to the diagnostic categories TS1 or TS2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] source

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  • May combine two claims.

    Premisecitation

    Precipitants of thyroid storm in a patient with previously compensated thyrotoxicosis include abrupt cessation of ATDs, thyroidectomy, or nonthyroidal surgery in a patient with unrecognized or inadequately treated thyrotoxicosis, and a number of acute illnesses unrelated to thyroid disease.

    “Precipitants of thyroid storm in a patient with previously compensated thyrotoxicosis include abrupt cessation of ATDs, thyroidectomy, or nonthyroidal surgery in a patient with unrecognized or inadequately treated thyrotoxicosis, and a number of acute illnesses unrelated to thyroid disease (72,186,228).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [72] source

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    • cites [186]

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    • cites [228]

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  • May combine two claims.

    Interpretationcitation

    A BWPS ≥45 appears more sensitive than a JTA classification of TS1 or TS2 in detecting patients with a clinical diagnosis of thyroid storm, but patients with a BWPS of 25-44 represent a group in whom the decision to use aggressive therapy should be based on sound clinical judgment and not based solely on diagnostic category in order to avoid overtreatment and the resultant risk of drug toxicity.

    “A BWPS ‡45 appears more sensitive than a JTA classification of TS1 or TS2 in detecting patients with a clinical diagnosis of thyroid storm, but patients with a BWPS of 25-44 represent a group in whom the decision to use aggressive therapy should be based on sound clinical judgment and not based solely on diagnostic category in order to avoid overtreatment and the resultant risk of drug toxicity.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [72] source

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    • cites [186]

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    • cites [226] source

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  • May combine two claims.

    Premisecitation

    Both plasmapheresis/plasma exchange and emergency surgery have been used to treat thyroid storm in patients who respond poorly to traditional therapeutic measures.

    “Both plasmapheresis/ plasma exchange and emergency surgery have been used to treat thyroid storm in patients who respond poorly to traditional therapeutic measures (233,234).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [233]

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    • cites [234]

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    In the BWPS system, a point total of ≥45 is consistent with thyroid storm, 25-44 points is classified as impending thyroid storm, and <25 points makes thyroid storm unlikely.

    “Points in the BWPS system are based on the severity of individual manifestations, with a point total of ‡45 consistent with thyroid storm, 25-44 points classified as impending thyroid storm, and <25 points making thyroid storm unlikely.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In hungry bone syndrome, reduced serum phosphate and increased serum potassium levels may be observed in addition to reduced serum calcium levels.

    “In addition to reduced serum calcium levels, reduced serum phosphate and increased serum potassium levels may be observed in hungry bone syndrome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Diagnostic criteria for thyroid storm in patients with severe thyrotoxicosis were first proposed in 1993 and subsequently widely adopted as the Burch-Wartofsky Point Scale (BWPS) for thyroid storm.

    “Diagnostic criteria for thyroid storm in patients with severe thyrotoxicosis were first proposed in 1993 and subsequently widely adopted as the BWPS for thyroid storm (26,72,186,226,228).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [26] source

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    • cites [72] source

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    • cites [186]

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  • May combine two claims.

    Premisecitation

    The nodule is rarely eradicated in patients with TA undergoing RAI therapy, which can lead to the need for continued surveillance.

    “The nodule is rarely eradicated in patients with TA undergoing RAI therapy, which can lead to the need for continued surveillance (225,257,260).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [225] source

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    • cites [257] source

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    • cites [260] source

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  • May combine two claims.

    Premisecitation

    For patients with TMNG, the risk of treatment failure or need for repeat treatment is <1% following near-total/total thyroidectomy, compared with a 20% risk of the need for retreatment following RAI therapy.

    “For patients with TMNG, the risk of treatment failure or need for repeat treatment is <1% following near-total and/ total thyroidectomy (246,247), compared with a 20% risk of the need for retreatment following RAI therapy (246,248).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [246] source

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    • cites [247] source

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    • cites [248] source

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  • May combine two claims.

    Premisecitation

    The prevalence of hypothyroidism varies from 2% to 3% following lobectomy for TA, although rates of hypothyroidism after lobectomy for nontoxic nodules have been reported to be as high as 20%, and lower after isthmusectomy when the TA is confined to the thyroid isthmus.

    “The prevalence of hypothyroidism varies from 2% to 3% following lobectomy for TA, although rates of hypothyroidism after lobectomy for nontoxic nodules have been reported to be as high as 20% (254-256), and lower after isthmusectomy in the unique circumstance in which the TA is confined to the thyroid isthmus.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [254] source

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    • cites [255] source

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    • cites [256] source

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  • May combine two claims.

    Premisecitation

    Initial free T4 concentration and goiter size did not predict a response to KI therapy.

    “Initial free T 4 concentration and goiter size did not predict a response to therapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] source

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  • May combine two claims.

    Premisecitation

    The inhibitory effects of iodine are greater in patients with a prior history of RAI exposure, suggesting a role for KI in patients who remain hyperthyroid after one dose of RAI and prefer to avoid a second dose.

    “The inhibitory effects of iodine are greater in patients with a prior history of RAI exposure (245) suggesting a role for KI in patients who remain hyperthyroid after one dose of RAI and prefer to avoid a second dose.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [245] source

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  • May combine two claims.

    Premisecitation

    For patients with TMNG who receive RAI therapy, the response is 50%-60% by 3 months and 80% by 6 months.

    “For patients with TMNG who receive RAI therapy, the response is 50%-60% by 3 months and 80% by 6 months (246,248,249).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [246] source

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    • cites [248] source

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    • cites [249] source

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  • May combine two claims.

    Premisecitation

    Among 44 Japanese patients who had adverse reactions to ATD and who were treated with KI alone, 66% were well controlled for an average of 18 years and 39% achieved a remission after 7 years.

    “Among 44 Japanese patients who had adverse reactions to ATD and who were treated with KI alone, 66% were well controlled for an average of 18 years (range 9-28 years), and 39% achieved a remission after 7 years (range 2-23 years) (243).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [243] source

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  • May combine two claims.

    Premisecitation

    Permanent hypoparathyroidism occurs in <2.0% and permanent RLN injury in <2.0% following near-total/total thyroidectomy.

    “Potential complications following near-total/total thyroidectomy include the risk of permanent hypoparathyroidism (<2.0%) or RLN injury (<2.0%) (261,262).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [261]

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    • cites [262] source

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  • May combine two claims.

    Premisecitation

    There is a 75% response rate by 3 months and 89% rate by 1 year following RAI therapy for TA.

    “There is a 75% response rate by 3 months and 89% rate by 1 year following RAI therapy for TA (225,257,258).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [225] source

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    • cites [257] source

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    • cites [258]

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  • May combine two claims.

    Premisecitation

    In a large retrospective series of patients with TMNG presenting with compressive symptoms, all patients undergoing total thyroidectomy had resolution of these symptoms after treatment, whereas only 46% of patients undergoing RAI had improvement in such symptoms.

    “In a large retrospective series of patients with TMNG presenting with compressive symptoms, all patients undergoing total thyroidectomy had resolution of these symptoms after treatment, whereas only 46% of patients undergoing RAI had improvement in such symptoms (252).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [252]

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  • May combine two claims.

    Premisecitation

    For patients with TA who receive RAI therapy, there is a 6%-18% risk of persistent hyperthyroidism and a 3%-5.5% risk of recurrent hyperthyroidism.

    “For patients with TA who receive RAI therapy there is a 6%-18% risk of persistent hyperthyroidism and a 3%-5.5% risk of recurrent hyperthyroidism (254,257).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [254] source

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    • cites [257] source

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  • May combine two claims.

    Premisecitation

    Among 15 nonresponders to KI, 11 (25% of all patients) escaped the inhibitory effects of iodine and four patients did not respond at all to KI.

    “Among 15 nonresponders, 11 (25% of all patients) escaped the inhibitory effects of iodine and four patients did not respond at all to KI.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [243] source

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  • May combine two claims.

    Premisecitation

    Overall, the success rate of RAI (definitive hypothyroidism or euthyroidism) is 93.7% in TA and 81.1% in TMNG patients.

    “Overall, the success rate of RAI (definitive hypothyroidism or euthyroidism) is high: 93.7% in TA and 81.1% in TMNG patients (266).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [266]

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  • May combine two claims.

    Premisecitation

    The prevalence of hypothyroidism after RAI for TA is progressive and hastened by the presence of antithyroid antibodies or a nonsuppressed TSH at the time of treatment.

    “The prevalence of hypothyroidism after RAI is progressive and hastened by the presence of antithyroid antibodies or a nonsuppressed TSH at the time of treatment (257,259,260).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [257] source

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    • cites [259] source

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    • cites [260] source

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  • May combine two claims.

    Premisecitation

    One large clinical series for TA demonstrated no surgical deaths and low complication rates.

    “One large clinical series for TA demonstrated no surgical deaths and low complication rates (254).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [254] source

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  • May combine two claims.

    Premisecitation

    High-volume thyroid surgeons tend to have better outcomes following lobectomy than low-volume surgeons, but the differences are not statistically significant.

    “Highvolume thyroid surgeons tend to have better outcomes following lobectomy than low-volume surgeons, but the differences are not statistically significant (198).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [198] source

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  • May combine two claims.

    Premisecitation

    For TA, 75% of patients were no longer hyperthyroid at 3 months, with nodule volume decreased by 35% at 3 months and by 45% at 2 years.

    “For TA, 75% of patients were no longer hyperthyroid at 3 months, with nodule volume decreased by 35% at 3 months and by 45% at 2 years (257).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [257] source

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  • May combine two claims.

    Premisecitation

    One study showed a 64% prevalence of hypothyroidism 24 years after RAI therapy for TMNG, with a higher prevalence among patients who required more than one treatment.

    “One study showed a 64% prevalence of hypothyroidism 24 years after RAI therapy for TMNG, with a higher prevalence among patients who required more than one treatment (250).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [250]

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  • May combine two claims.

    Premisecitation

    Goiter volume is decreased by 3 months after RAI for TMNG, with further reduction over 24 months, for a total size reduction of 40%.

    “Goiter volume is decreased by 3 months, with further reduction observed over 24 months, for a total size reduction of 40% (248).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [248] source

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  • May combine two claims.

    Premisecitation

    Both pretreatment with MMI allowing TSH to rise slightly and off-label use of rhTSH may reduce the total activity of RAI needed, but they increase the risk of hypothyroidism.

    “Both pretreatment with MMI allowing the TSH to rise slightly (270) and the off-label use of rhTSH (271) may reduce the total activity of RAI needed, but they increase the risk of hypothyroidism (see prior discussion Section [K1]).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [270] source

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    • cites [271] source

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  • May combine two claims.

    Premisecitation

    RAI therapy for TMNG results in resolution of hyperthyroidism in approximately 55% of patients at 3 months and 80% at 6 months, with an average failure rate of 15%.

    “RAI therapy for TMNG results in resolution of hyperthyroidism in approximately 55% of patients at 3 months and 80% of patients at 6 months, with an average failure rate of 15% (246-248).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [246] source

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    • cites [247] source

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    • cites [248] source

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  • May combine two claims.

    Premisecitation

    Studies conducted at the population level have demonstrated significantly higher rates of postoperative complications, longer length of hospital stay, and higher costs among elderly patients undergoing thyroidectomy.

    “Overall, however, studies conducted at the population level have demonstrated significantly higher rates of postoperative complications, longer length of hospital stay, and higher costs among elderly patients (198).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [198] source

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  • May combine two claims.

    Premisecitation

    A randomized trial of 97 patients with TA confirmed that higher RAI activity leads to earlier disappearance of hyperthyroidism and earlier appearance of hypothyroidism.

    “This study confirmed previous reports showing an earlier disappearance of hyperthyroidism and earlier appearance of hypothyroidism with higher RAI activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [279] source

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  • May combine two claims.

    Premisecitation

    Application of rhTSH before RAI therapy in nontoxic MNG or TMNG results in greater thyroid volume reduction but higher hypothyroidism rates than RAI therapy alone.

    “Similarly, a recent meta-analysis indicated that the application of recombinant human TSH (rhTSH) before RAI therapy in nontoxic MNG or TMNG results in greater thyroid volume reduction but higher hypothyroidism rates than RAI therapy alone (271).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [271] source

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  • May combine two claims.

    Premisenone given

    Higher activities of RAI result in more rapid resolution of hyperthyroidism and less need for retreatment, but a higher risk for early hypothyroidism.

    “Higher activities of RAI, even when appropriately calculated for the specific volume or mass of hyperthyroid tissue, result in more rapid resolution of hyperthyroidism and less need for retreatment, but a higher risk for early hypothyroidism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PTU is associated with an unacceptable risk of hepatotoxicity in children, with a risk of liver failure of 1 in 2000-4000 children taking the medication.

    “PTU is associated with an unacceptable risk of hepatotoxicity in children, with a risk of liver failure of 1 in 2000-4000 children taking the medication (326,327).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [326] source

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    • cites [327] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Ethanol ablation has been used following RAI to reduce nodule size.

    “Ethanol ablation also has been used following RAI to reduce nodule size (301).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [301] source

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  • May combine two claims.

    Premisecitation

    Ninety-three percent of patients achieved a functional cure (no uptake on RAI scintigraphy), and 92% had a >50% reduction in nodule size after ethanol ablation.

    “Ninety-three percent of patients achieved a functional cure (no uptake on RAI scintigraphy), and 92% had a >50% reduction in nodule size (299).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [299] source

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  • May combine two claims.

    Premisecitation

    Risks of thyroid cancer after external irradiation are highest in children <5 years of age, and they decline with advancing age.

    “Although there are sparse clinical data relating to RAI use in children with GD and subsequent thyroid cancer (313), it is known that risks of thyroid cancer after external irradiation are highest in children <5 years of age, and they decline with advancing age (314,315); see discussion of RAI therapy and cancer risk in Section [P3] below.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [314] source

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    • cites [315] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    All patients in the RFA report complained of pain during the procedure, but there were no complications.

    “All patients complained of pain during the procedure, but there were no complications (305).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [305] source

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  • May combine two claims.

    Premisecitation

    A retrospective multicenter report of RFA for TA in 44 patients achieved an 82% reduction in nodule volume, but 20% of nodules remained autonomous on scintigraphy, and 18% of patients remained hyperthyroid.

    “A retrospective multicenter report of RFA for TA in 44 patients utilized an 18-gauge electrode under ultrasound guidance with a mean follow-up of 20 months ( 305).An 82% reduction in nodule volume was achieved, but 20% of nodules remained autonomous on scintigraphy, and 18% of patients remained hyperthyroid.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [305] source

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  • May combine two claims.

    Premisecitation

    In 125 patients with TA followed for an average of 5 years, 2.4% refused further treatment because of pain, and 3.2% had complications including transient RLN palsy, abscess, or hematoma.

    “One hundred twenty-five patients with TA were followed for an average of 5 years; 2.4% refused further treatment because of pain, and 3.2% had complications including transient RLN palsy, abscess, or hematoma (299).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [299] source

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  • May combine two claims.

    Premisecitation

    A Korean study comparing RFA to surgery for nontoxic nodules found RFA was associated with an 85% reduction in nodule size, similar cost to surgery, fewer complications (RLN injury or hypoparathyroidism: 6% for surgery and 1% for RFA), and no patient who received RFA became hypothyroid.

    “A Korean study compared the use of RFA to surgery for nontoxic nodules (306).RFA was associated with an 85% reduction in nodule size, the cost was similar to surgery, there were fewer complications (RLN injury or hypoparathyroidism: 6% for surgery and 1% for RFA), and no patient who received RFA became hypothyroid (306).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [306] source

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  • May combine two claims.

    Premisecitation

    The FDA issued a black box warning regarding the use of PTU, noting that 32 cases of serious liver injury have been associated with PTU use.

    “For this reason, the FDA issued a black box warning regarding the use of PTU (328), noting that 32 (22 adult and 10 pediatric) cases of serious liver injury have been associated with PTU use (326,328).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [326] source

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    • cites [328]

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  • May combine two claims.

    Premisecitation

    MMI may also be associated with hepatotoxicity in children, but this tends to be milder and is typically cholestatic rather than hepatocellular.

    “MMI may also be associated with hepatotoxicity in children, but this tends to be milder and is typically cholestatic rather than hepatocellular (326).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [326] source

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  • May combine two claims.

    Premisecitation

    Data in adults do not support a need for divided doses of MMI and show that compliance with once-daily MMI therapy is superior to multiple daily doses of PTU (83% vs. 53%).

    “Although many practitioners give MMI in divided doses, data in adults do not support a need for such and show that compliance with once-daily MMI therapy is superior to multiple daily doses of PTU (83% vs. 53%) (319).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [319]

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  • May combine two claims.

    Premisecitation

    Meta-analyses suggest a higher prevalence of adverse events using block-and-replace regimens than dose titration, likely due to higher doses of MMI and the dose-related complications associated with MMI.

    “However, because meta-analyses suggest a higher prevalence of adverse events using block-and-replace regimens than dose titration (119,323), likely due to higher doses of MMI and the dose-related complications associated with MMI (324), we suggest that this practice be avoided.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [119]

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    • cites [323]

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    • cites [324] source

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  • May combine two claims.

    Premisecitation

    In another study of both TA and TMNG, 78% of cases achieved a functional cure, all nodules regressed, and there was no recurrent hyperthyroidism during 5 years of follow-up.

    “In another study of both TA and TMNG, 78% of cases achieved a functional cure, all nodules regressed, and there was no recurrent hyperthyroidism during 5 years of follow-up (300).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [300] source

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  • May combine two claims.

    Premisecitation

    Most side effects of MMI are dose-related and occur within the first 3 months of treatment.

    “Because most side effects of MMI are dose-related and occur within the first 3 months of treatment (128), high doses of MMI (e.g., >30 mg for an adolescent or adult) should rarely be used initially.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] source

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  • May combine two claims.

    Premisecitation

    Data in adults show only modest benefit of higher doses of MMI and only in severe thyrotoxicosis (free T4 > 7 ng/dL).

    “Although there may be a tendency to use higher rather than lower doses of MMI at treatment onset, data in adults show only modest benefit of higher doses and only in severe thyrotoxicosis (free T 4 > 7 ng/dL [0.554 pmol/L]) (115).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] source

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  • May combine two claims.

    Premisecitation

    The MMI dose typically used is 0.2-0.5 mg/kg daily, with a range from 0.1-1.0 mg/kg daily.

    “The MMI dose typically used is 0.2-0.5 mg/kg daily, with a range from 0.1-1.0mg/kg daily (320-322).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [320]

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    • cites [321]

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    • cites [322]

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  • May combine two claims.

    Premisecitation

    Excessive weight gain within 6 months of treatment is seen in children treated for GD, and the gain in weight can persist.

    “Excessive weight gain within 6 months of treatment is seen in children treated for GD, and the gain in weight can persist (325).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [325]

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  • May combine two claims.

    Premisecitation

    A meta-analysis demonstrated that RFA resulted in larger reductions in nodule size with fewer sessions than laser therapy.

    “A meta-analysis demonstrated that RFA resulted in larger reductions in nodule size with fewer sessions than laser therapy (304).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [304]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In one study, the average patient required four sessions at 2-week intervals for ethanol ablation.

    “In one study, the average patient required four sessions at 2-week intervals (299).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [299] source

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  • May combine two claims.

    Premisecitation

    Use of ethanol ablation has been limited due to pain associated with extravasation of ethanol to extranodular locations and other adverse effects, including transient thyrotoxicosis, permanent ipsilateral facial dysesthesia, paranodular fibrosis interfering with subsequent surgery, and toxic necrosis of the larynx and adjacent skin.

    “However, its use has been limited due to pain associated with extravasation of the ethanol to extranodular locations, and other adverse effects, which have included transient thyrotoxicosis, permanent ipsilateral facial dysesthesia, paranodular fibrosis interfering with subsequent surgery (302), and toxic necrosis of the larynx and adjacent skin (303).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [302]

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    • cites [303]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Two decades ago it was suggested that 25% of children with GD go into remission with every 2 years of continued treatment.

    “Although two decades ago it was suggested that 25% of children with GD go into remission with every 2 years of continued treatment (341), other studies of larger cohorts of pediatric patients with GD treated with ATDs for extended periods have not revealed similar remission rates (333,339,342).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [341] source

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  • May combine two claims.

    Premisecitation

    MMI-related adverse events include allergic reactions, rashes, myalgias, and arthralgias, as well as hypothyroidism from overtreatment.

    “MMI-related adverse events include allergic reactions, rashes, myalgias, and arthralgias (333,334), as well as hypothyroidism from overtreatment.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [333] source

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    • cites [334] source

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  • May combine two claims.

    Premisecitation

    Of 120 pediatric patients treated with ATDs at one center, after 1 year of therapy 25% were in remission; after 2 years, 26%; after 4 years, 37%; and after 4-10 years, 15%.

    “Of 120 pediatric patients treated with ATDs at one center, after 1 year of therapy with ATDs, 25% were in remission; after 2 years, 26%; after 4 years, 37%; and after 4-10 years, 15%.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [333] source

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  • May combine two claims.

    Premisecitation

    In another large cohort of 184 medically treated children, after 1 year of therapy with ATDs, 10% were in remission; after 2 years, 14%; after 3 years, 20%; and after 4 years, 23%.

    “In another large cohort of 184 medically treated children, after 1 year of therapy with ATDs, 10% were in remission; after 2 years, 14%; after 3 years, 20%; and after 4 years, 23% (339,342).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [339] source

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    • cites [342] source

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  • May combine two claims.

    Premisecitation

    Of the 639 patients of the 723 who discontinued ATD treatment after a mean of 3.8 years, 46.2% achieved remission, and 34.2% relapsed.

    “Of the 639 patients of the 723 who discontinued ATD treatment after a mean of 3.8 years (range 0.3 to 24.8 years), 46.2% achieved remission, and 34.2% relapsed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [343] source

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  • May combine two claims.

    Premisecitation

    Remission was achieved in 10 patients (28%) with similar rates among the three groups, whereas the time to remission tended to be longer in the small proportion of prepubertal children (median age, 6 years).

    “Remission was achieved in 10 patients (28%) with similar rates among the three groups, whereas the time to remission tended to be longer in the small proportion of prepubertal children (median age, 6 years) (336).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [336] source

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  • May combine two claims.

    Premisecitation

    In a retrospective analysis from Japan of 1138 children, 723 were continued on long-term ATD treatment, 271 underwent surgery or RAI, and 144 dropped out.

    “More recently, in a retrospective analysis from Japan of 1138 children, 723 were continued on long-term ATD treatment, 271 underwent surgery or RAI, and 144 dropped out.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [343] source

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  • May combine two claims.

    Premisecitation

    Retrospective studies have suggested that the chance of remission after 2 years of ATDs is low if the thyroid gland is large (more than 2.5 times normal size for age), the child is young (<12 years) or not Caucasian, serum TRAb levels are above normal on therapy, or free T4 levels are substantially elevated at diagnosis (>4 ng/dL, 50 pmol/L).

    “Retrospective studies have suggested that the chance of remission after 2 years of ATDs is low if the thyroid gland is large (more than 2.5 times normal size for age), the child is young (<12 years) or not Caucasian, serum TRAb levels are above normal on therapy, or free T 4 levels are substantially elevated at diagnosis (>4 ng/dL, 50 pmol/L) (339).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [339] source

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  • May combine two claims.

    Premisecitation

    The prevalence of adverse events associated with MMI and PTU were 21.4% and 18.8%, respectively.

    “The prevalence of adverse events associated with MMI and PTU were 21.4% and 18.8%, respectively (343).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [343] source

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  • May combine two claims.

    Premisecitation

    MMI may also be associated with ANCA-positive vasculitis, although this occurs far less frequently than with PTU.

    “MMI may also be associated with ANCA-positive vasculitis (329), although this occurs far less frequently than with PTU.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [329]

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  • May combine two claims.

    Premisecitation

    Iodine deficiency and exposure to radionuclides other than RAI may have contributed to the increased risk of thyroid cancer in young children after the Chernobyl reactor explosion.

    “It is also important to note that iodine deficiency and exposure to radionuclides other than RAI may have contributed to the increased risk of thyroid cancer in young children after the Chernobyl reactor explosion (315).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [315] source

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  • May combine two claims.

    Premisecitation

    There was no increase in the rate of spontaneous abortion or in the number of congenital anomalies in offspring.

    “There was no increase in the rate of spontaneous abortion or in the number of congenital anomalies in offspring.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] source

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  • May combine two claims.

    Premisecitation

    Some physicians restart ATDs after treatment with RAI, but this practice is seldom required in children.

    “Although some physicians restart ATDs after treatment with RAI (80), this practice is seldom required in children (309,310,350).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [80] source

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    • cites [309]

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    • cites [310] source

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    • cites [350] source

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  • May combine two claims.

    Premisecitation

    Physicians at some centers administer a fixed dose of about 15 mCi RAI to all children, whereas others calculate the activity from estimation or direct measurement of gland size and 123I uptake.

    “Physicians at some centers administer a fixed dose of about 15 mCi RAI to all children (350), whereas others calculate the activity from estimation or direct measurement of gland size and 123 I uptake (349).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [350] source

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    • cites [349] source

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  • May combine two claims.

    Interpretationreasoning

    If a small risk exists, a sample size of more than 10,000 children who were treated at <10 years of age would be needed to identify the risk, likely exceeding the number of such treated children.

    “If a small risk exists, a sample size of more than 10,000 children who were treated at <10 years of age would be needed to identify the risk, likely exceeding the number of such treated children.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Fewer than 10% of children complain of mild tenderness over the thyroid in the first week after therapy; it can be treated effectively with acetaminophen or nonsteroidal anti-inflammatory agents for 24-48 hours.

    “Fewer than 10% of children complain of mild tenderness over the thyroid in the first week after therapy; it can be treated effectively with acetaminophen or nonsteroidal anti-inflammatory agents for 24-48 hours (310,349).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [310] source

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    • cites [349] source

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  • May combine two claims.

    Premisecitation

    Data from one center suggest that if calcitriol is started 3 days before surgery (0.25 or 0.5 μg, twice daily), the need for postoperative calcium infusions is markedly reduced, leading to reduction in the length of stay.

    “Data from one center suggest that if calcitriol is started 3 days before surgery (0.25 or 0.5 lg, twice daily), the need for postoperative calcium infusions is markedly reduced, leading to reduction in the length of stay (318).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [318] source

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  • May combine two claims.

    Premisecitation

    Surgical complication rates are higher in children than in adults, with higher rates in younger than in older children.

    “Surgical complication rates are higher in children than in adults, with higher rates in younger than in older children (316,318).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [316] source

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    • cites [318] source

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  • May combine two claims.

    Premisecitation

    The administered activity of RAI to patients with very large goiters is high, and a tendency exists to underestimate the size of the gland and thereby administer insufficient RAI activities to these patients.

    “The administered activity of RAI to patients with very large goiters is high, and a tendency exists to underestimate the size of the gland (and thereby administer insufficient RAI activities to these patients) (90).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The patients ranged in age at treatment from 3 to 19 years.

    “The patients ranged in age at treatment from 3 to 19 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] source

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  • May combine two claims.

    Premisecitation

    Total-body radiation dose after RAI varies with age, and the same absolute activities of RAI will result in more radiation exposure to a young child than to an adolescent or adult.

    “Total-body radiation dose after RAI varies with age, and the same absolute activities of RAI will result in more radiation exposure to a young child than to an adolescent or adult (361).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [361] source

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  • May combine two claims.

    Premisecitation

    The risk of thyroid neoplasia is greatest with exposure to low-level external radiation (0.1-25 Gy; ~0.09-30 μCi/g or 3.33-1110 Bq/g), not with the higher administered activities used to treat GD.

    “The risk of thyroid neoplasia is greatest with exposure to low-level external radiation (0.1-25 Gy; *0.09-30 lCi/g or 3.33-1110 Bq/g) (314,315,352,354,357), not with the higher administered activities used to treat GD.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [314] source

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    • cites [315] source

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    • cites [352] source

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    • cites [354] source

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    • cites [357] source

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  • Classified as probably not a substantial claim.

    Premisereasoning

    RAI activities >150 μCi (>5.55 MBq/g) rather than smaller activities of RAI should be administered to achieve hypothyroidism.

    “Because of an increased risk of thyroid nodules and cancer associated with low-level thyroid irradiation in children (314,(352)(353)(354)) and poor remission rates with low-administered activities of RAI (88)(89)(90), it is important that RAI activities >150 lCi (>5.55 MBq/g) rather than smaller activities of RAI be administered to achieve hypothyroidism (312).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [312]

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  • May combine two claims.

    Premisecitation

    The average follow-up period was 10 years, and the mean administered activity of RAI to the thyroid was 88 Gy (approximately 80 μCi/g or 2.96 MBq/g equivalent), an activity known to be associated with thyroid neoplasia and below that recommended for treatment of GD.

    “The average follow-up period was 10 years, and the mean administered activity of RAI to the thyroid was 88 Gy (approximately 80 lCi/g or 2.96 MBq/g equivalent), an activity known to be associated with thyroid neoplasia and below that recommended for treatment of GD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [360] source

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  • May combine two claims.

    Premisecitation

    There are no data comparing outcomes of fixed versus calculated activities in children; in adults, similar outcomes have been reported with the two approaches.

    “There are no data comparing outcomes of fixed versus calculated activities in children; in adults, similar outcomes have been reported with the two approaches (356).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [356]

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  • May combine two claims.

    Study design and conductreasoning

    The sample size was small; thus, the statistical power was inadequate to address this issue fully.

    “It is important to note that the sample size was small; thus, the statistical power was inadequate to address this issue fully.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    No patient developed thyroid cancer or leukemia.

    “No patient developed thyroid cancer or leukemia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] source

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  • May combine two claims.

    Premisecitation

    The most recent data indicate that SH subjects appear to be at particular risk for the development of heart failure, especially older subjects and those with lower TSH levels.

    “The most recent data indicate that SH subjects appear to be at particular risk for the development of heart failure (381,388,392), especially older subjects (381,392) and those with lower TSH levels (392).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [381] source

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    • cites [388] source

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    • cites [392] source

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  • May combine two claims.

    Premisecitation

    Some other, smaller studies have reached similar conclusions, although other smaller studies have failed to find a correlation.

    “Some other, smaller studies have reached similar conclusions (374,383), although other smaller studies have failed to find a correlation (380,381,384,386).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [374] source

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    • cites [383] source

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    • cites [380] source

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    • cites [381] source

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    • cites [384] source

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    • cites [386] source

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  • May combine two claims.

    Premisecitation

    Some studies report increased overall mortality rates in SH subjects, especially older subjects, while others indicate no relation.

    “Some studies report increased overall mortality rates in SH subjects (374,379-383), especially older subjects, while others indicate no relation (384)(385)(386)(387).”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [374] source

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    • cites [379] source

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    • cites [380] source

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    • cites [381] source

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    • cites [382] source

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    • cites [383] source

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    • cites [384] source

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    • cites [385] source

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    • cites [386] source

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    • cites [387] source

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  • May combine two claims.

    Premisecitation

    Both analyses concluded that SH confers an increased risk of cardiovascular mortality, with hazard ratios of 1.52 and 1.29.

    “Both analyses concluded that SH confers an increased risk of cardiovascular mortality, with hazard ratios of 1.52 (390) and 1.29 (388).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [390] source

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    • cites [388] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Similar rates have been reported in studies from Europe, with higher levels in women and older subjects.

    “Similar rates have been reported in studies from Europe, with higher levels in women and older subjects (366,367).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [366] source

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    • cites [367] source

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  • May combine two claims.

    Premisecitation

    In a representative sample of U.S. subjects without known thyroid disease, 0.7% had suppressed TSH levels (<0.1 mU/L), and 1.8% had low TSH levels (<0.4 mU/L).

    “In a representative sample of U.S. subjects without known thyroid disease, 0.7% had suppressed TSH levels (<0.1 mU/L), and 1.8% had low TSH levels (<0.4 mU/L) (365).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [365] source

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  • May combine two claims.

    Premisecitation

    There have been two recent meta-analyses that examined this question, one of study-level data of 17 cohorts and the other of individual-level data in 52,674 participants.

    “There have been two recent meta-analyses that examined this question, one of study-level data of 17 cohorts (390) and the other of individual-level data in 52,674 participants (388).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [390] source

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    • cites [388] source

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  • May combine two claims.

    Premisecitation

    Mean serum TSH levels are lower in black non-Hispanic Americans, some of whom may have slightly low TSH levels without thyroid disease.

    “In addition, mean serum TSH levels are lower in black non-Hispanic Americans, some of whom may have slightly low TSH levels without thyroid disease (365).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [365] source

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  • May combine two claims.

    Premisecitation

    The natural history of SH is variable, with annualized rates of 0.5%-7% progression to overt hyperthyroidism and 5%-12% reversion to normal TSH levels.

    “The natural history of SH is variable (367,370-377), with annualized rates of 0.5%-7% progression to overt hyperthyroidism and 5%-12% reversion to normal TSH levels.”
    Quote in the paperSubstantial claim0 of 9 sources checked
    • cites [367] source

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    • cites [370]

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    • cites [371]

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    • cites [372] source

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    • cites [373]

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    • cites [374] source

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    • cites [375] source

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    • cites [376] source

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    • cites [377] source

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  • May combine two claims.

    Premisecitation

    Mechanistic correlates of these findings include increased left ventricular mass and impaired left ventricular function in SH that improve with treatment.

    “Mechanistic correlates of these findings include increased left ventricular mass and impaired left ventricular function in SH that improve with treatment (393-396).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [393] source

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    • cites [394] source

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    • cites [395] source

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    • cites [396] source

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  • May combine two claims.

    Premisecitation

    Absolute incidence rates of atrial fibrillation were much lower in younger subjects; women under 65 years had incidence rates of 2.3 events per 1000 person-years (relative risk 1.89), while women 65 years and older had incidence rates of 22.7 per 1000 person-years (relative risk 1.27).

    “However, absolute incidence rates of atrial fibrillation were much lower in younger subjects; for example, women under the age of 65 years had atrial fibrillation incidence rates of 2.3 events per 1000 personyears (relative risk of 1.89 compared to age-matched euthyroid women), while women 65 years and older had incidence rates of 22.7 per 1000 person-years (relative risk of 1.27 compared to age-”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [401] source

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  • May combine two claims.

    Premisecitation

    Three studies could find no correlation, while the fourth found a correlation between SH and lower physical performance in men only.

    “Three could find no correlation, while the fourth found a correlation between SH and lower physical performance in men only (425).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [425] source

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  • May combine two claims.

    Premisecitation

    A number of population-based studies have reported that certain groups of subjects with SH have increased fracture rates, including all adults, postmenopausal women, men, or subjects who progress to overt hyperthyroidism over time.

    “A number of population-based studies have reported that certain groups of subjects with SH have increased fracture rates, including all adults (407), postmenopausal women (408), men (409), or subjects who progress to overt hyperthyroidism over time (391).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [407] source

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    • cites [408] source

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    • cites [409] source

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    • cites [391] source

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  • May combine two claims.

    Premisecitation

    In the largest study to date (586,460 people followed for a median of 5.5 years), the highest relative risk for atrial fibrillation occurred in younger subjects and in subjects with lower TSH levels.

    “In the largest study to date (586,460 people followed for a median of 5.5 years), the highest relative risk for atrial fibrillation occurred in younger subjects, possibly because other causes predominate with age, and in subjects with lower TSH levels (401).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [401] source

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  • May combine two claims.

    Premisecitation

    Two studies have shown impaired glucose tolerance and decreased insulin sensitivity in SH, suggesting this may contribute to increased cardiovascular risk.

    “In addition, two studies have shown impaired glucose tolerance and decreased insulin sensitivity in SH, suggesting this may contribute to increased cardiovascular risk (397,398).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [397]

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    • cites [398]

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  • May combine two claims.

    Premisecitation

    Risks did not differ when stratified by age, although absolute fracture rates were lower in younger subjects.

    “Risks did not differ when stratified by age, although absolute fracture rates were lower in younger subjects.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [413]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A large body of literature has investigated possible correlations between SH and cognitive decline.

    “A large body of literature has investigated possible correlations between SH and cognitive decline [reviewed by Gan and Pearce (418), with more recent studies by others (419,420)].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [418] source

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    • cites [419] source

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    • cites [420]

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  • May combine two claims.

    Premisecitation

    Most studies of endogenous SH show decreased bone mineral density in postmenopausal women, but not in men or premenopausal women.

    “Most studies of endogenous SH show decreased bone mineral density in postmenopausal women, but not in men or premenopausal women (406).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [406] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Four studies have investigated whether SH is associated with self-reported functional capacity or objective measures of physical functioning.

    “Four studies have investigated whether SH is associated with self-reported functional capacity or objective measures of physical functioning (420, 423-425).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [420]

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    • cites [423] source

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    • cites [424] source

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    • cites [425] source

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  • May combine two claims.

    Premisenone given

    PTU-associated birth defects may occur in 2%-3% of children but mostly seem to be less severe.

    “PTU-associated birth defects are less well documented.They may occur in 2%-3% of children but they mostly seem to be less severe.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MMI-associated birth defects may be observed in 2%-4% of exposed children and include aplasia cutis; choanal atresia, esophageal, and other gut atresias; abdominal wall abnormalities including omphalocale; and eye, heart, and urinary tract malformations.

    “Defects that may be observed in 2%-4% of exposed children (462,463) have included aplasia cutis; choanal atresia, esophageal, and other types of gut atresias; abdominal wall abnormalities including omphalocale; and eye, heart, and urinary tract malformations.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [462] source

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    • cites [463] source

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  • May combine two claims.

    Premisenone given

    Both thyrotoxicosis and its therapy may seriously complicate the course and outcome of pregnancy.

    “Both the thyrotoxicosis and therapy of the disease may seriously complicate the course and outcome of pregnancy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hyperthyroidism due to Graves' disease occurs in 0.5%-1.0% of women in the reproductive age range.

    “Hyperthyroidism due to GD occurs in 0.5%-1.0% of women in the reproductive age range (432), and 0.1%-0.2% of them are treated with ATD during pregnancy (433,434).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [432] source

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The treatment of subclinical hyperthyroidism is similar to the treatment of overt hyperthyroidism.

    “The treatment of SH is similar to the treatment of overt hyperthyroidism.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Treatment of subclinical hyperthyroidism with TSH between 0.1 mU/L and the lower limit of the reference range improves clinical outcomes.

  • May combine two claims.

    Premisenone given

    Reference ranges for thyroid function tests are different during different stages of pregnancy, and these changes may be assay dependent.

    “A key point is that reference ranges for thyroid function tests are different during different stages of pregnancy, and these changes may be assay dependent.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    In 2004, a panel of experts determined that the evidence for benefit was sufficient to warrant therapy of SH in older individuals whose serum TSH level was <0.1 mU/L.

    “In 2004, a panel of experts determined that the evidence for benefit was sufficient to warrant therapy of SH in older individuals whose serum TSH level was <0.1 mU/L (427).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [427] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    A TSH level between 0.1 and 0.4 mU/L on repeated measurement over a 3- to 6-month period is considered persistent and effectively rules out transient thyroiditis as a cause.

    “A TSH level between 0.1 and 0.4 mU/ L on repeated measurement over a 3-to 6-month period is considered persistent, effectively ruling out transient thyroiditis as a cause.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The European Thyroid Association recently reviewed these data and published guidelines for the treatment of subclinical hyperthyroidism, which are largely concordant with recommendations presented here.

    “The European Thyroid Association recently reviewed these data and published guidelines for the treatment of subclinical hyperthyroidism, which are largely concordant with recommendations presented here (428).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [428] source

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  • May combine two claims.

    Premisecitation

    MMI and PTU both appear in breast milk in only small concentrations, and studies of breastfed infants of mothers taking antithyroid drugs have demonstrated normal thyroid function and subsequent normal intellectual development.

    “MMI and PTU both appear in breast milk in only small concentrations, and studies of breastfed infants of mothers taking ATDs have demonstrated normal thyroid function and subsequent normal intellectual development (109).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approximately 5% of patients with newly diagnosed Graves' hyperthyroidism are TRAb negative in older assays, and 3% are negative in third-generation assays, especially those with milder disease.

    “Approximately 5% of patients with newly diagnosed Graves' hyperthyroidism are TRAb negative in older assays (47,455), and 3% are negative in third-generation assays ( 57), especially those with milder disease.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [47] source

      Not checked in the free run.

    • cites [455]

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    • cites [57]

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  • May combine two claims.

    Premisenone given

    Clinical features that indicate hyperthyroidism in pregnancy include failure to gain weight, heat intolerance, excessive sweating, and tachycardia beyond that normally associated with pregnancy.

    “Clinical features that indicate the presence of hyperthyroidism include fail-ure to gain weight, heat intolerance, excessive sweating, and tachycardia beyond that normally associated with pregnancy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Excluding patients with TSH suppression or gestational thyrotoxicosis during the first trimester, Graves' disease is the most common cause of hyperthyroidism during pregnancy; nodular thyroid disease is less common.

    “Excluding patients with TSH suppression or gestational thyrotoxicosis during the first trimester, GD is the most common cause of hyperthyroidism during pregnancy (431,444); nodular thyroid disease is less common.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [431] source

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    • cites [444]

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  • May combine two claims.

    Premisenone given

    Both antithyroid drugs and TRAb pass through the placenta and can affect the fetal thyroid.

    “Both ATDs and TRAb pass through the placenta and can affect the fetal thyroid.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Although the second trimester is the safest time for thyroidectomy in pregnancy, it is not without risk, with a 4.5%-5.5% risk of preterm labor.

    “Although it is the safest time, it is not without risk (4.5%-5.5% risk of preterm labor) (67,68).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [67] source

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    • cites [68] source

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  • May combine two claims.

    Premisecitation

    Both agranulocytosis and liver failure developing during MMI and PTU therapy mostly occur during the initial 3 months of therapy, but this risk can recur when the drug is reintroduced after a relatively long period.

    “Another aspect to consider is that both agranulocytosis and liver failure developing during MMI and PTU therapy mostly occur during the initial 3 months of therapy (128), but this risk can recur when the drug is reintroduced after a relatively long period of time (177).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [128] source

      Not checked in the free run.

    • cites [177] source

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  • May combine two claims.

    Premisecitation

    The diagnostic sensitivity of good TRAb assays is around 95% and the specificity is 99%.

    “TRAb measurement is useful in the diagnosis of GD in pregnant women with newly diagnosed hyperthyroidism who do not have clinical signs specific for GD, keeping in mind that the diagnostic sensitivity of good assays is around 95% and the specificity is 99% (47).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Beta-adrenergic blocking agents have been studied extensively for treating hypertension in pregnancy, and no major side effects have been detected, although fetal growth restriction has been associated with prolonged use of especially atenolol.

    “These agents have been studied extensively when used for treating hypertension in pregnancy, and no major side effects have been detected, although fetal growth restriction has been associated with the prolonged use of especially atenolol (431,471).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [431] source

      Not checked in the free run.

    • cites [471] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The fetal thyroid gland is particularly susceptible to the inhibitory effects of excess iodine in the second half of gestation, and fetal goiter can occur with chronic therapy.

    “The fetal thyroid gland is particularly susceptible to the inhibitory effects of excess iodine in the second half of gestation, and fetal goiter can occur with chronic therapy (496).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [496] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a population-based U.S. study, pregnant women had worse clinical and economic outcomes following thyroid (and parathyroid) surgery than nonpregnant women, with disparities based on race/ethnicity, insurance, and access to high-volume surgeons.

    “In a population-based U.S. study, pregnant women had worse clinical and economic outcomes following thyroid (and parathyroid) surgery than nonpregnant women, with disparities in outcomes based on race/ethnicity, insurance, and access to high-volume surgeons (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thyroidectomy cures hyperthyroidism and is often followed by a gradual reduction in circulating TRAb.

    “Thyroidectomy cures the hyperthyroidism and is often followed by a gradual reduction in circulating TRAb (495).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [495] source

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  • May combine two claims.

    Premisecitation

    Smoking and orbitopathy predicted slow disappearance of TRAb (half-life 162 days, or 357 days if both factors were present), whereas TRAb levels decreased with a half-life of 94 days in the remaining patients.

    “Smoking and the presence of orbitopathy predicted slow disappearance of TRAb (half-life 162 days, or 357 days if both factors were present), whereas TRAb levels in serum decreased with a half-life of 94 days in the remaining patients (472).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [472]

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Both maternal thyroid dysfunction and therapy of hyperthyroidism may have negative effects on pregnancy outcome.

    “Both maternal thyroid dysfunction and therapy of the hyperthyroidism may have negative effects on the pregnancy outcome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Thyroidectomy is often followed by a decrease or disappearance of TRAb from circulation, whereas radioactive iodine therapy is often followed by a transient increase in TRAb.

    “Thyroidectomy is often followed by a decrease or disappearance of TRAb from circulation, whereas RAI is often followed by a transient increase in TRAb.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both MMI and PTU are effective therapies of hyperthyroidism in the majority of patients, and the major effect of both drugs is interaction with thyroid peroxidase-catalyzed thyroid hormone production.

    “Both MMI and PTU are effective therapies of hyperthyroidism in the majority of patients, and the major effect of both drugs is interaction with thyroid peroxidase-catalyzed thyroid hormone production (109).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MMI-associated defects are more severe, whereas PTU-associated defects tend to be less severe and may not be diagnosed immediately after birth.

    “The reason seems to be that MMIassociated defects are more severe, whereas PTU-associated defects tend to be less severe and may not be diagnosed immediately after birth (466).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [466]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with difficult-to-treat hyperthyroidism during pregnancy may show a high T3-low T4 pattern during ATD therapy, presumably caused by high type 1 deiodinase activity in the hyperactive thyroid and preferential T3 synthesis in the hyperstimulated thyroid made iodine deficient from ATD therapy.

    “Such patients may show a ''high T 3 -low T 4 pattern'' during ATD therapy (444) presumably caused by a high type 1 deiodinase activity in the hyperactive thyroid (493) and preferential T 3 synthesis in the hyperstimulated thyroid made iodine deficient from ATD therapy (494).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [444]

      Not checked in the free run.

    • cites [493]

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    • cites [494] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Disappearance of TRAb is an indication that ATD therapy may no longer be necessary, and its continuation may put the fetus at risk for hypothyroidism even if the mother is euthyroid on the medication.

    “Disappearance of TRAb is an indication that ATD therapy may no longer be necessary and its continuation may put the fetus at risk for hypothyroidism, even if the mother is euthyroid on the medication.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    TRAb (TBII or TSI) measurement may be useful to assist in the evaluation of disease activity in a woman being treated with ATDs for GD during pregnancy.

    “TRAb (TBII or TSI) measurement may be useful to assist in the evaluation of disease activity in a woman being treated with ATDs for GD during pregnancy (444,495).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [444]

      Not checked in the free run.

    • cites [495] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    Most often, the use of radioactive substances can be avoided and the diagnosis of postpartum thyrotoxicosis can be based on a combination of clinical presentation, TRAb measurement, and evaluation of serum T4 and T3.

    “Most often, the use of radioactive substances can be avoided and the diagnosis can be based on a combination of clinical presentation, TRAb measurement, and evaluation of serum T 4 and T 3 .”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Identified risk factors for GO include RAI therapy for hyperthyroidism, untreated hyperthyroidism, smoking, high serum pretreatment TRAb levels, and any delay in treating hypothyroidism after therapy for hyperthyroidism.

    “for GO are listed in Table 15, and the most pertinent ones to this discussion are RAI therapy for hyperthyroidism (531,532), untreated hyperthyroidism, smoking, high serum pretreatment TRAb levels (normal <1.75 IU/L, high risk for progression if >8.8 IU/L) (533), and any delay in treating hypothyroidism after therapy for hyperthyroidism (106,534).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [531] source

      Not checked in the free run.

    • cites [532] source

      Not checked in the free run.

    • cites [533] source

      Not checked in the free run.

    • cites [106] source

      Not checked in the free run.

    • cites [534] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    More recent studies do not identify a clear sex-related risk for GO, while some older studies point to a possible slightly increased risk for men.

    “More recent studies do not identify a clear sex-related risk for GO (517,518), while some older studies point to a possible slightly increased risk for men (519,520).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [517] source

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    • cites [518] source

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    • cites [519]

      Not checked in the free run.

    • cites [520] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In this study, tobacco smoking and bottle-feeding increased the risk of developing thyroiditis.

    “In this study, tobacco smoking and bottle-feeding increased the risk of developing thyroiditis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [507] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    After delivery, ATD delivered to the fetus via placental passage is rapidly metabolized by the neonate, whereas maternal TRAb disappears more slowly, with a half-life of around 3 weeks.

    “After delivery, ATD delivered to the fetus via placental passage is rapidly metabolized by the neonate, whereas the maternal TRAb disappears more slowly, with a half-life of around 3 weeks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TRAb may occasionally be measurable in patients with postpartum thyroiditis, suggesting that some patients may experience a combination of GD and destructive thyroiditis, but higher TRAb values are suggestive of GD.

    “TRAb may occasionally be measurable in patients with postpartum thyroiditis, suggesting that some patients may experience a combination of GD and destructive thyroiditis (509), but higher TRAb values are suggestive of GD.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [509] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Approximately a third of patients with Graves' hyperthyroidism have some signs and/or symptoms of GO, while only 5% have moderate-to-severe disease.

    “Approximately a third of patients with Graves' hyperthyroidism have some signs and/or symptoms of GO, while only 5% have moderate-to-severe disease (517,518).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [517] source

      Not checked in the free run.

    • cites [518] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The clinical activity score (CAS) ranges from 0 to 10 and predicts response to anti-inflammatory therapies.

    “The score ranges from 0 to 10 and predicts response to anti-inflammatory therapies (523,524).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [523] source

      Not checked in the free run.

    • cites [524] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hyperthyroidism caused by thyroid autonomy is very common in people having current or previous mild to moderate iodine deficiency, but it mostly develops in patients after the age of 50 years.

    “Hyperthyroidism caused by thyroid autonomy is very common in people having current (or previous) mild to moderate iodine deficiency (13), but it mostly develops in patients after the age of 50 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Propranolol and metoprolol are secreted into breast milk in only very low amounts, so no special monitoring is needed for breastfed infants of mothers on these medications.

    “Because propranalol and metoprolol are secreted into breast milk in only very low amounts, no special monitoring is needed for breastfed infants of mothers on these medications (514).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [514] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Levothyroxine therapy may be beneficial, at least transiently, for women with symptomatic hypothyroidism or those having TSH levels >10 mU/L.

    “Levothyroxine therapy may be beneficial, at least transiently, for women with symptomatic hypothyroidism or those having TSH levels >10 mU/L (506).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [506] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The fetus will not develop hyperthyroidism in parallel with the untreated hyperthyroid mother as happens during the second half of pregnancy in GD, and neonatal hyperthyroidism is not a risk.

    “Thus, the fetus will not develop hyperthyroidism in parallel with the untreated hyperthyroid mother as it happens during the second half of pregnancy in GD, and neonatal hyperthyroidism is not a risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a recent study of 47 newborns to mothers who were TRAb positive in pregnancy, nine had neonatal biochemical hyperthyroidism, and five of these (9% of all) needed ATD therapy.

    “In a recent study of 47 newborns to mothers who were TRAb positive in pregnancy, nine of the children had neonatal biochemical hyperthyroidism, and five of these (9% of all) needed ATD therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [504] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GO peaks in incidence in the fifth and sixth decade of life, with a higher prevalence of severe cases in the elderly population.

    “The disease peaks in incidence in the fifth and sixth decade of life (517,518,521,522) with a higher prevalence of severe cases in the elderly population (517).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [517] source

      Not checked in the free run.

    • cites [518] source

      Not checked in the free run.

    • cites [521]

      Not checked in the free run.

    • cites [522]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GO is an inflammatory eye disease that develops in the orbit in association with autoimmune thyroid disorders.

    “GO is an inflammatory eye disease that develops in the orbit in association with autoimmune thyroid disorders (516).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [516]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a Japanese hospital study, thyrotoxicosis caused by thyroiditis developed earlier after delivery than GD, although some overlap existed.

    “In a Japanese hospital study, thyrotoxicosis caused by thyroiditis developed earlier after delivery than GD, although some overlap existed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [508] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Thyroidal production of T3 compared with T4 is relatively high in GD, but not in destructive thyroiditis, and T3 tends to be fractionally more elevated above the upper reference limit compared with T4 in GD, whereas T4 is more elevated than T3 in destructive thyroiditis.

    “Thyroidal production of T 3 compared with T 4 is relatively high in GD, but not in destructive thyroiditis, and T 3 tends to be fractionally more elevated above the upper reference limit compared with T 4 in GD, whereas T 4 is more elevated than T 3 in destructive thyroiditis (50).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] source

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  • May combine two claims.

    Interpretationcitation

    The adverse effect of atenolol in neonates presumably develops because atenolol is <5% bound to maternal plasma proteins (vs 93% binding of propranolol), and thus accumulates in milk, and because of low kidney excretion of atenolol in small children with immature renal function.

    “This adverse effect presumably develops because atenolol is <5% bound to maternal plasma proteins (vs.93% binding of propranolol), and thus accumulates in milk, and because of low kidney excretion of atenolol in small children with immature renal function (515).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [515] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All patients who developed overt thyrotoxicosis within the first 3 months after delivery suffered from destructive thyroiditis, whereas GD developed after this 3-month period.

    “All patients who developed overt thyrotoxicosis within the first 3 months after delivery suffered from destructive thyroiditis, whereas GD developed after this 3-month period (508).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [508] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among 371 cases in 13 studies, 25% of patients had a triphasic pattern, 43% had hypothyroidism without preceding thyrotoxicosis, and 32% had thyrotoxicosis without subsequent hypothyroidism.

    “Among 371 cases in 13 studies, 25% of patients were found to have a triphasic pattern, 43% had hypothyroidism without preceding thyrotoxicosis, and 32% had thyrotoxicosis without subsequent hypothyroidism (506).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [506] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some eye changes seen in hyperthyroidism, like lid retraction or stare, result from the increased sympathetic state, and when present without associated eye changes, they are not considered to reflect GO.

    “However, some of the eye changes seen in hyperthyroidism, like lid retraction or stare, result from the increased sympathetic state, and when present without associated eye changes, they are not considered to reflect GO (69).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Smoking is the most important known risk factor for the development or worsening of GO, unrelated to type of therapy for GO, and consistent data from several studies show a detrimental effect of smoking on GO in patients treated with RAI.

    “Smoking is the most important known risk factor for the development or worsening of GO, unrelated to type of therapy for GO (535), and consistent data from several studies show a detrimental effect of smoking on GO in patients a ATDs or thyroidectomy are also recommended treatment options in each of these scenarios, and they are the preferred choice of therapy in patients with active and moderate-”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [535] source

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    • cites [69] source

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    • cites [531] source

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  • May combine two claims.

    Premisecitation

    A more recent study suggests that surgery might lead to a more rapid improvement in GO than ATDs, and it might thus be a better option for patients that are most concerned about GO changes.

    “Additionally, a more recent study suggests that surgery might lead to a more rapid improvement in GO than ATDs, and it might thus be a better option for patients that are most concerned about GO changes (548).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [548] source

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  • May combine two claims.

    Premisecitation

    Two randomized controlled trials found the risk of new GO development to be 6/78 (8%) for RAI compared with 1/74 (1%) for ATDs in one study, and 10/32 (32%) for RAI compared with 6/56 (11%) for ATDs and 6/58 (10%) for surgery in an older study.

    “Two randomized controlled trials found the risk to be 6/78 (8%) for RAI compared with 1/74 (1%) for ATDs (531) in one study, and 10/32 (32%) for RAI compared with 6/56 (11%) for ATDs and 6/58 (10%) for surgery (532) in the older study.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [531] source

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    • cites [532] source

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  • May combine two claims.

    Premisecitation

    In a recent Japanese trial, the rate of disease progression in the absence of risk factors was low (4.2%) and not impacted by glucocorticoid therapy.

    “The rate of disease progression in the absence of risk factors was low (4.2%) and not impacted by glucocorticoid therapy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [540] source

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  • May combine two claims.

    Premisecitation

    The most recent randomized controlled trial revealed an increased risk for new or worse GO in RAI-treated patients (38.7%) compared with ATD-treated patients (21.3%), mainly related to development of new GO cases, while worsening of preexisting GO occurred at a similar percentage in both groups (45% for RAI and 47% for ATD).

    “Finally, the most recent randomized controlled trial (69) revealed an increased risk for new or worse GO in RAI-treated patients (38.7% of the group) compared with ATD-treated patients (21.3% of the group), to be mainly related to development of new GO cases, while worsening of preexisting GO occurred at a similar percentage in both groups (45% for RAI and 47% for ATD).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] source

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  • May combine two claims.

    Premisecitation

    In a series of 42 patients with progressive GO treated with total thyroidectomy, exophthalmos was stable in 60% of cases and improved in the remainder, suggesting that surgery is not detrimental to GO and may be associated with improvement in some patients.

    “In another series of 42 patients with progressive GO treated with total thyroidectomy, exophthalmos was stable in 60% of cases and improved in the remainder (547), suggesting that surgery is not detrimental to GO and may be associated with improvement in some patients.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [547] source

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  • May combine two claims.

    Premisecitation

    A large, more recent randomized controlled trial studying mainly patients with previously treated GD showed RAI therapy to be associated with an increased risk of GO progression (RR 5.8 in comparison with ATDs) and found the risk to be eliminated with concurrent corticosteroid administration.

    “A large, more recent randomized controlled trial studying mainly patients with previously treated GD showed RAI therapy to be associated with an increased risk of GO progression (RR of 5.8 in comparison with ATDs) and found the risk to be eliminated with concurrent corticosteroid administration (531).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [531] source

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  • May combine two claims.

    Premisecitation

    The risk of GO from smoking is proportional to the number of cigarettes smoked per day, and former smokers have significantly lower risk than current smokers, even after adjusting for lifetime cigarette consumption.

    “The risk is proportional to the number of cigarettes smoked per day, and former smokers have significantly lower risk than current smokers, even after adjusting for lifetime cigarette consumption (537).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [537] source

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  • May combine two claims.

    Premisecitation

    One prospective but nonrandomized cohort study identified no difference among ATD, surgery, and RAI treatment, with an overall 4.9%-7.1% frequency of GO development.

    “In contrast, one prospective but nonrandomized cohort study identified no difference among ATD, surgery, and RAI treatment, with an overall 4.9%-7.1% frequency of GO development (541).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [541] source

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  • May combine two claims.

    Premisecitation

    High pretreatment levels of T3 and T4 were each reported to have a predictive role in GO, but these conclusions were not validated by subsequent studies.

    “High pretreatment levels of T 3 and T 4 were each reported to have a predictive role in GO, but these conclusions were not validated by subsequent studies (69,106,532,534), suggesting the possibility of higher TRAb values measured on less sensitive assays early-on being partly responsible for this variation.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [69] source

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    • cites [106] source

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    • cites [532] source

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    • cites [534] source

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  • May combine two claims.

    Premisecitation

    Cases of new or worse GO were usually mild, with only 6/168 patients in the second trial requiring specific therapy for GO.

    “Fortunately, the cases of new or worse GO were usually mild, with only 6/ 168 patients in this second trial (four in the RAI group, one in the ATD group, and one in the surgical group) requiring specific therapy for GO.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [532] source

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  • May combine two claims.

    Premisecitation

    In the Japanese trial, most GO cases were mild, and only 7 cases (2.4%) required GO-directed therapy.

    “Ultimately, most GO cases were mild, and only 7 cases (2.4%) required GO-directed therapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [540] source

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  • May combine two claims.

    Premisecitation

    Other studies suggest that ATDs may not adversely impact mild active GO, but they do not address severe GO.

    “Other studies suggest that ATDs may not adversely impact mild active GO, but they do not address severe GO (531).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [531] source

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  • May combine two claims.

    Premisecitation

    Long-term use of ATDs is relatively safe and effective at preserving euthyroidism while waiting for GO to enter remission.

    “Alternatively, if ATDs are selected for GD therapy, there are reassuring data that long-term use is relatively safe and effective at preserving euthyroidism while waiting for GO to enter remission (66,549).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66]

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    • cites [549]

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  • May combine two claims.

    Premisecitation

    The presence of risk factors for GO (high thyroid stimulating antibody, CAS ≥1) increased the risk of progression, again without a benefit from low-dose steroid prophylaxis.

    “The presence of risk factors for GO (high thyroid stimulating antibody, CAS ‡1) increased that risk, again without a benefit from low-dose steroid prophylaxis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [540] source

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  • May combine two claims.

    Premisecitation

    Type 2 AIT typically responds to treatment even if amiodarone therapy is continued, but continuation may lead to a more prolonged time to recovery and a higher rate of future recurrences of AIT.

    “In addition, type 2 AIT typically responds to treatment even if amiodarone therapy is continued (585-587), but continuation may lead to a more prolonged time to recovery and a higher rate of future recurrences of AIT (588).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [585] source

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    • cites [586] source

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    • cites [587] source

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    • cites [588] source

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  • May combine two claims.

    Premisecitation

    Two distinct mechanisms have been proposed in the development of AIT: an iodine-induced form of hyperthyroidism (type 1 AIT) due to the high iodine content of amiodarone (37% by molecular weight) and a destructive thyroiditis (type 2 AIT) due to direct toxicity of amiodarone on follicular cells.

    “Two distinct mechanisms have been proposed in the development of AIT, including an iodine-induced form of hyperthyroidism (type 1 AIT) due to the high iodine content of amiodarone (37% by molecular weight) and a destructive thyroiditis (type 2 AIT) due to direct toxicity of amiodarone on follicular cells.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [579] source

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    • cites [580] source

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    • cites [581]

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    • cites [582] source

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  • May combine two claims.

    Premisecitation

    A recent US case-control study found that iodinated contrast exposure in patients without baseline thyroid abnormality resulted in hyperthyroidism (defined only as a suppressed TSH value) with an odds ratio of 1.98 (95% CI, p = 0.03), and that 23 patients would need to be exposed before encountering one case of iodine-induced thyrotoxicosis.

    “A recent case-control study in the United States found that iodinated contrast exposure in patients without baseline thyroid abnormality resulted in hyperthyroidism (defined only as a suppressed TSH value) with an odds ratio of 1.98 ([95% CI,, p = 0.03), and that 23 patients would need to be exposed before encountering one case of iodineinduced thyrotoxicosis (570).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [570] source

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  • May combine two claims.

    Premisecitation

    In an Australian study from a region of iodine sufficiency, 2 of 72 (2.8%) patients developed overt hyperthyroidism and an additional two patients developed subclinical hyperthyroidism within 8 weeks of iodinated contrast exposure.

    “an Australian study from a region of iodine sufficiency found that 2 of 72 (2.8%) of patients developed overt hyperthyroidism and an additional two patients developed subclinical hyperthyroidism within 8 weeks of iodinated contrast exposure (562).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [562] source

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  • May combine two claims.

    Premisecitation

    Elderly patients with autonomously functioning nodular goiters are the most susceptible to iodine-induced hyperthyroidism; less commonly, patients with occult GD or prior GD in remission after ATDs are susceptible.

    “Individuals who are the most susceptible are elderly patients with autonomously functioning nodular goiters (557) and, less commonly, patients with occult GD (558) or patients with a prior history of GD who are in remission after a course of ATDs (559).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [557] source

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    • cites [558] source

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    • cites [559]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Only two of these cases had preexistent inactive GO.

    “Only two of these cases had preexistent inactive GO.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [550] source

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  • May combine two claims.

    Premisecitation

    Chronic iodine deficiency increases the prevalence of autonomous thyroid nodules, and iodine repletion in this setting has historically been linked to iodine-induced hyperthyroidism.

    “Chronic iodine deficiency increases the prevalence of autonomous thyroid nodules, and therefore iodine repletion in this setting has historically been linked to iodine-induced hyperthyroidism (561).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [561]

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  • May combine two claims.

    Premisecitation

    Amiodarone-induced thyrotoxicosis (AIT) occurs in up to 6% of patients taking amiodarone in iodine-sufficient areas and in up to 10% in iodine-deficient areas.

    “Amiodarone-induced thyrotoxicosis (AIT) occurs in up to 6% of patients taking this medication in iodine-sufficient areas of the world (573-575) and in up to 10% in iodinedeficient areas, such as parts of Europe (576).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [573]

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    • cites [574]

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    • cites [575]

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    • cites [576]

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  • May combine two claims.

    Premisecitation

    Iodine-induced hyperthyroidism is uncommon in modern series and generally self-limited, but it may occasionally persist for months and may be life-threatening.

    “Iodine-induced hyperthyroidism (the Jod-Basedow phenomenon) is uncommon in modern series and generally selflimited, but it may occasionally persist for months (551,552) and may be life-threatening (553-556).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [551]

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    • cites [552]

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    • cites [553]

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    • cites [554]

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    • cites [555]

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    • cites [556]

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    For most clinical circumstances, the likelihood of developing overt thyrotoxicosis after iodinated contrast exposure is too low to justify the risk of adverse effects associated with prophylactic ATD therapy.

    “For most clinical circumstances, the likelihood of developing overt thyrotoxicosis after iodinated contrast exposure is too low to justify the risk of adverse effects associated with prophylactic ATD therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The need for amiodarone discontinuation is controversial because amiodarone is frequently the only medication able to control cardiac arrhythmia, its effects may persist for many months, and it may have T3-antagonistic properties at the cardiac level and inhibit T4 to T3 conversion in the heart such that withdrawal may aggravate cardiac manifestations of thyrotoxicosis.

    “The need for amiodarone discontinuation is controversial because (i) this drug is frequently the only medication able to control cardiac arrhythmia, (ii) the effects of this fat-soluble drug may persist for many months, (iii) amiodarone may have T 3 -antagonistic properties at the cardiac level and inhibit T 4 to T 3 conversion in the heart ( 583) such that withdrawal may actually aggravate cardia”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [583]

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    • cites [573]

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  • May combine two claims.

    Interpretationreasoning

    In summary, iodine-induced hyperthyroidism is uncommon and generally subclinical, but it can occasionally be severe.

    “In summary, iodine-induced hyperthyroidism is uncommon and generally subclinical, but it can occasionally be severe.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a Boston study, 5 of 49 (10.2%) patients developed a suppressed TSH value 1-4 weeks following exposure to a single CT study with contrast, with only one patient developing overt hyperthyroidism.

    “A study of patients living in Boston showed that 5 of 49 (10.2%)developed a suppressed TSH value 1-4 weeks following exposure to a single computed tomography (CT) study with contrast, with only one patient developing overt hyperthyroidism (565).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [565] source

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  • May combine two claims.

    Premisecitation

    Type 1 AIT tends to occur in patients with underlying thyroid autonomy in a nodular goiter or GD, whereas type 2 AIT occurs as a result of direct damage or induction of apoptosis in thyrocytes by amiodarone.

    “Type 1 AIT tends to occur in patients with underlying thyroid autonomy in a nodular goiter, or GD, whereas type 2 AIT occurs as a result of direct damage or induction of apoptosis in thyrocytes by amiodarone (579-582).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [579] source

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    • cites [580] source

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    • cites [581]

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    • cites [582] source

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  • May combine two claims.

    Premisecitation

    Interleukin-6 levels and RAIU values overlap extensively between the two subtypes and are therefore not useful for distinguishing them.

    “Interleukin-6 levels and RAIU values, once promoted as useful for distinguishing between subtypes (590), actually overlap extensively between the two subtypes and are therefore also not useful (594).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [594]

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  • May combine two claims.

    Premisecitation

    Patients taking lithium for bipolar disorder are at a high risk of developing thyroid dysfunction, including both hypothyroidism and to a lesser extent thyrotoxicosis.

    “Patients taking lithium for bipolar disorder are at a high risk of developing thyroid dysfunction, including both hypothyroidism and to a lesser extent thyrotoxicosis (652).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [652] source

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  • May combine two claims.

    Premisenone given

    Normal thyroid function is reestablished by 12 months in most patients with painless thyroiditis, but 10%-20% have persistent hypothyroidism.

    “Normal thyroid function is reestablished by 12 months in most patients, but 10%-20% have persistent hypothyroidism.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Nineteen percent of patients (38/200) developed AIT a mean of 5.5 months after amiodarone was stopped, 36 of whom had type 2 AIT.

    “Nineteen percent of patients (38/200) developed AIT a mean of 5.5 months after the drug was stopped, 36 of whom had type 2 AIT.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [605] source

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  • May combine two claims.

    Premisenone given

    The thyrotoxic phase of subacute thyroiditis usually lasts 3-6 weeks, ending when the thyroid stores of preformed hormone are depleted.

    “The thyrotoxic phase usually lasts 3-6 weeks, ending when the thyroid stores of preformed hormone are depleted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Patients recovering from apparent type 2 AIT should be monitored for permanent hypothyroidism, which appears to occur more often with AIT than with subacute thyroiditis.

    “Patients recovering from apparent type 2 AIT should be monitored for permanent hypothyroidism, which appears to occur more often with AIT than with subacute thyroiditis (608).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [608] source

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  • May combine two claims.

    Premisecitation

    A case series of 24 patients with lithium-associated thyrotoxicosis identified GD in 12 (50%), painless thyroiditis in two patients, TMNG in three patients, and no identified etiology in seven patients.

    “A case series of 24 patients with lithium-associated thyrotoxicosis identified GD in 12 (50%), painless thyroiditis in two patients, TMNG in three patients, and no identified etiology in seven patients (655).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [655] source

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  • May combine two claims.

    Interpretationcitation

    Painless thyroiditis is probably an autoimmune disease manifested by positive anti-thyroid peroxidase antibodies in about 50% of patients and findings of lymphocytic infiltration on pathology.

    “Painless thyroiditis is probably an autoimmune disease manifested by positive anti-thyroid peroxidase antibodies in about 50% of patients and findings of lymphocytic infiltration on pathology (626,627).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [626] source

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    • cites [627] source

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  • May combine two claims.

    Premisecitation

    A recent study including 1233 patients who were euthyroid at baseline found that 79 (6.4%) patients developed a biphasic thyroiditis and an additional 57 (4.6%) patients developed a suppressed TSH value.

    “A recent study including 1233 patients who were euthyroid at baseline found that 79 (6.4%) patients developed a biphasic thyroiditis and an additional 57 (4.6%) patients developed a suppressed TSH value (638).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [638] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An epidemiological study of hyperthyroidism occurring over a 3-year period in Denmark identified lithium-associated thyrotoxicosis as the etiology in 0.7% of all cases.

    “An epidemiological study of hyperthyroidism occurring over a 3-year period in Denmark identified lithiumassociated thyrotoxicosis as the etiology in 0.7% of all cases (432).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [432] source

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  • May combine two claims.

    Premisecitation

    The tyrosine kinase inhibitors sunitinib, sorafenib, and nilotinib have each been associated with a transient thyrotoxicosis due to destructive thyroiditis.

    “The tyrosine kinase inhibitors sunitinib (642-647), sorafenib (648-650), and nilotinib (651) have each been associated with a transient thyrotoxicosis due to destructive thyroiditis.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [642]

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    • cites [643]

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    • cites [644]

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    • cites [645]

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    • cites [646]

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    • cites [647]

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    • cites [648]

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    • cites [649] source

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    • cites [650]

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    • cites [651]

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  • May combine two claims.

    Premisecitation

    A rapid response to combined corticosteroid and ATD therapy is believed to favor type 2 AIT and allows a reduction in ATDs, although some patients with type 2 AIT have a prolonged course, particularly those with larger thyroids or worse thyrotoxicosis at the time of diagnosis.

    “A rapid response to combined corticosteroid and ATD therapy is believed to favor type 2 AIT (594) and allows a reduction in ATDs, although some patients with type 2 AIT have a prolonged course, particularly those with larger thyroids or worse thyrotoxicosis at the time of diagnosis (611).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [594]

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    • cites [611]

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  • May combine two claims.

    Premisecitation

    Recurrence rates for painless thyroiditis are about 5%-10%, but may be higher in Japan, with one Japanese study reporting a long-term recurrence rate of 65%.

    “Recurrence rates are about 5%-10%, but may be higher in Japan, with one Japanese study reporting a long-term recurrence rate of 65% (626).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [626] source

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  • May combine two claims.

    Premisecitation

    In general, thyroid dysfunction caused by thyroiditis is less severe than that seen with other forms of endogenous thyrotoxicosis; RAIU is universally low during the thyrotoxic stage, owing to leaking of preformed thyroid hormone with suppression of serum TSH concentrations.

    “In general, thyroid dysfunction caused by thyroiditis is less severe than that seen with other forms of endogenous thyrotoxicosis (50); RAIU is universally low during the thyrotoxic stage, owing to leaking of preformed thyroid hormone with suppression of serum TSH concentrations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] source

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  • May combine two claims.

    Premisenone given

    The thyrotoxic phase occurs in 5%-20% of patients with painless thyroiditis and typically lasts 3-4 months.

    “The thyrotoxic phase occurs in 5%-20% of patients and typically lasts 3-4 months.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The patient should be counseled that while thyroidectomy in the setting of AIT carries with it significant morbidity and a high mortality rate (9%), delay or deferral of surgery imparts an even higher risk of death.

    “The patient should be counseled that while thyroidectomy in this setting carries with it significant morbidity and a high mortality rate (9%), delay or deferral of surgery imparts an even higher risk of death (612).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [612]

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  • May combine two claims.

    Premisecitation

    A recent study suggested that the rate of transient overt or subclinical thyrotoxicosis following parathyroid surgery may be as high as 30%, although there was likely ascertainment bias because not all patients had postoperative TSH levels measured.

    “However, a recent study suggested that the rate of transient overt or subclinical thyrotoxicosis following parathyroid surgery may be as high as 30%, although there was likely ascertainment bias because not all patients had postoperative TSH levels measured (637).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [637]

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  • May combine two claims.

    Premisecitation

    Most patients with subacute thyroiditis become euthyroid again within 12 months of disease onset, although 5%-15% have persistent hypothyroidism.

    “Most patients become euthyroid again within 12 months of disease onset, although 5%-15% have persistent hypothyroidism (24,620,621).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] source

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    • cites [620]

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    • cites [621]

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  • May combine two claims.

    Premisecitation

    In a recent series of 68 patients undergoing transsphenoidal surgery for TSH-secreting pituitary tumors, 75% normalized thyroid function after surgery, 58% normalized both pituitary imaging and TSH hypersecretion, 9% developed new deficiencies, and 3% experienced tumor recurrence.

    “In a recent series of 68 patients undergoing transsphenoidal surgery, 75% normalized thyroid function after surgery, 58% normalized both pituitary imaging and TSH hypersecretion, 9% developed new deficiencies, and 3% experienced tumor recurrence (659).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [659] source

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  • May combine two claims.

    Premisecitation

    In a recent case series of seven patients treated with octreotide without prior surgery, mean free T4 and T3 levels were reduced by nearly 50% in the first 3 months of therapy and six of seven patients experienced tumor volume reduction.

    “In a recent case series of seven patients treated with octreotide without prior surgery, mean free T 4 and T 3 levels were reduced by nearly 50% in the first 3 months of therapy and six of seven patients experienced tumor volume reduction (661).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [661] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another more recent series found that 1.4% of referrals to a thyroid clinic over a 12-year period were for lithium related thyrotoxicosis.

    “Another more recent series found that 1.4% of referrals to a thyroid clinic over a 12-year period were for lithium related thyrotoxicosis (656).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [656] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Recent data from the Swedish registry reported an incidence of 0.15 per 1 million inhabitants, with a prevalence of 2.8 cases per million.

    “Recent data from the Swedish registry reported an incidence of 0.15 per 1 million inhabitants, with a prevalence of 2.8 cases per million (658).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [658] source

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  • May combine two claims.

    Premisecitation

    Radiotherapy controlled thyroid hypersecretion in 37% of patients treated with this modality, but hypopituitarism occurred in 32% of those treated.

    “Radiotherapy controlled thyroid hypersecretion in 37% of patients treated with this modality, but hypopituitarism occurred in 32% of those treated (659).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [659] source

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  • May combine two claims.

    Premisecitation

    Treatment with octreotide results in a >50% reduction in serum TSH values in the majority of patients treated and a concurrent return to euthyroidism in most.

    “Treatment with octreotide results in a >50% reduction in serum TSH values in the majority of patients treated and a concurrent return to euthyroidism in most (43).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Typically, patients with thyrotoxicosis due to functional thyroid cancer metastases have either a very large primary follicular cancer or widely metastatic follicular thyroid cancer, and they may have coexisting TRAb as the proximate cause of the thyrotoxicosis or activating mutations in the TSH receptor.

    “Typically, patients have either a very large primary follicular cancer or widely metastatic follicular thyroid cancer, and they may have coexisting TRAb as the proximate cause of the thyrotoxicosis (673) or activating mutations in the TSH receptor (674).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [673]

      Not checked in the free run.

    • cites [674]

      Not checked in the free run.

    • Rests on an assumption: Thyrotoxicosis due to functional metastases in patients with thyroid cancer has been described in a handful of cases.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Historically, accidental thyroid hormone ingestion has occurred as a result of eating meat contaminated with animal thyroid tissue (hamburger thyrotoxicosis).

    “Historically, accidental thyroid hormone ingestion has occurred as a result of eating meat contaminated with animal thyroid tissue (''hamburger thyrotoxicosis'') (670).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [670]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Struma ovarii is defined as ectopic thyroid tissue existing as a substantial component of an ovarian tumor, and it is quite rare, representing <1% of all ovarian tumors.

    “Struma ovarii, defined as ectopic thyroid tissue existing as a substantial component of an ovarian tumor, is quite rare, representing <1% of all ovarian tumors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TSH-secreting pituitary adenomas are rare tumors and represent an even rarer cause of hyperthyroidism.

    “TSH-secreting pituitary adenomas are rare tumors and represent an even rarer cause of hyperthyroidism.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A reduction in tumor size has been observed in 20%-50% of patients treated with octreotide, but less impressive results have been obtained with bromocriptine therapy.

    “A reduction in tumor size has been observed in 20%-50% of patients treated with octreotide (43,660), but less impressive results have been obtained with bromocriptine therapy (660).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] source

      Not checked in the free run.

    • cites [660]

      Not checked in the free run.

324 of 324

  • The paper relies on this without support.

    Graves' disease is an autoimmune disorder in which thyrotropin receptor antibodies stimulate the TSH receptor, increasing thyroid hormone production and release.

    “GD is an autoimmune disorder in which thyrotropin receptor antibodies (TRAb) stimulate the TSH receptor, increasing thyroid hormone production and release.”

  • The paper relies on this without support.

    The model of a theoretical population of 100,000 enrollees in a managed care organization in the United States is representative of clinical practice for diagnosing Graves' disease.

    “In a study using a model of a theoretical population of 100,000 enrollees in a managed care organization in the United States, the use of TRAb measurements to diagnose GD compared to RAIU measurements reduced costs by 47% and resulted in a 46% quicker diagnosis (45).”

  • The paper relies on this without support.

    The systematic PubMed search identified the relevant literature for the guidelines.

    “The relevant literature was reviewed using a systematic PubMed search for primary references and reviews published after the submission of the 2011 guidelines, supplemented with additional published materials found on focused PubMed searches.”

  • The paper relies on this without support.

    Considerable new literature had been published since the 2011 guidelines, making updated evidence-based guidelines necessary.

    “Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed.”

  • The paper relies on this without support.

    High-volume thyroid surgeons have on average a lower risk of complications.

    “Whenever surgery is selected as treatment one should consider the use of expert high-volume thyroid surgeons with on average lower risk of complications; lack of that expertise should be considered against the known risk of alternative choices.”

  • The paper relies on this without support.

    Oral verapamil and diltiazem affect rate control in patients who do not tolerate or are not candidates for beta-adrenergic blocking agents.

    “Oral administration of calcium channel blockers, both verapamil and diltiazem, have been shown to affect rate control in patients who do not tolerate or are not candidates for b-adrenergic blocking agents.”

  • The paper relies on this without support.

    RAI is well tolerated and complications are rare, except for those related to orbitopathy.

    “It is well tolerated and complications are rare, except for those related to orbitopathy (see Section [U]).”

  • The paper relies on this without support.

    Most patients respond to RAI therapy with normalization of thyroid function tests and improvement of clinical symptoms within 4-8 weeks.

    “Most patients respond to RAI therapy with a normalization of thyroid function tests and improvement of clinical symptoms within 4-8 weeks.”

  • The paper relies on this without support.

    The transition to hypothyroidism after RAI more commonly occurs between 2 and 6 months.

    “This transition can occur rapidly but more commonly between 2 and 6 months, and the timing of thyroid hormone replacement therapy should be determined by results of thyroid function tests, clinical symptoms, and physical examination.”

  • The paper relies on this without support.

    In patients with transient hypothyroidism after RAI, the thyroid gland often remains palpable.

    “In such patients the thyroid gland often remains palpable.”

  • The paper relies on this without support.

    Most patients eventually develop hypothyroidism following RAI, indicated by a free T4 below the normal range.

    “Most patients eventually develop hypothyroidism following RAI, which is indicated by a free T 4 below normal range.”

  • The paper relies on this without support.

    TSH levels may not rise immediately with the development of hypothyroidism.

    “TSH levels may not rise immediately with the development of hypothyroidism and should not be used initially to determine the need for levothyroxine.”

  • The paper relies on this without support.

    The required levothyroxine dose may be less than typical full replacement, and careful titration is necessary owing to nonsuppressible residual thyroid function.

    “The required dose may be less than the typical full replacement, and careful titration is necessary owing to nonsuppressible residual thyroid function.”

  • The paper relies on this without support.

    TSH levels may remain suppressed for a month or longer after hyperthyroidism resolves.

    “Since TSH levels may remain suppressed for a month or longer after hyperthyroidism resolves, the levels should be interpreted cautiously and only in concert with free T 4 and total T 3 .”

  • The paper relies on this without support.

    ATDs do not cure Graves' hyperthyroidism, but when given in adequate doses they are very effective in controlling hyperthyroidism.

    “These medications do not cure Graves' hyperthyroidism; however, when given in adequate doses, they are very effective in controlling the hyperthyroidism.”

  • The paper relies on this without support.

    Carbimazole is rapidly converted to MMI in the serum, with 10 mg of carbimazole metabolized to approximately 6 mg of MMI.

    “Carbimazole is rapidly converted to MMI in the serum (10 mg of carbimazole is metabolized to approximately 6 mg of MMI).”

  • The paper relies on this without support.

    MMI and PTU are effective as a single daily dose.

    “Both are effective as a single daily dose.”

  • The paper relies on this without support.

    Adverse drug reactions are more frequent with higher MMI doses.

    “In addition, adverse drug reactions are more frequent with higher MMI doses.”

  • The paper relies on this without support.

    MMI has the benefit of once-a-day administration and a reduced risk of major side effects compared to PTU.

    “MMI has the benefit of once-a-day administration and a reduced risk of major side effects compared to PTU.”

  • The paper relies on this without support.

    ATD-associated agranulocytosis is uncommon but life-threatening.

    “Although ATD-associated agranulocytosis is uncommon, it is life-threatening.”

  • The paper relies on this without support.

    Hepatotoxicity is another major adverse effect of ATD therapy.

    “Hepatotoxicity is another major adverse effect of ATD therapy.”

  • The paper relies on this without support.

    Aside from hematologic and hepatic adverse effects, other rare side effects are associated with ATDs.

    “Aside from hematologic and hepatic adverse effects, other rare side effects are associated with ATDs.”

  • The paper relies on this without support.

    Serum free T4 levels may normalize despite persistent elevation of serum total T3.

    “Serum T 3 should be monitored because the serum free T 4 levels may normalize despite persistent elevation of serum total T 3 .”

  • The paper relies on this without support.

    Serum TSH may remain suppressed for several months after starting therapy and is therefore not a good parameter for monitoring therapy early in the course.

    “Serum TSH may remain suppressed for several months after starting therapy, and it is therefore not a good parameter for monitoring therapy early in the course.”
    “Serum TSH may remain suppressed for several months after starting therapy and is therefore not a good parameter for monitoring therapy early in the course.”

  • The paper relies on this without support.

    Patients with ATD-induced agranulocytosis are typically symptomatic.

    “Because patients are typically symptomatic, measuring WBC counts during febrile illnesses and at the onset of pharyngitis has been the standard approach to monitoring.”

  • The paper relies on this without support.

    PTU may cause transient elevations of serum transaminases in up to one-third of patients.

    “PTU may cause transient elevations of serum transaminases in up to one-third of patients.”

  • The paper relies on this without support.

    The onset of PTU-induced hepatotoxicity may be acute, difficult to appreciate clinically, and rapidly progressive.

    “The onset of PTU-induced hepatotoxicity may be acute, difficult to appreciate clinically, and rapidly progressive.”

  • The paper relies on this without support.

    Thyroidectomy has a high cure rate for the hyperthyroidism of GD.

    “Thyroidectomy has a high cure rate for the hyperthyroidism of GD.”

  • The paper relies on this without support.

    The risk of hypothyroidism and the requirement for exogenous thyroid hormone therapy is 100% after near-total/total thyroidectomy for TMNG.

    “However, the risk of hypothyroidism and the requirement for exogenous thyroid hormone therapy is 100% after near-total/ total thyroidectomy.”

  • The paper relies on this without support.

    Euthyroidism is achieved within days after surgery for TA.

    “Typically, euthyroidism is achieved within days after surgery.”

  • The paper relies on this without support.

    Thyroid storm occasionally occurs following RAI therapy.

    “Thyroid storm occasionally occurs following RAI therapy.”

  • The paper relies on this without support.

    Combined with ATDs in patients with severe thyrotoxicosis, inorganic iodine or oral cholecystographic agents result in rapid clinical improvement.

    “Combined with ATDs in patients with severe thyrotoxicosis, these agents result in rapid clinical improvement”

  • The paper relies on this without support.

    Two effective and relatively safe definitive treatment options exist for TMNG and TA: RAI therapy and thyroid surgery.

    “Two effective and relatively safe definitive treatment options exist for TMNG and TA: RAI therapy and thyroid surgery.”

  • The paper relies on this without support.

    TMNG and TA are an uncommon cause of hyperthyroidism in pregnancy and there is a lack of studies in this setting.

    “TMNG and TA are an uncommon cause of hyperthyroidism in pregnancy and there is a lack of studies in this setting.”

  • The paper relies on this without support.

    Risks of surgery are increased in the presence of thyrotoxicosis.

    “Risks of surgery are increased in the presence of thyrotoxicosis.”

  • The paper relies on this without support.

    Thyrotoxic crisis during or after the operation can result in extreme hypermetabolism, hyperthermia, tachycardia, hypertension, coma, or death.

    “Thyrotoxic crisis during or after the operation, can result in extreme hypermetabolism, hyperthermia, tachycardia, hypertension, coma, or death.”

  • The paper relies on this without support.

    Usually hyperthyroidism is less severe in patients with TMNG.

    “Usually hyperthyroidism is less severe in patients with TMNG, so that in most cases, patients with allergy to ATDs can be prepared for surgery, when necessary, with b-blockers alone.”

  • The paper relies on this without support.

    TMNG is more common in older patients.

    “TMNG is more common in older patients.”

  • The paper relies on this without support.

    Persistent or recurrent hyperthyroidism following surgery is indicative of inadequate surgery.

    “Persistent or recurrent hyperthyroidism following surgery is indicative of inadequate surgery.”

  • The paper relies on this without support.

    The required dose of MMI to restore the euthyroid state in TMNG or TA patients is usually low (5-10 mg/d).

    “The required dose of MMI to restore the euthyroid state in TMNG or TA patients is usually low (5-10 mg/d).”

  • The paper relies on this without support.

    Long-term, low-dose ATD treatment in nodular hyperthyroidism can be difficult to regulate.

    “Because long-term, low-dose ATD treatment in nodular hyperthyroidism can be difficult to regulate, frequent (every 3 months) monitoring is recommended initially, especially in the elderly (298), until stability has been documented, after which testing frequency can be decreased.”

  • The paper relies on this without support.

    PTU-induced liver injury is of rapid onset and can be rapidly progressive.

    “Because PTU-induced liver injury is of rapid onset and can be rapidly progressive, biochemical monitoring of liver function tests and transaminase levels has not been shown to be useful in surveillance for PTU-related liver injury.”

  • The paper relies on this without support.

    Typical manifestations of ANCA-positive vasculitis are polyarthritis, purpuric skin lesions, and occasionally pulmonary and/or renal involvement.

    “Typical manifestations of ANCA-positive vasculitis are polyarthritis, purpuric skin lesions, and occasionally pulmonary and/or renal involvement.”

  • The paper relies on this without support.

    Discontinuation of the drug generally results in resolution of ANCA-positive vasculitis symptoms, but in more severe cases, glucocorticoids or other immunosuppressive therapy may be needed.

    “Discontinuation of the drug generally results in resolution of the symptoms, but in more severe cases, glucocorticoids or other immunosuppressive therapy may be needed.”

  • The paper relies on this without support.

    Beta-blockers (atenolol, propranolol, metoprolol, or other) lead to a decrease in heart rate and symptoms of GD in children with suspected or confirmed Graves' hyperthyroidism and significant symptoms.

    “In children in whom the diagnosis of Graves' hyperthyroidism is strongly suspected or confirmed, and who are showing significant symptoms, including, but not limited to, tachycardia, muscle weakness, tremor, or neuropsychological changes, treatment with atenolol, propranolol, metoprolol, or other b-blockers leads to a decrease in heart rate and symptoms of GD.”

  • The paper relies on this without support.

    Depending on the severity of hyperthyroidism and the MMI dose, it can take several months for elevated thyroid hormone levels to fall into the normal range.

    “Depending on the severity of hyperthyroidism and the MMI dose, it can take several months for elevated thyroid hormone levels to fall into the normal range.”

  • The paper relies on this without support.

    Side effects from MMI usually occur within the first 3 months of starting therapy, but adverse events can occur later.

    “Side effects from MMI usually occur within the first 3 months of starting therapy, but adverse events can occur later.”

  • The paper relies on this without support.

    The prevalence of agranulocytosis in children is estimated to be very low.

    “Data on the prevalence of agranulocytosis in children are unavailable, but it is estimated to be very low.”

  • The paper relies on this without support.

    Agranulocytosis is rare and has a sudden onset, which is generally symptomatic.

    “While routine monitoring of WBC counts may occasionally detect early agranulocytosis, it is not recommended because of the rarity of the condition and its sudden onset, which is generally symptomatic.”

  • The paper relies on this without support.

    The risks of PTU are considered greater than the risks of RAI or surgery.

    “If children develop serious adverse reactions to MMI, RAI or surgery should be considered because the risks of PTU are considered greater than the risks of RAI or surgery.”

  • The paper relies on this without support.

    The likelihood of remission could best be predicted by the initial response to ATDs, with achievement of euthyroid state within 3 months suggesting higher likelihood.

    “One prospective study suggested that likelihood of remission could best be predicted by the initial response to ATDs, with achievement of euthyroid state within 3 months, suggesting higher likelihood.”

  • The paper relies on this without support.

    Age-related differences exist in responsiveness to ATDs.

    “Data also suggest that age-related differences exist in responsiveness to ATDs.”

  • The paper relies on this without support.

    Persistence of GD in children is correlated with the persistence of TRAb.

    “Persistence of GD in children is correlated with the persistence of TRAb.”

  • The paper relies on this without support.

    Following RAI therapy, normalization of total T4 and/or free T4 generally takes 2-4 months.

    “At that time patients should be placed on b-blockers (if not already taking) until total T 4 and/ or free T 4 levels normalize following RAI therapy, which generally takes 2-4 months.”

  • The paper relies on this without support.

    Thyroid hormone levels in children begin to fall within the first week following RAI therapy.

    “Thyroid hormone levels in children begin to fall within the first week following RAI therapy.”

  • The paper relies on this without support.

    ATDs can complicate assessment of posttreatment hypothyroidism since it could be the result of the MMI rather than the RAI therapy.

    “ATDs can complicate assessment of posttreatment hypothyroidism since it could be the result of the MMI rather than the RAI therapy.”

  • The paper relies on this without support.

    Hyperthyroidism can relapse in pediatric patients rendered hypothyroid with RAI, but this is very infrequent.

    “While there are reports that hyperthyroidism can relapse in pediatric patients rendered hypothyroid with RAI, this is very infrequent.”

  • The paper relies on this without support.

    RAI is excreted by saliva, urine, perspiration, tears, and stool.

    “RAI is excreted by saliva, urine, perspiration, tears, and stool.”

  • The paper relies on this without support.

    Significant radioactivity is retained within the thyroid for several days.

    “Significant radioactivity is retained within the thyroid for several days.”

  • The paper relies on this without support.

    TSH levels may remain suppressed for several months after correction of the hyperthyroid state, so TSH determinations may not be useful for assessing hypothyroidism.

    “Because TSH levels may remain suppressed for several months after correction of the hyperthyroid state, TSH determinations may not be useful in this setting for assessing hypothyroidism.”

  • The paper relies on this without support.

    Side effects of RAI therapy in children are uncommon apart from the lifelong hypothyroidism that is the goal of therapy.

    “Side effects of RAI therapy in children are uncommon apart from the lifelong hypothyroidism that is the goal of therapy.”

  • The paper relies on this without support.

    If residual thyroid tissue remains in young children after RAI treatment, a theoretical risk of development of thyroid cancer exists.

    “If residual thyroid tissue remains in young children after RAI treatment, a theoretical risk of development of thyroid cancer exists.”

  • The paper relies on this without support.

    No evidence suggests that children or adults treated for GD with more than 150 μCi/g of RAI have an increased risk of thyroid cancer directly attributable to RAI.

    “No evidence suggests that children or adults treated for GD with more than 150 lCi/g (5.55 MBq/g) of RAI have an increased risk of thyroid cancer directly attributable to RAI.”

  • The paper relies on this without support.

    Few studies have focused on populations exposed to RAI for the treatment of GD in childhood or adolescence.

    “While there are several studies of this issue in adults treated with RAI for GD (see Section [D2]), few studies have focused on populations exposed to RAI for the treatment of GD in childhood or adolescence.”

  • The paper relies on this without support.

    At present, there is no dosimetry information regarding RAI use in children with GD to assess total body exposure in children.

    “At present, we do not have dosimetry information regarding RAI use in children with GD to assess total body exposure in children.”

  • The paper relies on this without support.

    To date, long-term studies of children treated with RAI for GD have not revealed an increased risk of nonthyroid malignancies.

    “To date, long-term studies of children treated with RAI for GD have not revealed an increased risk of nonthyroid malignancies.”

  • The paper relies on this without support.

    Attempts to minimize the RAI activity will result in undertreatment and the possible need for additional RAI therapy and radiation exposure.

    “Attempts to minimize the RAI activity will result in undertreatment and the possible need for additional RAI therapy and radiation exposure.”

  • The paper relies on this without support.

    Postoperative hypocalcemia requiring intravenous calcium infusions appears to occur more frequently than in adults.

    “Postoperative hypocalcemia requiring intravenous calcium infusions appears to occur more frequently than in in adults.”

  • The paper relies on this without support.

    The prevalence of subclinical hyperthyroidism in an adult population depends on age, sex, and iodine intake.

    “The prevalence of subclinical hyperthyroidism (SH) in an adult population depends on age, sex, and iodine intake.”

  • The paper relies on this without support.

    The differential diagnosis of an isolated low or suppressed TSH level includes exogenous thyroid hormone use, nonthyroidal illness, drug effects, and pituitary/hypothalamic disease, all of which need to be ruled out before the diagnosis of SH can be established.

    “The differential diagnosis of an isolated low or suppressed TSH level includes exogenous thyroid hormone use, nonthyroidal illness, drug effects, and pituitary/hypothalamic disease, all of which need to be ruled out before the diagnosis of SH can be established in a patient with an isolated low or suppressed TSH level.”

  • The paper relies on this without support.

    The second most common cause of SH is GD, which is more prevalent in younger persons and is also common in patients who previously received ATD therapy.

    “The second most common cause of SH is GD, which is more prevalent in younger persons and is also common in patients who previously received ATD therapy.”

  • The paper relies on this without support.

    Other unusual causes of SH include solitary autonomously functioning nodules and various forms of thyroiditis.

    “Other unusual causes include solitary autonomously functioning nodules and various forms of thyroiditis, the latter of which would be more strictly termed ''subclinical thyrotoxicosis.''”

  • The paper relies on this without support.

    SH is a mild form of hyperthyroidism.

    “Since SH is a mild form of hyperthyroidism, it is not surprising that deleterious effects seen in overt hyperthyroidism might also occur in SH.”

  • The paper relies on this without support.

    Deleterious effects seen in overt hyperthyroidism might also occur in SH.

    “Since SH is a mild form of hyperthyroidism, it is not surprising that deleterious effects seen in overt hyperthyroidism might also occur in SH.”

  • The paper relies on this without support.

    Several longitudinal studies have examined correlations between SH and overall mortality, with variable results.

    “Several longitudinal studies have examined correlations between SH and overall mortality, with variable results.”

  • The paper relies on this without support.

    The most recent data provide evidence that relative risks of cardiovascular mortality and atrial fibrillation are elevated in younger, as well as older, patients with SH.

    “The most recent data provide evidence that relative risks of cardiovascular mortality and atrial fibrillation are elevated in younger, as well as older, patients with SH.”

  • The paper relies on this without support.

    The absolute risks of cardiovascular events and atrial fibrillation are very low in younger patients, so the risk/benefit ratio of treating younger SH patients is not clear.

    “However, the absolute risks of these events are very low in younger patients, so the risk/benefit ratio of treating younger SH patients is not clear.”

  • The paper relies on this without support.

    It is not clear that decreased bone mineral density in SH translates to increased fracture risk.

    “However, it is not clear that this finding translates to increased fracture risk.”

  • The paper relies on this without support.

    Approximately equal numbers of studies report significant associations between SH and measures of cognitive decline and the development of dementia, versus no associations.

    “Approximately equal numbers of studies report significant associations between SH and measures of cognitive decline and the development of dementia, versus no associations.”

  • The paper relies on this without support.

    Treatment of SH is controversial, since few intervention studies showing benefit have been performed, especially for clinically important endpoints such as cardiovascular events, atrial fibrillation, and fractures.

    “Treatment of SH is controversial, since few intervention studies showing benefit have been performed, especially for clinically important endpoints such as cardiovascular events, atrial fibrillation, and fractures.”

  • The paper relies on this without support.

    None of the intervention studies of SH treatment included a control arm.

    “Additionally, none of these studies included a control arm.”

  • The paper relies on this without support.

    There are insufficient data for or against treatment of SH in younger persons or premenopausal women with SH and serum TSH <0.1 mU/L.

    “There are insufficient data for or against treatment of SH in younger persons or premenopausal women with SH and serum TSH <0.1 mU/L.”

  • The paper relies on this without support.

    A TSH level of <0.1 mU/L on repeated measurement over a 3- to 6-month period is considered to be persistent, effectively ruling out transient thyroiditis as a cause.

    “A TSH level of <0.1 mU/L on repeated measurement over a 3-to 6-month period is considered to be persistent, effectively ruling out transient thyroiditis as a cause.”

  • The paper relies on this without support.

    The thyroid disorder underlying SH should be diagnosed, and is most commonly TMNG, GD, or TA.

    “The thyroid disorder underlying SH should be diagnosed, and is most commonly TMNG, GD, or TA.”

  • The paper relies on this without support.

    Treatment of subclinical hyperthyroidism with TSH between 0.1 mU/L and the lower limit of the reference range improves clinical outcomes.

    “However, there are no interventional data for or against treatment of individuals with serum TSH levels between 0.1 mU/L and the lower limit of the reference range.”

  • The paper relies on this without support.

    The epidemiologic associations between subclinical hyperthyroidism and adverse outcomes are causal and modifiable by treatment.

    “Some of these studies re-ported increased risks of overall mortality in older subjects (380,429), cardiovascular events (391), heart failure (381), and atrial fibrillation in all subjects (401) or in older subjects (384), and vertebral fractures in older women (408).”

  • The paper relies on this without support.

    Free T4 is the parameter most closely correlated with good fetal outcome.

    “Free T 4 is the parameter that has been most closely correlated with good fetal outcome.”

  • The paper relies on this without support.

    The two best indicators of the activity of GD during pregnancy are thyroid function in the untreated patient and measurement of TRAb levels in the serum.

    “The two best indicators of the activity of GD during pregnancy are thyroid function in the untreated patient and measurement of TRAb levels in the serum.”

  • The paper relies on this without support.

    Postpartum thyroid dysfunction occurs in up to 10% of pregnancies in the United States.

    “Postpartum thyroid dysfunction occurs in up to 10% of pregnancies in the United States.”

  • The paper relies on this without support.

    The natural history of GO is one of rapid deterioration followed by gradual improvement toward the baseline.

    “The natural history of the disease is one of rapid deterioration followed by gradual improvement toward the baseline.”

  • The paper relies on this without support.

    In many patients, GD gradually remits during pregnancy.

    “In many patients, GD gradually remits during pregnancy.”

  • The paper relies on this without support.

    Cross-stimulation of the TSH receptor by hCG only occurs at very high levels of hCG, because hCG is only a weak agonist for the TSH receptor.

    “This cross-stimulation only occurs at very high levels of hCG, since hCG is only a weak agonist for the TSH receptor.”

  • The paper relies on this without support.

    Clues to thyrotoxicosis factitia are an absence of goiter, a suppressed serum thyroglobulin level, and a decreased RAIU.

    “Clues to this diagnosis are an absence of goiter, a suppressed serum thyroglobulin level, and a decreased RAIU.”

  • The paper relies on this without support.

    In both painless thyroiditis and factitious thyrotoxicosis there will be elevated levels of T4, a high T4/T3 ratio (with exogenous levothyroxine), a small thyroid, and a low thyroidal RAIU.

    “In both situations there will be elevated levels of T 4 , a high T 4 /T 3 ratio (with exogenous levothyroxine), a small thyroid, and a low thyroidal RAIU.”

  • The paper relies on this without support.

    Thyroid ultrasound may be helpful in distinguishing painless thyroiditis from surreptitious thyroid hormone ingestion because the thyroid has a heterogeneous echotexture and is normal sized or slightly enlarged in painless thyroiditis, while it is small with a normal echotexture in an otherwise normal individual who is ingesting thyroid hormone surreptitiously.

    “Thyroid ultrasound may be helpful because the thyroid has a heterogeneous echotexture and is normal sized or slightly enlarged in painless thyroiditis, while it is small with a normal echotexture in an otherwise normal individual who is ingesting thyroid hormone surreptitiously.”

  • The paper relies on this without support.

    A disproportionately elevated T3 level suggests that the patient may be ingesting liothyronine or a combination T4/T3 preparation.

    “A disproportionately elevated T 3 level suggests that the patient may be ingesting liothyronine or a combination T 4 /T 3 preparation.”

  • The paper relies on this without support.

    Severe thyrotoxicosis and rarely, thyroid storm, have been reported following thyroid hormone overdose or poisoning.

    “Severe thyrotoxicosis and rarely, thyroid storm, have been reported following thyroid hormone overdose or poisoning.”

  • The paper relies on this without support.

    Thyrotoxicosis due to functional metastases in patients with thyroid cancer has been described in a handful of cases.

    “Thyrotoxicosis due to functional metastases in patients with thyroid cancer has been described in a handful of cases.”
98 of 98

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In cases where TRAb is negative or not available, thyroid scintigraphy will distinguish between Graves' disease (diffusely increased uptake) and destructive thyroiditis (reduced uptake).

    “In cases where TRAb is negative or not available, thyroid scintigraphy will distinguish between GD (diffusely increased uptake) and destructive thyroiditis (reduced uptake) [73];”

    From 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy (2019) · cites this paper as [73]

  • There have been two reported cases of remission of immune checkpoint inhibitor-associated diabetes mellitus.

    “There have been two reported cases of ICI-DM remission 76,77”

    From Endocrine toxicities of immune checkpoint inhibitors (2021) · cites this paper as [76]

  • Glucocorticoids are currently used in various conditions of Graves' disease including ophthalmopathy due to its anti-inflammatory action, and also in thyroid storm due to its blocking on thyroid hormone peripheral conversion.

    “Glucocorticoids are currently used in various conditions of Graves' disease including ophthalmopathy due to its anti-inflammatory action; and also in thyroid storm due to its blocking on thyroid hormone peripheral conversion (4).”

    From Thyrotoxic hypokalemic periodic paralysis triggered by dexamethasone administration (2020) · cites this paper as [4]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Radiation-safety dose equivalents conflict

    Major

    The stated equivalence of 7 mrem to 70 lSv implies that 500 mrem is 5 mSv, not the stated 0.5 mSv. The conflicting conversion concerns the patient-discharge radiation-safety limit.

  • Neonatal treatment percentage uses the wrong denominator result

    Minor

    The study describes 47 newborns and says five needed ATD therapy. Five of 47 is 10.6%, not 9%.

    Reported 9 · recomputed 10.638298

  • Free T4 concentration conversions conflict

    Minor

    The text equates 7 ng/dL with 0.554 pmol/L, but elsewhere equates the lower concentration of 4 ng/dL with the much higher value of 50 pmol/L. Both conversions cannot be correct.

  • Radioiodine activity is given in both Bq and MBq

    Minor

    The text equates 200 lCi per gram with 7.4 MBq per gram in one place and 7.4 Bq per gram in another, a million-fold difference.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 23

  1. Dumitrescu AM, , Refetoff S. 2015. Impaired sensitivity to thyroid hormone: defects of transport, metabolism and action. In: De Groot LJ, , Beck-Peccoz P, , Chrousos G, , Dungan K, , Grossman A, , Hershman JM, , Kock C, , McLachlan R, , New M, , Rebar R, , Singer F, , Vinik A, , Weickert MO, eds. Endotext [Internet]. MDText.com Inc., South Dartmouth, MA.
  2. McKee A, , Peyerl F. 2012. TSI assay utilization: impact on costs of Graves' hyperthyroidism diagnosis. Am J Manag Care, 18:e1–14.
  3. Zen XX, , Yuan Y, , Liu Y, , Wu TX, , Han S. 2007. Chinese herbal medicines for hyperthyroidism. Cochrane Database Syst Rev (2):CD005450.
  4. Abraham P, , Avenell A, , McGeoch SC, , Clark LF, , Bevan JS. 2010. Antithyroid drug regimen for treating Graves' hyperthyroidism. Cochrane Database Syst Rev, 1:CD003420.
  5. Warmock A, , Cooper DS, , Burch HB. 2014. Life-threatening thyrotoxicosis: thyroid storm and adverse effects of anti-thyroid drugs. In: Matflin D, ed. Medical Emergencies in Endocrinology. Endocrine Press, Endocrine Society, Washington, DC.
  6. Kaplan EL Angelos P Applewhite M Mercier F Grogan R. 2015 Chapter 21. Surgery of the thyroid. Thyroid Disease Manager. Available at: www.thyroidmanager.org/chapter/chapter-21surgery-of-the-thyroid/ (accessed December5 2015).
  7. Plummer HS. 1924. The value of iodine in exopthalmic goiter. J Iowa Med Soc, 14:66–73.
  8. Wood LC, , Maloof F. 1975. Thyroid failure after potassium iodide treatment of diffuse toxic goiter. Trans Assoc Am Physicians, 88:235–247.
  9. Cirocchi R, , Trastulli S, , Randolph J, , Guarino S, , Di Rocco G, , Arezzo A, , D'Andrea V, , Santoro A, , Barczynski M, , Avenia N. 2015. Total or near-total thyroidectomy versus subtotal thyroidectomy for multinodular non-toxic goitre in adults. Cochrane Database Syst Rev, 8:CD010370.
  10. Ma C, , Kuang A, , Xie J, , Liu G. 2008. Radioiodine treatment for pediatric Graves' disease. Cochrane Database Syst Rev, 3:CD006294.
  11. Committee to assess health risks from exposure to low levels of ionizing radiation Board on Radiation Effects Research Division on Earth and Life Sciences National Research Council of the National Academies. 2006. Health risks from exposure to low levels of ionizing radiation: BIER VII-Phase 2. National Academies Press Washington DC.
  12. Moore KL Persaud TVN Torchia MG. 2013. Human birth defects. The Developing Human: Clinically Oriented Embryology. 9th edition. Saunders/Elsevier Philadelphia PA pp 471–501.
  13. Yoshioka W, , Miyauchi A, , Ito M, , Kudo T, , Tamai H, , Nishihara E, , Kihara M, , Miya A, , Amino N. 2015. Kinetic analyses of changes in serum TSH receptor antibody values after total thyroidectomy in patients with Graves' disease. Endocr J
  14. Means J H. 1948. The response to iodine and to antithyroid drugs in Graves' disease. The Thyroid and Its Diseases. 2nd edition. Lippincott Philadelphia PA pp 341–374.
  15. Berta E, , Samson L, , Lenkey A, , Erdei A, , Cseke B, , Jenei K, , Major T, , Jakab A, , Jenei Z, , Paragh G, , Nagy EV, , Bodor M. 2010. Evaluation of the thyroid function of healthy pregnant women by five different hormone assays. Pharmazie, 65:436–439.
  16. Marcocci C, , Bartalena L, , Bogazzi F, , Panicucci M, , Pinchera A. 1989. Studies on the occurrence of ophthalmopathy in Graves' disease. Acta Endocrinol (Copenh), 120:473–478.
  17. Bartley GB. 1994. The epidemiologic characteristics and clinical course of ophthalmopathy associated with autoimmune thyroid disease in Olmsted County, Minnesota. Trans Am.Ophthalmol Soc, 92:477–588.
  18. Yeatts RP. 2005. Quality of life in patients with Graves ophthalmopathy. Trans Am Ophthalmol Soc, 103:368–411.
  19. Laurberg P, , Cerqueira C, , Ovesen L, , Rasmussen LB, , Perrild H, , Andersen S, , Pedersen IB, , Carle A. 2010. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res. Clin Endocrinol Metab, 24:13–27.
  20. Ozkan S, , Oysu AS, , Kayatas K, , Demirtunc R, , Eren M, , Uslu H, , Altuntas Y. 2013. Thyroid functions after contrast agent administration for coronary angiography: a prospective observational study in euthyroid patients. Anadolu Kardiyol Derg, 13:363–369.
  21. Lee KF, , Lee KM, , Fung TT. 2010. Amiodarone-induced thyroid dysfunction in the Hong Kong Chinese population. Hong Kong Med J, 16:434–439.
  22. Rudofsky GJr, , Grafe IA, , Metzner C, , Leowardi C, , Fohr B. 2009. Transient post-operative thyrotoxicosis after parathyroidectomy. Med Sci Monit, 15:CS41–3.
  23. Sarinnapakorn V, , Sridama V, , Sunthornthepvarakul T. 2007. Proptosis in normal Thai samples and thyroid patients. J Med Assoc Thai, 90:679–683.

Cited by

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Authors
Ross, D. S., Burch, H. B., Cooper, D. S., Greenlee, M. C., Laurberg, P., Maia, A. L., Rivkees, S. A., Samuels, M., Sosa, J. A., Stan, M. N., & Walter, M. A.
Affiliations
  • Massachusetts General Hospital (US)
  • Walter Reed National Military Medical Center (US)
  • Johns Hopkins University (US)
  • Western Slope Endocrinology
  • Aalborg University Hospital (DK)
  • Universidade Federal do Rio Grande do Sul (BR)
  • University of Florida Health (US)
  • Oregon Health & Science University (US)
  • Duke University (US)
  • Mayo Clinic (US)
  • University Hospital of Bern (CH)
Corresponding author
Ross, Douglas S.
ORCID
Venue
Thyroid®
Publisher
SAGE Publications
Published
2016-10
Volume
26
Issue
10
Pages
1343-1421
ISSN
  • 1050-7256 (ISSN-L)
  • 1557-9077
DOI
10.1089/thy.2016.0229
OpenAlex
W2510464317
Semantic Scholar
ba077c57d0464889fe037e5409c7c7b0b9e86709
Cited by
2,938
References
655
Citations by year
2026: 298 · 2025: 318 · 2024: 375 · 2023: 344 · 2022: 345 · 2021: 358 · 2020: 346 · 2019: 232 · 2018: 175 · 2017: 116 · 2016: 20 · 2014: 2
FWCI
181.76
Type
journal article
Language
en
Update notices
Open access
Licence
Locations
  • Thyroid (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion)
  • VBN Forskningsportal (Aalborg Universitet) (submittedVersion)
  • Open Access CRIS of the University of Bern
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Ophthalmology and Eye Disorders
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
Keywords
thyrotoxicosis, hyperthyroidism, Graves' disease, Graves' ophthalmopathy, toxic multinodular goiter, toxic adenoma, radioactive iodine, antithyroid drugs, thyroid surgery, subclinical hyperthyroidism, pregnancy, pediatric hyperthyroidism
MeSH terms
Combined Modality Therapy, Humans, Hyperthyroidism, Severity of Illness Index, Societies, Medical, Thyrotoxicosis, United States, Evidence-Based Medicine, Precision Medicine

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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