Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report
Open accessAbstract
There is a frequently encountered subset of hypothyroid patients who are refractory to standard thyroid hormone replacement treatment and require unexpectedly high doses of levothyroxine. In addition to clinical situations where hypothyroid patients are non-compliant, or where there is the possibility of excipient-induced disease exacerbation (gluten/celiac disease), therapeutic failure may be due to impaired absorption of the administered drug. The common approach to managing patients with unusual thyroxine needs is to escalate the dose of levothyroxine until targeted TSH levels are achieved. This approach can increase the risk for prolonged exposure to supratherapeutic doses of levothyroxine, which increase the chances of adverse outcomes. Repeated adjustments of levothyroxine can also escalate the costs of treatment, as frequent office visits and laboratory tests are required to determine and maintain the desired dose. Clinicians should take a systematic approach to managing patients whom they suspect of having treatment-refractory hypothyroidism. This may include searching for, and adjusting, occult medical conditions and/or other factors that may affect the absorption of levothyroxine, before up-titrating the dose of traditional levothyroxine therapy. Depending on the underlying pathology, another approach that may be considered is to try alternative formulations of levothyroxine that are less susceptible to intolerance issues related to excipients, or, in some cases, to malabsorption. The early discovery of these factors via a thoughtful patient work-up may avoid unnecessary thyroid medication adjustments and their consequences for both patients and clinicians.
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Written from the paper’s full text.
TL;DR
This expert consensus report reviews treatment-refractory hypothyroidism, defined as biochemical or clinical hypothyroidism despite levothyroxine doses beyond 1.9 μg/kg daily and/or TSH above the upper target, usually 4.5 mU/L after a 6-week interval following the last dose increase. It recommends a systematic eight-step work-up for compliance, absorption, interfering conditions, and alternative levothyroxine formulations before further dose escalation.
Key findings
- Refractory hypothyroidism is defined by TSH above the upper target (usually 4.5 mU/L after a 6-week interval after the last dosage increase) and/or unresolved hypothyroid symptoms despite levothyroxine doses beyond 1.9 μg/kg daily.
- Non-optimal thyroxine therapy is common: in five published studies, non-optimal therapy ranged from 32% to 48%; in a Brazilian multicenter study, 28% of 2292 hypothyroid patients had elevated TSH while on thyroid hormone therapy.
- Causes include non-compliance, generic levothyroxine substitution, GI disease/malabsorption (e.g., *H. pylori*, IBD, celiac disease, lactose intolerance, atrophic body gastritis, gastric bypass), PPIs, pregnancy, weight change, drugs increasing thyroxine turnover, Addison’s disease, and anti-thyroxine antibodies; 10–20% of cases remain idiopathic despite extensive work-up.
- Alternative formulations may help: in CONTROL Switch (99 patients), switching to levothyroxine gel caps reduced dose adjustments by 55% (P < 0.0001), with >85% experiencing ≤1 dose adjustment post-switch, and improved symptom control by 62% (P < 0.0001); in a liquid-formulation study of 152 patients, TSH declined at first (P < 0.05) and second control (P < 0.01), with FT4 and FT3 unchanged.
Methods
- Expert consensus report/narrative review; no systematic review, meta-analysis, or primary data collection is described. Evidence is drawn from published literature and the panel’s clinical experience.
- The paper synthesizes prior studies and proposes an eight-step diagnostic and management approach, including confirming diagnosis, assessing compliance, checking medication bottles/tablets, reviewing ingestion history, investigating malabsorption, considering increased turnover/excretion, performing a thyroxine absorption test when appropriate, and treating holistically.
Limitations
- The paper states that the prevalence of refractory hypothyroidism has not been precisely documented; the thyroxine absorption test is not standardized and should not be used routinely; and the benefits of combined T4/T3 therapy remain controversial.
- The paper notes controversy about whether long-term levothyroxine at suppressive or non-suppressive levels increases osteoporosis/fracture risk and calls for comprehensive definitive research.
- Evident from the text: this is an expert consensus report without a described systematic literature search, formal evidence grading, or prospective validation of the recommended eight-step algorithm.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 76 cited sources checked · 0 supported · 0 flagged
- Findingcitation
Suzuki and colleagues reported failure to identify a cause in approximately 10-20% of patients requiring greater than standard replacement doses of levothyroxine despite an extensive diagnostic work-up.
“Suzuki and colleagues reported failure to identify a cause in approximately 10–20% of patients requiring greater than standard replacement doses of levothyroxine despite an extensive diagnostic work-up”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [89] Suzuki Y, Takeshita E, Kano S, Hirata S, Sato S (1982) Impaired intestinal absorption of thyroid hormone in a case of Hashimoto’s disease with anti-T3 and anti-T4 antibody. Nihon Naibunpi Gakkai Zasshi 58:1487–1497
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- Findingcitation
Non-optimal thyroxine therapy, as evidenced by TSH levels above or below the reference range, is common in hypothyroid patients.
“Even though its prevalence has not been precisely documented, non-optimal thyroxine therapy, as evidenced by TSH levels above (or below) the reference range, is common (Table 2)”
Quote in the paperSubstantial claim0 of 7 sources checked- cites [11] Ross DS, Daniels GH, Gouveia D (1990) The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an out-patient endocrine clinic. J Clin Endocrinol Metab 71:764–769 source
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- cites [15] Vaisman F, Coeli CM, Ward LS et al (2013) How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study. J Endocrinol Invest 36:485–488
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- Findingcitation
In CONTROL HE, a retrospective study of 454 patients receiving levothyroxine for greater than 1 year, Ernst et al. reported a significant relationship between the number of levothyroxine dose or formulation changes and increased cost of patient care including drug therapy, laboratory tests, physician visits, and other healthcare costs (P < 0.05).
“In CONTROL HE, a retrospective study of 454 patients receiving levothyroxine for greater than 1 year, Ernst et al. reported a significant relationship between the number of levothyroxine dose or formulation changes and increased cost of patient care including drug therapy, laboratory tests, physician visits, and other healthcare costs (P < 0.05).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [104] Ernst FR, Barr P, Elmor R, Sandulli W et al (2017) The economic impact of levothyroxine dose adjustments: the CONTROL HE Study. Clin Drug Investig 37:71–83 source
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- Findingcitation
In a multicenter study from Brazil, 28% of 2292 hypothyroid patients had elevated serum TSH levels with a background of thyroid hormone therapy.
“The most recent data supporting this finding were reported by Vaisman in a multicenter study from Brazil, in which 28% of 2292 hypothyroid patients had elevated serum TSH levels with a background of thyroid hormone therapy”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Vaisman F, Coeli CM, Ward LS et al (2013) How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study. J Endocrinol Invest 36:485–488
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- Findingcitation
In a prospective study involving 100 post-thyroidectomy patients, the optimal dose of levothyroxine (μg) could be predicted using the formula: dose = weight (kg) − age (years) + 125.
“In a prospective study involving 100 post-thyroidectomy patients, the optimal dose of levothyroxine (µg) could be predicted using a simple formula: dose = weight (kg) − age (years) + 125”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [72] Mistry D, Atkin S, Atkinson H et al (2011) Predicting thyroxine requirements following total thyroidectomy. Clin Endocrinol (Oxf) 74:384–387 source
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- Findingcitation
In an observational cohort study of 17,684 patients >18 years old on long-term levothyroxine therapy, a twofold increase in fracture risk was reported in patients having undetectable TSH levels (≤0.03 mU/L) compared to those with TSH levels in the normal range.
“In a recent observational cohort study that examined the risk of fracture in 17,684 patients >18 years old (mean age: 60.3 females, 61.8 males) on long-term levothyroxine therapy, a twofold increase in fracture risk was reported in patients having undetectable TSH levels (≤0.03 mU/L) compared to those with TSH levels in the normal range”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [97] Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP (2010) Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab 9:186–193 source
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- Premisecitation
Evidence in the clinical literature suggests that there is an increased risk of bone fracture in individuals exposed to supratherapeutic doses of exogenous thyroid hormone for extended periods of time.
“Evidence in the clinical literature suggests that there is an increased risk of bone fracture in individuals who are exposed to supratherapeutic doses of exogenous thyroid hormone for extended periods of time.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [96] Bauer DC, Ettinger B, Nevitt MC, Stone KL (2001) Study of Osteoporotic Fractures Research Group. Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med 134:561–568 source
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- Premisecitation
FT3 measurement has limited utility in the diagnosis of hypothyroidism because FT3 values often fall in the normal range due to hyperstimulation of remaining functioning thyroid tissue by elevated TSH and up-regulation of deiodinase D2.
“FT3 measurement has somewhat limited utility, however, in the diagnosis of hypothyroidism, since FT3 values often fall in the normal range as a result of hyperstimulation of the remaining functioning thyroid tissue by elevated TSH and to up-regulation of deiodinase D2”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89 source
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- Premisecitation
A number of kinase inhibitors, including imatinib and sunitinib, appear to influence thyroxine requirements through what is likely a class effect.
“A number of kinase inhibitors, including imatinib and sunitinib, appear to influence thyroxine requirements through what is likely a class effect [114–116].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [114] de Groot JW, Zonnenberg BA, Plukker JT, van Der Graaf WT, Links TP (2005) Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther 78:433–438 source
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- cites [115] Sherman SI, Wirth LJ, Droz JP et al (2008) Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med 359:31–42 source
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- cites [116] Robinson SI, Hobday TJ, Sathananthan A, Morris JC 3rd, McWilliams RR (2007) Can sorafenib cause hypothyroidism? J Chemother 19:352–353 source
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- Premisecitation
Ingestion of one or more interfering substances at or close to the time of levothyroxine dosing can significantly change the dose requirement in individual patients, especially when done regularly.
“The ingestion of one or more of these at, or close to, the time of levothyroxine dosing can significantly change the dose requirement in individual patients, especially when done regularly [49].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [49] Liwanpo L, Hershman JM (2009) Conditions and drugs interfering with thyroxine absorption. Best Pract Res Clin Endocrinol Metab 23:781–792 source
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- Premisecitation
Levothyroxine absorption can be limited by gastrointestinal diseases including Helicobacter pylori infection, inflammatory bowel disease, celiac disease, lactose intolerance, atrophic body gastritis, gastric bypass, biliary pancreatic diversion, and gastroparesis.
“Levothyroxine absorption can be limited by a number of diseases of the gastrointestinal (GI) tract, including: Helicobacter pylori infection, inflammatory bowel disease (IBD), celiac disease, lactose intolerance, atrophic body gastritis (ABG), gastric bypass, biliary pancreatic diversion, and gastroparesis, among others”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [5] Centanni M, Gargano L, Canettieri G et al (2006) Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N Engl J Med 354:1787–1795 source
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- cites [10] Centanni M (2013) Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches. Endocrine 43:8–9 source
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- cites [17] Cellini M, Santaguida MG, Virili C et al (2017) Hashimoto’s thyroiditis and autoimmune gastritis. Front Endocrinol (Lausanne) 8:92 doi: 10.3389/fendo.2017.00092 source
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- cites [52] Ruchala M, Szczepanek-Parulska E, Zybek A (2012) The influence of lactose intolerance and other gastro-intestinal tract disorders on l-thyroxine absorption. Endokrynol Pol 63:318–323
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- cites [63] Fallahi P, Ferrari SM, Camastra S et al (2017) TSH normalization in bariatric surgery patients after the switch from l-thyroxine in tablet to an oral liquid formulation. Obes Surg 27:78–82 source
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- Interpretationcitation
TSH may be a poor indicator of peripheral thyroid levels in conditions such as chronic stress, chronic illness, diabetes, insulin resistance, obesity, leptin resistance, depression, chronic fatigue syndrome, fibromyalgia, premenstrual syndrome, and dieting or weight gain.
“As a result, TSH may be a poor indicator of peripheral thyroid levels in the presence of such conditions.”
Quote in the paperSubstantial claim0 of 9 sources checked- cites [29] Peeters RP, van der Geyten S, Wouters PJ et al (2005) Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 12:6498–6507 source
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- Premisecitation
Correction of malabsorption frequently normalizes, or at least improves, levothyroxine absorption in patients with these disorders.
“Frequently, correction of the malabsorption will normalize, or at least improve, levothyroxine absorption in patients with these disorders [10].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Centanni M (2013) Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches. Endocrine 43:8–9 source
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- Premisecitation
Levothyroxine is the first-line treatment for hypothyroidism.
“Since levothyroxine is the first-line treatment for hypothyroidism”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [18] Jonklaas J, Bianco AC, Bauer AJ et al (2014) Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid 24:1670–1751 source
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- cites [19] Biondi B, Bartalena L, Chiovato L et al (2016) Recommendations for treatment of hypothyroidism with levothyroxine and levotriiodothyronine: a 2016 position statement of the Italian Society of Endocrinology and the Italian Thyroid Association. J Endocrinol Invest 39:1465–1474 source
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- Premisecitation
More than 85% of patients experienced ≤1 dose adjustment post-switch.
“More than 85% of patients experienced ≤1 dose adjustment post-switch.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [122] Ernst FR, Sandulli W, Elmor R et al (2017) Retrospective study of patients switched from tablet formulations to a gel cap formulation of levothyroxine: results of the CONTROL Switch study. Drugs R D 17:103–115 source
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- Premisecitation
A high-dose levothyroxine absorption test can play an important role in the differential diagnosis of pseudomalabsorption and actual levothyroxine malabsorption.
“Using a high-dose levothyroxine, absorption test can play an important role in the differential diagnosis of pseudomalabsorption (which is a most common source of difficulties in obtaining euthyreosis in hypothyroid patients) and actual levothyroxine malabsorption [117, 118].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [117] Srinivas V, Oyibo SO (2010) Levothyroxine pseudomalabsorption and thyroxine absorption testing with use of high-dose levothyroxine: case report and discussion. Endocr Pract 16:1012–1015 source
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- cites [118] Müssig K, Mörike K, Klein R (2009) Hypothyroidism due to pseudo-malabsorption of levothyroxine—case 12/2009. Dtsch Med Wochenschr 134:2514 source
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- Premisecitation
Switching from traditional levothyroxine tablets to levothyroxine gel caps resulted in significant improvement in hypothyroid symptom control (+62%, P < 0.0001).
“Significant improvement in hypothyroid symptom control; +62% (P < 0.0001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [122] Ernst FR, Sandulli W, Elmor R et al (2017) Retrospective study of patients switched from tablet formulations to a gel cap formulation of levothyroxine: results of the CONTROL Switch study. Drugs R D 17:103–115 source
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- Premisecitation
As a last resort in those with continuing poor compliance, administration of thyroxine once weekly can be successful.
“As a last resort in those with continuing poor compliance, administration of thyroxine once weekly can be successful [119].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [119] Grebe SK, Cooke RR, Ford HC et al (1997) Treatment of hypothyroidism with once weekly thyroxine. J Clin Endocrinol Metab 82:870–875
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- Premisecitation
Among patients switched for efficacy reasons (n = 25), 64% experienced improved symptom control.
“Among patients switched for efficacy reasons (n = 25), 64% experienced improved symptom control.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [122] Ernst FR, Sandulli W, Elmor R et al (2017) Retrospective study of patients switched from tablet formulations to a gel cap formulation of levothyroxine: results of the CONTROL Switch study. Drugs R D 17:103–115 source
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- Premisecitation
Patients with nephrotic syndrome who excrete large quantities of albumin may have increased thyroxine requirements as a result of the binding of levothyroxine to the excreted albumin.
“Moreover, patients with nephrotic syndrome who excrete large quantities of albumin may also have increased thyroxine requirements as a result of the binding of levothyroxine to the excreted albumin [87].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [87] Junglee NA, Scanlon MF, Rees DA (2006) Increasing thyroxine requirements in primary hypothyroidism: don’t forget the urinalysis! J Postgrad Med 52:201–203
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- Interpretationreasoning
Repeated adjustments of levothyroxine can escalate the costs of treatment, as frequent office visits and lab tests are required to determine and maintain the desired dose.
“Repeated adjustments of levothyroxine can also escalate the costs of treatment, as frequent office visits and lab tests are required to determine and maintain the desired dose.”
Quote in the paperNot a substantial claim - Premisecitation
Pseudomalabsorption is a most common source of difficulties in obtaining euthyreosis in hypothyroid patients.
“pseudomalabsorption (which is a most common source of difficulties in obtaining euthyreosis in hypothyroid patients)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [117] Srinivas V, Oyibo SO (2010) Levothyroxine pseudomalabsorption and thyroxine absorption testing with use of high-dose levothyroxine: case report and discussion. Endocr Pract 16:1012–1015 source
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- cites [118] Müssig K, Mörike K, Klein R (2009) Hypothyroidism due to pseudo-malabsorption of levothyroxine—case 12/2009. Dtsch Med Wochenschr 134:2514 source
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- Interpretationcitation
Recent evidence suggests that either the softgel or liquid alternatives may eliminate a number of factors that contribute to levothyroxine tablet failure and refractory hypothyroidism.
“Recent evidence suggests that either the softgel or liquid alternatives may eliminate a number of factors that contribute to levothyroxine tablet failure and refractory hypothyroidism.”
Quote in the paperSubstantial claim - Premisecitation
Even intermittent oversuppression of TSH using levothyroxine can result in increased bone loss, cardiovascular, and other more serious medical conditions.
“Studies have demonstrated that even intermittent oversuppression of TSH using levothyroxine can result in increased bone loss, cardiovascular, and other more serious medical conditions [97, 99, 101].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [97] Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP (2010) Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab 9:186–193 source
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- cites [99] Shomon M The thyroid treatment/osteoporosis controversy: does thyroid treatment contribute to loss of bone density? http://www.thyroid-info.com/articles/osteoporosis.htm . Accessed 1 Oct 2016
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- cites [101] Lindner H Thyroid hormone: T3. http://www.hormonerestoration.com/thyroid.html . Accessed 1 Oct 2016
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- Premisecitation
Most patients with definite gastric disorders benefited by changing from traditional tablet formulations to the softgel levothyroxine preparation at a reduced dose.
“In particular, Santaguida et al. [121] have shown that most patients with definite gastric disorders benefited by changing from the traditional tablet formulations to the softgel levothyroxine preparation at a reduced dose.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [121] Santaguida MG, Virili C, Del Duca SC, Cellini M, Gatto I, Brusca N et al (2015) Thyroxine softgel capsule in patients with gastric-related T4 malabsorption. Endocrine 49:51–57 source
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- Interpretationnone given
There is a frequently encountered subset of hypothyroid patients who are refractory to standard thyroid hormone replacement treatment and require unexpectedly high doses of levothyroxine or who have erratic control of hypothyroidism, alternating between over-replacement and under-replacement.
“There is a frequently encountered subset of hypothyroid patients who are refractory to standard thyroid hormone replacement treatment and require unexpectedly high doses of levothyroxine or who have erratic control of hypothyroidism, alternating between over-replacement and under-replacement.”
Quote in the paperNot a substantial claim - Premisecitation
Following the switch to the liquid formulation, TSH levels among patients significantly declined compared to the basal value at both the first control (P < 0.05) and the second control (P < 0.01).
“Following the switch to the liquid formulation, TSH levels among patients significantly declined compared to the basal value at both the first control (P < 0.05) and the second control (P < 0.01).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [123] Fallahi P, Ferrari SM, Antonelli A (2016) Oral l-thyroxine liquid versus tablets in patients with hypothyroidism without malabsorption: a prospective study. Endocrine 52:597–601 source
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- Premisecitation
During normal pregnancy, women experience increased thyroxine requirements that may approach 50%.
“As mentioned above, during normal pregnancy, women experience increased thyroxine requirements that may approach 50% [41, 60].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [41] Morris JC (2009) How do you approach the problem of TSH elevation in a patient on high-dose thyroid hormone replacement? Clin Endocrinol 70:671–673 source
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- cites [60] Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR (2004) Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351:241–249 source
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- Premisecitation
Levels of both FT4 and FT3 were not significantly changed after switching to the liquid formulation.
“Levels of both FT4 and FT3 were not significantly changed [123].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [123] Fallahi P, Ferrari SM, Antonelli A (2016) Oral l-thyroxine liquid versus tablets in patients with hypothyroidism without malabsorption: a prospective study. Endocrine 52:597–601 source
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- Premisecitation
Switching primarily from branded or generic levothyroxine tablets to levothyroxine gel caps resulted in a significant reduction in dose adjustments (−55%, P < 0.0001).
“switching primarily from either branded or generic levothyroxine tablets to levothyroxine gel caps resulted in:Significant reduction in dose adjustments; −55% (P < 0.0001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [122] Ernst FR, Sandulli W, Elmor R et al (2017) Retrospective study of patients switched from tablet formulations to a gel cap formulation of levothyroxine: results of the CONTROL Switch study. Drugs R D 17:103–115 source
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- Interpretationreasoning
In addition to non-compliance or excipient-induced disease exacerbation (gluten/celiac disease), therapeutic failure in hypothyroid patients may be due to impaired absorption of the administered drug.
“In addition to clinical situations where hypothyroid patients are non-compliant, or where there is the possibility of excipient-induced disease exacerbation (gluten/celiac disease), therapeutic failure may be due to impaired absorption of the administered drug.”
Quote in the paperSubstantial claim - Interpretationnone given
Impaired absorption of levothyroxine is often the result of either patient pathophysiology (GI disease), the effects of other therapeutic agents, or diet (timing of ingestion relative to meals and beverages, including coffee).
“This is often the result of either patient pathophysiology (GI disease), the effects of other therapeutic agents, or diet (timing of ingestion relative to meals and beverages, including coffee).”
Quote in the paperNot a substantial claim
- May combine two claims. 7
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 9
May combine two claims.
FindingcitationIn the CONTROL Surveillance Project among 925 patients on levothyroxine, more than 21% reported taking thyroxine less than the recommended 30 min before eating, a practice that may significantly contribute to less-than-optimal drug absorption.
“More than 21% reported taking thyroxine less than the recommended 30 min before eating, a practice that may significantly contribute to less-than-optimal drug absorption”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] McMillan M, Rotenberg KS, Vora K et al (2016) Comorbidities, concomitant medications, and diet as factors affecting levothyroxine therapy: results of the CONTROL Surveillance Project. Drugs R D 16:53–68 source
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The quote only partly states this claim.
FindingcitationIn CONTROL TS, a survey involving 300 hypothyroid patients taking levothyroxine for more than 1 year, overall patient satisfaction with treatment was 44% lower among patients experiencing levothyroxine dose changes versus those without such changes (P < 0.001).
“Overall patient satisfaction with treatment was 44% lower among patients experiencing levothyroxine dose changes versus those without such changes (P < 0.001).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [105] McMillan M, Sterman A, Engelken D, Sandulli W (2016) Levothyroxine dose changes and hypothyroid patient satisfaction—results of the CONTROL TS Study. Abstract. 86th Annual Meeting of the American Thyroid Association, Denver source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
FindingcitationFlynn and colleagues concluded that there was an increased risk of cardiovascular disease, dysrhythmias, and fractures in patients having high or suppressed TSH, but not in patients with low, but unsuppressed, TSH levels.
“The researchers concluded that there was an increased risk of cardiovascular disease, dysrhythmias, and fractures in patients having high or suppressed TSH, but not in patients with low, but unsuppressed, TSH levels”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [97] Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP (2010) Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab 9:186–193 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA genetic variation in deiodinase D2 may help explain why some patients who fail to achieve control of hypothyroidism on levothyroxine respond to natural desiccated thyroid or combined levothyroxine and synthetic T3.
“It has been suggested that a genetic variation in deiodinase D2 (also called type 2 deiodinase, or 5′-deiodinase) may help to explain why some patients who fail to achieve control of hypothyroidism with a background of levothyroxine therapy respond to natural desiccated thyroid or to the combined therapy of levothyroxine and synthetic T3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [74] Bowthorpe J Is there a genetic reason many of us do lousy on T4? http://www.stopthethyroidmadness.com/2009/10/28/is-there-a-genetic-reason-many-of-us-do-lousy-on-t4 . Accessed 1 Oct 2016
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAccording to the American Thyroid Association, TSH is the most reliable marker of adequacy of replacement treatment, and a value within the reference range (0.4-4.0 mIU/L) should be considered the therapeutic target.
“According to the most recent guidelines from the American Thyroid Association (ATA), “TSH is the most reliable marker of adequacy of replacement treatment, and a value within the reference range (0.4–4.0 mIU/L) should be considered the therapeutic target””
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Jonklaas J, Bianco AC, Bauer AJ et al (2014) Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid 24:1670–1751 source
Not checked in the free run.
May combine two claims.
PremisecitationWhile serum T3 levels may decline by 30% and remain within the normal range, tissue T3 may decline by 70-80%, resulting in profound cellular hypothyroidism with normal serum TSH, FT4, and FT3 levels.
“While serum T3 levels may decline by 30%, which is significant, but still within the so-called “normal range”, tissue T3 may decline by 70–80%, resulting in profound cellular hypothyroidism with normal serum TSH, FT4, and FT3 levels”
Quote in the paperSubstantial claim0 of 10 sources checked- cites [29] Peeters RP, van der Geyten S, Wouters PJ et al (2005) Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 12:6498–6507 source
Not checked in the free run.
- cites [30] Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ et al (2005) Serum 3,3′,5′-triiodothyronine (rT3) and 3,5,3′-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 90:4559–4565 source
Not checked in the free run.
- cites [31] Docter R, Krenning EP, de Jong M, Hennemann G (1993) The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf) 39:499–518 source
Not checked in the free run.
- cites [32] Fliers E, Alkemade A, Wiersinga WM (2001) The hypothalamic-pituitary-thyroid axis in critical illness. Best Pract Res Clin Endocrinol Metab 15:453–464 source
Not checked in the free run.
- cites [33] Chopra IJ (1997) Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab 82:329–334 source
Not checked in the free run.
- cites [34] Nagaya T, Fujieda M, Otsuka G, Yang JP, Okamoto T, Seo H (2000) A potential role of activated NF-Kappa B in the pathogenesis of euthyroid sick syndrome. J Clin Invest 106:393–402 source
Not checked in the free run.
- cites [35] van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP (1990) Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 71:1567–1572 source
Not checked in the free run.
- cites [36] Stouthard JM, van der Poll T, Endert E et al (1994) Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans. J Clin Endocrinol Metab 79:1342–1346
Not checked in the free run.
- cites [37] Corssmit EP, Heyligenberg R, Endert E, Sauerwein HP, Romijn JA (1995) Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men. Clin Endocrinol Metab 80:3140–3144
Not checked in the free run.
- cites [38] Chopra IJ, Chopra U, Smith SR, Reza M, Solomon DH (1975) Reciprocal changes in serum concentrations of 3,3′,5-triiodothyronine (T3) in systemic illnesses. J Clin Endocrinol Metab 41:1043–1049 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationPrimary hypothyroidism is refractory to oral thyroxine when there is biochemical or clinical evidence of hypothyroidism (TSH above the upper target level, usually 4.5 mU/L after a 6-week interval after the last dose increase) and/or unresolved hypothyroid symptoms, despite increasing levothyroxine dosages beyond 1.9 μg/kg daily.
“Primary hypothyroidism is considered to be refractory to oral thyroxine when there is biochemical or clinical evidence of hypothyroidism [serum level of thyroid-stimulating hormone (TSH) above the upper target level, usually 4.5 mU/L following a 6-week interval after the dosage was last increased] and/or unresolved hypothyroid symptoms, despite increasing dosages of levothyroxine beyond 1.9 μg/kg”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Lips DJ, van Reisen MT, Voigt V, Venekamp W (2004) Diagnosis and treatment of levothyroxine pseudomalabsorption. Neth J Med 62:114–118
Not checked in the free run.
- cites [2] Virili C, Bassotti G, Santaguida MG et al (2012) Atypical celiac disease as cause of increased need for thyroxine: a systematic study. J Clin Endocrinol Metab 97:E419–E422 source
Not checked in the free run.
- cites [3] Cellini M, Santaguida MG, Gatto I et al (2014) Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine. J Clin Endocrinol Metab 99:E1454–E1458 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPoor compliance with daily dosing of levothyroxine has traditionally been viewed as the most common reason for unusually high doses of thyroid replacement therapy.
“For many years, poor compliance with the daily dosing of levothyroxine was reputed to be the most common reason for unusually high doses of thyroid replacement therapy”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Lips DJ, van Reisen MT, Voigt V, Venekamp W (2004) Diagnosis and treatment of levothyroxine pseudomalabsorption. Neth J Med 62:114–118
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Premisenone givenBy laboratory definition, frank primary hypothyroidism requires low levels of thyroid hormones (free FT4 and FT3) as well as elevated TSH.
“By laboratory definition, frank primary hypothyroidism requires low levels of thyroid hormones (free–FT4 and FT3) as well as elevated TSH.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe thyroxine absorption test is not standardized and is unlikely to be associated with a specific etiology.
“Because it is not standardized, and unlikely to be associated with a specific etiology, the absorption test should not be used routinely [9, 41, 51].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [9] Benvenga S (2013) When thyroid hormone replacement is ineffective? Curr Opin Endocrinol Diabetes Obes 20:467–477 source
Not checked in the free run.
- cites [41] Morris JC (2009) How do you approach the problem of TSH elevation in a patient on high-dose thyroid hormone replacement? Clin Endocrinol 70:671–673 source
Not checked in the free run.
- cites [51] Ward LS (2010) The difficult patient: drug interaction and the influence of concomitant diseases on the treatment of hypothyroidism. Arq Brasil Endocrinol Metab 54:435–442 source
Not checked in the free run.
May combine two claims.
InterpretationcitationEscalating the dose of levothyroxine until targeted TSH levels are achieved can increase the risk for prolonged exposure to supratherapeutic doses of levothyroxine, which increase the chances of adverse outcomes.
“This approach can increase the risk for prolonged exposure to supratherapeutic doses of levothyroxine which increase the chances of adverse outcomes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningEarly discovery of factors affecting thyroid replacement therapy via a thoughtful patient work-up may avoid unnecessary thyroid medication adjustments and their consequences for patients, clinicians, and the healthcare system.
“The early discovery of these factors via a thoughtful patient work-up may avoid unnecessary thyroid medication adjustments and their consequences for patients, clinicians, and the healthcare system.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S4 (based).
Interpretationnone givenSignificant swings in weight may also cause treatment-refractory hypothyroidism.
“Significant swings in weight may also cause treatment-refractory hypothyroidism.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningTreatment-refractory hypothyroidism is a condition that exists within the context of other important factors-GI disease, concomitant drug use, diet, and patient habits-whose presence may adversely affect thyroid replacement therapy.
“This holistic approach acknowledges that treatment-refractory hypothyroidism is a condition that exists within the context of other important factors—GI disease, concomitant drug use, diet, and patient habits—whose presence may adversely affect thyroid replacement therapy.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationIn a retrospective study of 99 hypothyroid patients, switching from traditional levothyroxine tablets to levothyroxine gel caps may preclude or reduce the need for levothyroxine dose or formulation changes while improving hypothyroid symptom control in some patients.
“CONTROL Switch, a recent retrospective study involving 99 hypothyroid patients being treated by endocrinologists, suggested that a strategy of switching therapy from the traditional levothyroxine tablets to levothyroxine gel caps may preclude or reduce the need for levothyroxine dose or formulation changes, while improving hypothyroid symptom control, in some patients [122].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [122] Ernst FR, Sandulli W, Elmor R et al (2017) Retrospective study of patients switched from tablet formulations to a gel cap formulation of levothyroxine: results of the CONTROL Switch study. Drugs R D 17:103–115 source
Not checked in the free run.
The paper relies on this without support.
The eight-step approach to diagnosing and managing refractory hypothyroidism has been validated through empirical use.
“We recommend the following eight-step approach, which has been validated through empirical use and should be considered as an alternative to the standard practice of escalating doses of levothyroxine”
The paper relies on this without support.
Early discovery of factors affecting levothyroxine absorption via a thoughtful patient work-up may avoid unnecessary thyroid medication adjustments and their consequences for patients and clinicians.
“The early discovery of these factors via a thoughtful patient work-up may avoid unnecessary thyroid medication adjustments and their consequences for both patients and clinicians.”
The paper relies on this without support.
Inter-individual variability in the efficiency of GI absorption is large and accounts for most of the range of dose requirements among compliant patients after adjustment for body size.
“Inter-individual variability in the efficiency of GI absorption is rather large, and such variability accounts for most of the range of dose requirements seen among compliant patients following adjustment for body size.”
The paper relies on this without support.
The first sign of malabsorption syndrome can be the need for unexpectedly high doses of levothyroxine in replacement therapy; malabsorption syndrome is frequently oligosymptomatic and previously undiagnosed.
“The first sign of malabsorption syndrome, which is frequently oligosymptomatic and previously undiagnosed, can be the need for unexpectedly high doses of levothyroxine in replacement therapy.”
The paper relies on this without support.
Phenytoin, carbamazepine, and rifampin increase turnover or excretion of thyroid hormone.
“These medications include phenytoin, carbamazepine, and rifampin.”
The paper relies on this without support.
Switching to generic levothyroxine products is correlated with sub-optimal outcomes.
“Switching to generic levothyroxine products has also been correlated with sub-optimal outcomes.”
The paper relies on this without support.
The common approach to managing patients with unusual thyroxine needs is to escalate the dose of levothyroxine until targeted TSH levels are achieved.
“The common approach to managing patients with unusual thyroxine needs is to escalate the dose of levothyroxine until targeted TSH levels are achieved.”
The paper relies on this without support.
A clinical test for estimating the absorption of thyroxine may have utility in some patients who have unexpectedly high thyroxine requirements.
“Although not standardized, a clinical test for estimating the absorption of thyroxine may have utility in some patients who have unexpectedly high thyroxine requirements.”
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?
The use of calcium salts in the post-operative period in patients with transient or permanent hypocalcemia results in interference with LT4 absorption.
“Furthermore, the use of calcium salts in the post-operative period in patients with transient or permanent hypocalcemia results in interference with LT4 absorption (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 [13]
The ‘Non-pathologic causes of refractory hypothyroidism’ section identifies calcium supplements among factors that can affect LT4 absorption. The ‘Key principle’ section says taking interfering supplements close to LT4 can change dose requirements. Neither passage establishes the claim specifically for post-operative patients with transient or permanent hypocalcemia. (LLM, conf=0.85)
Experimental — accuracy not yet measuredNon-tablet LT4 formulations (liquid solution and softgel capsule) have been manufactured and commercialized for clinical practice to overcome gastrointestinal absorption issues, although they are not available in every country.
“In an attempt to overcome the above-mentioned issues with gastrointestinal absorption (such as intake interference, drug interference, and pH dependence), non-tablet LT4 formulations, i.e., liquid solution (LS) and softgel capsule (SG), have been manufactured and commercialized for clinical practice, although they are not available in every country (13, 107).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [13]
The 'Alternative levothyroxine formulations' section says softgel and liquid LT4 are available and may address malabsorption and factors contributing to tablet failure. It does not say that these formulations are unavailable in some countries; that geographic qualification is unsupported by our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA levothyroxine absorption test must be used to differentiate true malabsorption from nonadherence or pseudo-malabsorption.
“In clinical practice, the levothyroxine absorption test is part of the workup of patients with “refractory hypothyroidism” to differentiate true malabsorption from nonadherence or pseudo-malabsorption [3, 6].”
From Levothyroxine Absorption Test With the Daily Levothyroxine Dose in Patients With “Refractory Hypothyroidism” (2025) · cites this paper as [3]
In 'Diagnosing and managing refractory hypothyroidism > Key principle' (page unavailable), the report says a supervised absorption test may be useful when poor adherence is suspected, supporting its possible role in the workup. It does not say the test must be used; it explicitly advises against routine use because the test is not standardized. (LLM, conf=0.89)
Experimental — accuracy not yet measuredOther 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 [13]
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 [13]
More than 15% of levothyroxine-treated patients fail to achieve the recommended serum TSH level.
“Despite a daily levothyroxine dose of more than 1.9 µg/kg/day, between 15% and 20% of levothyroxine-treated patients present hypothyroid symptoms or have TSH levels above the upper limit of the reference range [3, 4].”
From Levothyroxine Absorption Test With the Daily Levothyroxine Dose in Patients With “Refractory Hypothyroidism” (2025) · cites this paper as [3]
Pathological causes of refractory hypothyroidism include obesity and gastrointestinal disorders that cause levothyroxine malabsorption, as well as rarer conditions such as nephrotic syndrome, Addison's disease, and cystic fibrosis.
“Pathological causes include obesity and gastrointestinal disorders responsible for LT4 malabsorption, as well as other rare conditions such as nephrotic syndrome, Addison's disease, and cystic fibrosis.4,17”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [4]
In 10% to 20% of refractory hypothyroidism patients, no cause is identified, a situation called idiopathic refractory hypothyroidism.
“Studies indicate that in 10% to 20% of patients with RH, no identifiable cause is found, which is referred to as”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [4]
In 2017, it was proposed to classify the main causes of refractory hypothyroidism as pathological or nonpathological.
“In 2017, it was suggested to classify the main causes of RH as either pathological or nonpathological.4”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [4]
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.
Diagnostic requirement for low FT3 conflicts with earlier description
MajorThe diagnostic algorithm says frank primary hypothyroidism requires low FT4 and FT3, but the paper earlier says FT3 often remains normal in hypothyroidism. Requiring low FT3 would therefore exclude patients the paper otherwise describes as hypothyroid.
“By laboratory definition, frank primary hypothyroidism requires low levels of thyroid hormones (free–FT4 and FT3) as well as elevated TSH.”
“FT3 values often fall in the normal range as a result of hyperstimulation of the remaining functioning thyroid tissue by elevated TSH and to up-regulation of deiodinase D2, the enzyme that converts T4 to T3 [25].”
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The Colorado Thyroid Disease Prevalence Study
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“FT3 measurement has somewhat limited utility, however, in the diagnosis of hypothyroidism, since FT3 values often fall in the normal range as a result of hyperstimulation of the remaining functioning thyroid tissue by elevated TSH and to up-regulation of deiodinase D2, the enzyme that converts T4 to T3 [25].”
BackgroundGarber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber, K. A. (2012) · Endocrine Practice · doi:10.4158/ep12280.gl · Cited by 1,567 · cited 14× · see citing works
“1 3 hyperthyroid based on low serum TSH levels over many weeks or months [21].”
BackgroundMethodInfluentialGarber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., Pessah-Pollack, R., Singer, P. A., & Woeber for the American Association, K. A. (2012) · Thyroid · doi:10.1089/thy.2012.0205 · Cited by 1,053 · see citing works
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Motesanib Diphosphate in Progressive Differentiated Thyroid Cancer
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Risk for fracture in women with low serum levels of thyroid-stimulating hormone
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“In the absence of thyroid disease in severely ill patients, FT3 levels may be low because of reduced peripheral conversion of T4 to T3 and increased thyroid hormone inactivation [21, 26, 27].”
BackgroundCHOPRA, I. J., CHOPRA, U., SMITH, S. R., REZA, M., & SOLOMON, D. H. (1975) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-41-6-1043 · Cited by 424 · see citing works
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“03 mU/L) compared to those with TSH levels in the normal range [97].”
BackgroundEuthyroid Sick Syndrome: Is It a Misnomer?
Chopra, I. J. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.2.3745 · Cited by 374 · see citing works
The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism
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Thyroxine in Goiter, <i>Helicobacter pylori</i> Infection, and Chronic Gastritis
Centanni, M., Gargano, L., Canettieri, G., Viceconti, N., Franchi, A., Fave, G. D., & Annibale, B. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa043903 · Cited by 329 · cited 2× · see citing works
“Review the thyroxine ingestion history The most efficient way to take levothyroxine—and the most reproducible—is to ingest the tablets on an empty stomach and avoid other medications or food for 30–60 min (preferably 60) thereafter [4, 5, 48].”
BackgroundSelf-citationLevothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients
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“Thus, some patients may require a more “physiological” treatment than levothyroxine monotherapy [75].”
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“As reported by Taylor and colleagues [28], although a modest increase in the content of T4 (and T4-derived T3) found in the thyrotrophs will usually cause a substantial reduction in serum TSH in the setting of hypothyroidism, the same modest level of increase in peripheral tissues (liver, muscles, etc.”
BackgroundTumor Necrosis Factor: A Putative Mediator of the Sick Euthyroid Syndrome in Man*
POLL, T. V. D., ROMIJN, J. A., WIERSINGA, W. M., & SAUERWEIN, H. P. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-71-6-1567 · Cited by 270 · see citing works
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“In the appropriate clinical context, a subnormal serum FT4 level usually establishes the diagnosis of hypothyroidism, whether primary (elevated serum TSH) or central (normal or low serum TSH) [22, 23].”
BackgroundPeeters, R. P., Wouters, P. J., van Toor, H., Kaptein, E., Visser, T. J., & Van den Berghe, G. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0535 · Cited by 251 · see citing works
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Lean Body Mass Is a Major Determinant of Levothyroxine Dosage in the Treatment of Thyroid Diseases
Santini, F., Pinchera, A., Marsili, A., Ceccarini, G., Castagna, M. G., Valeriano, R., Giannetti, M., Taddei, D., Centoni, R., Scartabelli, G., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1306 · Cited by 226 · cited 1× · see citing works
“In a case series of 75 consecutive post-thyroidectomy patients, an inverse relationship between the dose of levothyroxine required to normalize TSH levels and body weight was reported [71].”
BackgroundConditions and drugs interfering with thyroxine absorption
Liwanpo, L., & Hershman, J. M. (2009) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2009.06.006 · Cited by 222 · cited 1× · see citing works
“The ingestion of one or more of these at, or close to, the time of levothyroxine dosing can significantly change the dose requirement in individual patients, especially when done regularly [49].”
BackgroundRadioimmunoassay of Human Plasma Thyrotropin*
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Overt and Subclinical Hypothyroidism
Khandelwal, D., & Tandon, N. (2011) · Drugs · doi:10.2165/11598070-000000000-00000 · Cited by 199 · see citing works
Timing of levothyroxine administration affects serum thyrotropin concentration
Bach-Huynh, T.-G., Nayak, B., Loh, J., Soldin, S., & Jonklaas, J. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0860 · Cited by 198 · cited 1× · see citing works
“Review the thyroxine ingestion history The most efficient way to take levothyroxine—and the most reproducible—is to ingest the tablets on an empty stomach and avoid other medications or food for 30–60 min (preferably 60) thereafter [4, 5, 48].”
Background(1993) · Europe PMC (PubMed Central) · Cited by 167 · see citing works
Imatinib induces hypothyroidism in patients receiving levothyroxine
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Prevalence of abnormal thyroid function test results in patients with acute medical illnesses
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“In the absence of thyroid disease in severely ill patients, FT3 levels may be low because of reduced peripheral conversion of T4 to T3 and increased thyroid hormone inactivation [21, 26, 27].”
BackgroundDelayed Intestinal Absorption of Levothyroxine
BENVENGA, S., BARTOLONE, L., SQUADRITO, S., GIUDICE, F. L., & TRIMARCHI, F. (1995) · Thyroid · doi:10.1089/thy.1995.5.249 · Cited by 156 · cited 1× · see citing works
“Review the thyroxine ingestion history The most efficient way to take levothyroxine—and the most reproducible—is to ingest the tablets on an empty stomach and avoid other medications or food for 30–60 min (preferably 60) thereafter [4, 5, 48].”
BackgroundSelf-citationTissue Thyroid Hormone Levels in Critical Illness
Peeters, R. P., van der Geyten, S., Wouters, P. J., Darras, V. M., van Toor, H., Kaptein, E., Visser, T. J., & Van den Berghe, G. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1013 · Cited by 145 · see citing works
Effects of acute and chronic interleukin-6 administration on thyroid hormone metabolism in humans.
Stouthard, J. M., van der Poll, T., Endert, E., Bakker, P. J., Veenhof, C. H., Sauerwein, H. P., & Romijn, J. A. (1994) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.79.5.7962327 · Cited by 139 · see citing works
Increased risk of primary hypothyroidism in preterm infants
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Occurrence and Risk Factors for Autoimmune Thyroid Disease in Patients with Atrophic Body Gastritis
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Self-citationHashimoto’s Thyroiditis and Autoimmune Gastritis
Cellini, M., Santaguida, M. G., Virili, C., Capriello, S., Brusca, N., Gargano, L., & Centanni, M. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00092 · Cited by 120 · cited 1× · see citing works
“Levothyroxine absorption can be limited by a number of diseases of the gastrointestinal (GI) tract, including: Helicobacter pylori infection, inflammatory bowel disease (IBD), celiac disease, lactose intolerance, atrophic body gastritis (ABG), gastric bypass, biliary pancreatic diversion, and gastroparesis, among othe…”
BackgroundSelf-citationAtypical celiac disease as cause of increased need for thyroxine: a systematic study
Virili, C., Bassotti, G., Santaguida, M. G., Iuorio, R., Del Duca, S. C., Mercuri, V., Picarelli, A., Gargiulo, P., Gargano, L., & Centanni, M. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1851 · Cited by 114 · see citing works
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Self-citationAbsorption of oral thyroxine in man
HAYS, M. T. (1968) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-28-6-749 · Cited by 111 · cited 1× · see citing works
“Whether or not this finding turns out to be clinically important, Hays further noted, remains to be seen [90].”
BackgroundFREE THYROID HORMONE MEASUREMENT
Stockigt, J. (2001) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70187-0 · Cited by 110 · cited 1× · see citing works
“Methods for determining T3 concentration by direct immunoassay are currently in use [21, 24].”
MethodA potential role of activated NF-κB in the pathogenesis of euthyroid sick syndrome
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Virili, C., & Centanni, M. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.01.053 · Cited by 105 · cited 1× · see citing works
“Recently, a possible role for an altered intestinal microbiota composition has also been conceived [94, 95].”
BackgroundPseudomalabsorption of levothyroxine
Ain, K. B. (1991) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1991.03470150090036 · Cited by 100 · cited 1× · see citing works
“Concomitant GI diseases Possibly misunderstood in the past, or even confused with pseudomalabsorption [62], malabsorption of levothyroxine is now widely recognized as a legitimate medical problem in a significant percentage of hypothyroid patients.”
BackgroundGakkai, N. N. (1925) · University of Michigan Library Repository · Cited by 100 · see citing works
Abrahamsen, B., Jørgensen, H. L., Laulund, A. S., Nybo, M., Bauer, D. C., Brix, T. H., & Hegedüs, L. (2015) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2416 · Cited by 98 · cited 1× · see citing works
“More recently, Abrahamsen and colleagues found the long-term risk of hip and other osteoporotic fractures among real-world patients to be strongly correlated with the cumulative duration of periods with low TSH—most likely a consequence of excessive replacement [98].”
BackgroundTreatment of Hypothyroidism with Once Weekly Thyroxine1
Grebe, S. K. G., Cooke, R. R., Ford, H. C., Fagerström, J. N., Cordwell, D. P., Lever, N. A., Purdie, G., & Feek, C. M. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.3.3830 · Cited by 95 · cited 1× · see citing works
“As a last resort in those with continuing poor compliance, administration of thyroxine once weekly can be successful [119].”
BackgroundAppelhof, B. C., Peeters, R. P., Wiersinga, W. M., Visser, T. J., Wekking, E. M., Huyser, J., Schene, A. H., Tijssen, J. G. P., Hoogendijk, W. J. G., & Fliers, E. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-0451 · Cited by 91 · cited 1× · see citing works
“However, the benefits of that treatment remain controversial [77, 78].”
BackgroundDibutyryl cAMP induction of type II 5′deiodinase activity in rat brain astrocytes in culture
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Pregnant Women on Thyroxine Substitution Are Often Dysregulated in Early Pregnancy
Hallengren, B., Lantz, M., Andreasson, B., & Grennert, L. (2009) · Thyroid · doi:10.1089/thy.2008.0206 · Cited by 88 · see citing works
Does microbiota composition affect thyroid homeostasis?
Virili, C., & Centanni, M. (2014) · Endocrine · doi:10.1007/s12020-014-0509-2 · Cited by 85 · cited 1× · see citing works
“Recently, a possible role for an altered intestinal microbiota composition has also been conceived [94, 95].”
BackgroundSelf-citationNew medications which decrease levothyroxine absorption
John-Kalarickal, J., Pearlman, G., & Carlson, H. E. (2007) · Thyroid · doi:10.1089/thy.2007.0060 · Cited by 82 · cited 1× · see citing works
“As noted above, a large and growing number of medications, supplements, and food items have been shown to alter the fraction of an ingested dose that is absorbed [109, 110].”
BackgroundAcute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men
Corssmit, E. P. M., Heyligenberg, R., Endert, E., Sauerwein, H. P., & Romijn, J. A. (1995) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.80.11.7593416 · Cited by 82 · see citing works
Fallahi, P., Ferrari, S. M., Camastra, S., Politti, U., Ruffilli, I., Vita, R., Navarra, G., Benvenga, S., & Antonelli, A. (2017) · Obesity Surgery · doi:10.1007/s11695-016-2247-4 · Cited by 81 · cited 1× · see citing works
“Levothyroxine absorption can be limited by a number of diseases of the gastrointestinal (GI) tract, including: Helicobacter pylori infection, inflammatory bowel disease (IBD), celiac disease, lactose intolerance, atrophic body gastritis (ABG), gastric bypass, biliary pancreatic diversion, and gastroparesis, among othe…”
BackgroundMetabolic and Clinical Consequences of Hyperthyroidism on Bone Density
Gorka, J., Taylor‐Gjevre, R. M., & Arnason, T. (2013) · International Journal of Endocrinology · doi:10.1155/2013/638727 · Cited by 80 · cited 1× · see citing works
“The first-line treatment of hypothyroidism dictates that thyroxine dosing be carefully monitored and adjusted as necessary to prevent ongoing bone loss [100].”
BackgroundThe Acute Effect of Calcium Carbonate on the Intestinal Absorption of Levothyroxine
Singh, N., Weisler, S. L., & Hershman, J. M. (2001) · Thyroid · doi:10.1089/105072501753211046 · Cited by 77 · cited 2× · see citing works
“As noted above, a large and growing number of medications, supplements, and food items have been shown to alter the fraction of an ingested dose that is absorbed [109, 110].”
BackgroundWhen thyroid hormone replacement is ineffective?
Benvenga, S. (2013) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000003 · Cited by 74 · cited 3× · see citing works
“Because it is not standardized, and unlikely to be associated with a specific etiology, the absorption test should not be used routinely [9, 41, 51].”
BackgroundSelf-citationDiagnosis and treatment of levothyroxine pseudomalabsorption.
Lips, D. J., Reisen, M. V., Voigt, V., & Venekamp, W. J. R. R. (2004) · PubMed · Cited by 73 · see citing works
Gaitonde, D. Y., Rowley, K. D., & Sweeney, L. B. (2012) · PubMed · Cited by 73 · see citing works
Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine
Cellini, M., Santaguida, M. G., Gatto, I., Virili, C., Del Duca, S. C., Brusca, N., Capriello, S., Gargano, L., & Centanni, M. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1217 · Cited by 72 · see citing works
Self-citationLiquid and softgel levothyroxine use in clinical practice: state of the art
Virili, C., Trimboli, P., Romanelli, F., & Centanni, M. (2016) · Endocrine · doi:10.1007/s12020-016-1035-1 · Cited by 71 · cited 1× · see citing works
“The efficacy and tolerability of these alternative formulations of levothyroxine have recently been reported in the scientific literature [120].”
BackgroundSelf-citationA. Irving, S., Vadiveloo, T., & Leese, G. P. (2015) · Clinical Endocrinology · doi:10.1111/cen.12559 · Cited by 69 · see citing works
The hypothalamic-pituitary-thyroid axis in critical illness
Fliers, E., Alkemade, A., & Wiersinga, W. M. (2001) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1053/beem.2001.0163 · Cited by 69 · see citing works
Thyroxine softgel capsule in patients with gastric-related T4 malabsorption
Santaguida, M. G., Virili, C., Duca, S. C. D., Cellini, M., Gatto, I., Brusca, N., De Vito, C., Gargano, L., & Centanni, M. (2015) · Endocrine · doi:10.1007/s12020-014-0476-7 · Cited by 68 · cited 1× · see citing works
“[121] have shown that most patients with definite gastric disorders benefited by changing from the traditional tablet formulations to the softgel levothyroxine preparation at a reduced dose.”
BackgroundSelf-citationMcMillan, M., Rotenberg, K. S., Vora, K., Sterman, A. B., Thevathasan, L., Ryan, M. F., Mehra, M., & Sandulli, W. (2016) · Drugs in R&D · doi:10.1007/s40268-015-0116-6 · Cited by 64 · cited 2× · see citing works
“More than 21% reported taking thyroxine less than the recommended 30 min before eating, a practice that may significantly contribute to less-than-optimal drug absorption [42].”
BackgroundRenal Involvement in Cystic Fibrosis
Yahiaoui, Y., Jablonski, M., Hubert, D., Mosnier-Pudar, H., Diaeresis]l, L.-H. A. A. G. A. N., Stern, M., Grenet, D., Grünfeld, J., Chauveau, D., & Fakhouri, F. (2009) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.00750209 · Cited by 60 · cited 1× · see citing works
“Cystic fibrosis can be complicated by amyloidosis [82, 83] that can have a direct effect on the thyroid [9, 84].”
BackgroundMorris, J. C. (2009) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2009.03536.x · Cited by 59 · cited 6× · see citing works
“What can be difficult is determining how often ‘occasionally’ actually occurs [41].”
BackgroundInfluentialCan urinary thyroid hormone loss cause hypothyroidism?
Fonseca, V., Thomas, M., Katrak, A., et al. (1991) · The Lancet · doi:10.1016/0140-6736(91)90546-2 · Cited by 57 · see citing works
Hennessey, J. V., Malabanan, A. O., Haugen, B. R., & Levy, E. G. (2010) · Endocrine Practice · doi:10.4158/ep0362.or · Cited by 56 · cited 1× · see citing works
“Most of the cases resulted in either mild symptoms of hypo-or hyperthyroidism and/ or unexpected thyroid function tests that were outside normal limits [43].”
BackgroundThyroxine treatment: absorption, malabsorption, and novel therapeutic approaches
Centanni, M. (2013) · Endocrine · doi:10.1007/s12020-012-9814-9 · Cited by 56 · cited 3× · see citing works
“1), which, based on increased thyroxine requirements [10], can help to establish the presence of concomitant GI disorders [111–113].”
BackgroundSelf-citationWard, L. S. (2010) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302010000500002 · Cited by 53 · cited 1× · see citing works
“Because it is not standardized, and unlikely to be associated with a specific etiology, the absorption test should not be used routinely [9, 41, 51].”
BackgroundHelicobacter pyloriinfection and drugs malabsorption
Lahner, E. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i30.10331 · Cited by 53 · see citing works
Fallahi, P., Ferrari, S. M., & Antonelli, A. (2016) · Endocrine · doi:10.1007/s12020-015-0836-y · Cited by 53 · see citing works
The economic impact of levothyroxine dose adjustments: the CONTROL HE study
Ernst, F. R., Barr, P., Elmor, R., Sandulli, W., Thevathasan, L., Sterman, A. B., Goldenberg, J., & Vora, K. (2017) · Clinical Drug Investigation · doi:10.1007/s40261-016-0462-3 · Cited by 53 · cited 1× · see citing works
“According to the authors, levothyroxine dose and formulation changes escalate the socioeconomic burden of hypothyroidism care by both increasing healthcare costs and decreasing work productivity [104].”
BackgroundGERD Symptoms in the General Population: Prevalence and Severity Versus Care-Seeking Patients
Cohen, E. R., Bolus, R. R., Khanna, D., Hays, R. D., Chang, L., MELMED, G. Y., Khanna, P. P., & Spiegel, B. M. R. (2014) · Digestive Diseases and Sciences · doi:10.1007/s10620-014-3181-8 · Cited by 51 · see citing works
Levothyroxine absorption in health and disease, and new therapeutic perspectives.
Ianiro, G., Mangiola, F., Rienzo, T. A. D., Bibbò, S., Franceschi, F., Greco, A. V., & Gasbarrini, A. (2014) · PubMed · Cited by 51 · see citing works
Predicting thyroxine requirements following total thyroidectomy: Thyroxine dose prediction
Mistry, D., Atkin, S., Atkinson, H., Gunasekaran, S., Sylvester, D., Rigby, A. S., & England, R. J. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2010.03940.x · Cited by 50 · cited 1× · see citing works
“In a prospective study involving 100 post-thyroidectomy patients, the optimal dose of levothyroxine (μg) could be predicted using a simple formula: dose = weight (kg) − age (years) + 125 [72].”
MethodVaisman (2014) · PubMed · doi:10.3275/8810 · Cited by 49 · cited 1× · see citing works
“The most recent data supporting this finding were reported by Vaisman in a multicenter study from Brazil, in which 28% of 2292 hypothyroid patients had elevated serum TSH levels with a background of thyroid hormone therapy [15].”
ResultBiondi, B., Bartalena, L., Chiovato, L., Lenzi, A., Mariotti, S., Pacini, F., Pontecorvi, A., Vitti, P., & Trimarchi, F. (2016) · Journal of Endocrinological Investigation · doi:10.1007/s40618-016-0511-z · Cited by 44 · cited 1× · see citing works
“Since levothyroxine is the first-line treatment for hypothyroidism [18, 19] and one of the most widely used drugs in the US with more than 115 million prescriptions dispensed in 2013 [20], a fresh examination of the causes of its frequent sub-optimal performance is warranted.”
BackgroundTrifirò, G., Parrino, F., Sultana, J., Giorgianni, F., Ferrajolo, C., Bianchini, E., Medea, G., Benvenga, S., Cricelli, I., Cricelli, C., et al. (2015) · Clinical Drug Investigation · doi:10.1007/s40261-015-0271-0 · Cited by 40 · see citing works
Self-citationLahner, E., Intraligi, M., Buscema, M., Centanni, M., Vannella, L., Grossi, E., & Annibale, B. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.563 · Cited by 40 · see citing works
Self-citationRuchała, M., Szczepanek‐Parulska, E., & Zybek, A. (2012) · PubMed · Cited by 38 · see citing works
Treatment-refractory hypothyroidism
Ramadhan, A., & Tamilia, M. (2011) · Canadian Medical Association Journal · doi:10.1503/cmaj.110994 · Cited by 37 · cited 3× · see citing works
“A supervised test for levothyroxine absorption may be useful if poor adherence to oral treatment is suspected [8, 106, 107].”
BackgroundThyroid function in children with cystic fibrosis
Luca, F. D., Trimarchi, F., Sferlazzas, C., Benvenga, S., Costante, G., Mamì, C., Pasquale, G. D., & Magazzù, G. (1982) · European Journal of Pediatrics · doi:10.1007/bf00442510 · Cited by 36 · see citing works
Self-citationRobertson, H. M. A., Narayanaswamy, A. K. P., Pereira, O., Copland, S. A., Herriot, R., McKinlay, A. W., Bevan, J. S., & Abraham, P. (2014) · Thyroid · doi:10.1089/thy.2013.0661 · Cited by 35 · see citing works
Pseudomalabsorption of Levothyroxine. A Case Report.
Ogawa, D., Otsuka, F., Mimura, Y., UENO, A., HASHIMOTO, H., Kishida, M., Ogura, T., & Makino, H. (2000) · Endocrine Journal · doi:10.1507/endocrj.47.45 · Cited by 35 · see citing works
DESTEVEBONETTI, L., Bennet, A., Malet, D., Hoff, M., Jp, L., & Caron, P. J. (2002) · Thyroid · doi:10.1089/105072502320288519 · Cited by 35 · cited 1× · see citing works
“A supervised test for levothyroxine absorption may be useful if poor adherence to oral treatment is suspected [8, 106, 107].”
BackgroundUnusual malabsorption of levothyroxine
Jauk, B., Mikosch, P., Gallowitsch, H. J., Kresnik, E., Molnar, M., Gomez, I., & Lind, P. (2000) · Thyroid · doi:10.1089/thy.2000.10.93 · Cited by 34 · see citing works
Increasing thyroxine requirements in primary hypothyroidism: don't forget the urinalysis!
Junglee, N. A., Scanlon, M., & Rees, D. A. (2007) · PubMed · Cited by 31 · see citing works
Castoro, C., Moli, R. L., Arpi, M. L., et al. (2016) · Journal of Endocrinological Investigation · doi:10.1007/s40618-016-0445-5 · Cited by 30 · see citing works
Tönjes, A., Karger, S., Koch, C. A., Paschke, R., Tannapfel, A., Stümvoll, M., & Führer, D. (2006) · Thyroid · doi:10.1089/thy.2006.16.1047 · Cited by 28 · see citing works
Amyloidosis in cystic fibrosis: A case series
Laughlin, A., Crotty, T. B., Egan, J. J., Watson, A. J., & Gallagher, C. G. (2005) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2005.09.010 · Cited by 26 · cited 1× · see citing works
“Cystic fibrosis can be complicated by amyloidosis [82, 83] that can have a direct effect on the thyroid [9, 84].”
BackgroundCopulsatile Release of Thyrotropin and Prolactin in Normal and Hypothyroid Subjects
Samuels, M. H., Veldhuis, J. D., & Ridgway, E. C. (1995) · Thyroid · doi:10.1089/thy.1995.5.369 · Cited by 25 · see citing works
Hasselström, K., Siersbæk‐Nielsen, K., Lumholtz, B., Faber, J. O., KIRKEGAARD, C., & Friis, T. (1985) · European Journal of Endocrinology · doi:10.1530/acta.0.1100483 · Cited by 25 · see citing works
Masked hypertension in newly diagnosed hypothyroidism: a pilot study
Piantanida, E., Gallo, D., Veronesi, G., Pariani, N., Masiello, E., Premoli, P., Sassi, L., Lai, A., Tanda, M. L., Ferrario, M., et al. (2016) · Journal of Endocrinological Investigation · doi:10.1007/s40618-016-0488-7 · Cited by 25 · cited 1× · see citing works
“The authors concluded that restoration of euthyroidism via thyroid replacement therapy can help lower blood pressure and cardiovascular risk among patients with MH [102].”
BackgroundGroener, J. B., Lehnhoff, D., Piel, D., Nawroth, P. P., Schanz, J., & Rudofsky, G. (2013) · American Journal of Case Reports · doi:10.12659/ajcr.883788 · Cited by 23 · see citing works
Srinivas, V., & Oyibo, S. O. (2010) · Endocrine Practice · doi:10.4158/ep10224.cr · Cited by 23 · cited 1× · see citing works
“Using a high-dose levothyroxine, absorption test can play an important role in the differential diagnosis of pseudomalabsorption (which is a most common source of difficulties in obtaining euthyreosis in hypothyroid patients) and actual levothyroxine malabsorption [117, 118].”
BackgroundErnst, F. R., Sandulli, W., Elmor, R., Welstead, J., Sterman, A. B., & Lavan, M. (2017) · Drugs in R&D · doi:10.1007/s40268-016-0150-z · Cited by 23 · see citing works
Physical performance in newly diagnosed hypothyroidism: a pilot study
Gallo, D., Piantanida, E., Veronesi, G., Lai, A., Sassi, L., Lombardi, V., Masiello, E., Premoli, P., Bianconi, E., Cusini, C., et al. (2017) · Journal of Endocrinological Investigation · doi:10.1007/s40618-017-0661-7 · Cited by 22 · cited 1× · see citing works
“The authors concluded that thyroid hormone replacement therapy may be helpful in reversing abnormalities of physical performance which may have a negative impact on patient well-being and quality of life [103].”
BackgroundFor Some, l-Thyroxine Replacement Might Not Be Enough: A Genetic Rationale
Kim, B. W., & Bianco, A. C. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-0410 · Cited by 18 · cited 1× · see citing works
“Kim and Bianco [76] postulated that some thyroid patients have a less effective deiodinase D2 enzyme for the conversion of T4 to T3.”
BackgroundIncreasing frequency and clinical significance of thyroid hormone autoantibodies
Benvenga, S., & Trimarchi, F. (2004) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/01.med.0000137759.57791.f8 · Cited by 18 · see citing works
Self-citationAmyloid Goiter in Cystic Fibrosis
Samuels, M. H., Thompson, N. W., LEICHTY, D., & Ridgway, E. C. (1995) · Thyroid · doi:10.1089/thy.1995.5.213 · Cited by 18 · cited 1× · see citing works
“Cystic fibrosis can be complicated by amyloidosis [82, 83] that can have a direct effect on the thyroid [9, 84].”
BackgroundFalsely raised TSH levels due to human anti-mouse antibody interfering with thyrotropin assay
Krishnan, S. G. S., Pathalapati, R., Kaplan, L. R., & Cobbs, R. (2006) · Postgraduate Medical Journal · doi:10.1136/pmj.2006.049809 · Cited by 17 · cited 1× · see citing works
“Several conditions such as age, pregnancy, and the presence of thyroid hormone antibodies may complicate the interpretation of TSH values [6, 8, 18].”
BackgroundSuzuki, Y., Takeshita, E., Kano, S., Hirata, S., & Sato, S. (1982) · Folia Endocrinologica Japonica · doi:10.1507/endocrine1927.58.12_1487 · Cited by 14 · cited 1× · see citing works
“Such patients have always existed [89].”
Kim, P. J., & Sachmechi, I. (2015) · AACE Clinical Case Reports · doi:10.4158/ep14051.cr · Cited by 14 · see citing works
Clinical Endocrinology in the near future: a post-modern challenge
Trimarchi, F. (2014) · Journal of Endocrinological Investigation · doi:10.1007/s40618-014-0181-7 · Cited by 13 · cited 1× · see citing works
“In all cases, we advocate that the eight-step algorithm presented be used to carefully assess patient needs before treatment choices are made; such a strategy offers an alternative to reductionism as stated by Trimarchi in 2015 [124].”
MethodThyroid Function and Insulin Sensitivity Before and After Bilio-pancreatic Diversion
Gniuli, D., Leccesi, L., Guidone, C., Iaconelli, A., Chiellini, C., Manto, A., Castagneto, M., Ghirlanda, G., & Mingrone, G. (2009) · Obesity Surgery · doi:10.1007/s11695-009-0005-6 · Cited by 13 · cited 1× · see citing works
“, certain malignancies, AIDS, malnutrition, and bariatric surgery) has also been associated with oral levothyroxine homeostasis [73].”
BackgroundFiorini, G., Bland, J. M., Hughes, E. A., Castelli, V., & Vaira, D. (2015) · Journal of Gastrointestinal and Liver Diseases · doi:10.15403/jgld.2014.1121.fio · Cited by 12 · see citing works
A curious case of refractory hypothyroidism due to selective malabsorption of oral thyroxine
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“Women with treated hypothyroidism, accordingly, may need to increase their dose of levothyroxine to prevent hypothyroidism and its attendant adverse outcomes for pregnancy [61].”
BackgroundSnyder, S., & Listecki, R. E. (2012) · PubMed · Cited by 8 · see citing works
Congenital Hypothyroidism and Cystic Fibrosis
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“, protection from light, moisture, and temperature extremes, as stated in the package insert) [108].”
BackgroundSelf-citationHypothyreose infolge einer Pseudomalabsorption von L-Thyroxin – Fall 12/2009
Müssig, K., Mörike, K., Klein, R., Sträter, J., Georges, G., Häring, H.-U., & Schnauder, G. (2009) · DMW - Deutsche Medizinische Wochenschrift · doi:10.1055/s-0028-1082836 · Cited by 5 · see citing works
Can Sorafenib Cause Hypothyroidism?
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“4% of patients (2/58) with non-autoimmune thyroid diseases [88].”
BackgroundLevothyroxine Dose Changes and Hypothyroid Patient Satisfaction-Results of the CONTROL TS Study
M, M. (2017) · Annals of Thyroid Research · doi:10.26420/annalsthyroidres.2017.1027 · Cited by 2 · see citing works
Atrophic Body Gastritis in Patients With Autoimmune Thyroid Disease: An Underdiagnosed Association
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Gastrointestinal malabsorption of thyroxine
Virili, C., Antonelli, A., Santaguida, M. G., Benvenga, S., & Centanni, M. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00168 · Cited by 164 · see citing works
Self-citationNew Formulations of Levothyroxine in the Treatment of Hypothyroidism: Trick or Treat?
Nagy, E. V., Perros, P., Papini, E., Katkó, M., & Hegedűs, L. D. (2020) · Thyroid · doi:10.1089/thy.2020.0515 · Cited by 65 · see citing works
“Dose adjustments may be triggered by patient non-adherence, concomitant medications, gastrointestinal co-morbidities, switching between generic and branded LT4 products, diet, and alterations in body weight (10).”
Virili, C., Giovanella, L., Fallahi, P., Antonelli, A., Santaguida, M. G., Centanni, M., & Trimboli, P. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00010 · Cited by 61 · see citing works
“, chronic atrophic gastritis, Helicobacter pylori infection) (7, 14), and concomitant intake of some drugs or ingestion of food or beverages (15, 16) can interfere with the LT4 absorption, thus reducing its efficacy.”
BackgroundSelf-citationThyro-entero-gastric autoimmunity: Pathophysiology and implications for patient management
Lahner, E., Conti, L., Cicone, F., Capriello, S., Cazzato, M. T., Centanni, M., Annibale, B., & Virili, C. (2019) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2019.101373 · Cited by 60 · see citing works
Self-citationLevothyroxine therapy in gastric malabsorptive disorders
Virili, C., Brusca, N., Capriello, S., & Centanni, M. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.621616 · Cited by 52 · see citing works
“In clinical practice, the timing of food intake and the interval before and after thyroxine ingestion seems not negligible for the subsequent intestinal absorption (31, 32).”
BackgroundSelf-citationThe levothyroxine absorption test: a four-year experience (2015-2018) at the Mayo Clinic
Gonzales, K. M., Stan, M. N., Morris, J. C., Bernet, V., & Castro, M. R. (2019) · Thyroid · doi:10.1089/thy.2019.0256 · Cited by 46 · see citing works
Novel thyroxine formulations: a further step toward precision medicine
Virili, C., Trimboli, P., & Centanni, M. (2019) · Endocrine · doi:10.1007/s12020-019-02049-x · Cited by 41 · see citing works
Self-citationPrecision Medicine in Autoimmune Thyroiditis and Hypothyroidism
Ferrari, S. M., Ragusa, F., Elia, G., Paparo, S. R., Mazzi, V., Baldini, E., Benvenga, S., Antonelli, A., & Fallahi, P. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.750380 · Cited by 41 · see citing works
“Refractory hypothyroidism and the need to increase the “normal dose” of L-T4 (Centanni et al., 2017; Fallahi et al., 2021) has led to the development of new L-T4 formulations, the oral liquid preparation and soft gel capsule, that have permitted a significant reduction in TSH variability in hypothyroidism, in comparis…”
BackgroundResultSelf-citationLevothyroxine absorption test to differentiate pseudomalabsorption from true malabsorption
Ghosh, S., Pramanik, S., Biswas, K., Bhattacharjee, K., Sarkar, R., Chowdhury, S., & Mukhopadhyay, P. (2020) · European Thyroid Journal · doi:10.1159/000504218 · Cited by 39 · see citing works
Anselmo, J., Scherberg, N. H., Dumitrescu, A. M., & Refetoff, S. (2019) · Thyroid · doi:10.1089/thy.2019.0080 · Cited by 37 · see citing works
“This is currently under investigation, as prolonged suppression of TSH was for many years advocated as standard treatment of differentiated thyroid cancer (16), and the mechanism of refractoriness to TH in some patients without THRB gene defects remains unresolved (17,18).”
Akirov, A., Fazelzad, R., Ezzat, S., Thabane, L., & Sawka, A. M. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00477 · Cited by 37 · see citing works
Centanni, M., Duntas, L., Feldt-Rasmussen, U., Koehrle, J., Peeters, R. P., Razvi, S., Trimboli, P., & Virili, C. (2025) · European Thyroid Journal · doi:10.1530/etj-25-0123 · Cited by 38 · see citing works
“…absorption (such as intake interference, drug interference, and pH dependence), non-tablet LT4 formulations, i.e., liquid solution (LS) and softgel capsule (SG), have been manufactured and commercialized for clinical practice, although they are not available in every country (13, 107).”
InfluentialSelf-citationAntonelli, A., Elia, G., Ragusa, F., Paparo, S. R., Cavallini, G., Benvenga, S., Ferrari, S. M., & Fallahi, P. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.633587 · Cited by 32 · see citing works
Self-citationDifferent formulations of levothyroxine for treating hypothyroidism: a real-life study
Trimboli, P., Scappaticcio, L., De Bellis, A., Maiorino, M. I., Knappe, L., Esposito, K., Bellastella, G., & Giovanella, L. (2020) · International Journal of Endocrinology · doi:10.1155/2020/4524759 · Cited by 27 · see citing works
“New LT4 formulations, namely, liquid solution (LS) and soft gel (SG) capsule, were manufactured to overcome the limitations of the tablet [4, 5].”
BackgroundUsai-Satta, P., Oppia, F., Lai, M., & Cabras, F. (2018) · Nutrients · doi:10.3390/nu10111705 · Cited by 25 · see citing works
“On the other hand, special attention should be paid to the therapeutic implications of neurological conditions and thyroid dysfunction frequently associated with CD [27,28].”
BackgroundFunctional and Symptomatic Individuality in the Response to Levothyroxine Treatment
Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00664 · Cited by 22 · see citing works
Levothyroxine treatment and gastric juice pH in humans: the proof of concept
Virili, C., Bruno, G., Santaguida, M. G., Gargano, L., Stramazzo, I., De Vito, C., Cicenia, A., Scalese, G., Porowska, B., Severi, C., et al. (2022) · Endocrine · doi:10.1007/s12020-022-03056-1 · Cited by 22 · see citing works
Self-citationCombination Thyroid Hormone Replacement; Knowns and Unknowns
Taylor, P. N., Eligar, V. S., Muller, I., Scholz, A., Dayan, C. M., & Okosieme, O. E. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00706 · Cited by 21 · see citing works
Trimboli, P., Virili, C., Centanni, M., & Giovanella, L. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00118 · Cited by 21 · see citing works
Self-citationL-T4 Therapy in Enteric Malabsorptive Disorders
Fallahi, P., Ferrari, S. M., Elia, G., Ragusa, F., Paparo, S. R., & Antonelli, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.626371 · Cited by 23 · see citing works
“iron or calcium salts, ferrous sulfate, phosphate binders, calcium carbonate, bile acid sequestrants), while the mechanism of action of raloxifene is unknown (27).”
BackgroundEndocrine complications of celiac disease: a case report and review of the literature
Walker, M. D., Zylberberg, H. M., Green, P. H. R., & Katz, M. S. (2018) · Endocrine Research · doi:10.1080/07435800.2018.1509868 · Cited by 21 · see citing works
“Suspicion for CD should be raised in patients with hypothyroidism who are compliant with levothyroxine but refractory to treatment, as CD can cause malabsorption of levothyroxine.(78) One study suggested that hypothyroid patients requiring higher daily doses of levothyroxine are more likely to have CD.”
BackgroundPirola, I., Gandossi, E., Brancato, D., Marini, F., Cristiano, A., Delbarba, A., Agosti, B., Castellano, M., & Cappelli, C. (2018) · Journal of Endocrinological Investigation · doi:10.1007/s40618-018-0867-3 · Cited by 21 · see citing works
“proton-pump inhibitors, sucralfate) [11].”
Ulcerative 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 · see citing works
“Several pharmacokinetic and clinical studies enlightened the role of various drugs and gastrointestinal diseases in determining an increased need for LT4, by interfering with the steps key to the efficacy of this treatment (4).”
BackgroundSelf-citationA new formulation of levothyroxine engineered to meet new specification standards
Lipp, H.-P., & Hostalek, U. (2019) · Current Medical Research and Opinion · doi:10.1080/03007995.2018.1545635 · Cited by 19 · see citing works
Benvenga, S. (2019) · Journal of Clinical & Translational Endocrinology · doi:10.1016/j.jcte.2019.100204 · Cited by 17 · see citing works
Self-citationAlternative routes of levothyroxine administration for hypothyroidism
Ritter, M. J., Gupta, S., & Hennessey, J. V. (2020) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000558 · Cited by 18 · see citing works
“Clinically refractory disease is characterized by unresolved symptoms of hypothyroidism after ample time has passed to assure tissue level equilibrium has been accomplished [11].”
BackgroundGuzmán-Prado, Y., Vita, R., & Samson, O. (2021) · Journal of General Internal Medicine · doi:10.1007/s11606-020-06403-y · Cited by 15 · see citing works
Santos, B. R., Cordeiro, J. M. D. A., Santos, L. C., Barbosa, E. M., Mendonça, L. D., Santos, E. O., de Macedo, I. O., de Lavor, M. S. L., Szawka, R. E., Serákides, R., et al. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.908240 · Cited by 15 · see citing works
Managing symptoms in hypothyroid patients on adequate levothyroxine: a narrative review
Razvi, S., Mrabeti, S., & Luster, M. (2020) · Endocrine Connections · doi:10.1530/ec-20-0205 · Cited by 15 · see citing works
Levothyroxine 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
EMPATHY: A New Tool for Identifying the Most Suitable Thyroxine Formulation in Hypothyroid Patients
Bellastella, G., Caputo, M., Maiorino, M. I., Longo, M., Scappaticcio, L., Giugliano, D., & Esposito, K. (2019) · Thyroid · doi:10.1089/thy.2018.0493 · Cited by 14 · see citing works
“As reported in a recent consensus statement, repeated adjustments of LT4 can also increase the cost of treatment, as frequent office visits and laboratory tests are required to determine and maintain the desired dose (30).”
Refractory hypothyroidism: unraveling the complexities of diagnosis and management
Quiroz-Aldave, J. E., Concepción-Zavaleta, M. J., Durand-Vásquez, M. D. C., Concepción-Urteaga, L. A., Gamarra-Osorio, E. R., Suárez-Rojas, J., Rafael-Robles, L. D. P., Paz-Ibarra, J., & Román-González, A. (2023) · Endocrine Practice · doi:10.1016/j.eprac.2023.09.003 · Cited by 14 · see citing works
Stagi, S., Municchi, G., Ferrari, M., & Wasniewska, M. G. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.859487 · Cited by 14 · see citing works
Jiang, T., Yang, X., Wu, B., Tao, R., Chen, R., Jin, L., Sun, D., & Weng, H. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1661211 · Cited by 15 · see citing works
Weekly Versus Daily Levothyroxine Tablet Replacement in Adults with Hypothyroidism: A Meta-Analyis
Chiu, H. H. C., Larrazabal, R. B., Uy, A. B., & Jimeno, C. (2021) · Journal of the ASEAN Federation of Endocrine Societies · doi:10.15605/jafes.036.02.07 · Cited by 12 · see citing works
Treatment with Intramuscular Levothyroxine in Refractory Hypothyroidism
Gamboa, M. D. L. Á. G., Sabán, M., & Curriá, M. (2019) · European Thyroid Journal · doi:10.1159/000503324 · Cited by 11 · see citing works
Bohinc Henderson, B. (2021) · International Medical Case Reports Journal · doi:10.2147/imcrj.s326481 · Cited by 10 · see citing works
Asamoah, E. (2021) · Clinical Case Reports · doi:10.1002/ccr3.4170 · Cited by 9 · see citing works
Santos Monteiro, S., Santos, T. S., Lopes, A. M., Oliveira, J. C., Freitas, C., & Couto Carvalho, A. (2022) · Endocrine Connections · doi:10.1530/ec-22-0355 · Cited by 9 · see citing works
Triiodothyronine 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
Kumarathunga, P. A. D. M., Kalupahana, N. S., & Antonypillai, C. N. (2021) · Endocrinology, Diabetes & Metabolism Case Reports · doi:10.1530/edm-21-0070 · Cited by 9 · see citing works
Ruchała, M., Bossowski, A. T., Brzózka, M. M., Gietka‐Czernel, M., Hubalewska–Dydejczyk, A., Kos‐Kudła, B., Lewiñski, A., Syrenicz, A., & Zgliczyński, W. (2022) · Endokrynologia Polska · doi:10.5603/ep.a2022.0078 · Cited by 7 · see citing works
Caron, P., Tudor, C., & Grunenwald, S. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf017 · Cited by 7 · see citing works
“In some patients, despite increasing levothyroxine dosage beyond 1.9 µg/kg/day, euthyroid state is not achieved [3, 4].”
InfluentialThyroxine overuse and clinical indices guiding successful treatment withdrawal
Livadas, S., Angelopoulos, N., Κόλλιας, Α., Paparodis, R. D., Androulakis, I., Anagnostis, P. G., Boniakos, A., Askitis, D. P., Μacut, D., Jaume, J. C., et al. (2025) · Journal of Endocrinological Investigation · doi:10.1007/s40618-025-02543-2 · Cited by 8 · see citing works
“Another major problem is the use of a TSH values as the sole marker of hypothyroidism diagnosis and index of treatment adequacy [13, 14].”
Refractory hypothyroidism to levothyroxine treatment: five cases of pseudomalabsorption
Elbasan, O. (2020) · Acta Endocrinologica (Bucharest) · doi:10.4183/aeb.2020.339 · Cited by 7 · see citing works
Elsherbiny, T. M. (2021) · Dubai Diabetes and Endocrinology Journal · doi:10.1159/000513927 · Cited by 6 · see citing works
Henderson, B. B., Smith, S. P., Mengelkamp, M. E., Rhymer, E. K., Gray, K. N., Jackson, A. G., Henry, S. F., Chuang, S., Stavrakas, E. H., Blair, O. M., et al. (2024) · Endocrine Practice · doi:10.1016/j.eprac.2024.03.005 · Cited by 6 · see citing works
Mazeto, G. M. F. D. S., Sgarbi, J. A., Ramos, H. E., Villagelin, D., Nogueira, C. R., Vaisman, M., Graf, H., & de Carvalho, G. A. (2022) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000545 · Cited by 7 · see citing works
A case of H. pylori infection presenting as refractory hypothyroidism
Gupta, P., Johnson, J. T., Soumya, S. L., Cherian, K. E., Kapoor, N., & Paul, T. V. (2020) · Journal of Family Medicine and Primary Care · doi:10.4103/jfmpc.jfmpc_729_20 · Cited by 6 · see citing works
“[4] In this situation after ensuring adequate adherence to therapy, factors interfering with drug absorption and/ or increased drug metabolism should be sought.[5] H.”
BackgroundAlhassan, A. A., Alidrisi, H. A., & Mansour, A. A. (2023) · Cureus · doi:10.7759/cureus.37776 · Cited by 6 · see citing works
“5 μU/ml after six weeks of dose increase is called TSH refractory hypothyroidism [4].”
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
Cherchir, F., Oueslati, I., Mouelhi, Y., Talbi, E., Feki, M., Yazidi, M., & Chihaoui, M. (2023) · SAGE Open Medical Case Reports · doi:10.1177/2050313x231209229 · Cited by 5 · see citing works
“4,9 Data regarding treatment-refractory hypothyroidism are increasingly published.”
BackgroundLiquid L-T4 therapy in hypothyroid patients with gastric diseases, an observational study
Fallahi, P., Ragusa, F., Patrizio, A., Mazzi, V., Botrini, C., Elia, G., Balestri, E., Barozzi, E., Rugani, L., Palmisano, E., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1386629 · Cited by 4 · see citing works
Self-citationYue, C. S., Scarsi, C., Bettazzi, E., Mautone, G., Celi, F. S., & Ducharme, M. P. (2024) · Endocrine Practice · doi:10.1016/j.eprac.2024.03.388 · Cited by 4 · see citing works
Amiyangoda, C. G. K., Antonypillai, C., Gunatilake, S. S. C. G., Weerathunge, T., Ediriweera, D., Kosgallana, S. G. P. D., Jayawardana, R. D. P., Thissera, H. A. N. D., Emalka, W. J., & Daraniyagala, D. H. U. (2024) · Endocrine Connections · doi:10.1530/ec-24-0277 · Cited by 3 · see citing works
Oueslati, I., Terzi, A., Yazidi, M., Kamoun, E., Feki, M., & Chihaoui, M. (2025) · Endocrine · doi:10.1007/s12020-025-04312-w · Cited by 3 · see citing works
“In patients with malabsorption, the underlying cause should be treated [4].”
InfluentialTopf, A., Pleininger, T., Motloch, L. J., Mirna, M., Kopp, K. L., Lichtenauer, M., Hoppe, U. C., & Salmhofer, H. (2021) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000349 · Cited by 4 · see citing works
Jamil, M. Z. Z., Salman, S., Akhtar, M., et al. (2022) · Cureus · doi:10.7759/cureus.21316 · Cited by 3 · see citing works
“6 mcg/kg/day) fails to achieve euthyroid status and TSH level remains persistently above target [14].”
BackgroundLaw, L. S., Kuu, N. W. X., Leong, M. H. T., et al. (2025) · Thyroid · doi:10.1177/10507256251409071 · Cited by 2 · see citing works
Analysis of dose-TSH response effect of levothyroxine soft-gel formulation
Trimboli, P., Piticchio, T., Dadda, Z., Stramazzo, I., Gamarra, E., Ruinelli, L., & Virili, C. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1340204 · Cited by 2 · see citing works
Levothyroxine malabsorption following sleeve gastrectomy
Gruneisen, E., Yang, J. W., & Pasqua, M. (2025) · Endocrinology Diabetes and Metabolism Case Reports · doi:10.1530/edm-24-0115 · Cited by 3 · see citing works
“Refractory primary hypothyroidism is de fi ned by biochemical or clinical evidence of hypothyroidism (TSH level above the upper target level, usually 4.5 mU/L) persistent at least 6 weeks after the last dose increase, despite a daily LT4 dose ≥ 1.9 μ g/kg (9).”
InfluentialIntramuscular and subcutaneous levothyroxine: success in treating refractory hypothyroidism
Chaudhury, N., Crasto, W., Saravanan, P., & Patel, V. (2025) · European Thyroid Journal · doi:10.1530/etj-25-0012 · Cited by 3 · see citing works
Shao, B., Hong, B., Gu, Q., Huang, C., Zeng, Y., Mei, Q., & Fan, J. (2025) · Pancreatology · doi:10.1016/j.pan.2025.07.417 · Cited by 2 · see citing works
Younes, N. (2022) · Acta Endocrinologica (Bucharest) · doi:10.4183/aeb.2022.375 · Cited by 2 · see citing works
Therapeutic Use of Levothyroxine: A Historical Perspective
Kahaly, G. J. (2021) · Springer eBooks · doi:10.1007/978-3-030-63277-9_1 · Cited by 2 · see citing works
Stupperich, S., Kotliarevskaia, J., Nies, R., Paparoupa, M., Wittig, A., & Schuppert, F. (2022) · Clinical Case Reports · doi:10.1002/ccr3.6223 · Cited by 2 · see citing works
Zhang, Y., Fan, W., Wang, Y., Dong, T., Liu, D., & Shao, Y. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1363018 · Cited by 1 · see citing works
Pseudo-Malabsorption in High Dose Levothyroxine–Resistant Hypothyroidism
Shimba, R., Harai, N., Yamazaki, M., Hosokawa, T., & Tsuchiya, K. (2025) · JCEM Case Reports · doi:10.1210/jcemcr/luaf085 · Cited by 2 · see citing works
“A significant increase in free thyroxine (T4) levels following the test suggests pseudo-malabsorption [1, 10, 11].”
InfluentialManaging Levothyroxine Malabsorption in Refractory Hypothyroidism: A Case Report
Rashwan, G., Jumani, A. I., Ibrahim, H. O., & AlNajjar, M. (2025) · Cureus · doi:10.7759/cureus.83123 · Cited by 1 · see citing works
“Refractory hypothyroidism is typically defined as requiring more than 1.9 mcg/kg/day of levothyroxine without achieving target thyroid-stimulating hormone (TSH) levels [6].”
InfluentialRole of triiodothyronine in hypothyroidism: Consensus statement from the Indian Thyroid Society
Joshi, S., Seshadri, K. G., Kalra, P., Ghosh, S., Menon, A. S., Pillai, M. G., Himagirish, K., Shenoy, M. T., George, J., Pradhan, R., et al. (2025) · Thyroid Research and Practice · doi:10.4103/trp.trp_33_25 · Cited by 1 · see citing works
Beyond the Gut: thyroxine malabsorption, pharmacokinetics, and delivery
Law, L. S., Kuu, N. W. X., Leong, M. H. T., Lo, E. A. G., Yeoh, S. F., & Yang, S. P. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag024 · Cited by 2 · see citing works
Alzenaidi, A., Alzenaidi, F., Aloraini, A., Alsulaim, K. M., Aloraini, A., Alharbi, T., Alajlan, A., & Alwabli, L. (2026) · Cureus · doi:10.7759/cureus.108163 · Cited by 1 · see citing works
“The complexities of managing levothyroxine during this period are further compounded by scenarios of noncompliance or malabsorption, which can lead to refractory hypothyroidism, characterized by persistently elevated thyrotropin levels despite seemingly adequate dosing [5].”
DOENÇA CELÍACA: AVALIAÇÃO CLÍNICA E COMPLICAÇÕES ENDOCRINOLÓGICAS
Garcia, S. M. T., Gebin, M. L., Paiva, G. C., et al. (2023) · Revista Ibero-Americana de Humanidades, Ciências e Educação · doi:10.51891/rease.v9i9.11242 · Cited by 1 · see citing works
Utility of T3 Therapy in Clinical Practice: A Narrative Review
Sanyal, D. (2025) · Archives of Endocrinology and Disorders · doi:10.46889/aed.2025.1101 · Cited by 1 · see citing works
“Refractory Hypothyroidism: Primary hypothyroidism is considered treatment refractory when clinical or biochemical signs of hypothyroidism (level of TSH above the target range, usually 5.5 mIU/L) persist despite increasing dosages of LT4 > 1.9μg/kg /day [14].”
InfluentialPatel, M. M., Patel, D. K., Patel, L. B., Dharaiya, C. B., Patel, D. M., Vasani, R. M., & Patel, M. V. (2025) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/ijem.ijem_256_24 · Cited by 1 · see citing works
A glimpse into the black box of celiac disease complications: a case report with a rare presentation
Рылова, Н. В., Arafat, A., Шакирова, А. Р., Shaidullina, I., & Zakirova, R. (2021) · Gastroenterology Review · doi:10.5114/pg.2021.106661 · Cited by 1 · see citing works
“It is suggested to suspect CD in patients with hypothyroidism those are not showing the expected response to levothyroxine, because the malabsorption that ensues CD might interfere with the treatment [13].”
BackgroundTherapy Resistant Hypothyroidism
Topaloğlu, O., & Çakır, B. (2018) · Ankara Medical Journal · doi:10.17098/amj.435289
Reva, Т. V., I. V., T., Shumko, G. І., et al. (2019) · Ukraïnsʹkij žurnal medicini bìologìï ta sportu · doi:10.26693/jmbs04.06.194
Umeh, C. A., Dubey, A., & Onyi, S. (2020) · American Journal of Medical Case Reports · doi:10.12691/ajmcr-8-12-3
“[3,11] The systematic approach to managing persistently elevated TSH in the presence of levothyroid therapy as outlined by Morris, 2009 and Centanni et al.”
BackgroundInfluentialThe Role of Metformin in patients with Primary Hypothyroidism
Al-Lehibi, K. I. (2019) · AL-Kindy College Medical Journal · doi:10.47723/kcmj.v15i1.86
Indu, K. C., Ghimire, S., & Deo, R. (2020) · Journal of Diabetes and Endocrine Association of Nepal · doi:10.3126/jdean.v4i2.34592
Alavinejad, P., Shahbazian, H. B., Jahanshahi, A., et al. (2021) · Jundishapur Journal of Chronic Disease Care · doi:10.5812/jjcdc.113481
Treatment Refractory Hypothyroidism Requiring High Dose Thyroxin Replacement
Afsana, F. (2021) · Global Journal of Otolaryngology · doi:10.19080/gjo.2021.23.556124
“If these diseases occur in hypothyroid patients, they seem to require increased need for thyroxine dosage [1].”
BackgroundInfluentialEnding Health Promotion Lethargy
Guzman-Garcia, P. A., Orozco-Quintana, E., Sepulveda-Gonzalez, D., Cooley-Magallanes, A., Salas-Velazquez, D., López-García, C., Ramírez-Treviño, A., Espinoza-Moran, A. L., Cabrera, M. V. L., & Segura-Azuara, N. D. L. Á. (2021) · Advances in medical education, research, and ethics (AMERE) book series · doi:10.4018/978-1-7998-8783-6.ch009
汚染防止形ふっ素樹脂塗料「Vフロン#200クリーン」 建築外装用ふっ素樹脂塗料で塗膜の汚れ防止
畑中, 昭., & 水野民雄 (1998) · 建築設備と配管工事
Drug-Induced Central Hypothyroidism
Gigliotti, B. J. (2022) · Springer eBooks · doi:10.1007/978-3-030-84367-0_12
7 Medical Management of Thyroiditis and Hypothyroidism
(2021) · Thieme Medical Publishers eBooks · doi:10.1055/b-0041-182782
Management of Endocrine Disorders and the Pharmacists' Role: Thyroid Disorders
Curley, L. E., Lin, J. C., & Chen, T. F. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812735-3.00525-2
Treatment-resistant hypothyroidism due to storage of levothyroxine at cold temperature
Barros, R. P. D. A., & Warszawski, L. (2022) · GSC Advanced Research and Reviews · doi:10.30574/gscarr.2022.12.1.0186
Newer Oral Levothyroxine Formulations: Is It Time to Switch Over?
Rajkumar, V. (2023) · EMJ Diabetes · doi:10.33590/emj/10306765
Hipotiroidismo refractario al tratamiento
Rosero, M. E. P., Viáfara, M. F. L., & Barrera, C. A. B. (2023) · Interdisciplinary Journal of Epidemiology and Public Health · doi:10.18041/2665-427x/ijeph.2.9905
“Es importante tener en cuenta que en hasta en el 52% de los pacientes no se encuentra una causa asociada (4).”
BackgroundInfluentialIpotiroidismo e vie alternative di somministrazione della levotiroxina
Retta, F., Rossi, M., & Pagano, L. (2023) · L Endocrinologo · doi:10.1007/s40619-023-01332-4
Signorino, C., Municchi, G., Ferrari, M., & Stagi, S. (2023) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2023.2023-9-12
“Proton-pump inhibitors, aluminium-containing antacids, iron and calcium salts, herbal remedies and nutritional supplements may worsen L-T4 absorption, modifying gastric pH or binding with L-T4 to create insoluble complexes (2,7,8,9).”
Resistance Training Program Design for Swimming Athletes With Down Syndrome
Lincoln, M. A., Guerin, G. D., Nixon, K. L., Leahy, S., Darr, R. L., & Guevarra, C. C. (2024) · Strength and conditioning journal · doi:10.1519/ssc.0000000000000836
“Additional considerations and recommendations”
Medication-Nonadherent Hypothyroidism Requiring Frequent Primary Care Visits to Achieve Euthyroidism
Kaul, S. (2024) · Federal Practitioner · doi:10.12788/fp.0461
Ipotiroidismo refrattario: gestione clinica
Selvaggio, L. D., & Bellastella, G. (2024) · L Endocrinologo · doi:10.1007/s40619-024-01440-9
“Incrementare la dose di L-T4 non è sempre l’intervento terapeutico più appropriato per il trattamento dell’ipotiroi-dismo refrattario, in quanto dosi sovra-terapeutiche possono essere associate a un aumento degli effetti avversi, in parti-colare cardiovascolari [1].”
Influential戴, 晓. (2024) · Advances in Clinical Medicine · doi:10.12677/acm.2024.1451494
Replacement Therapy for Hypothyroidism: Purpose and Indication for Correction
Степановна, М. Н., Алексеевич, Т. А., Matveyeva, Y. О., Олеговна, Щ. А., Кузина, И. А., Валерьевна, Г. Е., Эдуардовна, Т. М., & Petunina, N. A. (2024) · Effective Pharmacotherapy · doi:10.33978/2307-3586-2024-20-8-64-69
Refractory hypothyroidism in children: an overview
Metwalley, K. A., & Farghaly, H. S. (2024) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2024-0306 · Cited by 1 · see citing works
“…occur even with normal serum TSH (pituitary euthyroidism) and this attributed to insu ffi cient thyroid hormone levels in certain peripheral tissues [7] if the patients with RH advised higher dose of LT4 to overcome elevated TSH levels, symptoms of hyperthy-roidism as palpitations, sweating.…”
Influential
- Authors
- Centanni, M., Benvenga, S., & Sachmechi, I.
- Affiliations
- Sapienza University of Rome (IT)
- University of Messina (IT)
- Queens Hospital Center (US)
- Corresponding author
- Centanni, M.
- Venue
- Journal of Endocrinological Investigation
- Published
- 2017-07-10
- Volume
- 40
- Issue
- 12
- Pages
- 1289-1301
- ISSN
- 0391-4097 (ISSN-L)
- 1720-8386
- PMC
- PMC5680379
- OpenAlex
- W2734775767
- Semantic Scholar
- f7773e0f970a425911f864880f74f948e65cc28f
- Cited by
- 113
- References
- 122
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 13 · 2023: 8 · 2022: 11 · 2021: 18 · 2020: 9 · 2019: 16 · 2018: 9
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Journal of Endocrinological Investigation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
- Funders
- Akrimax Pharmaceuticals, LLC
- 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, thyroid hormone replacement, drug malabsorption, celiac disease, TSH monitoring, dose escalation, medication adherence
- MeSH terms
- Drug Resistance, Humans, Hypothyroidism, Disease Management, Hormone Replacement Therapy
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