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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Gastrointestinal malabsorption of oral levothyroxine is an emerging cause of refractory hypothyroidism and, although rare, is likely to be more frequent than previously believed.
“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]
The Concluding Remarks state that gastrointestinal malabsorption of oral thyroxine is more frequent than previously thought and may account for a significant fraction of refractory hypothyroidism. The paper also describes gastric-related malabsorption as increasingly recognized, but the passages do not establish the claim’s qualifier that it is rare. No page number is available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLevothyroxine absorption takes place primarily in the duodenum and jejunum of the small intestine.
“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]
In “How oral thyroxine is ingested,” the review says levothyroxine is absorbed throughout the small intestine, including the duodenum and upper jejunoileum. It also reports substantial absorption in the lower jejunoileum, so it does not establish that absorption occurs primarily in the duodenum and jejunum. The supplied passage has no page number. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe 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 [14]
The “Drugs interference at gastric level” section reports that calcium carbonate and other calcium preparations reduce T4 bioavailability or interfere with absorption. It does not establish this effect specifically in postoperative patients with transient or permanent hypocalcemia. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAntacids containing aluminum hydroxide or sucralfate may alternatively act by altering gastric acidity.
“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]
The “Drugs interference” section (page unavailable) links aluminum hydroxide to an increase in gastric pH. It calls sucralfate an antacid but discusses its binding to thyroxine in an acidic medium, not its alteration of gastric acidity. Thus the proposed mechanism is supported for aluminum hydroxide, but not established for sucralfate in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSeveral different variations of thyroid pathophysiology have been described in the elderly, including reduced lean body mass, reduced T4 absorption and outer ring deiodination, comorbidities, and drug use.
“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]
In “How oral thyroxine is ingested” (page not provided), the paper describes reduced lean body mass in elderly people and reports that T4 tablet absorption may decline with age, while noting that the absorption finding has been questioned. It also discusses conditions and drugs that impair levothyroxine absorption, but does not describe reduced outer-ring deiodination in the elderly. The claim therefore combines supported points with an unsupported one and presents the absorption finding more firmly than the paper does. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Some case reports 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 protein wasting disorders (nephrotic syndrome and protein-losing enteropathy).
“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]
In the section headed “ADVANCE ARTICLE: Endocrine Reviews” (page unavailable), the review reports decreased thyroid hormone absorption in cystic fibrosis and notes that cystic fibrosis frequently causes pancreatic insufficiency. It discusses impaired bile secretion in liver cirrhosis, not cystic fibrosis; the intestinal-disorders section associates altered transit with celiac disease. Our copy does not support the attributed nephrotic syndrome or protein-losing enteropathy cases. (LLM, conf=0.88)
Experimental — accuracy not yet measuredBoth liquid and soft gel formulations of levothyroxine can be trialled in cases of (unknown causes of) malabsorption.
“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]
The 'ALTERNATIVE Pharmacologic Perspectives' section (page unavailable) reports that switching to softgel levothyroxine helped patients with gastric-related malabsorption. The review also reports encouraging results with liquid levothyroxine for malabsorption associated with proton-pump inhibitors, lactose intolerance, atrophic gastritis, and bariatric surgery ('ADVANCE ARTICLE,' page unavailable). These passages support considering both formulations for malabsorption, but do not specifically address trialling them when the cause is unknown. (LLM, conf=0.85)
Experimental — accuracy not yet measuredLevothyroxine 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.
“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]
The Introduction (page not provided) says a consensus dose of 1.6–1.8 µg/kg/day restores TSH to the normal range in most hypothyroid patients. It does not give the claimed lower bound of 1.5 µg/kg/day or establish clinical euthyroidism specifically in patients with overt primary hypothyroidism. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSome types of foods and dietary supplements have been reported to reduce LT4 absorption, including soy, coffee, calcium, and grapefruit.
“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]
Other 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 [14]
Most commonly prescribed drugs act by sequestrating the hormone in the intestinal content, considerably decreasing LT4 bioavailability.
“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]
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 [14]
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.
“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]
Tablet LT4 requires disintegration in the gastric lumen, which is significantly dependent on the gastric juice pH.
“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]
In a fasted state, 60% to 80% of the orally administered levothyroxine dose is absorbed.
“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]
Low pH in the stomach is essential for optimal dissolution and proper ionization of levothyroxine tablets.
“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]
Generic and brand name LT4 tablets exhibit different dissolution-pH profiles, suggesting that excipients and manufacturing techniques influence tablet dissolution.
“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]
A lactose-free formulation or gluten-free diet can rid patients with lactose intolerance or celiac disease of impaired absorption.
“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]
L-T4 formulations (liquid, softgel) are refractory or much more resistant to interacting medications than tablet L-T4.
“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]
For primary hypothyroidism, levothyroxine is the standard drug treatment, usually given at an average daily dose of 1.6 to 1.8 mg/kg.
“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]
Levothyroxine is mainly absorbed in the jejunum and ileum, with 70% to 80% absorption when taken fasting, peak concentration at about 3 hours, and 70% to 80% bioavailability.
“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]
Levothyroxine tablets first disintegrate and dissolve in the stomach, a step needing an acidic gastric pH of 1.0 to 3.0 to remove the sodium ion and make levothyroxine lipophilic.
“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]
Even after Helicobacter pylori eradication, gastric mucosal atrophy may persist and further raise levothyroxine requirements.
“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]
Gastroparesis, whether diabetic, postsurgical, or idiopathic, has been reported to cause levothyroxine malabsorption requiring alternative formulations.
“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]
Chronic gastritis and gastric atrophy reduce gastric acid production, which can be blocked by PPIs; in H. pylori infection, ammonia partially counters acid, increasing levothyroxine requirements.
“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]
Lactose intolerance, Helicobacter pylori infection, and giardiasis are the conditions most associated with levothyroxine malabsorption.
“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]
Less frequent conditions such as autoimmune gastritis, gastrectomy, gastroparesis, cirrhosis, and ulcerative colitis can also alter levothyroxine bioavailability.
“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]
Celiac disease is more common in Hashimoto's thyroiditis and causes lymphocytic infiltration and enterocyte atrophy, reducing intestinal surface area for levothyroxine absorption and increasing dose needs; it can present without gastrointestinal symptoms.
“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]
Pancreatic insufficiency in cystic fibrosis lowers lipase secretion to about 10% of normal, causing steatorrhea and increased fecal T4 excretion.
“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]
Short bowel syndrome is a clear cause of levothyroxine malabsorption because surgical resection reduces absorptive surface area and alters intestinal motility.
“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]
Lactose as an excipient in LT4 tablets has no clinical relevance.
“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]
For obstructive liver disease or cirrhosis, apart from liver transplantation, there is no specific treatment.
“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]
Management of obstructive liver disease or cirrhosis is supportive and focuses on controlling protein and sodium intake.
“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]
Around 30% of patients fail to stably achieve the recommended serum TSH level (0.4-4.0 mIU/L) with a standard body-weight-based starting LT4 dose (typically 1.5-1.7 μg/kg/day in patients with residual endogenous thyroid function).
“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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- Fernandez N, Lopez C, Díez R, Garcia JJ, Diez MJ, Sahagun A, Sierra M. Drug interactions with the dietary fiber Plantago ovata husk. Expert Opin Drug Metab Toxicol. 2012;8(11):1377-1386.
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- 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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