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Gastrointestinal Malabsorption of Thyroxine
Open accessAbstract
Levothyroxine, a largely prescribed drug with a narrow therapeutic index, is often a lifelong treatment. The therapeutic efficacy of T4 may be marred by behavioral, pharmacologic, and pathologic issues acting as interfering factors. Despite a continuous search for an optimal T4 treatment, a significant number of patients fail to show a complete chemical and/or clinical response to this reference dose of T4. Gastrointestinal malabsorption of oral T4 represents an emerging cause of refractory hypothyroidism and may be more frequent than previously reputed. In this review, we examine the pharmacologic features of T4 preparations and their linkage with the intestinal absorption of the hormone. We have stressed the major biochemical and pharmacologic characteristics of T4 and its interaction with the putative transporter at the intestinal level. We have examined the interfering role of nutrients, foods, and drugs on T4 absorption at the gastric and intestinal levels. The impact of gastrointestinal disorders on T4 treatment efficacy has been also analyzed, in keeping with the site of action and the interfering mechanisms. Based on the evidence obtained from the literature, we also propose a schematic diagnostic workup for the most frequent and often hidden gastrointestinal diseases impairing T4 absorption.
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In the citing paper
“strointestinal malabsorption of oral levothyroxine is an emerging cause of refractory hypothyroidism and, although rare, is likely to be more frequent than previously believed.158”
From Hypothyroidism (2024) · cites this paper as [158]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Then, levothyroxine absorption takes place primarily in the duodenum and jejunum of the small intestine [1, 2].”
From Levothyroxine Absorption Test With the Daily Levothyroxine Dose in Patients With “Refractory Hypothyroidism” (2025) · cites this paper as [1]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These latter, however, may alternatively act by altering gastric acidity (14).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Several different variations of thyroid pathophysiology have been described in the elderly (92, 93). Reduced lean body mass, reduced T4 absorption and outer ring deiodination as well as the presence of comorbidities and the use of drugs are among them (14, 42, 51).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [14]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Some case reports also described LT4 malabsorption in patients with cystic fibrosis that was ascribed to pancreatic insufficiency, impaired biliary salt production and anomalies in intestinal transit, as well as the protein wasting disorders (nephrotic syndrome and protein-losing enteropathy) (14).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Additionally, both liquid and soft gel formulations of levothyroxine can be trialled in cases of (unknown causes of) malabsorption.158”
From Hypothyroidism (2024) · cites this paper as [158]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“levothyroxine doses between 1.5 to 1.8 µg/kg/day restore clinical euthyroidism and achieve TSH values in the reference range in most patients with overt primary hypothyroidism.”
From Levothyroxine Absorption Test With the Daily Levothyroxine Dose in Patients With “Refractory Hypothyroidism” (2025) · cites this paper as [1]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Some types of foods and dietary supplements have been reported to reduce LT4 absorption, including soy, coffee, calcium, and grapefruit (14, 46) (Table 1).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [14]
The cited source says what the claim attributes to it.
In the citing paper
“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 [14]
The cited source says what the claim attributes to it.
In the citing paper
“Most of the commonly prescribed drugs act by sequestrating the hormone in the intestinal content, thus considerably decreasing LT4 bioavailability.”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [14]
The cited source says what the claim attributes to it.
In the citing paper
“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 [14]
The cited source says what the claim attributes to it.
In the citing paper
“A number of disorders affecting the gastrointestinal tract have been referred to as factors interfering with sodium levothyroxine bioavailability, resulting in a spectrum from the need for a modestly increased dose of levothyroxine to frank levothyroxine malabsorption (14).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [14]
The cited source says what the claim attributes to it.
In the citing paper
“Tablet LT4 requires disintegration in the gastric lumen, which is significantly dependent on the gastric juice pH (14).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [14]
The cited source says what the claim attributes to it.
In the citing paper
“In a fasted state, 60% to 80% of the orally administered levothyroxine dose is absorbed”
From Levothyroxine Absorption Test With the Daily Levothyroxine Dose in Patients With “Refractory Hypothyroidism” (2025) · cites this paper as [1]
The cited source says what the claim attributes to it.
In the citing paper
“After oral administration, low pH in the stomach is essential for optimal dissolution and proper ionization of levothyroxine tablets.”
From Levothyroxine Absorption Test With the Daily Levothyroxine Dose in Patients With “Refractory Hypothyroidism” (2025) · cites this paper as [1]
In the citing paper
“Notably, generic and brand name tablets exhibit different dissolution–pH profiles, suggesting that excipients and manufacturing techniques influence tablet dissolution (14).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [14]
In the citing paper
“A lactose-free formulation or gluten-free diet can rid patients with lactose intolerance or celiac disease of impaired absorption, respectively (14, 64).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [14]
In the citing paper
“the availability of L-T4 formulations (liquid, softgel) that are refractory or much more resistant to IM than tablet L-T4 (9, 14, 98, 100, 109–114).”
From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [9]
In the citing paper
“The standard pharmacological treatment for patients with primary hypothyroidism is levothyroxine (LT4), 1 typically prescribed at an average daily dose of 1.6 to 1.8 mg/kg in most cases.2,3”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“LT4 is predominantly absorbed in the jejunum and ileum, 3 with absorption rates of 70% to 80% when taken on an empty stomach, and reaching its peak concentration in approximately 3 h, with a bioavailability of 70% to 80%.19”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“The metabolism of LT4 tablets begins with its disintegration and dissolution in the stomach, a process that requires an acidic gastric pH (1.0-3.0) to remove the sodium ion and convert LT4 into a lipophilic molecule.3,18”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Even with the eradication of Helicobacter pylori, gastric mucosal atrophy may still occur, further increasing LT4 requirements.3”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Cases have been reported in which gastroparesis (diabetic, postsurgical, and idiopathic) has caused LT4 malabsorption, necessitating the use of alternative LT4 formulations.3,61”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Patients with chronic gastritis and gastric atrophy show a decrease in gastric acid production, which can be blocked by PPIs.In other cases, gastric acid production is partially blocked and countered by ammonia in patients infected with Helicobacter pylori, leading to increased LT4 requirements.3”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Lactose intolerance, Helicobacter pylori infection, and giardiasis have been observed as the most associated diseases with LT4 malabsorption.”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Other less frequent conditions such as autoimmune gastritis, gastrectomy, gastroparesis, cirrhosis, and ulcerative colitis can also cause alterations in the bioavailability of LT4. 3”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Celiac disease is more prevalent in patients with Hashimoto's thyroiditis 62 and causes lymphocytic infiltration and enterocyte atrophy, leading to a progressive reduction in the available intestinal surface area for LT4 absorption, thereby increasing LT4 dosage requirements.3 It can also present atypically without gastrointestinal symptoms, further complicating its recognition.63”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Pancreatic insufficiency, occurring in cystic fibrosis, 53 reduces lipase secretion to approximately 10% of normal, resulting in steatorrhea and an increase in fecal excretion of T4. 3”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Short bowel syndrome is an evident cause of LT4 malabsorption, occurring as a result of issues requiring surgical resection of a significant portion of the small intestine.3,64 This reduces the available surface area for absorption and leads to alterations in intestinal motility.3”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Although it has traditionally been recommended to avoid LT4 tablets containing lactose as an excipient, this has no clinical relevance.3,69,79”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“For those with obstructive liver disease or cirrhosis, except for cases where liver transplantation is indicated, there is no specific treatment.”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“Management is supportive and focuses on controlling protein and sodium intake.3,69”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [3]
In the citing paper
“around 30% of patients fail to stably achieve the recommended serum level of thyroid-stimulating hormone (TSH; between 0.4 and 4.0 mIU/L, according to the American Thyroid Association guidelines) with a standard, body-weight-based starting dose of LT4 (typically 1.5 to 1.7 µg/kg/day in patients with residual endogenous thyroid function, such as those with auto-immune thyroiditis) [ 2 , 10 – 12 ].”
From Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults (2022) · cites this paper as [12]
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Metadata
- Authors
- Virili, C., Antonelli, A., Santaguida, M. G., Benvenga, S., & Centanni, M.
- Affiliations
- Sapienza University of Rome (IT)
- University of Pisa (IT)
- University of Messina (IT)
- Corresponding author
- Centanni, Marco
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2018-11-23
- Volume
- 40
- Issue
- 1
- Pages
- 118-136
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- OpenAlex
- W2901745461
- Cited by
- 164
- References
- 251
- Citations by year
- 2026: 11 · 2025: 27 · 2024: 17 · 2023: 15 · 2022: 25 · 2021: 31 · 2020: 18 · 2019: 19
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Reviews (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, other-oa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- levothyroxine, gastrointestinal malabsorption, thyroid hormone absorption, refractory hypothyroidism, drug interactions, gastrointestinal diseases, diagnostic workup
- MeSH terms
- Drug Interactions, Pharmaceutical Preparations, Gastrointestinal Diseases, Humans, Hypothyroidism, Thyroxine, Gastrointestinal Absorption
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