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Conditions and drugs interfering with thyroxine absorption
Best Practice & Research Clinical Endocrinology & Metabolism 23 (2009) 781–792
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Conditions and drugs interfering with thyroxine absorption Llanyee Liwanpo, MD, Doctor *, Jerome M. Hershman, MD, Professor Department of Endocrinology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Keywords: thyroxine absorption interfering drugs levothyroxine malabsorption hypothyroidism
Food, dietary fibre and espresso coffee interfere with the absorption of levothyroxine. Malabsorptive disorders reported to affect the absorption of levothyroxine include coeliac disease, inflammatory bowel disease, lactose intolerance as well as Helicobacter pylori (H. pylori) infection and atrophic gastritis. Many commonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine. Ó 2009 Elsevier Ltd. All rights reserved.
Following its introduction as a pharmaceutical agent, levothyroxine sodium has been fundamental in the treatment of various thyroid disorders, including primary hypothyroidism, nodular goitres and thyroid cancer. An understanding of its absorption was first derived from seminal studies conducted in the late 1960s. During the next two decades, various gastrointestinal conditions were identified that resulted in the malabsorption of levothyroxine. In the past several years, a number of medications that interfere with levothyroxine absorption have been identified. Despite the long history of levothyroxine use, understanding of its absorption and metabolism is still incomplete. In this article, we review gastrointestinal conditions and pharmacological agents that have been reported to interfere with the absorption of levothyroxine (Table 1).
Absorption of levothyroxine Approximately 62–82% of levothyroxine is absorbed after oral administration. This absorption occurs within the first 3 h of ingestion and is localised mainly in the jejunum and ileum.1 The absorption of levothyroxine is maximal when the stomach is empty, reflecting the importance of
* Corresponding author. VA Greater Los Angeles Healthcare System, Endocrinology 111D, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA. Tel.: þ1 310 478 3711x41362; Fax: þ1 310 268 4879. E-mail address: [email protected] (L. Liwanpo). 1521-690X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.06.006
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Table 1 Conditions and medications that may affect absorption of levothyroxine. Foods
Medical conditions
Drugs
Food intake Dietary fiber Espresso coffee
Jejunoileal bypass or other bowel resection Inflammatory bowel disease Celiac disease Lactose intolerance H. pylori infection Chronic gastritis of the stomach body
Cholestyramine Colesevelam Ferrous sulfate Sucralfate Calcium carbonate Aluminum hydroxide Sevelamer hydrochloride Lanthanum carbonate Raloxifene Proton pump inhibitors Orlistat
gastric acidity in this process. Patients with jejunoileal bypass surgery or other bowel resection have been reported to require higher doses of levothyroxine following surgery.2–4 Stone et al. noted reduced peak serum levels of thyroxine in patients with shortened bowel, though no consistent relationship was found between absorption and bowel length.5 Other factors, such as patient age, adherence to therapy, dietary habits, absorption kinetics and pre-existing gastrointestinal malabsorption, can also influence its absorption. Severe malabsorption due to various causes, including coeliac sprue and inflammatory bowel disease, can affect absorption of levothyroxine.6,7 Various methods have been developed to examine the mechanism of thyroxine absorption. Earlier methods used levothyroxine that was labelled with radioiodine. Hays first developed the doubleisotope equilibrium technique which involved simultaneous administration of oral 125I-thyroxine and intravenous 131I-thyroxine.8 The intestinal absorption of thyroxine was calculated from the ratio of serum 125I to 131I, and the mean absorption of thyroxine in euthyroid individuals was calculated to be 71%. By this method, it was found that hypothyroidism did not alter thyroxine absorption, which was estimated at 75% of the dose, compared with 68% in normal controls.9 Applying the same protocol with radiolabelled thyroxine, Hasselstrom et al. estimated the bioavailability of thyroxine more accurately using the ratio of the area under the curve (AUC) of the disappearance of the tracers.10 Eventually, a non-isotopic method was developed by Greenstadt et al. to determine oral thyroxine (T4) absorption.11 With the ingestion of oral liquid levothyroxine, the authors demonstrated a close correlation between the incremental rise in serum total T4 (DTT4) and values obtained from the standard doubleisotope method. Because enteral T4 distributes largely to the vascular and splanchnic organs in the first few hours after ingestion, serum DTT4 values should be proportional to the amount absorbed intestinally during the first 6 h following ingestion.9 To estimate the amount of T4 absorbed, DTT4 is multiplied by an individual’s estimated volume of distribution – which is calculated by a linear regression equation derived from the data of Nicoloff et al.12 Food and dietary fibre Absorption of levothyroxine has been shown to be influenced both by the timing of food intake and by certain foods. This was first reported by Wenzel et al. in their study comprising 37 patients.13 Subjects ingested either 100 mg or 3 mg of levothyroxine under two settings: (1) fasting, or (2) immediately before the consumption of two buttered rolls and a boiled egg. Using the double-isotope method developed by Hays, the authors showed that absorption was significantly better in the fasting state than with simultaneous food intake in all study groups. Benvenga et al. reported similar findings in four patients with nodular goitre, two of whom had Hashimoto’s thyroiditis.1 In these patients, ingesting levothyroxine 15 min prior to breakfast failed to suppress or normalise thyroid-stimulating hormone (TSH) levels. Compared to euthyroid and hypothyroid controls, absorption studies using 1000 mg of levothyroxine demonstrated delayed time to peak T4 absorption, reduced maximal absorption and decreased maximal increment in T4 absorption. In
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three of these patients, the first part of the T4 absorption curve was shifted to the right, suggesting an impairment in the early phase of the absorption. After a month of separating breakfast and levothyroxine ingestion by at least 60 min, the TSH levels in these patients became adequately suppressed. These findings form the basis of current recommendations to ingest oral levothyroxine 60 min prior to food intake. Dietary fibre also affects the bioavailability of levothyroxine, as noted by Liel et al. in patients requiring disproportionately high doses of levothyroxine.14 With fibre-enriched diets, 12 of the 13 patients exhibited elevated TSH levels or required higher doses of levothyroxine. However, when fibre was removed from the diet, TSH levels improved significantly. These patients obtained fibre through enriched bread, suggesting that soluble fibre was the culprit. The authors also performed in vitro experiments demonstrating a dose-dependent non-specific adsorption of T4 by wheat bran. These studies show that dietary fibre can reduce the bioavailability of T4. The association between dietary fibre and levothyroxine malabsorption has yet to be reproduced with fibre supplements, as Chiu and Sherman showed no interference by calcium polycarbophil or psyllium in healthy volunteers.15 Recently, Benvenga et al. suggested that espresso coffee may also interfere with the absorption of levothyroxine.16 In eight patients referred for management of inappropriately high or non-suppressed levels of TSH, the authors demonstrated elevated values that corresponded with concurrent coffee intake. When coffee intake was separated from levothyroxine, TSH levels improved. Absorption testing was performed in six of these cases and nine other healthy volunteers, in which 200 mg of levothyroxine was ingested with: (1) espresso coffee only; (2) water only or (3) water and then coffee 60 min later. Analysis of four indices, the average incremental rise of serum T4 (AIRST4), AUC, maximal incremental rise in T4 (MIRST4) and time to maximal incremental rise (TMIRST4), showed that the blunted effect occurred only with co-administration of levothyroxine and coffee. Pooled data comparing results with and without coffee revealed a significant 1.6-fold reduction in AIRST4 (p < 0.001), 1.6-fold decrease in AUC (p < 0.05), 1.4-fold reduction in MIRST4 (p < 0.05) and a prolonged TMIRST4 with concurrent ingestion of coffee. In healthy volunteers, this effect was also demonstrated but was smaller. When levothyroxine and coffee ingestion were separated by 60 min, no significant difference was seen in the four parameters in both the study and control groups. In vitro binding studies were also conducted with mixtures of coffee and known amounts of levothyroxine solution. Compared to saline, coffee was capable of sequestering T4, although the effect was lesser than that of other interfering agents such as bran fibre, sucralfate and aluminium hydroxide. No other studies have been published on this interaction, but this report strongly suggests that espresso coffee may decrease the efficacy of levothyroxine through sequestration in the intestine. Gastrointestinal disorders Both malabsorptive disorders and conditions that impair gastric acidity can affect the bioavailability of levothyroxine. Early reports described elevated serum TSH levels in patients with coeliac sprue and inflammatory bowel disease despite thyroxine doses that had previously normalised serum levels. These findings suggest that pre-existing malabsorption can reduce the bioavailability of levothyroxine. This association appears to be strongest with coeliac disease. More recently, a study has shown a similar phenomenon in patients with Helicobacter pylori (H. pylori) infection and atrophic gastritis – both of which impair gastric acidity.
Coeliac disease Multiple cases of levothyroxine malabsorption in patients with various manifestations of coeliac disease have been reported. One of the earlier cases, reported by D’Este`ve-Bonetti et al., concerned a 68-year-old post-thyroidectomy patient who showed no TSH response to increasing doses of levothyroxine.17 Her history was significant for persistent hypocalcaemia, chronic diarrhoea, anaemia and hypoalbuminaemia. Gastrointestinal work-up eventually diagnosed coeliac disease. After dietary restrictions were instituted, the patient’s serum TSH improved. Similar cases have been reported of patients with persistent hypothyroidism and occult symptoms of coeliac disease including weight loss,
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electrolyte abnormalities, anaemia and osteopaenia.18,19 In all of these cases, initiation of a gluten-free diet resulted in the reduction of levothyroxine dose requirements. Recently, McDermott et al. reported a case in which resistant hypothyroidism appeared to be the only major manifestation of coeliac disease.20 A 58-year-old woman was referred for symptoms of fatigue and cold intolerance. On presentation, her serum TSH was greater than 100 mU L1 (normal range: 0.6–4.3) and thyroid microsomal antibodies were positive – confirming autoimmune hypothyroidism. Routine blood tests including haemoglobin, electrolytes and albumin were normal, and the patient denied any history of gastrointestinal symptoms. After initiation of treatment with levothyroxine, her symptoms improved, but serum levels of TSH continued to be elevated despite escalating levothyroxine dosage. Work-up for malabsorption eventually diagnosed coeliac disease, which was confirmed on duodenal biopsy. After institution of a gluten-free diet, levothyroxine requirements in this patient decreased markedly. Coeliac disease occurs frequently with autoimmune thyroid disease. Because the symptoms of coeliac disease are often subtle, many authors suggest screening with anti-gliadin antibodies in patients with hypothyroidism who require higher than expected doses of levothyroxine. Lactose intolerance A case of levothyroxine malabsorption in the setting of lactose intolerance has been reported.21 A 55-year-old woman with primary hypothyroidism was referred for persistently elevated levels of TSH. She presented with symptoms of hypothyroidism and reported only mild gastrointestinal symptoms, consisting of sporadic episodes of watery diarrhoea over the past 7–8 years. Across an 8-month period following referral, the patient’s levothyroxine dose was increased up to 900 mg and a trial of triiodothyronine (T3) was also given. Despite these interventions, her TSH level failed to normalise. The patient was hospitalised for diagnostic testing and observation, but despite daily compliance with 300 mg of oral levothyroxine, her serum free T4 levels did not increase. Subsequent testing for malabsorption revealed an abnormal lactose-absorption test, indicating lactose intolerance. Thereafter, the patient was given levothyroxine intravenously, and her free T4 and free T3 levels normalised. With this diagnosis of oligo-symptomatic lactose intolerance, the patient was given a lactose-free formulation of levothyroxine (150 mg daily) and was started on a lactose-restricted diet. At follow-up 3 months later, the patient’s thyroid function tests were within the normal range and her symptoms had resolved. Helicobacter pylori and chronic gastritis Further highlighting the importance of gastric acidity in the absorption of levothyroxine, Centanni et al. demonstrated decreased TSH suppression in patients with H. pylori infection and atrophic gastritis of the body of the stomach.22 In H. pylori infection, bacterial production of urease neutralises gastric pH. In this case-control study, patients with non-toxic multinodular goitre were selected if clinical features of impaired gastric acid secretion were present. Using laboratory and histological testing, 53 patients were diagnosed with H. pylori infection and 60 patients with atrophic gastritis – of whom 31 also had concurrent H. pylori infection. Subjects were treated with thyroxine as suppressive therapy, starting at 50 mg daily and titrating up to maintain a serum TSH level of 0.05–0.20 mU L1. Thyroid function tests and daily dose requirements were followed up for at least 30 months. Compared to the reference group, doses needed to be increased by 22% in patients with H. pylori infection and by 27% in those with atrophic gastritis (p < 0.001). In patients with both H. pylori infection and atrophic gastritis, dosage increases were even more pronounced, up to 34% (p < 0.001). Additional data supporting this association was also obtained from 11 patients who were newly diagnosed with H. pylori infection during the course of the trial. These patients were initially part of the reference group and achieved suppression (median TSH level: 0.11 mU L1) with a median daily dose of 1.56 mg kg1 levothyroxine. With the development of H. pylori infection, all of these patients demonstrated increases in serum TSH level (median level: 1.35 mU L1). Following successful treatment of the infection, serum levels in all patients returned to suppression levels (median: 0.12 mU L1) with a slightly higher median dose of levothyroxine (1.7 mg kg1 per day).
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Medications Several commonly used oral medications have been shown to alter the bioavailability of levothyroxine, many of which interfere by forming an insoluble or non-absorbable complex with levothyroxine.
Bile acid sequestrants Several bile acid sequestrants have been reported to affect the absorption of levothyroxine. This effect was demonstrated with colestipol in rat studies but has not been reproduced in human studies to date.23 Northcutt conducted several experiments with cholestyramine after noting two cases of progressive hypothyroidism associated with cholestyramine treatment.24 In two patients who were on thyroid hormone replacement therapy, absorption tests were conducted by administering I131thyroxine with and without cholestyramine. A scanning-bed whole-body counter was used to determine the amount of 131I-thyroxine retained within the body. Urine and stool samples were collected and analysed for 131I-thyroxine. Treatment with cholestyramine was associated with a twofold increase in total stool radioactivity and decrease in urinary radioactivity, representing decreased intestinal absorption and subsequent loss of I131-thyroxine (Table 2). In vitro binding studies performed at pH 1.0 and 9.0 demonstrated that 50 mg of cholestyramine bound at least 3000 mg of levothyroxine. This interaction was not significantly perturbed by repeated washings or by addition of substances with high affinity for cholestyramine. Using rat intestinal sacs to examine transport of thyroxine, the authors demonstrated that only 2.3% of I131-thyroxine crosses the intestinal wall in the presence of cholestyramine, compared to 74% without cholestyramine. Lastly, in five healthy volunteers, the authors demonstrated that an interval of at least 4–5 h separating thyroxine and cholestyramine ingestion is required to attain near-normal absorption of levothyroxine. Even though the newer bile acid sequestrant, colesevelam hydrochloride, has a higher binding affinity to bile acids over other molecules, it was recently shown by Weitzman et al. to affect the absorption of levothyroxine in six healthy patients.25 On two separate occasions, 6-h pharmacokinetic studies were conducted with ingestion of 1 mg levothyroxine alone or with the addition of colesevelam 3.75 g. Co-administration with colesevelam significantly blunted the rise in serum T4 levels, as well as the AUC of T4 absorption. The authors showed that co-administration reduced absorption of levothyroxine by 96%. This is significantly larger than the 22% reduction reported in the manufacturer’s prescribing information with co-administration of levothyroxine 0.6 mg and colesevelam 3.75 g.26 The manufacturer recommends an interval of 4 h between ingestion of levothyroxine and colesevelam, although the optimal period has not been confirmed in separate studies.
Table 2 I 131-Thyroxine absorption studies in 2 patients with and without cholestyramine. Treatment
Source of sample radioactivity % of Administered Dose Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Cumulative
Pt 1 Control
Stool Urine Total body Cholestyramine resin Stool Urine Total body
Pt 2 Control
Stool Urine Total body Cholestyramine resin Stool Urine Total body
Adapted from Northcutt et al. JAMA 1969;208:1859.
0.24 8.86 100.0 0.02 3.00 100.0
0.28 8.66 75.6 0.02 1.41 93.4
16.43 2.70 63.5 1.73 1.22 90.5
8.66 2.18 . 39.30 1.18 51.1
12.00 2.15 39.6 36.80 0.94 .
3.34 2.02 30.2 4.43 0.73 15.6
0.59 1.68 26.4 1.50 0.87 13.5
0.27 7.49 100.0 0.00 2.38 100.0
12.03 10.92 . 0.00 2.78 93.8
20.58 8.83 . 3.40 2.30 71.1
7.12 5.03 31.0 66.85 1.82 .
0.00 3.11 24.4 0.00 1.08 .
5.62 2.03 21.0 11.57 0.64 8.9
1.79 1.55 19.1 1.09 0.47 8.2
41.54 28.25 83.80 9.35 47.41 38.96 82.91 11.47
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Ferrous sulphate Campbell et al. conducted the first trial to evaluate the effect of concurrent ingestion of ferrous sulphate and levothyroxine.27 In 14 patients with stable, treated primary hypothyroidism, 300 mg of ferrous sulphate was ingested simultaneously with their daily dose of levothyroxine for 12 weeks. Mean serum TSH increased from 1.6 0.4 to 5.4 2.8 mU L1 (p < 0.01). No significant decrease occurred in serum free T4 index (50.3 1.8–47.6 2.6 pmol L1; p ¼ 0.12) or total serum T4 (135 22–127 29 nmol L1; p ¼ 0.16). The authors explained that this discrepancy in thyroid hormone levels might reflect endogenous production stimulated by elevated TSH levels in patients who had residual thyroid function. In vitro spectrophotometric experiments indicated binding of Fe3þ to three T4 molecules to form an insoluble complex, which may be the basis of the in vivo interaction. Shakir et al. also noted this interaction in a pregnant 29-year-old woman with primary hypothyroidism who was given iron supplementation at various points during the peripartum period.28 The patient was instructed to separate the ingestion of levothyroxine and ferrous sulphate by at least 4–6 h. Nevertheless, on two separate periods of iron supplementation, the patient developed elevated serum TSH and low thyroxine levels, requiring increased doses of levothyroxine. Though pregnancy is known to be associated with increased thyroid hormone requirements, this was unlikely to be the cause in this patient’s worsening hypothyroidism since one of these instances occurred in the postpartum period. Those individuals most at risk for this interaction include elderly patients, menstruating women and pregnant women, and the authors recommended additional monitoring if concurrent therapy with levothyroxine and ferrous sulphate is planned in these patients. Sucralfate Sucralfate – an aluminium salt of sucrose sulphate – has been used to treat duodenal ulcer disease, gastritis and reflux disease. Being non-absorbable, it has been suggested to interfere with the intraluminal transport of thyroid hormone. Sherman et al. reported a case of resistant hypothyroidism in a 46-year-old woman whose elevated levels of TSH correlated with sucralfate therapy and reversed when sucralfate was discontinued.29 Using a modified protocol of Greenstadt’s non-isotopic method, the authors also conducted a pharmacokinetic study in which five healthy volunteers ingested: (1) levothyroxine 1000 mg only as control; (2) sucralfate 1 g every 6 h for four doses with the final dose coadministered with 1000 mg of levothyroxine and (3) sucralfate 2 g every 12 h with the administration of levothyroxine 8 h following the last dose. Concurrent ingestion of the two medications reduced the mean peak T4 absorption to 225 mg, compared to 796 mg with ingestion of levothyroxine alone (p ¼ 0.0029). Peak absorption was also delayed to 300 min, compared to 180 min without sucralfate. When the medications were separated by 8 h, peak hormone absorption and time to the peak were not significantly different from control values. These clinical observations may be explained by in vitro binding of thyroxine by sucralfate, which was demonstrated in binding studies conducted by Havrankova and Lahaie.30 This interaction was significant, as it persisted despite adding large amounts of levothyroxine to compete with binding. These results were not reproduced in a blinded crossover study of nine patients with primary hypothyroidism on replacement therapy.31 Subjects were randomised to take levothyroxine with placebo or sucralfate (1 g every 6 h). The first study medication was administered for 4 weeks, discontinued for 2 weeks and then the second medication was given for another 4 weeks. Treatment with sucralfate slightly reduced serum T4 index from 9.0 0.3 mg dL1 to 7.4 0.8 mg dL1 (p ¼ 0.038) but did not significantly increase serum TSH values. Though the authors acknowledged that monitoring is needed because of the reduction in serum free T4 index, they concluded that sucralfate probably does not significantly interact with levothyroxine. Aluminium-containing antacids Similar to sucralfate, aluminium-containing antacids also limit the absorbability of levothyroxine through the intestinal mucosa. In additional, the cationic aluminium may complex with levothyroxine, thus reducing its bioavailability. Sperber and Liel first noted this interaction in a patient with
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hypothyroidism who developed elevated levels of TSH during treatment with an aluminium-containing antacid.32 These levels normalised 2 weeks following the cessation of the antacid therapy and increased with subsequent re-challenge. In a separate study by the same group, TSH levels were followed up in five patients with stable, treated hypothyroidism who were given aluminium hydroxide for 2–4 weeks.33 The study medication was a combination of simethicone, magnesium hydroxide and aluminium hydroxide; study subjects received a total of 2256 mg of aluminium hydroxide daily in four divided doses. Mean levels of serum TSH increased significantly from pre-treatment levels of 2.6 0.8 mU L1 to 7.2 1.3 mU L1 (p ¼ 0.003). In vitro incubations of radiolabelled 125I-thyroxine and antacid preparations containing aluminium hydroxide showed a direct relationship between the percentage of T4 adsorbed and the concentration of aluminium hydroxide. This adsorption occurred even with small amounts of aluminium hydroxide that were 1/100 of a typical daily dose. Of note, the authors commented that magnesium hydroxide did not significantly adsorb levothyroxine. Mersebach et al. reported similar observations in two patients, with the second case involving magnesium oxide.34 Their in vitro binding studies also demonstrated dose-related adsorption of levothyroxine with aluminium hydroxide but not with magnesium oxide. Calcium carbonate Calcium carbonate is another commonly used medication that has been shown to affect the bioavailability of levothyroxine. Schneyer first reported elevations in serum TSH levels in three women on suppressive therapy for thyroid cancer who ingested calcium carbonate simultaneously.35 Interestingly, one patient did not have these changes with a different form of calcium carbonate, and the authors suggested that the interaction may be limited to certain calcium compounds. However, this finding has not been reported elsewhere. Singh et al. conducted a prospective cohort study to evaluate this interaction with calcium in 20 hypothyroid patients on stable doses of levothyroxine.36 Subjects ingested their usual replacement doses with 1200 mg of calcium (as calcium carbonate) for 3 months. Patients were followed during the study period and 2 months after discontinuation of calcium carbonate (Fig. 1). With co-administration of calcium, mean serum TSH levels increased significantly from 1.6 mIU L1 to 2.7 mIU L1, then decreased to 1.4 mIU L1 after discontinuation (p ¼ 0.008). Mean values of free and total T4 decreased with co-administration and reverted back to the baseline with discontinuation of calcium carbonate (Table 3). In four patients, the serum TSH rose above the normal range when levothyroxine was ingested with calcium carbonate. The authors also conducted in vitro binding studies and demonstrated significant adsorption of levothyroxine to calcium in an acidic pH of 2.0. To determine the acute effect of calcium on levothyroxine absorption, Singh et al. conducted a pharmacokinetic study in seven healthy volunteers who were randomised to 2 g of calcium or placebo.37 Subjects ingested 1 mg of levothyroxine simultaneously with the first study medication, then a month later with the second medication. Serum free T4, total T4, total T3 and TSH levels were monitored for 24 h, and the levels of absorption were calculated using the non-isotopic method. Maximum total T4 absorption peaked at 837 mg with levothyroxine alone but decreased to 579 mg with the co-administration of calcium. Time to peak total T4 absorption doubled with co-administration. The total T4 absorption over 6 h, calculated as the AUC, was greater with levothyroxine alone than with levothyroxine plus calcium (p ¼ 0.02) (Fig. 2). These experiments show that calcium carbonate acutely interferes with the bioavailability of levothyroxine. Phosphate binders Phosphate binders may also impair the absorption of levothyroxine. Calcium carbonate is also used as a phosphate binder in chronic renal failure and blocks the absorption of levothyroxine. A calciumfree cationic binder, sevelamer hydrochloride, has been suggested to interfere as well. In a study of 67 haemodialysis patients on concurrent levothyroxine and phosphate binder therapy (calcium carbonate, calcium acetate or sevelamer), TSH levels and levothyroxine doses were analysed according to the type and amount of treatment.38 Of the three agents, the use of sevelamer was associated with higher doses of levothyroxine (p ¼ 0.049) and significant dose increases after 6 months of therapy. The
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Fig. 1. Thyrotropin (TSH) levels in 20 patients with hypothyroidism. Reproduced with permission from Singh N et al. JAMA 2000;283:2824.
use of calcium carbonate and sevelamer were both associated with elevated mean levels of TSH, which were higher than those with calcium acetate. These levels also increased over time, despite increasing doses of levothyroxine in patients on sevelamer. John-Kalarickal et al. conducted a pharmacokinetic trial to study the acute effect of sevelamer on levothyroxine absorption in seven healthy patients.39 Subjects were first evaluated with 1 mg of levothyroxine alone, then with concurrent ingestion of 800 mg of sevelamer at least 2 weeks later. For each trial, serum T4 and TSH levels were serially monitored over 6 h after ingestion. Calculated AUC was significantly reduced from 2176 195 mg-min dL1 for levothyroxine alone to 1178 281 mg-min dL1 with levothyroxine plus sevelamer (p < 0.05). The rise in serum T4 was also blunted in subjects with sevelamer. These findings show that sevelamer acutely decreases the bioavailability of levothyroxine and contributes to resistant hypothyroidism.
Table 3 Effect of the concomitant administration of levothyroxine and calcium on thyroid function tests in 20 patients with hypothyroidism.a
Free T4, ng/dL TSH, mIU/L Total T4, mg/dL Total T3, mg/dL
Baseline: Levothyroxine
Visit 1: Levothyroxine þ Calcium
Visit 2: Levothyroxine þ Calcium
Final Visit: Levothyroxine
Overall Pb
1.34 0.04c 1.60 0.22c 9.21 0.46d 141.50 4.43
1.23 0.04 2.88 0.41 8.64 0.43 134.40 6.59
1.22 0.05 2.71 0.43 8.55 0.41 142.10 6.54
1.41 0.06c 1.44 0.21c 9.31 0.39d 142.2 7.03
<.001 .008 .03 .82
Reproduced with permission from Singh N et al. JAMA 2000;283:2824. a All values are expressed as mean SE. T4 indicates thyroxine; TSH, thyrotropin; and T3, triiodothyronine. To convert free T4 from ng/dL to pmol/L, multiply by 12.87; to convert total T4 from mg/dL to nmol/L, multiply by 12.87; and to convert total T3 from ng/dL, to nmol/L, multiply by 0.0154. b Overall P value from F test of repeated-measures multivariate analysis of variance (MANOVA) analyses that compare the means of the baseline levothyroxine group, the levothyroxine group plus calcium groups, and the final levothyroxine group. c P < .01 for between group comparison of levothyroxine plus calcium group (visit 1 þ visit 2) from a repeated measures MANOVA test. d P < 0.5 for between group comparison of levothyroxine plus calcium group (visit 1 þ visit 2) from a repeated measures MANOVA test.
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Fig. 2. Calculated levothyroxine (LT4) absorption after ingestion of LT4 1 mg or LT4 1 mg plus calcium 2 g. Each time point represents mean standard error of the mean (SEM) of seven subjects. Reproduced from Singh N et al. Thyroid 2001;11:968.
In the recent study by Weitzman et al., lanthanum carbonate – a new phosphate binder – was also shown to interfere with the absorption of levothyroxine.25 In an acidic environment, the drug dissociates and releases lanthanum ions that complex with dietary phosphate. In six healthy volunteers, pharmacokinetic studies were conducted with ingestion of 1 mg levothyroxine alone or with addition of 500 mg lanthanum carbonate. Co-administration with lanthanum carbonate significantly blunted the rise in serum T4 levels, as well as the AUC of T4 absorption. Raloxifene Separate from its effects on thyroxine-binding globulin, selective oestrogen receptor modulators (SERMs) may also influence the absorption of levothyroxine. Several case reports have described elevations in TSH levels with raloxifene.40,41 Siraj et al. first reported a possible interaction in a 79-yearold woman with a history of subtotal thyroidectomy for benign nodules who had been stable being maintained on levothyroxine 150 mg daily. Within 2–3 months of starting raloxifene, which she took with levothyroxine before breakfast, she developed symptoms of hypothyroidism with an elevated serum TSH of 14.5 mU ml1. Dose escalation of levothyroxine failed to normalise TSH levels. For two periods of 6–8-weeks duration, the patient separated ingestion of these two medications by 12 h, resulting in improvements in TSH levels. The authors also conducted 6-h absorption tests on levothyroxine (1 mg), with and without raloxifene (60 mg). The experiments were performed on two different occasions separated by 4 weeks. At all time points measured, serum levels of T4 were lower with levothyroxine plus raloxifene. Of note, although the patient had no overt symptoms of malabsorption, her history included pernicious anaemia that was treated with vitamin B12 replacement. Because she had been stable upon treatment with levothyroxine for several years, the authors felt that pernicious anaemia was an unlikely cause of her refractory hypothyroidism. Proton-pump inhibitors Given that gastric acidity appears to be important in absorption of levothyroxine, medications that suppress gastric acid secretion may interfere as well. Several reports have been published on the role of proton-pump inhibitors, but the findings have varied. In the study by Centanni et al. of patients with multinodular goitre on suppressive therapy, a subgroup of 10 patients with gastro-oesophageal reflux was treated with omeprazole.22 In all of these patients, initiation of proton-pump inhibitor therapy resulted in a variable increase in TSH levels (p ¼ 0.002) that required a 37% increase in the dose of levothyroxine to suppress TSH (p ¼ 0.001). Similar findings were reported by Sachmechi et al. in a retrospective analysis of lansoprazole use in 37 patients with primary hypothyroidism on levothyroxine therapy when proton-pump-inhibitor therapy was initiated.42 Comparison of TSH levels before and at least 2 months following commencement of lansoprazole treatment showed a mean increase of 0.69 1.9 mIU mL1 that was statistically significant (p ¼ 0.035). Nineteen percent of the patients had TSH levels >5 mIU mL1 after starting lansoprazole and required dosage increases in levothyroxine.
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Table 4 Pharmacokinetic properties of levothyroxine without and after treatment with pantoprazole.
Gastrin (pg/ml) AUC T4 (mmol sec/l) AUC FT4E (sec)
Baseline
On pantoprazole
Relative difference
p value
50.1 5.9a 1.09 0.06a 28829.9 1252.0a
70.8 10.9a 0.96 0.10a 25944.1 1791.0a
41.3% 12.4% 10.0%
0.001b 0.60c 0.09c
Adapted from Dietrich et al. Horm Metab Res 2006;38:59. a Mean value SEM. b t-test for paired samples. c Wilcoxon signed rank test.
These observations were not reproduced in studies investigating the acute effects of proton-pumpinhibitor therapy. In an open crossover study by Dietrich et al., pharmacokinetic trials were performed in 20 healthy volunteers under two settings: (1) ingestion of levothyroxine alone (4 mg kg1) and (2) 1 week of levothyroxine ingestion with pantoprazole (40 mg daily).43 Serum TSH, T4 and free thyroxine equivalents (FT4E) were serially monitored over a 10-h period, and the total absorption levels were calculated as the AUC. The suppression of gastric acidity by pantoprazole was confirmed by elevated gastrin levels. Contrary to the author’s expectations, no significant differences in AUCs for serum T4 and FT4E were observed with pantoprazole (Table 4). In a similar trial, Ananthakrishnan et al. performed 8h absorption tests in 30 healthy patients who ingested esomeprazole (40 mg daily) simultaneously with levothyroxine (600 mg daily) for 1 week.44 In comparing values before and after esomeprazole therapy, no significant changes were noted in peak T4 levels or mean AUC for T4 absorption. Of note, famotidine was also included in this study and no significant differences in absorption were observed. The conflicting findings regarding proton-pump inhibitor therapy may be due to differences in length of therapy. In the studies of Centanni and Sachmechi, patients were treated with proton-pump inhibitors for up to 6 months, but the other studies administered it for only 1 week, which may have been too brief to detect changes in enterohepatic metabolism, clearance and absorption of levothyroxine. Orlistat Licensed as an anti-obesity drug, orlistat inhibits gastric and pancreatic lipases to reduce fat. It has already been reported to interfere with absorption of several drugs, including warfarin, amiodarone and cyclosporine. Possible interference with levothyroxine absorption was reported by Madhava and Hardley in a patient after thyroidectomy for papillary cancer.45 Her serum TSH had been stably suppressed on 250 mg of levothyroxine daily, but within 2 weeks of starting orlistat, the patient experienced symptoms of fatigue, lethargy and cold intolerance. Blood tests confirmed the diagnosis of hypothyroidism with an elevated serum TSH of 74 mU L1. Within 2 weeks of discontinuing orlistat and increasing levothyroxine to 300 mg daily, her symptoms improved and the serum TSH became adequately suppressed. Although orlistat may have reduced levothyroxine absorption, the patient’s levothyroxine was also increased to 300 mg at the same time as she discontinued orlistat, which could also contribute to TSH suppression. To our knowledge, no similar reports have been published and further research will be needed to confirm this observation. Conclusion Various endogenous and exogenous factors can change the absorption kinetics of levothyroxine. The timing of food intake in relation to levothyroxine administration is important, and it is recommended to delay food by at least 60 min following ingestion. Fibre and espresso coffee have been shown to interfere, indicating that the content of dietary intake is also important. Disorders of malabsorption or impaired gastric acidity can reduce the absorption of levothyroxine, and resistant hypothyroidism may be the only presenting symptom in some of these disorders. Medications that interfere with intestinal transport, including bile acid sequestrants, sucralfate, aluminium-containing antacids and phosphate binders, have also been shown to interfere with levothyroxine absorption. This
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phenomenon will likely become more prevalent, as commonly used medications such as ferrous sulphate, calcium carbonate, raloxifene and proton-pump inhibitors have been identified as interfering agents. Further research is needed on sucralfate and proton-pump inhibitors because of inconsistent results, as well as raloxifene and orlistat, which have limited reports. These factors need to be considered in patients with persistently elevated levels of TSH. In patients whose medications include levothyroxine and known interfering agents, administration should be separated by at least 4–6 h. Practice points Hypothyroidism that persists despite escalation of levothyroxine dose should prompt investigation into underlying gastrointestinal malabsorption or medication interference. Patients should be recommended to ingest levothyroxine on an empty stomach, at least 60 min prior to any food intake. For medications such as colesevelam, it is recommended to separate its administration from that of levothyroxine by at least 4 h. Clinicians should be aware that commonly used medications, such as ferrous sulphate, aluminium-containing antacids, raloxifene, bile acid sequestrants, calcium carbonate and proton-pump inhibitors, can interfere with the absorption of levothyroxine.
Research agenda Other medications that affect intestinal transport may also interfere with absorption of levothyroxine. Raloxifene and orlistat have been reported to affect levothyroxine bioavailability, but additional case-controlled studies and in vitro pharmacokinetic trials are needed to confirm these observations. Though it is currently recommended to separate levothyroxine administration from ingestion of interfering drugs by 4–6 h, additional pharmacokinetic trials are needed to determine optimal intervals for different medications.
Conflict of interest The authors have no conflicts of interest to declare.
References *1. Benvenga S, Bartolone L, Squadrito S et al. Delayed intestinal absorption of levothyroxine. Thyroid 1995; 5: 249–253. 2. Azizi F, Belur R & Albano J. Malabsorption of thyroid hormones after jejunoileal bypass for obesity. Annals of Internal Medicine 1979; 90: 941–942. 3. Topliss DJ, Wright JA & Volpe´ R. Increased requirement for thyroid hormone after a jejunoileal bypass operation. Canadian Medical Association Journal 1980; 123: 765–766. 4. Bevan JS & Munro JF. Thyroxine malabsorption following intestinal bypass surgery. International Journal of Obesity 1986; 10: 245–246. 5. Stone E, Leiter LA, Lambert JR et al. L-thyroxine absorption in patients with short bowel. The Journal of Clinical Endocrinology and Metabolism 1984; 59: 139–141. 6. Vanderschueren-Lodeweyckx M, Eggermont E, Cornette C et al. Decreased serum thyroid hormone levels and increased TSH response to TRH in infants with celiac disease. Clinical Endocrinology (Oxford) 1977; 6: 361–367. 7. Csako G, McGriff NJ, Rotman-Pikielny P et al. Exaggerated levothyroxine malabsorption due to calcium carbonate supplementation in gastrointestinal disorders. Annals of Pharmacotherapy 2001; 35: 1578–1583. 8. Hays MT. Absorption of oral thyroxine in man. The Journal of Clinical Endocrinology and Metabolism 1968; 28: 749–756. 9. Read DG, Hays MT & Hershman JT. Absorption of oral thyroxine in hypothyroid and normal man. The Journal of Clinical Endocrinology and Metabolism 1970; 30: 798–799. 10. Hasselstro¨m K, Siersbaek-Nielsen K, Lumholtz IB et al. The bioavailability thyroxine and 3,5,30 -triiodothyronine in normal subjects and in hyper- and hypothyroid patients. Acta Endocrinologica (Copenh) 1985; 110: 483–486. *11. Greenstadt MA, Spencer CA, Lum SMC et al. Non-isotopic method for determination of oral thyroxine absorption. In Gueriguian JL, Bransome ED & Outschoorn AS (eds.). Hormone drugs: proceedings of the FDA-USP workshop on drug and
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Altered intestinal absorption of L-thyroxine caused by coffee. Thyroid 2008; 18: 293–301. D’Este`ve-Bonetti L, Bennet AP, Malet D et al. Gluten-induced enteropathy (coeliac disease) revealed by resistance to treatment with levothyroxine and alfacalcidol in a sixty-eight-year-old patient: a case report. Thyroid 2002; 12: 633–636. Silva CM & Souza MV. Autoimmune hypothyroidism nonresponsive to high doses of levothyroxine and severe hypocalcemia. Arquivos Brasileiros de Endocrinologia e Metabologia 2005; 49: 599–603. Caputo M, Brizzolara R, Schiavo M et al. Occurrence of overt celiac disease in the elderly following total thyroidectomy. Journal of Endocrinological Investigation 2006; 29: 831–833. McDermott JH, Coss A & Walsh CH. Celiac disease presenting as resistant hypothyroidism. Thyroid 2005; 15: 386–388. ˜ oz-Torres M, Varsavsky M & Alonso G. Lactose intolerance revealed by severe resistance to treatment with levoMun thyroxine. Thyroid 2006; 16: 1171–1173. Centanni M, Gargano L, Canettieri G et al. Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. The New England Journal of Medicine 2006; 354: 1787–1795. Phillips WA, Schultz JR & Stafford WW. Effects of colestipol hydrochloride on drug absorption in the rat. I. Aspirin, L-thyroxine, phenobarbital, cortisone, and sulfadiazine. Journal of Pharmaceutical Sciences 1974; 63: 1097–1101. Northcutt RC, Stiel JN, Hollifield JW et al. The influence of cholestyramine on thyroxine absorption. The Journal of the American Medical Association 1969; 208: 1857–1861. Weitzman SP, Ginsburg KC & Carlson HE. Colesevelam hydrochloride and lanthanum carbonate interfere with the absorption of levothyroxine. Thyroid 2009; 19: 77–79. Daiichi Sankyo, Inc. Welchol(r) prescribing information. Available from: www. Welchol.com/pdf/Welchol_PI.pdf. Campbell RC, Hasinoff BB, Stalts H et al. Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism. Annals of Internal Medicine 1992; 117: 1010–1013. Shakir KM, Chute JP, Aprill BS et al. Ferrous sulfate-induced increase in requirement for thyroxine in a patient with primary hypothyroidism. Southern Medical Journal 1997; 90: 637–639. Sherman SI, Tielens ET & Ladenson PW. Sucralfate causes malabsorption of L-thyroxine. American Journal of Medicine 1994; 90: 531–535. Havrankova J & Lahaie R. Levothyroxine binding by sucralfate. Annals of Internal Medicine 1992; 117: 445–446. Campbell JA, Schmidt BA & Bantle JP. Sucralfate and the absorption of L-thyroxine. Annals of Internal Medicine 1994; 121: 152. Sperber AD & Liel Y. Evidence for interference with the intestinal absorption of levothyroxine sodium by aluminum hydroxide. Archives of Internal Medicine 1992; 152: 183–184. Liel Y, Sperber AD & Shany S. Nonspecific intestinal adsorption of levothyroxine by aluminum hydroxide. American Journal of Medicine 1994; 97: 363–365. Mersebach H, Rasmussen AK, Kirkegaard L et al. Intestinal adsorption of levothyroxine by antacids and laxatives: case stories and in vitro experiments. Pharmacology & Toxicology 1999; 84: 107–109. Schneyer CR. Calcium carbonate and reduction of levothyroxine efficacy [Letter]. The Journal of the American Medical Association 1998; 279: 750. Singh N, Singh PN & Hershman JM. Effect of calcium carbonate on the absorption of levothyroxine. The Journal of the American Medical Association 2000; 283: 2822–2825. Singh N, Weisler SL & Hershman JM. The acute effect of calcium carbonate on the intestinal absorption of levothyroxine. Thyroid 2001; 11: 967–971. Diskin CJ, Stokes TJ, Dansby LM et al. Effect of phosphate binders upon TSH and L-thyroxine dose in patients on thyroid replacement. International Urology and Nephrology 2007; 39: 599–602. John-Kalarickal J, Pearlman G & Carlson HE. New medications which decrease levothyroxine absorption. Thyroid 2007; 17: 763–765. Siraj ES, Gupta MK & Reddy SS. Raloxifene causing malabsorption of levothyroxine. Archives of Internal Medicine 2003; 163: 1367–1370. Garwood CL, Van Schepen KA, McDonough RP et al. Increased thyroid-stimulating hormone levels associated with concomitant administration of levothyroxine and raloxifene. Pharmacotherapy 2006; 26: 881–885. Sachmechi I, Reich DM, Aninyei M et al. Effect of proton pump inhibitors on serum thyroid-stimulating hormone level in euthyroid patients treated with levothyroxine for hypothyroidism. Endocrine Practice 2007; 13: 345–349. Dietrich JW, Gieselbrecht K, Holl RW et al. Absorption kinetics of levothyroxine is not altered by proton-pump inhibitor therapy. Hormone and Metabolic Research 2006; 38: 57–59. Ananthakrishnan S, Braverman LE, Levin RM et al. The effect of famotidine, esomeprazole, and ezetimibe on levothyroxine absorption. Thyroid 2008; 18: 493–498. Madhava K & Hartley A. Hypothyroidism in thyroid carcinoma follow-up: orlistat may inhibit the absorption of thyroxine [Letter]. 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Conditions and drugs interfering with thyroxine absorption Llanyee Liwanpo, MD, Doctor *, Jerome M. Hershman, MD, Professor Department of Endocrinology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA
Keywords: thyroxine absorption interfering drugs levothyroxine malabsorption hypothyroidism
Food, dietary fibre and espresso coffee interfere with the absorption of levothyroxine. Malabsorptive disorders reported to affect the absorption of levothyroxine include coeliac disease, inflammatory bowel disease, lactose intolerance as well as Helicobacter pylori (H. pylori) infection and atrophic gastritis. Many commonly used drugs, such as bile acid sequestrants, ferrous sulphate, sucralfate, calcium carbonate, aluminium-containing antacids, phosphate binders, raloxifene and proton-pump inhibitors, have also been shown to interfere with the absorption of levothyroxine. Ó 2009 Elsevier Ltd. All rights reserved.
Following its introduction as a pharmaceutical agent, levothyroxine sodium has been fundamental in the treatment of various thyroid disorders, including primary hypothyroidism, nodular goitres and thyroid cancer. An understanding of its absorption was first derived from seminal studies conducted in the late 1960s. During the next two decades, various gastrointestinal conditions were identified that resulted in the malabsorption of levothyroxine. In the past several years, a number of medications that interfere with levothyroxine absorption have been identified. Despite the long history of levothyroxine use, understanding of its absorption and metabolism is still incomplete. In this article, we review gastrointestinal conditions and pharmacological agents that have been reported to interfere with the absorption of levothyroxine (Table 1).
Absorption of levothyroxine Approximately 62–82% of levothyroxine is absorbed after oral administration. This absorption occurs within the first 3 h of ingestion and is localised mainly in the jejunum and ileum.1 The absorption of levothyroxine is maximal when the stomach is empty, reflecting the importance of
* Corresponding author. VA Greater Los Angeles Healthcare System, Endocrinology 111D, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA. Tel.: þ1 310 478 3711x41362; Fax: þ1 310 268 4879. E-mail address: [email protected] (L. Liwanpo). 1521-690X/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2009.06.006
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Table 1 Conditions and medications that may affect absorption of levothyroxine. Foods
Medical conditions
Drugs
Food intake Dietary fiber Espresso coffee
Jejunoileal bypass or other bowel resection Inflammatory bowel disease Celiac disease Lactose intolerance H. pylori infection Chronic gastritis of the stomach body
Cholestyramine Colesevelam Ferrous sulfate Sucralfate Calcium carbonate Aluminum hydroxide Sevelamer hydrochloride Lanthanum carbonate Raloxifene Proton pump inhibitors Orlistat
gastric acidity in this process. Patients with jejunoileal bypass surgery or other bowel resection have been reported to require higher doses of levothyroxine following surgery.2–4 Stone et al. noted reduced peak serum levels of thyroxine in patients with shortened bowel, though no consistent relationship was found between absorption and bowel length.5 Other factors, such as patient age, adherence to therapy, dietary habits, absorption kinetics and pre-existing gastrointestinal malabsorption, can also influence its absorption. Severe malabsorption due to various causes, including coeliac sprue and inflammatory bowel disease, can affect absorption of levothyroxine.6,7 Various methods have been developed to examine the mechanism of thyroxine absorption. Earlier methods used levothyroxine that was labelled with radioiodine. Hays first developed the doubleisotope equilibrium technique which involved simultaneous administration of oral 125I-thyroxine and intravenous 131I-thyroxine.8 The intestinal absorption of thyroxine was calculated from the ratio of serum 125I to 131I, and the mean absorption of thyroxine in euthyroid individuals was calculated to be 71%. By this method, it was found that hypothyroidism did not alter thyroxine absorption, which was estimated at 75% of the dose, compared with 68% in normal controls.9 Applying the same protocol with radiolabelled thyroxine, Hasselstrom et al. estimated the bioavailability of thyroxine more accurately using the ratio of the area under the curve (AUC) of the disappearance of the tracers.10 Eventually, a non-isotopic method was developed by Greenstadt et al. to determine oral thyroxine (T4) absorption.11 With the ingestion of oral liquid levothyroxine, the authors demonstrated a close correlation between the incremental rise in serum total T4 (DTT4) and values obtained from the standard doubleisotope method. Because enteral T4 distributes largely to the vascular and splanchnic organs in the first few hours after ingestion, serum DTT4 values should be proportional to the amount absorbed intestinally during the first 6 h following ingestion.9 To estimate the amount of T4 absorbed, DTT4 is multiplied by an individual’s estimated volume of distribution – which is calculated by a linear regression equation derived from the data of Nicoloff et al.12 Food and dietary fibre Absorption of levothyroxine has been shown to be influenced both by the timing of food intake and by certain foods. This was first reported by Wenzel et al. in their study comprising 37 patients.13 Subjects ingested either 100 mg or 3 mg of levothyroxine under two settings: (1) fasting, or (2) immediately before the consumption of two buttered rolls and a boiled egg. Using the double-isotope method developed by Hays, the authors showed that absorption was significantly better in the fasting state than with simultaneous food intake in all study groups. Benvenga et al. reported similar findings in four patients with nodular goitre, two of whom had Hashimoto’s thyroiditis.1 In these patients, ingesting levothyroxine 15 min prior to breakfast failed to suppress or normalise thyroid-stimulating hormone (TSH) levels. Compared to euthyroid and hypothyroid controls, absorption studies using 1000 mg of levothyroxine demonstrated delayed time to peak T4 absorption, reduced maximal absorption and decreased maximal increment in T4 absorption. In
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three of these patients, the first part of the T4 absorption curve was shifted to the right, suggesting an impairment in the early phase of the absorption. After a month of separating breakfast and levothyroxine ingestion by at least 60 min, the TSH levels in these patients became adequately suppressed. These findings form the basis of current recommendations to ingest oral levothyroxine 60 min prior to food intake. Dietary fibre also affects the bioavailability of levothyroxine, as noted by Liel et al. in patients requiring disproportionately high doses of levothyroxine.14 With fibre-enriched diets, 12 of the 13 patients exhibited elevated TSH levels or required higher doses of levothyroxine. However, when fibre was removed from the diet, TSH levels improved significantly. These patients obtained fibre through enriched bread, suggesting that soluble fibre was the culprit. The authors also performed in vitro experiments demonstrating a dose-dependent non-specific adsorption of T4 by wheat bran. These studies show that dietary fibre can reduce the bioavailability of T4. The association between dietary fibre and levothyroxine malabsorption has yet to be reproduced with fibre supplements, as Chiu and Sherman showed no interference by calcium polycarbophil or psyllium in healthy volunteers.15 Recently, Benvenga et al. suggested that espresso coffee may also interfere with the absorption of levothyroxine.16 In eight patients referred for management of inappropriately high or non-suppressed levels of TSH, the authors demonstrated elevated values that corresponded with concurrent coffee intake. When coffee intake was separated from levothyroxine, TSH levels improved. Absorption testing was performed in six of these cases and nine other healthy volunteers, in which 200 mg of levothyroxine was ingested with: (1) espresso coffee only; (2) water only or (3) water and then coffee 60 min later. Analysis of four indices, the average incremental rise of serum T4 (AIRST4), AUC, maximal incremental rise in T4 (MIRST4) and time to maximal incremental rise (TMIRST4), showed that the blunted effect occurred only with co-administration of levothyroxine and coffee. Pooled data comparing results with and without coffee revealed a significant 1.6-fold reduction in AIRST4 (p < 0.001), 1.6-fold decrease in AUC (p < 0.05), 1.4-fold reduction in MIRST4 (p < 0.05) and a prolonged TMIRST4 with concurrent ingestion of coffee. In healthy volunteers, this effect was also demonstrated but was smaller. When levothyroxine and coffee ingestion were separated by 60 min, no significant difference was seen in the four parameters in both the study and control groups. In vitro binding studies were also conducted with mixtures of coffee and known amounts of levothyroxine solution. Compared to saline, coffee was capable of sequestering T4, although the effect was lesser than that of other interfering agents such as bran fibre, sucralfate and aluminium hydroxide. No other studies have been published on this interaction, but this report strongly suggests that espresso coffee may decrease the efficacy of levothyroxine through sequestration in the intestine. Gastrointestinal disorders Both malabsorptive disorders and conditions that impair gastric acidity can affect the bioavailability of levothyroxine. Early reports described elevated serum TSH levels in patients with coeliac sprue and inflammatory bowel disease despite thyroxine doses that had previously normalised serum levels. These findings suggest that pre-existing malabsorption can reduce the bioavailability of levothyroxine. This association appears to be strongest with coeliac disease. More recently, a study has shown a similar phenomenon in patients with Helicobacter pylori (H. pylori) infection and atrophic gastritis – both of which impair gastric acidity.
Coeliac disease Multiple cases of levothyroxine malabsorption in patients with various manifestations of coeliac disease have been reported. One of the earlier cases, reported by D’Este`ve-Bonetti et al., concerned a 68-year-old post-thyroidectomy patient who showed no TSH response to increasing doses of levothyroxine.17 Her history was significant for persistent hypocalcaemia, chronic diarrhoea, anaemia and hypoalbuminaemia. Gastrointestinal work-up eventually diagnosed coeliac disease. After dietary restrictions were instituted, the patient’s serum TSH improved. Similar cases have been reported of patients with persistent hypothyroidism and occult symptoms of coeliac disease including weight loss,
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electrolyte abnormalities, anaemia and osteopaenia.18,19 In all of these cases, initiation of a gluten-free diet resulted in the reduction of levothyroxine dose requirements. Recently, McDermott et al. reported a case in which resistant hypothyroidism appeared to be the only major manifestation of coeliac disease.20 A 58-year-old woman was referred for symptoms of fatigue and cold intolerance. On presentation, her serum TSH was greater than 100 mU L1 (normal range: 0.6–4.3) and thyroid microsomal antibodies were positive – confirming autoimmune hypothyroidism. Routine blood tests including haemoglobin, electrolytes and albumin were normal, and the patient denied any history of gastrointestinal symptoms. After initiation of treatment with levothyroxine, her symptoms improved, but serum levels of TSH continued to be elevated despite escalating levothyroxine dosage. Work-up for malabsorption eventually diagnosed coeliac disease, which was confirmed on duodenal biopsy. After institution of a gluten-free diet, levothyroxine requirements in this patient decreased markedly. Coeliac disease occurs frequently with autoimmune thyroid disease. Because the symptoms of coeliac disease are often subtle, many authors suggest screening with anti-gliadin antibodies in patients with hypothyroidism who require higher than expected doses of levothyroxine. Lactose intolerance A case of levothyroxine malabsorption in the setting of lactose intolerance has been reported.21 A 55-year-old woman with primary hypothyroidism was referred for persistently elevated levels of TSH. She presented with symptoms of hypothyroidism and reported only mild gastrointestinal symptoms, consisting of sporadic episodes of watery diarrhoea over the past 7–8 years. Across an 8-month period following referral, the patient’s levothyroxine dose was increased up to 900 mg and a trial of triiodothyronine (T3) was also given. Despite these interventions, her TSH level failed to normalise. The patient was hospitalised for diagnostic testing and observation, but despite daily compliance with 300 mg of oral levothyroxine, her serum free T4 levels did not increase. Subsequent testing for malabsorption revealed an abnormal lactose-absorption test, indicating lactose intolerance. Thereafter, the patient was given levothyroxine intravenously, and her free T4 and free T3 levels normalised. With this diagnosis of oligo-symptomatic lactose intolerance, the patient was given a lactose-free formulation of levothyroxine (150 mg daily) and was started on a lactose-restricted diet. At follow-up 3 months later, the patient’s thyroid function tests were within the normal range and her symptoms had resolved. Helicobacter pylori and chronic gastritis Further highlighting the importance of gastric acidity in the absorption of levothyroxine, Centanni et al. demonstrated decreased TSH suppression in patients with H. pylori infection and atrophic gastritis of the body of the stomach.22 In H. pylori infection, bacterial production of urease neutralises gastric pH. In this case-control study, patients with non-toxic multinodular goitre were selected if clinical features of impaired gastric acid secretion were present. Using laboratory and histological testing, 53 patients were diagnosed with H. pylori infection and 60 patients with atrophic gastritis – of whom 31 also had concurrent H. pylori infection. Subjects were treated with thyroxine as suppressive therapy, starting at 50 mg daily and titrating up to maintain a serum TSH level of 0.05–0.20 mU L1. Thyroid function tests and daily dose requirements were followed up for at least 30 months. Compared to the reference group, doses needed to be increased by 22% in patients with H. pylori infection and by 27% in those with atrophic gastritis (p < 0.001). In patients with both H. pylori infection and atrophic gastritis, dosage increases were even more pronounced, up to 34% (p < 0.001). Additional data supporting this association was also obtained from 11 patients who were newly diagnosed with H. pylori infection during the course of the trial. These patients were initially part of the reference group and achieved suppression (median TSH level: 0.11 mU L1) with a median daily dose of 1.56 mg kg1 levothyroxine. With the development of H. pylori infection, all of these patients demonstrated increases in serum TSH level (median level: 1.35 mU L1). Following successful treatment of the infection, serum levels in all patients returned to suppression levels (median: 0.12 mU L1) with a slightly higher median dose of levothyroxine (1.7 mg kg1 per day).
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Medications Several commonly used oral medications have been shown to alter the bioavailability of levothyroxine, many of which interfere by forming an insoluble or non-absorbable complex with levothyroxine.
Bile acid sequestrants Several bile acid sequestrants have been reported to affect the absorption of levothyroxine. This effect was demonstrated with colestipol in rat studies but has not been reproduced in human studies to date.23 Northcutt conducted several experiments with cholestyramine after noting two cases of progressive hypothyroidism associated with cholestyramine treatment.24 In two patients who were on thyroid hormone replacement therapy, absorption tests were conducted by administering I131thyroxine with and without cholestyramine. A scanning-bed whole-body counter was used to determine the amount of 131I-thyroxine retained within the body. Urine and stool samples were collected and analysed for 131I-thyroxine. Treatment with cholestyramine was associated with a twofold increase in total stool radioactivity and decrease in urinary radioactivity, representing decreased intestinal absorption and subsequent loss of I131-thyroxine (Table 2). In vitro binding studies performed at pH 1.0 and 9.0 demonstrated that 50 mg of cholestyramine bound at least 3000 mg of levothyroxine. This interaction was not significantly perturbed by repeated washings or by addition of substances with high affinity for cholestyramine. Using rat intestinal sacs to examine transport of thyroxine, the authors demonstrated that only 2.3% of I131-thyroxine crosses the intestinal wall in the presence of cholestyramine, compared to 74% without cholestyramine. Lastly, in five healthy volunteers, the authors demonstrated that an interval of at least 4–5 h separating thyroxine and cholestyramine ingestion is required to attain near-normal absorption of levothyroxine. Even though the newer bile acid sequestrant, colesevelam hydrochloride, has a higher binding affinity to bile acids over other molecules, it was recently shown by Weitzman et al. to affect the absorption of levothyroxine in six healthy patients.25 On two separate occasions, 6-h pharmacokinetic studies were conducted with ingestion of 1 mg levothyroxine alone or with the addition of colesevelam 3.75 g. Co-administration with colesevelam significantly blunted the rise in serum T4 levels, as well as the AUC of T4 absorption. The authors showed that co-administration reduced absorption of levothyroxine by 96%. This is significantly larger than the 22% reduction reported in the manufacturer’s prescribing information with co-administration of levothyroxine 0.6 mg and colesevelam 3.75 g.26 The manufacturer recommends an interval of 4 h between ingestion of levothyroxine and colesevelam, although the optimal period has not been confirmed in separate studies.
Table 2 I 131-Thyroxine absorption studies in 2 patients with and without cholestyramine. Treatment
Source of sample radioactivity % of Administered Dose Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Cumulative
Pt 1 Control
Stool Urine Total body Cholestyramine resin Stool Urine Total body
Pt 2 Control
Stool Urine Total body Cholestyramine resin Stool Urine Total body
Adapted from Northcutt et al. JAMA 1969;208:1859.
0.24 8.86 100.0 0.02 3.00 100.0
0.28 8.66 75.6 0.02 1.41 93.4
16.43 2.70 63.5 1.73 1.22 90.5
8.66 2.18 . 39.30 1.18 51.1
12.00 2.15 39.6 36.80 0.94 .
3.34 2.02 30.2 4.43 0.73 15.6
0.59 1.68 26.4 1.50 0.87 13.5
0.27 7.49 100.0 0.00 2.38 100.0
12.03 10.92 . 0.00 2.78 93.8
20.58 8.83 . 3.40 2.30 71.1
7.12 5.03 31.0 66.85 1.82 .
0.00 3.11 24.4 0.00 1.08 .
5.62 2.03 21.0 11.57 0.64 8.9
1.79 1.55 19.1 1.09 0.47 8.2
41.54 28.25 83.80 9.35 47.41 38.96 82.91 11.47
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Ferrous sulphate Campbell et al. conducted the first trial to evaluate the effect of concurrent ingestion of ferrous sulphate and levothyroxine.27 In 14 patients with stable, treated primary hypothyroidism, 300 mg of ferrous sulphate was ingested simultaneously with their daily dose of levothyroxine for 12 weeks. Mean serum TSH increased from 1.6 0.4 to 5.4 2.8 mU L1 (p < 0.01). No significant decrease occurred in serum free T4 index (50.3 1.8–47.6 2.6 pmol L1; p ¼ 0.12) or total serum T4 (135 22–127 29 nmol L1; p ¼ 0.16). The authors explained that this discrepancy in thyroid hormone levels might reflect endogenous production stimulated by elevated TSH levels in patients who had residual thyroid function. In vitro spectrophotometric experiments indicated binding of Fe3þ to three T4 molecules to form an insoluble complex, which may be the basis of the in vivo interaction. Shakir et al. also noted this interaction in a pregnant 29-year-old woman with primary hypothyroidism who was given iron supplementation at various points during the peripartum period.28 The patient was instructed to separate the ingestion of levothyroxine and ferrous sulphate by at least 4–6 h. Nevertheless, on two separate periods of iron supplementation, the patient developed elevated serum TSH and low thyroxine levels, requiring increased doses of levothyroxine. Though pregnancy is known to be associated with increased thyroid hormone requirements, this was unlikely to be the cause in this patient’s worsening hypothyroidism since one of these instances occurred in the postpartum period. Those individuals most at risk for this interaction include elderly patients, menstruating women and pregnant women, and the authors recommended additional monitoring if concurrent therapy with levothyroxine and ferrous sulphate is planned in these patients. Sucralfate Sucralfate – an aluminium salt of sucrose sulphate – has been used to treat duodenal ulcer disease, gastritis and reflux disease. Being non-absorbable, it has been suggested to interfere with the intraluminal transport of thyroid hormone. Sherman et al. reported a case of resistant hypothyroidism in a 46-year-old woman whose elevated levels of TSH correlated with sucralfate therapy and reversed when sucralfate was discontinued.29 Using a modified protocol of Greenstadt’s non-isotopic method, the authors also conducted a pharmacokinetic study in which five healthy volunteers ingested: (1) levothyroxine 1000 mg only as control; (2) sucralfate 1 g every 6 h for four doses with the final dose coadministered with 1000 mg of levothyroxine and (3) sucralfate 2 g every 12 h with the administration of levothyroxine 8 h following the last dose. Concurrent ingestion of the two medications reduced the mean peak T4 absorption to 225 mg, compared to 796 mg with ingestion of levothyroxine alone (p ¼ 0.0029). Peak absorption was also delayed to 300 min, compared to 180 min without sucralfate. When the medications were separated by 8 h, peak hormone absorption and time to the peak were not significantly different from control values. These clinical observations may be explained by in vitro binding of thyroxine by sucralfate, which was demonstrated in binding studies conducted by Havrankova and Lahaie.30 This interaction was significant, as it persisted despite adding large amounts of levothyroxine to compete with binding. These results were not reproduced in a blinded crossover study of nine patients with primary hypothyroidism on replacement therapy.31 Subjects were randomised to take levothyroxine with placebo or sucralfate (1 g every 6 h). The first study medication was administered for 4 weeks, discontinued for 2 weeks and then the second medication was given for another 4 weeks. Treatment with sucralfate slightly reduced serum T4 index from 9.0 0.3 mg dL1 to 7.4 0.8 mg dL1 (p ¼ 0.038) but did not significantly increase serum TSH values. Though the authors acknowledged that monitoring is needed because of the reduction in serum free T4 index, they concluded that sucralfate probably does not significantly interact with levothyroxine. Aluminium-containing antacids Similar to sucralfate, aluminium-containing antacids also limit the absorbability of levothyroxine through the intestinal mucosa. In additional, the cationic aluminium may complex with levothyroxine, thus reducing its bioavailability. Sperber and Liel first noted this interaction in a patient with
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hypothyroidism who developed elevated levels of TSH during treatment with an aluminium-containing antacid.32 These levels normalised 2 weeks following the cessation of the antacid therapy and increased with subsequent re-challenge. In a separate study by the same group, TSH levels were followed up in five patients with stable, treated hypothyroidism who were given aluminium hydroxide for 2–4 weeks.33 The study medication was a combination of simethicone, magnesium hydroxide and aluminium hydroxide; study subjects received a total of 2256 mg of aluminium hydroxide daily in four divided doses. Mean levels of serum TSH increased significantly from pre-treatment levels of 2.6 0.8 mU L1 to 7.2 1.3 mU L1 (p ¼ 0.003). In vitro incubations of radiolabelled 125I-thyroxine and antacid preparations containing aluminium hydroxide showed a direct relationship between the percentage of T4 adsorbed and the concentration of aluminium hydroxide. This adsorption occurred even with small amounts of aluminium hydroxide that were 1/100 of a typical daily dose. Of note, the authors commented that magnesium hydroxide did not significantly adsorb levothyroxine. Mersebach et al. reported similar observations in two patients, with the second case involving magnesium oxide.34 Their in vitro binding studies also demonstrated dose-related adsorption of levothyroxine with aluminium hydroxide but not with magnesium oxide. Calcium carbonate Calcium carbonate is another commonly used medication that has been shown to affect the bioavailability of levothyroxine. Schneyer first reported elevations in serum TSH levels in three women on suppressive therapy for thyroid cancer who ingested calcium carbonate simultaneously.35 Interestingly, one patient did not have these changes with a different form of calcium carbonate, and the authors suggested that the interaction may be limited to certain calcium compounds. However, this finding has not been reported elsewhere. Singh et al. conducted a prospective cohort study to evaluate this interaction with calcium in 20 hypothyroid patients on stable doses of levothyroxine.36 Subjects ingested their usual replacement doses with 1200 mg of calcium (as calcium carbonate) for 3 months. Patients were followed during the study period and 2 months after discontinuation of calcium carbonate (Fig. 1). With co-administration of calcium, mean serum TSH levels increased significantly from 1.6 mIU L1 to 2.7 mIU L1, then decreased to 1.4 mIU L1 after discontinuation (p ¼ 0.008). Mean values of free and total T4 decreased with co-administration and reverted back to the baseline with discontinuation of calcium carbonate (Table 3). In four patients, the serum TSH rose above the normal range when levothyroxine was ingested with calcium carbonate. The authors also conducted in vitro binding studies and demonstrated significant adsorption of levothyroxine to calcium in an acidic pH of 2.0. To determine the acute effect of calcium on levothyroxine absorption, Singh et al. conducted a pharmacokinetic study in seven healthy volunteers who were randomised to 2 g of calcium or placebo.37 Subjects ingested 1 mg of levothyroxine simultaneously with the first study medication, then a month later with the second medication. Serum free T4, total T4, total T3 and TSH levels were monitored for 24 h, and the levels of absorption were calculated using the non-isotopic method. Maximum total T4 absorption peaked at 837 mg with levothyroxine alone but decreased to 579 mg with the co-administration of calcium. Time to peak total T4 absorption doubled with co-administration. The total T4 absorption over 6 h, calculated as the AUC, was greater with levothyroxine alone than with levothyroxine plus calcium (p ¼ 0.02) (Fig. 2). These experiments show that calcium carbonate acutely interferes with the bioavailability of levothyroxine. Phosphate binders Phosphate binders may also impair the absorption of levothyroxine. Calcium carbonate is also used as a phosphate binder in chronic renal failure and blocks the absorption of levothyroxine. A calciumfree cationic binder, sevelamer hydrochloride, has been suggested to interfere as well. In a study of 67 haemodialysis patients on concurrent levothyroxine and phosphate binder therapy (calcium carbonate, calcium acetate or sevelamer), TSH levels and levothyroxine doses were analysed according to the type and amount of treatment.38 Of the three agents, the use of sevelamer was associated with higher doses of levothyroxine (p ¼ 0.049) and significant dose increases after 6 months of therapy. The
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Fig. 1. Thyrotropin (TSH) levels in 20 patients with hypothyroidism. Reproduced with permission from Singh N et al. JAMA 2000;283:2824.
use of calcium carbonate and sevelamer were both associated with elevated mean levels of TSH, which were higher than those with calcium acetate. These levels also increased over time, despite increasing doses of levothyroxine in patients on sevelamer. John-Kalarickal et al. conducted a pharmacokinetic trial to study the acute effect of sevelamer on levothyroxine absorption in seven healthy patients.39 Subjects were first evaluated with 1 mg of levothyroxine alone, then with concurrent ingestion of 800 mg of sevelamer at least 2 weeks later. For each trial, serum T4 and TSH levels were serially monitored over 6 h after ingestion. Calculated AUC was significantly reduced from 2176 195 mg-min dL1 for levothyroxine alone to 1178 281 mg-min dL1 with levothyroxine plus sevelamer (p < 0.05). The rise in serum T4 was also blunted in subjects with sevelamer. These findings show that sevelamer acutely decreases the bioavailability of levothyroxine and contributes to resistant hypothyroidism.
Table 3 Effect of the concomitant administration of levothyroxine and calcium on thyroid function tests in 20 patients with hypothyroidism.a
Free T4, ng/dL TSH, mIU/L Total T4, mg/dL Total T3, mg/dL
Baseline: Levothyroxine
Visit 1: Levothyroxine þ Calcium
Visit 2: Levothyroxine þ Calcium
Final Visit: Levothyroxine
Overall Pb
1.34 0.04c 1.60 0.22c 9.21 0.46d 141.50 4.43
1.23 0.04 2.88 0.41 8.64 0.43 134.40 6.59
1.22 0.05 2.71 0.43 8.55 0.41 142.10 6.54
1.41 0.06c 1.44 0.21c 9.31 0.39d 142.2 7.03
<.001 .008 .03 .82
Reproduced with permission from Singh N et al. JAMA 2000;283:2824. a All values are expressed as mean SE. T4 indicates thyroxine; TSH, thyrotropin; and T3, triiodothyronine. To convert free T4 from ng/dL to pmol/L, multiply by 12.87; to convert total T4 from mg/dL to nmol/L, multiply by 12.87; and to convert total T3 from ng/dL, to nmol/L, multiply by 0.0154. b Overall P value from F test of repeated-measures multivariate analysis of variance (MANOVA) analyses that compare the means of the baseline levothyroxine group, the levothyroxine group plus calcium groups, and the final levothyroxine group. c P < .01 for between group comparison of levothyroxine plus calcium group (visit 1 þ visit 2) from a repeated measures MANOVA test. d P < 0.5 for between group comparison of levothyroxine plus calcium group (visit 1 þ visit 2) from a repeated measures MANOVA test.
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Fig. 2. Calculated levothyroxine (LT4) absorption after ingestion of LT4 1 mg or LT4 1 mg plus calcium 2 g. Each time point represents mean standard error of the mean (SEM) of seven subjects. Reproduced from Singh N et al. Thyroid 2001;11:968.
In the recent study by Weitzman et al., lanthanum carbonate – a new phosphate binder – was also shown to interfere with the absorption of levothyroxine.25 In an acidic environment, the drug dissociates and releases lanthanum ions that complex with dietary phosphate. In six healthy volunteers, pharmacokinetic studies were conducted with ingestion of 1 mg levothyroxine alone or with addition of 500 mg lanthanum carbonate. Co-administration with lanthanum carbonate significantly blunted the rise in serum T4 levels, as well as the AUC of T4 absorption. Raloxifene Separate from its effects on thyroxine-binding globulin, selective oestrogen receptor modulators (SERMs) may also influence the absorption of levothyroxine. Several case reports have described elevations in TSH levels with raloxifene.40,41 Siraj et al. first reported a possible interaction in a 79-yearold woman with a history of subtotal thyroidectomy for benign nodules who had been stable being maintained on levothyroxine 150 mg daily. Within 2–3 months of starting raloxifene, which she took with levothyroxine before breakfast, she developed symptoms of hypothyroidism with an elevated serum TSH of 14.5 mU ml1. Dose escalation of levothyroxine failed to normalise TSH levels. For two periods of 6–8-weeks duration, the patient separated ingestion of these two medications by 12 h, resulting in improvements in TSH levels. The authors also conducted 6-h absorption tests on levothyroxine (1 mg), with and without raloxifene (60 mg). The experiments were performed on two different occasions separated by 4 weeks. At all time points measured, serum levels of T4 were lower with levothyroxine plus raloxifene. Of note, although the patient had no overt symptoms of malabsorption, her history included pernicious anaemia that was treated with vitamin B12 replacement. Because she had been stable upon treatment with levothyroxine for several years, the authors felt that pernicious anaemia was an unlikely cause of her refractory hypothyroidism. Proton-pump inhibitors Given that gastric acidity appears to be important in absorption of levothyroxine, medications that suppress gastric acid secretion may interfere as well. Several reports have been published on the role of proton-pump inhibitors, but the findings have varied. In the study by Centanni et al. of patients with multinodular goitre on suppressive therapy, a subgroup of 10 patients with gastro-oesophageal reflux was treated with omeprazole.22 In all of these patients, initiation of proton-pump inhibitor therapy resulted in a variable increase in TSH levels (p ¼ 0.002) that required a 37% increase in the dose of levothyroxine to suppress TSH (p ¼ 0.001). Similar findings were reported by Sachmechi et al. in a retrospective analysis of lansoprazole use in 37 patients with primary hypothyroidism on levothyroxine therapy when proton-pump-inhibitor therapy was initiated.42 Comparison of TSH levels before and at least 2 months following commencement of lansoprazole treatment showed a mean increase of 0.69 1.9 mIU mL1 that was statistically significant (p ¼ 0.035). Nineteen percent of the patients had TSH levels >5 mIU mL1 after starting lansoprazole and required dosage increases in levothyroxine.
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Table 4 Pharmacokinetic properties of levothyroxine without and after treatment with pantoprazole.
Gastrin (pg/ml) AUC T4 (mmol sec/l) AUC FT4E (sec)
Baseline
On pantoprazole
Relative difference
p value
50.1 5.9a 1.09 0.06a 28829.9 1252.0a
70.8 10.9a 0.96 0.10a 25944.1 1791.0a
41.3% 12.4% 10.0%
0.001b 0.60c 0.09c
Adapted from Dietrich et al. Horm Metab Res 2006;38:59. a Mean value SEM. b t-test for paired samples. c Wilcoxon signed rank test.
These observations were not reproduced in studies investigating the acute effects of proton-pumpinhibitor therapy. In an open crossover study by Dietrich et al., pharmacokinetic trials were performed in 20 healthy volunteers under two settings: (1) ingestion of levothyroxine alone (4 mg kg1) and (2) 1 week of levothyroxine ingestion with pantoprazole (40 mg daily).43 Serum TSH, T4 and free thyroxine equivalents (FT4E) were serially monitored over a 10-h period, and the total absorption levels were calculated as the AUC. The suppression of gastric acidity by pantoprazole was confirmed by elevated gastrin levels. Contrary to the author’s expectations, no significant differences in AUCs for serum T4 and FT4E were observed with pantoprazole (Table 4). In a similar trial, Ananthakrishnan et al. performed 8h absorption tests in 30 healthy patients who ingested esomeprazole (40 mg daily) simultaneously with levothyroxine (600 mg daily) for 1 week.44 In comparing values before and after esomeprazole therapy, no significant changes were noted in peak T4 levels or mean AUC for T4 absorption. Of note, famotidine was also included in this study and no significant differences in absorption were observed. The conflicting findings regarding proton-pump inhibitor therapy may be due to differences in length of therapy. In the studies of Centanni and Sachmechi, patients were treated with proton-pump inhibitors for up to 6 months, but the other studies administered it for only 1 week, which may have been too brief to detect changes in enterohepatic metabolism, clearance and absorption of levothyroxine. Orlistat Licensed as an anti-obesity drug, orlistat inhibits gastric and pancreatic lipases to reduce fat. It has already been reported to interfere with absorption of several drugs, including warfarin, amiodarone and cyclosporine. Possible interference with levothyroxine absorption was reported by Madhava and Hardley in a patient after thyroidectomy for papillary cancer.45 Her serum TSH had been stably suppressed on 250 mg of levothyroxine daily, but within 2 weeks of starting orlistat, the patient experienced symptoms of fatigue, lethargy and cold intolerance. Blood tests confirmed the diagnosis of hypothyroidism with an elevated serum TSH of 74 mU L1. Within 2 weeks of discontinuing orlistat and increasing levothyroxine to 300 mg daily, her symptoms improved and the serum TSH became adequately suppressed. Although orlistat may have reduced levothyroxine absorption, the patient’s levothyroxine was also increased to 300 mg at the same time as she discontinued orlistat, which could also contribute to TSH suppression. To our knowledge, no similar reports have been published and further research will be needed to confirm this observation. Conclusion Various endogenous and exogenous factors can change the absorption kinetics of levothyroxine. The timing of food intake in relation to levothyroxine administration is important, and it is recommended to delay food by at least 60 min following ingestion. Fibre and espresso coffee have been shown to interfere, indicating that the content of dietary intake is also important. Disorders of malabsorption or impaired gastric acidity can reduce the absorption of levothyroxine, and resistant hypothyroidism may be the only presenting symptom in some of these disorders. Medications that interfere with intestinal transport, including bile acid sequestrants, sucralfate, aluminium-containing antacids and phosphate binders, have also been shown to interfere with levothyroxine absorption. This
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phenomenon will likely become more prevalent, as commonly used medications such as ferrous sulphate, calcium carbonate, raloxifene and proton-pump inhibitors have been identified as interfering agents. Further research is needed on sucralfate and proton-pump inhibitors because of inconsistent results, as well as raloxifene and orlistat, which have limited reports. These factors need to be considered in patients with persistently elevated levels of TSH. In patients whose medications include levothyroxine and known interfering agents, administration should be separated by at least 4–6 h. Practice points Hypothyroidism that persists despite escalation of levothyroxine dose should prompt investigation into underlying gastrointestinal malabsorption or medication interference. Patients should be recommended to ingest levothyroxine on an empty stomach, at least 60 min prior to any food intake. For medications such as colesevelam, it is recommended to separate its administration from that of levothyroxine by at least 4 h. Clinicians should be aware that commonly used medications, such as ferrous sulphate, aluminium-containing antacids, raloxifene, bile acid sequestrants, calcium carbonate and proton-pump inhibitors, can interfere with the absorption of levothyroxine.
Research agenda Other medications that affect intestinal transport may also interfere with absorption of levothyroxine. Raloxifene and orlistat have been reported to affect levothyroxine bioavailability, but additional case-controlled studies and in vitro pharmacokinetic trials are needed to confirm these observations. Though it is currently recommended to separate levothyroxine administration from ingestion of interfering drugs by 4–6 h, additional pharmacokinetic trials are needed to determine optimal intervals for different medications.
Conflict of interest The authors have no conflicts of interest to declare.
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