Managing symptoms in hypothyroid patients on adequate levothyroxine: a narrative review
Open accessAbstract
The current standard of care for hypothyroidism is levothyroxine (LT4) monotherapy to reduce levels of thyrotropin (thyroid-stimulating hormone, TSH) within its reference range and amelioration of any symptoms. A substantial minority continues to report hypothyroid-like symptoms despite optimized TSH, however. These symptoms are not specific to thyroid dysfunction and are frequent among the euthyroid population, creating a therapeutic dilemma for the treating clinician as well as the patient. We present a concise, narrative review of the clinical research and evidence-based guidance on the management of this challenging population. The clinician may endeavor to ensure that the serum TSH is within the target range. However, the symptomatic patient may turn to alternative non-evidence-based therapies in the hope of obtaining relief. Accordingly, it is important for the clinician to check for conditions unrelated to the thyroid that could account for the ongoing symptoms such as other autoimmune conditions, anemia or mental health disorders. Systematic and thorough investigation of the potential causes of persistent symptoms while receiving LT4 therapy will resolve the problem for most patients. There may be some patients that may benefit from additional treatment with liothyronine (LT3), although it is unclear as yet as to which patient group may benefit the most from combined LT4 + LT3 therapy. In the future, personalized treatment with LT4 + LT3 may be of benefit for some patients with persistent symptoms of hypothyroidism such as those with polymorphisms in the deiodinase enzyme 2 (DIO2). For now, this remains a subject for research.
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Symptoms resembling those of hypothyroidism also occur in medical conditions like chronic fatigue, anemia, stress, and changes in body weight.
“Symptoms resembling those of hypothyroidism also occur in medical conditions like chronic fatigue, anemia, stress, and changes in body weight [38].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [38]
Dissatisfaction with LT4 outcomes in hypothyroid patients is related to previous negative experiences with health care workers.
“Many studies report that dissatisfaction with LT4 outcomes in hypothyroid patients is related to previous negative experiences with health care workers [32,38,40,43,44].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [38]
The section ‘Is the patient using LT4 correctly?’ discusses dissatisfaction with LT4 and the importance of maintaining physician–patient trust, but does not link dissatisfaction to previous negative experiences with health care workers. Searches for negative experiences, prior encounters and physician–patient relationships found no passage addressing that link. (LLM, conf=0.73)
Experimental — accuracy not yet measuredA minority of patients continue to report hypothyroidism-like symptoms despite achieving TSH within the reference range, even after exclusion of other possible causes.
“However, a minority of patients continue to report hypothyroidism-like symptoms despite achieving levels of TSH within the reference range, even after exclusion of other possible causes of these symptoms (reviewed elsewhere) 12 .”
From A review of the safety of triiodothyronine in combination with levothyroxine for the management of hypothyroidism (2024) · cites this paper as [12]
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“LT4 monotherapy [33,34], but a benefit for the combination for improved quality of life or other outcomes is not supported by systematic reviews or meta-analyses conducted as recently as 2018 [35-39].”
BackgroundIncreased requirement of replacement doses of levothyroxine caused by liver cirrhosis.
Benvenga, S., Capodicasa, G., Perelli, S., Ferrari, S. M., Fallahi, P., & Antonelli, A. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00150 · Cited by 25 · cited 1× · see citing works
“Liver cirrhosis also increases the dose requirement for LT4 [86,87].”
BackgroundCortés, J. M. R., & Zerón, H. M. (2019) · Folia Medica · doi:10.2478/folmed-2018-0078 · Cited by 24 · see citing works
Climacteric symptoms are related to thyroid status in euthyroid menopausal women
Słopień, R., Owecki, M., Słopień, A., Bala, G., & Męczekalski, B. (2019) · Journal of Endocrinological Investigation · doi:10.1007/s40618-019-01078-7 · Cited by 23 · cited 1× · see citing works
“Variations of TSH levels within the euthyroid range have been reported to correlate with increased risk of a first adverse cardiovascular event [61], and with menopausal symptoms [62] or decreased bone mineral density/increased fracture risk [63] in perimenopausal or menopausal women.”
BackgroundA systematic review of genetic studies of thyroid disorders in Taiwan
Huang, C.-J., & Jap, T. (2014) · Journal of the Chinese Medical Association · doi:10.1016/j.jcma.2014.09.010 · Cited by 22 · cited 2× · see citing works
“Further research will be needed to confirm whether genetic variations in deiodinases, and indeed in other sites of cellular access or action of thyroid hormones (such as membrane transporters, nuclear receptors and other sites) may facilitate individualised treatment of hypothyroid patients in the future [44,50-52].”
BackgroundTandon, A., Singh, R., Gupta, S., & Saroja, K. (2017) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/ijem.ijem_165_17 · Cited by 21 · cited 1× · see citing works
“Data from a case control study suggested that LT4 therapy was effective in improving symptoms associated with hypothyroidism, but this was mainly associated with correcting aberrant TSH levels [65].”
BackgroundUlcerative colitis as a novel cause of increased need for levothyroxine
Virili, C., Stramazzo, I., Santaguida, M. G., Bruno, G., Brusca, N., Capriello, S., Cellini, M., Severi, C., Gargano, L., & Centanni, M. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00233 · Cited by 20 · cited 1× · see citing works
“For example, one study showed that people with ulcerative colitis and hypothyroidism required doses of LT4 that were 26% higher compared with those without ulcerative colitis [81].”
BackgroundRazvi, S., & Gottwald‐Hostalek, U. (2019) · Current Medical Research and Opinion · doi:10.1080/03007995.2019.1570769 · Cited by 16 · cited 1× · see citing works
“Correcting the level of TSH to within its reference range may be sufficient for most patients [1-3,58-60].”
BackgroundSelf-citationLevothyroxine absorption test results in patients with TSH elevation resistant to treatment
Yildirim Simsir, I., Soyaltin, U. E., & Ozgen, A. G. (2019) · Endocrine · doi:10.1007/s12020-019-01889-x · Cited by 16 · cited 1× · see citing works
“Alternatively, the use of a LT4 absorption test may help to differentiate cases of true malabsorption from patients with poor adherence to therapy [85].”
BackgroundLevothyroxine pseudo-malabsorption: testing and treatment in the outpatient setting
Rdzak, G. M., Whitman, L. M., & Inzucchi, S. E. (2018) · Therapeutic Advances in Endocrinology and Metabolism · doi:10.1177/2042018818771433 · Cited by 14 · see citing works
Benvenga, S., Pantano, R., Saraceno, G., Lipari, L., Alibrando, A., Inferrera, S., Pantano, G., Simone, G., Tamà, S., Scoglio, R., et al. (2019) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2019.100189 · Cited by 14 · see citing works
Cracking the code for thyroid hormone signaling.
Bianco, A. C. (2013) · PubMed · Cited by 12 · see citing works
Combined therapy with levothyroxine and liothyronine for hypothyroidism
Fischman, A., & Domínguez, J. M. (2018) · Medwave · doi:10.5867/medwave.2018.08.7375 · Cited by 7 · cited 1× · see citing works
“LT4 monotherapy [33,34], but a benefit for the combination for improved quality of life or other outcomes is not supported by systematic reviews or meta-analyses conducted as recently as 2018 [35-39].”
BackgroundTreatment-refractory hypothyroidism
McNally, L. J., Ofiaeli, C. I., & Oyibo, S. O. (2019) · BMJ · doi:10.1136/bmj.l579 · Cited by 5 · see citing works
Adherence of levothyroxine treatment in primary hypothyroid patients in Turkey: a multicenter study
Yavuz, D. G., Keskin, L., Atmaca, A., Dikbaş, O., Hekimsoy, Z., Şahin, İ., Yalın, S., Yılmaz, M., Uygur, M., Yazıcı, D., et al. (2014) · Endocrine Abstracts · doi:10.1530/endoabs.35.p1048 · Cited by 1 · see citing works
Flagged first, then by citations
1 of the 89 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Low awareness and under-diagnosis of hypothyroidism
Gottwald‐Hostalek, U., & Schulte, B. (2021) · Current Medical Research and Opinion · doi:10.1080/03007995.2021.1997258 · Cited by 43 · see citing works
Use of levothyroxine in the management of hypothyroidism: A historical perspective
Kahaly, G. J., & Gottwald-Hostalek, U. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1054983 · Cited by 24 · see citing works
T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity
Wiersinga, W. M. (2021) · Endocrinology and Metabolism · doi:10.3803/enm.2021.501 · Cited by 21 · see citing works
“The expression of these enzymes varies between tissues, and it has been suggested that a polymorphism in the deiodinase 2 gene (Thr92Ala) may cause slight changes in deiodinase activity but important changes in thyroid hormone bioavailability [38].”
BackgroundInfluentialComorbidities of hypothyroidism
Brenta, G., & Gottwald‐Hostalek, U. (2025) · Current Medical Research and Opinion · doi:10.1080/03007995.2025.2476075 · Cited by 15 · see citing works
“A substantial minority of people with hypothyroidism who receive LT4 continue to report hypothyroid-like symptoms, despite normalisation of TSH and other thyroid hormones to within the reference range 80,81 .”
Ashraf, H., Heydari, M., Shams, M., Zarshenas, M. M., Tavakoli, A., & Sayadi, M. (2022) · Evidence-Based Complementary and Alternative Medicine · doi:10.1155/2022/5456855 · Cited by 13 · see citing works
“,e pathophysiology of persistent hypothyroid symptoms despite adequate hormone replacement therapy is not well understood [11, 12], and no definitive treatment is available [13, 14].”
BackgroundTriiodothyronine alongside levothyroxine in the management of hypothyroidism?
Gottwald-Hostalek, U., & Kahaly, G. J. (2021) · Current Medical Research and Opinion · doi:10.1080/03007995.2021.1984219 · Cited by 9 · see citing works
Gottwald‐Hostalek, U., & Tayrouz, Y. (2021) · Current Medical Research and Opinion · doi:10.1080/03007995.2021.1978959 · Cited by 7 · see citing works
Does Myocardial Atrophy Represent Anti-Arrhythmic Phenotype?
Bačová, B. S., Andelová, K. O., Sýkora, M., Beňová, T. E., Barančı́k, M., Kurahara, L. H., & Tribulová, N. (2022) · Biomedicines · doi:10.3390/biomedicines10112819 · Cited by 7 · see citing works
Gottwald-Hostalek, U., & Tayrouz, Y. (2024) · Current Medical Research and Opinion · doi:10.1080/03007995.2024.2435460 · Cited by 6 · see citing works
“However, a minority of patients continue to report hypothyroidism-like symptoms despite achieving levels of TSH within the reference range, even after exclusion of other possible causes of these symptoms (reviewed elsewhere) 12 .”
Effects of Bailing capsules combined with levothyroxine sodium on autoimmune thyroiditis
Su, B.-Y., Wu, T., Huo, L.-S., Qu, Z., & Gao, B. (2024) · Medicine · doi:10.1097/md.0000000000040713 · Cited by 3 · see citing works
Vuletić, M., Žnidar, V., Žižić, A. B., Sladić, S., Kaličanin, D., Lovrić, V. T., Cvek, M., Punda, A., & Perica, V. B. (2025) · Biomolecules · doi:10.3390/biom15111510 · Cited by 3 · see citing works
“Although levothyroxine (LT4) replacement therapy remains the standard treatment for hypothyroidism, many patients continue to experience residual symptoms and immune dysregulation despite achieving biochemical euthyroidism [3,4].”
Tańska, K., Glinicki, P., Rebizant, B., Dudek, P., Zgliczyński, W., & Gietka‐Czernel, M. (2024) · Biomedicines · doi:10.3390/biomedicines12112628 · Cited by 2 · see citing works
“It has previously been observed that hypothyroid patients receiving replacement therapy with LT4 had non-physiological thyroid hormone levels, even after achieving an optimal TSH concentration, i.e., higher fT4 and lower fT3 concentrations in comparison to euthyroid subjects [47,48].”
Effects of essential metals (iron, zinc, and copper) on thyroid diseases - a narrative review
Wei, H., Li, Z., Liu, Z., Wu, B., Li, R., Xu, M., Yang, X., Yin, J., Zhang, Y., & Liu, Y. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1786788 · Cited by 2 · see citing works
“It is recommended that Fe-containing preparations be administered at least 4 h apart from L-T4 to avoid impaired L-T4 absorption (20).”
Factors linked to poor self-rated health in thyroid disorder patients: findings from LASI Wave-I
Kumar, P., Sen, A., Priyanshu, P., Khatib, M. N., Roopashree, R., Kaur, M., Srivastava, M., Barwal, A., Prasad, G. V. S., Rajput, P., et al. (2025) · Thyroid Research · doi:10.1186/s13044-025-00229-8 · Cited by 1 · see citing works
Ali, Z., Abdulridha, M. K., & Alzajaji, Q. B. (2024) · Al Mustansiriyah Journal of Pharmaceutical Sciences · doi:10.32947/ajps.v24i4.1089
- Authors
- Razvi, S., Mrabeti, S., & Luster, M.
- Affiliations
- Newcastle University (GB)
- 2Medical Affairs EMEA, Merck Serono Middle East FZ-LLC, Dubai, United Arab Emirates
- Universitätsklinikum Gießen und Marburg (DE)
- Corresponding author
- Razvi, Salman
- Venue
- Endocrine Connections
- Publisher
- Bioscientifica
- Published
- 2020-11
- Volume
- 9
- Issue
- 11
- Pages
- R241-R250
- ISSN
- 2049-3614 (ISSN-L)
- PMC
- PMC7774765
- OpenAlex
- W3091833302
- Cited by
- 15
- References
- 89
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2022: 3 · 2021: 4
- FWCI
- 0.27
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Endocrine Connections (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Newcastle University ePrints (Newcastle Univesity)
- 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, thyroid-stimulating hormone, liothyronine, autoimmune disease comorbidity, anemia, mental illness, symptom management
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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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