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Cited by 139Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryHormonal and reproductive studies

Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study

Open access
Thayakaran, Rasiah, Adderley, Nicola J, Sainsbury, Christopher, Torlinska, Barbara, Boelaert, Kristien, Šumilo, Dana, Price, Malcolm, Thomas, G Neil +2 more·2019·BMJ
DOI 10.1136/bmj.l4892PMC PMC6719286
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Abstract

Objective: To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. Design: Retrospective cohort study. Setting: The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. Participants: Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. Exposure: TSH concentration in patients with hypothyroidism. Main outcome measures: Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. Results: 162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). Conclusions: In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.

AI snapshot

Written from the paper’s full text.

TL;DR

In UK primary care patients with incident hypothyroidism, TSH concentrations within the recommended normal range were not associated with clinically meaningful differences in long-term mortality, cardiovascular disease, or fracture outcomes. Adverse outcomes were seen mainly when TSH was outside normal limits, especially above 10 mIU/L.

Key findings

  • Compared with TSH 2-2.5 mIU/L, high TSH (>10 mIU/L) was associated with increased ischaemic heart disease (HR 1.18, 95% CI 1.02 to 1.38; P=0.03) and heart failure (HR 1.42, 95% CI 1.21 to 1.67; P<0.001).
  • Low TSH was associated with lower heart failure risk: HR 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and HR 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L.
  • Mortality was increased at both low and high TSH: HR 1.18 (1.08 to 1.28; P<0.001) for <0.1 mIU/L, HR 1.29 (1.22 to 1.36; P<0.001) for 4-10 mIU/L, and HR 2.21 (2.07 to 2.36; P<0.001) for >10 mIU/L.
  • Fragility fracture risk was increased at TSH >10 mIU/L (HR 1.15, 95% CI 1.01 to 1.31; P=0.03); no association was found for all fractures.

Methods

  • Retrospective cohort study using The Health Improvement Network (THIN), a UK primary care electronic records database, including adults with incident hypothyroidism from 1 January 1995 to 31 December 2017.
  • The analysis included 162,369 patients with hypothyroidism and 863,072 TSH measurements; median follow-up was 6 years, and 23.2% were men and 76.8% women.
  • TSH was modelled as a time-varying categorical covariate (annual mean; reference 2-2.5 mIU/L) in extended Cox proportional hazards models for ischaemic heart disease, heart failure, stroke/TIA, atrial fibrillation, all fractures, fragility fractures, and mortality, adjusted for baseline covariates; subgroup analyses were by age and sex.

Limitations

  • The paper states that it did not differentiate cause of hypothyroidism; assay variability, interference, macro-TSH, age-related TSH shifts, and obesity may affect the sample; some subclinical hypothyroidism may have been miscoded; baseline covariates may have varied over time; median follow-up of 6 years may not capture all long-term outcomes; cause-specific mortality is not recorded in THIN; reverse causality is possible; and osteoporosis is poorly recorded.
  • The paper also notes that pituitary disease was not excluded in the primary analysis, although a sensitivity analysis excluding 1,416 (0.9%) patients with pituitary disease had no effect on mortality findings.
  • Evident from the text: this is an observational database study, so residual confounding cannot be excluded, and reliance on Read codes and primary care records may introduce misclassification.

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

Integrity signals

Registry

Crossref · 10.1136/bmj.l4892

Cites

52 of 52 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 23 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Increased mortality was observed at TSH <0.1 mIU/L (hazard ratio 1.18, 95% CI 1.08 to 1.28, P<0.001).

    “Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L.”
    Quote in the paperSubstantial claim
  • Findingown data

    TSH >10 mIU/L compared with 2-2.5 mIU/L was not associated with stroke/transient ischaemic attack.

    “This was not the case for stroke/transient ischaemic attack; however, the risk was marginally reduced at TSH concentrations of 3-3.5 mIU/L”
    Quote in the paperSubstantial claim
  • Findingown data

    A protective effect for heart failure was seen at TSH 0.1-0.4 mIU/L (hazard ratio 0.76, 95% CI 0.62 to 0.92, P=0.006).

    “A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L).”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared with the reference TSH category (2-2.5 mIU/L), risk of heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.42, 95% CI 1.21 to 1.67, P<0.001).

    “Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively).”
    Quote in the paperSubstantial claim
  • Findingown data

    TSH 3-3.5 mIU/L compared with 2-2.5 mIU/L was associated with marginally reduced risk of stroke/transient ischaemic attack (HR 0.86, 95% CI 0.75 to 0.99, P=0.04).

    “the risk was marginally reduced at TSH concentrations of 3-3.5 mIU/L (hazard ratio 0.86 (0.75 to 0.99; P=0.04)”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 24
  • The quote only partly states this claim. 4

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

    Findingown data

    The mean age of patients at the time of diagnosis of hypothyroidism was 58.43 (SD 17.15) years.

    “The mean age of patients at the time of diagnosis of hypothyroidism was 58.43 (SD 17.15) years.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The study included 162 369 patients with hypothyroidism and 863 072 TSH measurements.

    “162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis.”
    • Also stated in: § Results · plain
      “The study population included 162 369 patients with hypothyroidism; we excluded 1930 patients with a baseline TSH measurement only and no subsequent measurement.”
    • Also stated in: § Results · plain
      “A total of 863 072 TSH measurements were collected for the analysis.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The remaining 160 439 included patients contributed a total of 1 073 038 person years, with a median follow-up of 6 years.

    “The remaining 160 439 included patients contributed a total of 1 073 038 person years, with a median follow-up of 6 years (supplementary table A);”
    Quote in the paperNot a substantial claim

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

    Findingown data

    23.2% (n=37 226) of patients were men, and 76.8% (n=123 213) were women.

    “23.2% (n=37 226) of patients were men, and 76.8% (n=123 213) were women.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    TSH >10 mIU/L compared with 2-2.5 mIU/L was associated with increased all-cause mortality (HR 2.21, 95% CI 2.07 to 2.36, P<0.001).

    “both the lowest and highest TSH concentrations were associated with increased mortality compared with the reference TSH category (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    TSH <0.1 mIU/L compared with 2-2.5 mIU/L was associated with increased all-cause mortality (HR 1.18, 95% CI 1.08 to 1.28, P<0.001).

    “both the lowest and highest TSH concentrations were associated with increased mortality compared with the reference TSH category (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Results were similar in age (≤65 and >65 years) and sex stratified analyses.

    “We obtained similar results in age (≤65 and >65 years) and sex stratified analyses (supplementary tables B-E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was no increase in risk of ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, and fractures in hypothyroid patients across TSH concentrations within the specified normal range.

    “Similarly, we observed no increase in risk of ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, and fractures in patients with hypothyroidism across TSH concentrations within the specified normal range.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mortality was higher in the lowest TSH category (<0.1 mIU/L) and for concentrations above 4 mIU/L.

    “however, mortality was higher in the lowest TSH category (<0.1 mIU/L) and for concentrations above 4 mIU/L.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The risk of heart failure was elevated when TSH was above 10 mIU/L and lower when TSH was below 0.4 mIU/L.

    “The risk of heart failure was elevated when TSH was above 10 mIU/L and lower when TSH was below 0.4 mIU/L.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The association between TSH >10 mIU/L and fragility fracture was non-significant in men and patients aged 65 years or under.

    “the association was non-significant in men and patients aged 65 years or under.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a higher risk of fragility fractures for TSH above 10 mIU/L, driven predominantly by women and patients aged over 65 years.

    “Interestingly, we found a higher risk of fragility fractures for TSH above 10 mIU/L, driven predominantly by women and patients aged over 65 years.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    TSH 0.1-0.4 mIU/L compared with 2-2.5 mIU/L was associated with a marginal protective effect for atrial fibrillation (HR 0.86, 95% CI 0.74 to 1.00, P=0.05).

    “However, we found a marginal protective effect at TSH concentrations of 0.1-0.4 mIU/L (hazard ratio 0.86 (0.74 to 1.00; P=0.05)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the study dataset, 11.6% and 32.4% of annual TSH measures were below <0.4 mIU/L or above >4 mIU/L, respectively.

    “In the study dataset, 11.6% and 32.4% of the annual TSH measures were below (<0.4 mIU/L) or above (>4 mIU/L) the recommended optimal range, respectively”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    TSH 4-10 mIU/L compared with 2-2.5 mIU/L was associated with increased all-cause mortality (HR 1.29, 95% CI 1.22 to 1.36, P<0.001).

    “both the lowest and highest TSH concentrations were associated with increased mortality compared with the reference TSH category (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Levothyroxine is one of the most commonly prescribed drugs in Western countries.

    “consequently, levothyroxine is one of the most commonly prescribed drugs in Western countries,2 3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites 2 3

      Not checked in the free run.

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

    Premisecitation

    Current guidelines in Europe and the US recommend that replacement therapy should be aimed at resolving symptoms and achieving 'normalisation' of TSH.

    “Current guidelines in Europe and the US recommend that replacement therapy should be aimed at resolving symptoms and achieving “normalisation” of TSH.7 8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 7 8

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Study design and conductreasoning

    In the UK, GPs are required to maintain a mandatory register of patients with ischaemic heart disease, heart failure, stroke/transient ischaemic attack, and atrial fibrillation as part of the Quality and Outcomes Framework; these diagnoses are therefore well recorded in primary care.

    “In the UK, GPs are required to maintain a mandatory register of patients with ischaemic heart disease, heart failure, stroke/transient ischaemic attack, and atrial fibrillation as part of the Quality and Outcomes Framework; these diagnoses are therefore well recorded in primary care.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Premisecitation

    From a physiological standpoint, a continuum of effects may plausibly occur across the spectrum of normal TSH concentrations.

    “from a physiological standpoint, a continuum of effects may plausibly occur across the spectrum of normal TSH concentrations9”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] source

      Not checked in the free run.

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

    Premisecitation

    Hypothyroidism is a highly prevalent global health problem that can substantially affect patients' wellbeing.

    “Hypothyroidism is a highly prevalent global health problem that can substantially affect patients’ wellbeing.1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] source

      Not checked in the free run.

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

    Premisecitation

    Levothyroxine prescription is likely to increase further in the foreseeable future.

    “and this is likely to increase further in the foreseeable future.4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

      Not checked in the free run.

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

    Study design and conductown data

    The study did a sensitivity analysis for the mortality outcome by using multiple imputation to impute missing TSH values.

    “In addition, we did a sensitivity analysis for the mortality outcome by using multiple imputation to impute missing TSH values; covariates used in the imputation were sex, age, body mass index, fifth of Townsend deprivation, smoking status, diabetes, hypertension, and levothyroxine prescription (supplementary methods 1).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Evidence suggests that free thyroxine concentrations are the main driver of the above clinical outcomes.

    “This is further challenged by evidence suggesting that free thyroxine concentrations are the main driver of the above clinical outcomes.23 24”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 23 24

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Guidelines propose a wide range for TSH, 0.4-4.0 mIU/L, as an indication for optimal replacement.

    “which suggest a wide range for TSH, 0.4-4.0 mIU/L, as an indication for optimal replacement,7 8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 7 8

      Not checked in the free run.

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

    Study design and conductown data

    For mortality, the Cox model was also adjusted for Charlson comorbidity index.

    “For mortality, the model was also adjusted for Charlson comorbidity index.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Mortality data and clinical codes for cardiovascular diseases in THIN have been previously validated.

    “Mortality data and clinical codes for cardiovascular diseases in THIN have been previously validated.27 28 29”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites 27 28 29

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Cause-specific mortality is not recorded in THIN, so cause of death could not be ascertained.

    “Cause specific mortality is not recorded in THIN, so we could not ascertain cause of death.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    Because diagnoses could not be confirmed, a small proportion of patients with subclinical hypothyroidism may have been miscoded as having hypothyroidism in general practice.

    “As we could not confirm diagnoses, a small proportion of patients with subclinical hypothyroidism may have been miscoded as having hypothyroidism in general practice.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Osteoporosis is poorly recorded in primary care, so osteoporosis could not be included as an outcome; fragility fracture was used as an alternative.

    “Osteoporosis is poorly recorded in primary care, so we could not include osteoporosis as an outcome; we used fragility fracture as an alternative.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    The findings corroborate the current recommendations for management of hypothyroid patients.

    “In clinical terms, these findings corroborate the current recommendations for management of hypothyroid patients.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    TSH was treated as a time-varying covariate; for other variables, baseline values were included in the model, but these may have varied over time.

    “We treated TSH as a time varying covariate; for other variables, we included baseline values in the model, but these too (for example, smoking status, body mass index, and drugs) may have varied over time.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    In the primary analysis, patients with pituitary disease were not excluded.

    “In the primary analysis, we did not exclude patients with pituitary disease, in whom TSH concentrations may not accurately reflect circulating thyroid hormone concentrations owing to TSH deficiency being caused by inadequate secretion of TSH.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The subgroup findings may be the result of multiple testing, although each result occurs within the 3-4 mIU/L concentration range.

    “These findings may be the result of multiple testing, although each result occurs within the 3-4 mIU/L concentration range.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    Assay variability, potential interference with rheumatoid factors or heterophilic antibodies, occasional cases of macro-TSH, the age-related shift towards higher TSH concentrations in older iodine-sufficient patients, and obesity may affect this population-based sample to an extent.

    “Furthermore, assay variability, potential interference with rheumatoid factors or heterophilic antibodies, occasional cases of macro-TSH, the observed age related shift towards higher TSH concentrations in older iodine sufficient patients, and obesity may affect this population based sample to an extent.45 46 47 48”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] source

      Not checked in the free run.

    • cites [46] source

      Not checked in the free run.

    • cites [47] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Rigorous selection of covariates and a large and well-powered study population enabled exploration of a comprehensive list of relevant outcomes reflecting the full spectrum of cardiovascular disease.

    “This, combined with the rigorous selection of covariates and a large and well powered study population, enabled us to explore a comprehensive list of relevant outcomes reflecting the full spectrum of cardiovascular disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    An earlier study by Flynn et al included multiple TSH measures for each patient but used these to create a single weighted mean value that was used to assign patients to one of four categories (suppressed, low, normal, and high TSH); the method did not account for changes in TSH concentration or category during follow-up.

    “An earlier study by Flynn et al included multiple TSH measures for each patient but used these to create a single weighted mean value that was used to assign patients to one of four categories (suppressed, low, normal, and high TSH)6; the method did not account for changes in TSH concentration or category during the follow-up period.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] source

      Not checked in the free run.

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

    Premisecitation

    The proportion of annual TSH measures outside the recommended optimal range is largely in line with previous relevant reports.

    “which is largely in line with previous relevant reports.44”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    By showing effects on all-cause mortality when hypothyroidism is suboptimally treated, the findings challenge the notion of a benign disease and underline the need for diligent monitoring.

    “However, by showing effects on all cause mortality when hypothyroidism is suboptimally treated, our findings challenge the notion of a “benign” disease and underline the need for diligent monitoring”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The study did not differentiate the cause of hypothyroidism (for example, autoimmune, post-radioiodine or thyroidectomy, and thyroiditis).

    “Firstly, we did not differentiate the cause of hypothyroidism (for example, autoimmune, post-radioiodine or thyroidectomy, and thyroiditis).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The median follow-up period was six years; this may not be sufficient to observe all long-term outcomes.

    “The median follow-up period was six years; this may not be sufficient to observe all long term outcomes.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationown data

    From a clinical perspective, the study provides strong support for current recommendations on the clinical management of hypothyroid patients and validates with hard evidence the latest American Thyroid Association and British Thyroid Association guidelines.

    “From a clinical perspective, this study provides strong support for the current recommendations on the clinical management of hypothyroid patients and validates with hard evidence the latest American Thyroid Association and British Thyroid Association guidelines.7 8”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] source

      Not checked in the free run.

    • cites [8] source

      Not checked in the free run.

41 of 41

  • The authors state this as an assumption.

    The remaining TSH categories (0.1-0.4 and 4-10 mIU/L) include subclinical thyroid dysfunction.

    “We assumed the remaining categories (TSH 0.1-0.4 and 4-10 mIU/L) to include subclinical thyroid dysfunction, serving both ease of interpretation and biological plausibility.”

  • The paper relies on this without support.

    Determining an individual's set point for TSH is not part of routine clinical practice.

    “but determining an individual’s set point is not part of routine clinical practice, and replacement treatment is generally targeted in a wide reference range.”

  • The paper relies on this without support.

    TSH concentrations in the wide target range may be achieved by different doses of levothyroxine.

    “TSH concentrations in this wide target range may be achieved by different doses of levothyroxine.”

  • The paper relies on this without support.

    Lifelong treatment with thyroid hormone is needed when persistent thyroid hormone deficiency is confirmed.

    “Lifelong treatment with thyroid hormone (replacement therapy) is needed when the diagnosis of persistent thyroid hormone deficiency is confirmed;”

  • The paper relies on this without support.

    No specific optimal target for thyroid stimulating hormone (TSH) concentration exists in the context of thyroid hormone replacement.

    “No specific optimal target for thyroid stimulating hormone (TSH) concentration exists in the context of thyroid hormone replacement”

  • The paper relies on this without support.

    Whether variation in TSH concentration within normal limits may significantly affect patients' outcomes remains unclear.

    “Whether variation in TSH concentration within normal limits may significantly affect patients’ outcomes remains unclear”
6 of 6

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 younger individuals, increased risks of adverse outcomes were observed in patients with TSH concentrations less than 0.1 mIU/L (but not 0.1-0.4 mIU/L), in terms of all-cause mortality, atrial fibrillation, and stroke risk.

    “In younger individuals, increased risks of adverse outcomes were observed in patients with TSH concentrations less than 0•1 mIU/L (but not 0•1-0•4 mIU/L), in terms of all-cause mortality, 160 atrial fibrillation, and stroke risk.161”

    From Hypothyroidism (2024) · cites this paper as [160]

    The Results (Cardiovascular diseases) report no increased atrial-fibrillation risk in the lowest TSH category and no association between TSH below 0.4 mIU/L and stroke/transient ischaemic attack. In patients aged 65 or under, TSH of 0.1–0.4 mIU/L was protective for atrial fibrillation. The Results (All cause mortality) report increased mortality at TSH below 0.1 mIU/L overall, but that association became non-significant in age-stratified analysis. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • These risks were particularly more pronounced in those with serum TSH levels consistently at extremes (<0.1 or >10.0 mU/L).

    “These risks were particularly more pronounced in those with serum TSH levels that are consistently at the extremes (<0.1 or >10.0 mU/L).”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [72]

    The Results (All cause mortality) report increased mortality at both <0.1 and >10 mIU/L, and the Results (Cardiovascular diseases; Fractures) report several increased risks at >10 mIU/L. But the Methods (Exposure, outcomes, and covariates) analyze TSH as an annually measured, time-varying category, not whether levels were consistently extreme. Risks also did not uniformly increase at <0.1 mIU/L: heart-failure risk was lower there. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Analyses of real-world data from patient registries have demonstrated that serum TSH levels outside reference intervals in LT4-treated hypothyroidism are associated with adverse health outcomes, including ischemic heart disease events, cardiac dysrhythmias, fractures, and heart failure.

    “Analyses of real-world data from patient registries have demonstrated that the levels of serum TSH outside the reference intervals, in patients with LT4-treated hypothyroidism, are associated with adverse health outcomes, including ischemic heart disease events, cardiac dysrhythmias, fractures, and heart failure (5, 72, 73).”

    From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [72]

    The Abstract Results and Results > Cardiovascular diseases report increased risks of ischaemic heart disease and heart failure at TSH >10 mIU/L; the Abstract Results also report increased fragility fractures in that category. But Results > Cardiovascular diseases found no increased risk of atrial fibrillation (a cardiac dysrhythmia) in the lowest or highest TSH categories. The adverse associations reported here are chiefly for high TSH, not uniformly for levels outside the reference interval. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Excessive levothyroxine treatment in patients of high age is associated with increased mortality.

    “Excessive LT4 treatment in patients of high age is associated with an increased mortality.”

    From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [43]

  • A recent retrospective cohort study of more than 150,000 patients with incident hypothyroidism showed an association between the highest TSH concentration and increased risk of heart failure both in patients younger and older than 65 years.

    “A recent retrospective cohort study of more than 150,000 patients with incident hypothyroidism of whom 97% received LT4 therapy during the follow-up period, showed that there was an association between the highest TSH concentration and increased risk of heart failure both in patients younger and older than 65 years; whereas, the increased risk of ischemic heart disease remained significant only in”

    From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [43]

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.

  • Abstract overstates the number of patients included in the analysis

    Minor

    The abstract says 162,369 patients were included, but the Results section says 1,930 of those patients were excluded, leaving 160,439 included patients.

1 of 1

Cites

1 retracted

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2 of the 54 references couldn’t be matched to a known paper.

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Related

Authors
Thayakaran, R., Adderley, N. J., Sainsbury, C., Torlinska, B., Boelaert, K., Šumilo, D., Price, M., Thomas, G. N., Toulis, K. A., & Nirantharakumar, K.
Affiliations
  • University of Birmingham (GB)
  • NHS Greater Glasgow and Clyde (GB)
  • 424 General Military Hospital (GR)
  • Health Data Research UK (GB)
Corresponding author
Nirantharakumar, Krishnarajah
ORCID
Venue
BMJ
Publisher
BMJ
Published
2019-09-03
Volume
366
Pages
l4892
ISSN
  • 1756-1833 (ISSN-L)
  • 0959-8138
DOI
10.1136/bmj.l4892
PMC
PMC6719286
OpenAlex
W2971614705
Semantic Scholar
bf5bdeaf372dfe7b221183446c75c400d3f317b4
Cited by
138
References
54
Citations by year
2026: 9 · 2025: 18 · 2024: 30 · 2023: 16 · 2022: 23 · 2021: 27 · 2020: 12 · 2019: 2
FWCI
12.98
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc)
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 › Hormonal and reproductive studies
Keywords
hypothyroidism, thyroid-stimulating hormone, thyroid hormone replacement, levothyroxine, all-cause mortality, cardiovascular disease, ischemic heart disease, heart failure, stroke, atrial fibrillation, fracture, fragility fractures, TSH suppression, time-varying covariates, primary care, Health Improvement Network, health outcomes, dose-response relationship
MeSH terms
Adult, Aged, Cardiovascular Diseases, Female, Humans, Hypothyroidism, Longitudinal Studies, Male, Middle Aged, Reference Values, Retrospective Studies, Risk Factors, Thyroid Gland, Thyrotropin, Thyroxine, Fractures, Bone

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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.

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