Levothyroxine Interactions with Food and Dietary Supplements–A Systematic Review
Abstract
:1. Introduction
2. Results and Discussion
2.1. Eligible Studies
2.2. Aspects of Levothyroxine Pharmacokinetics
2.3. Schedules of Levothyroxine Administration
2.4. Impact of Food Intake on Pharmacokinetics and Pharmacodynamics of Levothyroxine
2.4.1. Tablets
2.4.2. Liquid Form
2.4.3. Soft Gel Capsule
2.5. Levothyroxine–Fiber Interaction
2.6. Levothyroxine-Soy Products Interaction
2.7. Levothyroxine–Milk Interaction
2.8. Levothyroxine–Coffee Interaction
2.9. Levothyroxine-Fruit Interaction
2.9.1. Fruit Juices
2.9.2. Papaya
2.10. Interaction of Levothyroxine with Essential and Trace Elements
2.10.1. Calcium
2.10.2. Iron
2.10.3. Aluminium
2.10.4. Chromium
2.11. Levothyroxine—Vitamin C Interaction
2.12. Levothyroxine—Enteral Nutrition Interaction
2.13. Limitations of Studies
2.14. Recommendations
3. Materials and Methods
3.1. Search Strategy
3.2. Inclusion and Exclusion Criteria
3.3. Data Extraction
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
EN | Enteral nutrition |
fT3 | Free T3 |
fT4 | Free T4 |
L-T4 | Levothyroxine (L-thyroxine) |
MCT | Monocarboxylate transporter family |
NTCP | Sodium-taurocholate co-transporting polypeptide transporters |
OATP | Organic anion-transporting polypeptide family |
PDA | Prolonged Dose Adjustment |
PPI | Pomp proton inhibitors |
RCT | Randomized control trial |
T3 | Triiodothyronine |
T4 | Thyroxine |
TFT | Thyroid function tests |
TSH | Thyroid-stimulating hormone |
TT4 | Serum total thyroxine level |
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Study | Participants | L-T4 Dose (µg/Day) | L-T4 Formulation | Type of Food | Observed Effect |
---|---|---|---|---|---|
Wenzel et al. [34] | not specified | 100 | Tablets | not specified | ↓ L-T4 absorption (by 15%) |
Lamson et al. [35] | 48, healthy | 600 | Tablets | breakfast, 950 kcal | ↓ AUC0-48 h (by 38–40%), ↓ Cmax (by 40–49%) |
Perez et al. [38] | 42, hypothyroid | 98 ± 35 | Tablets | breakfast, 162–381 kcal | ↑ TSH level (by 64%) |
Marina et al. [40] | 14, hypothyroid | 200 | liquid form | breakfast, 132 kcal | no significant changes in fT4 levels |
Morelli et al. [41] | 59, hypothyroid | not specified | liquid form | patient’s usual breakfast | no significant changes in TSH levels |
Cappelli et al. [42] | 77, hypothyroid | 75 | liquid form | patient’s usual breakfast | no significant changes in TSH, fT4 and fT3 levels |
Pirola et al. [43] | 761, hypothyroid | 75 | liquid form | patient’s usual breakfast | no significant changes in TSH levels |
Cappelli et al. [46] | 1, hypothyroid | 75 | liquid form | Lunch | no significant changes in thyroid hormonal profiles |
Cappelli et al. [47] | 60, euthyroid | 106 ± 24 | soft gel capsules | patient’s usual breakfast | no significant changes in TSH levels, ↓ fT4 and fT3 levels (by 7% both) |
Liel et al. [49] | 13, hypothyroid | 50–470 | Not specified | fiber (whole wheat bread, bran, granola, psyllium) | ↑ TSH level (ranging from 7,4 to > 50 mU/L) |
Chiu et al. [50] | 8, healthy | 600 | Tablets | fiber (psyllium) | ↓ L-T4 absorption (by 8%) |
Fruzza et al. [55] | 1, hypothyroid | 50 | Not specified | soy-based infant formula | ↑ TSH level (216 mU/L), ↓ fT4 level (4.0 μg/dL) |
1, hypothyroid | 112 | Not specified | soy-based infant formula | ↑ TSH level (248 mU/L), ↓ fT4 level (<0.4ng/dL) | |
Conrad et al. [56] | 78, hypothyroid | 7.4 per kg | Not specified | soy-based infant formula | 62.5% patients with TSH > 10 mU/L after 4 months |
Bell et al. [57] | 1, hypothyroid | 200 | Tablets | soy-protein containing cocktail | difficulty in suppressing TSH level |
Persiani et al. [58] | 12, hypothyroid | 25–125 | Tablets | soy-containing supplement | no significant changes in thyroid hormones levels |
Chon et al. [59] | 10, healthy | 1000 | Tablets | cow milk | ↓ peak serum TT4 level by 7.8%, ↓ AUC by 8% |
Benvenga et al. [61] | 6, hypothyroid | 200 | Tablets | espresso | average T4 ↓ 36%, peak T4 ↓ 30%, tmax delayed by 38 min. |
9, healthy | 200 | Tablets | espresso | average T4 ↓ 29%, peak T4 ↓ 19%, tmax delayed by 43 min. | |
Sindoni et al. [62] | 6, hypothyroid | 1.6–2.2 per kg | Tablets | espresso and barley coffee | failure to normalize TSH levels |
Węgrzyn [63] | 1, hypothyroid | 175 | Tablets | drip coffee | clinical signs of hypothyroidism (TSH level—8.27 mU/L) |
Vita et al. [64] | 8, hypothyroid | 1.6–2.8 per kg | soft gel capsules | coffee | comparable TSH levels for coffee 5 min. and 1h after L-T4 |
Cappelli et al. [65] | 54, hypothyroid | 73±14 | liquid form | coffee | comparable TSH, fT3 and fT4 levels for coffee 30 min. before and with L-T4 |
Lilja et al. [69] | 1, hypothyroid | 100 | Not specified | grapefruit juice | ↑ TSH level (63.7 mU/L), ↓ fT4 level (6.4 pmol/L) |
10, healthy | 600 | Not specified | grapefruit juice | ↓ AUC (by 9%), ↓ Cmax (by 11%) | |
Tesic et al. [71] | 1, hypothyroid | 200–700 | Tablets | juice and mint tea | ↑ TSH level (> 100 mU/L), ↓ fT4 level (5.9 pmol/L), undetectable fT3 level |
Deiana et al. [72] | 1, hypothyroid | 1.6 per kg | Not specified | papaya | ↑ TSH level (25 mU/L) |
1, hypothyroid | 1.6 per kg | Not specified | papaya | ↑ TSH level (from 0.8 to 15 mU/L), ↓fT3 and fT4 levels | |
Singh et al. [77] | 20, hypothyroid | > 1 per kg | Not specified | calcium carbonate | ↓fT4 level, ↑ TSH level in 20% of patients |
Singh et al. [79] | 7, healthy | 1000 | Tablets | calcium carbonate | ↓ L-T4 absorption (from 83.7% to 53.7%), tmax delayed (from 2 to 4 h) |
Schneyer et al. [80] | 3, hypothyroid | 125–325 | Not specified | calcium carbonate | ↑ TSH level (ranging from 7.3 to 13.3 mU/L) |
Csako et al. [81] | 1, hypothyroid | 175–188 | Not specified | calcium carbonate | ↑ TSH level (41.4 mU/L) |
Butner et al. [82] | 1, hypothyroid | 150 | Not specified | calcium carbonate | ↑ TSH level (21.85 mU/L) |
Mazokopakis et al. [83] | 1, hypothyroid | 88 | Not specified | calcium carbonate | ↑ TSH level (9.8 mIU/L),↓fT4 level (0.2 ng/dL) |
Irving et al. [11] | 450, hypothyroid | not specified | Tablets | calcium carbonate | ↑ TSH level (up to over 5 mU/L) in 4.4% of patients |
Diskin et al. [84] | 65, hypothyroid | 95–98 | Not specified | calcium carbonate | ↑ TSH level (23.8 ± 19.5 mU/L) |
Zamfirescu et al. [85] | 8, healthy | 1000 | Tablets | calcium carbonate, calcium citrate, calcium acetate | ↓ L-T4 absorption (by 20–25%) |
Morini et al. [86] | 50, hypothyroid | 1.47 per kg | Tablets | calcium supplements | ↑ TSH level (3.33 ± 1.93 mU/L) |
Benvenga et al. [87] | 12, hypothyroid | 1.7 per kg | liquid form and tablets | calcium carbonate | ↓ TSH for liquid form vs. tablet (2.15 ± 1,4 mU/L vs. 8.74 ± 7.2 mU/L) |
Campbell et al. [89] | 14, hypothyroid | 75-150 | Not specified | ferrous sulfate | ↑ TSH level (from 1.6 to 5.4 mU/L) |
Shakir et al. [90] | 1, hypothyroid | 150 | Not specified | ferrous sulfate | ↑ TSH level (56 mU/L), ↓ fT4 level (0,48 ng/dL) |
Leger et al. [92] | 1, hypothyroid | not specified | Not specified | ferrous fumarate | ↑ TSH level (243 mU/L), ↓ fT4 level (<0.52 pmol/L) |
Irving et al. [11] | 429, hypothyroid | not specified | Tablets | iron supplements | ↑ TSH level in 7.5% of patients |
Benvenga et al. [87] | 8, hypothyroid | 1.7 per kg | liquid form and tablets | ferrous sulfate | ↓ TSH for liquid form vs. tablet (1.68 ± 0.9 mU/L vs. 8.74 ± 7.2 mU/L) |
Liel et al. [75] | 5, hypothyroid | not specified | Not specified | aluminium hydroxide | ↑ TSH level (from 2.62 to 7.19 mU/L) |
John-Kalarickal et al. [98] | 7, hypothyroid | 1000 | Not specified | chromium picolinate | ↓ L-T4 bioavailability (by 17%) |
Jubiz et al. [99] | 31, hypothyroid | 100 | Tablets | vitamin C | ↓ TSH level (by 69%), normalized TSH in 54.8% of patients |
Antunez et al. [100] | 28, hypothyroid | >1.7 per kg | Tablets | vitamin C | ↓ TSH level (from 9.01 ± 5.51 mU/L to 2.27±1.61 mU/L) |
Dickerson et al. [102] | 13, hypothyroid | not specified | not specified | enteral nutrition | hypothyroidism subclinical (TSH—6–10 mU/L) or overt (TSH >10 mU/L) |
Pirola et al. [105] | 20, euthyroid | 1.6 per kg | liquid form and crushed tablets | enteral nutrition | comparable thyroid hormones profile for both formulations |
Food Interacting with L-thyroxine | Sources of Evidence | Mechanism of Interaction | Effects of Interaction | Recommendations for Health Professionals |
---|---|---|---|---|
Fiber (whole wheat bread, bran) | case series [49], non-randomized cross-over study [50] | non-specific adsorption of l-T4 to the fiber | malabsorption of l-T4, impaired efficacy of treatment | advise to separate fiber and l-T4 intake by 1 h monitor thyroid parameters more frequently, adjust L-T4 doses when needed |
Soy products (soy-protein cocktails, soy-based infant formulas) | case reports [52,53,55,57], case series [54], retrospective cohort study [56] | adsorption of l-T4 on the surface of soy protein | malabsorption of l-T4, impaired efficacy of treatment | advise to separate soy protein and l-T4 intake by 1 h monitor thyroid parameters more frequently, adjust l-T4 doses when needed |
Cow milk | non-randomized cross-over study [59] | probable adsorption of l-T4 on casein | impaired bioavailability of l-T4 | cannot be made due to the insufficient evidence |
Coffee (espresso, drip coffee, barley coffee) | case report [63], case series [61,62], uncontrolled clinical study [65], non-randomized cross-over study [64] | the sequestration of l-T4 by coffee | malabsorption of l-T4, impaired efficacy of treatment | advise to delay coffee intake by 1 h after l-T4 administration consider changing formulation from tablets to oral liquid form/gel capsules |
Juice (grapefruit juice, orange juice, apple juice) | case report [69], randomized clinical trial (against interaction) [69] | blocking of OATP transporters | malabsorption of l-T4, impaired efficacy of treatment | cannot be made due to insufficient evidence advise to avoid excessive intake |
Fruit (papaya) | case report [72] | unknown | malabsorption of l-T4, impaired efficacy of treatment | cannot be made due to the insufficient evidence advise to avoid excessive intake |
Calcium (carbonate, acetate, citrate) | case reports [81,82,83], case series [80], retrospective cohort studies [11,84,86], prospective cohort study [77], uncontrolled clinical study [87], non-randomized cross-over study [85] | unspecific adsorption of l-T4, creating insoluble or sparingly soluble complexes in the intestine | malabsorption of l-T4, impaired efficacy of treatment | advise to delay intake by 2–4 h after l-T4 administration consider changing formulation from tablets to oral liquid form/gel capsules monitor thyroid parameters more frequently |
Iron (ferrous citrate and fumarate) | case reports [89,90,91], retrospective cohort study [11,93], uncontrolled clinical study [88] | unspecific adsorption of l-T4, creating insoluble or sparingly soluble complexes in the intestine | malabsorption of l-T4, impaired efficacy of treatment | advise to delay intake by 2–4 h after l-T4 administration consider changing formulation from tablets to oral liquid form/gel capsules monitor thyroid parameters more frequently |
Aluminium (hydroxide) | case reports [93,94], uncontrolled clinical study [75] | unspecific adsorption of l-T4, creating insoluble or sparingly soluble complexes in the intestine | malabsorption of l-T4, impaired efficacy of treatment | advise to delay intake by 2–4 h after l-T4 administration consider changing formulation from tablets to oral liquid form/gel capsules monitor thyroid parameters more frequently |
Chromium (picolinate) | non-randomized cross-over study [98] | unspecific adsorption of l-T4, creating insoluble or sparingly soluble complexes in the intestine | malabsorption of l-T4, impaired efficacy of treatment | advise to delay intake by 3–4 h after l-T4 administration consider changing formulation from tablets to oral liquid form/gel capsules monitor thyroid parameters more frequently |
Vitamin C | uncontrolled clinical study [100], non-randomized cross-over study [99] | lowering of gastric pH | enhanced absorption of l-T4 | consider advising concomitant ingestion of vitamin C and l-T4 |
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Wiesner, A.; Gajewska, D.; Paśko, P. Levothyroxine Interactions with Food and Dietary Supplements–A Systematic Review. Pharmaceuticals 2021, 14, 206. https://doi.org/10.3390/ph14030206
Wiesner A, Gajewska D, Paśko P. Levothyroxine Interactions with Food and Dietary Supplements–A Systematic Review. Pharmaceuticals. 2021; 14(3):206. https://doi.org/10.3390/ph14030206
Chicago/Turabian StyleWiesner, Agnieszka, Danuta Gajewska, and Paweł Paśko. 2021. "Levothyroxine Interactions with Food and Dietary Supplements–A Systematic Review" Pharmaceuticals 14, no. 3: 206. https://doi.org/10.3390/ph14030206