CoChat
Sign Up
Cited by 75Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryThyroid Cancer Diagnosis and Treatment

Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?

Open access
Ettleson, Matthew D, Bianco, Antonio C·2020·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgaa430PMC PMC7382053
Open this paper in CoChat — free account

Abstract

Context: It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist, and what is the role of combination therapy with LT4 and liothyronine (LT3), are questions that remain unclear. Here we explore evidence of abnormal thyroid hormone (TH) metabolism in LT4-treated patients, and offer a rationale for why some patients perceive LT4 therapy as a failure. Evidence Acquisition: This review is based on a collection of primary and review literature gathered from a PubMed search of “hypothyroidism,” “levothyroxine,” “liothyronine,” and “desiccated thyroid extract,” among other keywords. PubMed searches were supplemented by Google Scholar and the authors’ prior knowledge of the subject. Evidence Synthesis: In most LT4-treated patients, normalization of serum thyrotropin levels results in decreased serum T3/T4 ratio, with relatively lower serum T3 levels; in at least 15% of the cases, serum T3 levels are below normal. These changes can lead to a reduction in TH action, which would explain the slower rate of metabolism and elevated serum cholesterol levels. A small percentage of patients might also experience persistent symptoms of hypothyroidism, with impaired cognition and tiredness. We propose that such patients carry a key clinical factor, for example, specific genetic and/or immunologic makeup, that is well compensated while the thyroid function is normal but might become apparent when compounded with relatively lower serum T3 levels. Conclusions: After excluding other explanations, physicians should openly discuss and consider therapy with LT4 and LT3 with those hypothyroid patients who have persistent symptoms or metabolic abnormalities despite normalization of serum thyrotropin level. New clinical trials focused on symptomatic patients, genetic makeup, and comorbidities, with the statistical power to identify differences between monotherapy and combination therapy, are needed.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1210/clinem/dgaa430

Cites

158 of 158 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

  • More recent studies with a larger number of subjects confirmed the association between the DIO2 polymorphism and reduced effectiveness of LT4.

    “However, more recent studies with a larger number of subjects confirmed the association between the DIO2 polymorphism and the reduced effectiveness of LT4.”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [31]

    The Conclusions (page unavailable) describe the evidence on Thr92Ala-DIO2 as conflicting. They report lower T3 levels in LT4-treated carriers in an Italian study, but also state that a Netherlands study found no effect on response to LT4 monotherapy. The References identify the Netherlands study as a large population-based cohort, contrary to the claim that larger studies confirmed reduced LT4 effectiveness. (LLM, conf=0.85)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Responsiveness to therapy containing T3 depends on multiple factors, including genetic background, presence of comorbidities/autoimmune disorders, and other yet unidentified biological/environmental factors.

    “This suggests that “responsiveness to therapy containing T3” depends on multiple factors, including genetic background, presence of comorbidities/autoimmune disorders, as well as other yet unidentified biological/environmental factors ( 25 ).”

    From Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine+Liothyronine in Hypothyroidism (2021) · cites this paper as [25]

    The Conclusions report an association between a genetic variant and enhanced response to combination therapy, and recommend screening future trial participants for genetic, autoimmune, and other interfering variables. The paper proposes that individual factors contribute to persistent symptoms on T4, but it does not establish that comorbidities or unidentified environmental factors determine responsiveness to T3-containing therapy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Compounding factors such as genetic background and comorbidities might impair even further the effectiveness of therapy with LT4, leading to residual symptoms despite normalization of serum TSH levels.

    “These observations led to the idea that compounding factors such as genetic background and comorbidities might impair even further the effectiveness of therapy with LT4, leading to residual symptoms despite the normalization of serum TSH levels (31).”

    From Emerging Therapies in Hypothyroidism (2024) · cites this paper as [31]

    The Conclusions propose a genetic or other patient-specific “second hit” that could compound relatively low T3 levels and contribute to persistent symptoms despite normal TSH. They also name coexisting chronic diseases as possible alternative causes of similar symptoms, but do not establish that comorbidities impair LT4 effectiveness. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

  • The scientific basis of the low tissue T3 hypothesis is sound.

    “The scientific basis of the “low tissue T3 hypothesis” is thus sound, and individualized therapy for hypothyroidism could be indicated, as LT4 monotherapy may provide dissatisfaction in a subset of patients [7].”

    From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [7]

  • Combined T4 and T3 therapy aims to more closely mimic the body's natural thyroid hormone secretion patterns.

    “Combined therapy, involving both LT4 and liothyronine (LT3), aims to more closely mimic the body’s natural thyroid hormone secretion patterns”

    From Evaluating the effectiveness of combined T4 and T3 therapy or desiccated thyroid versus T4 monotherapy in hypothyroidism: a systematic review and meta-analysis (2024) · cites this paper as [8]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

3 of the 161 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. [48]48. Pitt-Rivers R. The thyroid hormones: historical aspects. In: Li CH, ed. Hormonal Proteins and Peptides: Thyroid Hormones. Vol. 6. New York: Academic Press; 1978:391-422. [Google Scholar]
  2. [139]139. American Diabetes Association. Introduction. Diabetes Care. 2020;43(Suppl 1):S1-S2. [DOI] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Related

Authors
Ettleson, M. D., & Bianco, A. C.
Affiliations
University of Chicago (US)
Corresponding author
Bianco, Antonio C
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2020-07-02
Volume
105
Issue
9
Pages
e3090-e3104
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgaa430
PMC
PMC7382053
OpenAlex
W3038615190
Cited by
75
References
161
Citations by year
2026: 4 · 2025: 8 · 2024: 16 · 2023: 15 · 2022: 13 · 2021: 17 · 2020: 2
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (DK58538, DK65055, DK77148)
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 › Thyroid Cancer Diagnosis and Treatment
Keywords
hypothyroidism, levothyroxine, liothyronine, combination thyroid hormone therapy, T3/T4 ratio, thyroid hormone metabolism, desiccated thyroid extract, serum cholesterol
MeSH terms
Drug Resistance, Drug Therapy, Combination, Humans, Hypothyroidism, Practice Patterns, Physicians', Thyroid Function Tests, Thyrotropin, Thyroxine, Triiodothyronine, Treatment Failure, Hormone Replacement Therapy, Precision Medicine

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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 ›

Are you an author, or do you see a problem with this page? Request a review