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Cited by 13Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryAdrenal Hormones and Disorders

L-T4 therapy in the presence of pharmacological interferents

Open access
Benvenga, Salvatore·2020·Frontiers in Endocrinology
DOI 10.3389/fendo.2020.607446PMC PMC7783463
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Abstract

Pharmacological interference on L-thyroxine (L-T4) therapy can be exerted at several levels, namely from the hypothalamus/pituitary through the intestine, where the absorption of exogenous L-T4 takes place. A number of medications interfere with L-T4 therapy, some of them also being the cause of hypothyroidism. The clinician should be aware that some medications simply affect thyroid function tests with no need of modifying the dose of L-T4 that the patient was taking prior to their prescription. Usually, the topic of pharmacological interference on L-T4 therapy addresses the patient with primary hypothyroidism, in whom periodic measurement of serum thyrotropin (TSH) is the biochemical target. However, this minireview also addresses the patient with central hypothyroidism, in whom the biochemical target is serum free thyroxine (FT4). This minireview also addresses two additional topics. One is the costs associated with frequent monitoring of the biochemical target when L-T4 is taken simultaneously with the interfering drug. The second topic is the issue of metabolic/cardiovascular complications associated with undertreated hypothyroidism.

AI snapshot

Written from the paper’s full text.

TL;DR

This minireview summarizes how medications can interfere with L-T4 therapy at hypothalamic/pituitary, thyroid, absorption, transport, and metabolism levels, and it argues that clinicians should monitor and adjust therapy accordingly. It also highlights undertreatment, metabolic/cardiovascular consequences, and costs associated with frequent monitoring when L-T4 is taken with interfering medications.

Key findings

  • Pharmacological interference is a major cause of undertreatment: ≈20% of patients with primary hypothyroidism and ≈20% or 40% of patients with central hypothyroidism are undertreated. In 2,292 patients with primary hypothyroidism, 42.7% had abnormal serum TSH (28.3% undertreated, 14.4% overtreated), and only 52.1% were told not to take L-T4 with interfering medications.
  • In the author’s experience with 210 L-T4-treated adults, 27 (13%) had undertreated hypothyroidism; in 8/27 (30%; 4% of 210), the explanation was pharmacological, all taking ≥1 drug causing L-T4 malabsorption (proton-pump inhibitors, calcium carbonate, ferrous sulfate). In 114 L-T4-treated primary hypothyroidism patients exposed to interfering medications, TSH rose from 1.27 ± 1.34 to 2.81 ± 3.62 mU/L (+121%), and TSH >4.12 mU/L rose from 4.7% to 18.5%; 76 patients (67%) had complications.
  • Calcium carbonate co-administration increased TSH in 13/20 patients (65%) over 3 months, with TSH >4.0 mU/L in 4 (20%) and overall TSH rising from 1.60 ± 0.22 to 2.71 ± 0.43 mU/L (+69%). In 50 postmenopausal women, undertreated hypothyroidism occurred in 9/50 (18%) when calcium was taken ≤2 h after L-T4; TSH rose from 1.93 ± 0.51 to 3.33 ± 1.93 mU/L (+73%), but all had TSH <4.12 mU/L when calcium was taken 6–8 h after L-T4.
  • Cost simulations estimated that five TSH tests at €20 each in 125,840 or 1,031,888 patients would cost €12,584,000 to €103,188,800. In another study, resource utilization was higher in patients with ≥1 L-T4 dose adjustment ($5,824/patient) than controls ($3,166/patient), peaking in the ≥3-dose-adjustment subgroup ($8,220/patient), with lost productivity of $1,381 vs $984.

Methods

  • Narrative minireview, not a systematic review or meta-analysis; it synthesizes guidelines, prior reviews, book chapters, and cited observational studies, retrospective cohorts, simulations, and trials.
  • The paper presents two tables: Table 1 summarizes American Thyroid Association recommendations on medications interfering with L-T4 therapy, and Table 2 lists medications, mechanisms, and suggested management.
  • No new primary data collection or formal quantitative synthesis is described; the author also reports his own clinical experience and cites studies with samples including 210 L-T4-treated adults, 10,496 persons, 114 enrolled patients, 5,426 L-T4 users, 10,999 Scottish residents, and 50 postmenopausal women.

Limitations

  • The paper states that few data are available on metabolic/cardiovascular complications and on costs of frequent assays in interfering-medication-associated undertreated hypothyroidism, and that more research is needed to substantiate outcomes in this setting.
  • The author states that the minireview disregards endocrine disruptors and does not emphasize clinically inconsequential interfering medications; it also notes that some cited vitamin C trials lack formal pharmacokinetics studies and challenge with interfering medications, and that one lenalidomide article fails to specify how many patients were under L-T4 or needed increased doses.
  • Evident from the text: this is a narrative minireview with no systematic search or risk-of-bias assessment, many cited studies are observational, retrospective, small, or case reports, and the author reports a conflict of interest with IBSA Institut Biochimique SA and IBSA Farmaceutici Italia s.r.l.

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

Integrity signals

Registry

Crossref · 10.3389/fendo.2020.607446

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 138 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    In 8 of 27 patients with undertreated hypothyroidism (30%; 4% of 210), the explanation was pharmacological, all eight taking at least one drug that causes L-T4 malabsorption (proton-pump inhibitors, calcium carbonate, ferrous sulfate).

    “In 8/27 (30%; 4% of 210), the explanation was pharmacological, all eight taking ≥1 drug that causes L-T4 malabsorption (proton-pump inhibitors [PPIs], calcium carbonate, ferrous sulfate) (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Benvenga, 2013, When thyroid hormone replacement is ineffective, Curr Opin Endocrinol Diabetes Obes source

      Not checked in the free run.

  • Findingcitation

    Of 210 L-T4-treated adult patients referred to SB in one year, 27 (13%) had undertreated hypothyroidism.

    “Of 210 L-T4-treated adult patients (tablet formulations) who were referred to SB in one year, 27 (13%) had UTH (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Benvenga, 2013, When thyroid hormone replacement is ineffective, Curr Opin Endocrinol Diabetes Obes source

      Not checked in the free run.

  • Interpretationnone given

    Pharmacological interference on L-T4 therapy can be exerted at several levels, from the hypothalamus/pituitary through the intestine, where absorption of exogenous L-T4 takes place.

    “Pharmacological interference on L-thyroxine (L-T4) therapy can be exerted at several levels, namely from the hypothalamus/pituitary through the intestine, where the absorption of exogenous L-T4 takes place.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Some medications simply affect thyroid function tests with no need of modifying the L-T4 dose.

    “some medications simply affect thyroid function tests with no need of modifying the dose of L-T4 that the patient was taking prior to their prescription.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Thalmann, 2013

      Not checked in the free run.

  • Premisecitation

    Only 52.1% of patients were told not to take L-T4 along with interfering medications.

    “Strikingly, only 52.1% of patients were told not to take L-T4 along with IM (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Vaisman, 2013, How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study, J Endocrinol Invest source

      Not checked in the free run.

  • May combine two claims. 53
  • Classified as probably not a substantial claim. 6
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingcitation

    In 50 postmenopausal women with L-T4-treated primary hypothyroidism who started taking 600-1000 mg/d calcium carbonate ≤2 h after L-T4, undertreated hypothyroidism (TSH >4.12 mU/L) occurred in 9/50 women (18%); overall TSH increased from 1.93 ± 0.51 to 3.33 ± 1.93 mU/L (+73%), but when all women took calcium 6-8 h after L-T4, all had TSH <4.12 mU/L (2.16 ± 0.54 mU/L).

    “Fifty postmenopausal women with L-T4-treated PH started taking 600–1000 mg/d calcium carbonate ≤2 h after L-T4. UTH (TSH >4.12 mU/L) occurred in 9/50 women (18%). Overall, TSH increased from 1.93 ± 0.51 mU/L to 3.33 ± 1.93 mU/L (+73%), but when all women took calcium 6–8 h after L-T4, all had TSH <4.12 mU/L (2.16 ± 0.54 mU/L) (44).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Morini, 2019, L-thyroxine malabsorption due to calcium carbonate impairs blood pressure, total cholesterolemia, and fasting glycemia, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    For every 1.0 mU/L increase within the TSH range of 0.85-6.9 mU/L, total cholesterolemia, fasting glycemia, systolic blood pressure, and diastolic blood pressure increased by 12.1 mg/dl, 3.12 mg/dL, 2.31 mmHg, and 2.0 mmHg, respectively.

    “For every 1.0 mU/L increase within the TSH range of 0.85–6.9 mU/L, TC, FG, SBP, and DBP increased by 12.1 mg/dl, 3.12 mg/dL, 2.31 mmHg, and 2.0 mmHg, respectively (44).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Morini, 2019, L-thyroxine malabsorption due to calcium carbonate impairs blood pressure, total cholesterolemia, and fasting glycemia, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In 50 postmenopausal L-T4-treated primary hypothyroidism women, TSH increased significantly from 1.93 ± 0.51 (before calcium; setting 1) to 3.33 ± 1.93 mU/L (calcium taken ≤2 h after L-T4; setting 2), and was significantly lower than 2.16 ± 0.54 mU/L (calcium taken 6-8 h after L-T4; setting 3); total cholesterolemia, fasting glycemia, systolic and diastolic blood pressure were also significantly

    “In the above study on 50 postmenopausal L-T4-treated PH women (44), TSH increased significantly from 1.93 ± 0.51 (before calcium; setting 1) to 3.33 ± 1.93 mU/L (calcium taken ≤2 h after L-T4; setting 2), and was significantly lower than 2.16 ± 0.54 mU/L (calcium taken 6–8 h after L-T4; setting 3). Total cholesterolemia (TC), fasting glycemia (FG), systolic and diastolic blood pressure (SBP and D”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Morini, 2019, L-thyroxine malabsorption due to calcium carbonate impairs blood pressure, total cholesterolemia, and fasting glycemia, Endocrine source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A number of medications interfere with L-T4 therapy, and some of them also cause hypothyroidism.

    “A number of medications interfere with L-T4 therapy, some of them also being the cause of hypothyroidism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Jonklaas, 2013, Treatment of hypothyroidism

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L-T4 monotherapy is the standard treatment for primary hypothyroidism, central hypothyroidism, and subclinical hypothyroidism patients candidate for replacement.

    “L-thyroxine (L-T4) monotherapy is the standard treatment for PH (4–6) and CH (4, 5, 7), and SCH patients candidate for replacement (4, 5, 8).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [4] Garber, 2012, American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association, Thyroid source

      Not checked in the free run.

    • cites [5] Jonklaas, 2014, American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement, Thyroid source

      Not checked in the free run.

    • cites [6] Wiersinga, 2012, ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism, Eur Thyroid J source

      Not checked in the free run.

    • cites [7] Persani, 2018, European Thyroid Association (ETA) Guidelines on the diagnosis and management of central hypothyroidism, Eur Thyroid J source

      Not checked in the free run.

    • cites [8] Pearce, 2013, ETA Guideline: Management of Subclinical Hypothyroidism, Eur Thyroid J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approximately 20% of patients with primary hypothyroidism and approximately 20% or 40% of patients with central hypothyroidism are undertreated, with co-administration of interfering medications being one major cause.

    “≈20% of patients with PH (10–13) and ≈20% (14) or 40% (15) of patients with CH are undertreated, co-administration of interfering medications (IM) being one major cause.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [10] Jonklaas, 2013, Treatment of hypothyroidism

      Not checked in the free run.

    • cites [11] Benvenga, 2013, When thyroid hormone replacement is ineffective, Curr Opin Endocrinol Diabetes Obes source

      Not checked in the free run.

    • cites [12] Vaisman, 2013, How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study, J Endocrinol Invest source

      Not checked in the free run.

    • cites [13] Taylor, 2014, Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study, JAMA Intern Med source

      Not checked in the free run.

    • cites [14] Benvenga, 2017, Perelli S. L-Thyroxine in an oral liquid or softgel formulation ensures more normal serum levels of free T4 in patients with central hypothyroidism, Front Endocrinol source

      Not checked in the free run.

    • cites [15] Koulouri, 2011, Diagnosis and treatment of hypothyroidism in TSH deficiency compared to primary thyroid disease: pituitary patients are at risk of under-replacement with levothyroxine, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 37 primary hypothyroidism patients under stable L-T4 replacement who subsequently received proton-pump inhibitors, TSH increased by 28%, with seven patients (19%) having post-PPI TSH >5 mU/L; a mean increase of 20 μg/d L-T4 (+35%) was necessary.

    “Confirming previous data (45), in 37 PH patients under stable L-T4 replacement and in whom PPIs were administered subsequently, TSH increased by 28%, with seven patients (19%) having post-PPI TSH levels >5 mU/L (46). A mean increase of 20 μg/d L-T4 (+35%) was necessary (46).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Sachmechi, 2007, Effect of proton pump inhibitors on serum thyroid-stimulating hormone levels in euthyroid patients treated with levothyroxine for hypothyroidism, Endocr Pract source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 10,999 Scottish residents prescribed L-T4 before starting interfering medications, iron, calcium, proton-pump inhibitors, and estrogens increased TSH significantly, with an increase >5 mU/L in 7.5%, 4.4%, 5.6%, and 4.3% of patients, respectively.

    “A retrospective study evaluated TSH changes in 10,999 Scottish residents who were prescribed L-T4 before starting IM (25). Iron, calcium, PPI, and estrogens increased TSH significantly, with an increase >5 mU/L in 7.5, 4.4, 5.6, and 4.3% patients, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Irving, 2015, Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS), Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Furosemide, heparin, salicylates, and other nonsteroidal anti-inflammatory drugs inhibit T4 binding to plasma proteins, thus increasing serum FT4, and are clinically inconsequential interfering medications.

    “Such medications are those listed at the end of Table 2 (furosemide, heparin, salycylates, and other nonsteroidal anti-inflammatory drugs), which inhibit T4 binding to plasma proteins thus increasing serum FT4, and the unlisted propranolol (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Thalmann, 2013

      Not checked in the free run.

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

    Premisecitation

    No recommendation for managing immune reconstitution therapy-related thyropathies addressed possible changes in L-T4 doses.

    “No recommendation for managing IRT-related thyropathies addressed possible changes in L-T4 doses (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Muller, 2019, European Thyroid Association Guidelines on the management of thyroid dysfunction following immune reconstitution therapy, Eur Thyroid J source

      Not checked in the free run.

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

    Premisecitation

    Central hypothyroidism was considered 1,000-fold rarer than primary hypothyroidism, but it may be just 20-fold rarer.

    “Central hypothyroidism (CH) was considered 1,000-fold rarer than PH, but it may be just 20-fold rarer (3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Benvenga, 2018, Less known aspects of central hypothyroidism: Part 1- Acquired etiologies, J Clin Transl Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A meta-analysis on 6,241 multidrug-resistant tuberculosis patients showed that primary hypothyroidism prevalence in MDR-TB patients averaged 17.0%, with ethionamide and para-aminosalicylic acid being the most frequently reported drugs associated with hypothyroidism.

    “After initial reports (48–50), a meta-analysis on 6,241 MDR-TB patients (31) showed that PH prevalence in MDR-TB patients averaged 17.0%, with ethionamide and PAS were the most frequently reported drugs associated with hypothyroidism.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Tola, 2019, Is hypothyroidism rare in multidrug resistance tuberculosis patients on treatment? A systematic review and meta-analysis, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Of 69 HIV-infected MDR-TB patients under anti-TB and antiretroviral therapies, 37 (54%) had primary hypothyroidism; co-administration of para-aminosalicylic acid and ethionamide doubled the risk of hypothyroidism (RR = 1.93).

    “Of 69 HIV-infected MDR-TB patients under anti-TB and antiretroviral therapies, 37 (54%) had PH (51). Co-administration of PAS and ethionamide doubled the risk of hypothyroidism (RR = 1.93) (51).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Andries, 2013, High rate of hypothyroidism in multidrug-resistant tuberculosis patients co-infected with HIV in Mumbai, India, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In MDR-TB patients receiving anti-TB, one-fourth developed primary hypothyroidism: 32% in patients who received a regimen containing ethionamide, 35% in those with para-aminosalicylic acid, and 44% in HIV-positive patients on antiretroviral therapy.

    “In MDR-TB patients receiving anti-TB, one-fourth developed PH: 32% in patients who received a regimen containing ethionamide, 35% in patients who received a regimen containing PAS, and 44% in HIV-positive patients on ART (52).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Munivenkatappa, 2016, Drug-Induced Hypothyroidism during anti-tuberculosis treatment of multidrug-resistant tuberculosis: Notes from the field, J Tuberc Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A 3-month supplementation of 1,200 mg/d calcium carbonate reversibly increased TSH in 13/20 patients (65%), with TSH >4.0 mU/L in four (20%); overall TSH increased from 1.60 ± 0.22 to 2.71 ± 0.43 mU/L (+69%).

    “For instance, a 3-month supplementation of 1,200 mg/d calcium carbonate reversibly increased TSH in 13/20 patients (65%), with TSH >4.0 mU/L in four (20%) (41). Overall, TSH increased from 1.60 ± 0.22 to 2.71 ± 0.43 mU/L (+69%).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Singh, 2000, Effect of calcium carbonate on the absorption of levothyroxine, JAMA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Of 2,292 patients with primary hypothyroidism, 42.7% had abnormal serum TSH, with 28.3% undertreated and 14.4% overtreated.

    “Of 2,292 patients with PH (12), 42.7% had abnormal serum TSH (28.3% undertreated and 14.4% overtreated).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Vaisman, 2013, How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study, J Endocrinol Invest source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lack of thyroid remnant, time interval between starting rifampin and TSH measurement, and baseline L-T4 dose/kg body weight were significant risks for undertreated hypothyroidism in patients starting rifampin.

    “Lack of thyroid remnant, time interval between starting rifampin and TSH measurement, and baseline L-T4 dose/kg body weight were significant risks for UTH (47).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Kim, 2017, Effect of Rifampin on Thyroid Function Test in Patients on Levothyroxine Medication, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the same Scottish study, TSH decreased significantly (0.17 mU/L) in patients on statins and changed insignificantly in patients on H2 receptor antagonists or glucocorticoids.

    “TSH decreased significantly (0.17 mU/L) in patients on statins and changed insignificantly in patients on H2 receptor antagonists or glucocorticoids (25).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Irving, 2015, Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS), Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Calcium carbonate adsorbed T4 dose-dependently at pH 2 but not pH 7.4, thus explaining L-T4 malabsorption, and reduced T4 pharmacokinetics.

    “Calcium carbonate adsorbed T4 dose-dependently at pH 2 but not pH 7.4, thus explaining L-T4 malabsorption (41), and reduced T4 pharmacokinetics (42).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Singh, 2000, Effect of calcium carbonate on the absorption of levothyroxine, JAMA source

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    • cites [42] Singh, 2001, The acute effect of calcium carbonate on the intestinal absorption of levothyroxine, Thyroid source

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  • May combine two claims.

    Premisecitation

    In a study of 10,496 persons, 730 (7.0%) had L-T4-treated primary hypothyroidism, of whom 391 (5.4%; 3.7% of 10,496) were taking interfering medications, with 114 enrolled; proton-pump inhibitors were the leading interfering medication (95/114 [83%]), followed by calcium salts (18/114 [16%]).

    “Of 10,496 persons, 730 (7.0%) had L-T4-treated PH, of whom 391 (5.4%; 3.7% of 10,496) were taking those IM, with 114 enrolled (age 65.6 ± 12.7 years). PPIs were the leading IM (95/114 [83%]), either alone (n = 71 [62%]) or associated with other IM (n = 24 [21%]), followed by calcium salts (18/114 [16%]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Benvenga, 2019, Alecci U. A minimum of two years of undertreated primary hypothyroidism, as a result of drug-induced malabsorption of l-thyroxine, may have metabolic and cardiovascular consequences, J Clin Transl Endocrinol source

      Not checked in the free run.

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

    Premisecitation

    Women develop overt or subclinical hypothyroidism three times more frequently than men (25.8 vs. 8.7%), with prevalence among women exceeding 50% by the age of 65 years.

    “Indeed, women develop OH or SCH three times more frequently than men (25.8 vs. 8.7%), with prevalence among women exceeding 50% by the age of 65 years (35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Lazarus, 2009, Lithium and thyroid, Best Pract Res Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Of 32 women under aminoglutethimide + hydrocortisone for advanced breast cancer, 17 (53%) had hyperthyrotropinemia before treatment; in 15/17 patients, TSH increased further, with seven developing overt hypothyroidism.

    “Of 32 women under aminoglutethimide + hydrocortisone for ABC, 17 (53%) had hyperthyrotropinemia before treatment. In 15/17 patients, TSH increased further, with seven developing OH (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Bruning, 1984, Pros and cons of aminoglutethimide for advanced postmenopausal breast cancer, Breast Cancer Res Treat source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Based on data of the UK Medicines Information pharmacists, only two cases of interaction between orlistat and L-T4 were reported, most likely via T4 malabsorption; it was recommended that L-T4 and orlistat should be separated by 4 hours, and increased monitoring of thyroid hormone levels may be prudent.

    “Based on data of the UK Medicines Information pharmacists (79), only two cases of interaction between orlistat and L-T4 were reported (80, 81), most likely via T4 malabsorption. It was recommended that L-T4 and orlistat “should be separated by 4 hours, and increased monitoring of […] thyroid hormone levels may be prudent” (79).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [79] Medicines Q&As. Is there an interaction between orlistat and levothyroxine

      Not checked in the free run.

    • cites [80] Madhava, 2005, Hypothyroidism in thyroid carcinoma follow-up: Orlistat may inhibit the absoprtion of thyroxine, Clin Oncol (R Coll Radiol) source

      Not checked in the free run.

    • cites [81] Chiffoleau, 2010, Interaction between orlistat and levothyroxine: a first French case report, Fundam Clin Pharmacol

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During tricyclic antidepressant therapy, TSH levels are unchanged, and T4 and FT4 levels decrease within the euthyroid range, though other studies reported unchanged thyroid function tests.

    “During tricyclic antidepressant therapy, TSH levels are unchanged, and T4 and FT4 levels decrease within the euthyroid range, though other studies reported unchanged thyroid function tests (TFTs) (72).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] de Carvalho, 2009, Effects of selective serotonin reuptake inhibitors on thyroid function in depressed patients with primary hypothyroidism or normal thyroid function, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unmasking of central hypothyroidism and increased L-T4 doses occurred in 30/84 (36%) and 25/159 (16%) patients, respectively, after growth hormone replacement.

    “Unmasking of CH and increased L-T4 doses occurred in 30/84 (36%) and 25/159 (16%) patients, respectively (84).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Agha, 2007, Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Selective serotonin reuptake inhibitors affect thyroid function tests variably, usually with no or downward changes of FT4 and FT3, and no or upward change of TSH within the corresponding reference range.

    “Selective serotonin reuptake inhibitors (SSRIs) affect TFTs variably, usually with no or downward changes of FT4 and FT3, and no or upward change of TSH within the corresponding reference range (72).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] de Carvalho, 2009, Effects of selective serotonin reuptake inhibitors on thyroid function in depressed patients with primary hypothyroidism or normal thyroid function, Thyroid source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Switch from lopinavir/ritonavir to nelfinavir failed to achieve euthyroidism, which was restored when dolutegravir was substituted for lopinavir-ritonavir.

    “Switch from lopinavir/ritonavir to nelfinavir failed to achieve euthyroidism (55), which was restored when dolutegravir was substituted for lopinavir–ritonavir (54).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] Touzot, 2006, Dramatic interaction between levothyroxine and lopinavir/ritonavir in a HIV-infected patient, AIDS source

      Not checked in the free run.

    • cites [54] Sahajpal, 2017, Probable interaction between levothyroxine and ritonavir: Case report and literature review, Am J Health Syst Pharm source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rates of hypothyroidism are 0-40% for nivolumab, 0-11.5% for pembrolizumab, 0-9% for ipilimumab, and 0-5% for tremelimumab.

    “Rates of hypothyroidism are 0–40% (nivolumab), 0–11.5% (pembrolizumab), 0–9% (ipilimumab), and 0–5% (tremelimumab) (38).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] González-Rodríguez, 2016, Immune checkpoint inhibitors: review and management of endocrine adverse effects, Oncologist source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anti-CTLA-4 antibodies and anti-PD-1 antibodies induce autoimmune hypophysitis, with rates of 0-17.4% for ipilimumab, 0-2.6% for tremelimumab, 0-0.9% for nivolumab, and 0-1.2% for pembrolizumab.

    “Anti-CTLA-4 Ab and anti-PD-1 Ab induce autoimmune hypophysitis (27, 37–39), with rates of 0–17.4% (ipilimumab), 0–2.6% (tremelimumab), 0–0.9% (nivolumab), and 0–1.2% (pembrolizumab) (38).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [27] Torino, 2013, Thyroid dysfunction as an unintended side effect of anticancer drugs, Thyroid source

      Not checked in the free run.

    • cites [37] Corsello, 2013, Endocrine side effects induced by immune checkpoint inhibitors, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [38] González-Rodríguez, 2016, Immune checkpoint inhibitors: review and management of endocrine adverse effects, Oncologist source

      Not checked in the free run.

    • cites [39] Costa, 2017, Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials, Oncotarget source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overt or subclinical hypothyroidism develops in up to 15% or 34% of lithium-treated patients, with an annual rate of developing primary hypothyroidism of 1.5% (6.4% in thyroid antibody-positive and 0.8% in thyroid antibody-negative individuals).

    “OH or SCH develop in up to 15 or 34% of lithum-treated patients (20), the annual rate of developing PH being 1.5%, (6.4% in thyroid antibody-positive and 0.8% in thyroid antibody-negative individuals) (70).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Thalmann, 2013

      Not checked in the free run.

    • cites [70] Bocchetta, 2007, Fifteen-year follow-up of thyroid function in lithium patients, J Endocrinol Investig source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autoimmune thyroiditis is caused by monoclonal antibodies to programmed cell death-1 receptor (nivolumab and pembrolizumab) and to cytotoxic T lymphocyte-associated antigen-4 (ipilimumab, tremelimumab).

    “Autoimmune thyroiditis is also caused by monoclonal Ab to programmed cell death-1 receptor (nivolumab and pembrolizumab), and Ab to cytotoxic T lymphocyte-associated antigen-4 (ipilimumab, tremelimumab) (27, 37–39).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [27] Torino, 2013, Thyroid dysfunction as an unintended side effect of anticancer drugs, Thyroid source

      Not checked in the free run.

    • cites [37] Corsello, 2013, Endocrine side effects induced by immune checkpoint inhibitors, J Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [38] González-Rodríguez, 2016, Immune checkpoint inhibitors: review and management of endocrine adverse effects, Oncologist source

      Not checked in the free run.

    • cites [39] Costa, 2017, Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials, Oncotarget source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Through acceleration of both thyroid hormone and cortisol metabolism, initiation of growth hormone replacement may unmask central hypothyroidism and hypoadrenalism; patients already under L-T4 replacement need increased L-T4 doses.

    “Through acceleration of both thyroid hormone and cortisol metabolism, initiation of growth hormone (GH) replacement may unmask CH and hypoadrenalism (82–84). Also, patients already under L-T4 replacement need increased L-T4 doses (82, 84).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [82] Feldt-Rasmussen, 2018, Interactions between hypothalamic pituitary thyroid axis and other pituitary dysfunctions, Endocrine source

      Not checked in the free run.

    • cites [83] Fierro, 2020, Treatment of the adult growth hormone deficiency syndrome with growth hormone: What are the implications for other hormone replacement therapies for hypopituitarism, Growth Horm IGF Res source

      Not checked in the free run.

    • cites [84] Agha, 2007, Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Of 170 patients under lenalidomide, 6% had thyroid dysfunction (hypothyroidism > thyrotoxicosis), which prevailed in patients with known vs. unknown thyroid dysfunction (17 vs 6%).

    “Of 170 patients under lenalidomide, 6% had thyroid dysfunction (hypothyroidism > thyrotoxicosis), which prevailed in patients with known vs. unknown thyroid dysfunction (17 vs 6%) (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Figaro, 2011, Thyroid abnormalities in patients treated with lenalidomide for hematological malignancies: Results of a retrospective case review, Am J Hematol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    L-T4 requirements increased in nine L-T4-treated hypothyroid patients under sertraline; in two patients under TSH-suppressive L-T4 therapy, TSH levels rose into the normal range.

    “L-T4 requirements increased in nine L-T4-treated hypothyroid patients under sertraline (73). Confirming the sertraline-T4 interaction, in two patients under TSH-suppressive L-T4 therapy, TSH levels rose into the normal range (73).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] McCowen, 1997, Elevated serum thyrotropin in thyroxine-treated patients with hypothyroidism given sertraline, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although dopamine and its agonists, somatostatin analogs, dobutamine, amphetamines and corticosteroids inhibit TSH, patients taking chronically these medications have no sustained decreases of thyroid function tests; consequently, central hypothyroidism does not develop.

    “Though dopamine and its agonists (bromocriptine, cabergoline), somatostatin analogs (octreotide), dobutamine, amphetamines and corticosteroids inhibit TSH, patients taking chronically these medications have no sustained decreases of TFTs. Consequently, CH does not develop (34, 85).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Haugen, 2009, Drugs that suppress TSH or cause central hypothyroidism, Best Pract Res Clin Endocrinol Metab source

      Not checked in the free run.

    • cites [85] Brabant, 1989, The role of glucocorticoids in the regulation of thyrotropin, Acta Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subclinical hypothyroidism may occur reversibly following administration of antiepileptic drugs, particularly carbamazepine, phenytoin, valproate, oxcarbazepine, but not lamotrigine, levetiracetam, tiagabine and vigabatrin.

    “SCH may occur reversibly following administration of antiepileptic drugs (AED), particularly carbamazepine, phenytoin, valproate (77), oxcarbazepine, but not lamotrigine, levitracetam, tiagabine and vigabatrine (36).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [77] Verrotti, 2008, Antiepileptic drugs and thyroid function, J Pediatr Endocrinol Metab source

      Not checked in the free run.

    • cites [36] Hamed, 2015, The effect of antiepileptic drugs on thyroid hormonal function: causes and implications, Expert Rev Clin Pharmacol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tyrosine kinase inhibitors may cause de novo hyperthyroidism or hypothyroidism, or worsen pre-existing hypothyroidism and increase L-T4 requirements.

    “Tyrosine kinase inhibitors (TKI) may cause de novo hyperthyroidism or hypothyroidism, or worsen pre-existing hypothyroidism and increase L-T4 requirements (27–29).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Torino, 2013, Thyroid dysfunction as an unintended side effect of anticancer drugs, Thyroid source

      Not checked in the free run.

    • cites [28] Fallahi, 2014, Thyroid dysfunctions induced by tyrosine kinase inhibitors, Expert Opin Drug Saf source

      Not checked in the free run.

    • cites [29] Ferrari, 2019, Autoimmune endocrine dysfunctions associated with cancer immunotherapies, Int J Mol Sci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Among 133 hypothyroid patients hospitalized in intensive care units, thyroid function tests were not performed in 29 (21.8%), replacement therapy was not prescribed for >7 days in 23 (17.3%) and was omitted in three (2.2%).

    “Among 133 such patients, TFTs were not performed in 29 (21.8%), replacement therapy was not prescribed for >7 days in 23 (17.3%) and was omitted in three (2.2%) (95).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Barrett, 2012, Management of long-term hypothyroidism: a potential marker of quality of medicines reconciliation in the intensive care unit, Int J Pharm Pract source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compared to controls, patients requiring L-T4 dose adjustments had significantly higher TSH (5.07 ± 11.04 vs. 2.57 ± 2.51 U/ml) and more frequent TSH tests (84 vs. 73%).

    “Compared to controls, patients requiring adjustments had significantly higher TSH (5.07 ± 11.04 vs. 2.57 ± 2.51 U/ml), and more frequent TSH tests (84 vs. 73%) (99).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Ernst, 2017, The economic impact of levothyroxine dose adjustments: The CONTROL HE Study, Clin Drug Investig source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In the same study, 76 patients (67%) had complications (aggravation of pre-existing or de novo onset of metabolic syndrome, impaired fasting glycemia, diabetes, dyslipidemia, hypertension, cardiovascular disease), whose rates of TSH >4.12 or >2.50 mU/L were significantly greater than in the 36 complication-free patients (22 vs. 11%, or 35 vs. 17%); TSH in patients with complications vs. 1.58 ± 1.9

    “Some complications ensued: aggravation of pre-existing or de novo onset of any of metabolic syndrome (MS), impaired fasting glycemia (IFG), diabetes, dyslipidemia, hypertension, cardiovascular disease (CVD). Seventy-six patients (67%) had complications, whose rates of TSH >4.12 or >2.50 mU/L were significantly greater than in the 36 complication-free patients (22 vs. 11%, or 35 vs. 17%). TSH in”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Benvenga, 2019, Alecci U. A minimum of two years of undertreated primary hypothyroidism, as a result of drug-induced malabsorption of l-thyroxine, may have metabolic and cardiovascular consequences, J Clin Transl Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The retinoid bexarotene causes central hypothyroidism in almost all patients, via TSH suppression and non-deiodinase-mediated thyroid hormone increased metabolism.

    “The retinoid bexarotene causes CH in almost all patients (22), via TSH suppression (93) and non-deiodinase-mediated thyroid hormone increased metabolism (94).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Montanelli, 2018, Drugs and other substances interfering with thyroid function

      Not checked in the free run.

    • cites [93] Sherman, 1999, Central hypothyroidism associated with retinoid X receptor-selective ligands, N Engl J Med source

      Not checked in the free run.

    • cites [94] Smit, 2007, Bexarotene-induced hypothyroidism: Bexarotene stimulates the peripheral metabolism of thyroid hormones, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 114 L-T4-treated primary hypothyroidism patients, exposure to interfering medications (32.1 ± 6.9 months) significantly increased TSH from 1.27 ± 1.34 to 2.81 ± 3.62 mU/L (+121%), and proportions of TSH >4.12 mU/L from 4.7 to 18.5% and >2.50 mU/L from 20.2 to 53.5% compared to the non-exposure period (35.4 ± 9.7 months).

    “In the aforementioned study on 114 L-T4-treated PH patients (23), exposure to IM (32.1 ± 6.9 months) significantly increased TSH from 1.27 ± 1.34 to 2.81 ± 3.62 mU/L (+121%), and proportions of TSH >4.12 mU/L from 4.7 to 18.5% and >2.50 mU/L from 20.2 to 53.5% compared to the non-exposure period (35.4 ± 9.7 months).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Benvenga, 2019, Alecci U. A minimum of two years of undertreated primary hypothyroidism, as a result of drug-induced malabsorption of l-thyroxine, may have metabolic and cardiovascular consequences, J Clin Transl Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The increased L-T4 requirements in ICU patients were attributed to increased gastric pH by H2-blockers (and subsequent decreased L-T4 absorption) and increased T4 to reverse-T3 shunting (due to enhanced type-III deiodinase activity during critical illnesses).

    “The increased L-T4 requirements were attributed to increased gastric pH by H2-blockers (and subsequent decreased L-T4 absorption) and increased T4 to reverse-T3 shunting (due to enhanced type-III deiodinase activity during critical illnesses) (96).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Imberti, 2010, Increased levothyroxine requirements in critically ill patients with hypothyroidism, Minerva Anestesiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Five women with mitotane-treated adrenocortical carcinoma showed features of central hypothyroidism, namely low FT4, normal FT3 and TSH, with impaired TSH response to TRH; mitotane increased serum FT3/FT4 ratio, suggesting enhanced T4 to T3 conversion, a compensatory mechanism of hypothyroidism.

    “Five women with mitotane-treated ACC showed features of CH, namely low FT4, normal FT3 and TSH, with impaired TSH response to TRH (91). Mitotane increased serum FT3/FT4 ratio, suggesting enhanced T4 to T3 conversion, a compensatory mechanism of hypothyroidism (91).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Russo, 2016, Mitotane treatment in patients with adrenocortical cancer causes central hypothyroidism, Clin Endocrinol (Oxf) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The ≥1-dose-adjustment group experienced a 40.3% increase in lost productivity vs controls ($1,381 vs $984), with a peak in the ≥3-dose adjustment subgroup ($1,833).

    “The ≥1-dose-adjustment group experienced a 40.3% increase in lost productivity vs. controls ($1,381 vs. $984), with a peak in the ≥3-dose adjustment subgroup ($1,833).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Ernst, 2017, The economic impact of levothyroxine dose adjustments: The CONTROL HE Study, Clin Drug Investig source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single oral dose of clofibrate decreased significantly hyperthyrotropinemia of primary hypothyroidism patients; clofibrate did not change discernibly basal and TRH-induced TSH secretion in euthyroids; similar results were given by meclofenoxate hydrochloride, suggesting both drugs inhibit TSH secretion in primary hypothyroidism patients possibly acting on the hypothalamus/pituitary.

    “A single oral dose of clofibrate decreased significantly hyperthyrotropinemia of PH patients (87). Clofibrate did not change discernibly basal and TRH-induced TSH secretion in euthyroids. Similar results were given by meclofenoxate hydrochloride (87), suggesting that both drugs inhibit TSH secretion in PH patients possibly acting on the hypothalamus/pituitary (87).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Kobayashi, 1980, Clofibrate and a Related Compound Suppress TSH Secretion in Primary Hypothyroidism, Acta Endocrinol (Copenh) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After chronic administration of metformin, FT4 was unchanged and TSH decreased in L-T4-treated or L-T4-untreated hypothyroid diabetics, but not in euthyroid subjects.

    “After its chronic administration, FT4 was unchanged and TSH decreased in L-T4-treated or L-T4-untreated hypothyroid diabetics, but not in euthyroid subjects (86).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Cappelli, 2009, TSH-lowering effect of metformin in type 2 diabetic patients: differences between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy patients, Diabetes Care source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In nine hypothyroid patients who stayed at ICU for 12-45 days and received H2-blockers, after the first 4-8 days at ICU with L-T4 doses unchanged, TSH of all patients increased significantly to 5.69 mU/L (IQR = 3.87-6.83) from 1.52 mU/L (IQR = 0.79-3.8) at admission; L-T4 dose was increased in 8/9 patients (88.9%) from 86.1 ± 41.6 to 125 ± 39.5 μg/d (54.4 ± 31.6%); upon discharge, TSH returned to

    “Nine hypothyroid patients who stayed at ICU for 12–45 days received H2-blockers as routine prophylaxis against gastroduodenal bleeding and were nasogastrically fed a calorically dense solution (96). This solution was stopped 2 h before and resumed 2 h after L-T4 administration (crushed tablets) nasogastrically. After the first 4–8 days at ICU, with L-T4 doses unchanged, TSH of all patients”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Imberti, 2010, Increased levothyroxine requirements in critically ill patients with hypothyroidism, Minerva Anestesiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overall resource utilization is higher in hypothyroid patients with ≥1 L-T4 dose adjustment ($5,824/patient) than in controls ($3,166/patient), peaking in the ≥3-dose-adjustment subgroup ($8,220/patient).

    “Overall resource utilization was higher in the ≥1-dose-adjustment group ($5,824/patient) vs. controls (USD 3,166/patient), peaking in the ≥3-dose-adjustment subgroup ($8,220/patient).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Ernst, 2017, The economic impact of levothyroxine dose adjustments: The CONTROL HE Study, Clin Drug Investig source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 17 patients with radically resected adrenocortical carcinoma, mitotane was administered associated with glucocorticoid replacement therapy; excluding three patients under L-T4 treatment and one with subclinical hypothyroidism, during the first year, FT4 became subnormal in 12/13 evaluable patients (92%), with L-T4 replacement started after 9 months in four.

    “In 17 patients with radically resected ACC, mitotane was administered associated with glucocorticoid replacement therapy (90). Excluding three patients under L-T4 treatment and one with SCH, during the first year, FT4 became subnormal in 12/13 evaluable patients (92%), with L-T4 replacement started after 9 months in four.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Daffara, 2008, Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly, Endocr Relat Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin lowers serum TSH in L-T4-treated overt hypothyroidism and L-T4-untreated subclinical hypothyroidism patients, but not in euthyroid patients.

    “Metformin lowers serum TSH in L-T4-treated OH and L-T4-untreated SCH patients, but not in euthyroid patients (33).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Lupoli, 2014, Effects of treatment with metformin on TSH levels: a meta-analysis of literature studies, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subclinical hypothyroidism might favor diabetic complications with an odds ratio of 1.74 for nephropathy, 1.42 for retinopathy, 1.85 for peripheral arterial disease, and 1.87 for peripheral neuropathy.

    “Moreover, SCH might favor diabetic complications with an OR of 1.74 (nephropathy), 1.42 (retinopathy), 1.85 (peripheral arterial disease), and 1.87 (peripheral neuropathy) (103).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Han, 2015, Subclinical hypothyroidism and type 2 diabetes: A systematic review and meta-analysis, PloS One source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cardiovascular disease mediates 14.3% of the association between subclinical hypothyroidism and all-cause mortality and 5.9% of the association between high-normal TSH and all-cause mortality.

    “with CVD mediating 14.3 and 5.9% of the association, respectively (104).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Inoue, 2020, Association of subclinical hypothyroidism and cardiovascular disease with mortality, JAMA Netw Open source

      Not checked in the free run.

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

    Premisecitation

    Residual functioning thyroid tissue is a major factor for a given interacting medication to cause thyroid dysfunction and L-T4 dose adjustments.

    “the residual functioning thyroid tissue is a major factor for a given IM to cause thyroid dysfuntion and L-T4 dose adjustments”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Garber, 2012, American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association, Thyroid source

      Not checked in the free run.

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

    Premisecitation

    There are a number of other drugs with decreased absorption at high intragastric pH, such as ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin, dipyridamole, raltegravir, alendronate, digoxin, and nifedipine.

    “there are a number of other drugs with decreased absorption at high intragastric pH, such as ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin, dipyridamole, raltegravir, alendronate, digoxin, and nifedipine, to name a few (117).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Mitra A and Kesisoglou, 2013, Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development, Mol Pharm source

      Not checked in the free run.

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

    Premisecitation

    Development of formulations that can minimize or mitigate the effects of increased gastric pH on bioavailability is another way to solve the problem.

    “The other way is the development of “formulations that can minimize or mitigate the effects of increased gastric pH on the bioavailability” (117).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [117] Mitra A and Kesisoglou, 2013, Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development, Mol Pharm source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both 2-month-long trials with vitamin C lack formal pharmacokinetics studies and challenge of patients with IM-associated undertreated hypothyroidism.

    “Both 2-month-long trials with vitamin C (115, 116) lack formal pharmacokinetics studies and challenge of patients with IM-associated UTH.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [115] Antúnez, 2011, Vitamin C improves the apparent absorption of levothyroxine in a subset of patients receiving this hormone for primary hypothyroidism, Rev Argent Endocrinol Metab

      Not checked in the free run.

    • cites [116] Jubiz W and Ramirez, 2014, Effect of Vitamin C on the absorption of levothyroxine in patients with hypothyroidism and gastritis, J Clin Endocrinol Metab source

      Not checked in the free run.

57 of 57

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?

  • Most commonly prescribed drugs act by sequestrating the hormone in the intestinal content, considerably decreasing LT4 bioavailability.

    “Most of the commonly prescribed drugs act by sequestrating the hormone in the intestinal content, thus considerably decreasing LT4 bioavailability.”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [12]

    Table 2 (The Pharmacological Interference on L-T4 Therapy; page unavailable) lists several drugs that physically interact with T4, and the section on thyroid dysfunction says calcium carbonate adsorbs T4 and reduces its bioavailability. But the paper describes multiple mechanisms of interference and identifies proton-pump inhibitors—not a drug class described as sequestering T4—as the leading interfering medication in one patient group. It does not support the claim that most commonly prescribed drugs act by intestinal sequestration. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Other causes of LT4 treatment failure, such as nutritional, pharmacological, or pathological interferences, may be equally relevant.

    “Nowadays, we know that other causes may be equally relevant, as in the case of nutritional, pharmacological or pathological interferences (12, 13, 14).”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [12]

  • Use of drugs interacting and/or interfering with different formulations of levothyroxine may represent a significant issue when treating patients in a real life setting.

    “The use of drugs interacting and/or interfering with the different formulations of levothyroxine may represent a significant issue when treating patients in a ‘real life’ setting.”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [12]

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.

  • Overall high-TSH rate exceeds both subgroup rates

    Major

    The paper reports TSH >2.50 mU/L in 53.5% of the 114 patients during exposure. It later gives rates of 35% among patients with complications and 17% among complication-free patients; an overall rate cannot exceed both subgroup rates.

  • Setting 2 TSH is described as lower than a smaller value

    Minor

    The stated mean TSH in setting 2 is 3.33 mU/L, which is higher-not lower-than the 2.16 mU/L stated for setting 3.

  • Interfering-medication percentage uses the wrong denominator

    Minor

    The 391 patients taking interfering medications were 53.6% of the 730 patients with L-T4-treated primary hypothyroidism, not 5.4%. The accompanying 3.7% of 10,496 is consistent.

    Reported 5.4 · recomputed 53.561644

3 of 3

Cites

Flagged first, then by citations

4 of the 118 references couldn’t be matched to a known paper.

Research works printed but not linked: 6

  1. Jonklaas, 2013, Treatment of hypothyroidism
  2. Singer, 2013, Primary hypothyroidism due to other causes
  3. Montanelli, 2018, Drugs and other substances interfering with thyroid function
  4. Ali, 2017, Pomalidomide-induced hypothyroidism, Endocrinol Diabetes Metab Case Rep, 2017, 17, 10.1530/edm-17-0110 · DOI
  5. de Carvalho, 2010, Response to McCowe and Geber, Thyroid, 20, 10.1089/thy.2009.0387 · DOI
  6. Chiffoleau, 2010, Interaction between orlistat and levothyroxine: a first French case report, Fundam Clin Pharmacol, 24, 1

Cited by

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Related

Authors
Benvenga, S.
Affiliations
University of Messina (IT)
Corresponding author
Benvenga, Salvatore
ORCID
Benvenga, Salvatore
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2020-12-22
Volume
11
Pages
607446-607446
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2020.607446
PMC
PMC7783463
OpenAlex
W3113848700
Semantic Scholar
a8b27bdcf44820d1e71778b11ebe1bdc9ab6d939
Cited by
13
References
118
Citations by year
2025: 5 · 2024: 3 · 2022: 4 · 2021: 1
FWCI
0.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
levothyroxine, drug interactions, primary hypothyroidism, central hypothyroidism, thyroid function tests, serum TSH, free thyroxine, thyroid hormone absorption, cardiovascular complications, monitoring costs
MeSH terms
Drug Interactions, Humans, Hypothyroidism, Thyroid Function Tests, Thyroid Hormones, Thyroxine

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 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

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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