The enigma of persistent symptoms in hypothyroid patients treated with levothyroxine: A narrative review
Open accessAbstract
A significant minority of patients with hypothyroidism report persistent symptoms despite achieving normal thyroid biochemistry after levothyroxine (L‐T4) replacement. Four principal lines of thinking, which are not mutually exclusive, may explain this enigma. The ‘low tissue liothyronine hypothesis’ emphasizes the potential imperfections of L‐T4 replacement therapy that may lead to hypothyroidism in some tissues such as the brain, while others (eg hypothalamus) are euthyroid. The ‘Somatic Symptom and Related Disorders hypothesis’ draws attention to an incidental coexistence of a diagnosis of Somatic Symptom and Related Disorders in patients with treated hypothyroidism. The ‘autoimmune neuroinflammation hypothesis’ highlights the potential consequences of inflammatory mediators due to thyroid autoimmunity (the commonest cause of hypothyroidism) on the brain. The ‘comorbidities and psychosocial hypothesis’ implicates a variety of physical and psychosocial factors that have been noted to be associated with a diagnosis of hypothyroidism, which may be primarily the cause of persistent complaints. Over the past twenty years, a great deal of time and effort has been expended pursuing the ‘low tissue liothyronine hypothesis’, which has failed to yield results that translate to patient benefits. This has skewed the balance in clinical practice, in favour of pursuing answers relating to L‐T4 and liothyronine combination treatment, while the alternative explanations have been downplayed and potentially useful interventions have been given insufficient attention.
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Persistent symptoms in patients treated for hypothyroidism are common.
“Persistent symptoms in patients treated for hypothyroidism are common.”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [7]
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 [44]
Perros et al. describe that patients with SSRD have multiple medical consultations and thyroid function tests are ordered; approximately 10% of SSRD patients may also have thyroid dysfunction, usually subclinical hypothyroidism; if symptoms are assumed due to hypothyroidism, LT4 is prescribed but will not resolve symptoms if the actual diagnosis is SSRD.
“Perros et al. [44] elegantly describe the sequence of affairs: “Patients with SSRD have multiple medical consultations and inevitably thyroid function tests are ordered.” “Approximately 10% of SSRD patients may also have thyroid dysfunction, usually subclinical hypothyroidism. If patient and doctor assume the symptoms are due to hypothyroidism, LT4 is prescribed but will not be followed by symptom”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [44]
Patients with persistent symptoms may have somatic symptom and related disorders (SSRD) as proposed by Perros et al.
“These patients may have somatic symptom and related disorders (SSRD) as proposed by Perros et al. [44].”
From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [44]
A proportion of individuals have significant dissatisfaction with levothyroxine, including ongoing significant impairment in psychological well-being compared to controls of similar age and sex.
“a proportion of individuals have significant dissatisfaction with it, including ongoing significant impairment in psychological well -being compared to controls of similar age and sex. 4 -8”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [7]
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References 73 · Cited by 65
Research works printed but not linked: 1
- Carle A, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Laurberg P. Gender differences in symptoms of hypothyroidism: a population-based DanThyr study. Clin Endocrinol (Oxf). 2015;83(5):717-725.
- Authors
- Perros, P., Van Der Feltz‐Cornelis, C., Papini, E., Nagy, E. V., Weetman, A. P., & Hegedüs, L.
- Affiliations
- Royal Victoria Infirmary (GB)
- Department of Health Sciences HYMS University of York York UK
- Ospedale Regina Apostolorum (IT)
- University of Debrecen (HU)
- University of Sheffield (GB)
- Department of Endocrinology Odense University Hospital Odense Denmark
- Corresponding author
- Perros, Petros
- Venue
- Clinical Endocrinology
- Publisher
- Wiley
- Published
- 2021-04-11
- Volume
- 98
- Issue
- 4
- Pages
- 461-468
- ISSN
- 0300-0664 (ISSN-L)
- 1365-2265
- OpenAlex
- W3152157360
- Cited by
- 65
- References
- 73
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 14 · 2023: 10 · 2022: 12 · 2021: 9
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- 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 › Psychiatry and Mental health › Psychosomatic Disorders and Their Treatments
- Keywords
- hypothyroidism, levothyroxine, persistent symptoms, somatic symptom and related disorders, autoimmune neuroinflammation, thyroid autoimmunity, comorbidities, psychosocial factors
- MeSH terms
- Medically Unexplained Symptoms, Humans, Hypothyroidism, Thyroxine, Triiodothyronine
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